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Acute myelogenous leukaemia (AML) originates and is maintained by leukaemic stem cells (LSCs) that are inherently resistant to antiproliferative therapies, indicating that a critical strategy for overcoming chemoresistance in AML therapy is to eradicate LSCs. In this work, we investigated the anti-AML activity of bortezomib (BTZ), emphasizing its anti-LSC potential, using KG-1a cells, an AML cell line with stem-like properties. BTZ presented potent cytotoxicity to both solid and haematological malignancy cells and reduced the stem-like features of KG-1a cells, as observed by the reduction in CD34- and CD123-positive cells. A reduction in NF-κB p65 nuclear staining was observed in BTZ-treated KG-1a cells, in addition to upregulation of the NF-κB inhibitor gene NFΚBIB. BTZ-induced DNA fragmentation, nuclear condensation, cell shrinkage and loss of transmembrane mitochondrial potential along with an increase in active caspase-3 and cleaved PARP-(Asp 214) level in KG-1a cells. Furthermore, BTZ-induced cell death was partially prevented by pretreatment with the pancaspase inhibitor Z-VAD-(OMe)-FMK, indicating that BTZ induces caspase-mediated apoptosis. BTZ also increased mitochondrial superoxide levels in KG-1a cells, and BTZ-induced apoptosis was partially prevented by pretreatment with the antioxidant N-acetylcysteine, indicating that BTZ induces oxidative stress-mediated apoptosis in KG-1a cells. At a dosage of 0.1 mg/kg every other day for 2 weeks, BTZ significantly reduced the percentage of hCD45-positive cells in the bone marrow and peripheral blood of NSG mice engrafted with KG-1a cells with tolerable toxicity. Taken together, these data indicate that the anti-LSC potential of BTZ appears to be an important strategy for AML treatment.
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Bortezomib , Leucemia Mieloide Aguda , FN-kappa B , Células Madre Neoplásicas , Estrés Oxidativo , Bortezomib/farmacología , Estrés Oxidativo/efectos de los fármacos , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/metabolismo , Animales , FN-kappa B/metabolismo , Línea Celular Tumoral , Ratones , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Apoptosis/efectos de los fármacos , Antineoplásicos/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto , Ratones SCIDRESUMEN
PURPOSE: Breast cancer (BrCa) is a predominant type of cancer with a disparate molecular nature. MicroRNAs (miRNAs) have emerged as promising key players in the regulation of pathological processes in BrCa. Proteasome inhibitors (PIs) emerged as promising anticancer agents for several human malignancies, including BrCa, inhibiting the function of the proteasome. Aiming to shed light on the miRNA regulatory effect in BrCa after treatment with PIs, we used two PIs, namely bortezomib and carfilzomib. MATERIALS AND METHODS: Four BrCa cell lines of distinct molecular subtypes were treated with these PIs. Cell viability and IC50 concentrations were determined. Total RNA was extracted, polyadenylated, and reversely transcribed. Next, the levels of specific miRNAs with a significant role in BrCa were determined using relative quantification, and their regulatory effect was assessed. RESULTS: High heterogeneity was discovered in the levels of miRNAs in the four cell lines, after treatment. The miRNA levels fluctuate with distinct patterns, in 24, 48, or 72 hours. Interestingly, miR-1-3p, miR-421-3p, and miR-765-3p appear as key molecules, as they were found deregulated, in almost all combinations of cell lines and PIs. In the SK-BR-3 cell line, the majority of the miRNAs were significantly downregulated in treated compared to untreated cells, with miR-21-5p being the only one upregulated. Finally, various significant biological processes, molecular functions, and pathways were predicted to be affected. CONCLUSIONS: The diversity of pathways predicted to be affected by the diversity in miRNA expression after treatment with PIs paves the way for the recognition of new regulatory axes in BrCa.
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Background: Amyloid light chain (AL) amyloidosis is characterized by amyloid fibril deposition derived from monoclonal immunoglobulin light chains, resulting in multiorgan dysfunction. Limited data exist on the clinical features of AL amyloidosis. Objective: This study aims to describe the clinical characteristics, treatments, and outcomes in Colombian patients with AL amyloidosis. Methods: A retrospective descriptive study was conducted at three high-complexity centers in Medellín, Colombia. Adults with AL amyloidosis diagnosed between 2012 and 2022 were included. Clinical, laboratory, histological, treatment, and survival data were analyzed. Results: The study included 63 patients. Renal involvement was most prevalent (66%), followed by cardiac involvement (61%). Multiorgan involvement occurred in 61% of patients. Amyloid deposition was most commonly detected in renal biopsy (40%). Bortezomib-based therapy was used in 68%, and 23.8% received high-dose chemotherapy with autologous hematopoietic stem cell transplantation (HDCT-ASCT). Hematological response was observed in 95% of patients with available data. Cardiac and renal organ responses were 15% and 14%, respectively. Median overall survival was 45.1 months (95% CI: 22.2-63.8). In multivariate analysis, cardiac involvement was significantly associated with inferior overall survival (HR 3.27; 95% CI: 1.23-8.73; p=0.018), HDCT-ASCT had a non-significant trend towards improved overall survival (HR 0.25; 95% CI: 0.06-1.09; p=0.065). Conclusions: In this study of Colombian patients with AL amyloidosis, renal involvement was more frequent than cardiac involvement. Overall survival and multiorgan involvement were consistent with data from other regions of the world. Multivariate analysis identified cardiac involvement and HDCT-AHCT as possible prognostic factors.
