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1.
Brasília; CONITEC; out. 2020.
No convencional en Portugués | BRISA/RedTESA | ID: biblio-1141497

RESUMEN

INTRODUÇÃO: O câncer renal é responsável por aproximadamente 3% dos cânceres de adultos nos países ocidentais, é o sétimo câncer mais comum em homens e o nono mais comum em mulheres. O Carcinoma de Células Renais (CCR), também conhecido como adenocarcinoma de células renais, é o tipo mais comum, com aproximadamente nove casos em cada dez cânceres renais. O prognóstico do CCR está relacionado ao estágio da doença quando o diagnóstico é realizado - os estágios do câncer renal variam de I a IV. No Brasil, no âmbito do SUS, o tratamento é direcionado pelas Diretrizes Diagnósticas e Terapêuticas (DDT) do CCR. PERGUNTA: O cabozantinibe é eficaz, efetivo e seguro como primeira linha de tratamento de pacientes com CCR avançado/metastático que apresentam risco intermediário a alto, quando comparado às demais quimioterapias paliativas disponíveis no SUS? EVIDÊNCIAS CIENTÍFICAS: Após revisão sistemática da literatura, sete estudos foram incluídos no corpo de evidências (1 Ensaio Clínico Randomizado [ECR] fase II e seu estudo de extensão, e 5 Revisões Sistemáticas [RS] com meta-análise em rede). Todos os estudos reportavam resultados exclusivamente do mesmo ECR (CHOUEIRI et al, 2017), que apresenta problemas metodológicos. Não foi identificada diferença estatisticamente significativa entre cabozantinibe, sunitinibe e pazopanibe para o desfecho de sobrevida global nas meta-análises, sendo que o ECR apresenta resultados conflitantes com sua extensão. No desfecho de sobrevida livre de progressão, o cabozantinibe demonstrou melhor desempenho em comparação ao sunitinibe, porém apenas na análise de subgrupo dos pacientes com risco intermediário. Não foi possível avaliar o pazopanibe para a população de risco intermediário/alto. A maioria dos estudos relatou não haver diferença entre as intervenções para o desfecho de incidência de eventos adversos graves, embora para esse desfecho a análise de subgrupo não tenha sido realizada. Quanto à qualidade metodológica, todas as RS apresentaram qualidade criticamente baixa, e o ECR apresentou risco de viés incerto. AVALIAÇÃO ECONÔMICA: Foi realizada uma análise econômica do tipo árvore de decisão, com o objetivo de avaliar a relação de custo-efetividade do cabozantinibe em comparação ao sunitinibe em pacientes com CCR metastático ou avançado de risco alto/intermediário. A perspectiva adotada foi a do SUS, em um horizonte temporal de 36 meses. Foram considerados como estados de transição: pré-progressão, progressão e morte. Os custos assumidos foram os de aquisição dos medicamentos e de monitoramento dos pacientes em tratamento. Os desfechos de efetividade considerados na avaliação foram: a sobrevida livre de progressão e sobrevida global. A análise realizada estimou uma razão de custo-efetividade incremental para o cabozantinibe de R$ 21.618,10 por Mês de Vida Ganho (MVG), considerando os preços assumidos pelo demandante; e de R$ 15.365,32 por MVG quando utilizado o preço de aquisição do sunitinibe em compras públicas. ANÁLISE DE IMPACTO ORÇAMENTÁRIO: O Impacto Orçamentário (IO) apresentado pelo demandante foi recalculado por apresentar algumas limitações. O novo modelo proposto manteve a população pretendida pelo demandante, a saber, pacientes com CCR metastático de risco intermediário/alto, na perspectiva do Sistema Único de Saúde e em um horizonte temporal de cinco anos. Os custos assumidos foram restritos aos de aquisição dos medicamentos. Para o cálculo da população elegível foram propostos dois cenários, com as populações mínima e máxima estimadas de acordo com os dados encontrados na literatura, sobre a projeção da população do IBGE. Ao longo do horizonte temporal, além de aplicarmos a incidência de novos casos ano a ano, também consideramos a saída de pacientes em cada ano, aplicando os dados de sobrevida global relatados nos ECR dos medicamentos. Dessa forma, o IO estimado utilizando os preços apresentados pelo demandante variou de R$ 34,7 milhões a 102,1 milhões acumulados em cinco anos, a depender das prevalências utilizadas. Na análise de sensibilidade, aplicando os custos reais dos medicamentos em compras públicas, o custo incremental acumulado em cinco anos ficou entre R$ 10,7 milhões e R$ 99,49 milhões em cinco anos, dependendo das prevalências aplicadas. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: Foram detectados três medicamentos potenciais para a indicação terapêutica em questão: o belzutifan, o savolitinibe e o tivozanibe. CONSIDERAÇÕES FINAIS: As evidências disponíveis na literatura demonstram que o cabozantinibe apresenta benefício para pacientes com CCR avançado que apresentam risco intermediário no desfecho de sobrevida livre de progressão. Para os demais desfechos e subgrupos avaliados não foram identificadas diferenças entre as intervenções. A análise econômica demonstrou uma RCEI de R$ 15.365,32 a R$ 21.618,10 por MVG, a depender do preço do sunitinibe. A análise de IO estimou um custo incremental de até R$ 147,3 milhões acumulados em cinco anos, decorrente da eventual incorporação do cabozantinibe. RECOMENDAÇÃO PRELIMINAR DA CONITEC: O Plenário da Conitec, em sua 89ª Reunião Ordinária, no dia 05 de agosto de 2020, deliberou que a matéria fosse disponibilizada em Consulta Pública com recomendação preliminar desfavorável à incorporação no SUS de cabozantinibe para tratamento de primeira linha de pacientes adultos com Câncer de Células Renais avançado e risco intermediário a alto. Os membros da Conitec consideraram a ausência de evidências acerca de benefícios adicionais quanto à sobrevida nos pacientes que utilizaram cabozantinibe, quando comparado às demais terapias disponíveis no SUS. Além disso, verificou-se que as evidências disponíveis apresentam importantes incertezas, especialmente por conta dos dados de cabozantinibe serem provenientes de um único ensaio clínico de fase II. CONSULTA PÚBLICA: A Consulta Pública nº 44 foi realizada entre os dias 24/08/2020 e 14/09/2020. Foram recebidas 29 contribuições, sendo 19 pelo formulário para contribuições técnico-científicas e 10 pelo formulário para contribuições sobre experiência ou opinião de pacientes, familiares, amigos ou cuidadores de pacientes, profissionais de saúde ou pessoas interessadas no tema. Não foram apresentadas novas evidências científicas para o cabozantinibe. O demandante apresentou uma proposta comercial de redução de preço do medicamento para R$366,67 por comprimido. Após apreciação das contribuições encaminhadas por meio da Consulta Pública e da apresentação da proposta de redução de preço pelo demandante, e considerando a ausência de evidências acerca de benefícios adicionais quanto à sobrevida nos pacientes que utilizaram cabozantinibe quando comparado às demais terapias disponíveis no SUS, o Plenário da Conitec entendeu que não houve argumentação suficiente para alterar a recomendação inicial. RECOMENDAÇÃO FINAL DA CONITEC: A Conitec, em sua 91ª reunião ordinária, no dia 08 de outubro de 2020, recomendou a não incorporação do cabozantinibe para tratamento de pacientes com carcinoma de células renais (CCR) avançado. A recomendação considerou que a ausência de evidências acerca de benefícios adicionais quanto à sobrevida dos pacientes que utilizaram cabozantinibe, quando comparado às demais terapias disponíveis no SUS. Além disso, verificou-se que as evidências disponíveis apresentam importantes incertezas, especialmente em razão dos dados de cabozantinibe serem provenientes de um único ensaio clínico de fase II. Por fim, foi assinado o Registro de Deliberação nº 564/2020. DECISÃO: Não incorporar o cabozantinibe para tratamento de primeira linha de câncer renal avançado, no âmbito do Sistema Único de Saúde - SUS, conforme Portaria nº 52, publicada no Diário Oficial da União nº 217, seção 1, página 145, em 13 de novembro de 2020.


