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1.
Hematology ; 26(1): 408-414, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34053416

RESUMO

BACKGROUND: Chronic myelogenous leukemia (CML) is one of the most common cancers in the world. Imatinib is one of the most effective therapeutic strategies to inhibit the BCR-ABL tyrosine Kinase in patients with CML, but resistance is increasingly encountered. MATERIAL AND METHODS: Microarray data GSE7114, GSE92624 and GSE97562 were downloaded and analyzed from Gene Expression Omnibus (GEO) to identify the candidate genes in the imatinib-resistant CML cells. The differentially expressed genes (DEGs) were appraised, and the protein-protein interaction (PPI) network was created by using STRING and Cytoscape. RESULTS: We screened a total of 217 DEGs, including 151 upregulated genes and 66 downregulated genes. The enriched functions and pathways of genes include insulin-like growth factor I binding, cysteine-type endopeptidase inhibitor activity involved in apoptotic process, cell adhesion, positive regulation of nitric oxide biosynthetic process and hematopoietic cell lineage. Nine hub genes were appraised and Gene Ontology enrichment analysis revealed that these genes are mainly enriched in cell cycle, peptidase inhibitor activity and cell division. Several genes such as BIRC5, CCNE2 and MCM4 were identified in survival analysis and these genes alteration are significantly associated with worse overall survival and disease-free survival. CONCLUSIONS: These genes have the potential to become surrogate markers for a clinical evaluation of imatinib-resistant CML patients. Our results provide potential target genes for diagnosis and treatment of imatinib-resistant CML patients.


Assuntos
Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Antineoplásicos/farmacologia , Biologia Computacional , Bases de Dados Genéticas , Perfilação da Expressão Gênica , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Ontologia Genética , Redes Reguladoras de Genes/efeitos dos fármacos , Humanos , Mesilato de Imatinib/farmacologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Mapas de Interação de Proteínas/efeitos dos fármacos
2.
BMJ Case Rep ; 14(5)2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-33962926

RESUMO

Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. Dedifferentiation in these tumours occurs rarely, and when it does occurs most commonly after prolonged treatment with imatinib. We report the case of a 64-year-old man who presented with a mass of 8×7×3 cm dimensions involving the duodenum and head of the pancreas. On histopathology, areas of anaplastic tumour cells were negative for DOG-1, c-kit, CD-34, desmin and panCK along with a molecular level study showing wild-type KIT and PDGFRA (platelet-derived growth factor receptor alpha) gene. Based on focal GIST-like areas and CD117 positivity and absence of prior therapy, the diagnosis of a de novo dedifferentiated GIST was made. These tumours need to be reported as they pose a diagnostic challenge and their predicted response rated to targeted molecular therapies are unclear as compared with their c-kit positive counterparts.


Assuntos
Tumores do Estroma Gastrointestinal , Duodeno , Tumores do Estroma Gastrointestinal/diagnóstico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/genética , Humanos , Mesilato de Imatinib/uso terapêutico , Mutação , Proteínas Proto-Oncogênicas c-kit/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética
3.
Gan To Kagaku Ryoho ; 48(4): 560-562, 2021 Apr.
Artigo em Japonês | MEDLINE | ID: mdl-33976048

RESUMO

A 61‒year‒old woman observed that she had a lower limb edema approximately 1 month ago and began to feel a general malaise. The symptom was caused by multiple liver metastases, and the primary lesion was suspected to be an ovarian cancer. Peritoneal disseminations throughout the abdominal cavity were found in the exploratory laparotomy. No obvious primary lesion could be found in the searchable gastrointestinal tract. The patient was diagnosed with a gastrointestinal stromal tumor(GIST)based on the biopsy results of the peritoneal dissemination. Treatment with imatinib mesylate(imatinib) was initiated 13 days after surgery. The severe lower extremity edema disappeared within 2 months. Computed tomography (CT)scan showed a reduction of the multiple liver metastases and peritoneal dissemination, and the appearance and increase of calcifications in the tumor and cystic degeneration inside the liver metastasis. The abnormal accumulation observed by bone scintigraphy also disappeared. Imatinib has a long‒term effect on GIST of unknown primary origin with multiple liver metastases, peritoneal dissemination, and bone metastasis. Five years after the initiation of the treatment, the patient is still alive, and new lesions have not developed.


