RESUMEN
The neuron-to-neuron propagation of misfolded α-synuclein (αSyn) aggregates is thought to be key to the pathogenesis of synucleinopathies. Recent studies have shown that extracellular αSyn aggregates taken up by the endosomal-lysosomal system can rupture the lysosomal vesicular membrane; however, it remains unclear whether lysosomal rupture leads to the transmission of αSyn aggregation. Here, we applied cell-based αSyn propagation models to show that ruptured lysosomes are the pathway through which exogenous αSyn aggregates transmit aggregation, and furthermore, this process was prevented by lysophagy, i.e., selective autophagy of damaged lysosomes. αSyn aggregates accumulated predominantly in lysosomes, causing their rupture, and seeded the aggregation of endogenous αSyn, initially around damaged lysosomes. Exogenous αSyn aggregates induced the accumulation of LC3 on lysosomes. This LC3 accumulation was not observed in cells in which a key regulator of autophagy, RB1CC1/FIP200, was knocked out and was confirmed as lysophagy by transmission electron microscopy. Importantly, RB1CC1/FIP200-deficient cells treated with αSyn aggregates had increased numbers of ruptured lysosomes and enhanced propagation of αSyn aggregation. Furthermore, various types of lysosomal damage induced using lysosomotropic reagents, depletion of lysosomal enzymes, or more toxic species of αSyn fibrils also exacerbated the propagation of αSyn aggregation, and impaired lysophagy and lysosomal membrane damage synergistically enhanced propagation. These results indicate that lysophagy prevents exogenous αSyn aggregates from escaping the endosomal-lysosomal system and transmitting aggregation to endogenous cytosolic αSyn via ruptured lysosomal vesicles. Our findings suggest that the progression and severity of synucleinopathies are associated with damage to lysosomal membranes and impaired lysophagy.
Asunto(s)
Enfermedad de Parkinson , Sinucleinopatías , Humanos , alfa-Sinucleína/metabolismo , Macroautofagia , Sinucleinopatías/metabolismo , Enfermedad de Parkinson/metabolismo , Lisosomas/metabolismoRESUMEN
BACKGROUND: Hematopoietic cell transplantation (HCT) is a promising treatment for hematological diseases, yet access barriers like cost and limited transplant centers persist. Telemedicine-based patient navigation (PN) has emerged as a solution. This study presents a cost-free PN telemedicine clinic (TC) in collaboration with the National Marrow Donor Program. AIM: to assess its feasibility and impac on HCT access determined by the cumulative incidence of transplantation. METHODS: In this single-center cohort study, patients of all ages and diagnoses referred for HCT participated. Two transplant physician-navigators established patient relationships via video calls, collecting medical history, offering HCT education and recommending pretransplant tests. The analysis involved descriptive statistics and intent-to-transplant survival assessment. RESULTS: One hundred and three patients were included of whom n = 78 were referred for allogeneic HCT (alloHCT), with a median age of 28 years. The median time from initial contact to the first consult was 5 days. The cumulative incidence of transplantation was 50% at 6 months and 61% at 12 months, with varying outcomes based on HCT type. Notably, 49 patients were not transplanted, primarily due to refractory disease, progression or relapse (57.1%). Autologous HCT candidates and physician referrals were correlated with higher transplant success compared to alloHCT candidates and patients who were not referred by a physician. CONCLUSION: Our pretransplant TC was feasible, facilitating access to HCT. Disease relapse posed a significant barrier. Enhancing timely physician referrals should be a focus for future efforts.
RESUMEN
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive accumulation of α-synuclein aggregates in form of Lewy bodies. Genome-wide association studies have revealed that human leukocyte antigen (HLA) class II is a PD-associated gene, although the mechanisms linking HLA class II and PD remain elusive. Here, we identified a novel function of HLA class II in the transport of intracellular α-synuclein to the outside of cells. HLA class II molecules and α-synuclein formed complexes and moved to the cell surface at various degrees among HLA-DR alleles. HLA-DR with a DRB5∗01:01 allele, a putative PD-risk allele, substantially translocated normal and conformationally abnormal α-synuclein to the cell surface and extracellular vesicles. α-Synuclein/HLA class II complexes were found in A2058 melanoma cells, which express intrinsic α-synuclein and HLA-DR with DRB5∗01:01. Our findings will expand our knowledge of unconventional HLA class II function from autoimmune diseases to neurodegenerative disorders, shedding light on the association between the GWAS-prioritized PD-risk gene HLA-DR and α-synuclein.
