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1.
BMC Infect Dis ; 20(1): 161, 2020 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-32085740

RESUMEN

BACKGROUND: Cancer and sepsis comorbidity is a major public health problem in most parts of the world including Zimbabwe. The microbial aetiologies of sepsis and their antibiograms vary with time and locations. Knowledge on local microbial aetiologies of sepsis and their susceptibility patterns is critical in guiding empirical antimicrobial treatment choices. METHODS: This was a descriptive cross-sectional study which determined the microbial aetiologies of sepsis from blood cultures of paediatric and adult cancer patients obtained between July 2016 and June 2017. The TDR-X120 blood culture system and TDR 300B auto identification machine were used for incubation of blood culture bottles and identification plus antimicrobial susceptibility testing, respectively. RESULTS: A total of 142 participants were enrolled; 50 (35.2%) had positive blood cultures, with 56.0% Gram positive, 42.0% Gram-negative bacteria and 2.0% yeast isolated. Common species isolated included coagulase negative Staphylococcus spp. (CoNS) (22.0%), E. coli (16.0%), K. pneumoniae (14.0%), E. faecalis (14.0%) and S. aureus (8.0%). Gram-negative isolates exhibited high resistance to gentamicin (61.9%) and ceftriaxone (71.4%) which are the empiric antimicrobial agents used in our setting. Amikacin and meropenem showed 85.7 and 95.2% activity respectively against all Gram-negative isolates, whilst vancomycin and linezolid were effective against 96.2 and 100.0% of all Gram-positive isolates respectively. We isolated 10 (66.7%) extended spectrum ß-lactamase (ESBL) amongst the E. coli and K. pneumoniae isolates. Ten (66.7%) of the Staphylococcus spp. were methicillin resistant. CONCLUSIONS: CoNS, E. coli, K. pneumoniae, E. faecalis and S. aureus were the major microbial drivers of sepsis amongst cancer patients in Zimbabwe. Most isolates were found to be resistant to commonly used empirical antibiotics, with isolates exhibiting high levels of ESBL and methicillin resistance carriage. A nationwide survey on microbial aetiologies of sepsis and their susceptibility patterns would assist in the guidance of effective sepsis empiric antimicrobial treatment among patients with cancer.


Asunto(s)
Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Hongos/efectos de los fármacos , Neoplasias/microbiología , Sepsis/microbiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Bacterias/aislamiento & purificación , Niño , Preescolar , Estudios Transversales , Farmacorresistencia Microbiana , Femenino , Hongos/aislamiento & purificación , Humanos , Lactante , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Neoplasias/epidemiología , Sepsis/epidemiología , Adulto Joven , Zimbabwe/epidemiología
2.
Haematologica ; 102(5): 895-902, 2017 05.
Artículo en Inglés | MEDLINE | ID: mdl-28183846

RESUMEN

In the phase 3 LYM-3002 study comparing intravenous VR-CAP with R-CHOP in patients with newly-diagnosed, measurable stage II-IV mantle cell lymphoma, not considered or ineligible for transplant, the median progression-free survival was significantly improved with VR-CAP (24.7 versus 14.4 months with R-CHOP; P<0.001). This post-hoc analysis evaluated the association between the improved outcomes and quality of responses achieved with VR-CAP versus R-CHOP in LYM-3002. Patients were randomized to six to eight 21-day cycles of VR-CAP or R-CHOP. Outcomes included progression-free survival, duration of response (both assessed by an independent review committee), and time to next anti-lymphoma treatment, evaluated by response (complete response/unconfirmed complete response and partial response), MIPI risk status, and maximum reduction of lymph-node measurements expressed as the sum of the product of the diameters. Within each response category, the median progression-free survival was longer for patients given VR-CAP than for those given R-CHOP (complete response/unconfirmed complete response: 40.9 versus 19.8 months; partial response: 17.1 versus 11.7 months, respectively); similarly, the median time to next anti-lymphoma treatment was longer among the patients given VR-CAP than among those treated with R-CHOP (complete response/unconfirmed complete response: not evaluable versus 26.6 months; partial response: 35.3 versus 24.3 months). Within the complete/unconfirmed complete and partial response categories, improvements in progression-free survival, duration of response and time to next anti-lymphoma treatment were more pronounced in patients with low-and intermediate-risk MIPI treated with VR-CAP than with R-CHOP. In each response category, more VR-CAP than R-CHOP patients had a sum of the product of the diameters nadir of 0 during serial radiological assessments. Results of this post-hoc analysis suggest a greater duration and quality of response in patients treated with VR-CAP in comparison with those treated with R-CHOP, with the improvements being more evident in patients with low- and intermediate-risk MIPI. LYM-3002 ClinicalTrials.gov: NCT00722137.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma de Células del Manto/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Ciclofosfamida/administración & dosificación , Doxorrubicina/administración & dosificación , Femenino , Humanos , Estimación de Kaplan-Meier , Linfoma de Células del Manto/patología , Masculino , Persona de Mediana Edad , Prednisona/administración & dosificación , Inducción de Remisión , Rituximab/administración & dosificación , Vincristina/administración & dosificación
3.
Cancer ; 122(13): 2050-6, 2016 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-27191689

