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Background: Regorafenib improves overall survival (OS) of patients with advanced progressive gastrointestinal stromal tumors (GISTs) after standard chemotherapy in phase III trials in the 3rd-line setting. This large-scale, prospective observational study evaluated the safety and effectiveness of regorafenib in Japanese patients with GIST in a real-world clinical setting. Methods: Patients with GIST received oral regorafenib at a maximum daily dose of 160 mg for weeks 1-3 of each 4-week cycle (dose could be modified at investigator's discretion). The primary objective was to assess safety, particularly significant adverse drug reactions (ADRs), as well as the frequency of occurrence of ADRs, hand and foot syndrome (HFS), discontinuation of treatment due to disease progression and adverse events. A Cox proportional hazards model was used to evaluate associations between OS or time to treatment failure (TTF) and baseline characteristics or HFS. Results: Between August 2013 and March 2021, 143 evaluable patients were enrolled. ADRs occurred in 90.2% of patients and led to treatment discontinuation in 28.3%. The most frequent ADRs were HFS, hypertension, and liver injury. The overall response rate was 11.3% and disease control rate 56.5% (RECIST) based on investigators' assessments. Median OS was 17.4 months (95% CI 14.24-23.68). Median TTF was 5.3 (95% CI 4.0-6.5) months. Improved OS and TTF responses occurred in patients with an Eastern Cooperative Oncology Group performance status (ECOG-PS) of 0 or 1. Conclusion: The outcomes in this real-world study were consistent with those seen in clinical trials. No new safety concerns were identified. Clinical trial registration: https://clinicaltrials.gov, identifier NCT01933958.
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Normal receptor tyrosine kinases (RTKs) need to reach the plasma membrane (PM) for ligand-induced activation, whereas its cancer-causing mutants can be activated before reaching the PM in organelles, such as the Golgi/trans-Golgi network (TGN). Inhibitors of protein export from the endoplasmic reticulum (ER), such as brefeldin A (BFA) and 2-methylcoprophilinamide (M-COPA), can suppress the activation of mutant RTKs in cancer cells, suggesting that RTK mutants cannot initiate signaling in the ER. BFA and M-COPA block the function of ADP-ribosylation factors (ARFs) that play a crucial role in ER-Golgi protein trafficking. However, among ARF family proteins, the specific ARFs inhibited by BFA or M-COPA, that is, the ARFs involved in RTKs transport from the ER, remain unclear. In this study, we showed that M-COPA blocked the export of not only KIT but also PDGFRA/EGFR/MET RTKs from the ER. ER-retained RTKs could not fully transduce anti-apoptotic signals, thereby leading to cancer cell apoptosis. Moreover, a single knockdown of ARF1, ARF3, ARF4, ARF5, or ARF6 could not block ER export of RTKs, indicating that BFA/M-COPA treatment cannot be mimicked by the knockdown of only one ARF member. Interestingly, simultaneous transfection of ARF1, ARF4, and ARF5 siRNAs mirrored the effect of BFA/M-COPA treatment. Consistent with these results, in vitro pulldown assays showed that BFA/M-COPA blocked the function of ARF1, ARF4, and ARF5. Taken together, these results suggest that BFA/M-COPA targets at least ARF1, ARF4, and ARF5; in other words, RTKs require the simultaneous activation of ARF1, ARF4, and ARF5 for their ER export.