Asunto(s)
Humanos , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Neoplasias Renales/tratamiento farmacológico , Evaluación de la Tecnología Biomédica , Sistema Único de Salud , Brasil , Análisis Costo-Beneficio/economía
2.
Dermatol Online J ; 26(6)2020 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-32815690

RESUMEN

Chronic myelogenous leukemia (CML) is characterized by a reciprocal translocation between the long arms of chromosomes 9 and 22 leading to the formation of a constitutively active tyrosine kinase. Tyrosine kinase inhibitors (TKIs) are the treatment of choice for patients diagnosed with CML and have many associated side effects including the rarely-reported eruption of squamous cell carcinomas (SCCs). Herein, we report a patient with CML who presented with sudden onset of multiple scaly lesions on his legs and trunk after beginning treatment with nilotinib, a novel TKI. Six biopsies were performed at his initial presentation and four of these lesions were confirmed to be keratoacanthoma-type SCCs. One month later, the patient reported the development of multiple new similar lesions on his legs, arms, and face. Four more biopsies were performed revealing keratoacanthoma-type and well-differentiated SCCs. Certain tyrosine kinase inhibitors such as sorafenib and quizartinib have been reported to cause eruptive keratoacanthoma (KA)-type SCCs as seen in our patient. However, there is only one other report in the literature of nilotinib promoting the development of SCCs or KAs. Physicians should be aware of this potential adverse effect and patients taking nilotinib should be closely monitored by a dermatologist.


