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An Amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Patients with acute myeloid leukaemia (AML) often achieve remission after therapy, but subsequently die of relapse1 that is driven by chemotherapy-resistant leukaemic stem cells (LSCs)2,3. LSCs are defined by their capacity to initiate leukaemia in immunocompromised mice4. However, this precludes analyses of their interaction with lymphocytes as components of anti-tumour immunity5, which LSCs must escape to induce cancer. Here we demonstrate that stemness and immune evasion are closely intertwined in AML. Using xenografts of human AML as well as syngeneic mouse models of leukaemia, we show that ligands of the danger detector NKG2D-a critical mediator of anti-tumour immunity by cytotoxic lymphocytes, such as NK cells6-9-are generally expressed on bulk AML cells but not on LSCs. AML cells with LSC properties can be isolated by their lack of expression of NKG2D ligands (NKG2DLs) in both CD34-expressing and non-CD34-expressing cases of AML. AML cells that express NKG2DLs are cleared by NK cells, whereas NKG2DL-negative leukaemic cells isolated from the same individual escape cell killing by NK cells. These NKG2DL-negative AML cells show an immature morphology, display molecular and functional stemness characteristics, and can initiate serially re-transplantable leukaemia and survive chemotherapy in patient-derived xenotransplant models. Mechanistically, poly-ADP-ribose polymerase 1 (PARP1) represses expression of NKG2DLs. Genetic or pharmacologic inhibition of PARP1 induces NKG2DLs on the LSC surface but not on healthy or pre-leukaemic cells. Treatment with PARP1 inhibitors, followed by transfer of polyclonal NK cells, suppresses leukaemogenesis in patient-derived xenotransplant models. In summary, our data link the LSC concept to immune escape and provide a strong rationale for targeting therapy-resistant LSCs by PARP1 inhibition, which renders them amenable to control by NK cells in vivo.
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Evasão da Resposta Imune , Leucemia Mieloide Aguda/patologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Células-Tronco Neoplásicas/imunologia , Células-Tronco Neoplásicas/patologia , Evasão Tumoral , Animais , Antígenos CD34/metabolismo , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Células Matadoras Naturais/imunologia , Leucemia Mieloide Aguda/imunologia , Ligantes , Masculino , Camundongos , Células-Tronco Neoplásicas/metabolismo , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Poli(ADP-Ribose) Polimerase-1/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Antileukemia immunity plays an important role in disease control and maintenance of tyrosine kinase inhibitor (TKI)-free remission in chronic myeloid leukemia (CML). Thus, antigen-specific immunotherapy holds promise for strengthening immune control in CML but requires the identification of CML-associated targets. In this study, we used a mass spectrometry-based approach to identify naturally presented HLA class I- and class II-restricted peptides in primary CML samples. Comparative HLA ligandome profiling using a comprehensive dataset of different hematological benign specimens and samples from CML patients in deep molecular remission delineated a panel of novel frequently presented CML-exclusive peptides. These nonmutated target antigens are of particular relevance because our extensive data-mining approach suggests the absence of naturally presented BCR-ABL- and ABL-BCR-derived HLA-restricted peptides and the lack of frequent tumor-exclusive presentation of known cancer/testis and leukemia-associated antigens. Functional characterization revealed spontaneous T-cell responses against the newly identified CML-associated peptides in CML patient samples and their ability to induce multifunctional and cytotoxic antigen-specific T cells de novo in samples from healthy volunteers and CML patients. Thus, these antigens are prime candidates for T-cell-based immunotherapeutic approaches that may prolong TKI-free survival and even mediate cure of CML patients.
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Antígenos de Neoplasias/imunologia , Linfócitos T CD4-Positivos/imunologia , Epitopos de Linfócito T/imunologia , Proteínas de Fusão bcr-abl/imunologia , Antígenos HLA/imunologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/imunologia , Linfócitos T Citotóxicos/imunologia , Antígenos de Neoplasias/metabolismo , Epitopos de Linfócito T/metabolismo , Antígenos HLA/metabolismo , Humanos , Imunoterapia , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , LigantesRESUMO
Three randomized controlled trials in early severe systemic sclerosis demonstrated that autologous hematopoietic stem cell transplantation was superior to standard cyclophosphamide therapy. This European Society for Blood and Marrow Transplantation multi-center prospective non-interventional study was designed to further decipher efficacy and safety of this procedure for severe systemic sclerosis patients in real-life practice and to search for prognostic factors. All consecutive adult systemic sclerosis patients undergoing a first autologous hematopoietic stem cell transplantation between December 2012 and February 2016 were prospectively included in the study. Primary endpoint was progression free survival. Secondary endpoints were overall survival, non-relapse mortality, response and incidence of progression. Eighty systemic sclerosis patients were included. Median follow-up duration was 24 (6-57) months after stem cell transplantation using cyclophosphamide plus antithymocyte globulins conditioning for all, with CD34+ selection in 35 patients. At 2 years, progression free survival was 81.8%, overall survival was 90%, response was 88.7% and incidence of progression was 11.9%. The 100 days non-relapse mortality was 6.25% (n=5) with four deaths from cardiac event, including three due to cyclophosphamide toxicity. Modified Rodnan skin score and forced vital capacity improved with time (p< 0.001). By multivariate analysis, baseline skin score >24 and older age at transplant were associated with lower progression free survival (Hazard ration 3.32) and 1.77, respectively). CD34+-selection was associated with better response (Hazard ration: 0.46). This study confirms the efficacy of autologous stem cell transplantation in real-life practice for severe systemic sclerosis using non myeloablative conditioning. Careful cardio-pulmonary assessment to identify organ involvement at patient referral, reduced cyclophosphamide doses and CD34+ selection may improve outcomes. The study was registered at ClinicalTrials.gov: NCT02516124.