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Fator 1 de Ribosilação do ADP , Fatores de Ribosilação do ADP , Brefeldina A , Retículo Endoplasmático , Transporte Proteico , Humanos , Fatores de Ribosilação do ADP/metabolismo , Fatores de Ribosilação do ADP/genética , Retículo Endoplasmático/metabolismo , Fator 1 de Ribosilação do ADP/metabolismo , Fator 1 de Ribosilação do ADP/genética , Brefeldina A/farmacologia , Transporte Proteico/efeitos dos fármacos , Receptores ErbB/metabolismo , Receptores ErbB/genética , Células HeLaRESUMO
The Japan Society of Clinical Oncology Clinical Practice Guidelines 2022 for gastrointestinal stromal tumor (GIST) have been published in accordance with the Minds Manual for Guideline Development 2014 and 2017. A specialized team independent of the working group for the revision performed a systematic review. Since GIST is a rare type of tumor, clinical evidence is not sufficient to answer several clinical and background questions. Thus, in these guidelines, we considered that consensus among the experts who manage GIST, the balance between benefits and harms, patients' wishes, medical economic perspective, etc. are important considerations in addition to the evidence. Although guidelines for the treatment of GIST have also been published by the National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology (ESMO), there are some differences between the treatments proposed in those guidelines and the treatments in the present guidelines because of the differences in health insurance systems among countries.
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Tumores do Estroma Gastrointestinal , Oncologia , Tumores do Estroma Gastrointestinal/terapia , Humanos , Japão , Oncologia/normas , Neoplasias Gastrointestinais/terapia , Sociedades Médicas , Guias de Prática Clínica como Assunto , População do Leste AsiáticoRESUMO
Approximately 10% of gastrointestinal stromal tumors (GISTs) harbor reportedly no KIT and PDGFRA mutations (wild-type GISTs). The clinicopathological features and oncologic outcomes of wild-type GISTs based on molecular profiles are unknown. We recruited 35 wild-type GIST patients from the two registry studies of high-risk GISTs between 2012 and 2015 and primary GISTs between 2003 and 2014. Molecular profiling of wild-type GISTs was performed by targeted next-generation sequencing (NGS) using formalin-fixed paraffin-embedded tumor samples. Among 35 wild-type GISTs, targeted NGS analysis detected NF1, SDH, or BRAF mutation: 16 NF1-GISTs with various NF1 mutations, 12 SDH-GISTs (4 with SDHA mutations, 4 with SDHB mutations, and 4 with SDHB-negative staining), and 5 BRAF-GISTs with the V600E mutation. Two GISTs showed no mutations based on our targeted NGS analysis. Additional gene mutations were infrequent in primary wild-type GISTs and found in TP53, CREBBP, CDKN2A, and CHEK2. Most NF1-GISTs were located in the small intestine (N = 12; 75%) and showed spindle cell features (N = 15; 94%) and multiple tumors (N = 6, 38%) with modest proliferation activities. In contrast, SDH-GISTs were predominantly found in the stomach (N = 11; 92%), exhibiting epithelioid cell (N = 6; 50%) and multiple (N = 6, 50%) features. The overall survival of patients with SDH-GISTs appeared to be better than that of BRAF-GISTs (p = 0.0107) or NF1-GISTs (p = 0.0754), respectively. In conclusion, major molecular changes in wild-type GISTs include NF1, SDH, and BRAF. NF1-GISTs involved multifocal spindle cell tumors in the small intestine. SDH-GISTs occurred in young patients and were multifocal in the stomach and clinically indolent.
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Tumores do Estroma Gastrointestinal , Humanos , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/patologia , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , Receptores Proteína Tirosina Quinases/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Succinato Desidrogenase/genéticaRESUMO
BACKGROUND: In the short term, pylorus-preserving gastrectomy (PPG) has been reported to have advantages over distal gastrectomy (DG) with regard to postprandial symptoms and dumping syndrome. We aimed to evaluate the quality of life after PPG for early gastric cancer in the long term in comparison to that after DG. METHODS: Twenty-six patients who underwent gastrectomy (11 PPG, 15 DG) for early gastric cancer at Osaka University Hospital participated and were followed for more than 4 years. Body weight changes, nutritional status, dual-phase scintigraphy findings, endoscopic survey results, and questionnaire responses after gastrectomy were examined. RESULTS: There were significantly lower ratios of weight changes in PPG than in DG, 5 years after surgery. There were no differences in the clinicopathological characteristics, nutritional parameters, questionnaire responses, and endoscopic findings between the two groups. Based on gastric scintigraphy, although the gastric emptying of liquids showed similar curves in the two groups, gastric emptying of solids was significantly slower in the PPG group than in the DG group (P = .039). DISCUSSION: PPG had advantages with regard to long-term outcomes over DG in terms of weight maintenance and the prevention of rapid gastric emptying. PPG might be efficient in patients with early gastric cancer.
