Treatment Of Gastrointestinal Stromal Tumors Research Articles

A bibliometric analysis of interstitial cells of Cajal research

ObjectiveThe significance of interstitial cells of Cajal (ICC) in the gastrointestinal tract has garnered increasing attention. In recent years, approximately 80 articles on ICC have been published annually in various journals. However, no bibliometric study has specifically focused on the literature related to ICC. Therefore, we conducted a comprehensive bibliometric analysis of ICC to reveal dynamic scientific developments, assisting researchers in exploring hotspots and emerging trends while gaining a global perspective.MethodsWe conducted a literature search in the Web of Science Core Collection (WoSCC) from January 1, 2013, to December 31, 2023, to identify relevant literature on ICC. We employed bibliometric software, namely VOSviewer and CiteSpace, to analyze various aspects including annual publication output, collaborations, research hotspots, current status, and development trends in this domain.ResultsA total of 891 English papers were published in 359 journals by 928 institutions from 57 countries/regions. According to the keyword analysis of the literature, researchers mainly focused on “c-Kit,” “expression,” “smooth muscle,” and “nitric oxide” related to ICC over the past 11 years. However, with “SIP syncytium,” “ANO1,” “enteric neurons,” “gastrointestinal stromal tumors (GIST),” and “functional dyspepsia (FD),” there has been a growing interest in the relationship between ANO1, SIP syncytium, and ICC, as well as the role of ICC in the treatment of GIST and FD.ConclusionBibliometric analysis has revealed the current status of ICC research. The association between ANO1, SIP syncytium, enteric neurons and ICC, as well as the role of ICC in the treatment of GIST versus FD has become the focus of current research. However, further research and collaboration on a global scale are still needed. Our analysis is particularly valuable to researchers in gastroenterology, oncology, and cell biology, providing insights that can guide future research directions.

GASTRIC GASTROINTESTINAL STROMAL TUMOR WITH SUCCINATE DEHYDROGENASE B DEFICIENCY: CLINICAL CASE

Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors found in the gastrointestinal tract, constituting a diverse group of c-Kit positive mesenchymal (stromal or connective tissue) tumors. Their development is primarily associated with mutations in the c-Kit proto-oncogene, leading to structural alterations in the type III transmembrane tyrosine kinase receptor (Kit). This receptor is crucial for regulating mitotic activity and cell differentiation. The activation of the Kit-receptor in tumor cells is identified through the expression of the immunohistochemical marker CD 117 (tyrosine kinase receptor protein), with approximately 80-90% of GISTs testing positive for CD 117. The objective of our study is to improve the diagnosis and treatment of gastrointestinal stromal tumors. The clinical case underscores the challenge of diagnosing gastrointestinal stromal tumors (GISTs) due to the absence of specific and definitive symptoms. In this instance, only radical surgical intervention facilitated an accurate diagnosis. Given the location of the tumor in the pyloric part of the gastric submucosal layer, a reliable biopsy during video esophagogastroduodenoscopy was unfeasible, as the gastric mucosa above the tumor appeared unaffected. Consequently, surgery with complete tumor excision and subsequent pathohistological and immunohistochemical analysis emerged as the primary diagnostic and therapeutic approach. These investigations confirmed the presence of a gastrointestinal stromal tumor of the stomach with succinate dehydrogenase B deficiency. In approximately 80% of GIST cases, succinate dehydrogenase deficiency plays a pivotal role. The absence of succinate dehydrogenase disrupts the Krebs cycle, leading to an accumulation of succinate, an oncometabolite that fuels carcinogenesis. Such tumors exhibit distinctive clinical characteristics, prognostic outcomes, and responsiveness to targeted therapies. Succinate dehydrogenase deficiency can arise from mutations or epigenomic alterations affecting gene expression. Notably, mutations or epigenomic disruptions in any succinate dehydrogenase subunit inevitably result in the loss of subunit B expression.

RAF1 facilitates KIT signaling and serves as a potential treatment target for gastrointestinal stromal tumor.