Antecedentes: La amiloidosis por amiloide de cadenas ligeras (AL) se caracteriza por el depósito de fibrillas amiloides derivadas de cadenas ligeras de inmunoglobulinas monoclonales, lo que resulta en disfunción multiorgánica. Existen datos limitados sobre las características clínicas de la amiloidosis AL. Objetivo: Este estudio tiene como objetivo describir las características clínicas, tratamientos y desenlaces en pacientes colombianos con amiloidosis AL. Métodos: Se llevó a cabo un estudio descriptivo retrospectivo en tres centros de alta complejidad en Medellín, Colombia. Se incluyeron adultos con diagnóstico de amiloidosis AL entre 2012 y 2022. Se analizaron datos clínicos, de laboratorio, histológicos, de tratamiento y de supervivencia. Resultados: El estudio incluyó 63 pacientes. La afectación renal fue más prevalente (66%), seguida de la afectación cardíaca (61%). El 61% de los pacientes presentaron afectación multiorgánica. El depósito amiloide se detectó con mayor frecuencia en la biopsia renal (40%). El tratamiento basado en bortezomib se utilizó en el 68%, y el 23.8% recibió altas dosis de quimioterapia con trasplante autólogo de progenitores hematopoyéticos (ADQT-TAPH). Se observó respuesta hematológica en el 95% de los pacientes con datos disponibles. La respuesta de órgano cardíaca y renal fue del 15% y 14%, respectivamente. La mediana de la supervivencia global fue de 45.1 meses (IC del 95%: 22.2-63.8). En el análisis multivariado, la afectación cardíaca se asoció significativamente con una supervivencia global inferior (HR 3.27; IC del 95%: 1.23-8.73; p=0.018), ADQT-TAPH mostró una tendencia no significativa hacia una mejora en la supervivencia global (HR 0.25; IC 95%: 0.06-1.09; p=0.065). Conclusiones: En este estudio de pacientes colombianos con amiloidosis AL, la afectación renal fue más frecuente que la afectación cardíaca. La supervivencia global y la afectación multiorgánica fueron consistentes con datos de otras regiones del mundo. El análisis multivariado identificó la afectación cardíaca y ADQT-TAPH como posibles factores pronósticos.
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Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas , Adulto , Humanos , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/terapia , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/tratamiento farmacológico , Colombia/epidemiología , Estudios Retrospectivos , Resultado del Tratamiento , Bortezomib/uso terapéuticoRESUMEN
Background: Amyloid light chain (AL) amyloidosis is characterized by amyloid fibril deposition derived from monoclonal immunoglobulin light chains, resulting in multiorgan dysfunction. Limited data exist on the clinical features of AL amyloidosis. Objective: This study aims to describe the clinical characteristics, treatments, and outcomes in Colombian patients with AL amyloidosis. Methods: A retrospective descriptive study was conducted at three high-complexity centers in Medellín, Colombia. Adults with AL amyloidosis diagnosed between 2012 and 2022 were included. Clinical, laboratory, histological, treatment, and survival data were analyzed. Results: The study included 63 patients. Renal involvement was most prevalent (66%), followed by cardiac involvement (61%). Multiorgan involvement occurred in 61% of patients. Amyloid deposition was most commonly detected in renal biopsy (40%). Bortezomib-based therapy was used in 68%, and 23.8% received high-dose chemotherapy with autologous hematopoietic stem cell transplantation (HDCT-ASCT). Hematological response was observed in 95% of patients with available data. Cardiac and renal organ responses were 15% and 14%, respectively. Median overall survival was 45.1 months (95% CI: 22.2-63.8). In multivariate analysis, cardiac involvement was significantly associated with inferior overall survival (HR 3.27; 95% CI: 1.23-8.73; p=0.018), HDCT-ASCT had a non-significant trend towards improved overall survival (HR 0.25; 95% CI: 0.06-1.09; p=0.065). Conclusions: In this study of Colombian patients with AL amyloidosis, renal involvement was more frequent than cardiac involvement. Overall survival and multiorgan involvement were consistent with data from other regions of the world. Multivariate analysis identified cardiac involvement and HDCT-AHCT as possible prognostic factors.