RESUMEN

BACKGROUND: Previous results from an interim analysis of an open-label, randomized, phase 3 study demonstrated that bortezomib combined with pegylated liposomal doxorubicin (PLD) was superior to bortezomib monotherapy in patients with relapsed/refractory multiple myeloma who had previously received one or more lines of therapy. Protocol-defined final survival data from that study are provided here. METHODS: Patients were randomized (1:1) to receive either bortezomib alone (1.3 mg/m(2) intravenously on days 1, 4, 8, and 11 of every 21-day cycle) or bortezomib-PLD (bortezomib plus PLD 30 mg/m(2) intravenously on day 4). The primary endpoint was the time to progression. Secondary efficacy endpoints included overall survival (OS), progression-free survival, and the overall response rate. RESULTS: In total, 646 patients (bortezomib-PLD, n = 324; bortezomib alone, n = 322) were randomized between December, 2004, and March, 2006. On the clinical cutoff date (May 16, 2014) for the final survival analysis, at a median follow-up of 103 months, 79% of patients had died (bortezomib-PLD group: 253 of 324 patients; 78%; bortezomib alone group: 257 of 322 patients; 80%). The median OS in the bortezomib-PLD group was 33 months (95% confidence interval [CI], 28.9-37.1) versus 30.8 months (95% CI, 25.2-36.5) in the bortezomib alone group (hazard ratio, 1.047; 95% CI, 0.879-1.246; P = .6068). Salvage therapies included conventional and novel drugs, which were well balanced between the two treatment groups. CONCLUSIONS: Despite inducing a superior time to progression, long-term follow-up revealed that PLD-bortezomib did not improve OS compared with bortezomib alone in patients with relapsed/refractory multiple myeloma. The inability to sustain the early observed survival advantage may have been caused by the effects of subsequent lines of therapy, and underscores the need for long-term follow-up of phase 3 trials while recognizing the challenge of having adequate power to detect long-term differences in OS. Cancer 2016;122:2050-6. © 2016 American Cancer Society.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Bortezomib/administración & dosificación , Doxorrubicina/análogos & derivados , Mieloma Múltiple/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Administración Intravenosa , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bortezomib/uso terapéutico , Supervivencia sin Enfermedad , Doxorrubicina/administración & dosificación , Doxorrubicina/uso terapéutico , Esquema de Medicación , Femenino , Humanos , Masculino , Mieloma Múltiple/mortalidad , Polietilenglicoles/administración & dosificación , Polietilenglicoles/uso terapéutico , Resultado del Tratamiento
4.
Blood ; 124(16): 2498-506, 2014 Oct 16.
Artículo en Inglés | MEDLINE | ID: mdl-25202139

RESUMEN

CAN2007 was a phase 1/2 study of once- and twice-weekly single-agent bortezomib in relapsed primary systemic amyloid light chain amyloidosis (AL) amyloidosis. Seventy patients were treated, including 18 and 34 patients at the maximum planned doses on the once- and twice-weekly schedules. This prespecified final analysis provides mature response and long-term outcomes data after 3-year additional follow-up since the last report. In the once-weekly 1.6 mg/m(2) and twice-weekly 1.3 mg/m(2) bortezomib groups, final hematologic response rates were 68.8% and 66.7%; 80% of patients in each group sustained their response for ≥1 year. One-year progression-free rates were 72.2% and 76.8%. Median overall survival (OS) was 62.1 months and not reached; 4-year OS rates were 75.0% and 63.0%. Low baseline difference in κ/λ free light-chain level was associated with higher hematologic complete response rates and longer OS. At data cutoff, 40 (57%) patients had received subsequent therapy, including 19 (27%) retreated with bortezomib, 11 (58%) of whom achieved complete or partial hematologic responses. Four patients received prolonged bortezomib for between 3.5 and 5.6 years, with no new safety concerns, highlighting the feasibility of long-term therapy. Single-agent bortezomib produced durable hematologic responses and promising long-term OS in relapsed AL amyloidosis. This trial was registered at www.clinicaltrials.gov as #NCT00298766.


Asunto(s)
Amiloidosis/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Ácidos Borónicos/uso terapéutico , Pirazinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Ácidos Borónicos/efectos adversos , Bortezomib , Femenino , Estudios de Seguimiento , Humanos , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas , Masculino , Persona de Mediana Edad , Pirazinas/efectos adversos , Recurrencia , Análisis de Supervivencia
5.
Ann Hematol ; 95(12): 2033-2041, 2016 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-27738789

RESUMEN

Bortezomib-melphalan-prednisone (VMP) is a standard-of-care for previously untreated, transplant-ineligible multiple myeloma (MM). Here, we compared outcomes between VMP regimens in the VISTA trial (9-cycle VMP schedule, including 4 cycles of twice weekly bortezomib) and the PETHEMA/GEM05 trial (less intensive 6-cycle VMP schedule with 1 cycle of twice weekly and 5 cycles of weekly bortezomib, then bortezomib-based maintenance). A total of 113 patient pairs matched by propensity score (estimated using logistic regression and incorporating eight exposure/outcome-related parameters) were included in this retrospective analysis. Median cumulative bortezomib dose was higher in PETHEMA/GEM05 than VISTA (49.6 vs 37.0 mg/m2); median dose intensity was lower (2.0 vs 5.1 mg/m2/month). Median progression-free survival (PFS) and time-to-progression (TTP) were significantly longer in PETHEMA/GEM05 than VISTA (PFS, 30.5 vs 20.0 months, p = 0.0265; TTP, 33.8 vs 24.2 months, p = 0.0049) after a median follow-up of 77.2 and 26.0 months, respectively. Median overall survival (OS) was similar (61.3 vs 61.0 months, p = 0.6528; median follow-up, 77.6 vs 60.1 months). Post-induction complete response rate was lower in PETHEMA/GEM05 than VISTA (19 vs 31 %; p = 0.03318); on-study (including maintenance) rate was similar (30 vs 31 %; p = 0.89437). This analysis suggests that the less-intensive PETHEMA/GEM05 VMP regimen plus maintenance may improve PFS and TTP, but not OS, compared with the VISTA VMP regimen. TRIAL REGISTRATIONS: NCT00111319, NCT00443235.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Bortezomib/administración & dosificación , Melfalán/administración & dosificación , Mieloma Múltiple/tratamiento farmacológico , Prednisona/administración & dosificación , Anciano , Esquema de Medicación , Femenino , Estudios de Seguimiento , Humanos , Masculino , Análisis por Apareamiento , Mieloma Múltiple/diagnóstico , Estudios Retrospectivos , Factores de Tiempo , Resultado del Tratamiento
6.
Oncologist ; 18(1): 27-36, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23299777

