RESUMO
According to the European legislation, thermal treatment of category 2 slaughterhouse by-products at 140⯰C, 4-5â¯bar for 20â¯min is obligatory for their hygienization prior to disposal. This process is known as "rendering". The product of the rendering process is rich in lipids and proteins making it an appropriate feedstock for biogas plants. The mathematical modeling of biogas production from slaughterhouse wastes after the rendering process has been studied adjusting the anaerobic digestion model (ADM1). For this purpose, two mesophilic (38-39⯰C) continuous stirred tank reactors (CSTRs) have been operated in parallel under a hydraulic retention time of 21.5⯱â¯2.14â¯d, while the organic load was increased from 50 to 149.6â¯g COD L-1. Recirculation of the mixed liquor suspended solids (MLSS) took place in one of the CSTRs, resulting in a different solids' concentration in it. The ADM1 was calibrated by estimating key kinetic parameters, such as the maximum specific consumption rate constant and the half-saturation constants of volatile fatty acids and verified. The degradation kinetics of this type of waste seemed to be faster, as a result of its emulsification through rendering, while the coefficient yields of the acidogens were lower than the default values of ADM1. The structure of the model was proven suitable for predicting the response of both bioreactors under small or medium step transitions, but not for abrupt impulse disturbances in the organic loading rate.
Assuntos
Matadouros , Anaerobiose , Biocombustíveis , Reatores Biológicos , Ácidos Graxos Voláteis , MetanoRESUMO
Type I diabetes mellitus (T1DM) is an organ-specific autoimmune disorder affecting the insulin-producing pancreatic cells. T1DM genetic association studies have so far revealed the involvement of more than 40 loci, with particularly strong associations for the human leucocyte antigens (HLA). Further to the well-established HLA class II associations, the immunomodulatory elements in the telomeric major histocompatibility complex locus, specifically nonclassical HLA class I, were also associated with T1DM, either in conferring susceptibility or by contributing to the overall pathogenesis. This study investigates the involvement of a 14-bp deletion polymorphism (rs371194629) at the 3' untranslated region of HLA-G in the context of T1DM and age of onset. The frequency of the polymorphism was determined in unrelated T1DM Cypriot patients and findings that emerge from this study show a strong association between the HLA-G 14-bp polymorphism and T1DM with respect to the age of onset. Specifically, the deletion/deletion (DEL/DEL) genotype was found to be associated with an early age of onset (P = 0.001), while the presence of the insertion allele (INS) was associated to a later age of onset (P = 0.0001), portraying a possible dominant effect over the deletion allele, a role in delaying disease onset and an overall involvement of HLA-G in the pathogenesis of type I diabetes mellitus.
Assuntos
Idade de Início , Diabetes Mellitus Tipo 1/genética , Antígenos HLA-G/genética , Deleção de Sequência/genética , Regiões 3' não Traduzidas/genética , Adolescente , Adulto , Alelos , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/patologia , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Lactente , Recém-Nascido , MasculinoRESUMO
OBJECTIVE: Real-life data for vaccination against COVID-19 are sorely needed. This was a population-based analysis aiming at investigating the hospitalization risk for COVID-19 of 98,982 subjects and compare features of vaccinated and unvaccinated patients. PATIENTS AND METHODS: Hospitalized patients with COVID-19 between 01/07/2021 and 11/02/2022 were included in the study. RESULTS: 582 patients were included in the analysis [males: 58.6% (n=341), vaccinated patients: 28.5% (n=166), unvaccinated patients: 71.5% (n=416)]. Median age of vaccinated patients was significantly higher compared to median age of unvaccinated [74.0 (95% CI: 72.0-77.0) vs. 59.0 (95% CI: 57.0-62.0), p=0.0001]. Mean latency time (±SD) from the second dose to hospitalization was 5.7±2.6 months. Between 01/07/2021 and 01/12/2021, unvaccinated subjects had higher risk for hospitalization compared to vaccinated [HR: 2.82, 95% CI: 2.30-3.45, p<0.0001]. Between 02/12/2021 and 11/02/2022, unvaccinated subjects presented with higher risk for hospitalization than subjects that had received booster dose [HR: 2.07, 95% CI: 1.44-2.98, p=0.005], but not than subjects that got two doses. Median value of hospitalization days was higher in unvaccinated patients compared to vaccinated [7.0 (95% CI: 7.0-8.0) vs. 6.0 (95% CI: 5.0-7.0), p=0.02]. Finally, age-adjusted analysis showed that hospitalized unvaccinated patients presented with significantly higher mortality risk compared to hospitalized vaccinated patients [HR: 2.59, 95% CI: 1.69-3.98, p<0.0001]. CONCLUSIONS: Vaccination against COVID-19 remains the best way to contain the pandemic. There is an amenable need for booster dose during the omicron era.
