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1.  Reduced Intensity Conditioning, Combined Transplantation of Haploidentical Hematopoietic Stem Cells and Mesenchymal Stem Cells in Patients with Severe Aplastic Anemia 
PLoS ONE  2014;9(3):e89666.
We examined if transplantation of combined haploidentical hematopoietic stem cells (HSC) and mesenchymal stem cells (MSC) affected graft failure and graft-versus-host disease (GVHD) in patients with severe aplastic anemia (SAA). Patients with SAA-I (N = 17) received haploidentical HSCT plus MSC infusion. Stem cell grafts used a combination of granulocyte colony-stimulating factor (G-CSF)-primed bone marrow and G-CSF-mobilized peripheral blood stem cells of haploidentical donors and the culture-expanded third-party donor-derived umbilical cord MSCs (UC-MSCs), respectively. Reduced intensity conditioning consisted of fludarabine (30 mg/m2·d)+cyclosphamide (500 mg/m2·d)+anti-human thymocyte IgG. Transplant recipients also received cyclosporin A, mycophenolatemofetil, and CD25 monoclonal antibody. A total of 16 patients achieved hematopoietic reconstitution. The median mononuclear cell and CD34 count was 9.3×108/kg and 4.5×106/kg. Median time to ANC was >0.5×109/L and PLT count >20×109/L were 12 and 14 days, respectively. Grade III-IV acute GVHD was seen in 23.5% of the cases, while moderate and severe chronic GVHD were seen in 14.2% of the cases. The 3-month and 6-month survival rates for all patients were 88.2% and 76.5%, respectively; mean survival time was 56.5 months. Combined transplantation of haploidentical HSCs and MSCs on SAA without an HLA-identical sibling donor was safe, effectively reduced the incidence of severe GVHD, and improved patient survival.
PMCID: PMC3940616  PMID: 24594618
2.  Decreased Infection-Related Mortality and Improved Survival in Severe Aplastic Anemia in the Past Two Decades 
Survival in aplastic anemia has markedly improved in recent decades. In multivariate analysis, the introduction of newer antifungal agents and a decrease in fungal infections were independent predictors for survival in the months following immunosuppression among patients with persistent neutropenia.
Background. Persistent neutropenia associated with severe aplastic anemia (SAA) is an important risk factor for development of life-threatening infections. Earlier studies underscored the high mortality associated with invasive fungal infections (IFIs) in SAA. However, little is known about the current patterns of infections and the impact of advances in anti-infective therapy on survival in SAA.
Methods. We reviewed the records of 174 patients with SAA admitted to the Hematology Branch at NHLBI from 1989 to 2008 who were unresponsive to initial immunosuppressive therapy (IST) at 6 months. Three patient groups determined by IST protocol and time interval were compared: group 1 (43 patients; December 1989–October 1996), group 2 (51 patients; November 1996–October 2002), and group 3 (80 patients; November 2002–April 2008). Outcome variables included infections, patterns of resistance, survival, and infection-related mortality.
Results. During the past 2 decades, infection-related mortality decreased from 37% in group 1 to 11% in group 3 (P<.001), and the frequency of IFIs decreased from 49% in group 1 to 8% in group 3 (P<.001). Overall 5-year survival for all patients (n = 420) increased from 64% in group 1 to 79% in group 3 (P<.001). Among non-responders (n = 174), it increased from 23% in group 1 to 57% in group 3 (P<.001). In multivariate analysis, younger age, absolute neutrophil count >200 cells/μL before IST, absence of IFIs, and use of voriconazole were independently predictive of survival.
Conclusion. During the past 2 decades, there has been a significant decrease in IFIs, infection-related mortality, and overall mortality in patients with SAA unresponsive to initial IST.
PMCID: PMC3106262  PMID: 21367725
3.  Evaluation of early discharge after hospital treatment of neutropenic fever in acute myeloid leukemia (AML) 
Leukemia Research Reports  2013;2(1):26-28.
Hospital admission for neutropenic fever in patients with AML is a standard practice. However, discharge practices vary once patients become afebrile, with many patients hospitalized until rise in the absolute neutrophil count (ANC) to >500 (ANC recovery). Data to support this practice are sparse. We hypothesized that patients admitted for neutropenic fever, particularly if in complete remission (CR) or about to enter CR following the chemotherapy course associated with neutropenic fever, might be safely discharged earlier (ED). Benefits of ED are less exposure to hospital pathogens, reduced cost, increased availability of beds for patients more in need of urgent care, and potentially, enhanced psychological well-being.
We identified patients age 18–70 with newly diagnosed AML who were admitted to the University of Washington Medical Center with neutropenic fever between January 2008 and May 2010. We compared subsequent (within 30 days of discharge) deaths, intensive care unit (ICU) admissions, and readmissions for neutropenic fever according to discharge ANC, regarded as a numerical variable using the Mann–Whitney U test and as <500 vs >500 using the Fisher Exact test. We used the Mann–Whitney U or Spearman correlation to analyze the relation between ANC at discharge and other covariates that might have affected outcome: age, ECOG performance status at admission for neutropenic fever, days inpatient, remission status, and type of infection (pneumonia, gram negative bacteremia, others).