Asunto(s)
Enfermedad de Parkinson , alfa-Sinucleína , Humanos , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo , Estudio de Asociación del Genoma Completo , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , Cuerpos de Lewy/metabolismo , Antígenos HLARESUMEN
Lipid interaction with α-synuclein (αSyn) has been long implicated in the pathogenesis of Parkinson's disease (PD). However, it has not been fully determined which lipids are involved in the initiation of αSyn aggregation in PD. Here exploiting genetic understanding associating the loss-of-function mutation in Synaptojanin 1 (SYNJ1), a phosphoinositide phosphatase, with familial PD and analysis of postmortem PD brains, we identified a novel lipid molecule involved in the toxic conversion of αSyn and its relation to PD. We first established a SYNJ1 knockout cell model and found SYNJ1 depletion increases the accumulation of pathological αSyn. Lipidomic analysis revealed SYNJ1 depletion elevates the level of its substrate phosphatidylinositol-3,4,5-trisphosphate (PIP3). We then employed Caenorhabditis elegans model to examine the effect of SYNJ1 defect on the neurotoxicity of αSyn. Mutations in SYNJ1 accelerated the accumulation of αSyn aggregation and induced locomotory defects in the nematodes. These results indicate that functional loss of SYNJ1 promotes the pathological aggregation of αSyn via the dysregulation of its substrate PIP3, leading to the aggravation of αSyn-mediated neurodegeneration. Treatment of cultured cell line and primary neurons with PIP3 itself or with PIP3 phosphatase inhibitor resulted in intracellular formation of αSyn inclusions. Indeed, in vitro protein-lipid overlay assay validated that phosphoinositides, especially PIP3, strongly interact with αSyn. Furthermore, the aggregation assay revealed that PIP3 not only accelerates the fibrillation of αSyn, but also induces the formation of fibrils sharing conformational and biochemical characteristics similar to the fibrils amplified from the brains of PD patients. Notably, the immunohistochemical and lipidomic analyses on postmortem brain of patients with sporadic PD showed increased PIP3 level and its colocalization with αSyn. Taken together, PIP3 dysregulation promotes the pathological aggregation of αSyn and increases the risk of developing PD, and PIP3 represents a potent target for intervention in PD.
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Enfermedad de Parkinson , Humanos , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo , Encéfalo/patología , Lípidos , Neuronas/patología , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , Fosfatos de Fosfatidilinositol/metabolismoRESUMEN
BACKGROUND: Despite the improvements in supportive care for allogeneic-hematopoietic cell transplantation (allo-HCT) recipients, infectious complications and infection-related mortality (IRM) continue to be a major issue for transplantation centers. METHODS: We herein report the infectious complications and IRM of 107 and 89 patients that underwent haploidentical (haplo-HCT) or HLA-identical HCT at a tertiary referral center during 2013-2020. Patients in the haplo-HCT group received post-transplant cyclophosphamide (PT-Cy), and all received reduced-intensity conditioning regimens. RESULTS: More haplo-HCT recipients presented severe infections in the pre-engraftment period (22.4% vs. 6.7%, p = 0.003). Viral (14.9% vs. 4.5%, p = 0.016) and fungal (12.1% vs. 1.1%, p = 0.003) etiologies were more common in this period in this group. The 100-day and 2-year cumulative incidence of IRM was 15% and 21% for the haplo-HCT and 5.6% and 17% for the HLA-identical group; no significant differences were observed between the groups. Fungal pathogens mainly contributed to IRM (33.3%). Infections were the most common cause of mortality (40/81, 49.4%). There were significant differences in donor/recipient CMV serostatus between transplant groups (0.002). CONCLUSIONS: No differences in IRM were observed based on allo-HCT type, with more haplo-HCT patients suffering from severe infections in the pre-engraftment period. Studies to assess future prevention, diagnostic, and treatment strategies to reduce IRM are warranted.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Humanos , Pacientes Ambulatorios , Enfermedad Injerto contra Huésped/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Ciclofosfamida , Donantes de Tejidos , Acondicionamiento Pretrasplante , Estudios RetrospectivosRESUMEN
This paper presents an approach to integrate tire wear buildup and rainfall-runoff models to simulate tire wear buildup on road surfaces and its subsequent transport in stormwater runoff events. To do so, a buildup model is presented based on vehicle kilometers traveled, vehicle type, vehicle speed, and road roughness within a watershed. This buildup model was integrated into an EPA SWMM model that simulated the runoff of tire wear particles in twelve watersheds in the San Francisco, CA bay area. Results demonstrate that tire wear particle buildup within the watersheds ranged between 0.4 and 0.51 (kg/km2) per hour. Applied to the SWMM model, total event mean tire wear concentrations ranged between 0.5 and 67 µg/L. These concentrations were linearly correlated to depth-integrated samples collected at the outlet of each of the watersheds (R2 = 0.66). The proposed modeling approach can ultimately be applied to create solutions to an emerging stormwater contaminant.
