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author:("girault, S")
1.  Differential Neuroprotective Effects of 5′-Deoxy-5′-Methylthioadenosine 
PLoS ONE  2014;9(3):e90671.
5′-deoxy-5′-methylthioadenosine (MTA) is an endogenous compound produced through the metabolism of polyamines. The therapeutic potential of MTA has been assayed mainly in liver diseases and, more recently, in animal models of multiple sclerosis. The aim of this study was to determine the neuroprotective effect of this molecule in vitro and to assess whether MTA can cross the blood brain barrier (BBB) in order to also analyze its potential neuroprotective efficacy in vivo.
Neuroprotection was assessed in vitro using models of excitotoxicity in primary neurons, mixed astrocyte-neuron and primary oligodendrocyte cultures. The capacity of MTA to cross the BBB was measured in an artificial membrane assay and using an in vitro cell model. Finally, in vivo tests were performed in models of hypoxic brain damage, Parkinson's disease and epilepsy.
MTA displays a wide array of neuroprotective activities against different insults in vitro. While the data from the two complementary approaches adopted indicate that MTA is likely to cross the BBB, the in vivo data showed that MTA may provide therapeutic benefits in specific circumstances. Whereas MTA reduced the neuronal cell death in pilocarpine-induced status epilepticus and the size of the lesion in global but not focal ischemic brain damage, it was ineffective in preserving dopaminergic neurons of the substantia nigra in the 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine (MPTP)-mice model. However, in this model of Parkinson's disease the combined administration of MTA and an A2A adenosine receptor antagonist did produce significant neuroprotection in this brain region.
MTA may potentially offer therapeutic neuroprotection.
PMCID: PMC3944389  PMID: 24599318
2.  High Risk of Graft Failure in Patients with Anti-HLA Antibodies Undergoing Haploidentical Stem Cell Transplantation 
Transplantation  2009;88(8):1019-1024.
While donor-specific anti-HLA antibodies (DSA) have been implicated in graft rejection in solid organ transplantation, their role in hematopoietic stem cell transplantation (HSCT) remains unclear.
To address the hypothesis that the presence of DSA contributes to the development graft failure, we tested 24 consecutive patients for the presence of anti-HLA antibodies determined by a highly sensitive and specific solid-phase/single-antigen assay. The study included a total of 28 haploidentical transplants, each with 2–5 HLA allele mismatches, at a single institution, from 9/2005 to 8/2008.
DSA were detected in five patients (21%). Three out of 4 (75%) patients with DSA prior to the first transplant failed to engraft, compared with 1 out of 20 (5%) without DSA (p=0.008). All 4 patients who experienced primary graft failure had second haploidentical transplants. One patient developed a second graft failure with persistent high DSA levels, while 3 engrafted, 2 of them in the absence of DSA. No other known factors that could negatively influence engraftment were associated with the development of graft failure in these patients.
These results suggest that donor-specific anti-HLA antibodies are associated with a high rate of graft rejection in patients undergoing haploidentical stem cell transplantation. Anti-HLA sensitization should be evaluated routinely in hematopoietic stem cell transplantation with HLA mismatched donors.
PMCID: PMC4324621  PMID: 19855248
Donor-specific anti-HLA antibodies; primary graft failure; haploidentical stem cell transplantation
3.  Long-term outcome of reduced-intensity allogeneic hematopoietic SCT in patients with AML in CR 
Bone marrow transplantation  2011;47(2):212-216.
A total of 36 consecutive patients with AML in CR underwent reduced-intensity allogeneic hematopoietic SCT (RISCT) with fludarabine and melphalan conditioning. All patients were ineligible for myeloablative transplantation because of age or comorbidity. In total, 30 patients were in first CR and six patients were in second CR. Donors were siblings in 21 (58%) patients and were unrelated in 15 (42%) patients. Hematopoietic cell transplant specific comorbidity scores ≥3 were present in 26 (72%) patients. With a median follow-up of 52 months (range, 34–103 months), OS and PFS rates at 4 years were 71% (s.e., 8%) and 68% (s.e., 8%), respectively. At 4 years, the cumulative incidence of non-relapse mortality was 20% (s.e., 7%) and of relapse mortality was 8% (s.e., 5%). Neither OS nor PFS was affected by older age (>60 years), unrelated donor, melphalan dose, or comorbidity score. At last follow up, of the 24 surviving patients, 21 (88%) had performance status (ECOG) of 0 without any active chronic GVHD requiring steroids. Hence, RISCT with fludarabine and melphalan conditioning produces durable long-term remission in older patients with AML.
