Summary Background Reduced-intensity conditioning regimens have been developed to minimise early toxic effects and deaths after allogeneic haemopoietic cell transplantation. However, the efficacy of ...these regimens before this procedure has not been investigated in a randomised trial. In this prospective, open-label randomised phase 3 trial we compared a reduced-intensity fludarabine-based conditioning regimen with a standard regimen in patients with acute myeloid leukaemia in first complete remission. Methods Patients were aged 18–60 years and had intermediate-risk or high-risk acute myeloid leukaemia (defined by cytogenetics) in first complete remission; an available HLA-matched sibling donor or an unrelated donor with at least nine of ten HLA alleles; and adequate renal, cardiac, pulmonary, and neurological function. Between Nov 15, 2004, and Dec 31, 2009, patients were randomly assigned (1:1, by a computer-based minimisation procedure that balanced patients for age, cytogenetic risk, induction therapy, and donor type) to receive either reduced-intensity conditioning of four doses of 2 Gy of total-body irradiation and 150 mg/m2 fludarabine or standard conditioning of six doses of 2 Gy of total-body irradiation and 120 mg/kg cyclophosphamide. All patients were given ciclosporin and methotrexate as prophylaxis against graft-versus-host disease. Neither investigators nor patients were blinded to study treatment. Our primary endpoint was the incidence of non-relapse mortality, analysed in the intention-to-treat population. The trial is registered with ClinicalTrials.gov , number NCT00150878. Findings The trial was stopped early on Dec 31, 2009, because of slow accrual of patients. 99 patients were randomly assigned to receive reduced-intensity conditioning and 96 to receive standard conditioning. The incidence of non-relapse mortality did not differ between the reduced-intensity and standard conditioning groups (cumulative incidence at 3 years 13% 95% CI 6–21 vs 18% 10–26; HR 0·62 95% CI 0·30–1·31). Relapse incidence (cumulative incidence 3 years 28% 95% CI 19–38 vs 26% 17–36; HR 1·10 95% CI 0·63–1·90), disease-free survival (3 year disease-free survival 58% 95% CI 49–70 vs 56% 46–67; HR 0·85 95% CI 0·55–1·32), and overall survival (3 year overall survival 61% 95% CI 50–74 vs 58% 47–70; HR 0·77 95% CI 0·48–1·25) did not differ significantly between groups. Grade 3–4 of oral mucositis was less common in the reduced-intensity group than in the standard conditioning group (50 patients in the reduced-intensity conditioning group vs 73 patients in the standard conditioning group); the frequency of other side-effects such as graft-versus-host disease and increased concentrations of bilirubin and creatinine did not differ significantly between groups. Interpretation Reduced-intensity conditioning results in a similar incidence of non-relapse mortality and reduced toxic effects compared with standard conditioning without affecting survival outcomes, and thus could be preferentially used in patients younger than 60 years with acute myeloid leukaemia transplanted in first complete remission. Funding Medical Faculty of Dresden University.
The purpose of the study was to assess the contribution of age and disease variables to the outcome of untreated patients with acute myeloid leukemia (AML) receiving varying intensive induction ...chemotherapy.
Patients 16 to 85 years of age with primary AML, known karyotype, and uniform postremission chemotherapy enrolled onto two consecutive trials were eligible and were randomly assigned to induction either with a standard-dose (cytarabine, daunorubicin, and 6-thioguanine) and a high-dose (cytarabine and mitoxantrone) combination, or with two courses of the high-dose combination. Subgroups were defined by karyotype, nucleophosmin and FLT3 mutation, WBC count, serum lactate dehydrogenase, and residual blasts.
In 1,284 patients, the overall survival at 4 years in those younger and older than 60 years was 37% versus 16% (P < .001) and the ongoing remission duration was 46% versus 22% (P < .001). Similar age-related differences in outcome were found for all defined subgroups. No difference in outcome according to randomly assigned treatment regimen was observed in any age group or prognostic subset. Regarding prognostic subgroups, molecular factors were also considered.