Antecedentes: La amiloidosis por amiloide de cadenas ligeras (AL) se caracteriza por el depósito de fibrillas amiloides derivadas de cadenas ligeras de inmunoglobulinas monoclonales, lo que resulta en disfunción multiorgánica. Existen datos limitados sobre las características clínicas de la amiloidosis AL. Objetivo: Este estudio tiene como objetivo describir las características clínicas, tratamientos y desenlaces en pacientes colombianos con amiloidosis AL. Métodos: Se llevó a cabo un estudio descriptivo retrospectivo en tres centros de alta complejidad en Medellín, Colombia. Se incluyeron adultos con diagnóstico de amiloidosis AL entre 2012 y 2022. Se analizaron datos clínicos, de laboratorio, histológicos, de tratamiento y de supervivencia. Resultados: El estudio incluyó 63 pacientes. La afectación renal fue más prevalente (66%), seguida de la afectación cardíaca (61%). El 61% de los pacientes presentaron afectación multiorgánica. El depósito amiloide se detectó con mayor frecuencia en la biopsia renal (40%). El tratamiento basado en bortezomib se utilizó en el 68%, y el 23.8% recibió altas dosis de quimioterapia con trasplante autólogo de progenitores hematopoyéticos (ADQT-TAPH). Se observó respuesta hematológica en el 95% de los pacientes con datos disponibles. La respuesta de órgano cardíaca y renal fue del 15% y 14%, respectivamente. La mediana de la supervivencia global fue de 45.1 meses (IC del 95%: 22.2-63.8). En el análisis multivariado, la afectación cardíaca se asoció significativamente con una supervivencia global inferior (HR 3.27; IC del 95%: 1.23-8.73; p=0.018), ADQT-TAPH mostró una tendencia no significativa hacia una mejora en la supervivencia global (HR 0.25; IC 95%: 0.06-1.09; p=0.065). Conclusiones: En este estudio de pacientes colombianos con amiloidosis AL, la afectación renal fue más frecuente que la afectación cardíaca. La supervivencia global y la afectación multiorgánica fueron consistentes con datos de otras regiones del mundo. El análisis multivariado identificó la afectación cardíaca y ADQT-TAPH como posibles factores pronósticos.
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BACKGROUND: Survival in multiple myeloma (MM) has improved in the past years with the introduction of immunomodulators and proteasome inhibitors. However, chemotherapy-induced peripheral neuropathy (CIPN) is associated with both drug classes affecting Health-Related Quality of Life (HRQoL) and activities of daily living (ADL). OBJECTIVE: We evaluated CIPN in MM patients to identify associated factors and impacts on HRQoL and ADL. METHODS: This is a cross-sectional study with Brazilian patients from public and private health services. Patients were interviewed using validated tools to measure CIPN and HRQoL, along with sociodemographic and clinical questions. Logistic regression was used to assess the association of CIPN with sociodemographic, clinical, and HRQoL variables. RESULTS: In total, 217 patients were eligible for the study. The median age was 67, 50.9% were women, 51.6% had low income, 47.5% had low education, and 55.3% attended private health services. The chemotherapy regimen most used was the combination of cyclophosphamide, thalidomide, and dexamethasone (17.5%) among the 24 types of regimens found. Most patients (90.3%) had at least one CIPN symptom: 62.7% were severe, and 51.62% were extremely bothered ADL. Numbness was the most common symptom (40.6%). CIPN was independently associated with education, hospitalization, chemotherapy, side effects, disease symptoms, and global health status in HRQoL. CONCLUSION: MM patients showed a high frequency of CIPN, which affected ADL and impaired HRQoL. Early and accurate detection of CIPN and dose management in patients with thalidomide and bortezomib-based regimens should be performed to provide better treatment outcomes and avoid permanent disabilities.
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BACKGROUND: Multiple myeloma (MM) is an incurable cancer of plasma cells; the survival of which has improved over the years with the emergence of new treatments. In Brazil, the availability of treatment-regimens is different from developed countries. Real-world evidence with Brazilian patients is lacking. OBJECTIVES: Our aim was to evaluate the effectiveness and the safety of MM treatments in a Brazilian metropolis. METHODS: This was a retrospective cohort study with MM patients, beginning MM treatment from 2009 to 2020 (i.e., before bortezomib became available in public health services). Patients' medical records were revised to obtain clinical variables. The primary outcomes were Overall Survival (OS) and Progression Free Survival (PFS, measured as time to next treatment), and the secondary outcomes were Adverse Events (AE). Kaplan-Meier curves were obtained and the Cox proportional hazards model was performed for univariate and multivariate analyses. The incidence of AE was estimated and the chi-squared test was performed to evaluate the association between AE and MM regimens. RESULTS: In total, 278 patients participated in the study with median age of 64 years; 50.4 % were females, 55.8 % attended a private clinic, 34.9 % received autologous stem cell transplantation (ASCT) and 32.4 % were on polypharmacy. Most patients from public services used thalidomide-based regimens (40.3 %) and at private clinics used bortezomib-based regimens (38.1 %) as first-line treatment. Patients had a median OS of 99 months. Patients had median PFS of 28 months in first-line treatment, which was significantly different for age (p = 0.0055), polypharmacy (p = 0.0094) and ASCT (p < 0.0001). PFS was independently associated to polypharmacy and ASCT. The incidence of peripheral neuropathy (39.6 %) was high. In contrast, the incidence of severe AE was low. We found significant difference between first-line T + B-based regimens and leukopenia (p = 0.012). CONCLUSION: Our study showed that patients on polypharmacy and who did not receive ASCT had worse PFS. Similar to other Latin countries, most patients used thalidomide- and bortezomib-based regimens as first-line treatments having similar OS and PFS. Treatments were considered relatively safe, especially regarding serious AE.