Assuntos
Antineoplásicos , Tumores do Estroma Gastrointestinal , Neoplasias Hepáticas , Neoplasias Primárias Desconhecidas , Antineoplásicos/uso terapêutico , Feminino , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/cirurgia , Humanos , Mesilato de Imatinib/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Pessoa de Meia-Idade
4.
Gan To Kagaku Ryoho ; 48(3): 385-387, 2021 Mar.
Artigo em Japonês | MEDLINE | ID: mdl-33790163

RESUMO

A 50s old woman admitted to our hospital with anal pain, who was diagnosed as rectal gastrointestinal stromal tumor (GIST). After neoadjuvant therapy with imatinib mesylate for 6 months, the tumor reduced by 75% from its original size and anus preserving operation(low anterior resection)was performed. After operation adjuvant therapy with imatinib mesylate was performed for 2 years and 6 months. The patient is alive without recurrence 5 years after surgery. It is suggested that neoadjuvant therapy with imatinib mesylate is useful and safety for large rectal GIST, from the standpoint of anal preservation.


Assuntos
Antineoplásicos , Tumores do Estroma Gastrointestinal , Laparoscopia , Neoplasias Retais , Canal Anal/cirurgia , Antineoplásicos/uso terapêutico , Feminino , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/cirurgia , Humanos , Mesilato de Imatinib/uso terapêutico , Terapia Neoadjuvante , Recidiva Local de Neoplasia , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/cirurgia
5.
Zhonghua Xue Ye Xue Za Zhi ; 42(2): 101-108, 2021 Feb 14.
Artigo em Chinês | MEDLINE | ID: mdl-33858039

RESUMO

Objective: To explore the clinical characteristics, treatment patterns, and outcomes in newly diagnosed patients with chronic myeloid leukemia in the chronic phase (CML-CP) by age. Methods: Clinical data of consecutive ≥14 years old newly diagnosed CML-CP patients were retrospectively analyzed. Results: This study included 957 patients. Of the patients, 597 (62.4%) were male. The median age was 40 years (range, 14-83 years) . The patients were stratified into three age groups: <40 years (n=470; 49.1%) , 40-59 years (n=371; 38.8%) , and ≥60 years (n=116; 12.1%) . The proportions of the patients who had splenomegaly (P<0.001) , WBC ≥100 × 10(9)/L (P<0.001) , anemia (P<0.001) , PLT<450 × 10(9)/L (P=0.022) , more blasts in the blood (P=0.010) , and clonal chromosome abnormalities in Philadelphia chromosome-positive cells (P=0.006) at diagnosis significantly decreased with age. However, the proportions of those with comorbidities (P<0.001) , intermediate or high Sokal risk (P<0.001) , and receiving imatinib as front-line therapy (P<0.001) significantly increased with age. No significant differences in gender and the EUTOS Long-Term Survival risks were noted across the three age groups. The multivariate analysis showed that ≥60 years was an adverse predictor for overall survival. However, age was not significantly associated with tyrosine kinase inhibitor (TKI) therapy responses and other outcomes. The incidences of nonhematological toxicity were significantly increased with age during TKI therapy (P<0.001) . However, those of hematological toxicity was similar across the three age groups. The proportions of the patients maintaining imatinib therapy (P=0.026) and receiving low-dose TKI therapy (P<0.001) significantly increased with age at the end of follow-up. Conclusions: Significant differences exist in clinical characteristics, TKI response, overall survival rates, and nonhematological toxicity among newly diagnosed CML-CP patients of different ages.