Under harmonized conditions, older and younger patients with AML show modest differences in their risk profiles and equally no dose response to intensified chemotherapy. Their observed fundamental difference in outcome across all subgroups remains unexplained. Further molecular investigation may elucidate the age effect in AML and identify new targets.
In patients with acute myeloid leukemia (AML), differential indications for matched sibling and unrelated hematopoietic stem-cell transplantation (HCT) are considered, and arbitrary age limits for ...HCT exist. We sought to determine whether donor type is a prognostic factor in elderly patients in the era of high-resolution DNA-based HLA typing.
We performed univariate and multivariate analyses of event-free survival (EFS) and overall survival (OS) in patients older than 50 years with standard- or high-risk AML who had received an allogeneic HCT between 1995 and 2005. Available DNA from donors and recipients of unrelated HCT was retyped so that the HLA-A, -B, -C, and -DRB1 alleles could be characterized in detail. Unrelated donors (UDs) were classified as matched (8/8), possibly matched (matched, but incomplete information), partially matched (one mismatch), or poorly matched (two or more mismatches) according to the final typing results.
Data from 368 patients with a median age of 57 years (range, 50 to 73 years) were included. Multivariate Cox regression analysis revealed that patients' disease status at HCT (P < .001) and the cytogenetic risk (P < .001) highly significantly predicted EFS and OS. Compared with patients with matched sibling donors, the adjusted relative risk of EFS was 0.7 (95% CI, 0.4 to 1.1) for patients with matched UDs and 1.0 (95% CI, 0.7 to 1.6) for patients with partially matched UDs.
Donor type is not a major prognostic factor for HCT in elderly patients with standard- or high-risk AML.
Intensification by high-dose cytarabine in postremission or induction therapy and prolonged maintenance are established strategies to improve the outcome in patients with acute myeloid leukemia ...(AML). Whether additional intensification can add to this effect has not yet been determined.
A total of 1,770 patients (age 16 to 85 years) with de novo or secondary AML or high-risk myelodysplastic syndrome (MDS) were randomly assigned upfront for induction therapy containing one course with standard dose and one course with high-dose cytarabine, or two courses with high-dose cytarabine, and in the same step received postremission prolonged maintenance or busulfan/cyclophosphamide chemotherapy with autologous stem-cell transplantation.
The complete remission rate in patients younger than 60 and > or = 60 years of age was 70% and 53%, respectively. The overall survival at 3 years in the two age groups was 42% and 19%, the relapse-free survival was 40% and 19%, and the ongoing remission duration was 48% and 22%, respectively. There were no significant differences in these results between the two randomized induction arms or between the two postremission therapy arms. There was no significant difference in any prognostic subgroup according to secondary AML/MDS, cytogenetics, WBC, lactate dehydrogenase, and early blast clearance.
The regimen of one course with standard-dose cytarabine and one course with high-dose cytarabine for induction, and prolonged maintenance for postremission chemotherapy in patients with AML is not improved by additional escalation in cytotoxic treatment.
Vascular endothelial growth factor (VEGF), a multifunctional cytokine, potently stimulates angiogenesis including tumor neovascularization. Although well established in solid tumors, the role of VEGF ...in bone marrow neoangiogenesis and paracrine tumor-stromal cell interactions in lymphohematopoietic malignancies has not been fully elucidated. In multiple myeloma (MM), marrow neovascularization parallels disease progression. This parallel prompted us to investigate the expression and secretion of VEGF by myeloma cells and its potential effects in myeloma-marrow stroma interactions. The biologically active splice variants VEGF165 and VEGF121 were expressed and secreted by myeloma cell lines and plasma cells isolated from the marrow of patients with MM. As shown by immunocytochemistry or RT-PCR, myeloma cells did not express or weakly expressed the VEGF receptors FLT-1 and FLK-1/KDR, indicating that autocrine stimulation is unlikely. In contrast, FLK-1/KDR was abundantly expressed by marrow stromal cells. Therefore, we studied the effects of VEGF on marrow stroma, focusing on the secretion of interleukin-6 (IL-6), a potent growth factor for myeloma cells and an inhibitor of plasma cell apoptosis. Exposure of stromal and microvascular endothelial cells to recombinant human (rh) VEGF165 or VEGF121 induced a time- and dose-dependent increase in IL-6 secretion (14- to 27-fold at 50 ng/mL after 24 hours, P < .001). Conversely, rhIL-6 stimulated VEGF expression and secretion in myeloma cell lines (40%-60%; P < .05) and to a variable degree (up to 5.3-fold; P < .005) in plasma cells purified from the marrow of patients with MM. This mutual stimulation suggests paracrine interactions between myeloma and marrow stromal cells triggered by VEGF and IL-6.