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Trasplante de Células Madre Hematopoyéticas , Mieloma Múltiple , Femenino , Humanos , Persona de Mediana Edad , Masculino , Bortezomib/efectos adversos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/epidemiología , Talidomida/efectos adversos , Brasil/epidemiología , Estudios Retrospectivos , Resultado del Tratamiento , Trasplante Autólogo , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
Several studies have shown that diverse components of the bone marrow (BM) microenvironment play a central role in the progression, pathophysiology, and drug resistance in multiple myeloma (MM). In particular, the dynamic interaction between BM mesenchymal stem cells (BM-MSC) and MM cells has shown great relevance. Here we showed that inhibiting both PKC and NF-κB signalling pathways in BM-MSC reduced cell survival in the MM cell line H929 and increased its susceptibility to the proteasome inhibitor bortezomib. PKC-mediated cell survival inhibition and bortezomib susceptibility induction were better performed by the chimeric peptide HKPS than by the classical enzastaurin inhibitor, probably due to its greatest ability to inhibit cell adhesion and its increased capability to counteract the NF-κB-related signalling molecules increased by the co-cultivation of BM-MSC with H929 cells. Thus, inhibiting two coupled signalling molecules in BM-MSC was more effective in blocking the supportive cues emerging from the mesenchymal stroma. Considering that H929 cells were also directly susceptible to PKC and NF-κB inhibition, we showed that treatment of co-cultures with the HKPS peptide and BAY11-7082, followed by bortezomib, increased H929 cell death. Therefore, targeting simultaneously connected signalling elements of BM-MSC responsible for MM cells support with compounds that also have anti-MM activity can be an improved treatment strategy.
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Células Madre Mesenquimatosas , Mieloma Múltiple , Humanos , Bortezomib/farmacología , Bortezomib/uso terapéutico , Mieloma Múltiple/metabolismo , FN-kappa B/metabolismo , Línea Celular Tumoral , Células Madre Mesenquimatosas/metabolismo , Microambiente TumoralRESUMEN
INTRODUCTION: Bortezomib is proteasome inhibitor used in multiple myeloma treatment. The reactivation of herpes simplex virus (HSV) and varicella-zoster virus (VZV) during bortezomib-based therapy is a well-known adverse event. Antiviral prophylaxis is mandatory. Nevertheless, reports of herpesviral encephalitis are scarce. CASE REPORT: A 57-year-old multiple myeloma patient who during CyBorD protocol (Bortezomib, cyclophosphamide, and dexamethasone), after a transient suspension of antiviral prophylaxis presented progressive headaches unresponsive to conventional analgesics, asthenia, fever, episodic visual hallucinations, and vesicular lesions in the right supraorbital and frontal region. Herpetic encephalitis was diagnosed after detecting herpes zoster in cerebrospinal fluid. MANAGEMENT & OUTCOME: The patient was treated with acyclovir 500mg every 6 hours for 21 days, and subsequent valacyclovir prophylaxis achieving an excellent clinical evolution. Anti-myeloma treatment was changed to lenalidomide and dexamethasone achieving a durable complete response. Herpesviral encephalitis is a rare but severe complication associated with the use of Bortezomib, especially when patients did not receive acyclovir prophylaxis. However, a rapid detection based on the clinical suspicion, and the prompt start of treatment, may lead to overcome this adverse event.
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Amiloidosis , Antineoplásicos , Encefalitis por Herpes Simple , Mieloma Múltiple , Aciclovir/efectos adversos , Amiloidosis/inducido químicamente , Amiloidosis/complicaciones , Amiloidosis/tratamiento farmacológico , Antineoplásicos/efectos adversos , Antivirales/efectos adversos , Ácidos Borónicos/efectos adversos , Bortezomib/efectos adversos , Dexametasona/efectos adversos , Encefalitis por Herpes Simple/inducido químicamente , Encefalitis por Herpes Simple/complicaciones , Encefalitis por Herpes Simple/tratamiento farmacológico , Herpesvirus Humano 3/fisiología , Humanos , Persona de Mediana Edad , Mieloma Múltiple/complicaciones , Mieloma Múltiple/tratamiento farmacológico , PirazinasRESUMEN
Introducción: el mieloma múltiple (MM) continúa siendo una enfermedad incurable sin embargo, el trasplante autólogo de médula ósea (TAH), y las drogas antineoplásicas han permitido mejorar la sobrevida global (SG) de los pacientes. Materiales y métodos: estudio de cohorte retrospectivo de 50 pacientes con diagnóstico de MM en el hospital Naval Almirante Nef, desde 2005 a 2013. Los pacientes se dividieron en dos cohortes, según la eligibilidad a trasplante, y analizados acordes a la primera línea de tratamiento y la sobrevida global (SG) hasta abril de 2019. Resultados: mediana de edad 73 años (47-88 años), SG 49 meses, y 50% en etapa-II del Sistema de Etapificación Internacional. La SG de los 39 no candidatos a TAH fue 46 meses; con un mayor número de respuestas completas y sobrevida, con el esquema melfalán-prednisona-talidomida. La SG de los 11 candidatos a TAH fue 66 meses, siendo el esquema bortezomib-ciclofosfamida-dexame-tasona el que concentró un mayor número de respuestas completas libres de progresión. Se trasplantó el 45% de los candidatos, con una mediana de sobrevida de 79 meses versus a los 51 meses de aquellos no trasplantados. Tres casos de neuropatía asociada a talidomida y uno a bortezomib. La SG a los seis meses y a los cinco años de todos los pacientes fue 86% y 44%, respectivamente. Conclusión: la incorpo-ración de nuevos fármacos permitió obtener mejores resultados de sobrevida lo que se condice con estudios nacionales e internacionales.
