RESUMEN
The transcription factor MYB plays a pivotal role in haematopoietic homoeostasis and its aberrant expression is involved in the genesis and maintenance of acute myeloid leukaemia (AML). We have previously demonstrated that not all AML subtypes display the same dependency on MYB expression and that such variability is dictated by the nature of the driver mutation. However, whether this difference in MYB dependency is a general trend in AML remains to be further elucidated. Here, we investigate the role of MYB in human leukaemia by performing siRNA-mediated knock-down in cell line models of AML with different driver lesions. We show that the characteristic reduction in proliferation and the concomitant induction of myeloid differentiation that is observed in MLL-rearranged and t(8;21) leukaemias upon MYB suppression is not seen in AML cells with a complex karyotype. Transcriptome analyses revealed that MYB ablation produces consensual increase of MAFB expression in MYB-dependent cells and, interestingly, the ectopic expression of MAFB could phenocopy the effect of MYB suppression. Accordingly, in silico stratification analyses of molecular data from AML patients revealed a reciprocal relationship between MYB and MAFB expression, highlighting a novel biological interconnection between these two factors in AML and supporting new rationales of MAFB targeting in MLL-rearranged leukaemias.
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Leucemia Mieloide Aguda , Humanos , Línea Celular , Leucemia Mieloide Aguda/metabolismo , Factor de Transcripción MafB/genética , Proteína de la Leucemia Mieloide-Linfoide/genética , Fenotipo , ARN Interferente PequeñoRESUMEN
INTRODUCTION: The organization of the healthcare system has significantly changed after the recent COVID-19 outbreak, with a negative impact on the management of oncological patients. The present survey reports data collected by the Italian Association for Neuroendocrine Tumors on the management of patients with neuroendocrine neoplasia (NEN) during the pandemic dissemination. METHODS: A survey with 57 questions was sent to NEN-dedicated Italian centers regarding the management of patients in the period March 9, 2020, to May 9, 2020 RESULTS: The main modification in the centers' activity consisted of decreases in newly diagnosed NEN patients (- 76.8%), decreases in performed surgical procedures (- 58%), delays to starting peptide receptor radionuclide therapy (45.5%), postponed/canceled follow-up examinations (26%), and canceled multidisciplinary teams' activity (20.8%). A low proportion of centers (< 10%) reported having to withdraw systemic anti-tumor medical treatment due to concerns about the pandemic situation, whereas PRRT was withdrawn from no patients. CONCLUSION: Although the COVID-19 outbreak induced the centers to reduce some important activities in the management of NEN patients, the Italian network was able to provide continuity in care without withdrawing anti-tumor treatment for the majority of patients.
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COVID-19 , Tumores Neuroendocrinos/terapia , Pandemias , Adulto , Antineoplásicos/uso terapéutico , Continuidad de la Atención al Paciente , Femenino , Humanos , Italia/epidemiología , Masculino , Oncología Médica/estadística & datos numéricos , Tumores Neuroendocrinos/cirugía , Grupo de Atención al Paciente/estadística & datos numéricos , Encuestas y CuestionariosRESUMEN
Immune checkpoint inhibitors have shown promising results in different cancers, and correlation between immune infiltration, expression of programmed death-ligand 1 (PD-L1) by tumor cells and response to immunotherapy has been reported. There is limited knowledge regarding the immune microenvironment of small bowel (SB) neuroendocrine tumors (NETs). This work was aimed at characterizing the immune landscape of SB NETs. Expression of PD-L1 and programmed death-1 (PD-1) was evaluated by immunohistochemistry in 102 surgically resected, primary NETs of the duodenum, jejunum and ileum. Extent and characteristics of the tumor-associated immune infiltrate were also assessed and investigated in their prognostic potential. We detected the expression of PD-L1 in ≥1 and ≥50% of tumor cells in 40/102 (39%; 95% CI, 30-49%) and 14/102 (14%; 95% CI, 8-22%) cases respectively. Intratumor host immune response was apparently absent in 35/102 cases (34%; 95% CI, 25-44%), mild to moderate in 46/102 samples (45%, 95% CI, 35-55%), intense in 21/102 tumors (21%, 95% CI, 13-30%). Expression of PD-L1 and extent of immune infiltration were significantly higher in duodenal NETs as compared with jejunal/ileal NETs. A marked peritumoral host response was organized as ectopic lymph node-like structures in 18/102 cases (18%; 95% CI, 11-26%). Neither PD-L1 expression nor the degree of immune infiltration showed any prognostic significance. Overall, the immune landscape of SB NETs is heterogeneous, with adaptive immune resistance mechanisms prevailing in duodenal NETs. Clinical trials of immune checkpoint inhibitors should take into account the immune heterogeneity of SB NETs.