PMCID: PMC4320641  PMID: 21423123
reduced intensity allogeneic transplantation; AML; hematopoietic SCT
4.  Proceedings from the National Cancer Institute’s Second International Workshop on the Biology, Prevention, and Treatment of Relapse After Hematopoietic Stem Cell Transplantation: Part III. Prevention and Treatment of Relapse after Allogeneic Transplantation 
In the 2nd NCI Workshop on the Biology, Prevention, and Treatment of Relapse After Hematopoietic Stem Cell Transplantation, the Scientific/Educational Session on the Prevention and Treatment of Relapse after Allogeneic Transplantation highlighted progress in developing new therapeutic approaches since the 1st Relapse Workshop. Recent insights that might provide a basis for the development of novel, practical clinical trials were emphasized, including utilization of newer agents, optimization of donor lymphocyte infusion (DLI), and investigation of novel cellular therapies. Dr. de Lima discussed preemptive and maintenance strategies to prevent relapse after transplantation, e.g., recent promising results suggestive of enhanced graft-versus-tumor activity with hypomethylating agents. Dr. Schmid provided an overview of adjunctive strategies to improve cell therapy for relapse, including cytoreduction prior to DLI, combination of targeted agents with DLI, and considerations in use of second transplants. Dr. Porter addressed strategies to enhance T-cell function, including ex-vivo activated T cells and T-cell engineering, and immunomodulatory approaches to enhance T-cell function in vivo, including exogenous cytokines and modulation of costimulatory pathways.
PMCID: PMC3938421  PMID: 24018392
5.  Neurotrophin receptor p75NTR mediates Huntington’s disease–associated synaptic and memory dysfunction 
The Journal of Clinical Investigation  2014;124(10):4411-4428.
Learning and memory deficits are early clinical manifestations of Huntington’s disease (HD). These cognitive impairments have been mainly associated with frontostriatal HD pathology; however, compelling evidence provided by several HD murine models suggests that the hippocampus may contribute to synaptic deficits and memory dysfunction in HD. The neurotrophin receptor p75NTR negatively regulates spine density, which is associated with learning and memory; therefore, we explored whether disturbed p75NTR function in the hippocampus could contribute to synaptic dysfunction and memory deficits in HD. Here, we determined that levels of p75NTR are markedly increased in the hippocampus of 2 distinct mouse models of HD and in HD patients. Normalization of p75NTR levels in HD mutant mice heterozygous for p75NTR prevented memory and synaptic plasticity deficits and ameliorated dendritic spine abnormalities, likely through normalization of the activity of the GTPase RhoA. Moreover, viral-mediated overexpression of p75NTR in the hippocampus of WT mice reproduced HD learning and memory deficits, while knockdown of p75NTR in the hippocampus of HD mice prevented cognitive decline. Together, these findings provide evidence of hippocampus-associated memory deficits in HD and demonstrate that p75NTR mediates synaptic, learning, and memory dysfunction in HD.
PMCID: PMC4191006  PMID: 25180603
6.  Symptoms and Quality of Life in Diverse Patients Undergoing Hematopoietic Stem Cell Transplantation 
Symptoms and quality of life (QOL) are critically important in hematopoietic stem cell transplantation (HSCT). However, few studies have examined these factors by transplant type among diverse cultures.
To identify and compare QOL and symptom severity and prevalence by transplant type in a diverse population having HSCT.
The M. D. Anderson Symptom Inventory Blood and Marrow Transplantation (MDASI-BMT) module measured symptom severity and its impact. The Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) measured QOL.
Symptom data were collected from 164 patients at eight points (pretransplant to 100 days post-transplant) and QOL data at four times. Over time, symptom severity was significantly correlated with QOL and patients who had allogeneic transplants with myeloablative regimens showed more severe sleep disturbance and poorer QOL than patients having autologous transplants. Male patients reported less fatigue than female patients. However, ethnicity was not significant. Patients whose functional status was good had fewer of the five worst symptoms and higher QOL than patients with a poor functional status. Patients with acute graft-versus-host disease had more severe symptoms than those who did not.
Type of transplant and preparative regimen are the most important aspects to consider when managing symptoms and QOL. This information is important for providing anticipatory guidance and support needed during the transplantation experience, to explore in future research the mechanisms involved in symptoms after HSCT, and to develop additional effective interventions.
PMCID: PMC4270122  PMID: 22699091
Hematopoietic stem cell transplantation; symptoms; quality of life; ethnic diversity; transplant type
7.  Dietary Habits in Patients with Ischemic Stroke: A Case-Control Study 
PLoS ONE  2014;9(12):e114716.
Background and Aims
Diet appears to have some role in stroke development. The objective of our study was to describe the dietary habits in patients admitted with acute ischemic stroke and compare selected dietary components with healthy controls. Adherence to healthy diet behaviors was also assessed.
A case-control study of consecutive patients with acute ischemic stroke admitted to the Neurology Department of Hospital del Mar from 2007 to 2010. Patients were matched by age and sex with control subjects. A previously validated nutritional survey was administered to patients and controls. Demographic data, vascular risk factors, caloric intake and dietary nutrients were evaluated. Intention to follow a healthy diet was also assessed in both groups.
A total of 300 acute ischemic stroke patients and 300 controls with evaluation of dietary habits. No differences were observed in vascular risk factors, except smoking habit, diabetes and ischemic heart disease. Stroke patients reported a higher caloric intake: 2444.8(1736.8–3244.5) vs 2208.7(1753.1–2860.7) Kcal, p = 0.001. After adjusting for energy intake, patients had higher intake of proteins (p<0.001; OR 1.02), total cholesterol (p = 0.001; OR 1.04), and breaded foods (p = 0.001; OR 1.94) and lower consumption of probiotic yogurt (p = 0.002; OR 0.88). Compared to patients, control participants indicated greater intention to eat vegetables (p = 0.002; OR 1.5) and whole foods (p = 0.000; OR 2.4) and reduce their intake of salt (p = 0.002; OR 1.7), fat (p = 0.000; OR 3.7) and sweets (p = 0.004; OR 1.7) than patients.