Principles of perioperative coagulopathy Innerhofer, Petra, MD; Kienast, Joachim, MD
Best practice & research. Clinical anaesthesiology,
03/2010, Letnik:
24, Številka:
1
Journal Article
Recenzirano
Perioperative coagulopathy impacts on patient outcome by influencing final blood loss and transfusion requirements. The recognition of pre-existing disturbances and the basic understanding of the ...principles of and dynamic changes of haemostasis during surgery are pre-conditions for safe patient management. The newly developed cellular model of coagulation facilitates the understanding of coagulation, thereby underscoring the importance of the tissue factor-bearing cell and the activated platelet. Amount of blood loss as well as amount and type of fluids used are the main factors involved in the development of dilutional coagulopathy, which is the most frequently observed cause of coagulopathy in the otherwise healthy surgical patient. Recent data from studies using viscoelastic coagulation studies confirm the central role of fibrinogen in stable clot formation and provide essential knowledge about its changes during blood loss and fluid administration. Besides early decrease in clot firmness during mild-to-moderate dilution, profound dilution results in a critical decrease in thrombin generation as well as a reduction in numbers and function of platelets. Although our knowledge of perioperative coagulopathy has dramatically increased over the past few years, several questions such as critical thresholds for fibrinogen, platelets, impact of FXIII and TAFI remain unanswered and need to be investigated further.
Background Allogeneic hematopoietic cell transplantation is considered the preferred post-remission therapy in patients with acute myeloid leukemia cytogenetically defined as being at high risk. To ...substantiate evidence for allogeneic hematopoietic cell transplantation in first complete remission in these high-risk patients we performed a landmark analysis within a single prospective multicenter treatment trial.
By the time of analysis, 2,347 patients had been accrued into the AMLCG 99 trial between 1999 - 2007. Out of this population, 243 patients under 60 years old fulfilled the criteria for high-risk cytogenetics. Landmark analyses were performed with a control cohort, who remained in first complete remission at least the median time from complete remission to transplantation in the intervention group.
After standardized induction therapy, 111 patients under 60 years old achieved complete remission. A matched allogeneic donor was identified for 59 patients (30 sibling donors, 29 unrelated donors). Fifty-five patients received an allogeneic hematopoietic cell transplant after a median time of 88 days in first complete remission. Of the remaining 56 patients, 21 relapsed within 90 days after achieving first complete remission and for 7 patients with relevant comorbidities no donors search was initiated, leaving 28 patients given conventional post-remission therapy as the control cohort. The median follow-up of surviving patients was 60.4 months. Patients with an allogeneic donor had substantially better 5-year overall and relapse-free survival rates than the control group (48% versus 18%, P=0.004 and 39% versus 10%, P<0.001, respectively). A survival benefit from transplantation was evident regardless of donor type, age and monosomal karyotype. Conclusions Beyond evidence available for subgroups of high-risk patients, the findings of this study establish in a broader manner that allogeneic hematopoietic cell transplantation is a preferable consolidation treatment for patients with acute myeloid leukemia and high-risk cytogenetics. The study was registered at Clinicaltrials.gov as NCT00266136.
Objectives. The present study investigated current management strategies as well as the clinical course of acute major pulmonary embolism.
Background. The clinical outcome of patients with acute ...pulmonary embolism who present with overt or impending right heart failure has not yet been adequately elucidated.
Methods. The 204 participating centers enrolled a total of 1,001 consecutive patients. The inclusion criteria were based on the clinical findings at presentation and the results of electrocardiographic, echocardiographic, nuclear imaging and cardiac catheterization studies.