RESUMEN

The outlook for transplant-ineligible multiple myeloma patients has improved enormously over recent years with the incorporation of new agents into standard regimens. Novel regimens combine melphalan and prednisone (MP) with bortezomib (VMP), with thalidomide (MPT), and with lenalidomide with (MPR-R) and without (MPR) lenalidomide maintenance. The efficacy, safety, and cost-effectiveness of these regimens have not yet been compared; therefore, we conducted a pharmacoeconomic analysis using data from randomized controlled trials versus MP. Using a Markov model developed from a U.S. payer's perspective, we compared VMP with MPT and MPR-R over a lifetime horizon. MPT and MPR-R were chosen because, like VMP, they are superior to MP in response and outcomes. Data from the Velcade as Initial Standard Therapy in Multiple Myeloma (VISTA; VMP), Intergroupe Francophone du Myelome (IFM) 99-06 (MPT), and MM-015 (MPR-R) trials were used. The IFM 99-06 study was selected because of the superior activity in this study compared with other MPT studies. Using patient-level (VMP) and published (MPT, MPR-R) data, we estimated the health-state transition and adverse event probabilities for each regimen, related costs, and state-specific utility estimates. Costs (in 2010 U.S. dollars) and health outcomes were discounted at 3%. Discounted lifetime direct medical costs were lowest with VMP at $119,102. MPT cost $142,452 whereas MPR-R cost $248,358. Incremental cost-effectiveness ratio calculations projected that VMP would confer cost savings and better health outcomes relative to MPT and MPR-R. We conclude that VMP is highly likely to be cost-effective compared with MP, MPT, and MPR-R.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/economía , Análisis Costo-Beneficio/economía , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/economía , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Ácidos Borónicos/administración & dosificación , Bortezomib , Ensayos Clínicos Controlados como Asunto , Femenino , Humanos , Lenalidomida , Masculino , Cadenas de Markov , Melfalán/administración & dosificación , Mieloma Múltiple/patología , Estadificación de Neoplasias , Prednisona/administración & dosificación , Pirazinas/administración & dosificación , Talidomida/administración & dosificación , Talidomida/análogos & derivados , Estados Unidos
7.
Blood ; 118(4): 865-73, 2011 Jul 28.
Artículo en Inglés | MEDLINE | ID: mdl-21562045

RESUMEN

This first prospective phase 2 study of single-agent bortezomib in relapsed primary systemic AL amyloidosis evaluated the recommended (maximum planned) doses identified in phase 1 testing (1.6 mg/m² once weekly [days 1, 8, 15, and 22; 35-day cycles]; 1.3 mg/m² twice weekly [days 1, 4, 8, and 11; 21-day cycles]). Among all 70 patients enrolled in the study, 44% had ≥ 3 organs involved, including 73% and 56% with renal and cardiac involvement. In the 1.6 mg/m² once-weekly and 1.3 mg/m² twice-weekly groups, the hematologic response rate was 68.8% and 66.7% (37.5% and 24.2% complete responses, respectively); median time to first/best response was 2.1/3.2 and 0.7/1.2 months, and 78.8% and 75.5% had response durations of ≥ 1 year, respectively. One-year hematologic progression-free rates were 72.2% and 74.6%, and 1-year survival rates were 93.8% and 84.0%, respectively. Outcomes appeared similar in patients with cardiac involvement. Among all 70 patients, organ responses included 29% renal and 13% cardiac responses. Rates of grade ≥ 3 toxicities (79% vs 50%) and discontinuations/dose reductions (38%/53% vs 28%/22%) resulting from toxicities appeared higher with 1.3 mg/m² twice-weekly versus 1.6 mg/m² once-weekly dosing. Both bortezomib dose schedules represent active, well-tolerated regimens in relapsed AL amyloidosis. This study was registered at www.clinicaltrials.gov as #NCT00298766.


Asunto(s)
Amiloidosis/tratamiento farmacológico , Ácidos Borónicos/administración & dosificación , Inhibidores de Proteasas/administración & dosificación , Pirazinas/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Ácidos Borónicos/efectos adversos , Ácidos Borónicos/uso terapéutico , Bortezomib , Femenino , Humanos , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas , Masculino , Persona de Mediana Edad , Inhibidores de Proteasas/efectos adversos , Inhibidores de Proteasas/uso terapéutico , Pirazinas/efectos adversos , Pirazinas/uso terapéutico , Recurrencia
8.
Blood ; 116(19): 3743-50, 2010 Nov 11.
Artículo en Inglés | MEDLINE | ID: mdl-20628153