We observed different dietary patterns between stroke patients and controls. Stroke patients have a higher caloric intake and are less concerned about maintaining healthy nutritional habits.
PMCID: PMC4266513  PMID: 25506934
8.  Myeloablative reduced-toxicity IV busulfan-fludarabine and allogeneic hematopoietic stem cell transplant for patients with acute myeloid leukemia or myelodysplastic syndrome in the sixth through eighth decades of life 
The optimal pretransplant regimen for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) in patients ≥55 years of age remains to be determined. The myeloablative reduced-toxicity 4-day regimen IV busulfan (Bu) (130 mg/m2)-IV fludarabine (Flu) (40 mg/m2) is associated with low morbidity and mortality. We analyzed 79 patients ≥55 years of age (median, 58 years) with AML (n=63) or MDS (n=16) treated with IV Bu-Flu conditioning regimens between 2001 and 2009 (median follow-up, 24 months). The patients who received this regimen had a good performance status. The 2-year overall survival rates for patients in first complete remission (CR1), second CR (CR2), refractory disease and for all patients at time of transplantation were 71%, 44%, 32%, and 46%, respectively; 2-year event-free survival rates for patients in CR1, CR2, or refractory disease at time of transplantation and for all patients were 68%, 42%, 30%, and 44%, respectively. One-year transplant-related mortality (TRM) rates for patients who were in CR or who had active disease at the time of transplantation were 19% and 20%, respectively. Grade II-IV acute graft-versus-host disease was diagnosed in 40% of the patients. Our results suggest that age alone should not be the primary reason for exclusion from receiving myeloablative reduced-toxicity conditioning with IV Bu-Flu preceding transplantation in patients with AML/MDS.
PMCID: PMC4261630  PMID: 21338705
9.  The Role of HbA1c Determination in Detecting Unknown Glucose Disturbances in Ischemic Stroke 
PLoS ONE  2014;9(12):e109960.
To evaluate the usefulness of hemoglobin A1c (HbA1c) determinations during the acute ischemic stroke (IS) to identify undiagnosed glucose disturbances in a prospective series of patients with first-ever IS.
Retrospective analysis of a prospective series of first-ever IS patients. Patients with previous diagnosis of diabetes mellitus (DM) were excluded from the study. Patients were classified as non-DM (HbA1c<5.7% and no previous evidence of 2 or more fasting blood glucose> = 126 mg/dL), prediabetes (HbA1c from 5.7% to 6.4%), and new suspected DM (HbA1c> = 6.5% independently of current blood glucose). Medical charts from hospital discharge to July 2014 of all suspected DM patients were reviewed to confirm the DM diagnosis.
The initial cohort included 1283 patients, of which 393 were excluded because of previous DM diagnosis and 136 because HbA1c during acute stroke phase was not available. No demographic differences were observed between patients with and without HbA1c determinations. The final cohort was composed of 754 patients with first-ever IS and unknown DM history. HbA1c determination suggested new DM in 87 cases (11.5%) and detected 273 patients with prediabetes (36.2%). New DM cases were identified in all etiological stroke subtypes. After discharge, DM diagnosis was confirmed in 80.2% of patients with available follow-up.
HbA1c determination detected both undiagnosed DM and prediabetes in IS patients without taking into account the blood glucose values during admission, and independently of etiological stroke subtype. HbA1c determination should be included in the systematic screening of all IS patients.
PMCID: PMC4259295  PMID: 25485761
10.  B-type natriuretic peptides and mortality after stroke 
Neurology  2013;81(23):1976-1985.
To measure the association of B-type natriuretic peptide (BNP) and N-terminal fragment of BNP (NT-proBNP) with all-cause mortality after stroke, and to evaluate the additional predictive value of BNP/NT-proBNP over clinical information.
Suitable studies for meta-analysis were found by searching MEDLINE and EMBASE databases until October 26, 2012. Weighted mean differences measured effect size; meta-regression and publication bias were assessed. Individual participant data were used to estimate effects by logistic regression and to evaluate BNP/NT-proBNP additional predictive value by area under the receiver operating characteristic curves, and integrated discrimination improvement and categorical net reclassification improvement indexes.
Literature-based meta-analysis included 3,498 stroke patients from 16 studies and revealed that BNP/NT-proBNP levels were 255.78 pg/mL (95% confidence interval [CI] 105.10–406.47, p = 0.001) higher in patients who died; publication bias entailed the loss of this association. Individual participant data analysis comprised 2,258 stroke patients. After normalization of the data, patients in the highest quartile had double the risk of death after adjustment for clinical variables (NIH Stroke Scale score, age, sex) (odds ratio 2.30, 95% CI 1.32–4.01 for BNP; and odds ratio 2.63, 95% CI 1.75–3.94 for NT-proBNP). Only NT-proBNP showed a slight added value to clinical prognostic variables, increasing discrimination by 0.028 points (integrated discrimination improvement index; p < 0.001) and reclassifying 8.1% of patients into correct risk mortality categories (net reclassification improvement index; p = 0.003). Neither etiology nor time from onset to death affected the association of BNP/NT-proBNP with mortality.
