RESUMEN
Fibroblast growth factors (FGFs) act as proangiogenic and mitogenic cytokines in several cancers, including multiple myeloma (MM). Indeed, corrupted FGF autocrine and paracrine secretion induces an aberrant activation of the FGF receptor (FGFR) signaling sustaining cancer cell spreading and resistance to pharmacological treatments. Thus, FGF traps may represent a promising anti-cancer strategy to hamper the ligand-dependent activation of the FGF/FGFR system. We previously identified NSC12 as the first orally available small molecule FGF trap able to inhibit the growth and progression of several FGF-dependent tumor models. NSC12 is a pregnenolone derivative carrying a 1,1-bis-trifluoromethyl-1,3-propanediol chain in position 17 of the steroid nucleus. Investigation of structure-activity relationships (SARs) provided more potent and specific NSC12 steroid derivatives and highlighted that the C17-side chain is pivotal for the FGF trap activity. Here, a scaffold hopping approach allowed to obtain two FGF trap compounds (22 and 57) devoid of the steroid nucleus and able to efficiently bind FGF2 and to inhibit FGFR activation in MM cells. Accordingly, these compounds exert a potent anti-tumor activity on MM cell lines both in vitro and in vivo and on MM patient-derived primary cells, strongly affecting the survival of both proteasome-inhibitor sensitive and resistant MM cells. These results propose a new therapeutic option for relapsed/refractory MM patients and set the bases for the development of novel FGF traps prone to chemical diversification to be used in the clinic for the treatment of those tumors in which the FGF/FGFR system plays a pivotal role, including MM.
Asunto(s)
Antineoplásicos , Factores de Crecimiento de Fibroblastos , Mieloma Múltiple , Receptores de Factores de Crecimiento de Fibroblastos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/metabolismo , Humanos , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Antineoplásicos/química , Línea Celular Tumoral , Receptores de Factores de Crecimiento de Fibroblastos/antagonistas & inhibidores , Receptores de Factores de Crecimiento de Fibroblastos/metabolismo , Factores de Crecimiento de Fibroblastos/metabolismo , Relación Estructura-Actividad , Descubrimiento de Drogas , Ratones , Factor 2 de Crecimiento de Fibroblastos/metabolismoAsunto(s)
Betacoronavirus/inmunología , Técnicas de Laboratorio Clínico/métodos , Infecciones por Coronavirus/mortalidad , Citometría de Flujo , Subgrupos Linfocitarios/inmunología , Neumonía Viral/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Betacoronavirus/patogenicidad , COVID-19 , Prueba de COVID-19 , Separación Celular , Infecciones por Coronavirus/sangre , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/inmunología , Femenino , Interacciones Microbiota-Huesped/inmunología , Humanos , Estimación de Kaplan-Meier , Recuento de Linfocitos , Subgrupos Linfocitarios/metabolismo , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/sangre , Neumonía Viral/diagnóstico , Neumonía Viral/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Factores de Riesgo , SARS-CoV-2 , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: Intermittent treatment with tyrosine kinase inhibitors (TKIs) is an option for elderly chronic myeloid leukemia (CML) patients who are often candidates for life-long treatment. MATERIALS AND METHODS: The Italian phase III multicentric randomized Optimize TKIs Multiple Approaches (OPTkIMA) study aimed to evaluate if a progressive de-escalation of TKIs is able to maintain the molecular remission (MR)3.0 and to improve Health-Related Quality of Life (HRQoL) in CML elderly patients. RESULTS: A total of 215 patients in stable MR3.0/MR4.0 were randomized to receive an intermittent TKI schedule 1 month ON-1 month OFF for 3 years (FIXED arm; n = 111) vs. a progressive de-escalation TKI dose up to one-third of the starting dose at the 3rd year (PROGRESSIVE arm; n = 104). Two hundred three patients completed the 3rd year of OPTkIMA study. At the last follow-up, MR3.0 loss was 27% vs. 46% (P = .005) in the FIXED vs PROGRESSIVE arm, respectively. None of these patients experienced disease progression. The 3-year probability of maintaining the MR3.0 was 59% vs. 53%, respectively (P = .13). HRQoL globally improved from the baseline to the 3rd year, without any significant difference between the 2 arms. After the 3rd year, the proportion of patients who was address to TKI discontinuation in the 2 arms was 36% (FIXED) vs. 58% (PROGRESSIVE) (P = .03). CONCLUSIONS: The intensification of intermittent TKI therapy is associated with a higher incidence of MR3.0 loss, but those patients who maintain the MR3.0 molecular response at the end of the study have been frequently considered eligible for TFR. The HRQoL generally improved during the de-escalation therapy in both randomization arms.
