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1.
J Infect Chemother ; 28(1): 103-107, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34649758

RESUMO

Imatinib is a crucial therapeutic strategy against chronic myeloid leukemia. Though superficial edema is a common adverse effect of imatinib, massive fluid retention is rarely reported. Here, we report the case of an adolescent who had tolerated imatinib for a long time, and then presented with massive pleural/pericardial effusion during an episode of Campylobacter jejuni bacteremia. A stepwise and comprehensive survey excluded all other plausible causes of disease. The Naranjo scale was used to assess the probability of an adverse effect of medication, and the score turned out to be 9, indicating severe fluid retention to be a definite reaction to imatinib. Drug discontinuation, antibiotic administration, and invasive procedures improved this condition. After this episode, the patient could tolerate imatinib again, illustrating the transient and reversible nature of this reaction. Since prolonged imatinib usage is crucial for chronic myeloid leukemia control, alertness to drug-related adverse effects is recommended, even if the subject has previously shown a good tolerance to the drug due to various physical conditions, especially physiological stressors, like infection or inflammation.


Assuntos
Antineoplásicos , Bacteriemia , Campylobacter , Leucemia Mielogênica Crônica BCR-ABL Positiva , Derrame Pericárdico , Adolescente , Antineoplásicos/efeitos adversos , Bacteriemia/tratamento farmacológico , Dasatinibe/uso terapêutico , Humanos , Mesilato de Imatinib/efeitos adversos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico
2.
Korean J Intern Med ; 36(6): 1450-1458, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34742178

RESUMO

BACKGROUND/AIMS: Adherence to tyrosine kinase inhibitors (TKIs) has become a critical aspect of care in chronic myeloid leukemia (CML). We aimed to examine the association of TKI adherence with overall survival (OS) outcomes in Korean patients diagnosed with CML and treated with TKIs using data from the National Health Information Database. METHODS: This study included 2,870 CML patients diagnosed between 2005 and 2013. Drug adherence was evaluated according to the medication possession ratio (MPR) and classified as high adherence (i.e., MPR ≥ 0.95 [upper 50%]), moderate adherence (i.e., MPR ≥ 0.68 and < 0.95 [middle 25%]), and low adherence (i.e., MPR < 0.68 [lower 25%]). RESULTS: The median MPR was 0.95 (range, 0 to 4.67). Male sex (p = 0.003), age < 70 years (p < 0.001), high income (≥ 30%, p < 0.001), and maintaining frontline TKI (< 0.001) were associated with better adherence. Adherence to dasatinib was the lowest (vs. imatinib or nilotinib, p < 0.001). Compared with high MPR patients, those with moderate MPR (hazard ratio [HR], 4.90; 95% confidence interval [CI], 3.87 to 6.19; p < 0.001) and low MPR (HR, 11.6; 95% CI, 9.35 to 14.42; p < 0.001) had poorer OS. CONCLUSION: Adherence to TKI treatment is an important factor predicting survival outcomes in Korean CML patients. Male sex, age < 70 years, high income, and maintaining frontline TKI are associated with high adherence to TKI. Thus, those without these characteristics should be closely monitored for treatment adherence.


Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Idoso , Dasatinibe , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Masculino , Adesão à Medicação , Inibidores de Proteínas Quinases/efeitos adversos
3.
BMC Surg ; 21(1): 400, 2021 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-34798856

RESUMO

OBJECTIVE: To investigate the clinicopathological features and clinical efficacy among 101 cases of rectal gastrointestinal stromal tumors (GISTs) and to investigate the significance of imatinib mesylate (IM) neoadjuvant therapy. METHODS: The clinicopathological features, treatment methods, perioperative data, and prognosis of the patients were summarized and analysed in 101 patients with rectal GISTs who received treatment in the Gastrointestinal Surgery of West China Hospital of Sichuan University and the Affiliated Hospital of Guizhou Medical University from August 2002 to November 2020 in China. RESULTS: A total of 101 patients, including 64 males and 37 females, were aged from 22 to 79 years (55.4 ± 12.2 years). Among the 70 patients who underwent direct surgery, 8 were very low risk cases, 10 were low risk cases, 7 were intermediate risk cases, and 45 were high risk cases. Cox regression analysis showed that postoperative IM adjuvant treatment improved the disease-free survival (DFS) and overall survival (OS) of 52 intermediate and high risk patients. Among the 31 patients who received neoadjuvant therapy, the objective response rate (ORR) was 83.9% (26/31), and the disease control rate (DCR) reached 96.8% (30/31). Subgroup analysis was also conducted based on the tumour diameter. (1) Among the 36 patients with a diameter ≤ 5 cm, two patients received IM neoadjuvant therapy, while 34 patients received direct surgery. Neither univariate nor Cox regression analysis found that neoadjuvant therapy affected DFS and OS. (2) Among the 65 patients with a diameter > 5 cm, 29 received IM neoadjuvant therapy, and 36 received direct surgery. Patients who underwent neoadjuvant therapy had less blood loss (P = 0.022), shorter postoperative hospital stay (P = 0.001), increased anal retention rate (93.1% vs. 72.2%, P = 0.031), and decreased enterostomy rate (10.3% vs. 33.3%, P = 0.037) than those who underwent direct surgery. Cox regression analysis suggested that neoadjuvant therapy and postoperative IM adjuvant therapy improved DFS. CONCLUSION: Rectal GISTs are relatively rare and highly malignant tumors. Postoperative oral IM therapy can improve the DFS and OS of intermediate and high risk patients. In patients with rectal GISTs with diameters > 5 cm, IM neoadjuvant therapy can improve anal retention rate, preserve the structure and function of the organs, reduce enterostomy rate, and improve prognosis.