Assuntos
COVID-19 , Masculino , Humanos , COVID-19/prevenção & controle , Hospitalização , Vacinação , PandemiasRESUMO
OBJECTIVES: To apply therapeutic drug monitoring and dose-individualization of intravenous Busulfan to paediatric patients and evaluate the impact of syringe-pump induced Busulfan infusion lag-time after in vitro estimation. METHODS: 76 children and adolescents were administered 2 h intravenous Busulfan infusion every 6 h (16 doses). Busulfan plasma levels, withdrawn by an optimized sampling scheme and measured by a validated HPLC-PDA method, were used to estimate basic PK parameters, AUC, Cmax, kel, t1/2, applying Non-Compartmental Analysis. In vivo infusion lag-time was simulated in vitro and used to evaluate its impact on AUC estimation. KEY FINDINGS: Mean (%CV) Busulfan AUC, Cmax, clearance and t1/2 for pediatric population were found 962.3 µm × min (33.1), 0.95 mg/L (41.4), 0.27 L/h/kg (33.3), 2.2 h (27.8), respectively. TDM applied to 76 children revealed 6 (7.9%) being above and 25 (32.9%) below therapeutic-range (AUC: 900-1350 µm × min). After dose correction, all patients were measured below toxic levels (AUC < 1500 µm × min), no patient below 900 µm × min. Incorporation of infusion lag-time revealed lower AUCs with 17.1% more patients and 23.1% more younger patients, with body weight <16 kg, being below the therapeutic-range. CONCLUSIONS: TDM, applied successfully to 76 children, confirmed the need for Busulfan dose-individualization in paediatric patients. Infusion lag-time was proved clinically significant for younger, low body-weight patients and those close to the lower therapeutic-range limit.
Assuntos
Transplante de Medula Óssea , Bussulfano/administração & dosagem , Monitoramento de Medicamentos , Infusões Intravenosas/métodos , Administração Intravenosa , Adolescente , Adulto , Fatores Etários , Área Sob a Curva , Peso Corporal , Bussulfano/sangue , Bussulfano/farmacocinética , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/sangue , Imunossupressores/farmacocinética , Lactente , Masculino , Pediatria , Adulto JovemRESUMO
Human herpesvirus 6 (HHV-6) is frequently detected after allogeneic hematopoietic cell transplantation (allo-HCT); however, the clinical interpretation of HHV-6 viremia in a transplant patient is challenging as it may signify asymptomatic reactivation, chromosomal integration of the virus genome in the donor or recipient with no clinical significance, or severe HHV-6 disease. Here we present a case of HHV-6 disease after allo-HCT presenting as pure red cell aplasia, secondary graft failure, and severe immunosuppression causing multiple severe bacterial super-infections. Examination of pre-transplant patient and donor samples as well as serial determination of HHV-6 DNA copy numbers after transplantation were necessary to definitively interpret HHV-6 viremia as active HHV-6 infection with a causative role in pancytopenia and immune suppression. Foscarnet treatment resulted both in viral load decline and disappearance of HHV-6-related bone marrow suppression and predisposition to severe infections. Clinicians should be aware of the wide array of clinical manifestations and the diagnostic pitfalls of post-transplant HHV-6 disease. These issues are extremely challenging, as they may result either in dangerous underestimation of HHV-6 disease or in the institution of unnecessary antiviral therapy. Late bone marrow aplasia and late severe infections after allo-HCT without other obvious causes may be HHV-6 related.