RESUMEN

The phase 3 Velcade as Initial Standard Therapy in Multiple Myeloma: Assessment with Melphalan and Prednisone study in newly diagnosed multiple myeloma patients ineligible for high-dose therapy demonstrated that bortezomib-melphalan-prednisone (VMP) was superior to melphalan-prednisone across all efficacy end points. We assessed the prognostic impact of response on time-to-event parameters in the intent-to-treat population. Patients received nine 6-week cycles of treatment. Time to progression, time to next therapy, and treatment-free interval were associated with quality of response. When European Group for Blood and Marrow Transplantation criteria were used, complete response (CR) was associated with significantly longer time to progression (hazard ratio [HR] = 0.45, P = .004), time to next therapy (HR = 0.46, P = .0004), and treatment-free interval (HR = 0.38, P < .0001) versus partial response, but there was no significant difference in overall survival (HR = 0.87, P = .54); similar differences were seen with CR versus very good partial response by uniform criteria. Quality of response improved with prolonged VMP treatment, with 28% of CRs achieved during cycles 5-9. CR duration appeared similar among patients with "early" (cycles 1-4) and "late" CRs (cycles 5-9) and among patients receiving 9 versus < 9 cycles of bortezomib within VMP. These results highlight that CR is an important treatment goal and support prolonged VMP therapy to achieve maximal response. This study is registered at http://www.clinicaltrials.gov as NCT00111319.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Ácidos Borónicos/administración & dosificación , Melfalán/administración & dosificación , Mieloma Múltiple/tratamiento farmacológico , Prednisona/administración & dosificación , Pirazinas/administración & dosificación , Anciano , Bortezomib , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Mieloma Múltiple/mortalidad , Análisis Multivariante , Pronóstico , Inducción de Remisión , Factores de Tiempo , Resultado del Tratamiento
9.
Haematologica ; 97(12): 1925-8, 2012 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-22689676

RESUMEN

The phase III MMY-3021 study compared safety and efficacy of subcutaneous versus intravenous administration of the proteasome inhibitor bortezomib in patients with relapsed myeloma. The initial report demonstrated non-inferior efficacy with subcutaneous versus intravenous bortezomib for the primary end point: overall response rate after four cycles of single-agent bortezomib. We report updated outcome analyses after prolonged follow up. Best response rate (after up to ten cycles of bortezomib ± dexamethasone) remained 52% in each arm, including 23% and 22% complete or near-complete responses with subcutaneous and intravenous bortezomib, respectively. Time to progression (median 9.7 vs. 9.6 months; hazard ratio 0.872, P=0.462), progression-free survival (median 9.3 vs. 8.4 months; hazard ratio 0.846, P=0.319), and overall survival (1-year: 76.4% vs. 78.0%, P=0.788) were comparable with subcutaneous versus intravenous bortezomib. Peripheral neuropathy rates remained significantly lower with subcutaneous versus intravenous bortezomib, with increased rates of improvement/resolution at the time of this analysis.


Asunto(s)
Antineoplásicos/uso terapéutico , Ácidos Borónicos/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/mortalidad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/mortalidad , Pirazinas/uso terapéutico , Anciano , Anciano de 80 o más Años , Bortezomib , Femenino , Estudios de Seguimiento , Humanos , Inyecciones Intravenosas , Inyecciones Subcutáneas , Masculino , Pronóstico , Inducción de Remisión , Tasa de Supervivencia
10.
Eur J Haematol ; 89(1): 16-27, 2012 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-22469559

RESUMEN

OBJECTIVES: The phase 3 VISTA study (ClinicalTrials.gov NCT00111319) in transplant-ineligible myeloma patients demonstrated superior efficacy with bortezomib-melphalan-prednisone (VMP; nine 6-wk cycles) vs. melphalan-prednisone (MP) but also increased toxicity. Health-related quality of life (HRQoL; exploratory endpoint) was evaluated using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30). The phase 3 VISTA study (ClinicalTrials.gov NCT00111319) in transplant-ineligible myeloma patients demonstrated superior efficacy with bortezomib-melphalan-prednisone (VMP; nine 6-wk cycles) vs. melphalan-prednisone (MP) but also increased toxicity. Health-related quality of life (HRQoL; exploratory endpoint) was evaluated using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30). METHODS: EORTC QLQ-C30 was administered at screening, on day 1 of each cycle, at the end-of-treatment visit, and every 8 wk until progression. EORTC QLQ-C30 scores were evaluated among patients with a valid baseline and at least one post-baseline HRQoL assessment. RESULTS: At baseline, domain scores were similar between arms. By cycle 4, mean differences were clinically meaningful for most domains, indicating poorer health status with VMP. From cycle 5 onwards, improvements relative to baseline/MP were observed for all domains with VMP. Mean scores were generally improved by the end-of-treatment assessment vs. baseline in both arms. Among responding patients, mean scores generally improved from time of response to end-of-treatment assessment, substantially driven by patients achieving complete response (CR). Multivariate analysis showed a significant impact of duration of response/CR on improving global health status, pain, and appetite loss scores. Analyses by bortezomib dose intensity indicated better HRQoL in patients receiving lower dose intensity. CONCLUSIONS: These findings demonstrate clinically meaningful, transitory HRQoL decrements with VMP and relatively lower HRQoL vs. MP during early treatment cycles, associated with the expected additional toxicities. However, HRQoL is not compromised in the long term, recovering by the end-of-treatment visit to be comparable vs. MP.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Calidad de Vida , Anciano , Anciano de 80 o más Años , Ácidos Borónicos/administración & dosificación , Bortezomib , Femenino , Humanos , Masculino , Melfalán/administración & dosificación , Melfalán/uso terapéutico , Persona de Mediana Edad , Prednisona/administración & dosificación , Prednisona/uso terapéutico , Pirazinas/administración & dosificación , Resultado del Tratamiento
11.
PLoS One ; 17(8): e0273186, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35980979