Assuntos
Antineoplásicos , Tumores do Estroma Gastrointestinal , Neoplasias Retais , Antineoplásicos/uso terapêutico , Feminino , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/cirurgia , Humanos , Mesilato de Imatinib/uso terapêutico , Masculino , Terapia Neoadjuvante , Neoplasias Retais/terapia , Estudos Retrospectivos , Resultado do Tratamento
4.
Int J Mol Sci ; 22(19)2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34638557

RESUMO

Chronic myeloid leukemia (CML), a hematopoietic neoplasm arising from the fusion of BCR (breakpoint cluster region) gene on chromosome 22 to the ABL (Abelson leukemia virus) gene on chromosome 9 (BCR-ABL1 oncogene), originates from a small population of leukemic stem cells with extensive capacity for self-renewal and an inflammatory microenvironment. Currently, CML treatment is based on tyrosine kinase inhibitors (TKIs). However, allogeneic hematopoietic stem cell transplantation (HSCT-allo) is currently the only effective treatment of CML. The difficulty of finding a compatible donor and high rates of morbidity and mortality limit transplantation treatment. Despite the safety and efficacy of TKIs, patients can develop resistance. Thus, microRNAs (miRNAs) play a prominent role as biomarkers and post-transcriptional regulators of gene expression. The aim of this study was to analyze the miRNA profile in CML patients who achieved cytogenetic remission after treatment with both HSCT-allo and TKI. Expression analyses of the 758 miRNAs were performed using reverse transcription quantitative polymerase chain reaction (RT-qPCR). Bioinformatics tools were used for data analysis. We detected miRNA profiles using their possible target genes and target pathways. MiR-125a-3p stood out among the downregulated miRNAs, showing an interaction network with 52 target genes. MiR-320b was the only upregulated miRNA, with an interaction network of 26 genes. The results are expected to aid future studies of miRNAs, residual leukemic cells, and prognosis in CML.


Assuntos
Antineoplásicos/uso terapêutico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , MicroRNAs/metabolismo , Adulto , Biologia Computacional , Regulação para Baixo/efeitos dos fármacos , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Mapas de Interação de Proteínas/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
5.
Int J Mol Sci ; 22(19)2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34638938

RESUMO

Metabolic adaptation to increased oxidative phosphorylation (OXPHOS) has been found in gastrointestinal stromal tumor (GIST) upon imatinib treatment. However, the underlying mechanism of imatinib-induced OXPHOS is unknown. Discovering molecules that mediate imatinib-induced OXPHOS may lead to the development of therapeutic strategies synergizing the efficacy of imatinib. In this study, we explored the role of microRNAs in regulating OXPHOS in GIST upon imatinib treatment. Using a microarray approach, we found that miR-483-3p was one of the most downregulated miRNAs in imatinib-treated tumors compared to untreated tumors. Using an extended series of GIST samples, we further validated the downregulation of miR-483-3p in imatinib-treated GIST samples by RT-qPCR. Using both gain- and loss-of-function experiments, we showed that miR-483-3p could regulate mitochondrial respiratory Complex II expression, suggesting its role in OXPHOS regulation. Functionally, miR-483-3p overexpression could rescue imatinib-induced cell death. These findings provide the molecular link for imatinib-induced OXPHOS expression and the biological role of miR-483-3p in regulating cell viability upon imatinib treatment.


Assuntos
Antineoplásicos/farmacologia , Complexo II de Transporte de Elétrons/metabolismo , Neoplasias Gastrointestinais/metabolismo , Tumores do Estroma Gastrointestinal/metabolismo , Mesilato de Imatinib/farmacologia , MicroRNAs/metabolismo , Mitocôndrias/enzimologia , Transdução de Sinais/efeitos dos fármacos , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Regulação para Baixo/efeitos dos fármacos , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Mesilato de Imatinib/uso terapêutico , MicroRNAs/genética , Mitocôndrias/efeitos dos fármacos , Fosforilação Oxidativa/efeitos dos fármacos , RNA Mensageiro/genética , Transdução de Sinais/genética , Transfecção
6.
Pan Afr Med J ; 39: 234, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34659607

RESUMO

Gastrointestinal stromal tumours (GIST) are a rare form of neoplasm. The stomach is the commonest location while gastrointestinal bleeding and pain are the usual presentations. Rectal GIST has been reported in literature as a rare occurrence. We report the rare case of a 37-year-old man who presented with large bowel obstruction and acute urinary retention arising from a rectal GIST. Radiological investigations showed features in keeping with intestinal obstruction. He had a divided colostomy and tumour debulking. Histology of tumour revealed a rectal GIST and immunohistochemical staining was positive for CD34 and CD117. Postoperatively Imatinib was commenced and patient did well. We report this case to highlight the unusual symptoms that may arise from a rare pathology like rectal GIST and the need to consider an alternative diagnosis-such as GIST, in a young adult presenting with large bowel obstruction in the absence of risk factors for bowel adenocarcinoma.


