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1.
Medicine (Baltimore) ; 99(9): e19256, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32118733

RESUMEN

INTRODUCTION: We report here the case of a patient with chronic myeloid leukemia (CML) in the chronic phase who was diagnosed 1 year after receiving a diagnosis of autoimmune hemolytic anemia (AIHA). The objective was to assess if the CML patient progressed from AIHA and explore the underlying factors of the poor outcome after the achievement of molecular complete remission (MCR). PATIENT CONCERNS: A patient with AIHA underwent splenectomy because of poor response to immune inhibitors. The spleen biopsy showed reactive hyperplasia. DIAGNOSIS: The patient was diagnosed with CML because of over-expression of the BCR-ABL (P210) gene in the bone marrow (BM), 1 year after receiving the diagnosis of AIHA. INTERVENTIONS: The splenectomy was performed as the patient was unresponsive to the standard treatments consisting of immunoglobulin and dexamethasone. The removed spleen was sent for pathological examination. After she was diagnosed with CML, she received imatinib treatment. OUTCOMES: The spleen biopsy confirmed the translocation of 22q11/9q34. No BCR-ABL kinase domain mutation was detected and there was no expression of the WT1 or EVI1 genes. After splenectomy, the number of peripheral white blood cells was consistently higher than normal during the total therapy time for CML even though she showed MCR. Two years after CML was diagnosed, the patient died from severe infection. The BM gene array analysis displayed 3 types of chromosomal abnormalities: gain (14q32.33), uniparental disomy (UPD) Xp11.22-p11.1), and UPD Xp11.1-q13.1. LESSONS: AIHA may be a clinical phase of CML progression in this patient. Both splenectomy and prolonged oral tyrosine kinase inhibitors may have contributed to the high risk of infection and her subsequent death. In addition, the gain of chromosome 14q32.33 may be related to her poor outcome.


Asunto(s)
Anemia Hemolítica Autoinmune , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Adolescente , Resultado Fatal , Femenino , Proteínas de Fusión bcr-abl/genética , Humanos , Mesilato de Imatinib/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Esplenectomía
2.
Lancet ; 395(10226): 817-827, 2020 03 07.
Artículo en Inglés | MEDLINE | ID: mdl-32145796

RESUMEN

The development and approval of cyclin-dependent kinase (CDK) 4 and 6 inhibitors for hormone receptor-positive and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer represents a major milestone in cancer therapeutics. Three different oral CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, have significantly improved progression-free survival by a number of months when combined with endocrine therapy. More recently, improvement in overall survival has been reported with ribociclib and abemaciclib. The toxicity profile of all three drugs is well described and generally easily manageable with dose reductions when indicated. More myelotoxicity is observed with palbociclib and ribociclib, but more gastrointestinal toxicity is observed with abemaciclib. Emerging data is shedding light on the resistance mechanisms associated with CDK4/6 inhibitors, including cell cycle alterations and activation of upstream tyrosine kinase receptors. A number of clinical trials are exploring several important questions regarding treatment sequencing, combinatorial strategies, and the use of CDK4/6 inhibitors in the adjuvant and neoadjuvant settings, thereby further expanding and refining the clinical application of CDK4/6 inhibitors for patients with breast cancer.


Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/uso terapéutico , Ciclo Celular/efectos de los fármacos , Ensayos Clínicos como Asunto , Femenino , Predicción , Humanos , Receptores Estrogénicos , Receptores de Progesterona
3.
Cancer Treat Rev ; 85: 101994, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32113081

RESUMEN

Uncommon epidermal growth factor receptor (EGFR) mutations collectively account for 10% of EGFR mutations, harboring heterogeneous molecular alterations within exons 18-21 with clinically variable responses to EGFR tyrosine kinase inhibitors (TKIs) in advanced Non-Small Cell Lung Cancer (NSCLC) patients. In addition, with the introduction of different NGS gene approach an improvement of EGFR mutations detection was reported. Today, no specific studies have prospectively evaluated uncommon sensitizing mutations in detail and no firm standard of care has been established in the first-line setting. The aim of this comprehensive review is to critically consider the clinical role of uncommon EGFR mutations highlighting the results of several in vitro and in vivo studies, which singly evaluated the sensitivity of uncommon mutations to currently European of Medicines Agency (EMA)-approved EGFR TKIs in cell lines, xenograft models and humans, in order to obtain a practical guide for refining the clinical decision-making process.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Receptores ErbB/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptores ErbB/efectos de los fármacos , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Mutación/genética , Pronóstico , Resultado del Tratamiento
4.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(1): 136-140, 2020 Feb.
Artículo en Chino | MEDLINE | ID: mdl-32027266