The aberrant activation of RAS/RAF/MEK/ERK signaling is important for KIT mutation-mediated tumorigenesis of gastrointestinal stromal tumor (GIST). In this study, we found that inhibition of RAF1 suppresses the activation of both wild-type KIT and primary KIT mutations in GIST, with primary KIT mutations showing greater sensitivity. This suggests a positive feedback loop between KIT and RAF1, wherein RAF1 facilitates KIT signaling. We further demonstrated that RAF1 associates with KIT and the kinase activity of RAF1 is necessary for its contribution to KIT activation. Accordingly, inhibition of RAF1 suppressed cell survival, proliferation, and cell cycle progression in vitro mediated by both wild-type KIT and primary KIT mutations. Inhibition of RAF1 in vivo suppressed GIST growth in a transgenic mouse model carrying germline KIT/V558A mutation, showing a similar treatment efficiency as imatinib, the first-line targeted therapeutic drug of GIST, while the combination use of imatinib and RAF1 inhibitor further suppressed tumor growth. Acquisition of drug-resistant secondary mutation of KIT is a major cause of treatment failure of GIST following targeted therapy. Like wild-type KIT and primary KIT mutations, inhibition of RAF1 suppressed the activation of secondary KIT mutation, and the cell survival, proliferation, cell cycle progression in vitro, and tumor growth in vivo mediated by secondary KIT mutation. However, the activation of secondary KIT mutation is less dependent on RAF1 compared with that of primary KIT mutations. Taken together, our results revealed that RAF1 facilitates KIT signaling and KIT mutation-mediated tumorigenesis of GIST, providing a rationale for further investigation into the use of RAF1 inhibitors alone or in combination with KIT inhibitor in the treatment of GIST, particularly in cases resistant to KIT inhibitors.

Feasibility and efficacy of minimally invasive limited resection for primary duodenal gastrointestinal stromal tumors: a retrospective cohort study

BackgroundThe primary duodenal gastrointestinal stromal tumor (GIST) is a rare type of gastrointestinal tract tumor. Limited resection (LR) has been increasingly performed for duodenal GIST. However, only a few studies reported minimally invasive limited resection (MI-LR) for primary duodenal GIST.MethodsThe clinical data of 33 patients with primary duodenal GIST from December 2014 to February 2024 were retrospectively analyzed including 23 who received MI-LR and 10 who received laparoscopic or robotic pancreaticoduodenectomy (LPD/RPD).ResultsA total of 33 patients with primary duodenal GIST were enrolled and retrospectively reviewed. Patients received MI-LR exhibited less OT (280 vs. 388.5min, P=0.004), EBL (100 vs. 450ml, P<0.001), and lower morbidity of postoperative complications (52.2% vs. 100%, P=0.013) than LPD/RPD. Patients received LPD/RPD burdened more aggressive tumors with larger size (P=0.047), higher classification (P<0.001), and more mitotic count/50 HPF(P=0.005) compared with patients received MI-LR. The oncological outcomes were similar in MI-LR group and LPD/RPD group.All the patients underwent MI-LR with no conversion, including 12 cases of LLR and 11 cases of RLR. All of the clinicopathological data of the patients were similar in both groups. The median OT was 280(210-480) min and 257(180-450) min, and the median EBL was 100(20-1000) mL and 100(20-200) mL in the LLR and the RLR group separately. The postoperative complications mainly included DGE (LLR 4 cases, 33.4% and RLR 4 cases, 36.4%), intestinal fistula (LLR 2 cases, 16.7%, and RLR 0 case), gastrointestinal hemorrhage (LLR 0 case and RLR 1 case, 9.1%), and intra-abdominal infection (LLR 3 cases, 25.0% and RLR 1 case, 9.1%). The median postoperative length of hospitalization was 19.5(7-46) days in the LLR group and 19(9-38) days in the RLR group. No anastomotic stenosis, local recurrence or distant metastasis was observed during the follow-up period in the two groups.ConclusionsMinimally invasive limited resection is an optional treatment for primary duodenal GIST with satisfactory short-term and long-term oncological outcomes.