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Monitoreo del Ambiente , Monitoreo del Ambiente/métodosRESUMEN
Background and Objectives: Urinary incontinence (UI) is a condition that is more common in women than men and has an increasing prevalence with age. It provides a range of psychological and physical burdens that negatively affect the patient's quality of life (QoL). However, the economic burden for the healthcare system is being augmented due to the increasing life expectancy of the population. This article aims to identify the effectiveness of pelvic floor muscle training (PFMT) on the QoL in women with UI. Materials and Methods: A systematic review and meta-analysis were conducted in the PubMed, EMBASE, ProQuest medicine, Cochrane Library, and Google Scholar databases. The terms selected according to components of PICOS were women with urinary incontinence, pelvic floor muscle training, watchful or other types of therapies, quality of life, randomized controlled trials, and interventional or observational studies. The articles included were those published between November 2018 and November 2022. Ten articles were found for the systematic review and eight for the meta-analysis. Results: The QoL moderately increased when PFMT was used on women with UI, the results indicating an overall small effect on the QoL across the controlled studies and a moderate effect on the QoL across the one-group pre-post-studies. Conclusions: Specific QoL domains, such as social activities and general health, also demonstrated benefits from PFMT interventions. This study confirmed the effectiveness of PFMT on the QoL in women with UI, mainly for patients with stress urinary incontinence.
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Terapia por Ejercicio , Diafragma Pélvico , Incontinencia Urinaria , Femenino , Humanos , Diafragma Pélvico/fisiología , Calidad de Vida , Resultado del Tratamiento , Incontinencia Urinaria/terapiaRESUMEN
Polyphosphates (polyPs), chains of phosphate residues found in species across nature from bacteria to mammals, were recently reported to accelerate the amyloid fibril formation of many proteins. How polyPs facilitate this process, however, remains unknown. To gain insight into their mechanisms, we used various physicochemical approaches to examine the effects of polyPs of varying chain lengths on ultrasonication-dependent α-synuclein (α-syn) amyloid formation. Although orthophosphate and diphosphate exhibited a single optimal concentration of amyloid formation, triphosphate and longer-chain phosphates exhibited two optima, with the second at a concentration lower than that of orthophosphate or diphosphate. The second optimum decreased markedly as the polyP length increased. This suggested that although the optima at lower polyP concentrations were caused by interactions between negatively charged phosphate groups and the positive charges of α-syn, the optima at higher polyP concentrations were caused by the Hofmeister salting-out effects of phosphate groups, where the effects do not depend on the net charge. NMR titration experiments of α-syn with tetraphosphate combined with principal component analysis revealed that, at low tetraphosphate concentrations, negatively charged tetraphosphates interacted with positively charged "KTK" segments in four KTKEGV repeats located at the N-terminal region. At high concentrations, hydrated tetraphosphates affected the surface-exposed hydrophilic groups of compact α-syn. Taken together, our results suggest that long-chain polyPs consisting of 60 to 70 phosphates induce amyloid formation at sub-µM concentrations, which are comparable with the concentrations of polyPs in the blood or tissues. Thus, these findings may identify a role for polyPs in the pathogenesis of amyloid-related diseases.