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Doenças Autoimunes , Transplante de Células-Tronco Hematopoéticas , Esclerodermia Difusa , Escleroderma Sistêmico , Adulto , Idoso , Medula Óssea , Ciclofosfamida , Humanos , Estudos Prospectivos , Escleroderma Sistêmico/terapia , Condicionamento Pré-Transplante , Transplante AutólogoRESUMO
During development, hematopoietic stem cells (HSCs) emerge from aortic endothelial cells (ECs) through an intermediate stage called hemogenic endothelium by a process known as endothelial-to-hematopoietic transition (EHT). While Notch signaling, including its upstream regulator Vegf, is known to regulate this process, the precise molecular control and temporal specificity of Notch activity remain unclear. Here, we identify the zebrafish transcriptional regulator evi1 as critically required for Notch-mediated EHT In vivo live imaging studies indicate that evi1 suppression impairs EC progression to hematopoietic fate and therefore HSC emergence. evi1 is expressed in ECs and induces these effects cell autonomously by activating Notch via pAKT Global or endothelial-specific induction of notch, vegf, or pAKT can restore endothelial Notch and HSC formations in evi1 morphants. Significantly, evi1 overexpression induces Notch independently of Vegf and rescues HSC numbers in embryos treated with a Vegf inhibitor. In sum, our results unravel evi1-pAKT as a novel molecular pathway that, in conjunction with the shh-vegf axis, is essential for activation of Notch signaling in VDA endothelial cells and their subsequent conversion to HSCs.
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Proteínas de Ligação a DNA/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Proto-Oncogenes/fisiologia , Fatores de Transcrição/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Animais , Animais Geneticamente Modificados , Aorta/metabolismo , Proteínas de Ligação a DNA/genética , Diaminas/farmacologia , Embrião não Mamífero , Células Endoteliais/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proto-Oncogenes/genética , Receptores Notch/metabolismo , Tiazóis/farmacologia , Fatores de Transcrição/genética , Peixe-Zebra , Proteínas de Peixe-Zebra/genéticaRESUMO
Autologous stem cell transplantation (autoSCT) can achieve long-term remission in primary refractory or relapsed Hodgkin lymphoma (r/r HL); however, still up to 50% of patients relapse after autoSCT. In this retrospective analysis, we investigated the impact of autologous stem cell transplantation in a consecutive, unselected cohort of primary refractory and relapsed Hodgkin lymphoma patients (n = 66) with the majority of patients treated in the pre-brentuximab vedotin and immune checkpoint inhibitor era. In our cohort, a 5-year overall survival (OS) from autoSCT of 59.5% and a 5-year progression-free survival (PFS) after autoSCT of 46.1% was achieved. Multivariate analysis revealed primary refractory disease and early relapse (< 12 months) after initial therapy as well as the presence of B symptoms at relapse as independent risk factors associated with a higher risk for relapse and an inferior PFS and OS. Several other clinical factors, including the presence of extranodal disease at relapse and failure to achieve a complete response to salvage chemotherapy, were associated with a trend towards an inferior survival. Patients relapsing after autoSCT had a particularly poor outcome, regardless of eligibility to undergo allogeneic stem cell transplantation (alloSCT). We further evaluated recently published prognostic models for r/r HL patients undergoing autoSCT and could validate several risk scores in our independent "real world" cohort.