RESUMEN

OBJECTIVE: To analyze the relationship between cytogenetic changes and the progression in the patients with chronic myeloid leukemia (CML) during the treatment with tyrosine kinase inhibitor (TKI). METHODS: The chromosome G banding of 150 patients with CML treated in our hospital, was carried out to analyze the karyotype by the 24 h short-term culture or direct method of bone marrow cells, and the point mutation of the ABL kinase area was detected, the relationship between cytogenetic changes and the evolution of the disease course was analyzed. RESULTS: The indirect fluorescence in situ hybridization showed that the BCR-ABL fusion gene of 150 patients was positive, out of which 142 cases showed positive Philadelphia (Ph) (94.67%), 8 cases with Ph negative (5.33%). Among 142 cases with Ph positive on the first diagnosis, and 14 cases (9.86%) with additional chromosome abnormality (9.86%), 4 cases (2.82%) with mutation translocation with 124 cases (87.32%), standard translocation t (9; 22) (q34; Q11) were found. Out of the 14 patients with additional chromosomal abnormalities, 8 cases with "main pathmay" abnormalities, 2 case with -Y abnormalities, and 4 cases with "secondary pathway" abnormalities were observed. During TKI treatment, additional chromosomal abnormalities were found in 46 patients with standard translocation and abnormal number of chromosomes, and the incidence of disease progression and point mutation were higher (P<0.05). Compared with patients with the standard translocation, the disease-free survival rate of the patients diagnosed as CML at 1st visit and with additional chromosome abnormality was significantly decreased (P<0.05), but the overall survival rate showed no significantly different (P>0.05). Compared with patients without additional cvtogenetic aberrations, the disease free and overall survival rate of the patients with additional cytogenetic aberrations during the TKI treatment of CML in chronic phase were significantly decreased (P<0.05). CONCLUSION: Some CML patients may have additional chromosomal abnormalities during the onset and development of the disease, and these patients are at higher risk of disease progression.


Asunto(s)
Leucemia Mielógena Crónica BCR-ABL Positiva , Cromosoma Filadelfia , Inhibidores de Proteínas Quinasas/uso terapéutico , Aberraciones Cromosómicas , Análisis Citogenético , Citogenética , Humanos , Hibridación Fluorescente in Situ , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Translocación Genética
5.
Urologe A ; 59(2): 149-154, 2020 Feb.
Artículo en Alemán | MEDLINE | ID: mdl-32076796

RESUMEN

In view of a considerable risk of recurrence especially in patients with a high-risk profile after organ-sparing surgery or nephrectomy, adjuvant treatment seems to make sense in renal cell carcinoma. After the failed attempts using older immunotherapeutics or vaccination therapies, new hope was put in the panel of targeted VEGF/R inhibitors. But the results from these studies published so far are also disappointing. In this context the instruments for selecting the best suitable patients for adjuvant trials have to be discussed. It remains to be seen whether using the same selection criteria as in ongoing trials with checkpoint inhibitors will show better results.