Assuntos
Antineoplásicos , Leucemia Mielogênica Crônica BCR-ABL Positiva , Adolescente , Adulto , Antineoplásicos/uso terapêutico , Humanos , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Masculino , Inibidores de Proteínas Quinases/uso terapêutico , Estudos Retrospectivos , Resultado do Tratamento
6.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(2): 456-461, 2021 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-33812415

RESUMO

OBJECTIVE: To evaluate the clinical efficacy and safety of domestic imatinib (made in China) in patients with newly diagnosed chronic myeloid leukemia chronic phase(CML-CP). METHODS: Fifty-seven newly diagnosed CML-CP patients who did not receive any other anti-CML treatment were treated by domestic imatinib 400 mg once a day. The hematological, cytogenetic and molecular reactions and safety were observed and evaluated after 3, 6 and 12 months of treatment. RESULTS: Fifty-six patients were treated for ≥3 and 6 months, among which 50 patients were treated for ≥12 months. After 3 months of treatment, 49 patients underwent hematological examination, 47 patients (95.9%) achieved complete hematological response (CHR), 49 patients underwent cytogenetic examination, 39 patients (79.6%) achieved major cytogenetic response (MCyR), and 12 patients (24.5%) achieved complete cytogenetic response (CCyR). 49 patients underwent the level of BCR-ABL test, including 41 patients (83.7%) with BCR-ABLIS≤10%, and 5 patients (10.2%) with major molecular response (MMR: BCR-ABLIS ≤ 0.1%). After 6 months of treatment, 49 patients underwent hematological examination, and 49 patients (100%) all achieved CHR. 49 patients underwent cytogenetic examined, of which 41 cases (83.7%) obtained MCyR and 31 cases (65.3%) obtained CCyR. 49 patients underwent the level of BCR-ABL test, among which 33 patients (67.4%) showed BCR-ABLIS≤1%, and 15 patients(30.6%) reached MMR. After 12 months of treatment, 45 patients underwent hematological examination, and all the patients (100%) got CHR. 45 patients underwent cytogenetic examined, of which 41 cases (91.1%) obtained MCyR and 35 cases (77.8%) obtained CCyR. 45 cases were tested for BCR-ABL level, and 24 cases (55.3%) reached MMR. The incidence of grade Ⅲ leukopenia, thrombocytopenia and anemia were 14.0%, 8.7% and 10.5%, respectively. Non-hematological adverse reactions were edema (64.9%), nausea (50.9%), vomiting (35.1%), rash (24.5%), fever (15.8%), bone and joint muscle pain (38.6%), diarrhea(17.6%) and liver function damage (3.5%). There were no grade IV hematological and non-hematological adverse reactions. CONCLUSION: In the real world, Domestics imatinib mesylate is effective and safe in the treatment of newly diagnosed CML-CP patients, but long-term follow-up data are still necessary to verify its long-term efficacy.


Assuntos
Antineoplásicos , Leucemia Mielogênica Crônica BCR-ABL Positiva , Antineoplásicos/uso terapêutico , Benzamidas/uso terapêutico , China , Proteínas de Fusão bcr-abl/genética , Humanos , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Piperazinas , Pirimidinas/uso terapêutico , Resultado do Tratamento
7.
Rinsho Ketsueki ; 62(3): 180-185, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-33828011

RESUMO

We report the case of a 26-year-old male patient with chronic myelogenous leukemia in the chronic phase with the e13a3 (b2a3) variant of BCR-ABL1 fusion. Despite the presence of Philadelphia chromosome and fluorescence in situ hybridization-detectable BCR-ABL1 fusion signals, quantitative measurement of BCR-ABL1 on the ABL1 using a reverse primer in exon 2 of ABL1 failed to detect the fusion transcripts. PCR direct sequencing analysis with a sense primer for exon 13 of BCR and an antisense primer for exon 3 of ABL1 revealed the e13a3 variant of BCR-ABL1 fusion. The variant fusion transcript level was successfully monitored by the TaqMan assay using a forward primer and probe both in exon 13 of BCR and a reverse primer in exon 3 of ABL1. The patient responded extremely well to imatinib treatment, similar to previously reported e13a3 cases. The patient achieved a molecular response (undetectable e13a3 transcripts) after 12 months of treatment.