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Doença de Hodgkin/mortalidade , Doença de Hodgkin/terapia , Transplante de Células-Tronco , Adolescente , Adulto , Idoso , Autoenxertos , Intervalo Livre de Doença , Feminino , Seguimentos , Doença de Hodgkin/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Fatores de TempoRESUMO
Patients with the pre-leukemia bone marrow failure syndrome called severe congenital neutropenia (CN) have an approximately 15% risk of developing acute myeloid leukemia (AML; called here CN/AML). Most CN/AML patients co-acquire CSF3R and RUNX1 mutations, which play cooperative roles in the development of AML. To establish an in vitro model of leukemogenesis, we utilized bone marrow lin- cells from transgenic C57BL/6-d715 Csf3r mice expressing a CN patient-mimicking truncated CSF3R mutation. We transduced these cells with vectors encoding RUNX1 wild type (WT) or RUNX1 mutant proteins carrying the R139G or R174L mutations. Cells transduced with these RUNX1 mutants showed diminished in vitro myeloid differentiation and elevated replating capacity, compared with those expressing WT RUNX1. mRNA expression analysis showed that cells transduced with the RUNX1 mutants exhibited hyperactivation of inflammatory signaling and innate immunity pathways, including IL-6, TLR, NF-kappaB, IFN, and TREM1 signaling. These data suggest that the expression of mutated RUNX1 in a CSF3R-mutated background may activate the pro-inflammatory cell state and inhibit myeloid differentiation.
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Síndrome Congênita de Insuficiência da Medula Óssea/genética , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Células-Tronco Hematopoéticas/patologia , Células Mieloides/patologia , Mielopoese/genética , Neutropenia/congênito , Pré-Leucemia/genética , Receptores de Fator Estimulador de Colônias/genética , Animais , Divisão Celular , Ensaio de Unidades Formadoras de Colônias , Síndrome Congênita de Insuficiência da Medula Óssea/patologia , Subunidade alfa 2 de Fator de Ligação ao Core/fisiologia , Perfilação da Expressão Gênica , Imunidade Inata , Inflamação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neutropenia/genética , Neutropenia/patologia , Pré-Leucemia/patologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Receptores de Fator Estimulador de Colônias/fisiologia , Proteínas Recombinantes/genética , Organismos Livres de Patógenos EspecíficosRESUMO
BACKGROUND AND OBJECTIVES: In patients with multiple myeloma (MM), unexpected bleeding complications remain a major issue. Since routine coagulation parameters are often inconspicuous, diagnosis and treatment of the underlying coagulation disorders are challenging. PATIENTS AND METHODS: In our single-center observational study, we analyzed 164 patients with MM for coagulation disorders and bleeding complications. RESULTS: Prolonged closure times (CTs), measured by PFA-100, were the most common, abnormal coagulation test, found in 66% of bleeding patients vs 5% in non-bleeding, followed by qualitative defects of von Willebrand factor (VWF:CB/VWF:Ag ratios), found in 34% vs 1% in the non-bleeding group. Increased serum free light chains (SFLC) and SFLC ratios were significantly associated with prolonged CTs and acquired von Willebrand syndrome (AVWS). Prolonged CTs and AVWS were associated with disease progression, determined by dynamics of SFLC ratios (P < .001), serum creatinine level (P = .013), Beta-2 microglobulin (P = .03), LDH (P = .016), and bone marrow infiltration (P < .001). Of note, response to myeloma therapy was frequently correlated with normalization of coagulation parameters. CONCLUSIONS: Bleeding complications in MM are predominantly caused by defects in primary hemostasis and associated with disease progression. In a peri-interventional workup, determination of CTs and VWF:CB/VWF:Ag ratios are of significant importance to assess bleeding risk.
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Transtornos da Coagulação Sanguínea , Hemorragia , Hemostasia , Mieloma Múltiplo , Adulto , Idoso , Transtornos da Coagulação Sanguínea/sangue , Transtornos da Coagulação Sanguínea/etiologia , Transtornos da Coagulação Sanguínea/mortalidade , Feminino , Hemorragia/sangue , Hemorragia/etiologia , Hemorragia/mortalidade , Humanos , Cadeias Leves de Imunoglobulina/sangue , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue , Mieloma Múltiplo/mortalidade , Proteínas de Neoplasias/sangue , Fator de von Willebrand/metabolismoRESUMO