Asunto(s)
Leucemia Mielógena Crónica BCR-ABL Positiva , Inhibidores de Proteínas Quinasas , Calidad de Vida , Humanos , Anciano , Masculino , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Femenino , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Italia , Anciano de 80 o más Años , Resultado del TratamientoRESUMEN
BACKGROUND: The first Covid-19 epidemic outbreak has enormously impacted the delivery of clinical healthcare and hospital management practices in most of the hospitals around the world. In this context, it is important to assess whether the clinical management of non-Covid patients has not been compromised. Among non-Covid cases, patients with Acute Myocardial Infarction (AMI) and stroke need non-deferrable emergency care and are the natural candidates to be studied. Preliminary evidence suggests that the time from onset of symptoms to emergency department (ED) presentation has significantly increased in Covid-19 times as well as the 30-day mortality and in-hospital mortality. METHODS: We check, in a causal inference framework, the causal effect of the hospital's stress generated by Covid-19 pandemic on in-hospital mortality rates (primary end-point of the study) of AMI and stroke over several time-windows of 15-days around the implementation date of the State of Emergency restrictions for COVID-19 (March, 9th 2020) using two quasi-experimental approaches, regression-discontinuity design (RDD) and difference-in-regression-discontinuity (DRD) designs. Data are drawn from Spedali Civili of Brescia, one of the most hit provinces in Italy by Covid-19 during March and May 2020. FINDINGS: Despite the potential adverse effects on expected mortality due to a longer time to hospitalization and staff extra-burden generated by the first wave of Covid-19, the AMI and stroke mortality rates are overall not statistically different during the first wave of Covid-19 than before the first peak. The obtained results provided by RDD models are robust also when we account for seasonality and unobserved factors with DRD models. INTERPRETATION: The non-statistically significant impact on mortality rates for AMI and stroke patients provides evidence of the hospital ability to manage -with the implementation of a dual track organization- the simultaneous delivery of high-quality cares to both Covid and non-Covid patients.
Asunto(s)
COVID-19/patología , Infarto del Miocardio/mortalidad , Accidente Cerebrovascular/mortalidad , COVID-19/epidemiología , COVID-19/virología , Bases de Datos Factuales , Servicios Médicos de Urgencia , Mortalidad Hospitalaria , Hospitalización , Humanos , Italia/epidemiología , Infarto del Miocardio/patología , Pandemias , Estudios Retrospectivos , SARS-CoV-2/aislamiento & purificación , Accidente Cerebrovascular/patologíaRESUMEN
OBJECTIVES: Solitary plasmacytoma (SP) is characterized by a single mass of clonal plasma cells. Definitive RT can result in long-term local control of the SP. Due to the small number of patients and narrow range of doses, phase III randomized trials are lacking. The aim of this study is to further support the potential use of RT for the treatment of SP. METHODS: Clinical data of all patients treated for SP at our Institution between 1992 and 2018 were reviewed. A total of 42 consecutive patients were analyzed. RESULTS: The median follow-up was 84.8 months. Radiation dose did not differ significantly as a function of sex, type of SP (solitary bone plasmacytoma or as extramedullary plasmacytoma), tumor size; conversely differs significantly as a function of age (p = 0.04). The 5y-OS and 10y-OS were, respectively, 96 and 91%. Local recurrences developed in 21.4% of patients (9/42). 16 patients progressed to MM (38.1%). The 5y-progression to MM free survival (PMFS) and the 10y-PMFS were, respectively, 68.6 and 61.9%. CONCLUSIONS: Our data confirm that good results are achievable with RT to treat SP, but they don't allow defining a dose-effect correlation; therefore, it remains uncertain which is the most effective dose and whether lower doses can guarantee adequate disease control.