Asunto(s)
Carcinoma de Células Escamosas/inducido químicamente , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirimidinas/efectos adversos , Neoplasias Cutáneas/inducido químicamente , Anciano , Carcinoma de Células Escamosas/patología , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Masculino , Pirimidinas/uso terapéutico , Neoplasias Cutáneas/patología
3.
Nat Commun ; 11(1): 3935, 2020 08 07.
Artículo en Inglés | MEDLINE | ID: mdl-32769979

RESUMEN

GABAA/glycine-mediated neuronal inhibition critically depends on intracellular chloride (Cl-) concentration which is mainly regulated by the K+-Cl- co-transporter 2 (KCC2) in the adult central nervous system (CNS). KCC2 heterogeneity thus affects information processing across CNS areas. Here, we uncover a gradient in Cl- extrusion capacity across the superficial dorsal horn (SDH) of the spinal cord (laminae I-II: LI-LII), which remains concealed under low Cl- load. Under high Cl- load or heightened synaptic drive, lower Cl- extrusion is unveiled in LI, as expected from the gradient in KCC2 expression found across the SDH. Blocking TrkB receptors increases KCC2 in LI, pointing to differential constitutive TrkB activation across laminae. Higher Cl- lability in LI results in rapidly collapsing inhibition, and a form of activity-dependent synaptic plasticity expressed as a continuous facilitation of excitatory responses. The higher metaplasticity in LI as compared to LII differentially affects sensitization to thermal and mechanical input. Thus, inconspicuous heterogeneity of Cl- extrusion across laminae critically shapes plasticity for selective nociceptive modalities.


Asunto(s)
Sensibilización del Sistema Nervioso Central/fisiología , Cloruros/metabolismo , Plasticidad Neuronal/fisiología , Nocicepción/fisiología , Células del Asta Posterior/fisiología , Animales , Células Cultivadas , Masculino , Glicoproteínas de Membrana/antagonistas & inhibidores , Glicoproteínas de Membrana/metabolismo , Ratones , Modelos Neurológicos , Optogenética , Cultivo Primario de Células , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/metabolismo , Ratas , Receptor trkB/antagonistas & inhibidores , Receptor trkB/metabolismo , Simportadores/metabolismo
5.
Urol Clin North Am ; 47(3): 359-370, 2020 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-32600537

RESUMEN

The role for cytoreductive nephrectomy (CN) in the treatment of metastatic renal cell carcinoma (mRCC) has evolved with advancements in systemic therapy. During the cytokine-based immunotherapy era, CN provided a clear survival benefit and was considered standard of care in management of mRCC. The development of targeted systemic therapy directed at the vascular endothelial growth factor pathway altered the treatment paradigm and accentuated the importance of risk stratification in treatment selection. This article reviews the literature evaluating the benefit of CN during the evolution of systemic therapy and provides clinical recommendations for current utilization of CN in patients with mRCC.


Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/cirugía , Neoplasias Renales/cirugía , Antineoplásicos Inmunológicos/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Procedimientos Quirúrgicos de Citorreducción , Inhibidores Enzimáticos/uso terapéutico , Humanos , Inmunoterapia , Neoplasias Renales/tratamiento farmacológico , Terapia Molecular Dirigida , Recurrencia Local de Neoplasia/prevención & control , Nefrectomía , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Riesgo , Serina-Treonina Quinasas TOR/antagonistas & inhibidores
6.
Medicine (Baltimore) ; 99(29): e21275, 2020 Jul 17.
Artículo en Inglés | MEDLINE | ID: mdl-32702917

RESUMEN

This observational study evaluated the treatment outcomes of clinical factors on the patients with lung adenocarcinoma with epidermal growth factor receptor mutations who received tyrosine kinase inhibitors as first-line treatment.Patients with stage IIIb or IV lung adenocarcinoma with mutated epidermal growth factor receptor were enrolled retrospectively between March 2010 and December 2017. The hematologic markers on progression-free survival (PFS) and overall survival (OS) were analyzed.Totally 190 patients were enrolled. In univariate analysis by hematologic markers, lower lymphocyte percentage and higher platelet count were associated with significantly poor PFS and OS. Multivariate analysis showed lower lymphocyte percentage was independent poor prognostic factors for PFS and OS. Higher platelet count was an independent poor prognostic factor for OS only.Patients with lung adenocarcinoma receiving tyrosine kinase inhibitors with lower lymphocyte percentage and higher platelet count had poorer prognoses compared with other patients.