This retrospective study by the European Society for Blood and Marrow Transplantation analyzed the outcome of 2224 patients with myelofibrosis (MF) who underwent allogeneic stem cell transplantation (allo-SCT) between 2000 and 2014; 781 (35%) underwent myeloablative conditioning (MAC) and 1443 (65%) reduced-intensity conditioning (RIC). Median patient age was 52.9 years (range, 18 to 74 years) and 57.5 years (range, 21 to 76 years) in the MAC and RIC cohorts, respectively. Donor type was similar: matched sibling donors (MAC, 317 [41%]; RIC, 552 [38%]) and unrelated donors (MAC, 464 [59%]; RIC, 891 [62%]). Median time to both neutrophil and platelet (>20â¯×â¯109/L) engraftment did not differ between cohorts. Rates of grade II to IV acute GVHD were 28% (MAC) and 31% (RIC; P = NS). Cumulative chronic GVHD rates (limited/extensive) were 22%/27% (MAC) and 19%/31% (RIC; Pâ¯=â¯.10). Cumulative incidences of nonrelapse mortality (NRM) at 1, 3, and 5 years were 25.5%, 32.2%, and 34.6% (MAC) and 26.3%, 32.8%, and 34.4% (RIC), respectively. There was a trend toward a higher relapse rate with RIC regimens compared with MAC (Pâ¯=â¯.08); rates at 1, 3, and 5 years were 10.9%, 17.2%, and 20.1% (MAC) and 14%, 19.7%, and 23.2% (RIC), respectively. No significant difference in 5-year probabilities of overall survival (OS) was noted: MAC (53.0%; 95% confidence interval [CI], 49.1% to 56.9%) and RIC (51.0%; 95% CI, 48.3% to 53.7%); Pâ¯=â¯.78. Regarding the composite end point of GVHD-free/relapse-free survival (GRFS), the unadjusted Kaplan-Meier estimate of 5-year GRFS was 32.4% (95% CI, 29.0% to 36.1%) in the MAC group and 26.1% (95% CI, 23.9% to 28.2%) in the RIC group (Pâ¯=â¯.001). In the MAC cohort, multivariable analysis confirmed worse OS and NRM with older age (>50 years), using an unrelated donor and a Karnofsky Performance Status of 80 or less. For the RIC cohort, worse OS and NRM were associated with age 60 to 70 years compared with younger recipients, use of a mismatched donor, and poor performance status. In conclusion, although similar OS rates existed for both cohorts overall, this study suggests that MAC should still be used for younger individuals suitable for such an approach due to a trend toward less relapse and an overall suggested advantage of improved GRFS, albeit this should be examined in a more homogeneous cohort. RIC allo-SCT still offers significant survival advantage in the older, fitter MF allograft patient, and optimization to reduce significant relapse and NRM rates is required.
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Transplante de Células-Tronco Hematopoéticas , Mielofibrose Primária/mortalidade , Mielofibrose Primária/terapia , Condicionamento Pré-Transplante , Adolescente , Adulto , Idoso , Aloenxertos , Doença Crônica , Intervalo Livre de Doença , Europa (Continente) , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Sociedades Médicas , Taxa de SobrevidaRESUMO
We aimed to validate the MYelofibrosis SECondary to PV and ET prognostic model (MYSEC-PM) in 159 patients with myelofibrosis secondary to polycythemia vera (PV) and essential thrombocythemia (ET) from the European Society for Blood and Marrow Transplantation registry undergoing transplantation from matched siblings or unrelated donors. Furthermore, we aimed to test its prognostic performance in comparison with the Dynamic International Prognostic Scoring System (DIPSS). Score performance was analyzed using the concordance index (C): the probability that a patient who experienced an event had a higher risk score than a patient who did not (C > .5 suggesting predictive ability). Median follow-up of the total cohort was 41 months (range, 34 to 54), 45 months in post-PV and 38 months in post-ET myelofibrosis. Survival at 1, 2, and 4 years was 70% (95% CI, 63% to 77%), 61% (95% CI, 53% to 69%), and 52% (95% CI, 43% to 61%) for the total cohort; 70% (95% CI, 59% to 80%), 61% (95% CI, 49% to 73%), and 51% (95% CI, 38% to 64%) for post-PV; and 71% (95% CI, 61% to 81%), 61% (95% CI, 50% to 72%), and 54% (95% CI, 42% to 66%) for post-ET myelofibrosis (Pâ¯=â¯.78). Overall, the DIPSS was not significantly predictive of outcome (Pâ¯=â¯.28). With respect to the MYSEC-PM, overall survival at 4 years was 69% for the low-risk, 55% for the intermediate 1-risk, 47% for the intermediate 2-risk, and 22% (0% to 45%) for the high-risk groups. The prognostic model was predictive of survival overall (Pâ¯=â¯.05), whereas groups with intermediate 2 and high risk showed no significant difference (Pâ¯=â¯.44). Assessment of prognostic utility yielded a C-index of .575 (95% CI, .502 to .648) for the DIPSS, whereas assessment of the MYSEC-PM resulted in a C-statistics of .636 (95% CI, .563 to .708), indicating improvement in prediction of post-transplant survival using the new MYSEC-PM. In addition, transplantations from an unrelated donor in comparison with an HLA-identical sibling showed worse outcome (Pâ¯=â¯.04), and transplant recipients seropositive for cytomegalovirus in comparison with seronegative recipients (Pâ¯=â¯.01) showed worse survival. In conclusion, incorporating transplant-specific and clinical and mutational information together with the MYSEC-PM may enhance risk stratification.