Asunto(s)
Carcinoma de Células Renales/terapia , Quimioterapia Adyuvante/métodos , Neoplasias Renales/terapia , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptores de Factores de Crecimiento Endotelial Vascular/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Humanos , Neoplasias Renales/tratamiento farmacológico , Terapia Molecular Dirigida/métodos , Recurrencia Local de Neoplasia , Nefrectomía , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores
6.
Anticancer Res ; 40(2): 825-835, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32014925

RESUMEN

BACKGROUND: Despite extensive research into new treatment options, the prognosis for head and neck squamous cell carcinoma remains poor. Platelet-derived growth factor (PDGF) is up-regulated in HNSCC and expression levels decrease after surgery, suggesting its role in tumour development. The influence of HPV on the PDGF/PDGF receptor (PDGFR) pathway remains unclear. In this study, we investigated the effect of small-molecule tyrosine kinase inhibitors (TKIs) on the expression of PDGF and its receptor in vitro using squamous cancer cell lines with different human papillomavirus 16 (HPV16) status. MATERIALS AND METHODS: Two human HPV16-negative cell lines (UMSCC-11A/-14C) and one HPV16-positive cell line (CERV196) were used. Tumour cells were incubated with 20 µmol/l of TKIs nilotinib, dasatinib, afatinib, gefitinib and erlotinib for 24-96 h. Cell proliferation was assessed via proliferation assay and protein concentrations of PDGF-AA and BB and PDGFRα and -ß via sandwich enzyme-linked immunosorbent assay. For statistical analysis, the results were compared with those from an untreated negative control. RESULTS: PDGF-AA/BB and PDGFRα/-ß were detected in all three tested cell lines. The addition of TKI led to a significant (p<0.05) decrease of PDGF/PDGFR at different time points and cell lines. The strongest effects were seen for the expression of PDGF-AA, which was consistently inhibited by most drugs. The effects of the TKI were independent of the HPV status. CONCLUSION: Proteins of this pathway can effectively be inhibited by small molecule TKIs. PDGF-AA seems to be a promising target for future studies with selective TKIs.


Asunto(s)
Carcinoma de Células Escamosas/tratamiento farmacológico , Papillomavirus Humano 16/metabolismo , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Carcinoma de Células Escamosas/patología , Humanos
7.
J Korean Med Sci ; 35(5): e31, 2020 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-32030920

RESUMEN

BACKGROUND: Mechanism and predictive biomarkers for tyrosine kinase inhibitor (TKI) resistance of advanced clear cell renal cell carcinoma (ccRCC) have not been fully evaluated. METHODS: We performed gene expression profiling on samples from an acquired TKI resistance cohort that consisted of 10 cases of TKI-treated ccRCC patients with matched tumor tissues harvested at pre-treatment and TKI-resistant post-treatment periods. In addition, a public microarray dataset from patient-derived xenograft model for TKI-treated ccRCC (GSE76068) was retrieved. Commonly altered pathways between the datasets were investigated by Ingenuity Pathway Analysis using commonly regulated differently expressed genes (DEGs). The significance of candidate DEG on intrinsic TKI resistance was assessed through immunohistochemistry in a separate cohort of 101 TKI-treated ccRCC cases. RESULTS: TNFRSF1A gene expression and tumor necrosis factor (TNF)-α pathway were upregulated in ccRCCs with acquired TKI resistance in both microarray datasets. Also, high expression (> 10% of labeled tumor cells) of TNF receptor 1 (TNFR1), the protein product of TNFRSF1A gene, was correlated with sarcomatoid dedifferentiation and was an independent predictive factor of clinically unfavorable response and shorter survivals in separated TKI-treated ccRCC cohort. CONCLUSION: TNF-α signaling may play a role in TKI resistance, and TNFR1 expression may serve as a predictive biomarker for clinically unfavorable TKI responses in ccRCC.


Asunto(s)
Biomarcadores de Tumor , Carcinoma de Células Renales , Resistencia a Antineoplásicos , Neoplasias Renales , Inhibidores de Proteínas Quinasas , Receptores Tipo I de Factores de Necrosis Tumoral , Transducción de Señal , Factor de Necrosis Tumoral alfa , Adulto , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Renales/diagnóstico , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/terapia , Femenino , Humanos , Inmunohistoquímica , Neoplasias Renales/diagnóstico , Neoplasias Renales/metabolismo , Neoplasias Renales/terapia , Masculino , Persona de Mediana Edad , Pronóstico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptores Tipo I de Factores de Necrosis Tumoral/metabolismo , Análisis de Supervivencia , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/metabolismo
9.
Cancer Treat Rev ; 84: 101966, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32044644

