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1.
Gan To Kagaku Ryoho ; 48(2): 269-272, 2021 Feb.
Artigo em Japonês | MEDLINE | ID: mdl-33597378

RESUMO

A 67-year-old woman was admitted with melena. A colonoscopy detected a 50 mm submucosal tumor close to the dentate line. We diagnosed the rectal gastrointestinal stromal tumor by EUS-FNA. With the expectation of tumor shrinkage and strong hope of the patient, we started imatinib mesylate as neoadjuvant chemotherapy. A CT scan after 3 months after administration of imatinib mesylate showed the reduction of the size to 35 mm. We operated transanal endoscopic surgery considering the localization of the tumor. From histopathological findings, the tumor was low risk in the modified-Fletcher classification, and low risk in the Miettinen classification. Eight months after the operation, no recurrence was observed without further adjuvant chemotherapy. In this case, we were able to resect the tumor without injuring the film of tumor by operating transanal endoscopic surgery, because of tumor shrinkage with imatinib mesylate as neoadjuvant chemotherapy. I considered that using imatinib mesylate preoperatively was contributed to minimally invasive surgery.


Assuntos
Antineoplásicos , Tumores do Estroma Gastrointestinal , Neoplasias Retais , Idoso , Antineoplásicos/uso terapêutico , Feminino , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/cirurgia , Humanos , Mesilato de Imatinib/uso terapêutico , Procedimentos Cirúrgicos Minimamente Invasivos , Terapia Neoadjuvante , Recidiva Local de Neoplasia , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/cirurgia , Reto
2.
Gan To Kagaku Ryoho ; 48(1): 101-103, 2021 Jan.
Artigo em Japonês | MEDLINE | ID: mdl-33468734

RESUMO

A 71-year-old man underwent total gastrectomy with Roux-en-Y reconstruction for gastric GIST in October 2017. Liver metastasis was identified in June 2019, and chemotherapy with imatinib was started in July. In December, the patient presented with acute upper abdominal pain and back pain. Abdominal contrast-enhanced CT showed that the jejunum extending from the duodenal stump was dilated. In addition, part of the jejunum had a poor wall contrast effect, with ascites also found surrounding it. We suspected a strangulated ileus and immediately performed emergency surgery. We found an internal hernia with incarceration of the afferent loop at the Petersen's defect. The time from the onset of symptoms to the surgery was relatively short, and the surgery was completed with hernial repair and closure of the hernial orifice without the development of bowel necrosis; the patient's postoperative course was good. Although the frequency of internal hernia after gastrectomy is relatively low, there is a risk that it may be severe if it occurs. Therefore, care should be taken to not cause internal hernias during surgery, and an internal hernia should be considered in the event of sudden abdominal pain after gastric surgery.


Assuntos
Derivação Gástrica , Tumores do Estroma Gastrointestinal , Hérnia Abdominal , Laparoscopia , Neoplasias Hepáticas , Idoso , Gastrectomia , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/cirurgia , Hérnia Abdominal/cirurgia , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/cirurgia , Masculino
3.
BMJ Case Rep ; 13(12)2020 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-33318243

RESUMO

Imatinib is used to treat several haematological and solid malignancies. Cutaneous side effects could often limit the use of this medication. We present a case of a 62-year-old woman with a history of a gastrointestinal stromal tumour that developed a delayed cutaneous adverse reaction 10 days after starting imatinib 400 mg daily. She developed the same symptoms with reintroduction at a dose of 100 mg and with an alternative tyrosine kinase inhibitor, nilotinib 50 mg/day. Given that imatinib was considered her best treatment, she underwent a long induction of drug tolerance (IDT) protocol to imatinib. Patient tolerated the medication without further reactions for 6 months and had improvement of her cancer per last imaging studies. IDT should be considered in delayed hypersensitivity reactions to imatinib after a failed reintroduction of the drug or when no other equally effective agents are available.


Assuntos
Antineoplásicos/administração & dosagem , Tolerância a Medicamentos/fisiologia , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Mesilato de Imatinib/administração & dosagem , Antineoplásicos/efeitos adversos , Exantema/etiologia , Feminino , Tumores do Estroma Gastrointestinal/patologia , Humanos , Mesilato de Imatinib/efeitos adversos , Pessoa de Meia-Idade , Prurido/etiologia
4.
Nihon Shokakibyo Gakkai Zasshi ; 117(10): 914-918, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-33041303

RESUMO

A fifty-year-old man with a liver metastasis of a duodenal gastrointestinal stromal tumor (GIST) previously treated with imatinib. Thirty-three months following initiation of the therapy, he visited the emergency room of our hospital presenting with an upper abdominal pain. Dynamic CT scan revealed a ruptured liver metastasis of duodenal GIST. We used transcatheter arterial embolization to stop the bleeding. Due to the rarity of this condition, we herein report this case with an article review.