Asunto(s)
Plasmacitoma/radioterapia , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Óseas/diagnóstico , Neoplasias Óseas/mortalidad , Neoplasias Óseas/patología , Neoplasias Óseas/radioterapia , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Italia/epidemiología , Masculino , Persona de Mediana Edad , Mieloma Múltiple/mortalidad , Mieloma Múltiple/patología , Mieloma Múltiple/radioterapia , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/radioterapia , Plasmacitoma/diagnóstico , Plasmacitoma/mortalidad , Plasmacitoma/patología , Pronóstico , Estudios Retrospectivos , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
OBJECTIVES: Infections are the major cause of morbidity and mortality in patients with acute myeloid leukaemia (AML). They primarily occur during the first course of induction chemotherapy and may increase the risk of leukaemia relapse, due to a significant delay in consolidation therapy. The intensification of induction chemotherapy and the use of non-conventional drugs such as fludarabine are considered responsible for the increased risk of infections. METHODS: In this study, we retrospectively analysed the infections occurred in 224 newly diagnosed AML patients =65 yr, consecutively treated between 1997 and 2002 with an induction regimen including fludarabine, arabinosyl cytosine and idarubicin, with or without etoposide (FLAI/FLAIE), in the context of three multicentric prospective trials (AML97, AML99, AML02). RESULTS: During the induction phase, 146 (65%) patients experienced fever of undetermined origin (FUO), 30 (13%) and 47 (21%) patients had Gram-negative and positive bacteremias, respectively, and 10 (4%) patients developed a probable/proven invasive fungal infection (IFI). The fatality rate for Gram-negative, Gram-positive bacteremias and probable/proven IFI was 10%, 8% and 60% respectively. During consolidation, 75 (35%) patients had FUO, 43 (20%) and 40 (19%) patients had Gram-negative and positive bacteremias, respectively, and 5 (2%) patients developed a probable/proven IFI. The fatality rate for Gram-negative, Gram-positive bacteremias and probable/proven IFI was 14%, 5% and 80% respectively. Interestingly, the overall incidence of microbiologically documented infections during induction was 38% and the incidence of probable/proven IFIs during the induction/consolidation programme was 7%. No infections caused by viruses or opportunistic pathogens were observed neither during induction, nor during consolidation. CONCLUSIONS: These data, although retrospectively collected, suggest that fludarabine-based chemotherapy is not associated with an increased incidence of infections, in particular IFIs, compared to conventional regimens commonly used for AML induction.