RESUMEN

Anti-angiogenic treatment is an important option that has changed the therapeutic landscape in various tumors, particularly in patients affected by renal cell carcinoma (RCC). Agents that block signaling pathways governing tumor angiogenesis have raised high expectations among clinicians. Vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) comprise a heterogeneous class of drugs with distinct pharmacological profiles, including potency, selectivity, pharmacokinetics and drug-drug interactions. Among them, tivozanib is one of the last TKIs introduced in the clinical practice; this drug selectively targets VEGFRs, it is characterized by a favorable pharmacokinetics and safety profile and has been approved as first-line treatment for patients with metastatic RCC (mRCC). In this article, we describe the clinical pharmacology of selected VEGFR-TKIs used for the treatment of mRCC, highlighting the relevant differences; moreover we aim to define the main pharmacologic characteristics of these drug.


Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Inhibidores de la Angiogénesis/efectos adversos , Inhibidores de la Angiogénesis/uso terapéutico , Anilidas/efectos adversos , Anilidas/farmacología , Anilidas/uso terapéutico , Axitinib/efectos adversos , Axitinib/farmacología , Axitinib/uso terapéutico , Interacciones de Drogas , Humanos , Compuestos de Fenilurea/efectos adversos , Compuestos de Fenilurea/farmacología , Compuestos de Fenilurea/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridinas/efectos adversos , Piridinas/farmacología , Piridinas/uso terapéutico , Pirimidinas/efectos adversos , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Quinolinas/efectos adversos , Quinolinas/farmacología , Quinolinas/uso terapéutico , Sorafenib/efectos adversos , Sorafenib/farmacología , Sorafenib/uso terapéutico , Sulfonamidas/efectos adversos , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico , Sunitinib/efectos adversos , Sunitinib/farmacología , Sunitinib/uso terapéutico
10.
Zhonghua Zhong Liu Za Zhi ; 42(1): 74-77, 2020 Jan 23.
Artículo en Chino | MEDLINE | ID: mdl-32023774

RESUMEN

Gene mutations can impair the sensitivity of cancer cells to targeted drugs, and lead to individual differences of clinical therapeutic effects. Epidermal growth factor receptor (EGFR) mutation plays an important role in therapeutic decision-making. Furthermore, some co-existing gene mutations, such as TP53 mutation, can also affect the therapeutic effect and prognosis of patients. Whether EGFR mutation combined with TP53 mutation affects the sensitivity of lung cancer cells to tyrosine kinase inhibitor (TKI) and long-term prognosis of non-small cell lung cancer (NSCLC) patients is still unknown and has attracted more attentions. However, in the current clinical practice, TP53 mutation is not a key factor of therapeutic decision-making, so further studies are needed to clarify the impact of TP53 mutation (including each subtype) on the potential benefits of EGFR-targeted therapy of NSCLC.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Inhibidores de Proteínas Quinasas , Proteína p53 Supresora de Tumor , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Toma de Decisiones , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Mutación , Planificación de Atención al Paciente , Pronóstico , Inhibidores de Proteínas Quinasas/uso terapéutico , Resultado del Tratamiento , Proteína p53 Supresora de Tumor/genética
11.
Anticancer Res ; 40(2): 957-964, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32014940

RESUMEN

BACKGROUND/AIM: To describe real clinical outcomes when using systemic therapy to treat non-small cell lung cancer (NSCLC) patients who have anaplastic lymphoma kinase (ALK) fusion gene mutation. PATIENTS AND METHODS: We performed a retrospective chart review from April 2008 to March 2019 sourced from 16 medical institutes that cover a population of three million people. RESULTS: There were 129 ALK rearranged NSCLC patients. Among them, 103 patients including 40 recurrent disease cases received ALK-tyrosine kinase inhibitors (TKI) and chemotherapy. Our treatment results were comparable to previously reported clinical trials and clinical practice studies. First-line alectinib, treatment sequence of ALK-TKI followed by another ALK-TKI, and pemetrexed-containing chemotherapy contributed to the outcome of treatment. CONCLUSION: By arrangement of treatment such as treatment sequence of ALK-TKI and chemotherapy regimen, it might be possible to obtain a treatment outcome almost equivalent to those of clinical trials even in real clinical practice.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/etiología , Reordenamiento Génico , Neoplasias Pulmonares/etiología , Adulto , Anciano , Anciano de 80 o más Años , Quinasa de Linfoma Anaplásico/genética , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/terapia , Manejo de la Enfermedad , Femenino , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/terapia , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Proteínas de Fusión Oncogénica/genética , Pronóstico , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Estudios Retrospectivos , Resultado del Tratamiento , Carga Tumoral
12.
Anticancer Res ; 40(2): 1117-1121, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32014962