BNPs are associated with poststroke mortality independent of NIH Stroke Scale score, age, and sex. However, their translation to clinical practice seems difficult because BNP/NT-proBNP add only minor predictive value to clinical information.
PMCID: PMC3854833  PMID: 24186915
11.  Proceedings from the National Cancer Institute’s Second International Workshop on the Biology, Prevention, and Treatment of Relapse after Hematopoietic Stem Cell Transplantation: Part II. Autologous Transplantation — Novel Agents and Immunomodulatory Strategies 
In the National Cancer Institute’s Second International Workshop on the Biology, Prevention, and Treatment of Relapse after Hematopoietic Stem Cell Transplantation, the Scientific/Educational Session on Autologous Transplantation addressed the role of novel agents and immunomodulatory strategies in management of relapse after autologous hematopoietic stem cell transplantation (AHSCT). Concepts were illustrated through in-depth discussion of multiple myeloma, with broader discussion of areas relevant for relapse of other malignancies as well as in the setting of allogeneic transplantation. Dr. Hari provided an overview of the epidemiology of relapse after AHSCT in multiple myeloma, addressing clinical patterns, management implications, and treatment options at relapse, highlighting the implications of novel therapeutic agents in initial, maintenance and relapse treatment. Dr. Avigan discussed current concepts in tumor vaccine design, including whole-cell and antigen-specific strategies, use of an AHSCT platform to reverse tumor-associated immunosuppression and tolerance, and combining vaccines with immunomodulatory agents to promote establishment of durable antitumor immunity. Dr. Hsu reviewed the immunogenetics of natural killer (NK) cells and general NK biology, the clinical importance of autologous NK activity (e.g., lymphoma and neuroblastoma), as well as the impact of existing therapies on promotion of NK-cell activity (e.g., immunomodulatory drugs, monoclonal antibodies) and strategies for enhancing autologous and allogeneic NK-cell effects through NK-cell gene profiling.
PMCID: PMC3914636  PMID: 24018393
12.  Fludarabine, cyclophosphamide and antithymocyte globulin as total body irradiation-free conditioning for matched related and unrelated allogeneic stem cell transplantation in severe aplastic anemia 
Leukemia & lymphoma  2010;52(1):137-141.
Twenty severe aplastic anemia (SAA) patients underwent allogeneic stem cell transplantation (allo-SCT) with fludarabine (FLU), cyclophosphamide and antithymocyte globulin from a matched related (n=7, age ≥ 40) or unrelated donor (n=13, any age). Median age was 34 years (range 1–59). Median time from diagnosis to allo-SCT was 12 months (range 2–244). Seventeen out of 19 evaluable patients engrafted (90%). There were two secondary graft failures (10%). Median time to neutrophil recovery was 15 days (range 8–30). Chimerism studies indicated ≥90% donor-derived engraftment in 16/19 evaluable patients (75%). Four out of 20 patients (20%) developed acute (grade II–IV) GVHD, and 6/16 evaluable patients (37%) developed chronic GVHD. We observed EBV reactivation and viremia in seven patients, which was successfully treated with rituximab in all but one instance (where it was self-limiting). Thirteen patients (62%) are alive (including eight of the last nine treated) with a median follow-up of 30 months (range 3–112). Seven patients expired (graft rejection n=1, GVHD n=1, multiorgan failure n=1, infection n=2, EBV post-transplant lymphoproliferative disorder/PTLD n=2). Total body irradiation-free, FLU-based conditioning for matched related and unrelated allo-SCT is feasible with high engraftment rates. EBV PTLD remains a drawback of this approach.
PMCID: PMC4238067  PMID: 20939697
Aplastic anemia; bone marrow failure; stem cell transplantation; bone marrow transplantation; conditioning regimen; fludarabine
Haematologica  2008;93(2):257-264.
Background and Objective
The role of reduced-intensity conditioning (RIC) allogeneic stem cell transplantation (allo-SCT) in relapsed/refractory (R/R) Hodgkin’s lymphoma (HL) remains poorly defined. We hereby present an update of our single-center experience with fludarabine-melphalan (FM) as preparative regimen.
Design and Methods
Fifty-eight patients with R/R HL underwent RIC and allo-SCT from a matched related donor (MRD; n=25) or a matched unrelated donor (MUD; n=33). Forty-eight (83%) had received a prior autologous SCT. Disease status at transplant was refractory relapse (n=28) or sensitive relapse (n=30).
Cumulative day 100 and 2-year transplant-related mortality (TRM) were 7% and 15%, respectively (day 100 TRM MRD vs. MUD 8% vs. 6%, p=ns; 2-year MRD vs. MUD 13% vs. 16%, p=ns). The cumulative incidence of acute (grade II–IV) GVHD (first 100 days) was 28% (MRD vs. MUD 12% vs. 39%, p=0.04). The cumulative incidence of chronic GVHD at any time was 73% (MRD vs. MUD 57% vs. 85%, p=0.006). Projected 2-year overall (OS) and progression-free (PFS) survival are 64% (49–76) and 32% (20–45), with 2-year disease progression/relapse (PD) at 55% (43–70). There was no statistically significant difference between MRD and MUD transplants in OS, PFS and PD. There was a trend for the response status pretransplant to favorably impact PFS (p=0.07) and PD (p=0.049), but not OS (p=0.4).