Assuntos
Antivirais/uso terapêutico , Foscarnet/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Herpesvirus Humano 6/isolamento & purificação , Tolerância Imunológica , Aplasia Pura de Série Vermelha/etiologia , Infecções por Roseolovirus/complicações , Infecções por Roseolovirus/tratamento farmacológico , Adulto , Rejeição de Enxerto , Humanos , Masculino , Aplasia Pura de Série Vermelha/imunologia , Transplante Homólogo , Carga ViralRESUMO
We present a phase II study of fludarabine 5 x 30 mg/m(2), thiotepa 3 x 5 mg/kg as preparative regimen specifically for allogeneic second haematopoietic stem cell transplantation (HCT) after failure of previous HCT. Forty-nine patients (median age 52 years, range 27-68) received an allogeneic second HCT after failed autologous (n=29) or allogeneic (n=20) HCT. Diagnoses were AML (n=18), ALL (n=3), multiple myeloma (n=11), lymphoma (n=16) and CML (n=1). GVHD prophylaxis consisted of CYA and mainly low dose alemtuzumab (40 mg). The median follow-up for patients alive is 528 days (range 217-1344). In 43 of 49 (88%) evaluable patients response rates were CR=19, PR=14 and SD=10 at one month. At one year, the probability (95% confidence interval) of relapse is 55.1 (38.2-72)% and the nonrelapse mortality (NRM) is 29 (14.2-44.4)%. Estimated survival at one year is 42.6 (28.7-56.6)% and event free survival is 38.1 (24.4-51.8)%. Survival was significantly better for patients experiencing relapse beyond one year, than for patients relapsing within one year from first transplantation (51.2 (33.5-68.9)% vs 27 (7-48.5)%; P=0.013). We conclude that this regimen is feasible and well tolerated for allogeneic second HCT.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Tiotepa/administração & dosagem , Condicionamento Pré-Transplante/métodos , Vidarabina/análogos & derivados , Adulto , Idoso , Alemtuzumab , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Anticorpos Antineoplásicos/uso terapêutico , Ciclosporina/uso terapêutico , Feminino , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Leucemia Mieloide Aguda/terapia , Linfoma/terapia , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Recidiva , Taxa de Sobrevida , Condicionamento Pré-Transplante/efeitos adversos , Transplante Autólogo/efeitos adversos , Transplante Homólogo/efeitos adversos , Falha de Tratamento , Vidarabina/administração & dosagemRESUMO
The role of microchimerism in peripheral blood and urine of renal transplant recipients remains a matter of debate, depending on the sensitivity of the methods used for detection. We studied 17 female renal transplant recipients who had received renal allografts from male donors. Polymerase chain reaction (PCR) was applied to blood and urine for the microsatellite markers D1S80, DYZ1, TH01, and kalphai SE33. Detection of DYZ1 that is present only on the Y chromosome was considered proof for microchimerism. No microchimerism was detected in peripheral blood, whereas it could be detected in the urine of 8/17 (48%) patients. There were no differences between patients with and without microchimerism regarding patient age, dialysis vintage, immunosuppression, time post-transplantation, and allograft function as measured using serum creatinine, creatinine clearance, and proteinuria. Two patients in each group showed chronic allograft dysfunction. These findings raise questions regarding the role of microchimerism in renal transplantation.