Comparable long‑term survival outcomes of endoscopic treatment versus surgical treatment for gastrointestinal stromal tumors with a diameter of 5–10 cm

Currently, endoscopic treatment for small gastrointestinal stromal tumors (GIST) has been widely accepted. However, for tumors larger than 5 cm, endoscopic treatment has not been recognized by national guidelines as the standard therapy due to concerns about safety and adverse tumor outcomes. Therefore, this study compares the long-term survival outcomes of endoscopic treatment and surgical treatment for GIST in the range of 5–10 cm. We selected patients with GIST from the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2015. Kaplan–Meier analysis and the log-rank test were employed to compare the long-term survival outcomes between endoscopic treatment and surgical treatment. A multivariate Cox proportional hazards model was used for analysis to identify risk factors influencing patient prognosis. To balance baseline data, we performed 1:1 propensity score matching (PSM). A total of 1223 GIST patients were included, with 144 patients (11.8%) received endoscopic treatment and 1079 patients (88.2%) received surgical treatment. Before PSM, there was no significant difference in the long-term survival rates between the two groups [5-year OS (86.5% vs. 83.5%, P = 0.42), 10-year OS (70.4% vs. 66.7%, P = 0.42)]. After adjusting for covariates, we found that the overall survival (HR = 1.26, 95% CI 0.89–1.77, P = 0.19) and cancer-specific survival (HR = 1.69, 95% CI 0.99–2.89, P = 0.053) risks were comparable between the endoscopic treatment group and the surgical treatment group. In the analysis after PSM, there was no significant difference between the endoscopic treatment group and the surgical treatment group. Our study found that for GIST patients with tumor sizes between 5 and 10 cm, the long-term OS and CSS outcomes were similar between the endoscopic treatment group and the surgical treatment group.

Gastrointestinal stromal tumors : Where do we stand?

For more than 20 years gastrointestinal stromal tumors (GIST) have been aparadigm for atargeted treatment with tyrosine kinase inhibitors. Afundamental prerequisite for aneoadjuvant or adjuvant treatment of localized GIST or an additive treatment of metastatic GIST is the molecular typing of tumors, ideally at the initial diagnosis. In addition, the possibility of ahereditary or syndromic predisposition must be considered because this results in consequences for the treatment and adifferent follow-up strategy.

Abstract 3142: NN3201, a novel c-Kit targeting ADC, exhibits robust preclinical anti-tumor efficacy in SCLC and GIST models

Abstract c-Kit (CD117) is a type III receptor tyrosine kinase (RTK), which is known to be activated upon binding to its cognate ligand stem cell factor (SCF) to induce critical signaling pathways involved in cell proliferation, survival, and differentiation. Indicative of poor prognosis, overexpression and activating mutations of c-Kit have been implicated in a variety of human cancers including small cell lung cancer (SCLC), gastrointestinal stromal tumors (GIST), and acute myelogenous leukemia (AML). While imatinib, a small molecule c-Kit inhibitor, has been a beneficial treatment for GIST, resistance eventually develops to the drug, moreover, shows limited efficacy in c-Kit overexpressing tumors such as SCLC. Herein, we developed NN3201, a novel c-Kit targeting antibody-drug conjugate (ADC), comprised of fully human 2G4 antibody with a picomolar binding affinity to c-Kit and cytotoxic monomethyl auristatin E (MMAE) as the payload. NN3201 displayed potent in vitro cytotoxicity in various wild-type and mutant c-Kit positive SCLC and GIST cell lines with IC50 in the nanomolar range. In addition, NN3201 was rapidly internalized and inhibited c-Kit-mediated signaling., NN3201 treatment resulted in the increased proportions of the sub G1 and G2/M in the c-Kit positive cancer cell lines, indicating that release of MMAE induced cell cycle arrest. Moreover, bystander effect was confirmed by co-culturing c-Kit high and negative cell lines. Most importantly, in mouse xenograft models, NN3201 showed a remarkable tumor growth inhibition of several wild type, mutant c-Kit positive, and imatinib resistant SCLC and GIST cell lines. Enhanced anti-tumor activity and delayed tumor growth were observed in an SOC-treated (etoposide and carboplatin) SCLC xenograft model, by NN3201 in comparison to second line SOC (topotecan or irinotecan). In the GLP study, repeated intravenous administration of NN3201 was well tolerated at all doses (0.5, 1, 2 mg/kg Q3Wx3) without unscheduled death. Dose-dependent, yet transient, cytotoxicity of NN3201 was observed in the bone marrow. We confirmed HNSTD (Highest Non-Severely Toxic Dose) of NN3201 to be 2 mg/kg through exploratory and GLP repeat dose toxicity studies as no serious irreversible toxicity was observed. Accumulating data suggest that NN3201 is a promising therapeutic alternative for the treatment of SCLC and GIST regardless of wild-type or activating mutations in c-Kit. Citation Format: Chansik Kim, Jin Gu Cho, TaeMin Wi, Jiwoo Moon, Han-Jik Ko, Jina Lee, Jin Woo Park, Yeonjy Lee, Sanghee Kim, Jin-Ock Kim, Jaeyoung Song, Sun-Hwa Lee, Sang Gyu Park. NN3201, a novel c-Kit targeting ADC, exhibits robust preclinical anti-tumor efficacy in SCLC and GIST models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3142.