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Transplante de Células-Tronco Hematopoéticas/métodos , Policitemia Vera/terapia , Mielofibrose Primária/terapia , Trombocitemia Essencial/terapia , Transplante Homólogo/métodos , Adulto , Idoso , Humanos , Pessoa de Meia-Idade , Policitemia Vera/mortalidade , Mielofibrose Primária/mortalidade , Prognóstico , Análise de Sobrevida , Trombocitemia Essencial/mortalidade , Resultado do TratamentoRESUMO
Donor lymphocyte infusion (DLI) is an effective method to establish full donor chimerism or to prevent and treat relapse after allogeneic haematopoietic cell transplantation (allo-HCT). Usually, DLIs are collected from naïve donors as steady-state lymphocytes. When donor lymphocytes are collected during stem cell apheresis, donors are pre-treated with granulocyte colony-stimulating factor (G-CSF). However, the impact of G-CSF stimulation and the resulting composition of DLIs on beneficial anti-leukaemic responses and survival remain elusive. Therefore, we performed a retrospective analysis to evaluate the role of G-CSF-DLIs: 44 patients received either steady-state DLIs or G-CSF-DLIs to prevent and treat relapse or establish full donor chimerism after allo-HCT. The G-CSF-DLI patient cohort showed an improved conversion to full donor chimerism and a lower cumulative incidence of relapse or disease progression without a significantly increased cumulative incidence of graft-versus-host disease (GVHD). CD34+ cells, monocytic myeloid-derived suppressor cells and monocytes as well as donor age and the subsequent occurrence of chronic GVHD were identified as risk factors that significantly improve overall survival after DLI administration. In conclusion, our data suggest that administration of G-CSF-DLIs results in graft-versus-leukaemia effects without exacerbating GVHD, therefore, improving survival after DLIs.
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Efeito Enxerto vs Leucemia , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Transplante de Células-Tronco Hematopoéticas/métodos , Transfusão de Linfócitos/métodos , Adolescente , Adulto , Feminino , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Análise de Sobrevida , Transplante HomólogoRESUMO
OBJECTIVE: to report the first case of resection and partial liver segment 2-3 transplantation with delayed total hepatectomy (RAPID) from living donor in a patient affected of irresectable colorectal liver metastases (i-CRLM) BACKGROUND:: A renaissance of liver transplantation (LT) for i-CRLM has been recently observed. The Norwegian SECA trial demonstrated a 5-year overall survival rate of approximately 60%, notwithstanding early tumor recurrence. The RAPID technique was recently introduced as alternative to whole deceased donor LT, but it is limited by poor availability of splittable organs and many organisational aspects. In this context left lateral living donor LT may be the ideal solution. METHODS: Report about the technique and results of living donor RAPID procedure. TECHNIQUE: A 49 years old woman affected with i-CRLM from adenocarcinoma of right colon, underwent a left hepatectomy with ligation of right portal vein maintaining the right hepatic artery patent. Subsequently, the left lateral lobe from her son was implanted as auxiliary partial orthotopic LT. Two weeks later completion of hepatectomy was performed. RESULTS: The donor postoperative course was uneventful. The recipient developed postoperatively a slight small for size syndrome which spontaneously resolved. No graft dysfunction and no rejection were observed. At POM 5 micrometastases occurred in bones and lungs, which were treated with radiotherapy and chemotherapy, respectively. Almost 2 years later the patient is alive, in good general condition, although slight progression of bone and lung metastases. CONCLUSIONS: LT poses a valid treatment option for i-CRLM. In times of organ paucity, "living donor-RAPID" procedure may represent a paradigm shift in the management of i-CRLM.
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Neoplasias Colorretais/patologia , Hepatectomia/métodos , Neoplasias Hepáticas/cirurgia , Transplante de Fígado/métodos , Doadores Vivos , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Tomografia Computadorizada por Raios X , Ultrassonografia Doppler , Adulto JovemRESUMO
The aim of this study was to develop and validate a clinical and transplant-specific prognostic score using data from a large cohort of patients with myelodysplastic syndromes reported to the European Society for Blood and Marrow Transplantation registry. A Cox model was fitted to detect clinical and transplant-related variables prognostic of outcome. Then, cross-validation was performed to evaluate the validity and consistency of the model. Seven independent risk factors for survival were identified: age ≥50 years, matched unrelated donor, Karnofsky Performance Status <90%, very poor cytogenetics or monosomal karyotype, positive cytomegalovirus status of the recipient, blood blasts >1%, and platelet count ≤50 × 109/L prior to transplantation. Incorporating these factors into a four-level risk score yielded hazard ratios for death, with low-risk (score of 0-1) as reference, of 2.02 (95% CI: 1.41-2.90) for the intermediate-risk group (score of 2-3), 3.49 (95% CI: 2.45-4.97) for the high-risk group (score of 4-5), and 5.90 (95% CI: 4.01-8.67) for the very high-risk group (score of >5). The score was predictive of survival, relapse-free survival, relapse, and non-relapse mortality (P<0.001, respectively). Cross-validation yielded significant and reproducible improvement in prognostic ability with C-statistics being 0.609 (95% CI: 0.588-0.629) versus 0.555 for the Gruppo Italiano Trapianto di Midollo Osseo registry and 0.579 for the Center for Blood and Marrow Transplant Research registry. Prediction was even further augmented after applying a nomogram using age and platelets as continuous variables showing C-statistics of 0.628 (95% CI: 0.616-0.637). In conclusion, compared to existing prognostic systems, this proposed transplant-specific risk score offers improved performance with respect to post-transplant risk stratification in myelodysplastic syndromes.