Assuntos
Embolização Terapêutica , Tumores do Estroma Gastrointestinal , Neoplasias Hepáticas , Duodeno , Tumores do Estroma Gastrointestinal/diagnóstico por imagem , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Humanos , Mesilato de Imatinib/uso terapêutico , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/tratamento farmacológico , Masculino , Pessoa de Meia-Idade
5.
Drugs Today (Barc) ; 56(9): 561-571, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33025950

RESUMO

Avapritinib is a tyrosine kinase inhibitor (TKI) that has recently received Food and Drug Administration (FDA) approval for the treatment of metastatic or unresectable gastrointestinal stromal tumors harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation. Mutations in the activation loop of PDGFRA or KIT confer resistance to conventional TKIs due to structural changes in the receptor. Avapritinib was developed to selectively target these mutations, thereby offering a new treatment option for patients in whom imatinib, sunitinib, and regorafenib have failed. This review covers the basic science and preclinical studies that guided avapritinib's development, in addition to the data currently available from early clinical studies as well as those later-stage trials that led to its approval.


Assuntos
Tumores do Estroma Gastrointestinal/tratamento farmacológico , Pirazóis/uso terapêutico , Pirróis/uso terapêutico , Triazinas/uso terapêutico , Ensaios Clínicos como Assunto , Tumores do Estroma Gastrointestinal/genética , Humanos , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-kit/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Estados Unidos
6.
Medicine (Baltimore) ; 99(40): e22493, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33019445

RESUMO

RATIONALE: Gastrointestinal stromal tumors that present outside the gastrointestinal tract are known for extra-gastrointestinal stromal tumors (EGISTs) and they share the same morphological and immunohistochemical characteristics with gastrointestinal stromal tumors. Here we report a rare case of diffuse primary EGIST arising at peritoneum. PATIENT CONCERNS: A 57-year-old male presented to the hospital with abdominal pain and right lower abdominal tenderness. DIAGNOSIS: The core needle puncture biopsy showed epithelial-like cells and the nuclei were ovoid and focally elongated. Immunohistochemical examination was consistent with a primary EGIST of the peritoneum. INTERVENTIONS: The patient was treated with Imatinib mesylate. OUTCOMES: Five months later, there is no complication resulting from treatment. The follow-up abdominal contrast-enhanced CT showed the lesion was significantly decreased in size, and was evaluated as partial response. The patient continued the treatment with Imatinib as prescribed by the oncologist. LESSONS: EGISTs are rare and should be considered in the differential diagnosis of the peritoneal tumors and immunohistochemistry helps to confirm the diagnosis. Further study with longer follow-up is desired to characterize these uncommon tumors.


Assuntos
Tumores do Estroma Gastrointestinal/patologia , Neoplasias Peritoneais/patologia , Antineoplásicos/uso terapêutico , Tumores do Estroma Gastrointestinal/diagnóstico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Humanos , Mesilato de Imatinib/uso terapêutico , Masculino , Pessoa de Meia-Idade , Neoplasias Peritoneais/diagnóstico , Neoplasias Peritoneais/tratamento farmacológico
7.
Zhonghua Wei Chang Wai Ke Za Zhi ; 23(9): 840-844, 2020 Sep 25.
Artigo em Chinês | MEDLINE | ID: mdl-32927506

RESUMO

In patients with recurrent or metastatic gastrointestinal stromal tumor (GIST), imatinib is the mainstay treatment, which has significantly improved outcome. However, approximately half of patients who have initial respose to imatinib will develop secondary resistance within 2 years, leading to progressive disease. Available data suggest that cytoreductive surgery may be considered in patients with metastatic GIST who respond to imatinib and have relatively low tumor burden, particularly in whom a R0/R1 resection is anticipated. The evidence of benefit from surgery in patients with focal tumor progression on imatinib is limited, but after surgical resection of progressive lesions, shifting to second line therapy should be initiated. Patients with multifocal progression are not suitable for surgical intervention. In the meantime, surgery for patients treated with sunitinib is feasible, yet survival benefit remains controversial. Thus, surgery should be considered in patients with metastatic GIST whose disease responds to imatinib with a goal of performing R0/R1 resection. On a case-by-case basis, surgical intervention should be determined after careful multidisciplinary consultation to achieve safety, improvement of symptoms and long-term survival benefits.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Gastrointestinais/cirurgia , Tumores do Estroma Gastrointestinal/cirurgia , Mesilato de Imatinib/uso terapêutico , Recidiva Local de Neoplasia/cirurgia , Procedimentos Cirúrgicos de Citorredução , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/secundário , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Equipe de Assistência ao Paciente , Sunitinibe/uso terapêutico , Resultado do Tratamento , Carga Tumoral
8.
Zhonghua Wei Chang Wai Ke Za Zhi ; 23(9): 911-916, 2020 Sep 25.
Artigo em Chinês | MEDLINE | ID: mdl-32927518