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Amiloide/biosíntesis , Polifosfatos/farmacología , Agregado de Proteínas/efectos de los fármacos , alfa-Sinucleína/química , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , alfa-Sinucleína/metabolismoRESUMEN
BACKGROUND AND PURPOSE: The aim was to investigate the association between serum asymmetric dimethylarginine (ADMA) levels and the progression and prognosis of amyotrophic lateral sclerosis (ALS), and to compare cerebrospinal fluid (CSF) and serum ADMA levels with other biomarkers of ALS. METHODS: Serum ADMA levels of sporadic ALS patients (n = 68), disease control patients (n = 54) and healthy controls (n = 20) were measured using liquid chromatography tandem mass spectrometry. Correlations of the ADMA level and other markers (nitric oxide and neurofilament light chain levels) were analyzed. Changes in the ALS Functional Rating Scale Revised (ALSFRS-R) score from the onset of disease (ALSFRS-R pre-slope) was used to assess disease progression. Survival was evaluated using the Cox proportional hazards model and Kaplan-Meier analysis. RESULTS: The serum ADMA level was substantially higher in patients with ALS than in healthy controls and disease controls. Serum ADMA level correlated with CSF ADMA level (r = 0.591, p < 0.0001) and was independently associated with the ALSFRS-R pre-slope (r = 0.505, p < 0.0001). Patients with higher serum ADMA levels had less favorable prognoses. CSF ADMA level significantly correlated with CSF neurofilament light chain level (r = 0.456, p = 0.0002) but not with nitric oxide level (r = 0.194, p = 0.219). CONCLUSION: Serum ADMA level is an independent biomarker of ALS disease progression and prognosis and reflects the degree of motor neuron degeneration.
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Esclerosis Amiotrófica Lateral , Esclerosis Amiotrófica Lateral/diagnóstico , Arginina/análogos & derivados , Biomarcadores , Progresión de la Enfermedad , Humanos , Óxido Nítrico , PronósticoRESUMEN
INTRODUCTION: Historically, the measurement of serum procalcitonin (PCT) levels in patients with leukopenia has been rejected without sufficient prospective evidence to justify this argument. On the other hand, the accumulated use of broad spectrum antibiotics in these patients and their consequences make the use of PCT attractive in an effort to reduce its use. PATIENTS AND METHODS: We conducted a prospective study between 2016 and 2018, recruiting newly diagnosed FN patients, evaluating them with PCT levels during the first 24 h. After this we evaluate them with overall survival throughout the follow-up. RESULTS: A total of 81 episodes of FN in 72 patients were included. We report a mortality of 27.2% in our cohort. The mean serum PCT in these patients was 4.01 ng/mL compared to 0.42 ng/mL in the survivors group (p < 0.01). Using ROC curves, we determined a cut-off point to predict septic shock/death at 0.46 ng/mL. Patients with a procalcitonin >0.46 ng/mL had an increased risk of death, with a HR of 4.43, (p = 0.048). CONCLUSION: In conclusion, in our trial a single PCT on admission at a cut-off value of 0.46 ng/mL was able to predict the occurrence of septic shock and death in FN patients.
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Neutropenia Febril , Polipéptido alfa Relacionado con Calcitonina/sangre , Adulto , Supervivencia sin Enfermedad , Neutropenia Febril/sangre , Neutropenia Febril/mortalidad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Tasa de SupervivenciaRESUMEN
OBJECTIVE: Alpha-synuclein (α-syn) is a major component of Lewy bodies, which are the pathological hallmark in Parkinson's disease, and its genetic mutations cause familial forms of Parkinson's disease. Patients with α-syn G51D mutation exhibit severe clinical symptoms. However, in vitro studies showed low propensity for α-syn with the G51D mutation. We studied the mechanisms associated with severe neurotoxicity of α-syn G51D mutation using a murine model generated by G51D α-syn fibril injection into the brain. METHODS: Structural analysis of wild-type and G51D α-syn-fibrils were performed using Fourier transform infrared spectroscopy. The ability of α-syn fibrils forming aggregates was first assessed in in vitro mammalian cells. An in vivo mouse model with an intranigral injection of α-syn fibrils was then used to evaluate the propagation pattern of α-syn and related cellular changes. RESULTS: We found that G51D α-syn fibrils have higher ß-sheet contents than wild-type α-syn fibrils. The addition of G51D α-syn fibrils to mammalian cells overexpressing α-syn resulted in the formation of phosphorylated α-syn inclusions at a higher rate. Similarly, an injection of G51D α-syn fibrils into the substantia nigra of a mouse brain induced more widespread phosphorylated α-syn pathology. Notably, the mice injected with G51D α-syn fibrils exhibited progressive nigral neuronal loss accompanied with mitochondrial abnormalities and motor impairment. CONCLUSION: Our findings indicate that the structural difference of G51D α-syn fibrils plays an important role in the rapidly developed and more severe neurotoxicity of G51D mutation-linked Parkinson's disease. © 2019 International Parkinson and Movement Disorder Society.