Assuntos
Neoplasias Gastrointestinais/diagnóstico , Tumores do Estroma Gastrointestinal/diagnóstico , Neoplasias Retais/diagnóstico , Adulto , Antígenos CD34/metabolismo , Antineoplásicos/administração & dosagem , Terapia Combinada , Neoplasias Gastrointestinais/patologia , Neoplasias Gastrointestinais/terapia , Tumores do Estroma Gastrointestinal/patologia , Tumores do Estroma Gastrointestinal/terapia , Humanos , Mesilato de Imatinib , Obstrução Intestinal/etiologia , Masculino , Proteínas Proto-Oncogênicas c-kit/metabolismo , Neoplasias Retais/patologia , Neoplasias Retais/terapia , Retenção Urinária/etiologia
7.
Medicine (Baltimore) ; 100(35): e27134, 2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34477162

RESUMO

RATIONALE: Chronic myelogenous leukemia (CML) with thrombocytosis and complex chromosomal translocation is extremely rare in clinical setting. Here, we reported the clinical and pathological characteristics of CML patients, which were characterized by thrombocytosis and complex Philadelphia chromosome translocation. Moreover, we also introduced our therapeutic schedule for this patient as well as review relative literature. PATIENT CONCERNS: A 24-year-old female presented with night sweating, fatigue, and intermittent fever for 1 month. DIAGNOSIS: Fluorescence in situ hybridization results revealed that breakpoint cluster region (BCR)-Abelson (ABL) gene fusion in 62% of the cells and karyotyping showed a complex 3-way 46, XY, t(9;22;11) (q34;q11;q13) [19/20] translocation. This patient was diagnosed with CML complicated with thrombocytosis and complex Philadelphia chromosome translocation. INTERVENTIONS: The patients received continuously oral imatinib mesylate tablets (400 mg) once a day. OUTCOMES: After treatment with imatinib for 3 months, the BCR/ABLIS was less than 0.1% and achieved major molecular response. Moreover, the BCR/ABLIS of this patient achieved major molecular response. The BCR/ABLIS values at 6 months and 12 months were less than 0.01% and 0.0032%, respectively. And no BCR/ABL fusion was detected in the next 2 years follow-up period. LESSONS: Imatinib might represent a preferred therapeutic option for CML patients with rare thrombocytosis and complex chromosomal translocation. In addition, BCR/ABL fusion gene examination in patients with thrombocytosis might represent an effective strategy to avoid the misdiagnosis of this specific CML population.


Assuntos
Antineoplásicos/uso terapêutico , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Cromossomo Filadélfia , Trombocitose/etiologia , Feminino , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Adulto Jovem
8.
Transl Vis Sci Technol ; 10(11): 14, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34520512

RESUMO

Purpose: Dry eye disease (DED) is a multifactorial disorder of the tears and ocular surface accompanied by ocular discomfort, visual disturbance, tear film instability, and ocular surface inflammation. In the present study, we evaluated the efficacy of the tyrosine kinase inhibitor imatinib mesylate for the treatment of DED. Methods: Experimental models of DED were generated in Sprague Dawley rats using a combination of benzalkonium chloride (BAC) with atropine sulfate and in New Zealand White rabbits using BAC. The animals were treated twice daily with eye drops of vehicle, imatinib (0.01%-0.3%), or a positive control (Restasis). The improvement in DED due to imatinib was assessed by staining with fluorescein, lissamine green, impression cytology, and histological analysis. In addition, immunofluorescence staining was performed at the end of the study to evaluate the inflammatory response in the ocular surface. Results: Topical application of imatinib significantly reduced ocular surface damage compared with vehicle-treated animals. Imatinib restored the morphology and structure of the conjunctival epithelium and reduced the recruitment of immune cells in the corneal epithelium. Furthermore, imatinib significantly reduced the impression cytology score, thus demonstrating that imatinib prevents the loss of goblet cells in DED animal models. The therapeutic efficacy of imatinib was similar to or better than that of cyclosporine treatment. Conclusions: In this study, we provide an animal in vivo proof of concept of the therapeutic potential of imatinib for the treatment of DED. Translational Relevance: With this study we show the possibility of developing imatinib as a new ophthalmic drop to treat DED.


Assuntos
Síndromes do Olho Seco , Epitélio Corneano , Animais , Síndromes do Olho Seco/induzido quimicamente , Mesilato de Imatinib , Modelos Animais , Inibidores de Proteínas Quinases/uso terapêutico , Coelhos , Ratos , Ratos Sprague-Dawley
9.
Oncol Res Treat ; 44(10): 530-537, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34515193

RESUMO

BACKGROUND: MicroRNAs (miRNAs) have been observed to exhibit altered expression patterns in chronic myeloid leukemia (CML). Therefore, this study was aimed to evaluate the clinical importance of miR-126 and miR-122 expression in concert to imatinib response in CML patients. METHODS: The present study included 100 CML and 100 healthy subjects. The expression of the 2 miRNAs was performed using TaqMan probe chemistry, and snU6 was used as internal control. RESULTS: The expression of miR-126 and miR-122 was downregulated in CML patients, with a mean fold change ± SD 0.20 ± 0.33 and 0.22 ± 0.37, respectively. While the expression of both miRNAs was analysed before and after imatinib treatment, it was observed that the expression levels of both were increased after imatinib treatment by 26.25-fold (5.33 against 0.20) and 13.95-fold (3.07 against 0.22) and the increase was statistically significant (p < 0.0001 and p < 0.0001, respectively). The expression of miR-126 was not conclusive when compared in different clinical stages of the CML disease as it showed a decreased expression in patients with accelerated phase compared to chronic phase (mean fold change = 0.03 and 0.27, respectively), but patients with chronic phase and blastic phase had comparable expression (mean fold change = 0.27 and 0.24, respectively). We also observed an increased expression of both miRNAs after imatinib therapy in each clinical phase. CONCLUSION: The study concludes that expression of miR-126 and miR-122 increases after imatinib treatment in CML patients and that miR-126 defines the good responders of imatinib therapy.