Asunto(s)
Antineoplásicos/efectos adversos , Infecciones por Bacterias Gramnegativas/mortalidad , Infecciones por Bacterias Grampositivas/mortalidad , Leucemia Mieloide Aguda/mortalidad , Micosis/mortalidad , Vidarabina/análogos & derivados , Adulto , Antineoplásicos/administración & dosificación , Bacteriemia/inducido químicamente , Bacteriemia/mortalidad , Femenino , Fiebre/inducido químicamente , Fiebre/mortalidad , Infecciones por Bacterias Gramnegativas/inducido químicamente , Infecciones por Bacterias Grampositivas/inducido químicamente , Humanos , Incidencia , Leucemia Mieloide Aguda/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Micosis/inducido químicamente , Estudios Retrospectivos , Factores de Riesgo , Tasa de Supervivencia , Vidarabina/administración & dosificación , Vidarabina/efectos adversosRESUMEN
Bone marrow angiogenesis plays an important role in the pathogenesis and progression in multiple myeloma. Recent studies have shown that proteasome inhibitor bortezomib (Velcade, formerly PS-341) can overcome conventional drug resistance in vitro and in vivo; however, its antiangiogenic activity in the bone marrow milieu has not yet been defined. In the present study, we examined the effects of bortezomib on the angiogenic phenotype of multiple myeloma patient-derived endothelial cells (MMEC). At clinically achievable concentrations, bortezomib inhibited the proliferation of MMECs and human umbilical vein endothelial cells in a dose-dependent and time-dependent manner. In functional assays of angiogenesis, including chemotaxis, adhesion to fibronectin, capillary formation on Matrigel, and chick embryo chorioallantoic membrane assay, bortezomib induced a dose-dependent inhibition of angiogenesis. Importantly, binding of MM.1S cells to MMECs triggered multiple myeloma cell proliferation, which was also abrogated by bortezomib in a dose-dependent fashion. Bortezomib triggered a dose-dependent inhibition of vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6) secretion by the MMECs, and reverse transcriptase-PCR confirmed drug-related down-regulation of VEGF, IL-6, insulin-like growth factor-I, Angiopoietin 1 (Ang1), and Ang2 transcription. These data, therefore, delineate the mechanisms of the antiangiogenic effects of bortezomib on multiple myeloma cells in the bone marrow milieu.
Asunto(s)
Ácidos Borónicos/farmacología , Células Endoteliales/efectos de los fármacos , Mieloma Múltiple/irrigación sanguínea , Mieloma Múltiple/tratamiento farmacológico , Pirazinas/farmacología , Inhibidores de la Angiogénesis/farmacología , Angiopoyetina 1/biosíntesis , Angiopoyetina 1/genética , Angiopoyetina 2/biosíntesis , Angiopoyetina 2/genética , Animales , Antineoplásicos/farmacología , Bortezomib , Procesos de Crecimiento Celular/efectos de los fármacos , Células Cultivadas , Embrión de Pollo , Membrana Corioalantoides/irrigación sanguínea , Relación Dosis-Respuesta a Droga , Regulación hacia Abajo/efectos de los fármacos , Células Endoteliales/metabolismo , Humanos , Factor I del Crecimiento Similar a la Insulina/biosíntesis , Factor I del Crecimiento Similar a la Insulina/genética , Interleucina-6/antagonistas & inhibidores , Interleucina-6/biosíntesis , Interleucina-6/genética , Interleucina-6/metabolismo , Mieloma Múltiple/genética , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/genética , Neovascularización Patológica/patología , Neovascularización Fisiológica/efectos de los fármacos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Factor A de Crecimiento Endotelial Vascular/biosíntesis , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Experimental studies have demonstrated that thalidomide (Thal), a drug developed as a sedative, has antitumoural properties. The possible antitumour mechanisms of action involve: inhibition of angiogenesis, cytokine-mediated pathways, modulation of adhesion molecules, inhibition of cyclooxygenase-2 and stimulation of immuno response. Therefore, Thal is under clinical evaluation in oncology. This paper provides an overview of the data currently available in literature regarding, in terms of activity and toxicity, the use of Thal in cancer patients. Multiple myeloma is so far the most responsive malignancy. A moderate activity has been documented in certain solid tumours: glioblastoma multiforme, renal cell carcinoma and malignant melanoma. Tolerability is generally satisfactory with peripheral neuropathy being the most relevant dose-dependent toxicity. The more frequent, but moderate side effects are: somnolence, constipation, dizziness and fatigue. More studies are needed to properly evaluate the anticancer activity of Thal alone or in combination with other anticancer treatments. Preliminary studies suggest promising results of Thal in combinations with corticosteroids and cytotoxic drugs as front-line therapy of multiple myeloma. Regarding therapy of solid tumours in the adult, combination with chemotherapy, radiation therapy and molecular-targeting compounds are under investigation.