Assuntos
Quimerismo , Transplante de Rim/fisiologia , Quimeras de Transplante , Adulto , Creatinina/sangue , Feminino , Taxa de Filtração Glomerular , Humanos , Nefropatias/classificação , Nefropatias/cirurgia , Transplante de Rim/imunologia , Doadores Vivos , Masculino , Repetições de Microssatélites/genética , Repetições de Microssatélites/imunologia , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Terapia de Substituição Renal/estatística & dados numéricos , Reoperação/estatística & dados numéricos , Doadores de TecidosRESUMO
Here we investigated the influence of parameters known before hematopoietic stem cell transplantation (HSCT) as well as the relevance of graft-versus-host disease (GvHD) and cytomegalovirus (CMV) reactivation on post transplant lymphocyte reconstitution in 148 patients treated in our institution between 1996 and 2003. Median patient age was 42 (19-68) years, HSCT followed standard high dose (n=91) or reduced-intensity conditioning regimens (n=57) with bone marrow (BM, n=67) or peripheral blood stem cells (PBSC, n=81) from related (n=71) or unrelated (n=77) donors. In the first months, we observed a partially faster reconstitution of CD3+4+, CD3+8+ and CD4+45RA+ T cells in patients following peripheral blood stem cell transplantation when compared to bone marrow transplantation. Prolonged CD3+4+ and CD4+45RA+ lymphopenia was noted after unrelated donor HSCT and GvHD prophylaxis containing anti-T-lymphocyte globulin. Lymphocyte subset counts in patients older than the median age were comparable to those in patients transplanted at a younger age and not influenced by the conditioning regimen. CD3+8+ T cell reconstitution was strongly correlated with CMV reactivation, but not significantly affected by CMV serostatus before HSCT. Incidence or extent of GvHD did not significantly influence lymphocyte reconstitution. Therefore, the source of graft is the most predictive parameter in early lymphocyte reconstitution, but the differences in lymphocyte recovery completely resolved within the first year after HSCT.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Subpopulações de Linfócitos/imunologia , Adulto , Idoso , Infecções por Citomegalovirus/etiologia , Infecções por Citomegalovirus/imunologia , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/imunologia , Doenças Hematológicas/complicações , Doenças Hematológicas/imunologia , Doenças Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Células Matadoras Naturais/imunologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Recidiva , Estudos Retrospectivos , Fatores de Tempo , Condicionamento Pré-Transplante , Transplante HomólogoRESUMO
We analyzed the use of low-dose alemtuzumab in a cohort of 158 consecutive patients who underwent allogeneic PBSC transplantation. Patients with high-risk acute leukemia were prospectively screened for prophylactic donor lymphocyte infusion (pDLI). Lymphocytes were administered repeatedly at low and non-escalating doses (0.5-1 × 106/kg). Low-dose alemtuzumab was effective in prevention of acute GvHD after sibling or well-matched unrelated transplantation, whereas a more intensified approach was needed after mismatched transplantation. The cumulative incidence of chronic moderate/severe chronic-GvHD (cGvHD) was 15.6%. In total, 63 high-risk leukemia patients were eligible for pDLI. Only 1 out of the 39 pDLI recipients relapsed as compared with 7 out of the 24 recipients, who did not receive pDLI due to logistical hurdles. In multivariate analysis, the use of adjuvant lymphocyte therapy was significantly associated with reduced incidence of relapse and improved disease-free survival. In summary, low-dose alemtuzumab confers to a low cGvHD incidence and the administration of pDLIs in this context is very likely to reduce relapse risk in high risk leukemia patients. This is translated in an estimated 5-year probability of GvHD-free and relapse-free survival of 43.3% for the 136 leukemia patients.
Assuntos
Alemtuzumab/administração & dosagem , Aloenxertos , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia , Transfusão de Linfócitos , Irmãos , Doadores não Relacionados , Adolescente , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Leucemia/mortalidade , Leucemia/terapia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Fatores de TempoRESUMO
Both conventional chimerism analysis (CCA) and lineage-specific chimerism analysis (LCA) have potential pitfalls as diagnostic means for the detection of minimal residual disease after allogeneic hematopoietic cell transplantation (aHCT). Therefore, the present study examines the results of both methods in order to determine how predictive consecutive evaluations were, with respect to the risk that the patient would relapse during post-transplant follow-up and with respect to responsiveness to immunomodulatory treatment. A total of 168 individuals with acute myeloid leukemia (AML) (n = 137) and myelo dysplastic syndrome (n = 31) were investigated with CCA and LCA at mean intervals of 24 days (range: 11-116). The median follow-up after myeloablative aHCT was 22 months (range: 4-49). Of 168 patients, 65 experienced a clinical relapse after aHCT. CCA and LCA were comparatively sensitive and specific for relapse at the intervals of chimerism testing employed in this study. Of 32 patients, 10 who were offered donor lymphocyte infusions (DLI) treatment for increasing (n = 29) or stable (n = 3) mixed chimerism (MC) achieved at least transitory CC. The observation that all patients with increasing MC relapsed despite DLI treatment (54%) or withdrawal of immune suppression (24%) indicates that novel strategies to deal with rapidly evolving relapse in AML patients, such as shortening of chimerism monitoring intervals, need to be evaluated.
Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Imunoterapia Adotiva/métodos , Leucemia Mieloide/terapia , Transfusão de Linfócitos/métodos , Síndromes Mielodisplásicas/terapia , Quimeras de Transplante/imunologia , Linhagem da Célula/genética , Seguimentos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Recidiva , Indução de Remissão , Sensibilidade e Especificidade , Quimeras de Transplante/genética , Resultado do TratamentoRESUMO
Metabolic homeostasis of fatty acids is complex and well-regulated in all organisms. The biosynthesis of saturated fatty acids (SFA) in mammals provides substrates for ß-oxidation and ATP production. Monounsaturated fatty acids (MUFA) are products of desaturases that introduce a methylene group in cis geometry in SFA. Polyunsaturated fatty acids (n-6 and n-3 PUFA) are products of elongation and desaturation of the essential linoleic acid and α-linolenic acid, respectively. The liver processes dietary fatty acids and exports them in lipoproteins for distribution and storage in peripheral tissues. The three types of fatty acids are integrated in membrane phospholipids and determine their biophysical properties and functions. This study was aimed at investigating effects of fatty acids on membrane biophysical properties under varying nutritional and pathological conditions, by integrating lipidomic analysis of membrane phospholipids with functional two-photon microscopy (fTPM) of cellular membranes. This approach was applied to two case studies: first, pancreatic beta-cells, to investigate hormetic and detrimental effects of lipids. Second, red blood cells extracted from a genetic mouse model defective in lipoproteins, to understand the role of lipids in hepatic diseases and metabolic syndrome and their effect on circulating cells.
Assuntos
Ácidos Graxos/química , Fluidez de Membrana , Humanos , Metabolismo dos LipídeosRESUMO
In our study, we evaluated the safety and efficacy of Brentuximab vedotin (BV) with or without the addition of donor lymphocyte infusion (DLI) after allogeneic stem cell transplantation (allo-SCT) in 16 patients with advanced Hodgkin lymphoma (HL). Thirteen patients with relapsed HL after allo-SCT received BV as treatment for active disease. Three patients without progression of HL after allo-SCT received BV as consolidation. Twelve patients had been previously exposed to BV for treatment of relapse after autologous-SCT. Ten out of 16 patients received BV in combination with DLI. Among the 13 patients treated for active disease, CR and PR was observed in 7 and 2 patients, respectively. With a median follow-up of 13 months, 13 out of 16 patients are alive, while 3 died because of disease progression. The median PFS was 6 months. DLI-associated GVHD occurred in seven patients. Five patients with GVHD required immunosuppression, and in all cases, GVHD resolved after a short course of low dose steroids, implying that an anti-GVHD modulating effect could be induced by the concurrent administration of BV. No serious adverse event was observed in any of the patients.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Doença de Hodgkin/terapia , Imunoconjugados/administração & dosagem , Adolescente , Adulto , Brentuximab Vedotin , Terapia Combinada , Feminino , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Doença de Hodgkin/complicações , Doença de Hodgkin/mortalidade , Humanos , Imunoconjugados/efeitos adversos , Transfusão de Linfócitos , Masculino , Esteroides/uso terapêutico , Análise de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
Despite major improvements in allogeneic hematopoietic cell transplantation over the past decades, corticosteroid-refractory (SR) acute (a) and chronic (c) graft-versus-host disease (GVHD) cause high mortality. Preclinical evidence indicates the potent anti-inflammatory properties of the JAK1/2 inhibitor ruxolitinib. In this retrospective survey, 19 stem cell transplant centers in Europe and the United States reported outcome data from 95 patients who had received ruxolitinib as salvage therapy for SR-GVHD. Patients were classified as having SR-aGVHD (n=54, all grades III or IV) or SR-cGVHD (n=41, all moderate or severe). The median number of previous GVHD-therapies was 3 for both SR-aGVHD (1-7) and SR-cGVHD (1-10). The overall response rate was 81.5% (44/54) in SR-aGVHD including 25 complete responses (46.3%), while for SR-cGVHD the ORR was 85.4% (35/41). Of those patients responding to ruxolitinib, the rate of GVHD-relapse was 6.8% (3/44) and 5.7% (2/35) for SR-aGVHD and SR-cGVHD, respectively. The 6-month-survival was 79% (67.3-90.7%, 95% confidence interval (CI)) and 97.4% (92.3-100%, 95% CI) for SR-aGVHD and SR-cGVHD, respectively. Cytopenia and cytomegalovirus-reactivation were observed during ruxolitinib treatment in both SR-aGVHD (30/54, 55.6% and 18/54, 33.3%) and SR-cGVHD (7/41, 17.1% and 6/41, 14.6%) patients. Ruxolitinib may constitute a promising new treatment option for SR-aGVHD and SR-cGVHD that should be validated in a prospective trial.