RESUMEN

BACKGROUND/AIM: The survival benefit of first-line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy without pleurodesis in EGFR-mutant lung adenocarcinoma patients with malignant pleural effusions (MPE) remains unclear. PATIENTS AND METHODS: We retrospectively evaluated overall survival (OS) among EGFR wild-type lung adenocarcinoma patients with MPE who received chemotherapy with pleurodesis (CT+PLD) and without pleurodesis (CT-PLD), and EGFR-mutant lung adenocarcinoma patients with MPE who received EGFR-TKI therapy with pleurodesis (TKI+PLD) and without pleurodesis (TKI-PLD). RESULTS: There was no difference in OS between the CT+PLD and the CT-PLD groups (10.8 months vs. 7.4 months). As compared to the TKI+PLD group, OS tended to be longer in the TKI-PLD group (21.8 months vs. 31.1 months). Patients in the TKI-PLD group had no hypoalbuminemia or deterioration of performance status during management of MPE and could receive second- and further-line therapy. CONCLUSION: EGFR-mutant patients with MPE who received first-line EGFR-TKI therapy without pleurodesis may show a better prognosis than those with pleurodesis.


Asunto(s)
Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/mortalidad , Mutación , Derrame Pleural Maligno/patología , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/patología , Adulto , Anciano , Anciano de 80 o más Años , Receptores ErbB/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Derrame Pleural Maligno/tratamiento farmacológico , Pleurodesia , Pronóstico , Modelos de Riesgos Proporcionales , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Estudios Retrospectivos
13.
Anticancer Res ; 40(2): 1147-1152, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32014967

RESUMEN

BACKGROUND: Neoadjuvant treatment with imatinib mesylate (IM) has not been established for gastrointestinal stromal tumor (GIST). A case of a giant gastric GIST that was radically resected following neoadjuvant therapy with IM is reported. CASE REPORT: A 71-year-old woman with abdominal distension was referred to our hospital for treatment. Contrast-enhanced computed tomography showed a large (>30 cm), heterogeneous mass, with dilated vessels around the tumor. The diagnosis was a gastric GIST by endoscopic ultrasound-fine needle aspiration, and neoadjuvant therapy with 400 mg IM daily was started. Radical surgery was performed after 13 months. Since the tumor was not invasive, complete resection by partial gastrectomy was achieved without the need for combined resection of other organs. The patient remains alive without recurrence 12 months after surgery. CONCLUSION: A giant GIST, larger than 30 cm in size, is quite rare. Neoadjuvant IM treatment should be considered in the management of large GISTs.


Asunto(s)
Antineoplásicos/uso terapéutico , Gastrectomía , Tumores del Estroma Gastrointestinal/diagnóstico , Tumores del Estroma Gastrointestinal/terapia , Mesilato de Imatinib/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Biopsia , Terapia Combinada , Femenino , Gastrectomía/métodos , Humanos , Mesilato de Imatinib/administración & dosificación , Mesilato de Imatinib/efectos adversos , Terapia Neoadyuvante , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Tomografía Computarizada por Rayos X , Resultado del Tratamiento , Carga Tumoral
14.
Medicine (Baltimore) ; 99(3): e18888, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-32011516