Interpretation and Conclusions
FM as preparative regimen for RIC allo-SCT in R/R HL is associated with a significant reduction in TRM, with comparable results in MRD and MUD allografts. Optimizing pretransplant response status may improve patient outcome.
PMCID: PMC4238917  PMID: 18223284
Hodgkin’s lymphoma; Hodgkin’s disease; allogeneic stem cell transplantation; bone marrow transplantation; peripheral blood stem cell transplantation
14.  EdAl-2 (Educació en Alimentació) programme: reproducibility of a cluster randomised, interventional, primary-school-based study to induce healthier lifestyle activities in children 
BMJ Open  2014;4(11):e005496.
To assess the reproducibility of an educational intervention EdAl-2 (Educació en Alimentació) programme in ‘Terres de l'Ebre’ (Spain), over 22 months, to improve lifestyles, including diet and physical activity (PA).
Reproduction of a cluster randomised controlled trial.
Two semi-rural town-group primary-school clusters were randomly assigned to the intervention or control group.
Pupils (n=690) of whom 320 constituted the intervention group (1 cluster) and 370 constituted the control group (1 cluster). Ethnicity was 78% Western European. The mean age (±SD) was 8.04±0.6 years (47.7% females) at baseline. Inclusion criteria for clusters were towns from the southern part of Catalonia having a minimum of 500 children aged 7–8 year; complete data for participants, including name, gender, date and place of birth, and written informed consent from parents or guardians.
The intervention focused on eight lifestyle topics covered in 12 activities (1 h/activity/session) implemented by health promoting agents in the primary school over three academic years.
Primary and secondary outcomes
The primary outcome was obesity (OB) prevalence and the secondary outcomes were body mass index (BMI) collected every year and dietary habits and lifestyles collected by questionnaires filled in by parents at baseline and end-of-study.
At 22 months, the OB prevalence and BMI values were similar in intervention and control groups. Relative to children in control schools, the percentage of boys in the intervention group who performed ≥4 after-school PA h/week was 15% higher (p=0.027), whereas the percentage of girls in both groups remained similar. Also, 16.6% more boys in the intervention group watched ≤2 television (TV) h/day (p=0.009), compared to controls; and no changes were observed in girls in both groups.
Our school-based intervention is feasible and reproducible by increasing after-school PA (to ≥4 h/week) in boys. Despite this improvement, there was no change in BMI and prevalence of OB.
Trial registration number:
Clinical Trials NCT01362023.
PMCID: PMC4244435  PMID: 25412862
15.  Once Daily IV Busulfan and Fludarabine (IV Bu-Flu) Compares Favorably with IV Busulfan and Cyclophosphamide (IV BuCy2) as Pretransplant Conditioning Therapy in AML/MDS 
We postulated that fludarabine (Flu) instead of cyclophosphamide (Cy) combined with IV busulfan (Bu) as preconditioning for allogeneic hematopoietic stem cell transplantation (HSCT) would improve safety and retain antileukemic efficacy. 67 patients received BuCy2 and subsequently 148 patients received Bu-Flu. We used a Bayesian method to compare outcomes between these non-randomized patients. The groups had comparable pretreatment characteristics, except that Bu-Flu patients were older (46 vs. 39 years, p< 0.01), more often had unrelated donors (47.3% vs. 20.9%, p< 0.0003), and had shorter median follow-up (39.7 vs. 74.6 months). To account for improved supportive care and other unidentified factors that may affect outcome (“period” effects), 78 AML patients receiving Melphalan-Flu (“MF”), treated in parallel during this time (1997 to 2004) were used to estimate the period effect; The MF patients’ outcomes worsened during this period. Therefore, the period effect is unlikely to explain the greatly improved outcome with Bu-Flu. Patients transplanted with Bu-Flu in CR1 had a 3-year overall survival and event-free-survival (EFS) of 78% and 74%, respectively, while CR1 patients younger than age 41 had a 3-year EFS of 89%. These results support replacing BuCy±ATG with Bu-Flu±rabbit-ATG, and warrant a prospective comparison between allogeneic HSCT and conventional induction/consolidation chemotherapy for AML in CR1.