RESUMO

Imatinib has created the era of precise treatment of gastrointestinal stromal tumor (GIST). However, in recent years, there has been a lack of satisfactory drugs for imatinib resistance. Recently, the emergence of a series of new agents not only brings new hope to break this situation, but also verifies that the drug development of GIST treatment still needs to lock the driving gene as the main target. New drugs, such as avapritinib and ripretinib, have shown surprising therapeutic efficacy, which may lead to a new situation in the treatment of GIST. The precise treatment of GIST guided by different primary gene mutations and secondary drug resistance mutations will replace the traditional guidelines based on the number of treatment lines.


Assuntos
Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/genética , Antineoplásicos/farmacologia , Humanos , Mesilato de Imatinib/farmacologia , Mesilato de Imatinib/uso terapêutico , Naftiridinas/farmacologia , Naftiridinas/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Pirróis/farmacologia , Pirróis/uso terapêutico , Triazinas/farmacologia , Triazinas/uso terapêutico , Ureia/análogos & derivados , Ureia/farmacologia , Ureia/uso terapêutico
9.
Zhonghua Wei Chang Wai Ke Za Zhi ; 23(9): 917-921, 2020 Sep 25.
Artigo em Chinês | MEDLINE | ID: mdl-32927519

RESUMO

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumors in the gastrointestinal tract. Surgical resection is the only curative treatment, while imatinib is the first-line therapy for recurrent, metastatic, and unresectable GIST. However, more than half of GIST patients suffer from secondary resistance to imatinib within 2 years after treatment initiation. Therefore, early diagnosis, drug resistance and recurrence surveillance are critical for GIST patients. Liquid biopsy is a new method which utilizes the detection of tumor biomarkers in peripheral blood for early diagnosis and therapeutic efficacy assessment. In recent years, liquid biopsy has achieved significant research progress in several kinds of malignancy. This review aims at presenting an overview on research advance of liquid biopsy in GIST and may provide a new method for early diagnosis and therapeutic efficacy assessment of GIST.


Assuntos
Detecção Precoce de Câncer/métodos , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/patologia , Biópsia Líquida , Recidiva Local de Neoplasia/diagnóstico , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Neoplasias Gastrointestinais/sangue , Neoplasias Gastrointestinais/diagnóstico , Neoplasias Gastrointestinais/tratamento farmacológico , Tumores do Estroma Gastrointestinal/sangue , Tumores do Estroma Gastrointestinal/diagnóstico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Humanos , Mesilato de Imatinib/efeitos adversos , Mesilato de Imatinib/uso terapêutico , Recidiva Local de Neoplasia/etiologia
10.
Dermatol Online J ; 26(6)2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32815695

RESUMO

Pemphigus is an autoimmune bullous disease with a number of described associations, including medications, which have been grouped into three structural categories - thiol drugs, phenol drugs, and drugs with neither functional group [1]. Discontinuation of the offending medication is considered a mainstay of therapy. We report a patient in whom the onset of pemphigus foliaceus was associated with initiation of imatinib mesylate adjuvant therapy in a patient with resected gastrointestinal stromal tumor (GIST). Imatinib was continued because of the survival benefit to the patient with a resected, high risk GIST. Treatment with rituximab resulted in near resolution of his blistering rash and follow up enzyme-linked immunosorbent assay (ELISA) demonstrated reference range immunoreactivity for both desmoglein 1 and desmoglein 3. After dose increase of imatinib therapy owing to tumor growth, the patient subsequently again developed a similar eruption. Re-biopsy and ELISA were consistent with recurrence of pemphigus. In conclusion, although the patient's pemphigus was cleared with a single cycle of rituximab infusions while continuing imatinib therapy, the disease returned after imatinib dose was increased a year later, suggesting a dose-response relationship.