Assuntos
Proteínas de Fusão bcr-abl , Leucemia Mielogênica Crônica BCR-ABL Positiva , Adulto , Proteínas de Fusão bcr-abl/genética , Humanos , Mesilato de Imatinib/uso terapêutico , Hibridização in Situ Fluorescente , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Masculino , Inibidores de Proteínas Quinases/uso terapêutico
8.
Blood Adv ; 5(5): 1403-1411, 2021 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-33666650

RESUMO

Imatinib is the mainstay of treatment of patients with chronic myeloid leukemia (CML) in Tanzania. Monitoring molecular response to therapy by real-time polymerase chain reaction at defined milestones is necessary for early detection of treatment failure. However, this assay is not routinely performed in Tanzania; therefore, the depth of molecular response among patients with CML is not known. A total of 158 patients with previously diagnosed CML who received imatinib treatment were recruited from January 2019 and followed up through October 2020 at Ocean Road Cancer Institute. Information was obtained at the time of diagnosis and follow-up. Blood samples were collected in EDTA tubes to measure the BCR/ABL ratio on the Gene Xpert system for molecular response determination. The median age of the 158 adult patients was 45 years (range, 18-86). By reference to established treatment milestones, only 37 (23.4%) achieved optimal molecular response. Signs of advanced-stage disease, in particular the need for red cell transfusions before diagnosis (adjusted odds ratio [AOR], 3.4; 95% CI, 1.32-9.17) and cytopenias (AOR, 2.26; 95% CI, 1.03-4.96) necessitating drug interruptions were statistically validated predictors of treatment failure on multivariate, multinomial logistic regression. Patient survival at the 22-month follow-up was lowest, with 78.6% (95% CI, 69.4-85.4) in the failure-to-respond category and highest in patients achieving optimal response 97.0% (95% CI, 80.9-99.6). In summary, the majority of patients with CML treated with imatinib in Tanzania do not obtain deep molecular response. This outcome can be attributed to late diagnosis, the development of cytopenias requiring multiple drug interruptions, and poor adherence to treatment.


Assuntos
Antineoplásicos , Leucemia Mielogênica Crônica BCR-ABL Positiva , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Benzamidas/uso terapêutico , Humanos , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Pessoa de Meia-Idade , Piperazinas , Pirimidinas/uso terapêutico , Tanzânia/epidemiologia , Resultado do Tratamento , Adulto Jovem
9.
Ann Hematol ; 100(5): 1213-1219, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33677654

RESUMO

Tyrosine kinase inhibitors (TKIs), the backbone of treatment for chronic phase chronic myeloid leukemia patients (CP-CML), have changed the long-term outcome of the disease. Nonetheless, over 20% of patients fail front-line therapy due to intolerance or resistance. A head-to-head comparison of dasatinib and nilotinib as second-line treatment outside of sponsored clinical trials has not been reported. We retrospectively analyzed 131 CP-CML patients who, after front-line imatinib failure, switched to a second-line therapy with nilotinib (59, 45%) or dasatinib (72, 55%). Median duration of second-line treatment was 33 months (range 2-100). The reason for switching therapy was resistance in 83.2% and intolerance in 16.8% of patients. The overall survival of the entire cohort at 7 years was 78.9%, while it was 72% and 85.6% for patients treated with dasatinib and nilotinib, respectively (p=0.287). With regard to efficacy after 12 months of treatment, 108 patients were evaluable for molecular response: 47% achieved a major molecular response and 18.2% a deep molecular response with dasatinib, compared to 38% and 16.2% with nilotinib (p=ns). We observed 35% of grade 3-4 adverse events, more frequently in the dasatinib group (47%) compared to the nilotinib group (22%), without affecting molecular responses. Our study suggests that, in the real-life setting, dasatinib and nilotinib used as second-line treatment in CP-CML are equally effective, with high molecular response rates and an acceptable tolerability.