We evaluated 49 patients discharged after admission for neutropenic fever, 26 of whom were discharged with an ANC <500. Thirty five of the patients were in CR or entered CR following the chemotherapy course associated with their neutropenic fever admission. Patients who were discharged with lower ANC were more likely to be readmitted with neutropenic fever (Mann–Whitney U p=0.03), although this was not true using ANC categorized as < vs >500 (Fisher Exact p=0.24, 95% confidence interval −0.47, 0.11). There was no relation between ANC at discharge and subsequent admission to an ICU (Mann–Whitney U p=0.50, Fisher Exact p=0.64, 95% confidence interval 0.2, 0.34 using the 500 ANC cut off). One patient died: a 55 year old discharged with ANC 0 after successful treatment of neutropenic fever died 19 days after hospital readmission with fever of unknown origin. Stenotrophomonas maltophilia pneumonia and sepsis were discovered 14 days after readmission. Assuming a beta distribution and rates of death of 1/26 for discharge with ANC<500 and 0/23 for discharge with ANC>500, the probability that a discharge ANC with <500 is associated with a higher death rate is 0.019. The number of events was too small for a multivariate analysis. However, patients with better performance status (
Our results suggest that an ANC of 500 is an excessively high cut off for discharge following hospitalization for neutropenic fever. The rate of rise of the ANC, as well as its absolute value, may also play a role.
PMCID: PMC3850377  PMID: 24371771
Leukemia; Neutropenic; Fever; Discharge; Neutrophil
The Journal of pediatrics  2008;153(6):814-819.
To determine the long term outcomes in children with severe aplastic anemia (SAA) treated with anti-thymocyte globulin (ATG) and cyclosporine (CsA), we conducted a retrospective analysis of the pediatric patients treated at our institution in all protocols that included horse ATG + CsA.
Study design
From 1989 to 2006, 406 patients, of whom about 20% were children under the age of 18, received an initial course of immunosuppressive therapy (IST) at our institution. Here we report the outcome of 77 children who were treated with a horse ATG + CsA based regimen during this time.
The overall response rate at 6 months was 74% (57/77); the cumulative incidence of relapse at 10 years was 33%, and the median time to relapse was 558 days. The cumulative incidence of evolution following IST was 8.5%; all 3 such events occurred among partial responders. Overall, there were 13 deaths (17%): four occurred within the 3 months following IST in patients who had a pre-treatment ANC of less than 100/uL, and nine deaths occurred more than 6 months after initiating IST. The median time to death was 570 days. The overall 10-year survival for the entire cohort was 80%; long term survival in children who responded to IST was 89%.
The long term survival in pediatrics patients who respond to IST is excellent, at about 90%. IST remains a good alternative in pediatric patients who lack an HLA-matched sibling donor and should be offered as initial therapy, prior to an alternative HSCT.
PMCID: PMC3971527  PMID: 18672253
aplastic anemia; anti-thymocyte globulin; response; immunosuppression; pediatrics; survival
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment for severe aplastic anemia (SAA). However, graft failure and graft-versus-host disease (GVHD) are major causes of the early morbidity in Allo-HSCT.
To reduce graft failure and GVHD, we treated fifteen patients with SAA using high- dose of HSCT with both G-CSF mobilized PB and BMSCs from HLA-identical siblings to treat patients with SAA.
All patients had successful bone marrow engraftment. Only one patient had late rejection. Median time to ANC greater than 0.5 × 109/L and platelet counts greater than 20 × 109/L was 12 and 16.5 days, respectively. No acute GVHD was observed. The incidence of chronic GVHD was 6.67%. The total three-year probability of disease-free survival was 79.8%.
HSCT with both G-CSF mobilized PB and BMSCs is a promising approach for heavily transfused and/or allo-immunized patients with SAA.
PMCID: PMC3023734  PMID: 21194460
British journal of haematology  2008;144(2):206-216.
Horse anti-thymocyte globulin (h-ATG) and cyclosporine are the initial therapy for most patients with severe aplastic anaemia (SAA), but there is no practical and reliable method to predict response to this treatment. To determine whether pre-treatment blood counts discriminate patients with SAA who have a higher likelihood of haematological response at 6 months to immunosuppressive therapy (IST), we conducted a single institution retrospective analysis on 316 SAA patients treated with h-ATG-based IST from 1989 to 2005. In multivariate analysis, younger age, higher baseline absolute reticulocyte count (ARC), and absolute lymphocyte count (ALC) were highly predictive of response at 6 months. Patients with baseline ARC ≥ 25 × 109 /l and ALC ≥ 1 × 109 /l had a much greater probability of response at 6 months following IST compared to those with lower ARC and ALC (83% vs. 41%, respectively; p < 0.001). This higher likelihood of response translated to greater rate of 5-year survival in patients in the high ARC/ALC group (92%) compared to those with a low ARC/ALC (53%). In the era of IST, the baseline ARC and ALC together serve as a simple predictor of response following IST, which should guide in risk stratification among patients with SAA.