Assuntos
Antineoplásicos/efeitos adversos , Neoplasias Gastrointestinais/tratamento farmacológico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Mesilato de Imatinib/efeitos adversos , Fatores Imunológicos/uso terapêutico , Pênfigo/induzido quimicamente , Rituximab/uso terapêutico , Pele/patologia , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Biópsia , Relação Dose-Resposta a Droga , Neoplasias Gastrointestinais/complicações , Tumores do Estroma Gastrointestinal/complicações , Humanos , Mesilato de Imatinib/administração & dosagem , Masculino , Pênfigo/tratamento farmacológico , Pênfigo/patologia
11.
Surgery ; 168(4): 695-700, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32713755

RESUMO

BACKGROUND: The utility of adjuvant systemic therapy in small bowel gastrointestinal stromal tumor remains unclear. METHODS: We queried the National Cancer Data Base for individuals having enterectomy to negative margins for small bowel gastrointestinal stromal tumor between 2010 and 2015. Subjects were categorized by tumor size (2.1-5 cm, 5.1-10 cm, >10 cm) and histologic grade (≤5 mitoses/50 high-power field and >5 mitoses/50 high-power field). Cox proportional hazard analysis was performed to evaluate the association between adjuvant therapy and overall survival. RESULTS: One thousand five hundred fifty-nine patients met the inclusion criteria. On univariate comparison to resection alone, adjuvant therapy was associated with improved overall survival for individuals with high-grade tumors of intermediate and large size (85% vs 48%, P = .010; 75% vs 47%, P = .003) but not for those with high-grade tumors of small size or low-grade tumors of any size. On multivariable analysis adjusted for age, comorbid disease state, and tumor size, adjuvant therapy was independently associated with reduced risk of mortality for high-grade (hazard ratio 0.37, 95% confidence interval: 0.21-0.64) but not low-grade tumors. CONCLUSION: Adjuvant therapy after R0 resection for small bowel gastrointestinal stromal tumor should be administered after careful consideration of the size and grade of a patient's tumor.


Assuntos
Antineoplásicos/uso terapêutico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/cirurgia , Mesilato de Imatinib/uso terapêutico , Neoplasias Intestinais/tratamento farmacológico , Neoplasias Intestinais/cirurgia , Intestino Delgado/cirurgia , Idoso , Quimioterapia Adjuvante , Feminino , Tumores do Estroma Gastrointestinal/patologia , Humanos , Neoplasias Intestinais/patologia , Intestino Delgado/patologia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Modelos de Riscos Proporcionais , Estudos Retrospectivos
12.
Lancet Oncol ; 21(7): 935-946, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32615108

RESUMO

BACKGROUND: Targeting of KIT and PDGFRA with imatinib revolutionised treatment in gastrointestinal stromal tumour; however, PDGFRA Asp842Val (D842V)-mutated gastrointestinal stromal tumour is highly resistant to tyrosine kinase inhibitors. We aimed to assess the safety, tolerability, and antitumour activity of avapritinib, a novel KIT and PDGFRA inhibitor that potently inhibits PDGFRA D842V, in patients with advanced gastrointestinal stromal tumours, including patients with KIT and PDGFRA D842V-mutant gastrointestinal stromal tumours (NAVIGATOR). METHODS: NAVIGATOR is a two-part, open-label, dose-escalation and dose-expansion, phase 1 study done at 17 sites across nine countries (Belgium, France, Germany, Poland, Netherlands, South Korea, Spain, the UK, and the USA). Patients aged 18 years or older, with an Eastern Cooperative Oncology Group performance status of 2 or less, and with adequate end-organ function were eligible to participate. The dose-escalation part of the study included patients with unresectable gastrointestinal stromal tumours. The dose-expansion part of the study included patients with an unresectable PDGFRA D842V-mutant gastrointestinal stromal tumour regardless of previous therapy or gastrointestinal stromal tumour with other mutations that either progressed on imatinib and one or more tyrosine kinase inhibitor, or only received imatinib previously. On the basis of enrolment trends, ongoing review of study data, and evolving knowledge regarding the gastrointestinal stromal tumour treatment paradigm, it was decided by the sponsor's medical director together with the investigators that patients with PDGFRA D842V mutations would be analysed separately; the results from this group of patients is reported in this Article. Oral avapritinib was administered once daily in the dose-escalation part (starting dose of 30 mg, with increasing dose levels once daily in continuous 28-day cycles until the maximum tolerated dose or recommended phase 2 dose was determined; in the dose-expansion part, the starting dose was the maximum tolerated dose from the dose-escalation part). Primary endpoints were maximum tolerated dose, recommended phase 2 dose, and safety in the dose-escalation part, and overall response and safety in the dose-expansion part. Safety was assessed in all patients from the dose-escalation part and all patients with PDGFRA D842V-mutant gastrointestinal stromal tumour in the dose-expansion part, and activity was assessed in all patients with PDGFRA D842V-mutant gastrointestinal stromal tumour who received avapritinib and who had at least one target lesion and at least one post-baseline disease assessment by central radiology. This study is registered with ClinicalTrials.gov, NCT02508532. FINDINGS: Between Oct 26, 2015, and Nov 16, 2018 (data cutoff), 46 patients were enrolled in the dose-escalation part, including 20 patients with a PDGFRA D842V-mutant gastrointestinal stromal tumour, and 36 patients with a PDGFRA D842V-mutant gastrointestinal stromal tumour were enrolled in the dose-expansion part. At data cutoff (Nov 16, 2018), 38 (46%) of 82 patients in the safety population (median follow-up of 19·1 months [IQR 9·2-25·5]) and 37 (66%) of the 56 patients in the PDGFRA D842V population (median follow-up of 15·9 months [IQR 9·2-24·9]) remained on treatment. The maximum tolerated dose was 400 mg, and the recommended phase 2 dose was 300 mg. In the safety population (patients with PDGFRA D842V-mutant gastrointestinal stromal tumour from the dose-escalation and dose-expansion parts, all doses), treatment-related grade 3-4 events occurred in 47 (57%) of 82 patients, the most common being anaemia (14 [17%]); there were no treatment-related deaths. In the PDGFRA D842V-mutant population, 49 (88%; 95% CI 76-95) of 56 patients had an overall response, with five (9%) complete responses and 44 (79%) partial responses. No dose-limiting toxicities were observed at doses of 30-400 mg per day. At 600 mg, two patients had dose-limiting toxicities (grade 2 hypertension, dermatitis acneiform, and memory impairment in patient 1, and grade 2 hyperbilirubinaemia in patient 2). INTERPRETATION: Avapritinib has a manageable safety profile and has preliminary antitumour activity in patients with advanced PDGFRA D842V-mutant gastrointestinal stromal tumours. FUNDING: Blueprint Medicines.