RESUMEN

RATIONALE: The success of tyrosine kinase inhibitor (TKI) therapy has greatly prolonged the survival time of patients with chronic myeloid leukemia (CML), harboring the characteristic Philadelphia (Ph) chromosome. However, a fraction of patients, achieving complete cytogenetic response after TKI therapy, develop a myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) with additional clonal chromosomal abnormalities in Philadelphia-negative cells (CCA/Ph-). PATIENT CONCERNS: A 56-year-old woman with AML, developing from Philadelphia-negative CML after TKI therapy. She showed 6 kinds of somatic variants-CEBPA, ATRX, WT1, CSMD1, IKZF1, and LRP1B mutation after diagnosed as AML. DIAGNOSIS: The patient was diagnosed with chronic phase CML that developed to AML after achieving durable complete cytogenetic response (CCR) and major molecular response (MMR). INTERVENTIONS: The patient was treated with TKI therapy at the period of CML. When diagnosed with AML, she received induction chemotherapy regimens, consolidation therapy, and allogeneic hematopoietic stem cell transplantation subsequently. OUTCOMES: The patient has been CCR and MMR for nearly 4 years, and has achieved complete remission after intervention related to AML. She is now preparing for allogeneic hematopoietic stem cell transplantation. LESSONS: These rare occurrences highlight the importance of exploring the relevant pathogenesis of AML developing from CML after TKI therapy. In addition to monitoring molecular changes in the course of CML, cytogenetic analysis, or next-generation sequencing of CML patients should be performed.


Asunto(s)
Leucemia Mielógena Crónica BCR-ABL Positiva/complicaciones , Leucemia Mieloide Aguda/etiología , Antineoplásicos/uso terapéutico , Cromosomas Humanos Par 1 , Cromosomas Humanos Par 19 , Análisis Citogenético , Femenino , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Persona de Mediana Edad , Mutación , Inhibidores de Proteínas Quinasas/uso terapéutico , Translocación Genética
15.
Medicine (Baltimore) ; 99(3): e18892, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-32011517

RESUMEN

RATIONALE: Small cell carcinoma of the esophagus (SCCE) is an uncommon but lethal disease characterized by dismal prognosis. Only 10% of advanced SCCE patients survive longer than 1 year. Resection is a choice for limited-stage cases, whereas the optimal treatment regimen for primary SCCE is yet to be elucidated. To the best of our knowledge, the efficacy of S-1 plus apatinib for irinotecan-refractory SCCE has not been reported before. PATIENT CONCERNS: A 61-year old, previously healthy male was admitted for dysphagia and fatigue. Endoscopic biopsy revealed a tumor in the middle third of the esophagus. Further exams including abdomen computed tomography excluded distant metastasis. DIAGNOSES: Primary SCCE (pT1bN1M0, IIB) was established after salvage operation. INTERVENTIONS: The tumor was enlarged after 1 cycle of first-line chemotherapy using irinotecan plus cisplatin, which indicated drug resistance. Second-line oral apatinib (425 mg daily) plus S-1 (60 mg, twice daily for 4 weeks with a 2-week drug-free interval) for a month showed efficacy, as shown by decreased serum neuron-specific enolase and stable of the esophageal lesion. Thereafter, salvage minimally invasive Ivor-Lewis esophagectomy and 2-field lymph node dissection was performed, followed by oral apatinib plus S-1 at the prior dosage for 6 months. In addition, maintenance therapy using low-dose apatinib (250 mg daily) plus S-1 (40 mg, twice daily for 4 weeks with a 2-week interval) were administered for another 6 months. Then the patient was followed up irregularly at the outpatient clinic. OUTCOMES: The adverse events including hand-foot syndrome, hypertension, vomiting, leukopenia, impaired hepatic function, and fatigue were mainly tolerable. Forty months after the operation, he was readmitted for back pain and disseminated bone metastases appeared in magnetic resonance images. His progression-free survival could not be obtained precisely, and his overall survival was longer than 40 months up to September 2019. LESSONS: S-1 plus apatinib followed by a timely esophagectomy with curative intent might be an alternative option for chemotherapy-refractory SCCE in selected patients. Better evidence is warranted.


Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Carcinoma de Células Pequeñas/tratamiento farmacológico , Neoplasias Esofágicas/tratamiento farmacológico , Ácido Oxónico/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridinas/uso terapéutico , Tegafur/uso terapéutico , Carcinoma de Células Pequeñas/cirugía , Combinación de Medicamentos , Resistencia a Antineoplásicos , Quimioterapia Combinada , Neoplasias Esofágicas/cirugía , Esofagectomía , Humanos , Irinotecán/uso terapéutico , Masculino , Persona de Mediana Edad , Terapia Recuperativa
17.
J Enzyme Inhib Med Chem ; 35(1): 414-423, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31899991

RESUMEN

A novel series of cyclin-dependent kinases (CDKs) inhibitors, which play critical roles in the cell cycle control and regulation of cell transcription, were synthesised. A systematic study of enzymatic and cellular assays led to the identification of compound X22 with a nanomolar potency against CDK4 and CDK9 and potent antiproliferative activities against a panel of tumour cell lines. X22 could induce cell cycle arrest and cell apoptosis in cancer cell lines. X22 dose-dependently inhibits signalling pathways downstream of CDKs in cancer cells. In vivo antitumor activity assays, oral administration of X22 led to significant tumour regression in mouse model without obvious toxicity. Superior anti-cancer efficacy in vitro and in vivo of X22 demonstrated combined depletion of cell cycle and transcriptional CDK all contributed to antitumor activity. Taken together, concomitant inhibition of cell cycle and transcriptional CDK activities provided valuable guide for further structural optimisation.


Asunto(s)
Antineoplásicos/farmacología , Ciclo Celular/efectos de los fármacos , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Transcripción Genética/efectos de los fármacos , Animales , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Neoplasias/enzimología , Neoplasias/patología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/uso terapéutico , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de Xenoinjerto
18.
Lancet Haematol ; 7(3): e218-e225, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31978329

RESUMEN

BACKGROUND: A previous dasatinib discontinuation (DADI) trial showed that 31 (49%) of 63 patients with chronic-phase chronic myeloid leukaemia who were treated with second-line or subsequent dasatinib could discontinue the drug safely. However, the safety and efficacy of discontinuing first-line dasatinib remains unclear. In this trial (the first-line DADI trial) we aimed to assess molecular relapse-free survival at 6 months after discontinuation of dasatinib in patients with chronic myeloid leukaemia who had been treated with first-line dasatinib and had maintained deep molecular response for at least 1 year. METHODS: The first-line DADI trial was a single-arm, multicentre, phase 2 trial done at 23 hospitals in Japan. Patients with newly diagnosed chronic-phase chronic myeloid leukaemia without hepatosplenomegaly and extramedullary mass, who received at least 24-month dasatinib treatment and had a sustained deep molecular response (defined as BCR-ABL1/ABL1 international scale ≤0·0069% in at least four successive samples spanning a 12 month period) were enrolled. Other eligibility criteria were an age of 15 years or older, an Eastern Cooperative Oncology Group performance status score of 0-2, and no primary organ dysfunction. The primary outcome was molecular relapse-free survival (also known as treatment-free remission) after discontinuation of dasatinib at 6 months and was analysed in all patients who completed the 12-month consolidation phase. Safety was assessed in all patients who received treatment. This study closed early due to accrual and is registered with the UMIN Clinical Trials Registry (UMIN000011099). FINDINGS: Between Sept 20, 2013 and July 12, 2016, 68 patients who had a deep molecular response after receiving first-line dasatinib for at least 24 months were enrolled and assigned to the consolidation phase. Nine patients were excluded during the consolidation phase and one patient was excluded after study completion because of meeting exclusion criteria. 58 patients discontinued dasatinib and were assessed. 32 (55%) of 58 patients had treatment-free remission at 6 months after dasatinib discontinuation, and median follow-up was 23·3 months (IQR 11·7-31·0). Treatment-free remission at 6 months was 55·2% (95% CI 43·7-69·6). No non-haematological adverse events worse than grade 2 occurred before dasatinib discontinuation. The most common haematological adverse event was anaemia (14 [21%] of 68 treated patients); three (4%) of 68 treated patients had grade 3 neutropenia and one (1%) had grade 4 lymphopenia. INTERPRETATION: Our findings suggest that dasatinib could be safely discontinued after first-line treatment in patients with chronic myeloid leukaemia who had received at least 36 months of therapy and sustained deep molecular response; however, further confirmation in larger trials is needed. FUNDING: Epidemiological and Clinical Research Information Network.