RESUMEN

Coronavirus disease 2019 (COVID-19) is caused by a recently identified virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the disease is a pandemic. Although the hallmarks of severe COVID-19 have been established, the underlying mechanisms that promote severe pathology have not been thoroughly studied. A better understanding of the immune response in severe COVID-19 patients may help guide the development of therapeutic strategies and predict immuno-pathogenicity. This study was set to determine the lymphocyte and cytokine profiles associated with COVID-19 severity. A total of 43 hospitalised COVID-19 patients were recruited for the study and whole blood samples were drawn from each patient. Complete blood counts, lymphocyte subset profiles and C-reactive protein statuses of patients were determined. Cytometric bead array was performed to analyse the cytokine profiles of each patient. The demographic characteristics showed that the median age of the patients was 48.72 years, with an interquartile range from 40 to 60 years, and 69.77% of the patients were male. COVID-19 patients exhibited significantly low CD4+ lymphocyte expansion and leucocytosis augmented by elevated neutrophil and immature granulocytes. Stratification analysis revealed that reduced monocytes and elevated basophils and immature granulocytes are implicated in severe pathology. Additionally, cytokine results were noted to have significant incidences of interleukin 17A (IL-17A) expression associated with severe disease. Results from this study suggest that a systemic neutrophilic environment may preferentially skew CD4+ lymphocytes towards T-helper 17 and IL-17A promotion, thus, aggravating inflammation. Consequently, results from this study suggest broad activity immunomodulation and targeting neutrophils and blocking IL-17 production as therapeutic strategies against severe COVID-19.


Asunto(s)
COVID-19 , Adulto , Linfocitos T CD4-Positivos , Citocinas , Femenino , Humanos , Interleucina-17 , Masculino , Persona de Mediana Edad , Infiltración Neutrófila , SARS-CoV-2 , Células Th17
12.
Br J Haematol ; 153(2): 212-21, 2011 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-21375521

RESUMEN

Although haematological toxicities, such as anaemia, are common in multiple myeloma (MM), no clear consensus exists on the use and impact of erythropoiesis-stimulating agents (ESA) on outcomes in MM. This analysis characterizes haematological toxicities and associated interventions in the phase III VISTA (Velcade(®) as Initial Standard Therapy in Multiple Myeloma: Assessment with Melphalan and Prednisone) study of bortezomib plus melphalan/prednisone (VMP, n = 344) versus MP (n = 338) in previously untreated MM patients ineligible for high-dose therapy, and evaluates the impact of ESA use or red-blood-cell (RBC) transfusions on outcomes and thromboembolic risk. Incidence of haematological toxicities was similar with VMP and MP; similar rates of interventions and associated complications (e.g. bleeding, febrile neutropenia) were observed. Two hundred thirty three patients received ESA; 204 had RBC transfusions. Frequency of thromboembolic events was low and not affected by ESA use. Median time-to progression (TTP) was similar between ESA/non-ESA [hazard ratio: 1·03 (95% confidence interval 0·76-1·39); P = 0·8478] in both arms (VMP: 19·9/not reached; MP: 15·0/17·5 months). Three-year overall survival (OS) rates were similar between ESA/non-ESA in each arm. Patients receiving RBC transfusions had significantly shorter OS (P < 0·0001) versus non-RBC-transfusion patients. In conclusion, bortezomib did not add to melphalan haematological toxicity. Concomitant ESA use with VMP/MP in previously untreated MM patients did not adversely affect TTP or OS, or increase thromboembolic risk. However, RBC transfusion was associated with significantly shorter survival.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Transfusión de Eritrocitos , Hematínicos , Mieloma Múltiple , Tromboembolia , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ácidos Borónicos/administración & dosificación , Ácidos Borónicos/efectos adversos , Bortezomib , Supervivencia sin Enfermedad , Femenino , Hematínicos/administración & dosificación , Hematínicos/efectos adversos , Humanos , Incidencia , Masculino , Melfalán/administración & dosificación , Melfalán/efectos adversos , Persona de Mediana Edad , Mieloma Múltiple/mortalidad , Mieloma Múltiple/terapia , Prednisolona/administración & dosificación , Prednisolona/efectos adversos , Pirazinas/administración & dosificación , Pirazinas/efectos adversos , Tasa de Supervivencia , Tromboembolia/etiología , Tromboembolia/mortalidad , Tromboembolia/terapia
13.
N Engl J Med ; 359(9): 906-17, 2008 Aug 28.
Artículo en Inglés | MEDLINE | ID: mdl-18753647

RESUMEN

BACKGROUND: The standard treatment for patients with multiple myeloma who are not candidates for high-dose therapy is melphalan and prednisone. This phase 3 study compared the use of melphalan and prednisone with or without bortezomib in previously untreated patients with multiple myeloma who were ineligible for high-dose therapy. METHODS: We randomly assigned 682 patients to receive nine 6-week cycles of melphalan (at a dose of 9 mg per square meter of body-surface area) and prednisone (at a dose of 60 mg per square meter) on days 1 to 4, either alone or with bortezomib (at a dose of 1.3 mg per square meter) on days 1, 4, 8, 11, 22, 25, 29, and 32 during cycles 1 to 4 and on days 1, 8, 22, and 29 during cycles 5 to 9. The primary end point was the time to disease progression. RESULTS: The time to progression among patients receiving bortezomib plus melphalan-prednisone (bortezomib group) was 24.0 months, as compared with 16.6 months among those receiving melphalan-prednisone alone (control group) (hazard ratio for the bortezomib group, 0.48; P<0.001). The proportions of patients with a partial response or better were 71% in the bortezomib group and 35% in the control group; complete-response rates were 30% and 4%, respectively (P<0.001). The median duration of the response was 19.9 months in the bortezomib group and 13.1 months in the control group. The hazard ratio for overall survival was 0.61 for the bortezomib group (P=0.008). Adverse events were consistent with established profiles of toxic events associated with bortezomib and melphalan-prednisone. Grade 3 events occurred in a higher proportion of patients in the bortezomib group than in the control group (53% vs. 44%, P=0.02), but there were no significant differences in grade 4 events (28% and 27%, respectively) or treatment-related deaths (1% and 2%). CONCLUSIONS: Bortezomib plus melphalan-prednisone was superior to melphalan-prednisone alone in patients with newly diagnosed myeloma who were ineligible for high-dose therapy. (ClinicalTrials.gov number, NCT00111319.)