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Transplante de Células-Tronco Hematopoéticas/mortalidade , Modelos Estatísticos , Síndromes Mielodisplásicas/mortalidade , Nomogramas , Medição de Risco/normas , Adolescente , Adulto , Idoso , Estudos de Coortes , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/patologia , Síndromes Mielodisplásicas/terapia , Prognóstico , Fatores de Risco , Taxa de Sobrevida , Transplante Homólogo , Adulto JovemRESUMO
Graft-versus-host disease (GVHD) represents the major nonrelapse complication of allogeneic hematopoietic cell transplantation. Although rare, the CNS and the eye can be affected. In this study, manifestation in the retina as part of the CNS and T-cell epitopes recognized by the allogeneic T cells were evaluated. In 2 of 6 patients with posttransplantation retina diseases and 6 of 22 patients without ocular symptoms, antigen-specific T-cell responses against retina-specific epitopes were observed. No genetic differences between donor and recipient could be identified indicating T-cell activation against self-antigens (graft versus self). Transplantation of a preexisting immunity and cross-reactivity with ubiquitous epitopes was excluded in family donors and healthy individuals. In summary, an immunological reaction against retina cells represents a mechanism of graft-versus-host interaction following hematopoietic cell transplantation.
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Autoantígenos/imunologia , Epitopos de Linfócito T/imunologia , Doença Enxerto-Hospedeiro/imunologia , Doenças Retinianas/imunologia , Adulto , Idoso , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/patologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Doenças Retinianas/etiologia , Doenças Retinianas/patologia , Linfócitos T/imunologia , Transplante Homólogo/efeitos adversosRESUMO
BACKGROUND: T-cell-depleted, haploidentical transplantations (haplos) are commonly offered to patients who have high-risk, acute leukemia in the absence of a human leukocyte antigen (HLA) full-matched donor. METHODS: To determine the effect of transplantation period, the authors divided 308 adults with de novo, acute leukemia who underwent T-cell-depleted haplo from 2005 to 2015 into 2 groups, according the year in which they underwent transplantation (2005-2011 [n = 191] and 2012-2015 [n = 117]). RESULTS: The median age was 41 years in patients who underwent transplantation before 2012 and 46 years in those who underwent transplantation after 2012 (P = .04). Most patients had acute myeloid leukemia (75% vs 69%; P = .26) and were in first complete remission (CR1) (55% vs 64%; P = .12) at the time of transplantation. The cumulative incidence of grade 2, 3, and 4 acute graft-versus-host disease (GvHD) and chronic GvHD were not different between the 2 groups (acute GvHD: 20% vs 22% cumulative incidence in patients who underwent haplo before and after 2012, respectively [P = .67]; chronic GvHD: 19% vs 11% cumulative incidence, respectively; P = .12]. The 2-year relapse incidence was 20%, the nonrelapse mortality (NRM) rate was 48%, and no difference was observed over time (21% vs 19% [P = .72] and 54% vs 38% [P = .11] for patients who underwent haplo before and after 2012, respectively). The main cause of NRM was infection. Haplo after 2012 (hazard ratio [HR], 0.57; P = .01), younger age (HR, 0.82; P = .02), and receipt of a reduced-intensity conditioning (RIC) regimen (HR, 0.53; P = .01) were independently associated with lower NRM. The 2-year overall survival rate was 36% and improved after 2012 (29% vs 47% before 2012; P = .02); and it was higher for patients who underwent transplantation in CR1 (41% vs 29%; P = .01). In multivariate analysis, haplo after 2012 (HR, 0.54; P = .003) and receipt of a RIC regimen (HR, 0.54; P = .005) were independently associated with better overall survival. Similarly, leukemia-free survival and GvHD-free/relapse-free survival (GRFS) improved over time: the leukemia-free survival rate was 31% (25% vs 43% in the groups who underwent transplantation before and after 2012, respectively; P = .05), and the GRFS rate was 24% (19% vs 34%, respectively; P = .09). In addition, leukemia-free survival and GRFS improved among patients who received a RIC regimen. CONCLUSIONS: The outcome of patients with acute leukemia who underwent T-cell-depleted haplo has improved over time. Cancer 2018;124:2142-50. © 2018 American Cancer Society.