PMCID: PMC4230823  PMID: 18489993
IV Busulfan; Fludarabine; Cyclophosphamide; AML; MDS; Allogeneic Stem Cell Transplantation
17.  Proceedings from the National Cancer Institute’s Second International Workshop on the Biology, Prevention, and Treatment of Relapse After Hematopoietic Stem Cell Transplantation: Part I. Biology of Relapse after Transplantation 
In the National Cancer Institute’s Second Workshop on the Biology, Prevention, and Treatment of Relapse After Hematopoietic Stem Cell Transplantation, the Scientific/Educational Session on the Biology of Relapse discussed recent advances in understanding some of the host, disease and transplant-related contributions to relapse, emphasizing concepts with potential therapeutic implications. Relapse after hematopoietic stem cell transplantation (HSCT) represents tumor escape – from the cytotoxic effects of the conditioning regimen and from immunologic control mediated by reconstituted lymphocyte populations. Factors influencing the biology of the therapeutic graft-versus-malignancy (GVM) effect – and relapse – include conditioning regimen effects upon lymphocyte populations and homeostasis, immunologic niches, and the tumor microenvironment; reconstitution of lymphocyte populations and establishment of functional immune competence; and genetic heterogeneity within the malignancy defining potential for clonal escape. Recent developments in T- and NK-cell homeostasis and reconstitution are reviewed, with implications for prevention and treatment of relapse, as is the application of modern genome sequencing to defining the biologic basis of GVM, clonal escape and relapse after HSCT.
PMCID: PMC3922045  PMID: 24018395
18.  The Impact of Pre-Stem Cell Transplant Ferritin Level on Late Transplant Complications: An Analysis to Determine the Potential Role of Iron Overload on Late Transplant Outcomes 
Iron overload has been associated with increased non-relapse mortality (NRM) in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) undergoing hematopoietic stem cell transplantation (HSCT). Elevated ferritin level pre-HSCT has been used as a marker for iron overload. It is unclear whether the negative effect of iron overload as measured by elevated ferritin level extends beyond the first three months post HSCT, as this would suggest a potential role for active management of iron overload post HSCT.
Sixty-three patients with AML and MDS who underwent an allogeneic HSCT from a sibling or unrelated donor between January to December 2006, had a pre-HSCT ferritin level and were alive and disease free 90 days post HSCT.
Median age was 51. Patients with the lowest pre-HSCT ferritin level (Q1) had a trend towards improved overall survival and progression free survival when compared to patients with higher level (Q2–Q4) (P=0.06, and 0.125). Cumulative incidence of NRM at 2 years was 20 and 30% respectively (P=0.4).
Pre-HSCT ferritin level may still have an impact on HSCT events beyond 3 months post transplant, suggesting a role for research into active management of iron overload with either phlebotomy or chelation.
PMCID: PMC4209589  PMID: 25356072
Ferritin; Hematopoietic Stem Cell Transplant; Late Transplant Outcome; AML; MDS
19.  Hematopoietic progenitor cell collection in patients with chronic myelogenous leukemia in complete cytogenetic remission after imatinib mesylate therapy 
Leukemia & lymphoma  2010;51(8):1478-1484.
The introduction of BCR–ABL tyrosine kinase inhibitors such as imatinib has changed the treatment of chronic myelogenous leukemia (CML). More than 75% of patients achieve complete cytogenetic remission (CCR) after treatment with imatinib, which provides an opportunity to collect minimally involved hematopoietic progenitor stem cell (HPC) products. In order to assess the feasibility of HPC collection in patients with CML, we prospectively enrolled 24 patients who achieved CCR on therapy with imatinib. Two patients could not undergo HPC collection because of coagulopathy. A CD34+ cell yield of ≥2.0 × 106/kg body weight was obtained in 16/22 (73%) patients. Patients who stopped imatinib for at least 3 weeks prior to HPC collection had significantly higher CD34+ cell yields (median: 6.52 × 106/kg body weight) when compared with patients who continued imatinib through the collection (median: 3.74 × 106/kg body weight). Mobilization with granulocyte colony-stimulating factor (G-CSF) did not increase the levels of BCR–ABL transcript. With a mean follow-up of 46 months, all patients but one were in CCR. In conclusion, a significant number of CD34+ cells can be safely collected in patients with CML who are on imatinib therapy, but CD34+ cell yields improve when imatinib is temporarily withheld.
PMCID: PMC4188823  PMID: 20658954
CML; imatinib; hematopoietic progenitor cell
20.  A Randomized Phase II Trial of Fludarabine/Melphalan 100 versus Fludarabine/Melphalan 140 followed by Allogeneic Hematopoietic Stem Cell Transplantation for Patients with Multiple Myeloma 
Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a potentially curative treatment for multiple myeloma (MM); however, due to high-treatment related mortality (TRM) its role is not well defined.
Patients with newly diagnosed, relapsed, or primary refractory myeloma were enrolled in a randomized phase II trial of two reduced intensity conditioning regimens, fludarabine 120 mg/m2+ melphalan 100 mg/m2(FM100) versus fludarabine 120 mg/m2+ melphalan 140 mg/m2(FM140) before allo-HCT from related or unrelated donors.
Fifty patients underwent allo-HCT using FM100 (N=23) or FM140 (N=27) conditioning between April 2002 and 2011. There were no significant differences between FM100 and FM140 in time to neutrophil engraftment (p=0.21), acute grade II-IV GVHD (p=1.0), chronic GVHD (p=0.24), response rate (p=1.0), TRM (13% versus 15%, p=1.0), median progression-free survival (PFS), 11.7 versus 8.4 months, p=0.12, and median overall survival (OS), 35.1 versus19.7 months, p=0.38. Cumulative incidence of disease progression in FM100 and FM140 was 43% and 70%, respectively (p=0.08). Recurrent disease was the most common cause of death for both FM100 (26%) and FM140 (44%), p=0.24. On multivariate analysis, disease status at allo-HCT, complete response or very good partial response (VGPR) was significantly associated with longer PFS (15.6 versus 9.6 months in patients with < VGPR, p=0.05). OS was similar across all variables.