Assuntos
Corticosteroides/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Doença Enxerto-Hospedeiro/tratamento farmacológico , Neoplasias Hematológicas/complicações , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Pirazóis/uso terapêutico , Terapia de Salvação , Adulto , Idoso , Animais , Modelos Animais de Doenças , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/mortalidade , Neoplasias Hematológicas/terapia , Humanos , Janus Quinases/antagonistas & inibidores , Masculino , Camundongos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Nitrilas , Prognóstico , Pirimidinas , Recidiva , Estudos Retrospectivos , Taxa de Sobrevida , Transplante Homólogo , Adulto JovemRESUMO
Donor lymphocyte infusions (DLIs) provide effective therapy for patients with various hematological malignancies who have relapsed after allogeneic hematopoietic stem cell transplantation (HSCT). In patients with multiple myeloma (MM), DLIs can induce response rates of 40-52%. DLIs were employed as treatment for MM relapse or as prophylaxis for relapse in MM patients undergoing allo-HSCT. The clinically most relevant treatment-related morbidity with DLIs is the occurrence of graft-versus-host disease (GVHD). Secondly, graft failure and the immune escape of extramedullary plasmocytoma have been reported. The fact that previous clinical reports have documented graft-versus-myeloma (GVM) activity without GVHD suggests that at least two distinct immunocompetent cell populations mediating GVHD and/or GVM may exist. Further characterization of the effector cells such as T cells and/or NK cells and their targets may help to clarify the immune response that mediates the GVM effect. This review considers the results of clinical approaches with DLI for MM, with emphasis on strategies to prevent GVHD while preserving the GVM effect. Furthermore, currently investigated molecular antigenic targets for the GVM effect such as MM-specific idiotypic determinant of immunoglobulin variable regions, several PRAME epitopes and antigenic structures encoded by cancer germline-specific genes as candidates for immunotherapy trials are discussed.
Assuntos
Efeito Enxerto vs Leucemia , Transplante de Células-Tronco Hematopoéticas , Transfusão de Linfócitos , Mieloma Múltiplo/terapia , Recidiva Local de Neoplasia/terapia , Feminino , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/mortalidade , Transplante de Células-Tronco Hematopoéticas/tendências , Humanos , Transfusão de Linfócitos/tendências , MasculinoRESUMO
Mast cell leukemia (MCL) is a rare form of aggressive mastocytosis with a reported median survival below 6 months. Casuistic reports suggest the effectiveness of allogeneic bone marrow transplantation (BMT) for MCL. However, these reports lack clear evidence for a graft-versus-mast-cell (GvMC) effect. We prospectively investigated the GvMC at different time points after allogeneic BMT and donor-lymphocyte infusions (DLI). Samples were gathered from a patient with MCL treated with allogeneic BMT from an unrelated HLA identical donor. Parameters for detection of a GvMC effect included flow cytometrical analysis of mast cell (MC) populations in peripheral blood and BM, BM smear and histology, chimerism analysis of flow cytometrically sorted BM CD117+/CD34- MC and testing for anti-mast cell reactivity of donor lymphocytes by interferon (IFN)-gamma ELISPOT. DLIs reduced MC from 5 to 0.5%. MC chimerism analysis demonstrated a complete recipient genotype after BMT, suggesting that the persistent mastocytosis was part of residual neoplastic disease. At 3.7 years after BMT, there is some evidence for relapse. In summary, BMT and DLIs attenuated the mastocytosis from an aggressive to an indolent form and may have improved the patients' prognosis. The in vitro data of our study indicate for the first time the existence of a GvMC effect.