The GIST of it all: management of gastrointestinal stromal tumors (GIST) from the first steps to tailored therapy. A bibliometric analysis

PurposeImprovement of patient care is associated with increasing publication numbers in biomedical research. However, such increasing numbers of publications make it challenging for physicians and scientists to screen and process the literature of their respective fields. In this study, we present a comprehensive bibliometric analysis of the evolution of gastrointestinal stromal tumor (GIST) research, analyzing the current state of the field and identifying key open questions going beyond the recent advantages for future studies to assess.MethodsUsing the Web of Science Core Collection, 5040 GIST-associated publications in the years 1984–2022 were identified and analyzed regarding key bibliometric variables using the Bibliometrix R package and VOSviewer software.ResultsGIST-associated publication numbers substantially increased over time, accentuated from year 2000 onwards, and being characterized by multinational collaborations. The main topic clusters comprise surgical management, tyrosine kinase inhibitor (TKI) development/treatment, diagnostic workup, and molecular pathophysiology. Within all main topic clusters, a significant progress is reflected by the literature over the years. This progress ranges from conventional open surgical techniques over minimally invasive, including robotic and endoscopic, resection techniques to increasing identification of specific functional genetic aberrations sensitizing for newly developed TKIs being extensively investigated in clinical studies and implemented in GIST treatment guidelines. However, especially in locally advanced, recurrent, and metastatic disease stages, surgery-related questions and certain specific questions concerning (further-line) TKI treatment resistance were infrequently addressed.ConclusionIncreasing GIST-related publication numbers reflect a continuous progress in the major topic clusters of the GIST research field. Especially in advanced disease stages, questions related to the interplay between surgical approaches and TKI treatment sensitivity should be addressed in future studies.

Should Advanced Age Preclude Surgical Treatment of Gastrointestinal Stromal Tumor?

Introduction: Surgical resection is a gold standard treatment for gastrointestinal stromal tumors (GISTs). It can be performed by minimally invasive surgery approach in most of the patients. It has been shown that advanced age is not a clear poor prognostic factor in patients who underwent surgery for GIST. We hypothesized that elderly patients undergo elective surgery less often compared to younger population. We aim to evaluate the safety, efficacy and oncological results of GIST treatment in the elderly population in our Medical Center. Materials and Methods: All patients who underwent surgery for GIST in Shamir Medical Center from January 1, 2016, to July 31, 2023, were included in the study. The patients were divided into 2 groups. Group 1 included patients younger than 75 years, while patients older than 75 years were included in Group 2. The groups were compared according to demographics, clinical and surgical parameters, complications, and pathology results. Results: Overall, 49 patients were included in the study. Group 1 included 28 patients and Group 2 included 21 patients. Group 2 patients more often underwent emergency surgery (52.4% versus 14.3%, P < .05) and had increased open surgery rate (19% versus 0%, P < .05). No difference between the groups was noted in surgical parameters, complications, and length of hospital stay. Tumor size, number of mitoses, level of ki67%, and involvement of surgical margins were not significantly different. However, in Group 2 patients, tumor size was larger and there was a trend toward higher rate of ki67 > 5%. Conclusion: Elderly patients with GIST are less frequently undergoing electively surgery and relatively often undergo open surgery. Frequency of complications is similar in elderly patients compares to younger patients group.