Asunto(s)
Antineoplásicos , Neoplasias/tratamiento farmacológico , Talidomida/farmacología , Animales , Caquexia/tratamiento farmacológico , Caquexia/etiología , Neoplasias Hematológicas/tratamiento farmacológico , Humanos , Neoplasias/complicaciones , Neoplasias/patología , Talidomida/efectos adversos , Talidomida/farmacocinética , Talidomida/uso terapéuticoRESUMEN
One hundred and six patients aged =60 years with newly diagnosed acute myeloid leukaemia (AML) treated with fludarabine-based regimens (cases) were matched with 106 AML patients treated with conventional non-fludarabine-based regimens (controls). The cases and controls were matched by expression of the multidrug resistance P-glycoprotein (MDR-Pgp), measured by flow cytometry as mean fluorescence index (MFI), cytogenetics, and age. The complete remission (CR) rate of the cases was 61% among the MDR-Pgp-positive (pos(ve)) patients (MFI >/= 6) vs. 75% among the MDR-Pgp-negative (neg(ve)) ones (MFI < 6) (P = 0.16). Conversely, in the controls, the CR rate was 44% among the MDR-Pgp-pos(ve) patients vs. 67% among the MDR-Pgp-neg(ve) ones (P = 0.02). The 4-year disease-free survival (DFS) and overall survival (OS) of MDR-Pgp-pos(ve) cases were significantly longer than those of MDR-Pgp-pos(ve) controls (DFS, 28.1% vs. 6.5%, P = 0.004; OS, 33.5% vs. 9.6%, P = 0.01). This difference was not found among the MDR-Pgp-neg(ve) patients. By univariate (P = 0.007) and multivariate (P = 0.007) analysis, the MDR-Pgp-pos(ve) phenotype was negatively correlated with CR and it emerged as the most important independent negative prognostic factor, after cytogenetics. Our study confirms the prognostic impact of the MDR phenotype in AML and strongly suggests fludarabine-based induction treatments as a promising strategy for MDR-Pgp-pos(ve) AML patients. In this setting of patients, large prospective randomised studies should be planned.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resistencia a Múltiples Medicamentos , Leucemia Mieloide/tratamiento farmacológico , Vidarabina/análogos & derivados , Enfermedad Aguda , Adulto , Estudios de Casos y Controles , Distribución de Chi-Cuadrado , Supervivencia sin Enfermedad , Femenino , Humanos , Cariotipificación , Leucemia Mieloide/mortalidad , Masculino , Persona de Mediana Edad , Fenotipo , Pronóstico , Inducción de Remisión , Estadísticas no Paramétricas , Tasa de Supervivencia , Resultado del Tratamiento , Vidarabina/uso terapéuticoRESUMEN
Thymidine phosphorylase (TP), also known as platelet derived endothelial cell growth factor (PD-ECGF), is an enzyme involved in thymidine synthesis and degradation and exerts an angiogenic activity, whereas N4 pentyloxy-carbonyl- 5'-deoxy-5-fluorocytidine, commonly called capecitabine (CAP), is a TP-activated oral fluorpyrimidine, which generates 5-fluorouracil (5-FU) within tumours. In addition to its classic antitumour activity, recent studies suggest that CAP may act as an antiangiogenetic molecule. Assessment of tumour microvessel density as expressed by endothelial cell TP positivity may identify the most vascularized and hence CAP-sensitive tumours. This review summarizes: (i) the biochemical and tissue expression of TP; (ii) the pharmacological profile of CAP as an anti-cancer compound and the central role of TP in its activation; (iii) the potential antiangiogenetic role of TP-activated CAP in tumours.