Assuntos
Antineoplásicos , Leucemia Mielogênica Crônica BCR-ABL Positiva , MicroRNAs , Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Humanos , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , MicroRNAs/genética
10.
Aging (Albany NY) ; 13(18): 21866-21902, 2021 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-34531332

RESUMO

BACKGROUND: Many recent studies have investigated the role of drug interventions for coronavirus disease 2019 (COVID-19) infection. However, an important question has been raised about how to select the effective and secure medications for COVID-19 patients. The aim of this analysis was to assess the efficacy and safety of the various medications available for severe and non-severe COVID-19 patients based on randomized placebo-controlled trials (RPCTs). METHODS: We did an updated network meta-analysis. We searched the databases from inception until July 31, 2021, with no language restrictions. We included RPCTs comparing 49 medications and placebo in the treatment of severe and non-severe patients (aged 18 years or older) with COVID-19 infection. We extracted data on the trial and patient characteristics, and the following primary outcomes: all-cause mortality, the ratios of virological cure, and treatment-emergent adverse events. Odds ratio (OR) and their 95% confidence interval (CI) were used as effect estimates. RESULTS: From 3,869 publications, we included 61 articles related to 73 RPCTs (57 in non-severe COVID-19 patients and 16 in severe COVID-19 patients), comprising 20,680 patients. The mean sample size was 160 (interquartile range 96-393) in this study. The median duration of follow-up drugs intervention was 28 days (interquartile range 21-30). For increase in virological cure, we only found that proxalutamide (OR 9.16, 95% CI 3.15-18.30), ivermectin (OR 6.33, 95% CI 1.22-32.86), and low dosage bamlanivimab (OR 5.29, 95% CI 1.12-24.99) seemed to be associated with non-severe COVID-19 patients when compared with placebo, in which proxalutamide seemed to be better than low dosage bamlanivimab (OR 5.69, 95% CI 2.43-17.65). For decrease in all-cause mortality, we found that proxalutamide (OR 0.13, 95% CI 0.09-0.19), imatinib (OR 0.49, 95% CI 0.25-0.96), and baricitinib (OR 0.58, 95% CI 0.42-0.82) seemed to be associated with non-severe COVID-19 patients; however, we only found that immunoglobulin gamma (OR 0.27, 95% CI 0.08-0.89) was related to severe COVID-19 patients when compared with placebo. For change in treatment-emergent adverse events, we only found that sotrovimab (OR 0.21, 95% CI 0.13-0.34) was associated with non-severe COVID-19 patients; however, we did not find any medications that presented a statistical difference when compared with placebo among severe COVID-19 patients. CONCLUSION: We conclude that marked variations exist in the efficacy and safety of medications between severe and non-severe patients with COVID-19. It seems that monoclonal antibodies (e.g., low dosage bamlanivimab, baricitinib, imatinib, and sotrovimab) are a better choice for treating severe or non-severe COVID-19 patients. Clinical decisions to use preferentially medications should carefully consider the risk-benefit profile based on efficacy and safety of all active interventions in patients with COVID-19 at different levels of infection.


Assuntos
Anticorpos Monoclonais/uso terapêutico , COVID-19/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Azetidinas/uso terapêutico , COVID-19/mortalidade , Humanos , Mesilato de Imatinib/uso terapêutico , Metanálise em Rede , Oxazóis/uso terapêutico , Purinas/uso terapêutico , Pirazóis/uso terapêutico , SARS-CoV-2 , Índice de Gravidade de Doença , Sulfonamidas/uso terapêutico , Tioidantoínas/uso terapêutico , Resultado do Tratamento
11.
Int J Biol Macromol ; 190: 636-648, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34517025