Asunto(s)
Adenocarcinoma del Pulmón/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Receptores ErbB/genética , Neoplasias Pulmonares/tratamiento farmacológico , Recuento de Linfocitos , Recuento de Plaquetas , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Supervivencia sin Progresión , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Resultado del Tratamiento
7.
Endocrine ; 70(1): 6-10, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32681385

RESUMEN

Primary neuroendocrine tumors of the thymus are extremely rare. In patients with advanced disease, tumor growth control, and sometimes also syndrome control are the main goals of systemic therapy. Unfortunately, no standard therapies are available in clinical practice; therefore, clinical studies are strongly recommended. Axitinib (AXI) is a tyrosine kinase inhibitor, currently under investigation in an international phase II/III trial including thymic neuroendocrine tumors. Over the past 5 months, the entire world has been facing a devastating medical emergency brought about by a pandemic due to a novel coronavirus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which emerged in Wuhan, China, in late 2019. Since then, health professionals have been expending all their efforts on trying to provide the best available treatments for patients involved. Patients with cancer, especially those with thoracic involvement, are at higher risk of coronavirus disease 19 (COVID-19) and its complications because of their immunosuppressive status caused by the cancer and the anticancer therapies. As it remains unclear how to optimally manage such patients, we wished to report our experience with a patient with a metastatic neuroendocrine tumor of the thymus infected with SARS-CoV-2 in the hope that it may provide some insights and reflections on the management of cancer patients during this challenging time in our history.


Asunto(s)
Betacoronavirus , Tumor Carcinoide/tratamiento farmacológico , Infecciones por Coronavirus/epidemiología , Tumores Neuroendocrinos/tratamiento farmacológico , Neumonía Viral/epidemiología , Neoplasias del Timo/tratamiento farmacológico , Anciano , Axitinib/efectos adversos , Axitinib/uso terapéutico , Azitromicina/uso terapéutico , Tumor Carcinoide/epidemiología , Comorbilidad , Infecciones por Coronavirus/diagnóstico , Humanos , Hidroxicloroquina/uso terapéutico , Italia/epidemiología , Masculino , Tumores Neuroendocrinos/epidemiología , Pandemias , Neumonía Viral/diagnóstico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Ensayos Clínicos Controlados Aleatorios como Asunto , Neoplasias del Timo/epidemiología , Tomografía Computarizada por Rayos X , Resultado del Tratamiento
9.
Leukemia ; 34(8): 2125-2137, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32572189

RESUMEN

Bosutinib is approved for newly diagnosed Philadelphia chromosome-positive (Ph+) chronic phase (CP) chronic myeloid leukemia (CML) and for Ph+ CP, accelerated (AP), or blast (BP) phase CML after prior treatment with tyrosine kinase inhibitors (TKIs). In the ongoing phase 4 BYOND study (NCT02228382), 163 CML patients resistant/intolerant to prior TKIs (n = 156 Ph+ CP CML, n = 4 Ph+ AP CML, n = 3 Ph-negative/BCR-ABL1+ CML) received bosutinib 500 mg once daily (starting dose). As of ≥1 year after last enrolled patient (median treatment duration 23.7 months), 56.4% of Ph+ CP CML patients remained on bosutinib. Primary endpoint of cumulative confirmed major cytogenetic response (MCyR) rate by 1 year was 75.8% in Ph+ CP CML patients after one or two prior TKIs and 62.2% after three prior TKIs. Cumulative complete cytogenetic response (CCyR) and major molecular response (MMR) rates by 1 year were 80.6% and 70.5%, respectively, in Ph+ CP CML patients overall. No patient progressed to AP/BP on treatment. Across all patients, the most common treatment-emergent adverse events were diarrhea (87.7%), nausea (39.9%), and vomiting (32.5%). The majority of patients had confirmed MCyR by 1 year and MMR by 1 year, further supporting bosutinib use for Ph+ CP CML patients resistant/intolerant to prior TKIs.


Asunto(s)
Compuestos de Anilina/uso terapéutico , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Nitrilos/uso terapéutico , Quinolinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Compuestos de Anilina/efectos adversos , Femenino , Humanos , Leucemia Mieloide de Fase Crónica/genética , Leucemia Mieloide de Fase Crónica/psicología , Masculino , Persona de Mediana Edad , Nitrilos/efectos adversos , Cromosoma Filadelfia , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Calidad de Vida , Quinolinas/efectos adversos
10.
Molecules ; 25(11)2020 Jun 11.
Artículo en Inglés | MEDLINE | ID: mdl-32545268