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Piloro , Neoplasias Gástricas , Humanos , Piloro/cirurgia , Neoplasias Gástricas/cirurgia , Neoplasias Gástricas/patologia , Qualidade de Vida , Gastrectomia/métodos , Esvaziamento Gástrico/fisiologiaRESUMO
BACKGROUND: Imatinib contributes to improving prognosis of high-risk or unresectable gastrointestinal stromal tumors (GISTs). As therapeutic efficacy is limited by imatinib resistance and toxicity, the exploration of predictive markers of imatinib therapeutic efficacy that enables patients to utilize more effective therapeutic strategies remains urgent. METHODS: The correlation between FBXW7 and imatinib resistance via FBXW7-MCL1 axis was evaluated in vitro and in vivo experiments. The significance of FBXW7 as a predictor of imatinib treatment efficacy was examined in 140 high-risk patients with GISTs. RESULTS: The ability of FBXW7 to predict therapeutic efficacy of adjuvant imatinib in high-risk GIST patients was determined through 5-year recurrence-free survival (RFS) rates analysis and multivariate analysis. FBXW7 affects imatinib sensitivity by regulating apoptosis in GIST-T1 cells. FBXW7 targets MCL1 to regulate apoptosis. MCL1 involves in the regulation of imatinib sensitivity through inhibiting apoptosis in GIST-T1 cells. FBXW7 regulates imatinib sensitivity by down-regulating MCL1 to enhance imatinib-induced apoptosis in vitro. FBXW7 regulates imatinib sensitivity of GIST cells by targeting MCL1 to predict efficacy of imatinib treatment in vivo. CONCLUSIONS: FBXW7 regulates imatinib sensitivity by inhibiting MCL1 to enhance imatinib-induced apoptosis in GIST, and predicts efficacy of imatinib treatment in high-risk GIST patients treated with imatinib.
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Antineoplásicos , Proteína 7 com Repetições F-Box-WD , Neoplasias Gastrointestinais , Tumores do Estroma Gastrointestinal , Mesilato de Imatinib , Neoplasias Gástricas , Humanos , Antineoplásicos/uso terapêutico , Proteína 7 com Repetições F-Box-WD/metabolismo , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/patologia , Mesilato de Imatinib/uso terapêutico , Proteína de Sequência 1 de Leucemia de Células Mieloides/uso terapêutico , Neoplasias Gástricas/tratamento farmacológicoRESUMO
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.
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Antineoplásicos , Tumores do Estroma Gastrointestinal , Neoplasias Gástricas , Humanos , Mesilato de Imatinib/uso terapêutico , Antineoplásicos/uso terapêutico , Tumores do Estroma Gastrointestinal/patologia , Recidiva Local de Neoplasia/patologia , Neoplasias Gástricas/tratamento farmacológico , Sistema de Registros , Quimioterapia Adjuvante , Estudos RetrospectivosRESUMO
Aim: Tumor rupture has been indicated as a risk factor for recurrence of gastrointestinal stromal tumors (GISTs). The universal definition of tumor rupture was proposed. This study evaluated whether the universal definition was more accurate in identification of GISTs with high recurrent risk than subjective judgment. Methods: The study included 507 patients with high-risk GISTs who underwent complete resection between December 2012 and December 2015. We conducted a questionnaire survey in participating institutes to re-diagnose tumor rupture based on the universal definition according to their surgical and pathological findings. We compared the clinical outcomes of tumor rupture based on the definition to those based on the surgeon's judgment and clarified the clinical importance of the rupture. Results: Sixty-four patients were initially registered to have tumor rupture by surgeon's judgment, and it became 90 patients who had tumor rupture after reevaluation. Although there were significant differences in recurrence-free survival (RFS) between no rupture and rupture for both initial registration and reevaluation (p = 0.002, <0.001, respectively), a significant difference in overall survival was only observed after reevaluation (p = 0.011). Tumor rupture was significantly associated with large tumor size, mixed cell type in histology, R1 resection, frequent adjuvant therapy and recurrence, but not with location, mitosis, and genotype. Adjuvant therapy more than 3 years improved RFS of patients with tumor rupture. Conclusion: This study suggested that tumor rupture based on the universal definition more accurately identified GISTs with poor prognostic outcomes than the subjective judgment.