Development and validation of a preoperative risk nomogram prediction model for gastric gastrointestinal stromal tumors.

Gastrointestinal stromal tumors (GIST) carry a potential risk of malignancy, and the treatment of GIST varies for different risk levels. However, there is no systematic preoperative assessment protocol to predict the malignant potential of GIST. The aim of this study was to develop a reliable and clinically applicable preoperative nomogram prediction model to predict the malignant potential of gastric GIST. Patients with a pathological diagnosis of gastric GIST from January 2015 to December 2021 were screened retrospectively. Univariate and multivariate logistic analyses were used to identify independent risk factors for gastric GIST with high malignancy potential. Based on these independent risk factors, a nomogram model predicting the malignant potential of gastric GIST was developed and the model was validated in the validation group. A total of 494 gastric GIST patients were included in this study and allocated to a development group (n = 345) and a validation group (n = 149). In the development group, multivariate logistic regression analysis revealed that tumor size, tumor ulceration, CT growth pattern and monocyte-to- lymphocyte ratio (MLR) were independent risk factors for gastric GIST with high malignancy potential. The AUC of the model were 0.932 (95% CI 0.890-0.974) and 0.922 (95% CI 0.868-0.977) in the development and validation groups, respectively. The best cutoff value for the development group was 0.184, and the sensitivity and specificity at this value were 0.895 and 0.875, respectively. The calibration curves indicated good agreement between predicted and actual observed outcomes, while the DCA indicated that the nomogram model had clinical application. Tumor size, tumor ulceration, CT growth pattern and MLR are independent risk factors for high malignancy potential gastric GIST, and a nomogram model developed based on these factors has a high ability to predict the malignant potential of gastric GIST.

Lichenoid and psoriasiform drug induced rush during imatinib therapy: a clinical case

Tyrosine kinase inhibitor imatinib is a standard agent for treatment of gastrointestinal stromal tumors (GIST). Treatment courses are quite long and are usually well tolerated. However, skin rash can occur on treatment, with a prevalence of 7 to 88.9%. We describe a clinical case of a patient with GIST, who has been on treatment with imatinib at daily dose of 400 mg for one year. Several weeks from the treatment initiation, she had facial edema, and 4 months thereafter psoriasiform rash appeared which was initially considered to be psoriatic. After 8 months, the patient had lichenoid rash on the inguinal skin and oral, tongue and vulvar mucosae. Clinically, the lichenoid rash was similar with lichen ruber planus. To confirm the diagnosis, we performed biopsy of psoriasiform and lichenoid foci. Histological examination verified the drug-induced rash. Topical treatment of psoriasiform rash with glucocorticosteroids resulted in regression of some plaques, although a proportion of them persisted. Inguinal and vulvar lichenoid rashes completely regressed and numbers of oral and tongue foci decreased after a 6-week daily application of the 0.1% tacrolimus cream. Treatment with imatinib 400 mg daily was not interrupted. The clinical observation illustrates the possibility of skin and mucosal lichenoid and psoriasiform rash simultaneously during treatment with imatinib and demonstrates the first successful experience in the treatment of lichenoid rashes with 0.1% tacrolimus cream.

Cell-permeable PI3 kinase competitive peptide inhibits KIT mutant mediated tumorigenesis of gastrointestinal stromal tumor (GIST).

Mutations in the receptor tyrosine kinase KIT are the main cause of gastrointestinal stromal tumor (GIST), and the KIT mutants mediated PI3 kinase activation plays a key role in the tumorigenesis of GIST. In this study, we aimed to block PI3 kinase activation by cell-permeable peptide and investigate its possible application in the treatment of GIST. We designed cell-permeable peptides based on the binding domain of PI3 kinase subunit p85 to KIT or PI3 kinase subunit p110, respectively, in order to compete for the binding between p85 and KIT or p110 and therefore inhibit the activation of PI3 kinases mediated by KIT. The results showed that the peptide can penetrate the cells, and inhibit the activation of PI3 kinases, leading to reduced cell survival and cell proliferation mediated by KIT mutants in vitro. Treatment of mice carrying germline KIT/V558A mutation, which can develop GIST, with the peptide that can compete for the binding between p85 and p110, led to reduced tumorigenesis of GIST. The peptide can further enhance the inhibition of the tumor growth by imatinib which is used as the first line targeted therapy of GIST. Our results showed that cell-permeable PI3 kinase competitive peptide can inhibit KIT-mediated PI3 kinase activation and tumorigenesis of GIST, providing a rationale to further test the peptide in the treatment of GIST and even other tumors with over-activation of PI3 kinases.

