Final analysis of the randomized trial on imatinib as an adjuvant in localized gastrointestinal stromal tumors (GIST) from the EORTC Soft Tissue and Bone Sarcoma Group (STBSG), the Australasian Gastro-Intestinal Trials Group (AGITG), UNICANCER, French Sarcoma Group (FSG), Italian Sarcoma Group (ISG), Spanish Group for Research on Sarcomas (GEIS)

Gastrointestinal stromal tumors (GISTs) are the most common malignant mesenchymal tumors of the gastrointestinal tract. The most common sites of metastasis are the liver and the peritoneum, whereas metastasis to soft tissue is rare. The authors present the case of a 78-year-old male with a soft tissue metastasis of a GIST and the current literature is reviewed.

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Inhibition of AKT-Signaling Sensitizes Soft Tissue Sarcomas (STS) and Gastrointestinal Stromal Tumors (GIST) to Doxorubicin via Targeting of Homology-Mediated DNA Repair

International Journal of Molecular Sciences ◽

10.3390/ijms21228842 ◽

2020 ◽

Vol 21 (22) ◽

pp. 8842

Author(s):

Sergei Boichuk ◽

Firuza Bikinieva ◽

Ilmira Nurgatina ◽

Pavel Dunaev ◽

Elena Valeeva ◽

...

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Soft Tissue ◽

Gastrointestinal Stromal Tumors ◽

Topoisomerase Ii ◽

Soft Tissue Sarcomas ◽

Akt Signaling ◽

Chemotherapeutic Agents ◽

Tail Moment ◽

Stromal Tumors

Activation of the phosphoinositide 3-kinase (PI3K)/Akt/mTOR pathway is well documented for a broad spectrum of human malignancies supporting their growth and progression. Accumulating evidence has also implicated AKT as a potent modulator of anti-cancer therapies via regulation of DNA damage response and repair (DDR) induced by certain chemotherapeutic agents and ionizing radiation (IR). In the present study, we examined the role of AKT signaling in regulating of Rad51 turnover and cytotoxic effects of topoisomerase II inhibitor, doxorubicin (Dox) in soft tissue sarcomas (STS) and gastrointestinal stromal tumors (GIST) in vitro. Blocking of AKT signaling (MK-2206) enhanced cytotoxic and pro-apoptotic effects of Dox in vast majority of STS and GIST cell lines. The phosphorylated form of Akt co-immunoprecipitates with Rad51 after Dox-induced DNA damage, whereas Akt inhibition interrupts this interaction and decreases Rad51 protein level by enhancing protein instability via proteasome-dependent degradation. Inhibition of Akt signaling in Dox-treated cells was associated with the increased number of γ-H2AX-positive cells, decrease of Rad51 foci formation and its colocalization with γ-H2AX foci, thereby revealing unsuccessful DDR events. This was also in consistency with an increase of tail moment (TM) and olive tail moment (OTM) in Dox-treated GIST and STS cells cultured in presence of Akt inhibitor after Dox washout. Altogether, our data illustrates that inhibition of AKT signaling is STS and GIST might potentiate the cytotoxic effect of topoisomerase II inhibitors via attenuating the homology-mediated DNA repair.

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Surgery Prolongs the Survival of Patients with Metastatic, Recurrent, or Unresectable Locally Advanced Gastrointestinal Stromal Tumors Response to Imatinib Mesylate Treatment: A Systematic Review and Meta-analysis

10.21203/rs.3.rs-212183/v1 ◽

2021 ◽

Author(s):

Weihao Li ◽

Jianhong Peng ◽

Xinyue Li ◽

Rongxin Zhang ◽

Binyi Xiao ◽

...