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Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide Aguda/terapia , Depleção Linfocítica/métodos , Mortalidade/tendências , Recidiva Local de Neoplasia/epidemiologia , Transplante Haploidêntico/métodos , Adulto , Intervalo Livre de Doença , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/tendências , Humanos , Incidência , Leucemia Mieloide Aguda/mortalidade , Depleção Linfocítica/efeitos adversos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/prevenção & controle , Indução de Remissão/métodos , Taxa de Sobrevida , Linfócitos T/imunologia , Fatores de Tempo , Condicionamento Pré-Transplante/métodos , Transplante Haploidêntico/efeitos adversos , Transplante Haploidêntico/tendências , Adulto JovemRESUMO
BACKGROUND: The PTEN-hamartoma-tumor-syndrome (PHTS) is caused by germline mutations in Phosphatase and Tensin homolog (PTEN) and predisposes to the development of several typical malignancies. Whereas PTEN mutations have been implicated in the occurrence of malignant mesotheliomas, the genetic landscape of verrucous carcinomas (VC) is largely uncharted. Both VC and malignant peritoneal mesotheliomas (MPM) are exceedingly rare and a potential link between these malignancies and PHTS has never been reported. CASE PRESENTATION: We here describe the clinical course of a PHTS patient who, in addition to a typical thyroid carcinoma at the age of 36 years, developed a highly-differentiated oral VC and an epithelioid MPM six years later. The patient with a history of occupational asbestos exposure underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for MPM. The clinical diagnosis of PHTS was consequently corroborated by a germline PTEN deletion. Sequencing of tumor tissue revealed a second hit in PTEN in the thyroid carcinoma and VC, confirmed by a PTEN loss and activation of the PI3K/AKT pathway in immunohistochemistry. Furthermore, additional somatic mutations in the thyroid carcinoma as well as in the VC were detected, whereas the genetics of MPM remained unrevealing. DISCUSSION AND CONCLUSIONS: We here report the very unusual clinical course of a patient with rare tumors that have a germline mutation first hit in PTEN in common. Since this patient was exposed to asbestos and current evidence suggests molecular mechanisms that might render PHTS patients particularly susceptible to mesothelioma, we strongly recommend PHTS patients to avoid even minimal exposure.
Assuntos
Carcinoma Verrucoso/genética , Mutação em Linhagem Germinativa/genética , Neoplasias Pulmonares/genética , Mesotelioma/genética , Neoplasias Bucais/genética , PTEN Fosfo-Hidrolase/genética , Humanos , Mesotelioma Maligno , Doenças RarasRESUMO
No standard exists for the treatment of myelodysplastic syndrome relapsing after allogeneic stem cell transplantation. We performed a retrospective registry analysis of outcomes and risk factors in 698 patients, treated with different strategies. The median overall survival from relapse was 4.7 months (95% confidence interval: 4.1-5.3) and the 2-year survival rate was 17.7% (95% confidence interval: 14.8-21.2%). Shorter remission after transplantation (P<0.001), advanced disease (P=0.001), older age (P=0.007), unrelated donor (P=0.008) and acute graft-versus-host disease before relapse (P<0.001) adversely influenced survival. At 6 months from relapse, patients had received no cellular treatment, (i.e. palliative chemotherapy or best supportive care, n=375), donor lymphocyte infusion (n=213), or a second transplant (n=110). Treatment groups were analyzed separately because of imbalanced characteristics and difficulties in retrospectively evaluating the reason for individual treatments. Of the patients who did not receive any cellular therapy, 109 were alive at 6 months after relapse, achieving a median overall survival from this landmark of 8.9 months (95% confidence interval: 5.1-12.6). Their 2-year survival rate was 29.7%. Recipients of donor lymphocytes achieved a median survival from first infusion of 6.0 months (95% confidence interval: 3.7-8.3) with a 2-year survival rate of 27.6%. Longer remission after first transplantation (P<0.001) and younger age (P=0.009) predicted better outcome. Among recipients of a second transplant, the median survival from second transplantation was 4.2 months (95% confidence interval: 2.5-5.9), and their 2-year survival rate was 17.0%. Longer remission after first transplantation (P<0.001), complete remission at second transplant (P=0.008), no prior chronic graft-versus-host disease (P<0.001) and change to a new donor (P=0.04) predicted better outcome. The data enabled identification of patients benefiting from donor lymphocyte infusion and second transplantation, and may serve as a baseline for prospective trials.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide Aguda/etiologia , Síndromes Mielodisplásicas/patologia , Adolescente , Adulto , Idoso , Aloenxertos , Europa (Continente) , Feminino , Humanos , Transfusão de Linfócitos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/terapia , Recidiva , Sistema de Registros , Reoperação , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento , Adulto JovemRESUMO