Correlation Between N-Demethyl Imatinib Trough Concentration and Serious Adverse Reactions in Patients with Gastrointestinal Stromal Tumors: A Retrospective Cohort Study.

Imatinib is the first-line treatment for gastrointestinal stromal tumors; however, the clinical prognosis and adverse reactions of patients vary owing to individualized discrepancies in plasma exposure. To determine the safe interval for steady-state plasma trough concentrations (C min ) of imatinib and its active metabolite, N-demethyl imatinib (NDI), 328 plasma samples from 273 patients treated with imatinib were retrospectively analyzed. Imatinib C min and NDI C min were tested, and adverse reactions were recorded. The association between imatinib C min , NDI C min , and serious adverse reactions was evaluated. The C min range of imatinib was 209.5-4950.0 ng/mL, with the mean value and SD of 1491.8 ± 731.4 ng/mL. The C min range of NDI was 80.0-2390.0 ng/mL with the mean value and SD of 610.8 ± 281.5 ng/mL. NDI C min was positively correlated with imatinib C min , whereas the ratio of NDI C min to imatinib C min (NDI C min /imatinib C min ) was negatively correlated with imatinib C min . Univariate logistic regression analysis demonstrated that the treatment objective, daily dose, imatinib C min , NDI C min , and imatinib C min + NDI C min were significantly associated with serious adverse reactions. Multivariate logistic regression analysis showed that NDI C min was an independent risk factor for serious adverse reactions, with a threshold of 665 ng/mL. NDI C min was an independent risk factor for serious adverse reactions, with a threshold of 665 ng/mL. Monitoring NDI C min was beneficial for the rational application of imatinib and individualized treatment of patients with gastrointestinal stromal tumors.

A case-matched study of imatinib mesylate between different formulations on plasma trough concentration, adverse events, quality of life and outcomes in gastrointestinal stromal tumor patients.

Genike, the imatinib (IM)-alpha form is widely used in the treatment of gastrointestinal stromal tumor (GIST) patients in China. We wanted to investigate whether there are differences in IM plasma concentrations, adverse events, health-related quality of life (QOL) and outcomes between patients treated with Genike and Glivec. Thirty included GIST patients receiving IM treatment were matched to either Genike or Glivec according to gastrectomy, body weight, body surface area and sex. There was no statistically significant difference in IM trough plasma levels between the two groups. There were no significant differences in very common adverse events of IM between the Genike and Glivec groups. IM was well tolerated, although it was associated with a significant change in cognitive function (P < 0.001), fatigue (P = 0.015), pain (P = 0.015), nausea/vomiting (P = 0.029), insomnia (P = 0.019), diarrhea (P = 0.003) and financial difficulties (P < 0.001). Physical functioning, financial burden and insomnia were significantly different between the two groups (P = 0.026). Until Aug. 2022, there was no significant difference in time to imatinib treatment failure (TTF) between the two groups. In conclusion, there was no difference in IM plasma concentration and adverse events between Genike and Glivec. Both Genike and Glivec could partially decrease the QOL of GIST patients. Physical functioning was worse in Genike group than in Glivec group, while the economic burden and symptoms of insomnia in Glivec patients were worse. There was no significant difference in TTF between the two groups.

Factors associated with gastrointestinal stromal tumor rupture and pathological risk: A single-center retrospective study.