PMCID: PMC4149225  PMID: 19036108
Aplastic anaemia; antibody therapy; bone marrow failure
Arthritis Research  2000;2(2):142-144.
Acute-phase serum amyloid A (A-SAA) is a major component of the acute-phase response. A sustained acute-phase response in rheumatoid arthritis (RA) is associated with increased joint damage. A-SAA mRNA expression was confirmed in all samples obtained from patients with RA, but not in normal synovium. A-SAA mRNA expression was also demonstrated in cultured RA synoviocytes. A-SAA protein was identified in the supernatants of primary synoviocyte cultures, and its expression colocalized with sites of macrophage accumulation and with some vascular endothelial cells. It is concluded that A-SAA is produced by inflamed RA synovial tissue. The known association between the acute-phase response and progressive joint damage may be the direct result of synovial A-SAA-induced effects on cartilage degradation.
Serum amyloid A (SAA) is the circulating precursor of amyloid A protein, the fibrillar component of amyloid deposits. In humans, four SAA genes have been described. Two genes (SAA1 and SAA2) encode A-SAA and are coordinately induced in response to inflammation. SAA1 and SAA2 are 95% homologous in both coding and noncoding regions. SAA3 is a pseudogene. SAA4 encodes constitutive SAA and is minimally inducible. A-SAA increases dramatically during acute inflammation and may reach levels that are 1000-fold greater than normal. A-SAA is mainly synthesized in the liver, but extrahepatic production has been demonstrated in many species, including humans. A-SAA mRNA is expressed in RA synoviocytes and in monocyte/macrophage cell lines such as THP-1 cells, in endothelial cells and in smooth muscle cells of atherosclerotic lesions. A-SAA has also been localized to a wide range of histologically normal tissues, including breast, stomach, intestine, pancreas, kidney, lung, tonsil, thyroid, pituitary, placenta, skin and brain.
To identify the cell types that produce A-SAA mRNA and protein, and their location in RA synovium.
Materials and methods:
Rheumatoid synovial tissue was obtained from eight patients undergoing arthroscopic biopsy and at joint replacement surgery. Total RNA was analyzed by reverse transcription (RT) polymerase chain reaction (PCR) for A-SAA mRNA. PCR products generated were confirmed by Southern blot analysis using human A-SAA cDNA. Localization of A-SAA production was examined by immunohistochemistry using a rabbit antihuman A-SAA polyclonal antibody. PrimaryRA synoviocytes were cultured to examine endogenous A-SAA mRNA expression and protein production.
A-SAA mRNA expression was detected using RT-PCR in all eight synovial tissue samples studied. Figure 1 demonstrates RT-PCR products generated using synovial tissue from three representative RA patients. Analysis of RA synovial tissue revealed differences in A-SAA mRNA levels between individual RA patients.
In order to identify the cells that expressed A-SAA mRNA in RA synovial tissue, we analyzed primary human synoviocytes (n = 2). RT-PCR analysis revealed A-SAA mRNA expression in primary RA synoviocytes (n = 2; Fig. 2). The endogenous A-SAA mRNA levels detected in individual primary RA synoviocytes varied between patients. These findings are consistent with A-SAA expression in RA synovial tissue (Fig. 1). Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) levels were relatively similar in the RA synoviocytes examined (Fig. 2). A-SAA protein in the supernatants of primary synoviocyte cultures from four RA patients was measured using ELISA. Mean values of a control and four RA samples were 77.85, 162.5, 249.8, 321.5 and 339.04 μg/l A-SAA, respectively, confirming the production of A-SAA protein by the primary RA synoviocytes. Immunohistochemical analysis was performed to localize sites of A-SAA production in RA synovial tissue. Positive staining was present in both the lining and sublining layers of all eight RA tissues examined (Fig. 3a). Staining was intense and most prominent in the cells closest to the surface of the synovial lining layer. Positively stained cells were evident in the perivascular areas of the sublining layer. In serial sections stained with anti-CD68 monoclonal antibody, positive staining of macrophages appeared to colocalize with A-SAA-positive cells (Fig. 3b). Immunohistochemical studies of cultured primary RA synoviocytes confirmed specific cytoplasmic A-SAA expression in these cells. The specificity of the staining was confirmed by the absence of staining found on serial sections and synoviocyte cells treated with IgG (Fig. 3c).
This study demonstrates that A-SAA mRNA is expressed in several cell populations infiltrating RA synovial tissue. A-SAA mRNA expression was observed in all eight unseparated RA tissue samples studied. A-SAA mRNA expression and protein production was demonstrated in primary cultures of purified RA synoviocytes. Using immunohistochemical techniques, A-SAA protein appeared to colocalize with both lining layer and sublining layer synoviocytes, macrophages and some endothelial cells. The detection of A-SAA protein in culture media supernatants harvested from unstimulated synoviocytes confirms endogenous A-SAA production, and is consistent with A-SAA mRNA expression and translation by the same cells. Moreover, the demonstration of A-SAA protein in RA synovial tissue, RA cultured synoviocytes, macrophages and endothelial cells is consistent with previous studies that demonstrated A-SAA production by a variety of human cell populations.