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Neoplasias Intestinales/inmunología , Tumores Neuroendocrinos/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Antígeno B7-H1/inmunología , Femenino , Humanos , Tolerancia Inmunológica , Neoplasias Intestinales/patología , Linfocitos Infiltrantes de Tumor/inmunología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Tumores Neuroendocrinos/patología , Receptor de Muerte Celular Programada 1/inmunologíaRESUMEN
The capecitabine and temozolomide (CAPTEM) regimen is active in the treatment of metastatic pancreatic neuroendocrine tumors (pNETs), with response rates ranging from 30 to 70%. Small retrospective studies suggest that O(6)-methylguanine DNA methyltransferase (MGMT) deficiency predicts response to temozolomide. High tumor proliferative activity is also commonly perceived as a significant predictor of response to cytotoxic chemotherapy. It is unclear whether chromosomal instability (CIN), which correlates with alternative lengthening of telomeres (ALT), is a predictive factor. In this study, we evaluated 143 patients with advanced pNET who underwent treatment with CAPTEM for radiographic and biochemical response. MGMT expression (n=52), grade (n=128) and ALT activation (n=46) were investigated as potential predictive biomarkers. Treatment with CAPTEM was associated with an overall response rate (ORR) of 54% by RECIST 1.1. Response to CAPTEM was not influenced by MGMT expression, proliferative activity or ALT pathway activation. Based on these results, no biomarker-driven selection criteria for use of the CAPTEM regimen can be recommended at this time.
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Antimetabolitos Antineoplásicos/uso terapéutico , Antineoplásicos Alquilantes/uso terapéutico , Capecitabina/uso terapéutico , Dacarbazina/análogos & derivados , Tumores Neuroendocrinos , Neoplasias Pancreáticas , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Antimetabolitos Antineoplásicos/farmacología , Antineoplásicos Alquilantes/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Capecitabina/farmacología , Proteínas Co-Represoras , Metilasas de Modificación del ADN/metabolismo , Enzimas Reparadoras del ADN/metabolismo , Dacarbazina/farmacología , Dacarbazina/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Chaperonas Moleculares , Tumores Neuroendocrinos/tratamiento farmacológico , Tumores Neuroendocrinos/metabolismo , Tumores Neuroendocrinos/patología , Proteínas Nucleares/metabolismo , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Telómero , Temozolomida , Resultado del Tratamiento , Proteínas Supresoras de Tumor/metabolismo , Proteína Nuclear Ligada al Cromosoma X/metabolismoRESUMEN
Neuroendocrine tumors (NETs) are highly vascular neoplasms overexpressing vascular endothelial growth factor (VEGF) as well as VEGF receptors (VEGFR). Axitinib is a potent, selective inhibitor of VEGFR-1, -2 and -3, currently approved for the treatment of advanced renal cell carcinoma. We performed an open-label, two-stage design, phase II trial of axitinib 5mg twice daily in patients with progressive unresectable/metastatic low-to-intermediate grade carcinoid tumors. The primary end points were progression-free survival (PFS) and 12-month PFS rate. The secondary end points included time to treatment failure (TTF), overall survival (OS), overall radiographic response rate (ORR), biochemical response rate and safety. A total of 30 patients were enrolled and assessable for toxicity; 22 patients were assessable for response. After a median follow-up of 29months, we observed a median PFS of 26.7months (95% CI, 11.4-35.1), with a 12-month PFS rate of 74.5% (±10.2). The median OS was 45.3 months (95% CI, 24.4-45.3), and the median TTF was 9.6months (95% CI, 5.5-12). The best radiographic response was partial response (PR) in 1/30 (3%) and stable disease (SD) in 21/30 patients (70%); 8/30 patients (27%) were unevaluable due to early withdrawal due to toxicity. Hypertension was the most common toxicity that developed in 27 patients (90%). Grade 3/4 hypertension was recorded in 19 patients (63%), leading to treatment discontinuation in six patients (20%). Although axitinib appears to have an inhibitory effect on tumor growth in patients with advanced, progressive carcinoid tumors, the high rate of grade 3/4 hypertension may represent a potential impediment to its use in unselected patients.