Gastrointestinal stromal tumor (GIST) is a rare gastrointestinal mesenchymal tumor with potential malignancy. Once the tumor ruptures, regardless of tumor size and mitotic number, it can be identified into a high-risk group. It is of great significance for the diagnosis, treatment, and prognosis of GIST if non-invasive examination can be performed before surgery to accurately assess the risk of tumor. To identify the factors associated with GIST rupture and pathological risk. A cohort of 50 patients with GISTs, as confirmed by postoperative pathology, was selected from our hospital. Clinicopathological and computed tomography data of the patients were collected. Logistic regression analysis was used to evaluate factors associated with GIST rupture and pathological risk grade. Pathological risk grade, tumor diameter, tumor morphology, internal necrosis, gas-liquid interface, and Ki-67 index exhibited significant associations with GIST rupture (P < 0.05). Gender, tumor diameter, tumor rupture, and Ki-67 index were found to be correlated with pathological risk grade of GIST (P < 0.05). Multifactorial logistic regression analysis revealed that male gender and tumor diameter ≥ 10 cm were independent predictors of a high pathological risk grade of GIST [odds ratio (OR) = 11.12, 95% confidence interval (95%CI): 1.81-68.52, P = 0.01; OR = 22.96, 95%CI: 2.19-240.93, P = 0.01]. Tumor diameter ≥ 10 cm, irregular shape, internal necrosis, gas-liquid interface, and Ki-67 index ≥ 10 were identified as independent predictors of a high risk of GIST rupture (OR = 9.67, 95%CI: 2.15-43.56, P = 0.01; OR = 35.44, 95%CI: 4.01-313.38, P < 0.01; OR = 18.75, 95%CI: 3.40-103.34, P < 0.01; OR = 27.00, 95%CI: 3.10-235.02, P < 0.01; OR = 4.43, 95%CI: 1.10-17.92, P = 0.04). Tumor diameter, tumor morphology, internal necrosis, gas-liquid, and Ki-67 index are associated with GIST rupture, while gender and tumor diameter are linked to the pathological risk of GIST. These findings contribute to our understanding of GIST and may inform non-invasive examination strategies and risk assessment for this condition.

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 1.4months; 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.

Abstract A030: Treatment with sustained-release anagrelide reduces tumor volume and has antiproliferative effects in a patient-derived GIST xenograft mouse model

Abstract Anagrelide is a phosphodiesterase 3A inhibitor that is used to treat essential thrombocythemia. The drug stabilizes the interaction of PDE3A and Schlafen 12 (SLFN12), resulting in complex stabilization, activation of SLFN12 RNase activity and cytotoxic effects in cancer cells. Gastrointestinal stromal tumors (GIST) exhibit high levels of PDE3A expression compared to other cancers or healthy tissue. Orally administered anagrelide has shown antitumor effects in patient-derived GIST xenograft (PDX) mouse models. In this study, we investigated the efficacy of subcutaneously administered, sustained-release anagrelide in UZLX-GIST2B, a PDX mouse model characterized by a KIT mutation in exon 9 and typical dose-dependent imatinib sensitivity. We assessed changes in tumor volume and evaluated histological drug responses including hyalinization, fibrosis, myxoid generation, and tumor necrosis. Anagrelide was administered either orally (2.5 mg/kg, twice a day) or subcutaneously (35 mg/kg and 70 mg/kg, every fourth day) for a duration of 11 days. Treatments with both 35 mg/kg and 70 mg/kg doses resulted in a significant reduction in average tumor volume compared to untreated control mice (both doses 25% vs.129%, P &amp;lt; 0.001) or mice treated with oral anagrelide (25% vs. 61%, P =0 .08, P &amp;lt; 0.05, respectively). The histological response in tumor tissue was positively correlated with dose level, and tumors treated with the highest dose exhibited grade 3 to 4 responses in all cases. These results suggest that sustained-release anagrelide holds promise as a therapeutic option for the treatment of GIST. Further preclinical studies are warranted to investigate the pharmacokinetics and toxicity of this treatment approach. Citation Format: Kirsi Toivanen, Luna De Sutter, Agnieszka Wozniak, Tom Böhling, Patrick Schöffski, Harri Sihto. Treatment with sustained-release anagrelide reduces tumor volume and has antiproliferative effects in a patient-derived GIST xenograft mouse model [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A030.