Introduction: Multiple myeloma (MM) is still an incurable disease however, autologous stem cell transplantation (ASCT), and antineo-plastic drugs have allowed improving the overall survival (OS) of patients. Materials and methods: A retrospective cohort study of 50 patients diagnosed with MM at the Hospital Naval Almirante Nef, from 2005 to 2013. The patients were divided into two cohorts according to transplantation eligibility and analyzed about first-line treatment and overall survival (OS) up to April 2019. Results: Median age 73 years (47-88 years), OS 49 months, and 50% in stage-II International Staging System. OS of the 39 non-candidates for ASCT was 46 months: with a higher number of complete responses and survival, with the melphalan-prednisone-thalidomide scheme. The OS of the 11 candidates for ASCT was 66 months, with the bortezomib-cyclophosphamide-dexamethasone scheme being the one with the highest number of progression-free complete responses. Forty-five percent of the candidates were transplanted, with a median survival of 79 months versus 51 months for those not transplanted. Three cases of neuropathy were associated with thalidomide and one with bortezomib. OS at six months and five years for all patients was 86% and 44%, respectively. Conclusion: The incorporation of new drugs allowed to obtain better survival results, which is by national and international studies.
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Humanos , Persona de Mediana Edad , Anciano , Chile , Mieloma Múltiple , Pacientes , Sobrevida , Talidomida , Trasplante Autólogo , Estudios Retrospectivos , Bortezomib , HospitalesRESUMEN
Tumors of the nervous system including glioblastoma multiforme (GBM) are the most frequent and aggressive form of brain tumors; however, little is known about the impact of the circadian timing system on the formation, growth, and treatment of these tumors. We investigated day/night differences in tumor growth after injection of A530 glioma cells isolated from malignant peripheral nerve sheath tumor (MPNSTs) of NPcis (Trp53+/- ; Nf1+/- ) mice. Synchronized A530 cell cultures expressing typical glial markers were injected at the beginning of the day or night into the sciatic nerve zone of C57BL/6 mice subject to a 12:12 hours light/dark (LD) cycle or after being released to constant darkness (DD). Tumors generated in animals injected early at night in the LD cycle or in DD showed higher growth rates than in animals injected diurnally. No differences were found when animals were injected at the same time with cultures synchronized 12 hours apart. Similar experiments performed with B16 melanoma cells showed higher tumor growth rates in animals injected at the beginning of the night compared to those injected in the daytime. A higher tumor growth rate than that in controls was observed when mice were injected with knocked-down clock gene Bmal1 cells. Finally, when we compared day/night administration of different doses of the proteasome inhibitor Bortezomib (0.5-1.5 mg/kg) in tumor-bearing animals, we found that low-dose chemotherapy displayed higher efficacy when administered at night. Results suggest the existence of a precise temporal control of tumor growth and of drug efficacy in which the host state and susceptibility are critical.
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Neoplasias Encefálicas/patología , Ritmo Circadiano , Glioblastoma/patología , Fotoperiodo , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , Factores de Transcripción ARNTL/genética , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Bortezomib/administración & dosificación , Bortezomib/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Línea Celular Tumoral , Esquema de Medicación , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , Ratones , Ratones Endogámicos C57BL , Neurofibromina 1/genética , Células Tumorales Cultivadas , Proteína p53 Supresora de Tumor/genética , Ensayos Antitumor por Modelo de Xenoinjerto/normasRESUMEN
INTRODUCTION: Multiple myeloma (MM) remains an incurable disease, and patient survival requires a better understanding of this malignancy's molecular aspects. Heparanase (HPSE) is highly expressed in aggressive MM cells and related to tumor growth, metastasis, and bortezomib (BTZ) resistance. Thus, targeting HPSE seems to be a promising approach for MM treatment, and because microRNAs (miRNAs) have emerged as potential regulators of HPSE expression, the use of extracellular vesicles (EVs) can allow the efficient delivery of therapeutic miRNAs. METHODS: We used prediction algorithms to identify potential miRNAs that regulate negatively HPSE expression. RT-qPCR was performed to assess miRNAs and HPSE expression in MM lines (U266 and RPMI-8226). Synthetic miRNA mimics were electroporated in MM cells to understand the miRNA contribution in HPSE expression, glycosaminoglycans (GAGs) profile, cell proliferation, and cell death induced by BTZ. EVs derived from HEK293T cells were engineered with miRNAs to evaluate their therapeutic potential combined with BTZ. RESULTS: It revealed a direct association between BTZ sensitivity, HPSE, and miR-1252-5p expressions. Moreover, overexpression of miR-1252-5p significantly reduced HPSE expression and HPSE enzymatic activity in MM cells. The higher level of miR-1252-5p was correlated with a reduction of cell viability and higher sensitivity to BTZ. Further, EVs carrying miR-1252-5p increased MM cells' sensitivity to BTZ treatment. CONCLUSION: These results showed that miR-1252-5p could negatively regulate HPSE in MM, indicating the use of EVs carrying miR-1252-5p as a potential novel BTZ sensitization approach in MM cells.