RESUMO

SARS-CoV-2 nucleocapsid (N) protein undergoes RNA-induced phase separation (LLPS) and sequesters the host key stress granule (SG) proteins, Ras-GTPase-activating protein SH3-domain-binding protein 1 and 2 (G3BP1 and G3BP2) to inhibit SG formation. This will allow viral packaging and propagation in host cells. Based on a genomic-guided meta-analysis, here we identify upstream regulatory elements modulating the expression of G3BP1 and G3BP2 (collectively called G3BP1/2). Using this strategy, we have identified FOXA1, YY1, SYK, E2F-1, and TGFBR2 as activators and SIN3A, SRF, and AKT-1 as repressors of G3BP1/2 genes. Panels of the activators and repressors were then used to identify drugs that change their gene expression signatures. Two drugs, imatinib, and decitabine have been identified as putative modulators of G3BP1/2 genes and their regulators, suggesting their role as COVID-19 mitigation agents. Molecular docking analysis suggests that both drugs bind to G3BP1/2 with a much higher affinity than the SARS-CoV-2 N protein. This study reports imatinib and decitabine as candidate drugs against N protein and G3BP1/2 protein.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/química , COVID-19/tratamento farmacológico , Proteínas do Nucleocapsídeo de Coronavírus/química , DNA Helicases/química , Decitabina/química , Mesilato de Imatinib/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Proteínas de Ligação a Poli-ADP-Ribose/química , RNA Helicases/química , Proteínas com Motivo de Reconhecimento de RNA/química , Proteínas de Ligação a RNA/química , SARS-CoV-2/química , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , COVID-19/metabolismo , Proteínas do Nucleocapsídeo de Coronavírus/metabolismo , DNA Helicases/antagonistas & inibidores , DNA Helicases/metabolismo , Decitabina/farmacologia , Sistemas de Liberação de Medicamentos , Genômica , Mesilato de Imatinib/farmacologia , Fosfoproteínas/química , Fosfoproteínas/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose/antagonistas & inibidores , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , RNA Helicases/antagonistas & inibidores , RNA Helicases/metabolismo , Proteínas com Motivo de Reconhecimento de RNA/antagonistas & inibidores , Proteínas com Motivo de Reconhecimento de RNA/metabolismo , Proteínas de Ligação a RNA/antagonistas & inibidores , Proteínas de Ligação a RNA/metabolismo , SARS-CoV-2/metabolismo
12.
J Coll Physicians Surg Pak ; 31(9): 1089-1093, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34500527

RESUMO

OBJECTIVE: To analyse the gastrointestinal stromal tumours (GIST) patients' inter-demographics, histological type and association with secondary tumours. STUDY DESIGN: A case series. Place and Duration of the Study: Department of General Surgery, Haydarpasa Numune Training and Research Hospital, Istanbul, Turkey, between January 2010 and December 2018. METHODOLOGY: Fifty-eight patients diagnosed with GIST and operated at the study place were analysed retrospectively. The demographics, symptoms, diagnosis, treatment, tumour location, histopathology, risk classification, and prognosis were recorded. RESULTS: The mean age was 60.62 ± 10.63 (37-83) years and the male to female ratio was 1:1. The most common symptom was abdominal pain (51.7%). Tumour site was the stomach in the majority (86.2%), followed by the small intestine and colon. One patient also had a secondary malignancy. The most common histologic type was spindle cell, followed by mixed cell type. C-kit (CD117) and CD34 mutations were positive in 87.9% and 75.9% of the cases. One patient had liver metastasis on diagnosis and another had peritoneal implants per-operatively, who died after 36 months due to midgut volvulus. The mean follow-up period was 32.03 ± 13.67 months. Two patients developed liver metastasis in the early postoperative period. CONCLUSION: Surgical resection and imatinib treatment have been provided with good prognosis. The most common histology is spindle cell type. GISTs might be associated with other cancers which should be searched and analysed. Key Words: Gastrointestinal stromal tumour, Secondary malignancy, Treatment, Prognosis.


Assuntos
Neoplasias Gastrointestinais , Tumores do Estroma Gastrointestinal , Adulto , Idoso , Feminino , Neoplasias Gastrointestinais/diagnóstico , Tumores do Estroma Gastrointestinal/diagnóstico , Tumores do Estroma Gastrointestinal/terapia , Humanos , Mesilato de Imatinib , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteínas Proto-Oncogênicas c-kit , Estudos Retrospectivos
13.
Acta Oncol ; 60(11): 1527-1533, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34499575

RESUMO

BACKGROUND: A limited amount of data has been published in chronic-phase chronic myeloid leukemia (CP-CML) patients aged >75 years treated frontline with second-generation tyrosine kinase inhibitors. AIMS: To address this issue in a clinical 'real-life' setting, we retrospectively analyzed 45 CP-CML patients (pts) followed in 20 Italian Centers and treated frontline with dasatinib (DAS). PATIENTS AND METHODS: Median age was 78.4 years (range 75-89.2 years). DAS starting dose was 100 mg QD in 35 pts (77.7%), 80 mg QD in 1 pts (2.2%) and 50 mg QD in 9 pts (20.1%), respectively. The median follow-up was 42.6 months (IQR 20.4 - 63.3). RESULTS: Grade 3 and 4 side effects, both hematological and non-hematological, were detected in 6 (13.3%) and 12 (26.6%) pts, respectively. Pleural effusions of all grades occurred in 13 pts (28.8%) after a median period of DAS exposure of 14.7 months (IQR 3.0 - 33.1). The rates of DAS dose reduction and permanent drug discontinuation were 53.3% and 20.0%, respectively. As the best response, 42/45 patients (93.3%) achieved a complete cytogenetic response (CCyR), 35/45 (77.7%) a major molecular response (MMR) and 24/45 (53.3%) a deep molecular response (both MR 4.0 and MR 4.5). Only 1 patient (2.2%) progressed to the blast phase after 13 months of therapy; 8 deaths were observed (1 CML-related and 7 CML-unrelated). Cumulative event-free survival and overall survival at 36 months were 64.7% (95%, CI 49.4 - 80.0) and 82.3% (95%, CI 70.3-94.3), respectively. CONCLUSION: These findings, although evaluated in a limited and selected cohort of patients, suggest that DAS might be effective in older patients (aged >75 years) affected by CP-CML with acceptable toxicity.


Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Inibidores de Proteínas Quinases , Idoso , Idoso de 80 Anos ou mais , Dasatinibe/efeitos adversos , Seguimentos , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Estudos Retrospectivos , Resultado do Tratamento
14.
J Surg Oncol ; 124(8): 1442-1450, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34494280

RESUMO

BACKGROUND AND OBJECTIVES: This study aimed to compare outcomes between neoadjuvant imatinib and upfront surgery in patients with localized rectal gastrointestinal stromal tumors (GIST) patients. METHODS: Eighty-five patients with localized rectal GIST were divided into two groups: upfront surgery ± adjuvant imatinib (Group A, n = 33) and the neoadjuvant imatinib + surgery + adjuvant imatinib (Group B, n = 52). Baseline characteristics between groups were controlled for with inverse probability of treatment weighting (IPTW) adjusted analysis. RESULTS: The response rate to neoadjuvant imatinib was 65.9%. After the IPTW-adjusted analysis, patients who underwent neoadjuvant therapy had better distant recurrence-free survival (DRFS) and disease-specific survival (DSS) compared with those who underwent upfront surgery (5-year DRFS 97.8 vs. 71.9%, hazard ratio [HR], 0.15; 95% CI, 0.03-0.87; p = 0.03; 5-year DSS 100 vs. 77.1%; HR, 0.11; 95% CI, 0.01-0.92; p = 0.04). While no significant association was found between overall survival (OS) and treatment groups (p = 0.07), 5-year OS was higher for the neoadjuvant group than upfront surgery group (97.8% vs. 71.9%; HR, 0.2; 95% CI, 0.03-1.15). CONCLUSIONS: In patients with localized rectal GIST, neoadjuvant imatinib not only shrunk the tumor size but also decreased the risk of metastasis and tumor-related deaths when compared to upfront surgery and adjuvant imatinib alone.


Assuntos
Antineoplásicos/uso terapêutico , Procedimentos Cirúrgicos do Sistema Digestório/mortalidade , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/patologia , Mesilato de Imatinib/uso terapêutico , Terapia Neoadjuvante/mortalidade , Idoso , Estudos de Casos e Controles , Terapia Combinada , Feminino , Seguimentos , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/cirurgia , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/cirurgia , Humanos , Masculino , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
15.
Blood Adv ; 5(17): 3344-3353, 2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34477815

RESUMO

Since the introduction of imatinib, the management of chronic myeloid leukemia (CML) has changed considerably. Tyrosine kinase inhibitors (TKIs) are the mainstay of CML treatment; however, the high financial burden of TKIs can be problematic for both the patients and health care systems. After the emergence of generics, reimbursement policies of many countries have changed, and generics offered an alternative treatment option for CML patients. There are many papers published on the use of generics in CML patients with conflicting results regarding both efficacy and safety. In this paper, we systematically reviewed the current literature on generic imatinib use in CML, and 36 papers were evaluated. Both in vitro and in vivo studies of generic imatinib showed comparable results with branded imatinib in terms of bioequivalence and bioavailability. In most studies, generics were comparable with the original molecule in terms of efficacy and safety, both in newly diagnosed patients and after switching from Gleevec. Some generic studies showed contradictory findings regarding efficacy and toxicity, and these differences can be attributed to some factors including the use of different generics in different countries. Both in hypothetical models and in real life, introduction of generic imatinib caused significant reduction in health care costs. In conclusion, generics are not inferior to original imatinib in terms of efficacy with an acceptable toxicity profile. Notwithstanding the generally favorable efficacy and safety of generics worldwide to date, we most probably still need more time to draw firmer conclusions on the longer-term outcomes of generics.


Assuntos
Antineoplásicos , Leucemia Mielogênica Crônica BCR-ABL Positiva , Antineoplásicos/uso terapêutico , Medicamentos Genéricos/uso terapêutico , Custos de Cuidados de Saúde , Humanos , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico
16.
Rinsho Ketsueki ; 62(8): 1012-1023, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34497187

RESUMO

The chronic myeloid leukemia (CML) therapeutic landscape has dramatically changed with the development of tyrosine kinase inhibitors (TKIs), which allows for a near-normal life expectancy. Five TKIs have been currently approved for CML treatment in Japan, of which four have been indicated as first-line therapy (i.e., imatinib, nilotinib, dasatinib, and bosutinib). Nowadays, the long-term prognosis of patients with CML is determined not by the primary disease but rather by the comorbidities and treatment-related adverse events (AEs), including cardiovascular events. Assessment of risk profile and comorbidities at diagnosis is essential for the appropriate choice of TKI and long-term survival management. The ability of some patients who achieve deep molecular responses to discontinue therapy successfully is well documented. Long-term treatment-free remission with continued response to TKI therapy is now recognized as the most optimal treatment benefit for some patients.This article discusses treatment strategies, AE management, and future perspectives based on the latest CML treatment guidelines.