Assuntos
Neoplasias Gastrointestinais/tratamento farmacológico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Mutação , Pirazóis/uso terapêutico , Pirróis/uso terapêutico , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Triazinas/uso terapêutico , Idoso , Feminino , Seguimentos , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico
13.
Lancet Oncol ; 21(7): 923-934, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32511981

RESUMO

BACKGROUND: Resistance to approved inhibitors of KIT proto-oncogene, receptor tyrosine kinase (KIT), and platelet-derived growth factor receptor α (PDGFRA) is a clinical challenge for patients with advanced gastrointestinal stromal tumours. We compared the efficacy and safety of ripretinib, a switch-control tyrosine kinase inhibitor active against a broad spectrum of KIT and PDGFRA mutations, with placebo in patients with previously treated, advanced gastrointestinal stromal tumours. METHODS: In this double-blind, randomised, placebo-controlled, phase 3 study, we enrolled adult patients in 29 specialised hospitals in 12 countries. We included patients aged 18 years or older who had advanced gastrointestinal stromal tumours with progression on at least imatinib, sunitinib, and regorafenib or documented intolerance to any of these treatments despite dose modifications, and who had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Eligible patients were randomly assigned (2:1) to receive either oral ripretinib 150 mg once daily (ripretenib group) or placebo once daily (placebo group). Randomisation was done via an interactive response system using randomly permuted block sizes of six and stratified according to number of previous therapies and ECOG performance status. Patients, investigators, research staff, and the sponsor study team were masked to a patient's treatment allocation until the blinded independent central review (BICR) showed progressive disease for the patient. The primary endpoint was progression-free survival, assessed by BICR. The primary analysis was done in the intention-to-treat population and safety was assessed in patients who received at least one dose of study drug. Patients randomly assigned to placebo were permitted to cross over to ripretinib 150 mg at the time of disease progression. The INVICTUS study is registered with ClinicalTrials.gov, number NCT03353753, and with WHO International Clinical Trials Registry Platform, number EUCTR2017-002446-76-ES; follow-up is ongoing. FINDINGS: Between Feb 27, 2018, and Nov 16, 2018, 129 of 154 assessed patients were randomly assigned to receive either ripretinib (n=85) or placebo (n=44). At data cutoff (May 31, 2019), at a median follow-up of 6·3 months (IQR 3·2-8·2) in the ripretinib group and 1·6 months (1·1-2·7) in the placebo group, 51 patients in the ripretinib group and 37 in the placebo group had had progression-free survival events. In the double-blind period, median progression-free survival was 6·3 months (95% CI 4·6-6·9) with ripretinib compared with 1·0 months (0·9-1·7) with placebo (hazard ratio 0·15, 95% CI 0·09-0·25; p<0·0001). The most common (>2%) grade 3 or 4 treatment-related treatment-emergent adverse events in the ripretinib group (n=85) included lipase increase (four [5%]), hypertension (three [4%]), fatigue (two [2%]), and hypophosphataemia (two (2%]); in the placebo group (n=43), the most common (>2%) grade 3 or 4 treatment-related treatment-emergent adverse events were anaemia (three [7%]), fatigue (one [2%]), diarrhoea (one [2%]), decreased appetite (one [2%]), dehydration (one [2%]), hyperkalaemia (one [2%]), acute kidney injury (one [2%]), and pulmonary oedema (one [2%]). Treatment-related serious adverse events were reported in eight (9%) of 85 patients who received ripretinib and three (7%) of 43 patients who received placebo. Treatment-related deaths occurred in one patient in the placebo group (septic shock and pulmonary oedema) and one patient in the ripretinib group (cause of death unknown; the patient died during sleep). INTERPRETATION: Ripretinib significantly improved median progression-free survival compared with placebo and had an acceptable safety profile in patients with advanced gastrointestinal stromal tumours who were resistant to approved treatments. FUNDING: Deciphera Pharmaceuticals.