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ácidos Borónicos/administración & dosificación , Melfalán/administración & dosificación , Mieloma Múltiple/tratamiento farmacológico , Prednisona/administración & dosificación , Pirazinas/administración & dosificación , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ácidos Borónicos/efectos adversos , Bortezomib , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Melfalán/efectos adversos , Persona de Mediana Edad , Pirazinas/efectos adversos , Análisis de Supervivencia , Factores de Tiempo , Resultado del Tratamiento
14.
Blood ; 114(8): 1489-97, 2009 Aug 20.
Artículo en Inglés | MEDLINE | ID: mdl-19498019

RESUMEN

New treatment options are required for primary systemic AL amyloidosis (AL). This phase 1 dose-escalation component of a phase 1/2 study in relapsed AL aimed to determine the maximum tolerated dose (MTD) of bortezomib once weekly (0.7-1.6 mg/m(2); days 1, 8, 15, and 22; 35-day cycles) and twice weekly (0.7-1.3 mg/m(2); days 1, 4, 8, and 11; 21-day cycles) and assess preliminary hematologic responses. Thirty-one patients with relapsed AL were enrolled across 7 cohorts. Dose-limiting toxicity included grade 3 congestive heart failure in 2 patients (1 at once weekly, 1.6 mg/m(2), and 1 at twice weekly, 1.0 mg/m(2)). MTD was not defined for either schedule; the maximum doses of 1.6 mg/m(2) (once weekly) and 1.3 mg/m(2) (twice weekly) are being used in phase 2 evaluation. Most commonly reported toxicities on both schedules included gastrointestinal events, fatigue, and nervous system disorders. Discontinuations and dose reductions for toxicity were reported in 12 and 4 patients, respectively. No treatment-related deaths occurred. Hematologic responses occurred in 15 (50%) of 30 evaluable patients, including 6 (20%) complete responses. Median time to first response was 1.2 months. Once-weekly and twice-weekly bortezomib appear generally well tolerated in relapsed AL, with promising hematologic responses. This study is registered with http://ClinicalTrials.Gov under identifier NCT00298766.


Asunto(s)
Amiloidosis/tratamiento farmacológico , Ácidos Borónicos/administración & dosificación , Pirazinas/administración & dosificación , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Ácidos Borónicos/efectos adversos , Bortezomib , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Pirazinas/efectos adversos , Resultado del Tratamiento
15.
Eur J Haematol ; 86(1): 23-31, 2011 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-20874823

RESUMEN

OBJECTIVES: This subanalysis of the phase 3 VISTA trial aimed to assess the frequency, characteristics and reversibility of, and prognostic factors for, bortezomib-associated peripheral neuropathy (PN) in newly diagnosed patients with multiple myeloma ineligible for high-dose therapy who received bortezomib plus melphalan-prednisone. METHODS: Patients received nine 6-wk cycles of VMP (bortezomib 1.3 mg/m(2), days 1, 4, 8, 11, 22, 25, 29, 32, cycles 1-4, and days 1, 8, 22, 29, cycles 5-9; melphalan 9 mg/m(2), days 1-4, cycles 1-9; and prednisone 60 mg/m(2), days 1-4, cycles 1-9). RESULTS: Overall, 47% of patients receiving VMP developed PN, including 19% grade 2 and 13% grade ≥ 3 (<1% grade 4). The PN incidence was dose-related and reached a plateau at a cumulative bortezomib dose of approximately 45 mg/m(2). Median time to PN onset was 2.3 months. Bortezomib-associated PN was reversible; 79% of events improved by at least one NCI CTCAE grade within a median of 1.9 months and 60% completely resolved within a median of 5.7 months, with reversibility similar in responding and non-responding patients. By multivariate analysis, baseline neuropathy was the only consistent risk factor for any PN [hazard ratio (HR) 1.785, P=0.0065], grade ≥ 2 PN (HR 2.205, P=0.0032), and grade ≥ 3 PN (HR 2.438, P=0.023); age, pre-existing diabetes, International Staging System stage, obesity, and creatinine clearance did not affect the overall rate of PN. CONCLUSIONS: Rates of bortezomib-induced PN in the frontline setting were similar to those in relapsed patients and resolved in most cases.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Ácidos Borónicos/toxicidad , Mieloma Múltiple/complicaciones , Mieloma Múltiple/tratamiento farmacológico , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Pirazinas/toxicidad , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidad , Ácidos Borónicos/administración & dosificación , Bortezomib , Femenino , Humanos , Masculino , Melfalán/administración & dosificación , Melfalán/efectos adversos , Persona de Mediana Edad , Análisis Multivariante , Enfermedades del Sistema Nervioso Periférico/etiología , Prednisona/administración & dosificación , Prednisona/efectos adversos , Pirazinas/administración & dosificación , Factores de Riesgo
16.
Eur J Haematol ; 86(5): 372-84, 2011 May.
Artículo en Inglés | MEDLINE | ID: mdl-21366694