Assuntos
Antineoplásicos , Leucemia Mielogênica Crônica BCR-ABL Positiva , Antineoplásicos/uso terapêutico , Dasatinibe/uso terapêutico , Humanos , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico
17.
Zhonghua Wei Chang Wai Ke Za Zhi ; 24(9): 762-768, 2021 Sep 25.
Artigo em Chinês | MEDLINE | ID: mdl-34530556

RESUMO

Tumor rupture is a common clinical event in the process of tumorigenesis, progression, diagnosis and treatment of gastrointestinal stromal tumor, which is closely associated with tumor recurrence, metastasis and poor prognosis. Tumor rupture may be associated with some intrinsic biological aggressiveness qualities, such as large tumor size, high mitotic count, and KIT exon 11 deletion mutations involving codons 557 and 558, and may be relatively more frequent with small intestine GIST and excellent response to imatinib neoadjuvant therapy resulting in tumor tissue rapid liquefacient and necrosis. The triggering factors involve sudden increase in abdominal pressure, external pressure, collision and improper surgical operation, etc. Tumor rupture is considered as an important risk factor of recurrence after macroscopically complete resection of tumor, and an indication for determining interval or even lifelong adjuvant therapy with imatinib according to guidelines. However, there is no consensus or universally accepted definition of tumor rupture, and, consequently, its incidence varies greatly across reported series and lacks detailed epidemiological data. Without pre-defined criteria, it is difficult to assess the clinical significance of rupture. We reviewed the relevant literature and international guidelines, and generally divided tumor rupture into spontaneous rupture and iatrogenic rupture. Based on the Oslo criteria, we proposed the following six definitions for tumor rupture: (1) tumor fracture or spillage; (2) blood-stained ascites; (3) gastrointestinal perforation at the tumor site; (4) microscopic infiltration of an adjacent organ; (5) intralesional dissection or piecemeal resection; (6) incisional biopsy. The following types of minor defects of tumor integrity should not be defined as rupture: (1) mucosal defects or spillage contained within the gastrointestinal lumen; (2) microscopic tumor penetration of the peritoneum or iatrogenic damage only to the serosa; (3) uncomplicated transperitoneal needle biopsy; (4) R1 resection. In addition, we further emphasize the importance of identifying risk factors of tumor rupture, prevention and positive intervention.


Assuntos
Antineoplásicos , Tumores do Estroma Gastrointestinal , Antineoplásicos/uso terapêutico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Humanos , Mesilato de Imatinib/uso terapêutico , Recidiva Local de Neoplasia , Prognóstico , Estudos Retrospectivos , Ruptura Espontânea
18.
Zhonghua Wei Chang Wai Ke Za Zhi ; 24(9): 775-782, 2021 Sep 25.
Artigo em Chinês | MEDLINE | ID: mdl-34530558

RESUMO

Objective: To analyze the current adherence to imatinib in patients with gastrointestinal stromal tumors (GIST) in China and its influencing factors. Methods: A cross-sectional survey was conducted. Study period: from October 1, 2020 to November 31, 2020. Study subjects: GIST patients taking imatinib who were diagnosed and treated in public tertiary level A general hospitals or oncology hospitals; those who had not been pathologically diagnosed, those who never received imatinib, or those who had taken imatinib in the past but stopped afterwards were excluded. The Questionnaire Star online surgery platform was used to design a questionnaire about the adherence to adjuvant imatinib therapy of Chinese GIST patients. The link of questionnaire was sent through WeChat. The questionnaire contained basic information of patients, medication status and Morisky Medication Adherence Scale. Results: A total of 2162 questionnaires from 31 provinces, autonomous regions, and municipalities were collected, of which 2005 were valid questionnaires, with an effective rate of 92.7%. The survey subjects included 1104 males and 901 females, with a median age of 56 (22-91) years old. Working status: 609 cases (30.4%) in the work unit, 729 cases (36.4%) of retirement, 667 cases of flexible employment or unemployment (33.3%). Education level: 477 cases (23.8%) with bachelor degree or above, 658 cases (32.8%) of high school, 782 cases (39.0%) of elementary or junior high school, 88 cases (4.4%) without education. Marital status: 1789 cases (89.2%) were married, 179 cases (8.9%) divorced or widowed, 37 cases (1.8%) unmarried. Two hundred and ninety-four patients (14.7%) had metastasis when they were first diagnosed, including 203 liver metastases, 52 peritoneal metastases, and 39 other metastases. One thousand eight hundred and sixty-nine patients underwent surgical treatment, of whom 1642 (81.9%) achieved complete resection. The median time of taking imatinib was 25 (1-200) months. Common adverse reactions of imatinib included 1701 cases (84.8%) of periorbital edema, 1031 cases (51.4%) of leukopenia, 948 cases (47.3%) of fatigue, 781 cases (39.0%) of nausea and vomiting, 709 cases (35.4%) of rash, and 670 cases (33.4%) of lower extremity edema. The score of the Morisky Medication Adherence Scale showed that 392 cases (19.6%) had poor adherence, 1023 cases (51.0%) had moderate adherence, and 590 cases (29.4%) had good adherence. Univariate analysis showed that gender, age, work status, economic income, residence, education level, marriage, the duration of taking medication and adverse reactions were associated with adherence to adjuvant imatinib therapy (all P<0.05). Multivariate analysis showed that female (OR=1.264, P=0.009), non-retirement (OR=1.454, P=0.001), monthly income ≤4000 yuan (OR=1.280, P=0.036), township residents (OR=1.332, P=0.005), unmarried or divorced or widowed (OR=1.362, P=0.026), the duration of imatinib medication >36 months (OR=1.478, P<0.001) and adverse reactions (OR=1.719, P=0.048) were independent risk factors for poor adherence to adjuvant imatinib. Among patients undergoing complete resection, 324 (19.7%) had poor adherence, 836 (50.9%) had moderate adherence, and 482 (29.4%) had good adherence. Meanwhile, 55 patients with good adherence (11.4%) developed recurrence after surgery, 121 patients with moderate adherence (14.5%) developed recurrence, 61 patients with poor adherence (18.8%) developed recurrence, and the difference was statistically significant (P=0.017). Conclusions: The adherence to adjuvant therapy with imatinib in Chinese GIST patients is relatively poor. Females, non-retirement, monthly income ≤4000 yuan, township residents, unmarried or divorced or widowed, the duration of imatinib medication >36 months, and adverse reactions are independently associated with poor adherence of GIST patients. Those with poor adherence have a higher risk of recurrence after surgery. Positive interventions based on the above risk factors are advocated to improve the prognosis of patients with GIST.