Allogeneic hematopoietic cell transplantation (HCT) is the treatment of choice for high-risk myeloid and lymphoid leukemias. Relapse after allogeneic HCT is associated with a dismal prognosis and further therapeutic options are limited. One potential curative approach is a second allogeneic HCT. However, there is no consensus about optimal transplant modalities, suitable patients, and entities. We performed a retrospective analysis of our institutional database to evaluate risk factors that influence survival after a second allogeneic HCT for the treatment of relapsed acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). We identified 40 patients (AML, n = 29; ALL, n = 11) that received a second allogeneic HCT at our institution. At time of second HCT, 48% of patients were in complete remission (CR). Current overall survival (OS) was 14/40 patients with a median follow-up of 64 months (range 4-140) of patients alive resulting in a Kaplan-Meier estimated 2-year event-free survival (EFS) and OS of 32%, respectively. Cumulative incidence of non-relapse mortality (NRM) and relapse at 2 years was 31 and 37%, respectively. We identified several independent risk factors influencing OS: > 6 months from first to second transplant (p = 0.02), complete remission prior to transplant (p = 0.003), and the subsequent occurrence of chronic graft-versus-host disease (p = 0.003) were associated with a significantly improved OS. In conclusion, our data suggest that a second allogeneic HCT is a curative treatment option for relapsed acute leukemias in selected patients.
Assuntos
Bases de Dados Factuais , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adolescente , Adulto , Aloenxertos , Doença Crônica , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/mortalidade , Humanos , Leucemia Mieloide Aguda/sangue , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Recidiva , Estudos Retrospectivos , Fatores de Risco , Taxa de SobrevidaRESUMO
BACKGROUND AND OBJECTIVES: Protein Z (PZ) deficiency has been implicated both in bleeding diatheses and in thrombophilia. Considering its ambiguous nature and the conflicting clinical data so far, we set out to evaluate the impact of low PZ on perioperative bleeding in patients who underwent surgical (ENT) interventions involving a high risk of bleeding. PATIENTS AND METHODS: After exclusion of other coagulation disorders, 154 Patients were stratified into quartiles according to PZ plasma concentrations to evaluate the relation between PZ and bleeding complications. RESULTS: Low PZ levels were associated with increased blood loss (P < .001), increased need for blood transfusions (P < .001), and a higher rate of surgical revisions (P = .009) in a concentration-dependent fashion. Low PZ caused earlier (within 24 hours) and repetitive bleedings (P = .005). The number of major bleeding episodes was significantly increased when low PZ was combined with bleeding history (P < .05). Finally, ROC analyses confirmed the predictive value of low PZ for bleeding complications and PZ-thresholds for clinical practice were determined. CONCLUSIONS: Low PZ appears to be an underestimated risk factor for perioperative bleeding. Determination of PZ plasma concentrations might be useful in the preoperative workup in patients with a bleeding history, when detailed clotting analyses remain inconclusive.
Assuntos
Proteínas Sanguíneas , Hemorragia/sangue , Hemorragia/etiologia , Período Perioperatório , Procedimentos Cirúrgicos Operatórios/efeitos adversos , Adolescente , Adulto , Variação Biológica da População , Biomarcadores , Coagulação Sanguínea , Perda Sanguínea Cirúrgica , Criança , Feminino , Hemorragia/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC , Reprodutibilidade dos Testes , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Procedimentos Cirúrgicos Operatórios/métodos , Adulto JovemRESUMO
BACKGROUND AND OBJECTIVES: The role of local surgical procedures in patients with metastatic soft tissue sarcoma is still undefined. Few retrospective studies have reported survival benefits for patients with pulmonary metastases after complete surgical resection. Treatment decisions are therefore mainly based on personal experiences rather than on reproducible knowledge. METHOD: A total of 237 patients with metastatic sarcoma, treated between 1982 and 2015 at the University Hospital Tuebingen, Germany, were eligible for inclusion. Out of the 237 screened patients, 102 patients underwent at least one metastasectomy. Overall survival was defined as the primary endpoint in this study. For association of non-linear relationship to the endpoint, significant prognostic factors were included into a recursive partitioning model. A subgroup analysis for long-term survivors was also performed. RESULTS: The median overall survival was 64 months. The 3-, 5-, 10-, and 20-years overall survival rates were 70.7%, 50.3%, 24.7%, and 14.8%, respectively. The number of resections and the progression-free intervals were independent prognostic factors in three statistical models. CONCLUSION: Repeated resections of metastases from different localizations are a strong predictor for prolonged survival. We suggest that the progression-free interval after metastasectomy should be considered as a predictive factor for benefit from further surgery.