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Cuerpos de Lewy/patología , Enfermedad de Parkinson/patología , Sustancia Negra/patología , alfa-Sinucleína/metabolismo , Animales , Encéfalo/metabolismo , Encéfalo/patología , Humanos , Cuerpos de Inclusión/metabolismo , Cuerpos de Lewy/metabolismo , Masculino , Ratones Endogámicos C57BL , Mutación/genética , Enfermedad de Parkinson/genética , Fosforilación , Sustancia Negra/metabolismoRESUMEN
PURPOSE: To evaluate the safety and efficacy of ocular cyclosporine in the prevention of the development of ocular graft versus host disease (oGVHD) in patients undergoing allogeneic hematopoietic stem cell transplantation (AHSCT) in comparison with historic data. DESIGN: We developed a longitudinal, observational, prospective nonrandomized study. We evaluated the feasibility of prophylactic use of topical cyclosporine A (CsA) to prevent or decrease the incidence of oGVHD and compared this with historic data. METHODS: Patients undergoing AHSCT were treated with prophylactic topical CsA for 12 months after engraftment, followed by serial ophthalmic evaluations, including the Schirmer test. RESULTS: Twenty patients were included. No serious adverse effects were reported. Poor adherence was documented in 15% of patients. In spite of observing extra-ocular GVHD (acute and chronic GVHD incidence of 50 and 45%, respectively), only 1 in 20 patients developed oGVHD over the 20-month follow-up for the entire cohort. No statistically significant difference was observed in the incidence of oGVHD when compared to a historical cohort. CONCLUSIONS: Topical CsA as a prophylactic measure for oGVHD, administered over a period of 1 year after grafting, is safe and feasible and may decrease the incidence of ophthalmic manifestations of GVHD. These findings must be confirmed in a randomized trial.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Ciclosporina , Ojo , Humanos , Estudios ProspectivosRESUMEN
BACKGROUND: The impact of HLA-DPB1 compatibility and its role as a transplantation antigen in haploidentical-related hematopoietic stem cell transplant (haplo-R-HSCT) have not been established, and a negative effect on survival has been suggested. OBJECTIVE: The objective of the determine was to study the frequency and clinical effects of incompatibility at the HLA-DPB1 locus in the haplo-R-HSCT setting. METHODS: Clinical records and electronic files of 91 patients with a hematological disease who underwent haplo-HSCT from January 2009 to October 2017 in a university medical center were scrutinized. Overall survival (OS) was estimated by the Kaplan-Meier method; the cumulative incidence of transplant-related mortality (TRM) and relapse rates was determined. Acute graft-versus-host disease was assessed by binary logistic regression. Cox regression model with a 95% confidence interval was used to examine the association between the different variables and their effect on OS. RESULTS: Of the 91 donor-recipient pairs, 24 (26.37%) shared complete DPB1 identity, 60 (65.93%) had a mismatch at one allele, and 7 (7.70%) were mismatched at two alleles. Twenty-four different HLA-DPB1 alleles were found; the most frequent were DPB1*04:01 (34.1%) and DPB1*04:02 (27.5%). Two-year OS, the cumulative incidence of TRM and relapse was 51.3 ± 6.8%, 28 ± 6% and 60 ± 7.8% for all haplo-related transplants, respectively, with no statistical difference between HLA-DPB1 matched and partially matched patients. In Cox regression analysis, no risk factors associated with OS, TRM, or relapses were identified. CONCLUSION: HLA-DPB1 mismatching in the haplo-R-HSCT setting did not influence transplant outcomes and was clinically tolerable. A high degree of homozygosity was found.