The RA synovial lining layer is composed of activated macrophages and fibroblast-like synoviocytes. The macrophage is the predominant cell type and it has been shown to accumulate preferentially in the surface of the lining layer and in the perivascular areas of the sublining layer. Nevertheless, our observations strongly suggest that A-SAA is produced not only by synoviocytes, but also by synovial tissue macrophage populations. Local A-SAA protein production by vascular endothelial cells was detected in some, but not all, of the tissues examined. The reason for the variability in vascular A-SAA staining is unknown, but may be due to differences in endothelial cell activation, events related to angiogenesis or the intensity of local inflammation.
The value of measuring serum A-SAA levels as a reliable surrogate marker of inflammation has been demonstrated for several diseases including RA, juvenile chronic arthritis, psoriatic arthropathy, ankylosing spondylitis, Behçet's disease, reactive arthritis and Crohn's disease. It has been suggested that serum A-SAA levels may represent the most sensitive measurement of the acute-phase reaction. In RA, A-SAA levels provide the strongest correlations with clinical measurements of disease activity, and changes in serum levels best reflect the clinical course.
A number of biologic activities have been described for A-SAA, including several that are relevant to the understanding of inflammatory and tissue-degrading mechanisms in human arthritis. A-SAA induces migration, adhesion and tissue infiltration of circulating monocytes and polymorphonuclear leukocytes. In addition, human A-SAA can induce interleukin-1β, interleukin-1 receptor antagonist and soluble type II tumour necrosis factor receptor production by a monocyte cell line. Moreover, A-SAA can stimulate the production of cartilage-degrading proteases by both human and rabbit synoviocytes. The effects of A-SAA on protease production are interesting, because in RA a sustained acute-phase reaction has been strongly associated with progressive joint damage. The known association between the acute-phase response and progressive joint damage may be the direct result of synovial A-SAA-induced effects on cartilage degradation.
In contrast to noninflamed synovium, A-SAA mRNA expression was identified in all RA tissues examined. A-SAA appeared to be produced by synovial tissue synoviocytes, macrophages and endothelial cells. The observation of A-SAA mRNA expression in cultured RA synoviocytes and human RA synovial tissue confirms and extends recently published findings that demonstrated A-SAA mRNA expression in stimulated RA synoviocytes, but not in unstimulated RA synoviocytes.
PMCID: PMC17807  PMID: 11062604
acute-phase response; rheumatoid arthritis; serum amyloid A; synovial tissue
PLoS ONE  2014;9(11):e110787.
Idiopathic aplastic anemia (AA) is an immune-mediated bone marrow failure syndrome. Immune abnormalities such as decreased lymphocyte counts, inverted CD4/CD8 T-cell ratio and increased IFN-γ-producing T cells have been found in AA. CD30, a surface protein belonging to the tumor necrosis factor receptor family and releasing from cell surface as a soluble form (sCD30) after activation, marks a subset of activated T cells secreting IFN-γ when exposed to allogeneic antigens. Our study found elevated BM plasma levels of sCD30 in patients with SAA, which were closely correlated with disease severity, including absolute lymphocyte count (ALC) and absolute netrophil count (ANC). We also noted that sCD30 levels were positively correlated with plasma IFN-γ levels and CD4/CD8 T-cell ratio in patients with SAA. In order to explain these phenomena, we stimulated T cells with alloantigen in vitro and found that CD30+ T cells were the major source of IFN-γ, and induced CD30+ T cells from patients with SAA produced significantly more IFN-γ than that from healthy individuals. In addition, increased proportion of CD8+ T cells in AA showed enhanced allogeneic response by the fact that they expressed more CD30 during allogeneic stimulation. sCD30 levels decreased in patients responded to immunosuppressive therapy. In conclusion, elevated BM plasma levels of sCD30 reflected the enhanced CD30+ T cell-mediated immune response in SAA. CD30 as a molecular marker that transiently expresses on IFN-γ-producing T cells, may participate in mediating bone marrow failure in AA, which also can facilitate our understanding of AA pathogenesis to identify new therapeutic targets.
PMCID: PMC4226501  PMID: 25383872
Blood Cancer Journal  2011;1(3):e8-.
One of the major obstacles of immunosuppressive therapy (IST) in children with severe aplastic anemia (SAA) comes from the often months-long unpredictability of bone-marrow (BM) recovery. In this prospective study in children with newly diagnosed very severe AA (n=10), who were enrolled in the therapy study SAA-BFM 94, we found a dramatically reduced diversity of both CD4+ and CD8+ BM cells, as scored by comprehensive V-beta chain T-cell receptor (TCR) analysis. Strongly skewed TCR V-beta pattern was highly predictive for good or at least partial treatment response (n=6, CD8+ complexity scoring median 35.5, range 24–73). In contrast, IST in patients with rather moderate reduction of TCR V-beta diversity (n=4, CD8+ complexity scoring median 109.5, range 82–124) always failed (P=0.0095). If confirmed in a larger series of patients, TCR V-beta repertoire in BM may help to assign children with SAA up-front either to IST or to allogeneic stem-cell transplantation.