RESUMEN

OBJECTIVES: Bone disease is a key presenting feature of myeloma. This post hoc analysis of the phase III VISTA trial of bortezomib plus melphalan-prednisone (VMP) vs. MP in previously untreated myeloma patients assessed clinical bone disease events and changes in alkaline phosphatase (ALP), a marker for osteoblast activation, and serum Dickkopf-1 (DKK-1), an inhibitor of osteoblast differentiation, during treatment. METHODS: Patients received nine 6-wk cycles of VMP (bortezomib 1.3 mg/m(2) , days 1, 4, 8, 11, 22, 25, 29, 32, cycles 1-4, days 1, 8, 22, 29, cycles 5-9, plus melphalan 9mg/m(2) and prednisone 60mg/m(2) , days 1-4, cycles 1-9; N=344) or MP alone (N=338). RESULTS: Rates of bisphosphonates use during treatment (73% vs. 82%), progression because of worsening bone disease (3% vs. 11%), and requirement for subsequent radiotherapy (3% vs. 8%) were lower with VMP vs. MP. Median maximum ALP increase was significantly higher with VMP vs. MP overall (49.7% vs. 30.3%, P=0.029), and higher by response group (complete response [CR]: 68.7% vs. 43.9%; partial response [PR]: 41.5% vs. 31.2%). Greater maximum ALP increase was strongly associated with achievement of CR (P≤0.0001) and CR/PR (P≤0.01). Median DKK-1 decreased with VMP by 694.4pg/mL and increased with MP by 1273.3pg/mL from baseline to day 4 (P=0.0069). Available radiologic data revealed evidence of bone healing in 6/11 VMP-treated patients, who achieved best responses of three CR, one PR, and two stable disease. CONCLUSIONS: These results suggest a positive effect of bortezomib on bone metabolism and potentially bone healing in myeloma.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Enfermedades Óseas/prevención & control , Remodelación Ósea/efectos de los fármacos , Mieloma Múltiple/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Fosfatasa Alcalina/sangre , Biomarcadores/sangre , Enfermedades Óseas/etiología , Enfermedades Óseas/patología , Enfermedades Óseas/fisiopatología , Ácidos Borónicos/administración & dosificación , Bortezomib , Diferenciación Celular/efectos de los fármacos , Femenino , Humanos , Péptidos y Proteínas de Señalización Intercelular/sangre , Masculino , Melfalán/administración & dosificación , Persona de Mediana Edad , Mieloma Múltiple/complicaciones , Mieloma Múltiple/patología , Mieloma Múltiple/fisiopatología , Osteoblastos/efectos de los fármacos , Osteoblastos/metabolismo , Osteoblastos/patología , Prednisona/administración & dosificación , Pirazinas/administración & dosificación , Radioterapia Adyuvante
17.
Cancer Res ; 78(5): 1155-1168, 2018 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-29259009

RESUMEN

RAS mutations occur frequently in multiple myeloma (MM), but apart from driving progression, they can also stimulate antitumor effects by activating tumor-suppressive RASSF proteins. Although this family of death effector molecules are often silenced in cancers, functional data about RASSF proteins in MM are lacking. Here, we report that RASSF4 is downregulated during MM progression and correlates with a poor prognosis. Promoter methylation analysis in human cell lines revealed an inverse correlation between RASSF4 mRNA levels and methylation status. Epigenetic modulating agents restored RASSF4 expression. Enforced expression of RASSF4 induced G2-phase cell-cycle arrest and apoptosis in human cell lines, reduced primary MM cell viability, and blocked MM growth in vivo Mechanistic investigations showed that RASSF4 linked RAS to several pro-death pathways, including those regulated by the kinases MST1, JNK, and p38. By activating MST1 and the JNK/c-Jun pathway, RASSF4 sensitized MM cells to bortezomib. Genetic or pharmacological elevation of RASSF4 levels increased the anti-MM effects of the clinical relevant MEK1/2 inhibitor trametinib. Kinome analysis revealed that this effect was mediated by concomitant activation of the JNK/c-Jun pathway along with inactivation of the MEK/ERK and PI3K/mTOR/Akt pathways. Overall, our findings establish RASSF4 as a tumor-suppressive hub in MM and provide a mechanistic rationale for combining trametinib with HDAC inhibitors or bortezomib to treat patients with tumors exhibiting low RASSF4 expression.Significance: These findings provide a mechanistic rationale for combining trametinib with HDAC inhibitors or bortezomib in patients with multiple myeloma whose tumors exhibit low RASSF4 expression. Cancer Res; 78(5); 1155-68. ©2017 AACR.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Metilación de ADN , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Mieloma Múltiple/patología , Proteínas Supresoras de Tumor/metabolismo , Proteínas ras/genética , Animales , Apoptosis , Biomarcadores de Tumor/genética , Bortezomib/farmacología , Proliferación Celular , Progresión de la Enfermedad , Resistencia a Antineoplásicos , Femenino , Estudios de Seguimiento , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Sistema de Señalización de MAP Quinasas , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones SCID , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/genética , Mieloma Múltiple/metabolismo , Pronóstico , Regiones Promotoras Genéticas , Proteínas Proto-Oncogénicas c-akt/metabolismo , Piridonas/farmacología , Pirimidinonas/farmacología , Tasa de Supervivencia , Células Tumorales Cultivadas , Proteínas Supresoras de Tumor/genética , Ensayos Antitumor por Modelo de Xenoinjerto
18.
Haematologica ; 92(10): 1399-406, 2007 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-18024376