Assuntos
Neoplasias Gastrointestinais/tratamento farmacológico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Piridinas/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Método Duplo-Cego , Feminino , Seguimentos , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Adulto Jovem
14.
Eur J Cancer ; 134: 62-74, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32470848

RESUMO

BACKGROUND: Gastrointestinal stromal tumour (GIST) is commonly treated with tyrosine kinase inhibitors (TKIs), but most patients ultimately develop secondary resistance. Cabozantinib, a multi-targeted TKI inhibitor, has activity in patient-derived GIST mouse xenograft models and can overcome compensatory MET signalling occurring on TKI treatment. European Organisation for Treatment of Cancer (EORTC) 1317 'CaboGIST' assessed the safety and activity of cabozantinib in patients with GIST who had progressed on imatinib and sunitinib. METHODS: In this multi-center, open label, single arm phase II study, eligible GIST patients received oral cabozantinib (60 mg) once daily. Primary end-point was the progression-free survival rate at 12 weeks assessed by the local investigator per Response Evaluation Criteria in Solid Tumours 1·1. If at least 21 of the first 41 eligible and evaluable patients were progression-free at week 12, the activity of cabozantinib was sufficient to warrant further exploration according to the A'Hern one-stage study design. FINDINGS: A total of 50 eligible patients started treatment between 02/2017 and 08/2018, including four (8%) still continuing cabozantinib at clinical cut-off (09/2019). The number of 3-weekly treatment cycles ranged from 1 to 30. Among the first 41 eligible and evaluable patients, 24 were progression-free at week 12 (58·5%, 95% confidence interval [CI] 42·0-74·0%). Among all 50 patients, 30 were progression-free at week 12 (60%, 95% CI 45-74%). Seven patients achieved a partial response (14%, 95% CI 6-27%), and 34 had stable disease (68%, 95% CI 53-80%) as best response. Progression was seen in eight patients (16%, 95% CI 7-29%), and one was not evaluable. Disease control was achieved in 41 patients (82%, 95% CI 69-91%). Median progression-free survival was 5·5 months (95% CI 3·6-6·9). The most common adverse events were diarrhoea (76%), palmar-plantar erythrodysesthesia syndrome (60%), fatigue (50%), hypertension (42%), weight loss (40%) and oral mucositis (30%), with 32 (64%) patients requiring dose reductions, 27 (54%) having treatment interruptions and no cabozantinib-related deaths observed. INTERPRETATION: EORTC 1317 met its primary end-point, with 24/41 patients being progression-free at week 12 of treatment. The objective response was 14% with an encouraging disease control rate of 82%. Results of this trial confirm preclinical findings and warrant further exploration of cabozantinib in GIST. CLINICAL TRIAL NUMBERS: EORTC 1317, NCT02216578, EudraCT 2014-000501-13.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Gastrointestinais/tratamento farmacológico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Terapia de Salvação , Adulto , Idoso , Idoso de 80 Anos ou mais , Anilidas/administração & dosagem , Feminino , Seguimentos , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/secundário , Humanos , Mesilato de Imatinib/administração & dosagem , Masculino , Pessoa de Meia-Idade , Prognóstico , Piridinas/administração & dosagem , Sunitinibe/administração & dosagem , Taxa de Sobrevida
15.
Gan To Kagaku Ryoho ; 47(1): 180-182, 2020 Jan.
Artigo em Japonês | MEDLINE | ID: mdl-32381898