PMCID: PMC3255274  PMID: 22829127
aplastic anemia; T-cell receptor V-beta chain repertoire; children
PLoS ONE  2014;9(2):e88148.
To investigate the efficacy and safety of granulocyte transfusion combined with granulocyte colony stimulating factor (G-CSF) in severe infection patients with severe aplastic anemia (SAA).
Fifty-six patients in severe infections with SAA who had received granulocyte transfusions combined with G-CSF from 2006 to 2012 in our department were analyzed. A retrospective analysis was undertaken to investigate the survival rates (at 30 days, 90 days and 180 days), the responses to treatment (at 7 days and 30 days, including microbiological, radiographic and clinical responses), the neutrophil count and adverse events after transfusion.
All SAA patients with severe infections were treated with granulocyte transfusions combined with G-CSF. Forty-seven patients had received antithymocyte globulin/antilymphocyte globulin and cyclosporine A as immunosuppressive therapy. The median number of granulocyte components transfused was 18 (range, 3–75). The survival at 30 days, 90 days and 180 days were 50(89%), 39(70%) and 37(66%) respectively. Among 31 patients who had invasive fungal infections, the survival at 30 days, 90 days and 180 days were 27(87%), 18(58%) and 16(52%) respectively. Among the 25 patients who had refractory severe bacterial infections, the survival at 30 days, 90 days and 180 days were 23(92%), 21(84%) and 21(84%) respectively. Survival rate was correlated with hematopoietic recovery. Responses of patients at 7 and 30 days were correlated with survival rate. Common adverse effects of granulocyte transfusion included mild to moderate fever, chills, allergy and dyspnea.
Granulocyte transfusions combined with G-CSF could be an adjunctive therapy for treating severe infections of patients with SAA.
PMCID: PMC3914902  PMID: 24505406
To evaluate the efficacy of enhanced, intensive, immuno-suppressive therapy with umbilical cord blood support for severe aplastic anemia (SAA).
A total of 25 patients with SAA received enhanced, intensive, immuno-suppressive therapy and a cord blood transfusion. Therapy protocol: Anti-thymocyte globulin (ATG) 2.5 mg/(kg•d) × 5d; Cyclophosphamide 50 mg/(kg•d) × 2d; cyclosporin A (CsA) maintenance therapy.
25 patients were enrolled. 18 underwent a complete recovery, 4 made significant improvements, 1 did not respond, and 2 died. Therefore, the efficacy rate was 88%. The median follow-up time was 35 months (range 13-47 months), and the 3-year overall survival rate was 92%. Patients rapidly achieved reconstitution of hematopoiesis. The median time to neutrophil ANC > 0.5 × 109/L was 18 days (range 8-36), platelets >20 × 109/L was 34 days (range 12-123), and Hb > 100 g/L 95 dyas (range 35-173).
Enhanced, intensive, immuno-suppressive therapy with umbilical cord blood support may be an effective option for SAA therapy.
PMCID: PMC3128038  PMID: 21663651
BMC Cancer  2012;12:365.
Increase of Serum amyloid A (SAA) level has been observed in patients with a variety of cancers. The objective of this study was to determined whether SAA level could be used as a prognostic parameter in patients with esophageal squamous cell carcinoma (ESCC).
SAA levels were measured by rate nephelometry immunoassay in 167 healthy controls and 167 ESCC patients prior to surgical resection. Statistical associations between clinicopathological observations and SAA levels were determined using the Mann–Whitney U test. The clinical value of SAA level as a prognostic parameter was evaluated using the Cox’s proportional hazards model.
SAA levels were significantly higher in patients with ESCC compared to levels in healthy controls (13.88 ± 15.19 mg/L vs. 2.26 ± 1.66 mg/L, P < 0.001). Elevation of SAA levels (≥ 8.0 mg/L) was observed in 54.5% (91/167) of patients with ESCC but not in healthy controls. SAA levels were associated with tumor size (P < 0.001), histological differentiation (P = 0.015), T classification (P < 0.001), clinical stage (P < 0.001), lymph node metastasis (P < 0.001) and distant metastasis (P < 0.001), but not with the age and gender of the patients or tumor location. Multivariate analysis revealed that patients with an elevated level of SAA (≥ 8.0 mg/L) had significantly lower 5-year survival rate than those with non-elevated SAA (< 8.0 mg/L, log-rank P < 0.0001).
An elevated level of preoperative SAA was found to associate with tumor progression and poor survival in patients with ESCC.
PMCID: PMC3492207  PMID: 22917173
Serum amyloid A; Esophageal squamous cell carcinoma; Prognosis; Biomark
Archives of Disease in Childhood  1991;66(7):858-861.
Over 15 years, 42 children aged 2-14 years were diagnosed as having acquired aplastic anaemia. Adequate clinical details were available for 38 children who were categorised as very severe (n = 13), severe (n = 16), or nonsevere (n = 9) by the modified Camitta criteria. Treatment varied over the study period. Seven children received a bone marrow allograft from a full match family donor and three a matched unrelated donor transplant after failed treatment with antilymphocyte globulin. The remainder were treated with antilymphocyte globulin (n = 11), antilymphocyte globulin and oxymetholone (n = 4), oxymetholone with or without prednisolone (n = 12), or supportive treatment alone (n = 1). With a minimum follow up of one year since treatment, the five year survival was 70% for bone marrow transplantation with a family donor, 30% for antilymphocyte globulin, and 25% for oxymetholone. All three children with a matched unrelated donor transplant died. The prognosis of acquired aplastic anaemia remains poor for most children and new approaches to treatment are urgently required.