Asunto(s)
Dasatinib/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Anciano , Femenino , Estudios de Seguimiento , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Masculino , Persona de Mediana Edad , Pronóstico , Inducción de Remisión , Tasa de Supervivencia , Privación de Tratamiento
19.
Crit Rev Oncol Hematol ; 146: 102863, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31935617

RESUMEN

Lung cancer is the most frequent cancer for males and third most frequent cancer for females. Targeted therapy drugs based on molecular alterations, such as angiogenesis inhibitors, epidermal growth factor receptor (EGFR) inhibitors, and anaplastic lymphoma kinase (ALK) inhibitors are important part of treatment of NSCLC. However, the quality of the available tumor biopsy and/or cytology material is sometimes not adequate to perform the necessary molecular testing, which has prompted the search for alternatives. This review examines the use of tumor-educated platelet (TEP) as a liquid biopsy in lung cancer patients. The development of sensitive and accurate techniques have made it possible to detect the specific genetic alterations for which targeted therapies are already available. Liquid biopsy offers opportunities to detect resistance mechanisms at an early stage. To conclude, tumor-educated platelet has the potential to be used as liquid biopsy for a variety of clinical and investigational applications.


Asunto(s)
Biomarcadores de Tumor/sangre , Carcinoma de Pulmón de Células no Pequeñas/patología , Ácidos Nucleicos Libres de Células/sangre , ADN de Neoplasias/sangre , ADN de Neoplasias/genética , Biopsia Líquida/métodos , Neoplasias Pulmonares/patología , Biomarcadores de Tumor/genética , Plaquetas/patología , Carcinoma de Pulmón de Células no Pequeñas/sangre , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/terapia , Ácidos Nucleicos Libres de Células/genética , Receptores ErbB/genética , Femenino , Humanos , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Masculino , Mutación , Medicina de Precisión , Inhibidores de Proteínas Quinasas/uso terapéutico
20.
Cancer Sci ; 111(3): 932-939, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31961053

RESUMEN

The treatment for anaplastic lymphoma kinase (ALK)-positive lung cancer has been rapidly evolving since the introduction of several ALK tyrosine kinase inhibitors (ALK-TKI) in clinical practice. However, the acquired resistance to these drugs has become an important issue. In this study, we collected a total of 112 serial biopsy samples from 32 patients with ALK-positive lung cancer during multiple ALK-TKI treatments to reveal the resistance mechanisms to ALK-TKI. Among 32 patients, 24 patients received more than two ALK-TKI. Secondary mutations were observed in 8 of 12 specimens after crizotinib failure (G1202R, G1269A, I1171T, L1196M, C1156Y and F1245V). After alectinib failure, G1202R and I1171N mutations were detected in 7 of 15 specimens. G1202R, F1174V and G1202R, and P-gp overexpression were observed in 3 of 7 samples after ceritinib treatment. L1196M + G1202R, a compound mutation, was detected in 1 specimen after lorlatinib treatment. ALK-TKI treatment duration was longer in the on-target treatment group than that in the off-target group (13.0 vs 1.2 months). In conclusion, resistance to ALK-TKI based on secondary mutation in this study was similar to that in previous reports, except for crizotinib resistance. Understanding the appropriate treatment matching resistance mechanisms contributes to the efficacy of multiple ALK-TKI treatment strategies.


Asunto(s)
Quinasa de Linfoma Anaplásico/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Resistencia a Antineoplásicos/genética , Neoplasias Pulmonares/genética , Grupo de Ascendencia Continental Asiática , Carbazoles/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Crizotinib/uso terapéutico , Humanos , Lactamas Macrocíclicas/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Mutación/genética , Piperidinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Proteínas Recombinantes/genética , Sulfonas/uso terapéutico
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