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Bortezomib, an inhibitor of 26S proteasome, is an anti-cancer therapeutic agent used in different cancer types. It leads to the arrest of the cancerous cell cycle by inhibiting angiogenesis and inducing apoptosis. Liver is the vital organ for detoxification and excretion of toxic products. The treatment with chemotherapy is a challenge, drugs are used to destroy cancer cells, but healthy cells can be affected during cancer treatment as well. The main objective of this study was to analyze the histopathological and biochemical effects of bortezomib on liver. Twenty-four female C57BL/6 mice were distributed into 4 groups, bortezomib injected treatment groups (Btz1, Btz2) and saline injected control groups (C1, C2). Bortezomib and saline were treated twice per week for 6 weeks and sacrificed at the end of one day (Btz1, C1) and 4 weeks (Btz2, C2) after the last injection. Liver samples were examined for histopathological analysis and the serum samples processed for biochemical analysis. Tissue samples were fixed, routinely processed, sectioned, and stained with Hematoxylin and Eosin (H&E). Periodic Acid-Schiff (PAS), Sudan Black staining and Masson's trichrome histochemical staining methods were performed to characterize the lesions. Histopathological analysis of the Btz1 and Btz2 groups revealed acute hepatic morphological changes such as hepatocellular swelling (cloudy swelling), necro-inflammatory reaction, and increased mononuclear polyploidy. Based on the negative staining with PAS and Sudan Black staining, hepatocellular swelling was diagnosed as hydropic degeneration. Necro-inflammatory reaction observed in the form of acute hepatitis was composed of mainly mononuclear cell infiltration accompanied by multifocal necrotic foci. Kupffer cell proliferation was observed in parallel with degenerative and necrotic changes. An Increase in hepatocellular mononuclear polyploidy visualized as hepatocytes with a single enlarged nucleus was detected in all liver sections of Btz1 and Btz2 groups. Individual cases of cholestasis (n = 1) and mild hepatic fibrosis (n = 1) were also reported. Significant elevated levels of alanine aminotransferase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) were detected in bortezomib treated groups. Few clinical cases reported liver injury related to bortezomib used for cancer treatment. However, the liver was not considered as a target for bortezomib treatment. Our data suggesting that bortezomib caused liver damage and induces elevations in serum levels. The reported hepatic lesions including hepatocellular swelling, acute hepatitis and mononuclear polyploidy were mainly mild and moderate in severity. The increase of polyploidy in liver tissue of mice treated with bortezomib in this study was explained as a reaction of the liver facing the drug-induced hepatic damage. The mechanism leading to the hepatotoxicity of bortezomib treatment is not known but the production of a toxic metabolite through its metabolism in the liver can be suggested. Moreover, no recovery was also observed in histopathological and biochemical analyses suggesting that the bortezomib effect is non-reversible four weeks after the drug was withdrawn. Patients should be informed about the possibility of acute drug-induced hepatitis and hepatotoxicity of this chemotherapeutic agent after the treatment.(AU)
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Animales , Femenino , Ratones , Fenómenos Bioquímicos/efectos de los fármacos , Inhibidores de Proteasoma/uso terapéutico , Bortezomib , Hígado/efectos de los fármacos , RatonesRESUMEN
ABSTRACT Background: The treatment of multiple myeloma (MM) has evolved significantly in the past decade, and new drug combinations have improved the response rates and prolonged survival. Studies comparing different induction chemotherapy regimens have shown that triple combinations have better results than double combinations. However, comparisons among different triple combinations are rare in the literature. Methods: We retrospectively compared two triple combinations comprising bortezomib, cyclophosphamide and dexamethasone (VCD) versus thalidomide, cyclophosphamide and dexamethasone (CTD), and aimed at identifying which of the two combinations would yield better response rates following four induction cycles prior to hematopoietic cell transplantation in patients with untreated multiple myeloma. Results: We retrospectively reviewed the medical records of 311 patients from 24 different centers.The VCD regimen was used as induction therapy by 117 (37.6%) patients, whereas 194 (62.4%) patients received the CTD regimen. After four cycles of induction on an intention-to-treat basis, 54% of the patients in the VCD group achieved at least very good partial response versus 42.8% in the CTD group (p = 0.05). We observed no difference in neuropathy or thrombotic events rates among the two regimens. Conclusion: Our results corroborate the superiority of the triple combination regimes containing bortezomib over the triple combination with thalidomide as pre ASCT induction therapy in MM.
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Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica , Trasplante de Médula Ósea , Bortezomib , Mieloma Múltiple , Antineoplásicos , Talidomida , Dexametasona , Ciclofosfamida/uso terapéuticoRESUMEN
Relapsed or refractory acute lymphoblastic leukemia represents a major challenge in low- and middle-income countries where new therapies are not easily accessible. Combinations of cost-effective drugs should be considered as a bridge for hematopoietic stem cell transplantation. We retrospectively analyzed pediatric and adolescent and young adult patients who received reinduction with a protocol based on l-asparaginase, doxorubicin, vincristine, dexamethasone, and bortezomib (BZ). Fifteen patients were included. Total complete response (CR) was achieved by nine of 15 patients (60%); five patients achieved CR with negative minimal residual disease, two achieved complete morphological response (CR), and two complete morphological response without platelet recovery. Eleven patients (73%) were not hospitalized and 10 (66%) did not require any blood component transfusions. There were no cases of serious toxicity or mortality. Nine patients (60%) underwent transplant. Five-year overall survival was 40%. This BZ-based protocol is effective and safe when administered as an outpatient regimen and feasible in a low resource setting.