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Cadenas beta de HLA-DP , Enfermedades Hematológicas/cirugía , Trasplante de Células Madre Hematopoyéticas/métodos , Trasplante Haploidéntico , Adolescente , Adulto , Niño , Preescolar , Selección de Donante , Femenino , Enfermedades Hematológicas/mortalidad , Humanos , Lactante , Masculino , Persona de Mediana Edad , Selección de Paciente , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Autologous stem cell transplantation (ASCT) is an effective treatment for patients with relapsing myeloma or lymphoma, diseases associated with unsuccessful peripheral blood stem cell (PBSC) collection. Plerixafor is a potent mobilizing agent, allowing more CD34+ cells to be obtained; however, the main obstacle for its use is its high cost. Our aim was to demonstrate that of the use of reduced doses of plerixafor (RD-plerixafor) can be sufficient to collect at least 2 × 106 /Kg CD34+ PBSC in patients with multiple myeloma (MM) or lymphoma undergoing ASCT. STUDY DESIGN AND METHODS: Twenty patients were mobilized with filgrastim (10 µg/kg/4 days) plus a single dose of plerixafor 0.12 mg/kg in Day 4. Apheresis collection was performed on Day 5. One vial of plerixafor was used for two patients. Clinicaltrials.gov NCT03244930. RESULTS: Cell mobilization and collection was successful in 85% of patients (≥2 × 106 CD34+ cells per kilogram). The median collected CD34+ cell count was 4.62 × 106 /kg (range, 1.27-24.5). A 4.1-fold-increase in the median CD34+ PBSC pre-count was observed (from 10.4/µl to 42.4/µl) after RD-plerixafor administration. Seven patients had mild to moderate adverse events. CONCLUSION: RD-plerixafor is an effective, safe, and affordable strategy to ensure adequate PBSC mobilization in patients with MM or lymphoma who undergo ASCT.
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Trasplante de Células Madre Hematopoyéticas/métodos , Compuestos Heterocíclicos/administración & dosificación , Compuestos Heterocíclicos/uso terapéutico , Adulto , Anciano , Antígenos CD34/metabolismo , Bencilaminas , Eliminación de Componentes Sanguíneos , Ciclamas , Femenino , Movilización de Célula Madre Hematopoyética/métodos , Humanos , Linfoma/terapia , Masculino , Persona de Mediana Edad , Mieloma Múltiple/terapia , Prueba de Estudio Conceptual , Trasplante AutólogoRESUMEN
INTRODUCTION: The use of filgrastim biosimilars for healthy adult and pediatric donor mobilization in hematopoietic stem cell transplantation has been met with increased safety and efficacy concerns in contrast to generic small molecule drugs. In Mexico, several filgrastim-intended copies (FIC) have been available and marketed since 2001, while no clinical comparability studies to evaluate their use in this setting have been published and thus are not considered to be true biosimilars. In this study, we report our experience using three different FIC products currently available (Filatil, Dextrifyl, and Biofilgran). METHODS: We retrospectively evaluated 118 related donors of all ages who received any brand 5 µg/kg subcutaneously twice daily for 4 days and were harvested in a single apheresis system on day 5. RESULTS: Donors had a median age of 38 years (range, 1-69). A successful harvest defined as ≥2 × 106 CD34+ cells/kg of recipient weight was achieved in 95.8% of cases, with a median CD34+ cell dose of 9.4 × 106 /kg (range 1-42.8). A single apheresis session was performed in 89.8% of cases. No significant difference in cell yield between each brand was observed. All pediatric donors had a successful harvest with similar results to adult donors. No immediate severe adverse effects were documented in any case. CONCLUSIONS: In conclusion, three FICs available in Mexico were efficacious and without immediate severe adverse effects, resulting in significant cost savings. Evaluation of immunogenicity and establishment of a pharmacovigilance program with the use of FICs is warranted.