Assuntos
Antineoplásicos , Tumores do Estroma Gastrointestinal , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Quimioterapia Adjuvante , Estudos Transversais , Feminino , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Humanos , Mesilato de Imatinib/uso terapêutico , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico
19.
Zhonghua Wei Chang Wai Ke Za Zhi ; 24(9): 789-795, 2021 Sep 25.
Artigo em Chinês | MEDLINE | ID: mdl-34530560

RESUMO

Objective: To explore the significance of circulating tumor cell (CTC) monitoring in evaluating the efficacy of targeted therapy for gastrointestinal stromal tumor (GIST). Methods: A prospective cohort study was performed. The data of patients with locally advanced GIST or liver metastasis who were admitted to The Affiliated Hospital of Nantong University from August 2013 to December 2018 were collected. Inclusion criteria: (1) patients aged older than 18 years; (2) patients who were diagnosed with GIST based on pathology; (3) patients without surgery, whose preoperative imaging evaluation of GIST found the violations of the surrounding organs or partial transfer of an estimated difficulty to achieve R0 resection, or the maximum diameter of the tumor > 10 cm, or the liver metastasis, or the expectation of higher risk of surgical complications; (4) patients who were treated with the imatinib 400 mg/d for the first time; (5) Eastern Cooperative Oncology Group (ECOG) score of 0-2. Exclusion criteria: (1) genetic testing revealed a D842V mutation in exon 18 of the PDGFRA gene; (2) alanine aminotransferase and/or aspartate aminotransferase > 2.5 times the normal upper limit; (3) serum total bilirubin >1.5 times of normal upper limit; (4) neutrophil count < 1.5×10(9)/L, or platelet count < 75×10(9)/L, or hemoglobin < 60 g/L; (5) creatinine > normal upper limit; (6) patients had serious cardiovascular and cerebrovascular diseases within 12 months before enrollment; (7) female patients were pregnant or lactating; (8) patients suffered from other serious acute and chronic physical or mental problems, and were not suitable for participating in this study judged by researchers. The patients who could not tolerate treatment regimen, or developed serious adverse reactions and did not follow the medication scheme after enrollment were excluded. Before imatinib treatment and 1-month and 2-month after treatment, quantitative PCR was used to detect the DOG-1 expression of monocytes in peripheral blood, and the ratio of DOG-1/ß-actin > 3×10(-5) was used as the CTC positive threshold of GIST. The positive rate of CTC, the efficacy of imatinib treatment (complete response, partial response, stable disease, progressive disease, and occurrence of adverse reactions), and the relationship between CTC positive rate and clinicopathological characteristics of patients were analyzed. Furthermore, the ratio of DOG-1 decrease/baseline DOG-1 after 1-month of treatment was used as an indicator to evaluate whether targeted therapy was effective. The receiver operating characteristic (ROC) curve was rendered, and the area under the curve (AUC) was calculated. Results: A total of 68 GIST patients were enrolled in this study, including 39 cases of locally advanced GIST and 29 cases with liver metastases, 32 males and 36 females with the mean age of (51.2±11.8) (range 31 to 74) years. After 2-month of imatinib treatment, 43 cases were evaluated as partial response, 11 cases as stable disease, and 14 cases as progressive disease, with an effective rate of 79.4% (54/68). During the treatment of imatinib, the incidence of grade 3 or higher adverse reactions was 22.1% (15/68), including 12 cases of grade 3 neutropenia and 3 of grade 4 drug eruption, which were all relieved after conservative treatment. The positive rates of CTC in 68 patients before treatment, 1-month and 2-month after treatment were 66.2% (45/68), 41.2% (28/68) and 23.5% (16/68), respectively. The positive rate of CTC was associated with tumor size, liver metastasis, mitotic count and risk level (all P<0.05). By analyzing the effective group and the ineffective group of targeted therapy, it was found that the positive rate of CTC in the effective group showed a decreasing trend, while the positive rate of CTC in the ineffective group showed an increasing trend. The AUC of predicting the efficacy of targeted therapy for GIST was 0.823 by detecting the change trend of CTC 1-month after treatment (P<0.001). When the DOG-1 content decreased by more than 57.5% 1-month after treatment, it can be used as an indicator to judge the effectiveness of the treatment, whose sensitivity was 72.2% and specificity was 100%. Conclusion: The detection of peripheral blood CTC can evaluate the efficacy of targeted therapy in GIST patients and can provide decision-making basis for further clinical treatment.


Assuntos
Antineoplásicos , Tumores do Estroma Gastrointestinal , Células Neoplásicas Circulantes , Idoso , Antineoplásicos/uso terapêutico , Feminino , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/genética , Humanos , Mesilato de Imatinib/uso terapêutico , Lactação , Masculino , Estudos Prospectivos
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