RESUMEN

Flavonoids are widely used as phytomedicines. Here, we report on flavonoid phytomedicines with potential for development into prophylactics or therapeutics against coronavirus disease 2019 (COVID-19). These flavonoid-based phytomedicines include: caflanone, Equivir, hesperetin, myricetin, and Linebacker. Our in silico studies show that these flavonoid-based molecules can bind with high affinity to the spike protein, helicase, and protease sites on the ACE2 receptor used by the severe acute respiratory syndrome coronavirus 2 to infect cells and cause COVID-19. Meanwhile, in vitro studies show potential of caflanone to inhibit virus entry factors including, ABL-2, cathepsin L, cytokines (IL-1ß, IL-6, IL-8, Mip-1α, TNF-α), and PI4Kiiiß as well as AXL-2, which facilitates mother-to-fetus transmission of coronavirus. The potential for the use of smart drug delivery technologies like nanoparticle drones loaded with these phytomedicines to overcome bioavailability limitations and improve therapeutic efficacy are discussed.


Asunto(s)
Antivirales/farmacología , Betacoronavirus/efectos de los fármacos , Infecciones por Coronavirus/tratamiento farmacológico , Coronavirus Humano OC43/efectos de los fármacos , Flavonoides/farmacología , Peptidil-Dipeptidasa A/química , Neumonía Viral/tratamiento farmacológico , Glicoproteína de la Espiga del Coronavirus/química , Animales , Antivirales/química , Betacoronavirus/química , Betacoronavirus/crecimiento & desarrollo , Sitios de Unión , Cloroquina/química , Cloroquina/farmacología , Infecciones por Coronavirus/genética , Coronavirus Humano OC43/química , Coronavirus Humano OC43/crecimiento & desarrollo , Portadores de Fármacos/administración & dosificación , Portadores de Fármacos/química , Flavonoides/química , Humanos , Interleucinas/antagonistas & inhibidores , Interleucinas/química , Interleucinas/genética , Interleucinas/metabolismo , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/virología , Pulmón/efectos de los fármacos , Pulmón/patología , Pulmón/virología , Ratones , Simulación del Acoplamiento Molecular , Nanopartículas/administración & dosificación , Nanopartículas/química , Pandemias , Peptidil-Dipeptidasa A/genética , Peptidil-Dipeptidasa A/metabolismo , Fitoterapia/métodos , Neumonía Viral/genética , Cultivo Primario de Células , Unión Proteica , Dominios y Motivos de Interacción de Proteínas , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/química , Proteínas Tirosina Quinasas/genética , Proteínas Tirosina Quinasas/metabolismo , Glicoproteína de la Espiga del Coronavirus/antagonistas & inhibidores , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/metabolismo , Termodinámica , Internalización del Virus/efectos de los fármacos
11.
Ann Hematol ; 99(8): 1701-1707, 2020 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-32583086

RESUMEN

COVID-19 pandemia is a major health emergency causing hundreds of deaths worldwide. The high reported morbidity has been related to hypoxia and inflammation leading to endothelial dysfunction and aberrant coagulation in small and large vessels. This review addresses some of the pathways leading to endothelial derangement, such as complement, HIF-1α, and ABL tyrosine kinases. This review also highlights potential targets for prevention and therapy of COVID-19-related organ damage and discusses the role of marketed drugs, such as eculizumab and imatinib, as suitable candidates for clinical trials.


Asunto(s)
Betacoronavirus , Inactivadores del Complemento/administración & dosificación , Infecciones por Coronavirus/metabolismo , Sistemas de Liberación de Medicamentos/métodos , Endotelio Vascular/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Neumonía Viral/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Anticuerpos Monoclonales Humanizados/administración & dosificación , Ensayos Clínicos Fase II como Asunto/métodos , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/patología , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/patología , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/antagonistas & inhibidores , Mesilato de Imatinib/administración & dosificación , Pandemias/prevención & control , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/patología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología
12.
Int J Hematol ; 112(4): 584-591, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-32557125