PMCID: PMC1793235  PMID: 1863100
Although thrombocytosis has been reported in a variety of cancer types, the standard of thrombocytosis in gastric cancer (GC) and the association between thrombocytosis and the clinicopathological features of patients with GC remain unclear. In the present study, 1,763 GC patients were retrospectively filtered by preoperative thrombocytosis and compared with control group A (n=107) that had benign gastric lesions and control group B (n=100) that were GC patients with a normal platelet (PLT) count. Associations between clinical variables and preoperative PLT counts were assessed by univariate and multivariate analyses. Kaplan-Meier survival curves and Cox regression were used to evaluate the effect of thrombocytosis on prognosis. Sensitivities and specificities of the PLT counts in predicting recurrence were analyzed via area under the receiver operating characteristic curve (AUROC). The results indicated that the incidence of thrombocytosis in GC patients was higher than in benign gastric lesion patients, with 4.03% of GC patients having a PLT count >400×109/l (P=0.014) and 12.08% had a PLT count >300×109/l (P<0.001). For the patients with a PLT count >400×109/l, the frequency of abnormal PLT counts in GC correlated with tumor size (P<0.001), tumor, node and metastasis (TNM) classification (P=0.002), invasive degree (P=0.003) and D-dimer (P=0.013) and fibrinogen concentrations (P=0.042). Tumor size (P=0.002), TNM classification (P<0.001) and depth of penetration (P=0.001) were independent factors for thrombocytosis. However, thrombocytosis functioned as an independent prognostic factor for GC patients with a PLT count >400×109/l (relative risk, 1.538; 95% confidence interval, 1.041–2.271). In the majority of patients (17/24) with a high preoperative PLT count that decreased to a normal level following resection, PLT levels increased again at recurrence. Sensitivities and specificities of thrombocytosis for recurrence in those patients were 70.8 and 83.3%, respectively (AUROC, 0.847; P=0.01). Therefore, a PLT count of 400×109/l is a suitable threshold for defining thrombocytosis in GC. Thrombocytosis was shown to affect the blood hypercoagulable state and also have a negative prognostic value for GC patients. PLT monitoring following surgery was useful to predict the recurrence for specific GC patients that suffered preoperative thrombocytosis but had restored PLT levels following resection.
PMCID: PMC4061185  PMID: 24944610
gastric cancer; thrombocytosis; recurrence; survival analysis
PLoS ONE  2014;9(5):e98142.
Hepatitis-associated aplastic anemia (HAAA) is a variant of severe aplastic anemia (SAA) in which bone marrow failure follows an acute attack of hepatitis. Its pathogenesis is poorly understood. We investigated the prevalence of HAAA among cases of newly diagnosed SAA presenting to our hospital between January 1998 and February 2013, and analyzed the clinical and immune characteristics of HAAA and non-hepatitis-associated SAA (non-HASAA) patients. The prevalence of HAAA among cases of SAA was 3.8% (36/949), and the majority of patients (33/36) were seronegative for a known hepatitis virus. Compared with non-HASAA patients, HAAA patients had a larger proportion of CD8+ T cells, a lower ratio of CD4+/CD8+ T cells, and a smaller proportion of CD4+CD25+ regulatory T cells. There was no significant difference in peripheral blood count, bone marrow cellularity, or the number of blood transfusions received between HAAA and non-HASAA patients. HAAA patients had a higher early infection rate and more infection-related mortality in the first 2 years after diagnosis than non-HASAA patients, and their 2-year survival rate was lower. The results demonstrate that HAAA patients have a more severe T cell imbalance and a poorer prognosis than non-HASAA patients.
PMCID: PMC4028298  PMID: 24845454
Critically short telomeres produce apoptosis, cell senescence and chromosomal instability in tissue culture and animal models. Variations in telomere length have been reported in severe aplastic anemia (SAA) but their clinical significance is unknown.
To investigate the relationship between telomere length and clinical outcomes in SAA.
Design and Setting
Single institution analysis of SAA patients treated in sequential prospective protocols at NIH from 2000 to 2008.
We retrospectively analyzed pre-treatment leukocyte age-adjusted telomere length in 183 patients with SAA consecutively enrolled into immunosuppression protocols with anti-thymocyte globulin plus cyclosporine for correlation with clinical outcomes.
Main Outcomes Measures
The outcomes studied were hematologic response, relapse, clonal evolution and survival.