Assuntos
Transplante de Medula Óssea/fisiologia , Reação Enxerto-Hospedeiro/fisiologia , Leucemia de Mastócitos/terapia , Transfusão de Linfócitos , Adulto , Medula Óssea/patologia , Humanos , Leucemia de Mastócitos/patologia , Masculino , Mastócitos/patologia , Resultado do TratamentoRESUMO
Newer cytogenetic scoring systems for myelodysplastic syndromes (MDSs), like cytogenetic stratification of the revised international prognostic scoring system (IPSS-R) or monosomal karyotype, may also improve outcome prediction after hematopoietic SCT (HCT). We compared the prognostic value of specific cytogenetic abnormalities, IPSS-R karyotype and monosomal karyotype for HCT outcome in 98 patients with MDS and AML post MDS. Higher-risk IPSS-R karyotype, 3q21q26 and transformation to AML before HCT were associated with increased cumulative incidence of relapse (CIR), whereas OS was adversely influenced by del 5q/-5, abnormalities of chromosomes 11 and 17 and cytogenetic IPSS-R very poor category. Karyotype with ⩽2 abnormalities and no abnormalities of chromosomes 3, 5, 7, 11 and 17 was an independent prognostic factor of lower CIR (hazard ratio (HR)=0.2, P=0.01) and longer OS (HR=0.5, P=0.03). In conclusion, some specific cytogenetic abnormalities and high cytogenetic complexity, as reflected by IPSS-R very poor karyotype, rather than monosomal karyotype, were associated with higher CIR and shorter OS after HCT. Conversely, results were encouraging in patients lacking those abnormalities, who may be very good candidates for HCT.
Assuntos
Cariótipo Anormal , Cromossomos Humanos/genética , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Adulto , Aloenxertos , Intervalo Livre de Doença , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/mortalidade , Síndromes Mielodisplásicas/terapia , Valor Preditivo dos Testes , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
Invasive candidiasis is a life-threatening infection in patients with haematological malignancies. The objective of our study was to determine the incidence, microbiological characteristics and clinical outcome of candidaemia among hospitalized adult patients with haematological malignancies. This is a population-based, prospective, multicentre study of patients ≥ 18 years admitted to haematology and/or haematopoietic stem cell transplantation units of nine tertiary care Greek hospitals from January 2009 through to February 2012. Within this cohort, we conducted a nested case-control study to determine the risk factors for candidaemia. Stepwise logistic regression was used to identify independent predictors of 28-day mortality. Candidaemia was detected in 40 of 27,864 patients with haematological malignancies vs. 967 of 1,158,018 non-haematology patients for an incidence of 1.4 cases/1000 admissions vs. 0.83/1000 respectively (p <0.001). Candidaemia was caused predominantly (35/40, 87.5%) by non-Candida albicans species, particularly Candida parapsilosis (20/40, 50%). In vitro resistance to at least one antifungal agent was observed in 27% of Candida isolates. Twenty-one patients (53%) developed breakthrough candidaemia while receiving antifungal agents. Central venous catheters, hypogammaglobulinaemia and a high APACHE II score were independent risk factors for the development of candidaemia. Crude mortality at day 28 was greater in those with candidaemia than in control cases (18/40 (45%) vs. 9/80 (11%); p <0.0001). In conclusion, despite antifungal prophylaxis, candidaemia is a relatively frequent infection associated with high mortality caused by non-C. albicans spp., especially C. parapsilosis. Central venous catheters and hypogammaglobulinaemia are independent risk factors for candidaemia that provide potential targets for improving the outcome.