RESUMO

A 71-year-old male presented with abdominal distension and fever to our hospital. Abdominal CT revealed a huge tumor in abdomen, and non-curative surgery was performed. Peritoneal dissemination was widespread and the tumor invaded the bladder and sigmoid-colon mesenterium. Two months after the initial surgery, CT showed liver metastasis, and oral administration of imatinib mesylate was started. The peritoneal dissemination and liver metastasis showed a decrease, and this was well controlled for 45 months without severe side effects. Abdominal CT revealed peritoneal dissemination in the ileocecum after 43 months since the administration of imatinib. Therefore, sunitinib treatment was initiated. After 3 months of sunitinib administration, the tumor perforated. Emergency operation was performed to resect the ileocecum, and sunitinib was continued for 1 year. In GIST with liver metastasis and peritoneal dissemination, repeated surgical resection combined with chemotherapy is important to improve the patient's survival.


Assuntos
Antineoplásicos/uso terapêutico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Mesilato de Imatinib/uso terapêutico , Neoplasias do Jejuno/tratamento farmacológico , Neoplasias Hepáticas , Idoso , Tumores do Estroma Gastrointestinal/secundário , Humanos , Jejuno , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Masculino
17.
Oncology ; 98(7): 445-451, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32348984

RESUMO

BACKGROUND: Target therapy can cause various cardiovascular complications. The aim of this study was to evaluate the burden of cardiovascular complications related to treatment with anti-BCR-ABL tyrosine kinase inhibitors (TKIs) and to determine if there are differences between the latest- and first-generation TKIs. METHODS: A retrospective observational study was carried out on 55 patients (39 men, 16 women; mean age ± SD: 58 ± 11 years) treated with TKIs targeting Bcr-Abl for a median period of 3.5 years. Patients were divided in two groups according to the type of treatment. Group A included patients treated with latest-generation TKI (nilotinib, dasatinib, and ponatinib), while group B included patients treated with first-generation TKI (imatinib). Cardiological evaluation included electrocardiogram, echocardiogram with global longitudinal strain of left ventricle (GLS), and carotid ultrasound scan with arterial stiffness measurement (pulse wave velocity, PWV). Adverse cardiovascular events were recorded in both groups. RESULTS: Statistical analysis showed that cardiovascular adverse events (myocardial ischemia, peripheral artery disease, deep vein thrombosis, and pleural effusion) were significantly more frequent in group A than group B (p value = 0.044). Moreover, there was a significant reduction in GLS and PWV in group A when compared to group B (respectively, p = 0.03 and p = 0.004). CONCLUSIONS: Our study confirms that imatinib is a relatively safe drug, while it reveals that the latest-generation TKIs may cause a burden of cardiovascular complications. GLS and PWV allow detection of early signs of cardiac and vascular toxicity in oncohematologic patients treated with TKI, and their use is advisable.


Assuntos
Neoplasias Gastrointestinais/tratamento farmacológico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Idoso , Doença da Artéria Coronariana/induzido quimicamente , Dasatinibe/efeitos adversos , Dasatinibe/uso terapêutico , Feminino , Seguimentos , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Humanos , Mesilato de Imatinib/efeitos adversos , Mesilato de Imatinib/uso terapêutico , Imidazóis/efeitos adversos , Imidazóis/uso terapêutico , Masculino , Pessoa de Meia-Idade , Análise de Onda de Pulso , Piridazinas/efeitos adversos , Piridazinas/uso terapêutico , Pirimidinas/efeitos adversos , Pirimidinas/uso terapêutico , Estudos Retrospectivos , Resultado do Tratamento
18.
Int J Surg ; 77: 1-7, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32173609

RESUMO

OBJECTIVE: The optimal treatment for gastrointestinal stromal tumor (GIST) of the rectum is controversial due to the extremely low incidence of the disease. The aim of the present study was to compare the clinical outcomes of different treatment modalities for rectal GIST by reviewing the 14-year experience in our center. METHOD: Medical records of rectal GIST patients who received surgical treatment in our center between January 2004 to December 2017 were reviewed retrospectively. Overall survival (OS) and recurrence-free survival (RFS) were used as the observation endpoints. RESULTS: Included in this study were 71 GIST patients, including 42 patients who underwent local excision (LE) and 29 patients who underwent segmental resection (SR). There were differences in tumor size (P = 0.001) and malignant risk grade (P = 0.007). The LE approach achieved a lower rate of R0 resection than SR (29/42 vs.27/29, P = 0.015) and shorter hospital stay (P = 0.004). Preoperative imatinib mesylate (IM) therapy improved the rate of sphincter-sparing surgery for patients with tumors in the very low segment of the rectum (P = 0.012) and offered better R0 resection margins (P = 0.027). Multivariate analysis showed that the resection margin status (P = 0.014), risk stratification (P = 0.001) and IM therapy (P = 0.042) were independent factors affecting RFS of rectal GIST patients but not the surgical modalities (LE vs. SR, P = 0.802). Multivariate analysis showed no significant impact of these variables on OS. CONCLUSION: Selection of surgical modalities has no significant impact on the prognosis. Local excision is the preferred surgical modality for resectable rectal GIST by virtue of less injury and shorter hospital stay. IM therapy has proved to be associated with improved RFS for rectal GIST patients.