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Antineoplásicos/uso terapéutico , Imidazoles/uso terapéutico , Indazoles/uso terapéutico , Tumores Neuroendocrinos/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Adulto , Anciano , Antineoplásicos/efectos adversos , Axitinib , Neoplasias del Colon/tratamiento farmacológico , Femenino , Humanos , Hipertensión/inducido químicamente , Imidazoles/efectos adversos , Indazoles/efectos adversos , Neoplasias Intestinales/tratamiento farmacológico , Estimación de Kaplan-Meier , Neoplasias Pulmonares/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/efectos adversos , Neoplasias del Recto/tratamiento farmacológico , Neoplasias del Timo/tratamiento farmacológico , Resultado del TratamientoRESUMEN
Pasireotide long-acting repeatable (LAR) is a novel somatostatin analog (SSA) with avid binding affinity to somatostatin receptor subtypes 1, 2, 3 (SSTR1,2,3) and 5 (SSTR5). Results from preclinical studies indicate that pasireotide can inhibit neuroendocrine tumor (NET) growth more robustly than octreotide in vitro. This open-label, phase II study assessed the clinical activity of pasireotide in treatment-naïve patients with metastatic grade 1 or 2 NETs. Patients with metastatic pancreatic and extra-pancreatic NETs were treated with pasireotide LAR (60âmg every 4 weeks). Previous systemic therapy, including octreotide and lanreotide, was not permitted. Tumor assessments were performed every 3 months using Response Evaluation Criteria in Solid Tumors (RECIST) criteria. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS), overall radiographic response rate (ORR), and safety. Twenty-nine patients were treated with pasireotide LAR (60âmg every 4 weeks) and 28 were evaluable for response. The median PFS was 11 months. The most favorable effect was observed in patients with low hepatic tumor burden, normal baseline chromogranin A, and high tumoral SSTR5 expression. Median OS has not been reached; the 30-month OS rate was 70%. The best radiographic response was partial response in one patient (4%), stable disease in 17 patients (60%), and progressive disease in ten patients (36%). Although grade 3/4 toxicities were rare, pasireotide LAR treatment was associated with a 79% rate of hyperglycemia including 14% grade 3 hyperglycemia. Although pasireotide appears to be an effective antiproliferative agent in the treatment of advanced NETs, the high incidence of hyperglycemia raises concerns regarding its suitability as a first-line systemic agent in unselected patients. SSTR5 expression is a potentially predictive biomarker for response.
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Tumores Neuroendocrinos/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Somatostatina/análogos & derivados , Adulto , Anciano , Preparaciones de Acción Retardada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Tumores Neuroendocrinos/metabolismo , Tumores Neuroendocrinos/patología , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Estudios Prospectivos , Receptores de Somatostatina/metabolismo , Somatostatina/administración & dosificaciónRESUMEN
Objetivos. Evaluar la satisfacción y las preferencias sobre la colonoscopia (CL) y la entero-resonancia (ERM) de los pacientes que padecen enfermedad de Crohn a los que se les ha realizado ambas pruebas. Valorar también la eficacia del sistema de información para la recogida de estos datos. Método. Estudio piloto transversal, mediante una encuesta telefónica de satisfacción realizada a pacientes diagnosticados de enfermedad de Crohn (EC). Los pacientes del estudio se seleccionaron en la consulta del Servicio de Aparato Digestivo del Hospital Universitario Príncipe de Asturias. Se les realizaron las dos pruebas objeto del estudio durante el periodo comprendido entre el 1 de enero de 2011 y el 30 de junio de 2012. Las encuestas se efectuaron durante los meses de julio y agosto de 2012. Resultados. Han participado un total de 48 pacientes con enfermedad de Crohn. De ellos, 24 eran mujeres y 24 hombres. Con una media de edad de 43 años (DE: 13.8). La peor valoración se obtuvo en la preparación previa de ambas. Si los pacientes pudieran elegir, 23 preferían CL, 16 ERM y a 9 les era indiferente. Conclusiones. La preferencia de los pacientes hacia la CL pudo deberse a la administración previa de sedación. Una prueba como la CL, que a priori puede resultar desagradable para el paciente, resulta mucho mejor tolerada gracias a la sedación. En ambas pruebas las preparaciones previas se perciben como molestas. Nos plantearemos cómo poder mejorar la tolerancia a dicha preparación, quizá dando más información, puesto que muchas veces no se realiza correctamente y eso puede acentuar dicha percepción desagradable (AU)