Results. Echocardiography was the most frequently performed diagnostic procedure (74%). Lung scan or pulmonary angiography were performed in 79% of clinically stable patients but much less frequently in those with circulatory collapse at presentation (32%, p < 0.001). Thrombolytic agents were given to 478 patients (48%), often despite the presence of contraindications (193 40% of 478). The frequency of initial thrombolysis was significantly higher in clinically unstable than in normotensive patients (57% vs. 22%, p < 0.001). Overall in-hospital mortality rate ranged from 8.1% in the group of stable patients to 25% in those presenting with cardiogenic shock and to 65% in patients necessitating cardiopulmonary resuscitation. Major bleeding was reported in 92 patients (9.2%), but cerebral bleeding was uncommon (0.5%). Finally, recurrent pulmonary embolism occurred in 172 patients (17%).
Conclusions. Current management strategies of acute major pulmonary embolism are largely dependent on the degree of hemodynamic instability at presentation. In the presence of severe hemodynamic compromise, physicians often rely on the findings of bedside echocardiography and proceed to thrombolytic treatment without seeking further diagnostic certainty in nuclear imaging or angiographic studies.
Granulocyte colony-stimulating factor (G-CSF), alone or in combination with stem cell factor (SCF), can improve hemodynamic cardiac function after myocardial infarction. Apart from impairing the pump ...function, myocardial infarction causes an enhanced vulnerability to ventricular arrhythmias. Therefore, we investigated the electrophysiological effects of G-CSF/SCF and the underlying cellular events in a murine infarction model. G-CSF/SCF improved cardiac output after myocardial infarction. Although G-CSF/SCF led to a twofold increased, potentially proarrhythmic homing of bone marrow (BM)-derived cells to the area of infarction, <1% of these cells adopted a cardial phenotype. Inducibility of ventricular tachycardias during programmed stimulation was reduced 5 wk after G-CSF/SCF treatment. G-CSF/SCF increased cardiomyocyte diameter, arteriogenesis, and expression of connexin43 in the border zone of the infarction. An enhanced expression of the G-CSF receptor demonstrated in cardiomyocytes and other cell types of the infarcted myocardium indicates a sensitization of the heart to direct influences of this cytokine. In addition to paracrine effects potentially caused by the increased homing of BM-derived cells, these might contribute to the therapeutic effects of G-CSF.
The role of unrelated allogeneic stem-cell transplantation in acute lymphoblastic leukemia (ALL) patients is still not clear, and only limited data are available from the literature. We analyzed ...factors affecting clinical outcome of ALL patients receiving a related or unrelated stem-cell graft from matched donors.
The total study population was 264 adult patients receiving a myeloablative allogeneic stem-cell transplant for ALL at nine bone marrow transplantation centers between 1990 and 2002. Of these, 221 patients receiving a matched related or unrelated graft were analyzed. One hundred forty-eight patients received transplantation in complete remission; 62 patients were in relapse; and 11 patients were refractory to chemotherapy before transplant. Fifty percent of patients received bone marrow, and 50% received peripheral blood stem cell from a human leukocyte antigen-identical related (n = 103), or matched unrelated (n = 118) donor.
Disease-free survival (DFS) at 5 years was 28%, with 76 patients (34%) still alive (2.2 to 103 months post-transplantation), and 145 deceased (65 relapses, transplant-related mortality, 45%). We observed an advantage regarding DFS in favor of patients receiving transplantation during their first complete remission (CR) in comparison with patients receiving transplantation in or after second CR (P =.014) or who relapsed (P <.001). We observed a clear trend toward improved survival in favor of B-lineage ALL patients compared with T-lineage ALL patients (P =.052), and Philadelphia chromosome-positive patients had no poorer outcome than Philadelphia chromosome-negative patients. Total-body irradiation-based conditioning improved DFS in comparison with busulfan (P =.041).
Myeloablative matched related or matched unrelated allogeneic hematopoietic stem-cell transplantation in ALL patients should be performed in first CR.
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