Assuntos
Candida/classificação , Candidemia/epidemiologia , Candidemia/etiologia , Neoplasias Hematológicas/complicações , Adolescente , Adulto , Agamaglobulinemia/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Antifúngicos/uso terapêutico , Candidemia/microbiologia , Candidemia/mortalidade , Estudos de Casos e Controles , Cateteres Venosos Centrais/efeitos adversos , Feminino , Grécia/epidemiologia , Hospitalização , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Adulto JovemAssuntos
Antígenos CD34/biossíntese , Células Epiteliais/citologia , Hematopoese , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia/terapia , Mucosa/metabolismo , Adulto , Bochecha , Células Epiteliais/metabolismo , Epitélio/metabolismo , Humanos , Fatores de Tempo , Doadores de Tecidos , Transplante HomólogoRESUMO
The benefit of survival at the expense of new GVHD after DLI for acute leukemia following human allogeneic hematopoietic cell transplantation (allo-HCT) remains a matter of controversy. The detection of biological markers predicting this outcome would be an enormous breakthrough. The purpose of this study was the analysis of CT60 single-nucleotide polymorphism (SNP) of the CTLA-4 T-regulatory gene as a surrogate marker for DLI outcome in this difficult setting. Using Pyrosequencing, we genotyped the alleles of the CT60 SNP of 79 DLI donors and correlated them with the post-DLI outcome of their matching recipients. The presence of a donor 'AA' or 'AG' CT60 genotype vs a 'GG' genotype was an independent factor for remaining in complete chimerism/remission post-DLI (odds ratio (OR) 2.61 vs 0.42, respectively, P=0.05). Further, in cases with evident post-DLI allo-reactivity the importance of an 'AA' or 'AG' vs a 'GG' genotype gained significance for ongoing complete chimerism (OR 4.35 vs 0.32, P=0.03). Neither alterations in cumulative DLI dose nor any other clinical parameter significantly weakened the importance of CT60 SNP. Our results provide evidence for the necessity of genotyping CT60 SNP prior to DLI administration in patients with acute leukemia.
Assuntos
Antígeno CTLA-4/genética , Leucemia Mieloide Aguda/terapia , Linfócitos/citologia , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Biomarcadores , Feminino , Marcadores Genéticos , Genótipo , Humanos , Leucemia Mieloide Aguda/genética , Transfusão de Linfócitos/métodos , Masculino , Razão de Chances , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Indução de Remissão , Estudos Retrospectivos , Fatores de Tempo , Transplante Homólogo/métodos , Resultado do TratamentoRESUMO
To describe outcomes, treatment and prognostic factors that influence survival of adult patients with acute lymphoblastic leukemia (ALL), who relapsed after allogeneic hematopoietic cell transplantation (HCT), we retrospectively analyzed 465 ALL adult patients from European Group for Blood and Marrow Transplantation (EBMT) centers who relapsed after a first HCT performed in complete remission (CR1 65%, CR2/3 35%). Salvage treatments were: supportive care (13%), cytoreductive therapy (43%), donor lymphocyte infusion without or with prior chemotherapy (23%) and second HCT (20%). Median time from HCT to relapse was 6.9 months, median follow-up was 46 months and median survival after relapse was 5.5 months. Estimated 1-, 2- and 5-year post-relapse survival was 30 ± 2%, 16 ± 2% and 8 ± 1%, respectively. In a multivariate analysis, adverse factors for survival were: late CR (CR2/3) at transplant (P<0.012), early relapse after transplant (<6.9 months, P <0.0001) and peripheral blast percent at relapse (P <0.0001). On the basis of multivariate model for survival, three groups of patients were identified with estimated 2 year survival of 6 ± 2, 17 ± 3 and 30 ± 7%. Outcome of ALL patients relapsing after HCT is dismal and there is a need for new therapies. Our study provides the standard expectations in ALL relapse and may help in the decision of post-relapse therapy.