Gastrointestinal stromal tumor in North Africa and the middle east: updates in presentation and management from an 11-year retrospective cohort

ABSTRACT Objectives This study described the epidemiological, clinical, and survival profiles of patients with gastrointestinal stromal tumor (GIST) in North Africa and the Middle East (AfME). Methods This regional, multicenter, observational, retrospective study collected 11-year data on demographics, medical history, disease characteristics, current treatment approaches of GIST, the safety of the most common tyrosine kinase inhibitors (TKIs), second cancers, and survival status. Results Data of 201 eligible patients were analyzed: mean age was 56.9 ± 12.6 years; 111 (55.2%) patients were men, 21 (10.4%) patients had previous personal malignancy. The most common clinical presentation of GIST was dysphagia [92 (45.8%) patients]. The stomach was the most common primary site in 120 (60.7%) patients, 171 (85.1%) patients had localized disease at diagnosis. 198 (98.5%) GIST cases were CD117/CD34-positive. Imatinib was used in the neoadjuvant (18/21 patients), adjuvant (85/89 patients), and first-line metastatic treatment (28/33 patients) settings. The most common non-hematological toxicity associated with TKIs was vomiting in 32/85 (37.6%) patients. Overall, 100 (49.8%) patients (95%CI: 42.8–56.7%) were alive and disease-free while 30 (14.9%) patients were alive with active disease. Conclusion Presentation of GIST in our AfME population is consistent with global reports, being more frequent in patients >50 years old and having the stomach as the most common primary site. Unlike what is usually reported, though, we did have more patients with lymphatic spread of the disease. Despite the global trend and advances in the treatment of GIST according to molecular profile, this is still far to happen in our population given the lack of access to molecular profiles and the high associated cost.

Ripretinib for the treatment of advanced, imatinib-resistant gastrointestinal stromal tumors.

The discovery of the constitutive activation of KIT/PDGFRA tyrosine kinases in gastrointestinal stromal tumors (GISTs) led to the development of the targeted drug imatinib. However, the inevitable development of imatinib resistance remains a major issue. Ripretinib is a novel targeted drug that inhibits the activity of a broad spectrum of drug-resistant KIT/PDGFRA mutants. It was approved in 2020 and is currently recommended in major international guidelines as fourth-line and beyond therapy for advanced GISTs. Emerging evidence shows that ripretinib is superior to sunitinib as second-line treatment for KIT exon 11-mutated GISTs due to its activity against highly heterogeneous frequently occurring secondary mutations. This review summarizes current data on the use of ripretinib to treat advanced imatinib-resistant GISTs. We also propose future research directions to improve the precision of targeted GIST treatment. This article is protected by copyright. All rights reserved.

Liver resection for metastatic GIST tumor improves survival in the era of tyrosine kinase inhibitors: a systematic review and meta-analysis.

Survival for gastrointestinal stromal tumor (GIST) has been increasing over the years after the introduction of tyrosine kinase inhibitors. However, the role of metastasectomy for GIST is still controversial. Patients are currently treated with imatinib or sunitinib in case of imatinib failures as optimal medical therapy for metastatic GIST. The Pubmed, EMBASE, and Cochrane Library were systematically searched. Overall survival following liver resection ± tyrosine kinase inhibitor treatment for metastatic GIST was compared to treatment with tyrosine kinase inhibitors alone. Eleven studies including both randomized control trials and retrospective cohort studies were included in the final analysis with a total of 988 patients. Seven studies encompassed data on 556 patients with isolated liver metastases (219 surgery ± drug groups and 337 drug-only groups) were included. Overall survival was significantly improved in patients undergoing liver resection ± drug therapy in comparison to drug therapy alone. [HR (95%CI) = 2.10 (1.58, 2.79); p<0.00001]. Subgroup analysis showed that patients also had improved progression free survival based on 4 studies. [HR (95%CI) = 1.92 (1.43, 2.56); p<0.00001]. In case of concurrent liver and peritoneal metastases, patients showed improved overall survival with aggressive surgical approaches based on 10 studies. [HR (95%CI) = 1.90 (1.56, 2.31); p<0.00001]. This meta-analysis found that liver resection for patients with metastatic GIST regardless of peritoneal metastases improved progression free and overall survival in conjunction with tyrosine kinase inhibitors as compared with medical therapy alone. Furthermore, liver resections did not have any immediate detrimental impact on survival in the group of patients selected.