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Bortezomib/administración & dosificación , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Adolescente , Adulto , Bortezomib/efectos adversos , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , México/epidemiología , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
BACKGROUND: The treatment of patients with multiple myeloma (MM) has evolved in recent years, and the disease-associated prognosis has improved substantially. This improvement has been driven largely by the approval of novel agents, many of which are expensive and not universally available. Less expensive but effective approaches would be of value globally. PATIENTS AND METHODS: All consecutive MM patients diagnosed in the Centro de Hematología y Medicina Interna de Puebla after 1993 were included in this study. Patients were given oral thalidomide (100 mg/day), oral dexamethasone (36-40 mg/week), and aspirin 100 mg/day. Bor-tezomib (1.75 mg s.c. every week) was administered to those who could afford it. After 4-6 weeks of treatment, patients were offered an outpatient-based hematopoietic cell transplant (HCT). After the recovery of granulocytes following HCT, patients continued indefinitely on thalidomide; those who failed to tolerate thalidomide were switched to lenalidomide (25 mg/day). RESULTS: The median overall survival (OS) for all patients has not been reached and is >157 months. Median follow-up of the patients lasted 14 months (range 1.3-157). The median OS of patients with and without HCT was similar. The response rate (complete remission or very good partial remission) was 72% for those given thalidomide plus dexamethasone versus 88% for those given bortezomib, thalidomide, and dexamethasone before HCT, but OS was not different. As post-HCT maintenance, 37 patients received thalidomide; 26 of those (70%) could be maintained indefinitely on thalidomide, whereas 11 were switched to lenalidomide after a median of 7 months; median OS of patients maintained on thalidomide or lenalidomide after HCT was not different. CONCLUSION: In this series, a regimen incorporating low-cost novel agents and outpatient HCT was associated with excellent long-term survival in the treatment of MM patients. This approach may be a model for MM treatment in underprivileged circumstances.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Trasplante de Células Madre Hematopoyéticas , Quimioterapia de Mantención , Mieloma Múltiple/mortalidad , Mieloma Múltiple/terapia , Adulto , Anciano , Aloinjertos , Aspirina/administración & dosificación , Bortezomib/administración & dosificación , Dexametasona/administración & dosificación , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tasa de Supervivencia , Talidomida/administración & dosificaciónRESUMEN
BACKGROUND: The treatment of multiple myeloma (MM) has evolved significantly in the past decade, and new drug combinations have improved the response rates and prolonged survival. Studies comparing different induction chemotherapy regimens have shown that triple combinations have better results than double combinations. However, comparisons among different triple combinations are rare in the literature. METHODS: We retrospectively compared two triple combinations comprising bortezomib, cyclophosphamide and dexamethasone (VCD) versus thalidomide, cyclophosphamide and dexamethasone (CTD), and aimed at identifying which of the two combinations would yield better response rates following four induction cycles prior to hematopoietic cell transplantation in patients with untreated multiple myeloma. RESULTS: We retrospectively reviewed the medical records of 311 patients from 24 different centers.The VCD regimen was used as induction therapy by 117 (37.6%) patients, whereas 194 (62.4%) patients received the CTD regimen. After four cycles of induction on an intention-to-treat basis, 54% of the patients in the VCD group achieved at least very good partial response versus 42.8% in the CTD group (p=0.05). We observed no difference in neuropathy or thrombotic events rates among the two regimens. CONCLUSION: Our results corroborate the superiority of the triple combination regimes containing bortezomib over the triple combination with thalidomide as pre ASCT induction therapy in MM.
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Background The treatment of choice of newly diagnosed multiple myeloma (NDMM) is an induction with proteasome inhibitors followed autologous stem cell transplantation (HSCT). Since 2013, the treatment of these patients in the public system is based on CTD (cyclophosphamide, thalidomide, and dexamethasone). Aim To evaluate the response rates achieved with CTD, and the results of HSCT in patients with NDMM in the public setting. Material and Methods Data from patients considered as candidates for HSCT from different centers of the National Adult Antineoplastic Drug Program (PANDA, for its acronym in Spanish), diagnosed between 2013 and 2017, was analyzed. The response to treatment of first and second lines of treatment was evaluated, in addition to the results of HSCT. An optimal Response was defined as the sum of strict complete remission, complete remission and very good partial response (sCR, CR and VGPR). Results One hundred and seventy-seven patients were analyzed, 54% women, and 53% with IgG multiple myeloma. Information about the international staging system was retrieved in 127 patients (71%). Seventeen percent were ISS I, 22% in ISS II and 32% ISS III. CTD was used as first treatment in 106 patients (60%), and cyclophosphamide, bortezomib and dexamethasone (CyBorD) in 13 (7%). As first line, CTD had an overall response of 50.9%, and CyBorD of 76.9%. Thirty patients were treated with bortezomib as second line treatment. Forty patients (22%) underwent HSCT. The 5-year Overall Survival (OS) in transplanted patients and non-transplanted patients was 100 and 62% respectively (p < 0.01). Conclusions The response rate achieved by CTD in these patients is suboptimal. The response to CyBorD was better.