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BACKGROUND: Familial gastrointestinal stromal tumors (GISTs) are mesenchymal tumors of the digestive tract caused by germline gain-of-function mutations in the KIT gene or platelet-derived growth factor receptor alpha gene (PDGFRA). These mutations cause not only multiple GISTs but also diffuse hyperplasia of interstitial cells of Cajal (ICCs), which is related to esophageal motility disorder. CASE PRESENTATION: A 53-year-old man was referred to our hospital because of anemia and dysphagia. Fifteen years earlier, he had undergone a laparoscopic partial gastrectomy for multiple gastric GISTs with a germline mutation in exon 17 of the KIT gene. An upper gastrointestinal endoscopy revealed that the patient had multiple gastric GISTs and a large esophageal diverticulum directly above the esophagogastric junction. The largest gastric tumor was 7 cm, with a delle that might cause bleeding. Because the patient presented with dysphagia, we performed video-assisted thoracic esophagectomy and laparoscopic-assisted proximal gastrectomy simultaneously. The patient had survived without metastasis for 4 years after surgery and dysphagia had improved. CONCLUSIONS: This is the first report of successful laparoscopic-thoracoscopic surgery for a patient with familial gastric GISTs accompanied with a large esophageal diverticulum.
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Most gastrointestinal stromal tumors (GISTs) develop due to gain-of-function mutations in the tyrosine kinase gene, KIT. We recently showed that mutant KIT mislocalizes to the Golgi area and initiates uncontrolled signaling. However, the molecular mechanisms underlying its Golgi retention remain unknown. Here, we show that protein kinase D2 (PKD2) is activated by the mutant, which causes Golgi retention of KIT. In PKD2-inhibited cells, KIT migrates from the Golgi region to lysosomes and subsequently undergoes degradation. Importantly, delocalized KIT cannot trigger downstream activation. In the Golgi/trans-Golgi network (TGN), KIT activates the PKD2-phosphatidylinositol 4-kinase IIIß (PKD2-PI4KIIIß) pathway through phospholipase Cγ2 (PLCγ2) to generate a PI4P-rich membrane domain, where the AP1-GGA1 complex is aberrantly recruited. Disruption of any factors in this cascade results in the release of KIT from the Golgi/TGN. Our findings show the molecular mechanisms underlying KIT mislocalization and provide evidence for a strategy for inhibition of oncogenic signaling.
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Tumores do Estroma Gastrointestinal , Humanos , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/metabolismo , Tumores do Estroma Gastrointestinal/patologia , Proteína Quinase D2 , Fosfolipase C gama/metabolismo , Complexo de Golgi/metabolismo , Rede trans-Golgi/metabolismo , Proteínas Proto-Oncogênicas c-kit/metabolismoRESUMO
BACKGROUND: Neoadjuvant treatment is recommended for large GISTs due to their friability and risk of extensive operations; however, studies on the indications and long-term results of this approach are lacking. METHODS: Patients with large (≥ 10 cm) gastric GISTs were enrolled from multiple centers in Korea and Japan after a pathologic confirmation of c-KIT ( +) GISTs. Imatinib (400 mg/d) was given for 6-9 months preoperatively, and R0 resection was intended. Postoperative imatinib was given for at least 12 months and recommended for 3 years. RESULTS: A total of 56 patients were enrolled in this study, with 53 patients receiving imatinib treatment at least once and 48 patients undergoing R0 resection. The 5-year overall survival and progression-free survival rates were 94.3% and 61.6%, respectively. Even patients with stable disease by RECIST criteria responded well to preoperative imatinib treatment and could undergo R0 resection, with most being evaluated as partial response by CHOI criteria. The optimal reduction in tumor size was achieved with preoperative imatinib treatment for 24 weeks or more. No resumption of imatinib treatment was identified as an independent prognostic factor for recurrence after R0 resection. No additional size criteria for a higher risk of recurrence were identified in this cohort with a size of 10 cm or more. CONCLUSIONS: Neoadjuvant imatinib treatment is an effective treatment option for gastric GISTs 10 cm or larger. Postoperative imatinib treatment is recommended even after R0 resection to minimize recurrence.