Assuntos
Antineoplásicos/uso terapêutico , Dasatinibe/uso terapêutico , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Pirimidinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Mesilato de Imatinib/uso terapêutico , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/uso terapêutico , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento , Adulto Jovem
10.
Int J Hematol ; 113(5): 624-631, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33782818

RESUMO

The advent of tyrosine kinase inhibitors (TKIs) has dramatically improved the outcome of patients with chronic myeloid leukemia (CML). Currently, four TKIs are available for the frontline treatment, including the first-generation TKI (imatinib) and the second-generation TKIs (dasatinib, nilotinib, and bosutinib). The second-generation TKIs lead to a faster and deeper molecular response without a survival benefit compared with imatinib. However, the opportunity for the treatment discontinuation and functional cure requires the achievement of durable deep molecular remission. Therefore, the second-generation TKIs should be considered as initial therapy for chronic-phase CML. Switch of therapy is warranted in case of treatment failure, including resistance and/or intolerance. The life expectancy of patients with CML is approaching that of the general population. Given an expected lifespan, future perspectives should consider the strategy for the optimal choice of TKIs, allowing for long-duration of effective TKI therapy with less toxicity to aim for a functional cure. A novel prediction approach such as artificial intelligence-driven analysis on the accumulated data from clinical trials paves a promising path for the personalized recommendation on frontline TKIs and precise survival prediction.


Assuntos
Antineoplásicos/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Inibidores de Proteínas Quinases/uso terapêutico , Transplante de Células-Tronco , Compostos de Anilina/uso terapêutico , Animais , Inteligência Artificial , Dasatinibe/uso terapêutico , Gerenciamento Clínico , Humanos , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Nitrilas/uso terapêutico , Pirimidinas/uso terapêutico , Quinolinas/uso terapêutico , Transplante de Células-Tronco/métodos , Transplante Homólogo/métodos
11.
Vet Q ; 41(1): 163-171, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33745419

RESUMO

An 8-year-old neutered male Yorkshire Terrier dog presented with head pressing, vestibular ataxia, neck tenderness, and no oculocephalic reflex. A demarcated lesion in the pons was identified on MRI. The patient was tentatively diagnosed with a glioma and was treated with hydroxyurea plus imatinib and prednisolone. After 30 days of therapeutic treatment, the patient showed a clear improvement in neurological signs, which lasted for 1117 days. On day 569 after the initiation of treatment, 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) was performed with no significant findings on visual analysis. The average and maximal standardized uptake values (SUVs) were 1.92 and 2.29, respectively. The tumor-to-normal-tissue (T/N) ratio was 0.97. The first evidence of clinical deterioration was noticed on day 1147. On day 1155, 3,4-dihydroxy-6-[18F]-fluoro-l-phenylalanine (18F-FDOPA)-PET was performed. High uptake of 18F-FDOPA was observed in the intracranial lesion. The mean and maximal SUVs of the tumor were 1.59 and 2.29, respectively. The T/N ratio was 2.22. The patient was euthanized on day 1155 and histopathologic evaluations confirmed glioma (astrocytoma). This case shows that chemotherapy with hydroxyurea plus imatinib may be considered in the treatment of canine glioma. Furthermore, this is the first case describing the application of 18F-FDG and 18F-FDOPA in a dog with glioma.


Assuntos
Doenças do Cão/diagnóstico por imagem , Doenças do Cão/tratamento farmacológico , Glioma/veterinária , Tomografia por Emissão de Pósitrons/veterinária , Animais , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/veterinária , Di-Hidroxifenilalanina/análogos & derivados , Cães , Fluordesoxiglucose F18 , Glioma/diagnóstico por imagem , Glioma/tratamento farmacológico , Hidroxiureia/uso terapêutico , Mesilato de Imatinib/uso terapêutico , Transportador 1 de Aminoácidos Neutros Grandes/metabolismo , Masculino , Tomografia por Emissão de Pósitrons/métodos , Prednisolona/uso terapêutico , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo
12.
Mol Biol Rep ; 48(3): 2035-2046, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33709282