Objectives. To evaluate satisfaction and preferences in Crohn's disease patients who have undergone a colonoscopy (CL) and a MRI colonography (MRI). As well as evaluate the effectiveness of the information system to collect the data. Method. A sectional pilot study conducted through a satisfaction survey questionnaire for patients diagnosed with Crohns disease (CD). Study patients were selected from the Gastroenterology Department in the Principe de Asturias University Hospital, where both the colonoscopy and the entero magnetic resonance imaging tests were done from the 1st of January to the 30th of June 2012. Surveys were conducted during July and August 2012. Results. A total of 48 patients with Crohns disease participated. Out of these, 24 were women and 24 were men. The mean age was 43 years (SD: 13.8). The worst score was obtained at the time of preparation for both procedures. If patients could choose they would prefer CL 23, 16 MRI and 9 were indifferent. Conclusions. The patients preference for CL could be due to the administration of sedatives prior to the procedure. A procedure such as the CL which initially may result unpleasant for the patient is tolerated much better as a result of the sedation. In both tests, the preparations prior to the procedures are perceived as unpleasant. We will think about how to improve patients tolerance to these preparations, maybe by giving more information as patients, because we dont know often how to do it properly, which could magnify this unpleasant perception (AU)
Asunto(s)
Humanos , Masculino , Femenino , Satisfacción del Paciente , Enfermedad de Crohn/enfermería , Colonoscopía/métodos , Colonoscopía/enfermería , Imagen por Resonancia Magnética/enfermería , Espectroscopía de Resonancia Magnética/métodos , Aceptación de la Atención de Salud , Resultado del Tratamiento , Evaluación de Eficacia-Efectividad de Intervenciones , Encuestas Epidemiológicas/tendenciasRESUMEN
OBJECTIVES: To evaluate satisfaction and preferences in Crohn's disease patients who have undergone a colonoscopy (CL) and a MRI colonography (MRI). As well as evaluate the effectiveness of the information system to collect the data. METHOD: A sectional pilot study conducted through a satisfaction survey questionnaire for patients diagnosed with Crohn's disease (CD). Study patients were selected from the Gastroenterology Department in the Principe de Asturias University Hospital, where both the colonoscopy and the entero magnetic resonance imaging tests were done from the 1st of January to the 30th of June 2012. Surveys were conducted during July and August 2012. RESULTS: A total of 48 patients with Crohn's disease participated. Out of these, 24 were women and 24 were men. The mean age was 43 years (SD: 13.8). The worst score was obtained at the time of preparation for both procedures. If patients could choose they would prefer CL 23, 16 MRI and 9 were indifferent. CONCLUSIONS: The patients' preference for CL could be due to the administration of sedatives prior to the procedure. A procedure such as the CL which initially may result unpleasant for the patient is tolerated much better as a result of the sedation. In both tests, the preparations prior to the procedures are perceived as unpleasant. We will think about how to improve patients' tolerance to these preparations, maybe by giving more information as patients, because we don't know often how to do it properly, which could magnify this unpleasant perception.
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Colonoscopía , Enfermedad de Crohn/diagnóstico , Imagen por Resonancia Magnética , Prioridad del Paciente , Adolescente , Adulto , Anciano , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Adulto JovenAsunto(s)
Humanos , Masculino , Adulto , Colitis/complicaciones , Colitis/diagnóstico , Gastroenteritis/complicaciones , Colonoscopía , Biopsia , Gastroscopía , Colitis/cirugía , Colitis , Diagnóstico Diferencial , Diarrea/complicaciones , Eosinófilos/patología , Corticoesteroides/uso terapéutico , Cromolin Sódico/uso terapéuticoAsunto(s)
Humanos , Femenino , Adulto , Púrpura Trombocitopénica Idiopática/inducido químicamente , Púrpura Trombocitopénica Idiopática/complicaciones , Púrpura Trombocitopénica Idiopática/diagnóstico , Coagulación Sanguínea , Enfermedades Autoinmunes/inducido químicamente , Enfermedades Autoinmunes/complicacionesRESUMEN
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