RESUMEN

A 66-year-old man with hypertension was diagnosed with chronic myelogenous leukemia in 1996. Treatment was started with hydroxycarbamide and imatinib 400 mg in 1996 + 6, which was increased to 600 mg. Although he achieved a complete cytogenic response in 1996 + 9, he could not continue imatinib because of edema; the regimen was changed to nilotinib 800 mg in 1996 + 13. After he achieved a molecular response better than 4.5 in 1996 + 19, he was referred to our hospital. His urinalysis had shown urine protein since 1996 + 13, and his creatinine level increased in 1996 + 16. Renal biopsy, performed in 1996 + 20, revealed abdominal distention and massive ascites. After the nilotinib dosage was reduced to 400 mg, liver biopsy, also performed in 1996 + 20, revealed hypertrophy of renal small blood vessels and endothelial cells of the hepatic artery and loss of endothelial cells of the renal glomeruli, portal vein, and hepatic sinusoids. Both renal and liver biopsies revealed marked pathological vascular damage. The patient took oral imatinib for approximately 3.5 years and nilotinib for 11 years. Pathological findings indicated a tendency for thrombosis, which could induce vascular occlusive disease. Accumulation of cases, such as the present case, is needed to further analyze the pathophysiological processes.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/patología , Mesilato de Imatinib/efectos adversos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Inhibidores de Proteínas Quinasas/efectos adversos , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirimidinas/efectos adversos , Anciano , Sustitución de Medicamentos , Humanos , Hidroxiurea/administración & dosificación , Mesilato de Imatinib/administración & dosificación , Riñón/irrigación sanguínea , Riñón/patología , Hígado/irrigación sanguínea , Hígado/patología , Masculino , Pirimidinas/administración & dosificación , Factores de Tiempo , Resultado del Tratamiento
13.
Cochrane Database Syst Rev ; 5: CD013238, 2020 May 12.
Artículo en Inglés | MEDLINE | ID: mdl-32395825

RESUMEN

BACKGROUND: Glioblastoma is an uncommon but highly aggressive type of brain tumour. Significant gains have been achieved in the molecular understanding and the pathogenesis of glioblastomas, however clinical improvements are difficult to obtain for many reasons. The current standard of care involves maximal safe surgical resection followed by chemoradiation and then adjuvant chemotherapy European Organisation for Research and Treatment of Cancer and the NCIC Clinical Trials Group (EORTC-NCIC) protocol with a median survival of 14.6 months. Successive phase III international randomised controlled studies have failed to significantly demonstrate survival advantage with newer drugs. Epidermal growth factor receptor (EGFR) is observed to be aberrant in 30% to 60% of glioblastomas. The receptor aberrancy is driven by abnormal gene amplification, receptor mutation, or both, in particular the extracellular vIII domain. EGFR abnormalities are common in solid tumours, and the advent of anti-EGFR therapies in non-small cell lung cancer and colorectal adenocarcinomas have greatly improved clinical outcomes. Anti-EGFR therapies have been investigated amongst glioblastomas, however questions remain about its ongoing role in glioblastoma management. This review aimed to report on the available evidence to date and perform a systematic analysis on the risks and benefits of use of anti-EGFR therapies in glioblastomas. OBJECTIVES: To evaluate the efficacy and harms of anti-EGFR therapies for glioblastoma in adults. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, EBM Reviews databases, with supplementary handsearches to identify all available and relevant studies to 20 April 2020. SELECTION CRITERIA: All randomised controlled trials (RCTs) using anti-EGFR therapies in adults with glioblastoma were eligible for inclusion. Anti-EGFR therapies included tyrosine kinase inhibitors, monoclonal antibodies, or vaccines. The comparison included investigational product added to standard of care versus standard of care or placebo, or investigational product against standard of care or placebo. DATA COLLECTION AND ANALYSIS: The authorship team screened the search results and recorded the extracted data for analysis. We used standard Cochrane methodology to performed quantitative meta-analysis if two or more studies had appropriate and available data. Otherwise, we conducted a qualitative and descriptive analysis. We used the GRADE system to rate the certainty of the evidence. The analysis was performed along the two clinical settings: first-line (after surgery) and recurrent disease (after failure of first line treatment). Where information was available, we documented overall survival, progression-free survival, adverse events, and quality of life data from eligible studies. MAIN RESULTS: The combined searches initially identified 912 records (after removal of duplicates), and further screening resulted in 19 records for full consideration. We identified nine eligible studies for inclusion in the review. There were three first-line studies and six recurrent studies. Five studies used tyrosine kinase inhibitors (TKIs); two studies used monoclonal antibodies; and two studies used targeted vaccines. More recent studies presented greater detail in the conduct of their studies and thus had a lower risk of bias. We observed no evidence benefit in overall survival with the use of anti-EGFR therapy in the first-line or recurrent setting (hazard ratio (HR) 0.89, 95% confidence interval (CI) 0.76 to 1.04; 3 RCTs, 1000 participants, moderate-certainty evidence; and HR 0.79, 95% CI 0.51 to 1.21, 4 RCTs, 489 participants, low-certainty evidence, respectively). All the interventions were generally well tolerated with low-certainty evidence for lymphopenia (odds ratio (OR) 0.97, 95% CI 0.19 to 4.81; 4 RCTs, 1146 participants), neutropenia (OR 1.29, 95% CI 0.82 to 2.03; 4 RCTs, 1146 participants), and thrombocytopenia (OR 3.69, 95% CI 0.51 to 26.51; 4 RCTs, 1146 participants). A notable toxicity relates to ABT-414, where significant ocular issues were detected. The addition of anti-EGFR therapy showed no evidence of an increase in progression-free survival (PFS) in the first-line setting (HR 0.94, 95% CI 0.81 to 1.10; 2 RCTs, 894 participants, low-certainty evidence). In the recurrent setting, there was an increase in PFS with the use of anti-EGFR therapy (HR 0.75, 95% CI 0.58 to 0.96, 3 RCTs, 275 participants, low-certainty evidence). The available quality of life assessment data showed that anti-EGFR therapies were neither detrimental or beneficial when compared to standard care (not estimable). AUTHORS' CONCLUSIONS: In summary, there is no evidence of a demonstrable overall survival benefit with the addition of anti-EGFR therapy in first-line and recurrent glioblastomas. Newer drugs that are specially designed for glioblastoma targets may raise the possibility of success in this population, but data are lacking at present. Future studies should be more selective in pursuing people displaying specific EGFR targets.


Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Receptores ErbB/antagonistas & inhibidores , Glioblastoma/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Neoplasias Encefálicas/mortalidad , Vacunas contra el Cáncer/uso terapéutico , Progresión de la Enfermedad , Glioblastoma/mortalidad , Humanos , Linfopenia/etiología , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neutropenia/etiología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Ensayos Clínicos Controlados Aleatorios como Asunto , Trombocitopenia/etiología
14.
Leukemia ; 34(8): 2113-2124, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32472084

RESUMEN

This work investigated patient-specific genomic BCR-ABL1 fusions as markers of measurable residual disease (MRD) in chronic myeloid leukaemia, with a focus on relevance to treatment-free remission (TFR) after achievement of deep molecular response (DMR) on tyrosine kinase inhibitor (TKI) therapy. DNA and mRNA BCR-ABL1 measurements by qPCR were compared in 2189 samples (129 patients) and by digital PCR in 1279 sample (62 patients). A high correlation was found at levels of disease above MR4, but there was a poor correlation for samples during DMR. A combination of DNA and RNA MRD measurements resulted in a better prediction of molecular relapse-free survival (MRFS) after TKI stop (n = 17) or scheduled interruption (n = 25). At 18 months after treatment cessation, patients with stopped or interrupted TKI therapy who were DNA negative/RNA negative during DMR maintenance (green group) had an MRFS of 80% and 100%, respectively, compared with those who were DNA positive/RNA negative (MRFS = 57% and 67%, respectively; yellow group) or DNA positive/RNA positive (MRFS = 20% for both cohorts; red group). Thus, we propose a "traffic light" stratification as a TFR predictor based on DNA and mRNA BCR-ABL1 measurements during DMR maintenance before TKI cessation.


Asunto(s)
Proteínas de Fusión bcr-abl/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Reacción en Cadena de la Polimerasa/métodos , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Adulto , Anciano , Femenino , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/mortalidad , Masculino , Persona de Mediana Edad , Neoplasia Residual , ARN Mensajero/análisis , Inducción de Remisión , Privación de Tratamiento
16.
PLoS One ; 15(5): e0233720, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32459817

RESUMEN

Since patients with medullary thyroid cancer (MTC) often have metastatic disease at the time of diagnosis, the development of efficient systemic treatment options for MTC is important. Vandetanib and cabozantinib are two tyrosine kinase inhibitors (TKIs) that were recently approved by FDA and EMA for systemic treatment of metastatic MTC. Additionally, since MTC is of a neuroendocrine tumour type, treatment with radiolabelled somatostatin analogues (e.g. 177Lu-octreotate) is a valid option for patients with MTC. The aim of this study was to investigate the potentially increased therapeutic effect of combining radiation therapy with these TKIs for treatment of MTC in a mouse model. Nude mice carrying patient-derived MTC tumours (GOT2) were treated with external beam radiotherapy (EBRT) and/or one of the two TKIs vandetanib or cabozantinib. The tumour volume was determined and compared with that of mock-treated controls. The treatment doses were chosen to give a moderate effect as monotherapy to be able to detect any increased therapeutic effect from the combination therapy. At the end of follow-up, tumours were processed for immunohistochemical (IHC) analyses. The animals in the combination therapy groups showed the largest reduction in tumour volume and the longest time to tumour progression. Two weeks after start of treatment, the tumour volume for these mice was reduced by about 70-75% compared with controls. Furthermore, also EBRT and TKI monotherapy resulted in a clear anti-tumour effect with a reduced tumour growth compared with controls. The results show that an increased therapeutic effect could be achieved when irradiation is combined with TKIs for treatment of MTC. Future studies should evaluate the potential of using 177Lu-octreotate therapy in combination with TKIs in patients.