RESUMO

Polymorphism in metabolizing enzymes can influence drug response as well as the risk for adverse drug reactions. Nevertheless, there are still few studies analyzing the consequence of polymorphisms for the Glutathione-S-transferases (GST) gene to drug response in chronic myeloid leukemia (CML). This study reports, the influence of GSTP1*B and GSTT1/GSTM1null polymorphisms in response to imatinib in CML patients in a Brazilian population. One hundred thirty-nine CML patients from the Clinical Hospital of Goiânia, Goiás, Brazil, treated with imatinib were enrolled in this study. Genotyping of GSTT1 and GSTM1 genes deletions were performed by qPCR and of GSTP1 gene was performed by RFLP-PCR. The frequency of GSTP1*1B, GSTT1 and GSTM1null polymorphisms were determined for all patients. The influence of each patient's genotypes was analyzed with the patient's response to imatinib treatment. Brazilian CML patients revealed GSTT1 and GSTM1 genes deletions. GSTT1 deletion was found in 19.3% of patients and GSTM1 deletion in 48.7% of patients with CML. GSTT1/GSTM1 deletion was found in 11.7% in Brazilian CML patients. The "G allele" of GSTP1*B, is associated with later cytogenetic response in imatinib therapy. While, the gene presence combined with GG genotype (GSTM1 present/GSTPI-GG) conferred a tend to a later cytogenetic response to patients. GSTP1*B and GSTT1/GSTM1null polymorphisms influence treatment response in CML. Brazilian CML patients presenting GSTP1 AA/AG genotypes alone and in combination with GSTT1 null reach the cytogenetic response faster, while patients presenting GSTP1-GG and GSTMI positive genotypes may take longer to achieve cytogenetic response. As a result, it allows a better prognosis, with the use of an alternative therapy, other than reducing treatment cost.


Assuntos
Predisposição Genética para Doença , Glutationa S-Transferase pi/genética , Glutationa Transferase/genética , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Polimorfismo Genético , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Bases , Brasil , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Adulto Jovem
13.
BMJ Case Rep ; 14(3)2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33664035

RESUMO

We report a case of a 54-year-old man who developed an atypical systemic syndrome involving Raynaud's phenomenon, pulmonary fibrosis and skin thickening. These features were initially suggestive of newly diagnosed scleroderma. However, he displayed atypical clinical features of same, antinuclear antibody was negative and symptoms were refractory to various immunosuppressive therapies. CT imaging revealed a gastric mass, which later proved to be a gastrointestinal stromal tumour (GIST). Resection of the GIST leads to minimal symptomatic improvement. Surveillance imaging 1 year later revealed metastatic deposits. He was subsequently initiated on imatinib therapy, which led to a rapid improvement in fibrotic changes within weeks. While there have been previous descriptions of paraneoplastic fibrotic disorders, this is the first description of a scleroderma mimic in the setting of a GIST. It highlights an important potential overlap in the pathogenesis of these disease processes and the potential efficacy of tyrosine kinase inhibitors for scleroderma-like fibrotic disorders.


Assuntos
Tumores do Estroma Gastrointestinal , Doença de Raynaud , Esclerodermia Localizada , Escleroderma Sistêmico , Neoplasias Gástricas , Tumores do Estroma Gastrointestinal/complicações , Tumores do Estroma Gastrointestinal/diagnóstico , Humanos , Mesilato de Imatinib/uso terapêutico , Masculino , Pessoa de Meia-Idade , Doença de Raynaud/etiologia , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/diagnóstico
14.
Medicina (Kaunas) ; 57(2)2021 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-33670651

RESUMO

Background and Objectives: This study aimed to objectively determine microsatellite instability (MSI) status using a next-generation sequencing (NGS)-based MSI panel and to resolve the discrepancy regarding whether or not MSI is a rare phenomenon, irrespective of diverse genomic alterations in gastrointestinal stromal tumors (GISTs). Materials and Methods: Genomic DNA was subjected to MSI panel sequencing using an Ion AmpliSeq Microsatellite Instability Assay, as well as to cancer gene panel sequencing using an Oncomine Focus DNA Assay. Results: All of our GIST patients showed microsatellite-stable (MSS) status, which confirmed that MSI status did not affect the molecular pathogenesis of GIST. The KIT gene (79%, 38/48) was the most frequently mutated gene, followed by the PDGFRA (8%, 4/48), PIK3CA (8%, 4/48), and ERBB2 (4%, 2/48) mutations. KIT exon 11 mutant patients were more favorable in responding to imatinib than those with exon 9 mutant or wild-type GISTs, and compared to non-KIT exon 11 mutant GISTs (p = 0.041). The NGS-based MSI panel with MSICall confirmed a rare phenomenon of microsatellite instability in GISTs irrespective of diverse genomic alterations. Conclusion: Massively parallel sequencing can simultaneously provide the MSI status as well as the somatic mutation profile in a single test. This combined approach may help us to understand the molecular pathogenesis of GIST carcinogenesis and malignant progression.