Keyword(s):

Imatinib Mesylate ◽

Gastrointestinal Stromal Tumors ◽

Locally Advanced ◽

Progression Free Survival ◽

Final Analysis ◽

Cochrane Library ◽

Stromal Tumors ◽

Pooled Data ◽

Surgery Group ◽

The Impact

Abstract Background The role of surgery in patients with metastatic, recurrent or unresectable locally advanced gastrointestinal stromal tumors (GIST) who respond to imatinib mesylate (IM) treatment is still not formally defined. Therefore, we systemically searched and analyzed the available literature to evaluate the oncologic benefits of surgery in this specific population. Methods A systematic literature search of the PubMed, Embase, and Cochrane Library databases was performed to identify relevant articles on July 16, 2020. Pooled data analysis was also performed using Review Manager. Results Totally 10 studies including 1188 patients (410 patients in the surgery group and 778 patients in the no surgery group) were included in the final analysis. No significant differences in baseline clinical characteristics were found except that patients in the surgery group were significantly younger (WMD, -5.02, 95% CI, -8.38 to -1.67, P = 0.003). In the overall population, pooled data showed a significant improvement in overall survival (OS) (HR, 0.62; 95% CI, 0.53 to 0.73; P < 0.0001) and progression-free survival (PFS) (HR, 0.57; 95% CI, 0.44 to 0.72; P < 0.0001) with surgery. In the subgroup analysis, the impact of surgery on patient response to IM treatment was further confirmed (OS: HR, 0.67; 95% CI, 0.55 to 0.81; P < 0.0001; PFS: HR, 0.62; 95% CI, 0.46 to 0.82; P = 0.009). Conclusions Surgery prolongs the OS and PFS of patients with metastatic, recurrent, or unresectable locally advanced GIST who respond to IM treatment. Future prospective, multicenter RCTs are warranted.

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Soft Tissue Leiomyosarcomas and Malignant Gastrointestinal Stromal Tumors: Differences in Clinical Outcome and Expression of Multidrug Resistance Proteins

Journal of Clinical Oncology ◽

10.1200/jco.2000.18.18.3211 ◽

2000 ◽

Vol 18 (18) ◽

pp. 3211-3220 ◽

Cited By ~ 160

Author(s):

Boudewijn E. C. Plaat ◽

Harry Hollema ◽

Willemina M. Molenaar ◽

Gerben H. Torn Broers ◽

Justin Pijpe ◽

...

Keyword(s):

Multidrug Resistance ◽

Soft Tissue ◽

Clinical Outcome ◽

Gastrointestinal Stromal Tumors ◽

Abdominal Cavity ◽

Chemotherapy Resistance ◽

Multidrug Resistance Proteins ◽

Stromal Tumors ◽

Resistance Protein ◽

The Mean

PURPOSE: Several studies have reported clinical behavior and chemotherapy resistance in leiomyosarcomas, but these studies did not differentiate between soft tissue leiomyosarcomas (LMS) and malignant gastrointestinal stromal tumors (GIST). Multidrug resistance (MDR) has been associated with the expression of P-glycoprotein (P-gp), multidrug resistance protein (MRP1), and lung resistance protein (LRP). The aim of the present study was to compare LMS and GIST with respect to clinical outcome and MDR parameters. PATIENTS AND METHODS: Clinical outcome was evaluated in 29 patients with a primary deep-seated LMS and 26 patients with a primary malignant GIST. Paraffin-embedded material, available for 26 patients with LMS and 25 with GIST, was used for immunohistochemical detection of P-gp, MRP1, LRP, and c-kit. RESULTS: Mean overall survival (OS) was 72 months for LMS patients and 31 months for GIST patients (P < .05). Metastases occurred in 16 (59%) of 27 assessable LMS patients and in 10 (56%) of 18 assessable GIST patients. LMS predominantly metastasized to the lungs (14 of 16 patients), whereas GIST tended to spread to the liver (five of 10 patients) and the abdominal cavity (three of 10 patients; P < .001). P-gp and MRP1 expression was more pronounced in GIST than in LMS (P < .05): the mean percentage of P-gp expressing cells was 13.4% in patients with LMS and 38.4% in patients with GIST, and the mean percentage MRP1 expressing cells was 13.3% in patients with LMS and 35.4% in patients with GIST. LRP expression did not differ between LMS and GIST. c-kit was expressed in 5% of the LMS patients and in 68% of the GIST patients. CONCLUSION: LMS patients have a better survival than GIST patients, and the metastatic pattern is different. Expression of MDR proteins in LMS is less pronounced than in GIST.

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