There was no relationship between hematologic response and telomere length with response rates of 56.5%, 54.3%, 60%, and 56.5% in the first (n=46), second (n=46), third (n=45), and fourth quartiles (n=46), respectively. In multivariate analysis, telomere length was associated with relapse, clonal evolution, and mortality. Evaluated as a continuous variable, telomere length inversely correlated with the probability of hematologic relapse (HR=0.16; 95% CI, 0.03–0.69; p=0.01). The rate of clonal evolution was higher in patients in the first quartile (24.5%; 95% CI, 8.7%–37.5%) compared to quartiles 2–4 (8.4%; 95% CI, 3.2%–13.3%; p=0.009), and evolution to monosomy 7 or complex cytogenetics was more common in the first quartile (18.8%; 95% CI, 3.5%–31.6%) compared to quartiles 2–4 (4.5%; 95% CI, 0.5%–8.2%; p=0.002). Survival between these two groups differed, with 66% (95% CI, 52.9%–82.5%) surviving 6 years in the first quartile compared to 83.8% (95% CI, 77.3%–90.9%) in quartiles 2–4 (p=0.008).
In a cohort of patients with severe aplastic anemia receiving immunosuppressive therapy, telomere length was unrelated to response, but was associated with risk of relapse, clonal evolution, and overall survival.
PMCID: PMC3721502  PMID: 20858879
PLoS ONE  2013;8(7):e67956.
Increasing evidence suggests that neutrophils play a role in the host response to Mycobacterium tuberculosis. We determined whether neutrophil counts in peripheral blood are associated with tuberculosis (TB) and with mycobacterial load in sputum in HIV-infected patients.
Methodology/Principal Findings
Adults enrolling in an antiretroviral treatment (ART) clinic in a Cape Town township were screened for TB regardless of symptoms. Paired sputum samples were examined using liquid culture, fluorescence microscopy, and the Xpert MTB/RIF assay. Absolute neutrophil counts (ANC) were measured in blood samples. Of 602 HIV-infected patients screened, 523 produced one or more sputum samples and had complete results available for analysis. Among these 523 patients, the median CD4 count was 169×109/L (IQR, 96–232) and median ANC was 2.6×109/L (IQR, 1.9–3.6). Culture-positive pulmonary tuberculosis was diagnosed in 89 patients. Patients with TB had a median ANC of 3.4×109/L (IQR, 2.4–5.1) compared to 2.5×109/L (IQR, 1.8–3.4) among those who were culture negative (p<0.0001). In multivariable analyses, having pulmonary TB was associated with an adjusted risk ratio (aRR) of 2.6 (95%CI, 1.5–4.5) for having an ANC level that exceeded the median value (ANC ≥2.6×109/L; p = 0.0006) and an aRR of 6.8 (95%CI, 2.3–20.4) for having neutrophilia defined by a neutrophil count exceeding the upper limit of the normal range (ANC >7.5×109/L; p = 0.0005). Patients were then classified into four mutually exclusive groups with increasing sputum mycobacterial load as defined by the results of culture, Xpert MTB/RIF and sputum smear microscopy. Multivariable analyses demonstrated that increasing sputum mycobacterial load was positively associated with blood ANC ≥2.6×109/L and with neutrophilia.
Increased blood neutrophil counts were independently associated with pulmonary TB and sputum mycobacterial burden in this HIV-infected patient group. This observation supports the growing body of literature regarding the potential role for neutrophils in the host response to TB.
PMCID: PMC3706476  PMID: 23874476
With improvements in hematopoietic cell transplantation (HCT) outcomes for severe aplastic anemia (SAA), there is a growing population of SAA survivors following HCT. However, there is a paucity of information regarding late effects that occur after HCT in SAA survivors. This study describes the malignant and non-malignant late effects in survivors with SAA following HCT. A descriptive analysis was conducted of 1,718 patients post-HCT for acquired SAA between 1995–2006 reported to the CIBMTR. The prevalence and cumulative incidences of late effects are reported for 1-year HCT survivors with SAA. Of the HCT recipients, 1,176 (68.5%) and 542 (31.5%) patients underwent a matched sibling donor (MSD) or unrelated donor (URD) HCT, respectively. The median age at the time of HCT was 20 years. The median interval from diagnosis to transplant was 3 months for MSD HCT and 14 months for URD HCT. The median follow-up was 70 months and 67 months for MSD and URD HCT survivors, respectively. Overall survival at 1 year, 2 years, and 5 years for the entire cohort was 76% (95% confidence interval [CI]: 74–78), 73% (95% CI: 71–75), and 70% (95% CI: 68–72). Among 1-year survivors of MSD HCT, 6% had one late effect and 1% had multiple late effects. For 1-year survivors of URD HCT, 13% had one late effect and 2% had multiple late effects. Among survivors of MSD HCT, the cumulative incidences of developing late effects were all less than 3% and did not increase over time. In contrast, for recipients of URD HCT, the cumulative incidence of developing several late effects exceeded 3% by five years: gonadal dysfunction 10.5% (95% CI: 7.3–14.3), growth disturbance 7.2% (95% CI: 4.4–10.7), avascular necrosis 6.3% (95% CI: 3.6–9.7), hypothyroidism 5.5% (95% CI: 2.8–9.0), and cataracts 5.1% (95% CI: 2.9–8.0). Our results indicated that all patients undergoing HCT for SAA remain at-risk for late effects and must be counseled about and should be monitored for late effects for the remainder of their lives.