Assuntos
Tumores do Estroma Gastrointestinal , Tumores do Estroma Gastrointestinal/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mesilato de Imatinib/uso terapêutico , Instabilidade de Microssatélites , Mutação
15.
Eur J Med Chem ; 216: 113285, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33662676

RESUMO

The development of resistance poses a serious problem in the therapy of cancer due to the necessity of a multiple-drug and unlimited treatment of affected patients. In chronic myeloid leukemia (CML), the introduction of imatinib has revolutionized the therapy. The persistence of an untreatable cancer stem cell pool and other resistance-causing factors, however, also impede the cure of this malignancy. New therapeutic approaches are therefore essential to overcome current treatment drawbacks. In this regard, an intervention in the STAT5 signaling pathway can significantly improve drug response, as this central signaling node induces the formation of highly resistant CML cells. In the present study, we continued the design of efficient chemosensitizers derived from the partial PPARγ agonist telmisartan. The developed 2-carbonitriles or 2-carboxymethyl esters showed improved potency in sensitizing K562-resistant cells to imatinib treatment, even at concentrations, which are considered patient-relevant. At 5 µM, for instance, 2d sensitized the cells in such a manner that the resistance was fully overcome and the recovered efficacy of imatinib resulted in >76% cell death. Importantly, all compounds were non-cytotoxic per se. A transactivation experiment showed that only the carbonitriles are partial agonists of PPARγ, which does not seem to be involved in the mode of action. Yet, immunoassays revealed a suppression of the STAT5 phosphorylation status by co-application of the most active derivatives with imatinib. This mechanism consequently resulted in reduced cell proliferation and induction of cell death in resistant CML cells.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Nitrilas/química , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Células COS , Linhagem Celular Tumoral , Chlorocebus aethiops , Desenho de Fármacos , Regulação da Expressão Gênica , Humanos , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Nitrilas/farmacologia , PPAR gama/genética , PPAR gama/metabolismo , Fosforilação/efeitos dos fármacos , Fator de Transcrição STAT5/antagonistas & inibidores , Fator de Transcrição STAT5/genética , Fator de Transcrição STAT5/metabolismo , Telmisartan/química , Telmisartan/farmacologia , Ativação Transcricional/efeitos dos fármacos , Proteínas Supressoras de Tumor/antagonistas & inibidores , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
17.
Pediatr Hematol Oncol ; 38(4): 378-384, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33653209

RESUMO

Imatinib is a BCR-ABL tyrosine kinase inhibitor used for the treatment of a variety of diseases including Philadelphia chromosome positive (Ph+) leukemia. We report a 15 year old male patient presenting with symptomatic acute intracerebral hemorrhage (ICH) in midbrain while on imatinib more than three years after completion of therapy for Ph + B-ALL. The patient denied recent trauma history and consumption of other medication. Laboratory findings did not show any signs of relapse, coagulopathy nor thrombocytopenia. Under the impression of imatinib related ICH, imatinib was discontinued and with conservative management the patient recovered without neurologic sequalae. This case demonstrates the first pediatric case of spontaneous ICH as a rare complication of imatinib.


Assuntos
Antineoplásicos/efeitos adversos , Hemorragia Cerebral/induzido quimicamente , Mesilato de Imatinib/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Antineoplásicos/uso terapêutico , Humanos , Mesilato de Imatinib/uso terapêutico , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações
20.
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
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