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Tumores do Estroma Gastrointestinal , Mesilato de Imatinib , Neoplasias Gástricas , Humanos , Antineoplásicos/uso terapêutico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/cirurgia , Tumores do Estroma Gastrointestinal/patologia , Mesilato de Imatinib/uso terapêutico , Terapia Neoadjuvante/métodos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/cirurgiaRESUMO
Risk factors of gastrointestinal stromal tumors (GISTs) include tumor size, location, mitosis, and tumor rupture. Although the first three are commonly recognized as independent prognostic factors, tumor rupture is not a consistent finding. Indeed, tumor rupture may be subjectively diagnosed and is rarely observed. Moreover, the criteria used for diagnosis differ among oncologists, which may result in inconsistent outcomes. Based on these conditions, a universal definition of tumor rupture was proposed in 2019 and consists of six scenarios: tumor fracture, blood-stained ascites, gastrointestinal perforation at the tumor site, histologically proven invasion, piecemeal resection, and open incisional biopsy. Although the definition is considered appropriate for selection of GISTs with worse prognostic outcomes, each scenario lacks a high level of evidence and there is yet no consensus for some, including histological invasion and incisional biopsy. It may be, however, important to have common criteria for clinical decision-making, which may facilitate reliability, external validity, and comparability of clinical studies in rare GISTs. After the definition, several retrospective reports indicated that even with adjuvant therapy, tumor rupture was associated with high recurrence rates and poor prognostic outcomes. The prognosis of patients with ruptured GISTs is improved by 5-year adjuvant therapy compared with 3-year therapy. Nevertheless, the universal definition requires further evidence, and prospective clinical studies based on the definition are warranted.
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Gastrointestinal stromal tumours (GISTs) are soft-tissue sarcomas of the gastrointestinal tract. Surgery is the standard treatment for localised disease, but the risk of relapse and progression to more advanced disease is substantial. Following the discovery of the molecular mechanisms underlying GISTs, targeted therapies for advanced GIST were developed, with the first being the tyrosine kinase inhibitor (TKI) imatinib. Imatinib is recommended in international guidelines as first-line therapy to reduce the risk of GIST relapse in high-risk patients, and for locally advanced, inoperable and metastatic disease. Unfortunately, imatinib resistance frequently occurs and, therefore, second-line (sunitinib) and third-line (regorafenib) TKIs have been developed. Treatment options are limited for patients with GIST that has progressed despite these therapies. A number of other TKIs for advanced/metastatic GIST have been approved in some countries. Ripretinib is approved as fourth-line treatment of GIST and avapritinib is approved for GIST harbouring specific genetic mutations, while larotrectinib and entrectinib are approved for solid tumours (including GIST) with specific genetic mutations. In Japan, pimitespib, a heat shock protein 90 (HSP90) inhibitor, is now available as a fourth-line therapy for GIST. Clinical studies of pimitespib have indicated that it has good efficacy and tolerability, importantly not displaying the ocular toxicity of previously developed HSP90 inhibitors. Additional approaches for advanced GIST have been investigated, including alternative uses of currently available TKIs (such as combination therapy), novel TKIs, antibody-drug conjugates, and immunotherapies. Given the poor prognosis of advanced GIST, the development of new therapies remains an important goal.