We conclude that FM 100 and FM140 may result in similar patient outcomes after allo-HCT for MM.
PMCID: PMC4157818  PMID: 23872222
Myeloma; Allogeneic transplantation; Reduced intensity conditioning; Fludarabine; Melphalan
21.  Epimacular brachytherapy for wet AMD: current perspectives 
Age-related macular degeneration (AMD) is considered the most common cause of blindness in the over-60 age group in developed countries. There are basically two forms of presentation: geographic (dry or atrophic) and wet (neovascular or exudative). Geographic atrophy accounts for approximately 85%–90% of ophthalmic frames and leads to a progressive degeneration of the retinal pigment epithelium and the photoreceptors. Wet AMD causes the highest percentage of central vision loss secondary to disease. This neovascular form involves an angiogenic process in which newly formed choroidal vessels invade the macular area. Today, intravitreal anti-angiogenic drugs attempt to block the angiogenic events and represent a major advance in the treatment of wet AMD. Currently, combination therapy for wet AMD includes different forms of radiation delivery. Epimacular brachytherapy (EMBT) seems to be a useful approach to be associated with current anti-vascular endothelial growth factor agents, presenting an acceptable efficacy and safety profile. However, at the present stage of research, the results of the clinical trials carried out to date are insufficient to justify extending routine use of EMBT for the treatment of wet AMD.
PMCID: PMC4155998  PMID: 25210436
macular degeneration; radiation; vascular endothelial growth factor; combined therapy; intravitreal therapy; vitrectomy
22.  Randomized, Double-Blind, Placebo-Controlled Trial of Soluble Tumor Necrosis Factor Receptor: Enbrel (Etanercept) for the Treatment of Idiopathic Pneumonia Syndrome after Allogeneic Stem Cell Transplantation: Blood and Marrow Transplant Clinical Trials Network Protocol 
Idiopathic pneumonia syndrome (IPS) is a diffuse, noninfectious lung injury that occurs acutely after allogeneic hematopoietic cell transplantation (HCT). IPS-related mortality has been historically high (>50%) despite treatment with systemic corticosteroids and supportive care measures. We have now examined the role of tumor necrosis factor inhibition in a randomized, double-blind, placebo-controlled trial of corticosteroids with etanercept or placebo. Thirty-four subjects (≥18 years) with IPS after HCT were randomized to receive meth-ylprednisolone (2 mg/kg/day) plus etanercept (0.4 mg/kg twice weekly ≥ 4 weeks; n = 16) or placebo (n = 18). No active infections and a pathogen-negative bronchoscopy were required at study entry. Response (alive, with complete discontinuation of supplemental oxygen support) and overall survival were examined. This study, originally planned to accrue 120 patients, was terminated prematurely due to slow accrual. In the limited number of patients examined, there were no differences in response rates at day 28 of study. Ten of 16 patients (62.5% [95% confidence interval {CI}, 35.4% to 84.8%]) receiving etanercept and 12 of 18 patients (66.7% [95% CI, 41.0% to 86.7%]) receiving placebo met the day 28 response definition (P = 1.00). The median survival was 170 days (95% CI, 11 to 362) with etanercept versus 64 days (95% CI, 26 to 209) with placebo (P = .51). Among responders, the median time to discontinuation of supplemental oxygen was 9 days (etanercept) versus 7 days (placebo). Therapy was well tolerated, with 1 toxicity-related death from infectious pneumonia in the placebo arm. The treatment of IPS with corticosteroids in adult HCT recipients was associated with high early response rates (>60%) compared with historical reports, with poor overall survival. The addition of etanercept did not lead to further increases in response, although the sample size of this truncated trial preclude a definitive conclusion.
PMCID: PMC4128626  PMID: 24607553
Bone marrow transplantation; IPS; TNF; Pneumonia; Pulmonary
23.  Relevance of stroke subtype in vascular risk prediction 
Neurology  2013;81(6):575-580.
To ascertain the risk of a new vascular event (NVE) occurring after ischemic stroke and evaluate differences in risk based on stroke subtype.
This was a prospective observational study of consecutive patients with nonfatal stroke recruited at a single tertiary stroke center with follow-up ranging from 2 to 5 years (average, 31 ± 15.9 months). An NVE (vascular death, nonfatal stroke or myocardial infarction, and hospitalization for other atherothrombotic events) was defined according to criteria used in a previously developed large multicenter register of atherothrombotic patients (Reduction of Atherothrombosis for Continued Health Registry [REACH]). We analyzed age, sex, and atherosclerotic burden (AB) based on a number of vascular risk factors, affected vascular areas, and stroke subtype according to Stop Stroke Study Trial of Org 10172 in Acute Stroke Treatment (SSS-TOAST) criteria in cardioaortic, large artery atherosclerosis (LAA), unclassified (more than one causal mechanism), small-artery disease (SAD), and undetermined (without cause) stroke categories.