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Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Trasplante de Células Madre Hematopoyéticas/métodos , Mieloma Múltiple/terapia , Factores de Tiempo , Trasplante Autólogo , Dexametasona/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica , Estudios Retrospectivos , Terapia Combinada , Supervivencia sin Enfermedad , Ciclofosfamida/administración & dosificación , Estimación de Kaplan-Meier , Bortezomib/administración & dosificación , Mieloma Múltiple/mortalidadRESUMEN
ABSTRACT Background Renal failure (RF) is a common complication in patients with newly diagnosed multiple myeloma (NDMM). Aim To evaluate the frequency of RF in NDMM patients, and the prognostic impact of its reversibility. Material and Methods A retrospective study evaluating demographic and clinical characteristics of 154 consecutive patients with NDMM was carried out. Estimated glomerular filtration rate (eGFR) was calculated at the beginning and at the end of the induction therapy. In addition, we evaluated renal responses (RR) according to the International Myeloma Working Group (IMWG) criteria. The induction regimen was based on thalidomide in all cases. Results Fifty-three patients had RF (34.4%). Complete renal response (RR) was achieved in 51%. Three years overall survival in patients without RF, with RF and complete RR, and patients with RF and any other RR, was 66, 47 and 13%, respectively. Median survival was 53, 27 and 6 months, respectively (p < 0.01). In the multivariate analysis, RF and hypercalcemia were independent predictors of a worse outcome. Conclusions Achieving a complete RR in patients with NDMM, is associated with a better survival.
Antecedentes La falla renal (FR) es una complicación frecuente en pacientes con mieloma múltiple (MM). Objetivo Evaluar la frecuencia de FR en pacientes con reciente diagnóstico de MM y determinar la importancia pronóstica de su reversibilidad. Material y Métodos Se realizó un estudio retrospectivo de 154 pacientes consecutivos con MM. La función renal se evaluó mediante la tasa estimada de filtración glomerular al inicio y final de la terapia de inducción. Además, evaluamos las respuestas renales (RR) de acuerdo con los criterios del International Myeloma Working Group (IMWG). El régimen de inducción se basó en talidomida en todos los casos. Resultados Cincuenta y tres pacientes presentaron FR (34,4%) al diagnóstico. La RR completa se logró en 51%. La sobrevida global (SG) a 3 años en pacientes sin FR, con FR y RR completa, y pacientes con FR y cualquier otra RR, fue de 66, 47 y 13%, respectivamente. La SG media fue de 53, 27 y 6 meses (p < 0,01), respectivamente. En el análisis multivariado, la FR y la hipercalcemia fueron factores independientes de menor sobrevida. Conclusiones Lograr una RR completa en pacientes con MM recién diagnosticado se asocia con una mejor sobrevida.
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Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Insuficiencia Renal/etiología , Mieloma Múltiple/complicaciones , Pronóstico , Inducción de Remisión , Protocolos de Quimioterapia Combinada Antineoplásica , Análisis de Supervivencia , Estudios Retrospectivos , Tasa de Filtración Glomerular , Mieloma Múltiple/tratamiento farmacológico , Estadificación de NeoplasiasRESUMEN
ABSTRACT Background: Immunoglobulin light chain (AL) amyloidosis is a rare and underdiagnosed entity. Aim: To characterize patients with AL amyloidosis in Chilean public health centers. Material and Methods: We conducted a retrospective, multicenter study. Public centers of the Chilean Monoclonal Gammopathies Cooperative Group were asked to search for patients with AL amyloidosis in their databases. Epidemiological, clinical and laboratory characteristics were evaluated. Results: Forty-two patients aged 22 to 84 years were found. Twenty four percent had localized AL amyloidosis; 64% had a lambda light chain clone; 47% were associated with multiple myeloma and 9% with non-Hodgkin lymphoma. The most commonly involved organ was the kidney (76%). Serum free light chains were measured in 31% and an echocardiogram was performed in 74% of patients. Seventeen percent of patients received only palliative care, 17% were treated with bortezomib, 21% with thalidomide, and 40% with melphalan. No patient was transplanted. The mean overall survival (OS) of the group was 19 months. The 5-year OS was 28%. Conclusions: It is important to obtain these realistic, national data to initiate strategies to improve early diagnosis and proper management of this disease.
La amiloidosis AL es una entidad poco frecuente y subdiagnosticada. Mientras todo el mundo discute sobre las nuevas herramientas diagnósticas y terapéuticas, en Chile y en América Latina en general, estamos lejos de esa realidad. El objetivo del presente estudio fue caracterizar a los pacientes con amiloidosis AL en centros del sistema público de nuestro país. Se realizó un estudio retrospectivo, multicéntrico, descriptivo. Los centros públicos del grupo cooperativo hematológico chileno buscaron en sus bases de datos pacientes diagnosticados con amiloidosis AL. Se evaluaron las características epidemiológicas, clínicas y de laboratorio. La edad media fue de 65 años. A 24% de los pacientes se les diagnosticó amiloidosis AL localizada; 64% tuvo paraproteína con cadena ligera lambda; 47% se asoció con mieloma múltiple y 9% con linfoma no Hodgkin. El órgano afectado con mayor frecuencia fue el riñón (76%). Las cadenas ligeras libres de suero se realizaron en 31% y ecocardiograma en 74%. El 17% recibió solo cuidados paliativos, 17% recibió tratamiento con bortezomib, 21% con talidomida y 40% con melfalán. Ningún paciente fue trasplantado. La media de sobrevida global (SG) del grupo fue de 19 meses. La SG a 5 años fue de 28%. Es importante reportar estos resultados nacionales para iniciar estrategias que mejoren tanto el diagnóstico temprano como el tratamiento de esta patología. Por lo tanto, mejorar la sospecha diagnóstica es crucial.