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Antineoplásicos , Neoplasias Gastrointestinais , Tumores do Estroma Gastrointestinal , Neoplasias Gástricas , Humanos , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/patologia , Mesilato de Imatinib/uso terapêutico , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/patologia , Neoplasias Gástricas/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologiaRESUMO
BACKGROUND: Imatinib mesylate (IM) is the standard chemotherapy for patients with gastrointestinal stromal tumors (GISTs) and has a favorable safety profile. Pharmacokinetics (PK), such as plasma trough concentration (Cmin), varies among patients, requiring the need for therapeutic drug monitoring (TDM) during IM administration. Despite some reports from overseas, the relationship between Cmin, adverse events (AEs), and treatment efficacy in Japanese patients with GIST has still been lacking. This study aimed to investigate the relationship between IM plasma concentration and AEs in Japanese patients with GISTs. METHODS: This retrospective study analyzed the data of 83 patients who underwent IM treatment for GISTs at our institution between May 2002 and September 2021. RESULTS: The IM Cmin was associated with any grade of AEs (with AEs vs. without AEs = 1294 (260-4075) vs. 857 (163-1886) ng/mL, P < 0.001), edema (with edema vs. without edema = 1278 (634-4075) vs. 1036 (163-4069) ng/mL, P = 0.017), and fatigue (with fatigue vs. without fatigue = 1373 (634-4069) vs. 1046 (163-4075) ng/mL, P = 0.044). Moreover, a Cmin ≥ 1283 ng/mL was a risk factor for severe AEs. The median progression-free survival (PFS) was 3.04 years in the lowest Cmin tertile (T1, < 917 ng/mL) compared with 5.90 years for T2 and T3 (P = 0.010). CONCLUSION: Edema and fatigue are potentially associated with IM plasma trough concentrations of ≥ 1283 ng/mL in Japanese patients with GISTs. Further, maintaining an IM plasma trough concentration above 917 ng/mL may improve PFS.
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Antineoplásicos , Monitoramento de Medicamentos , Tumores do Estroma Gastrointestinal , Mesilato de Imatinib , Humanos , Antineoplásicos/efeitos adversos , Antineoplásicos/sangue , Antineoplásicos/uso terapêutico , População do Leste Asiático , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/patologia , Mesilato de Imatinib/efeitos adversos , Mesilato de Imatinib/sangue , Mesilato de Imatinib/uso terapêutico , Estudos Retrospectivos , Monitoramento de Medicamentos/métodos , Resultado do Tratamento , Edema/induzido quimicamente , Edema/etiologia , Fadiga/induzido quimicamente , Fadiga/etiologiaRESUMO
Despite the effectiveness of imatinib, most gastrointestinal stromal tumors (GISTs) develop resistance to the treatment, mainly due to the reactivation of KIT tyrosine kinase activity. Sunitinib, which inhibits the phosphorylation of KIT and vascular endothelial growth factor (VEGF) receptor, has been established as second-line therapy for GISTs. The recently-developed heat shock protein 90 (HSP90) inhibitor pimitespib (PIM; TAS-116) demonstrated clinical benefits in some clinical trials; however, the effects were limited. The aim of our study was therefore to clarify the effectiveness and mechanism of the combination of PIM with sunitinib for imatinib-resistant GISTs. We evaluated the efficacy and mechanism of the combination of PIM with sunitinib against imatinib-resistant GIST using imatinib-resistant GIST cell lines and murine xenograft models. In vitro analysis demonstrated that PIM and sunitinib combination therapy strongly inhibited growth and induced apoptosis in imatinib-resistant GIST cell lines by inhibiting KIT signaling and decreasing auto-phosphorylated KIT in the Golgi apparatus. In addition, PIM and sunitinib combination therapy enhanced antitumor responses in the murine xenograft models compared to individual therapies. Further analysis of the xenograft models showed that the combination therapy not only downregulated the KIT signaling pathway but also decreased the tumor microvessel density. Furthermore, we found that PIM suppressed VEGF expression in GIST cells by suppressing protein kinase D2 and hypoxia-inducible factor-1 alpha, which are both HSP90 client proteins. In conclusion, the combination of PIM and sunitinib is effective against imatinib-resistant GIST via the downregulation of KIT signaling and angiogenic signaling pathways.