The final cohort consisted of 748 patients. An NVE occurred in 162 patients (21.7%), equivalent to a rate of 0.084 events per patient/year. Multivariate analysis revealed that higher NVE risk was associated with AB and 3 stroke subtypes, namely cardioaortic (hazard ratio [HR] = 2.58; 95% confidence interval [CI] 1.27–5.22), LAA (HR = 4.17; 95% CI 2.03–8.56), and unclassified (HR = 5.70; 95% CI 2.49–13.08). Patients with SAD or stroke of undetermined cause had lower NVE risk.
Patients who survive stroke are at increased risk for NVEs. The risk for NVE varies according to stroke subtype.
PMCID: PMC3775680  PMID: 23825174
24.  Outcomes in Patients With Relapsed or Refractory Acute Promyelocytic Leukemia Treated With or Without Autologous or Allogeneic Hematopoietic Stem Cell Transplantation 
Outcomes in patients with acute promyelocytic leukemia have improved; however, a subset of patients relapse despite receiving all-trans-retinoic acid and/or arsenic-based therapies. Among 40 patients with acute promyelocytic leukemia who were treated at our institution (1980–2010), 24 received hematopoietic stem cell transplantation (HCT) (autologous HCT, 7; allogeneic HCT, 14; both, 3); 16 received chemotherapy only. All 3 strategies (autologous HCT, allogeneic HCT, chemotherapy) were feasible in patients with relapsed acute promyelocytic leukemia and result in long-term disease control in selected patients.
Outcomes in patients with acute promyelocytic leukemia (APL) have improved; however, a significant number of patients still relapse despite receiving all-trans-retinoic acid (ATRA) and arsenic-based therapies.
Patients and Methods
Outcomes of patients with relapsed APL who were treated at our institution (1980–2010) and who received HCT were compared with those who received chemotherapy (CT) only.
Among 40 patients, 24 received HCT (autologous [auto] HCT, 7; allogeneic [allo] HCT, 14; both, 3); 16 received CT only. The median age at diagnosis was 36 years (range, 13–50 years), 31 years (range, 16–58 years), and 44 years (range, 24–79 years) for the auto-HCT, allo-HCT, and CT groups, respectively. Ten (100%) patients who received auto-HCT and 12 (71%) who received allo-HCT were in complete remission at the time of the HCT. The median follow-ups in the auto-HCT, allo-HCT, and CT groups were 74 months (range, 26–135 months), 118 months (range, 28–284 months), and 122 months (range, 32–216 months), respectively. Transplantation-related mortality (1 year) after auto-HCT and allo-HCT were 10% and 29%, respectively. The 7-year event-free survival after auto-HCT and allo-HCT was 68.6% and 40.6%, respectively (P = .45). The 7-year overall survival was 85.7%, 49.4%, and 40% in the auto-HCT, allo-HCT, and CT groups, respectively (P = .48).
Both auto-HCT and allo-HCT are associated with durable remission and prolonged survival. All 3 strategies (auto-HCT, allo-HCT, CT) were found to be feasible in the relapsed APL setting and result in long-term disease control in selected patients. In this retrospective analysis, overall survival for patients who received HCT was not significantly better than patients who received CT only, but a trend toward better outcomes was seen in patients who underwent auto-HCT, although not statistically significant.
PMCID: PMC4112369  PMID: 23769669
Acute myeloid leukemia; Acute promyelocytic leukemia; Allogeneic transplantation; Autologous transplantation; Bone marrow transplantation; Stem cell transplantation
25.  A Phase III Study of Infliximab and Corticosteroids for the Initial Treatment of Acute Graft-versus-Host Disease 
Anti-Tumor Necrosis Factor Alpha (TNF-α) therapy with infliximab has shown to be effective for patients with steroid-refractory acute graft-versus-host disease (aGVHD). An open-labeled, phase III trial was conducted to determine if the addition of infliximab to steroids could improve results for patients with newly diagnosed grade II-IV aGVHD. A total of 63 patients were randomized either to 2 mg/kg/day methylprednisolone (MP) or infliximab + MP. Average age was 47 years (range: 20–70 years); 64% were male. Fifty-three percent and 51% of patients received a matched-sibling and/or bone marrow (BM) graft. Sixty-seven percent had grade II, 33% grade III-IV aGVHD; 62% had skin, 53% gastrointestinal (GI), and 7% had liver involvement. At days 7 and 28, the response rate for infliximab + MP versus MP was 52% versus 78%, P=.03 and 62% versus 58%, P=.7, respectively. Cumulative incidences of GVHD-related mortality, nonrelapse mortality (NRM), and overall survival (OS) were not significantly different between the 2 groups (GVHD-related mortality: 38% versus 32%, P=.6; NRM: 52% versus 36%, P=.3; OS: 17% and 28%, P=.4 for infliximab + MP versus MP, respectively). Patients with newly diagnosed aGVHD derive no benefit from the addition of anti-TNF-α therapy with infliximab when compared to corticosteroids alone.
PMCID: PMC4114035  PMID: 19896079
Acute GVHD; Infliximab

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