RESUMEN

There are a number of reports in literature data on the long-term outcomes of patients with multiple myeloma treated with high-dose therapy and autologous stem cell transplantation (HDT/SCT). While in general these data support the association between maximal tumor response and overall survival or progression-free survival after HDT/SCT, some trials have failed to find such correlation and there is no recent comprehensive literature analysis of this issue. We, therefore, performed a comprehensive literature review to identify prospective and retrospective studies on HDT/SCT in frontline multiple myeloma in which long-term outcomes were reported according to best tumor response observed. Following a prospectively defined search strategy we identified 21 studies (10 prospective and 11 retrospective studies) in which outcomes of 4,990 HDT/SCT patients according to their best tumor response were reported. The majority of these studies indicated a correlation between maximal response during or after HDT/SCT and long-term outcomes (overall survival and event-free/progression-free survival). The conclusions in individual studies report on the association between maximal response following induction therapy and long-term outcomes were more heterogeneous, possibly due to the low rate of complete response after standard induction therapy in each individual study. We, therefore, performed two types of meta-analyses, one based on the p-values reported for these associations in the individual studies, and one based on the primary response and outcome data provided in the individual studies. Both meta-analyses indicated highly significant associations between maximal response (complete response/near complete response/very good partial response) during or after HDT/SCT and long-term outcomes (overall survival and event-free/progression-free survival). Both meta-analyses also provided evidence of highly significant associations between maximal response following induction therapy and long-term outcomes (overall survival and event-free/progression-free survival).


Asunto(s)
Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/patología , Progresión de la Enfermedad , Relación Dosis-Respuesta a Droga , Humanos , Tasa de Supervivencia , Factores de Tiempo , Resultado del Tratamiento
19.
Surg Neurol Int ; 7(Suppl 15): S437-9, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27308093

RESUMEN

BACKGROUND: Chronic subdural hematomas (CSDHs) usually occur in elderly patients following minor head trauma. Their occurrence is usually linked to cerebral atrophy secondary to alcohol, old age, or human immunodeficiency virus (HIV) infection. Spontaneous CSDHs have also been documented but are rare. They are usually caused by coagulopathies and various pathologies resulting in intracranial hypotension. CASES: We have observed a number of spontaneous CSDHs in HIV patients with normal platelet counts and no appreciable cerebral atrophy possibly caused by platelet dysfunction, hence we report about two such cases. To the best of our knowledge, no such cases have been reported in literature before. CONCLUSION: It is important to include CSDHs in the differential diagnosis of HIV patients presenting with neurological deficits even without a history of trauma.

20.
J Clin Oncol ; 31(26): 3279-87, 2013 Sep 10.
Artículo en Inglés | MEDLINE | ID: mdl-23897961

RESUMEN

PURPOSE: To characterize efficacy and safety of bortezomib-based versus nonbortezomib-based induction regimens through an integrated analysis of data from phase III studies in transplantation-eligible patients with previously untreated myeloma. PATIENTS AND METHODS: Patient-level data from the IFM 2005-01 (bortezomib-dexamethasone v vincristine-doxorubicin-dexamethasone [VAD] induction), HOVON-65/GMMG-HD4 (bortezomib-doxorubicin-dexamethasone v VAD), and PETHEMA GEM05MENOS65 (bortezomib-thalidomide-dexamethasone v thalidomide-dexamethasone) studies were pooled in an integrated analysis of efficacy and safety. Study-level data from the GIMEMA MM-BO2005 study (bortezomib-thalidomide-dexamethasone v thalidomide-dexamethasone) supplemented the integrated patient-level analysis. Key efficacy end points were post-transplantation complete plus near-complete response (CR+nCR) rate and progression-free survival (PFS). RESULTS: Patient-level data for 1,572 patients (bortezomib-based induction, n = 787; nonbortezomib-based induction, n = 785) were included. Post-transplantation CR+nCR rate was significantly higher following bortezomib-based versus nonbortezomib-based induction (38% v 24%; odds ratio, 2.05; P < .001); the benefit remained similar (pooled odds ratio, 1.96) when GIMEMA MM-BO2005 data were included. Median PFS was 35.9 months versus 28.6 months with bortezomib-based versus nonbortezomib-based induction, respectively (hazard ratio, 0.75; P < .001); 3-year overall survival (OS) rates were 79.7% and 74.7%, respectively (hazard ratio for OS, 0.81; P = .0402). Median duration of induction treatment was 11 weeks in both treatment groups. Rates of peripheral neuropathy during induction were 34% versus 17% (grade ≥ 3, 6% v 1%). Overall, 3% and 4% of patients died during bortezomib-based and nonbortezomib-based induction, respectively. CONCLUSION: Bortezomib-based induction results in significant improvements in response and PFS/OS compared with nonbortezomib-based induction and is generally well tolerated, with a higher rate of peripheral neuropathy but no apparent increase in risk of death during induction.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Trasplante de Células Madre , Adulto , Anciano , Ácidos Borónicos/administración & dosificación , Bortezomib , Ensayos Clínicos Fase III como Asunto , Dexametasona/administración & dosificación , Método Doble Ciego , Doxorrubicina/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/mortalidad , Recurrencia Local de Neoplasia/mortalidad , Estadificación de Neoplasias , Pronóstico , Pirazinas/administración & dosificación , Ensayos Clínicos Controlados Aleatorios como Asunto , Inducción de Remisión , Tasa de Supervivencia , Talidomida/administración & dosificación , Trasplante Autólogo
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