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Antineoplásicos , Tumores do Estroma Gastrointestinal , Humanos , Animais , Camundongos , Mesilato de Imatinib/farmacologia , Mesilato de Imatinib/uso terapêutico , Sunitinibe/farmacologia , Sunitinibe/uso terapêutico , Tumores do Estroma Gastrointestinal/patologia , Fator A de Crescimento do Endotélio Vascular , Piperazinas/farmacologia , Pirimidinas , Resistencia a Medicamentos Antineoplásicos , Antineoplásicos/uso terapêutico , Proteínas Proto-Oncogênicas c-kit/metabolismo , Inibidores de Proteínas Quinases/farmacologiaRESUMO
Tyrosine kinase inhibitors (TKIs) improve the prognosis of patients with gastrointestinal stromal tumors (GISTs). We conducted a retrospective cohort study using cancer registries linked with health utilization data in Japan and Taiwan to assess TKI usage in older and non-older patients. Patients diagnosed with GIST (2012-2014) were categorized into the following: adjuvant and advanced/metastatic settings. The duration and patterns of imatinib therapy were compared between the older (aged ≥ 75 years) and non-older (< 75 years) groups. We included 232 Japanese and 492 Taiwanese patients in the adjuvant setting, and 235 Japanese and 401 Taiwanese patients in the advanced/metastatic setting. Older patients had higher proportions of starting with lower doses (< 400 mg/day) than the non-older patients (adjuvant: 22.5% vs. 4.3% [Japan]; 22.5% vs. 10.9% [Taiwan]; advanced/metastatic: 29.6% vs. 7.2% [Japan]; 32.6% vs. 8.1% [Taiwan]; all p < 0.01). The median time to stop imatinib was shorter in the older than in the non-older patients (adjuvant: 301 vs. 975 days [Japan], 366 vs. 1028 days [Taiwan]; advanced/metastatic: 423 vs. 542 days [Japan]; 366.5 vs. 837 days [Taiwan]). More older patients with GIST tended to have TKIs at a lower initial dose and a shorter imatinib duration than the non-older patients.
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Antineoplásicos , Neoplasias Gastrointestinais , Tumores do Estroma Gastrointestinal , Humanos , Idoso , Mesilato de Imatinib/uso terapêutico , Tumores do Estroma Gastrointestinal/patologia , Estudos Retrospectivos , Japão/epidemiologia , Taiwan/epidemiologia , Adjuvantes Imunológicos/uso terapêutico , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/patologia , Antineoplásicos/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
PURPOSE: Three years of adjuvant imatinib is the standard therapy for gastrointestinal stromal tumors (GISTs) with high-risk features. The prognostic effects of long-term adjuvant therapy are unknown. PATIENTS AND METHODS: The prospective registry study recruited 515 patients with high-risk GISTs between Dec. 2012 and Dec. 2015 were analyzed. The primary endpoint was recurrence-free survival (RFS), and secondary endpoints include overall survival (OS) and safety. The study was designed to compare RFS after 3.5 years of 3-year adjuvant therapy (3.0 ± 0.5 years: 3-year group) with that of more than 3.5 years (median 5.2 years: longer group). RESULTS: Five-year RFS and 5-year OS were 68.2% (95% confidence interval [CI] 63.8-72.1) and 92.3% (95% CI 89.5-94.4), respectively. The recurrence rate during adjuvant was estimated to be 2.9/100 person-years (95% CI 2.0-4.1) and those after the end of adjuvant, which appeared similar irrespective of the adjuvant duration or reason to stop adjuvant, were estimated 12.0/100 person-years (95% CI 10.2-14.0). The 5-year RFS rates of 3-year and longer groups were 78.7% (95% CI 70.8-84.7) and 92.7% (95% CI 85.2-96.4), respectively. RFS after 3.5 years of the longer group was significantly better than that of the 3-year group (adjusted hazard ratio [HR] 0.56; 95% CI 0.39-0.78; P < 0.001). CONCLUSION: The recurrence risk of high-risk GISTs after adjuvant therapy is similar irrespective of the adjuvant duration and imatinib adjuvant may not cure but may delay recurrence. RFS after long-term adjuvant therapy appeared better than that after 3-year adjuvant.