Asunto(s)
Anilidas/farmacología , Carcinoma Neuroendocrino/terapia , Quimioradioterapia , Proteínas de Neoplasias/antagonistas & inhibidores , Piperidinas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Piridinas/farmacología , Quinazolinas/farmacología , Neoplasias de la Tiroides/terapia , Animales , Carcinoma Neuroendocrino/enzimología , Carcinoma Neuroendocrino/patología , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Proteínas de Neoplasias/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Neoplasias de la Tiroides/enzimología , Neoplasias de la Tiroides/patología , Ensayos Antitumor por Modelo de Xenoinjerto
17.
Leukemia ; 34(8): 2102-2112, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32457354

RESUMEN

In CML, treatment-free remission (TFR) refers to having a stable deep molecular response without the need for ongoing tyrosine kinase inhibitor treatment. Whilst recommendations exist about the technical management of stopping and re-starting therapy, much is still unknown about the experiences of those considering and undertaking TFR. This study sought to obtain the patient perspective, identify areas of unmet needs and create recommendations for improvements. Fifty-six percent of patients reported fear or anxiety during treatment discontinuation, whereas only 7% of patients were asked if they needed psychological support during this period. Where patients re-initiated treatment; 59% felt scared or anxious, and 56% felt depressed. Twenty-six percent of re-initiated patients received psychological and/or emotional support at this time. Sixty percent of patients experienced withdrawal symptoms whilst discontinuing treatment, however, 40% of patients who experienced withdrawal symptoms reported that they were not fully supported by their doctor in managing all the symptoms. Healthcare professionals should further consider how they monitor the psychological well-being of patients who are discontinuing or re-initiating treatment, and review what support is offered in response to identified concerns. Surveillance of withdrawal symptoms should be a priority during treatment discontinuation, along with how healthcare professionals assist in the management of these.


Asunto(s)
Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Emociones , Femenino , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/psicología , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/efectos adversos , Inducción de Remisión , Síndrome de Abstinencia a Sustancias/epidemiología , Privación de Tratamiento , Adulto Joven
18.
J Med Chem ; 63(15): 8025-8042, 2020 08 13.
Artículo en Inglés | MEDLINE | ID: mdl-32338514

RESUMEN

Inhibition of monopolar spindle 1 (MPS1) kinase represents a novel approach to cancer treatment: instead of arresting the cell cycle in tumor cells, cells are driven into mitosis irrespective of DNA damage and unattached/misattached chromosomes, resulting in aneuploidy and cell death. Starting points for our optimization efforts with the goal to identify MPS1 inhibitors were two HTS hits from the distinct chemical series "triazolopyridines" and "imidazopyrazines". The major initial issue of the triazolopyridine series was the moderate potency of the HTS hits. The imidazopyrazine series displayed more than 10-fold higher potencies; however, in the early project phase, this series suffered from poor metabolic stability. Here, we outline the evolution of the two hit series to clinical candidates BAY 1161909 and BAY 1217389 and reveal how both clinical candidates bind to the ATP site of MPS1 kinase, while addressing different pockets utilizing different binding interactions, along with their synthesis and preclinical characterization in selected in vivo efficacy models.


Asunto(s)
Antineoplásicos/metabolismo , Proteínas de Ciclo Celular/metabolismo , Sistemas de Liberación de Medicamentos/métodos , Descubrimiento de Drogas/métodos , Puntos de Control de la Fase M del Ciclo Celular/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Huso Acromático/efectos de los fármacos , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Proteínas de Ciclo Celular/antagonistas & inhibidores , Línea Celular Tumoral , Perros , Femenino , Células HT29 , Células HeLa , Humanos , Puntos de Control de la Fase M del Ciclo Celular/fisiología , Masculino , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Estructura Terciaria de Proteína , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Ratas , Ratas Wistar , Huso Acromático/metabolismo , Resultado del Tratamiento
19.
Thorac Surg Clin ; 30(2): 147-156, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-32327173

RESUMEN

ROS1-rearranged non-small cell lung cancer (NSCLC) makes up approximately 1% to 2% of all NSCLC, is oncogenically driven by a constitutively activated ROS1 kinase paired with certain fusion partners, and can be detected by several different assays. These patients are initially treated with tyrosine kinase inhibitors (TKIs), which target the activated ROS1 kinase. Eventually these tumors develop resistance to initial TKI treatment through secondary kinase mutations that block TKI binding or activation of bypass signaling pathways, which subvert ROS1 as the driver of the malignancy. Investigation of several TKIs that have shown efficacy in secondary resistant patients is underway.


Asunto(s)
Neoplasias Pulmonares , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas , Proteínas Proto-Oncogénicas , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Resistencia a Antineoplásicos/fisiología , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Mutación , Farmacogenética , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/genética , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/genética
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