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Sustitución de Medicamentos/normas , Filgrastim/normas , Movilización de Célula Madre Hematopoyética/métodos , Adolescente , Adulto , Factores de Edad , Anciano , Antígenos CD34/análisis , Niño , Preescolar , Filgrastim/administración & dosificación , Movilización de Célula Madre Hematopoyética/economía , Movilización de Célula Madre Hematopoyética/normas , Humanos , Lactante , México , Persona de Mediana Edad , Estudios Retrospectivos , Donantes de Tejidos , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: The treatment of multiple myeloma (MM) has become costly and difficult to access for patients living in low-income to middle-income countries. METHODS: The current retrospective study included 148 patients in Mexico with newly diagnosed MM, and was performed to compare the outcomes of patients with and without access to novel agents. The records of 77 patients admitted to a public hospital (PubC) and 71 patients cared for within private health systems (PrivC) from November 2007 to July 2016 were reviewed. RESULTS: Compared with those treated in PrivC, patients receiving care at PubC were more likely to be diagnosed with advanced disease. A thalidomide-based regimen was the most common induction treatment used at PubC, whereas a bortezomib-based regimen was used most often in PrivC. The median follow-up was 41 months. Patients in PrivC demonstrated better response rates and survival; 65% of patients treated in PrivC versus 41% treated at PubC achieved a very good partial response or better (P = .005). The median progression-free survival and median overall survival were 23 months and 51 months, respectively, for patients treated at PubC and 41 months and 79 months, respectively, for those treated in PrivC (P<.001). More patients underwent autologous stem cell transplantation in PrivC. When adjustments were made for covariates, patients treated at PubC experienced a higher risk of death compared with patients receiving care in PrivC (hazard ratio, 2.0; 95% confidence interval, 1.0-4.3 [P = .04]). CONCLUSIONS: Stage at diagnosis, induction regimen, and autologous stem cell transplantation were found to be contributors to survival disparities between patients with MM treated at PubC compared with PrivC in Mexico. These findings underscore the need to improve access to novel agents and stem cell transplantation in public health systems. Cancer 2018;124:1946-53. © 2018 American Cancer Society.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Costos de los Medicamentos , Accesibilidad a los Servicios de Salud/economía , Disparidades en Atención de Salud/economía , Trasplante de Células Madre Hematopoyéticas/economía , Mieloma Múltiple/terapia , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/economía , Bortezomib/economía , Bortezomib/uso terapéutico , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Accesibilidad a los Servicios de Salud/estadística & datos numéricos , Disparidades en Atención de Salud/estadística & datos numéricos , Trasplante de Células Madre Hematopoyéticas/estadística & datos numéricos , Hospitales Privados/economía , Hospitales Privados/estadística & datos numéricos , Hospitales Públicos/economía , Hospitales Públicos/estadística & datos numéricos , Humanos , Masculino , México/epidemiología , Persona de Mediana Edad , Mieloma Múltiple/economía , Mieloma Múltiple/mortalidad , Mieloma Múltiple/patología , Estudios Retrospectivos , Talidomida/economía , Talidomida/uso terapéutico , Trasplante Autólogo/economía , Trasplante Autólogo/estadística & datos numéricos , Resultado del TratamientoAsunto(s)
Síndrome de Bronquiolitis Obliterante , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Humanos , Piperidinas , Linfocitos B , Esteroides , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Enfermedad Injerto contra Huésped/etiología , Enfermedad CrónicaRESUMEN
There is no information about XCL1 in patients with acute lymphoblastic leukemia (ALL). The objective of this study was to correlate the serum levels of XCL1 and survival in ALL patients. Only ALL patients older than 12 months were considered to participate. Serum XCL1 was measured at diagnosis, end of remission induction, and end of consolidation. Thirty-three ALL patients with median age of 21 years (1-78) were included. Higher XCL1 level (above 50 pg/mL) at ALL diagnosis correlated with higher survival (p = 0.038), whereas XCL1 level at end of induction and consolidation had no significant correlation. Concerning the behavior of serum XCL1 during treatment, higher survival at 5 years was observed in the group with progressively decreased levels of XCL1 (70%) than those with progressively increasing (29%) or no detectable XCL1 (14%). In conclusion, higher serum XCL1 levels at diagnosis and their progressive decline throughout chemotherapy could be correlated with higher survival.
Asunto(s)
Quimiocinas C/sangre , Proteínas de Neoplasias/sangre , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangre , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Adolescente , Adulto , Anciano , Niño , Preescolar , Supervivencia sin Enfermedad , Humanos , Lactante , Masculino , Persona de Mediana Edad , Proyectos Piloto , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Estudios Prospectivos , Tasa de SupervivenciaRESUMEN
Immune thrombocytopenia (ITP) results from platelet destruction and production suppression. Eltrombopag belongs to a new class of thrombopoietin-mimetic drugs that raise platelet counts in ITP patients. We performed a single-arm study to assess the response to a single course of dexamethasone (40 mg by mouth, days 1-4) in combination with eltrombopag (50 mg, days 5-32) in 12 adults with newly diagnosed ITP in an outpatient setting. Median follow-up was 12.5 months. After therapy (day 33), 100% of patients achieved at least ≥30 × 10(9)/L platelets. Four patients relapsed. Complete response at 6 months (platelets ≥100 × 10(9)/L) was achieved in 50% of patients and response at 6 months (platelets ≥30 <100 × 10(9)/L) was achieved in another 25%; relapse-free survival was 66.7% at 12 months (median response duration of 8.3 months). In conclusion, eltrombopag/dexamethasone is a feasible frontline therapy for ITP. This trial is registered at www.clinicaltrials.gov as NCT01652599.