Assuntos
Antineoplásicos , Neoplasias Gastrointestinais , Tumores do Estroma Gastrointestinal , Neoplasias Gástricas , Antineoplásicos/uso terapêutico , Quimioterapia Adjuvante , Neoplasias Gastrointestinais/tratamento farmacológico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Humanos , Mesilato de Imatinib/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Gástricas/tratamento farmacológicoRESUMO
BACKGROUND: Regorafenib is an oral multi-kinase inhibitor that has been established as third-line treatment for patients after the failure of imatinib and sunitinib. However, since clinical data of regorafenib in the Japanese population are still lacking, the management of regorafenib is mainly based on the clinical experience of each oncologist. The aim of this study was to evaluate the efficacy and safety of regorafenib in a Japanese population. METHODS: Thirty-three patients treated with regorafenib for metastatic and recurrent gastrointestinal stromal tumors were retrospectively enrolled. This study investigated the anti-tumor effect, including overall survival, progression-free survival, and safety, which was evaluated based on the incidence of adverse events. RESULTS: The median overall survival of patients treated with regorafenib was 23.8 months and the 1-year overall survival rate was 80.0%, the median progression-free survival was 7.1 months and the 1-year progression-free survival rate was 40.2%. The responses to regorafenib were partial response in 3 cases (9.1%), stable disease in 17 (51.5%), progressive disease in 10 (30.3%), and non-evaluable in 3 (9.1%). The disease control rate was 54.0%. Treatment-related adverse events were reported in all patients, with the most common being hand-foot syndrome (72.7%), followed by liver damage (36.4%) and diarrhea (27.3%), and six patients (20.0%) were discontinued due to adverse events. CONCLUSION: This is the first report of Japanese patients with gastrointestinal stromal tumors treated with regorafenib. Regorafenib showed efficacy and a manageable safety profile in Japanese patients with advanced gastrointestinal stromal tumors, which was comparable with previous studies.
Assuntos
Tumores do Estroma Gastrointestinal , Resistencia a Medicamentos Antineoplásicos , Tumores do Estroma Gastrointestinal/patologia , Humanos , Indóis/uso terapêutico , Japão , Recidiva Local de Neoplasia/tratamento farmacológico , Compostos de Fenilureia , Piridinas , Pirróis/uso terapêutico , Estudos RetrospectivosRESUMO
Background: Most gastrointestinal stromal tumors (GIST) harbor a mutation in KIT or platelet-derived growth factor receptor alfa (PDGFRA). Although genotyping is a useful predictive marker of tyrosine kinase inhibitors, whether it can predict prognosis remains controversial. Methods: Data on 402 patients with GIST who underwent macroscopically complete surgery and received no neoadjuvant/adjuvant therapy were selected from a prospective GIST database at the three, participating hospitals. The types and locations of KIT and PDGFRA mutations were analyzed by direct sequencing of the amplified genes. The association between the genotypic characteristics and prognosis was then examined. Results: Tumor genotypes were analyzed in 398 of 402 (99%) patients, and 120 mutation patterns were identified. KIT mutations had broad malignancy potential which differed according to the type of mutation. Deletion and deletion-insertion type mutations were associated with worse RFS while duplication and substitution type mutations were associated with favorable RFS KIT deletion/deletion-insertion, including codons 557 and 558, were especially associated with worse RFS on multivariate analysis both of all the patients and those with KIT mutations. Conclusions: Specific GIST genotypes were significantly associated with a risk of recurrence. Genotype analysis may be useful for predicting the prognosis and determining the indications for adjuvant imatinib in patients with GIST.