Assuntos
Tumores do Estroma Gastrointestinal/cirurgia , Neoplasias Retais/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/mortalidade , Humanos , Mesilato de Imatinib/uso terapêutico , Masculino , Pessoa de Meia-Idade , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/mortalidade , Estudos Retrospectivos
19.
Oncol Rep ; 43(3): 751-764, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32020209

RESUMO

Gastrointestinal stromal tumors (GISTs) are the most commonly observed mesenchymal tumors of the digestive tract, and they originate from the interstitial cells of Cajal. GISTs can be divided into KIT/PDGFRA­mutant GISTs and wild­type GISTs based on the presence or absence of KIT/PDGFRA mutations. Wild­type GISTs can be divided into succinate dehydrogenase complex (SDH)­deficient GISTs and non­SDH­deficient GISTs. Downstream signaling pathways activated by these mutations serve a pivotal role in the development of GISTs and are associated with the biological behavior, including risk stratification, clinical prognosis and drug resistance. Accurate medical care requires accurate molecular diagnosis, which in turn prolongs the survival of patients with GISTs and makes GIST a chronic disease. At present, there is a lack of effective treatment for imatinib/sunitinib/regorafenib resistant patients and KIT/PDGFRA­WT GISTs, which is undoubtedly a major challenge for future research. The present review summarizes the molecular pathogenesis of GISTs and the progress of related research.


Assuntos
Tumores do Estroma Gastrointestinal/tratamento farmacológico , Proteínas Proto-Oncogênicas c-kit/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Succinato Desidrogenase/genética , Resistencia a Medicamentos Antineoplásicos/genética , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/patologia , Heterogeneidade Genética , Humanos , Mesilato de Imatinib/uso terapêutico , Compostos de Fenilureia/uso terapêutico , Prognóstico , Piridinas/uso terapêutico , Sunitinibe/uso terapêutico
20.
BMC Cancer ; 20(1): 99, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32024476

RESUMO

BACKGROUND: Gastrointestinal stromal tumor (GIST) initiation and evolution is commonly framed by KIT/PDGFRA oncogenic activation, and in later stages by the polyclonal expansion of resistant subpopulations harboring KIT secondary mutations after the onset of imatinib resistance. Thus, circulating tumor (ct)DNA determination is expected to be an informative non-invasive dynamic biomarker in GIST patients. METHODS: We performed amplicon-based next-generation sequencing (NGS) across 60 clinically relevant genes in 37 plasma samples from 18 GIST patients collected prospectively. ctDNA alterations were compared with NGS of matched tumor tissue samples (obtained either simultaneously or at the time of diagnosis) and cross-validated with droplet digital PCR (ddPCR). RESULTS: We were able to identify cfDNA mutations in five out of 18 patients had detectable in at least one timepoint. Overall, NGS sensitivity for detection of cell-free (cf)DNA mutations in plasma was 28.6%, showing high concordance with ddPCR confirmation. We found that GIST had relatively low ctDNA shedding, and mutations were at low allele frequencies. ctDNA was detected only in GIST patients with advanced disease after imatinib failure, predicting tumor dynamics in serial monitoring. KIT secondary mutations were the only mechanism of resistance found across 10 imatinib-resistant GIST patients progressing to sunitinib or regorafenib. CONCLUSIONS: ctDNA evaluation with amplicon-based NGS detects KIT primary and secondary mutations in metastatic GIST patients, particularly after imatinib progression. GIST exhibits low ctDNA shedding, but ctDNA monitoring, when positive, reflects tumor dynamics.


Assuntos
Biomarcadores Tumorais , Ácidos Nucleicos Livres , DNA Tumoral Circulante , Tumores do Estroma Gastrointestinal/genética , Adulto , Idoso , Éxons , Feminino , Tumores do Estroma Gastrointestinal/sangue , Tumores do Estroma Gastrointestinal/diagnóstico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Biópsia Líquida , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Mutação , Metástase Neoplásica , Reação em Cadeia da Polimerase , Prognóstico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Carga Tumoral
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