PMCID: PMC3496823  PMID: 22863842
hematopoietic cell transplant; allogeneic; survivorship; severe aplastic anemia; late effects
PLoS ONE  2011;6(4):e18572.
Acquired severe aplastic anemia (SAA) is a rare and progressive disease characterized by an immune-mediated functional impairment of hematopoietic stem cells. Transplantation of these cells is a first-line treatment option if HLA-matched related donors are available. First-line immunosuppressive therapy may be offered as alternative. The aim was to compare the outcome of these patients in controlled trials.
A systematic search was performed in the bibliographic databases MEDLINE, EMBASE, and The Cochrane Library. To show an overview of various outcomes by treatment group we conducted a meta-analysis on overall survival. We evaluated whether studies reported statistically significant factors for improved survival.
26 non-randomized controlled trials (7,955 patients enrolled from 1970 to 2001) were identified. We did not identify any RCTs. Risk of bias was high except in 4 studies. Young age and recent year of treatment were identified as factors for improved survival in the HSCT group. Advanced age, SAA without very severe aplastic anemia, and combination of anti-lymphocyte globulin with cyclosporine A were factors for improved survival in the IST group. In 19 studies (4,855 patients), summary statistics were sufficient to be included in meta-analysis. Considerable heterogeneity did not justify a pooled estimate. Adverse events were inconsistently reported and varied significantly across studies.
Young age and recent year of treatment were identified as factors for improved survival in the transplant group. Advanced age, SAA without very severe aplastic anemia, and combination of anti-lymphocyte globulin with cyclosporine A were factors for improved survival in the immunosuppressive group. Considerable heterogeneity of non-randomized controlled studies did not justify a pooled estimate. Adverse events were inconsistently reported and varied significantly across studies.
PMCID: PMC3081818  PMID: 21541024
Seminars in hematology  2012;49(4):304-311.
It is now well accepted that a subgroup of patients with myelodysplastic syndromes (MDS) can recover from pancytopenia following immunosuppressive treatment (IST). For many years immunosuppression with antilymphocyte antibodies has been a standard treatment approach for patients with severe aplastic anemia. The initial concept of using immunosuppression to treat pancytopenic patients with MDS was based on the premise that MDS might share with severe aplastic anemia (SAA) an autoimmune basis for the bone marrow failure common to both conditions. The idea was supported by reports of favorable outcomes in occasional cases of MDS treated with antithymocyte globulin (ATG). Today, various forms of IST have been successfully used to restore hematopoiesis in MDS in many centers worldwide. In this review we outline the rationale for use of IST in MDS, and describe studies which help to define the patients with MDS likely to respond to IST. We summarize 18 published clinical trials using IST for MDS and discuss how these studies have helped to define the MDS subgroups likely to respond to treatment, the nature and durability of the response, the impact of IST on long-term outcome and the best treatment approach.
PMCID: PMC4157636  PMID: 23079060
Although recent advances in therapy offer the promise for improving survival in patients with severe aplastic anemia (SAA), the small size of the patient population, lack of a mechanism in North America for longitudinal follow-up of patients and inadequate cooperation among hematologists, scientists, and transplant physicians remain obstacles to conducting large studies that would advance the field. In order to address this issue, the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) convened a group of international experts in March 2010 to define the most important questions in the basic science, immunosuppressive therapy (IST), and bone marrow transplantation (BMT) of SAA and propose initiatives to facilitate clinical and biologic research. Key conclusions of the working group were: 1) new patients should obtain accurate, expert diagnosis and early identification of biological risk; 2) a population-based SAA outcomes registry should be established in North America to collect data on patients longitudinally from diagnosis through and after treatment; 3) a repository of biologic samples linked to the clinical data in the outcomes registry should be developed; 4) innovative approaches to unrelated donor BMT that decrease graft vs. host disease are needed, and 5) alternative donor transplantation approaches for patients lacking HLA-matched unrelated donors must be improved. A partnership of BMT, IST and basic science researchers will develop initiatives and partner with advocacy and funding organizations in order to address these challenges. Collaboration with similar study groups in Europe and Asia will be pursued.
PMCID: PMC3053041  PMID: 21034841
To investigate the clinical characteristics of seronegative hepatitis-associated aplastic anemia (AA) (SNHAA) and hepatitis B virus (HBV) infection complicating AA (HBVAA), and thereby compare the efficacy of immunosuppressive therapy (IST).
An analysis was conducted on the clinical data of ten patients with SNHAA out of 332 cases of AA from our center at AA diagnosis, and on the efficacy of IST. This was compared to 22 cases of HBVAA at AA onset as well as the associated IST outcomes.
Nine patients with SNHAA developed severe aplastic anemia, with a median age of 18 years. After IST, six (60%) of the SNHAA patients achieved complete remission and two achieved partial remission. The patients with HBVAA had a total response rate of 82.3%. The disease recurred in two HBVAA patients. No statistically significant differences were observed in response rate, mortality, and recurrence rate between both groups. As compared with HBVAA, patients with SNHAA had a shorter interval from the acute episode of hepatitis to AA onset (4 months versus 92 months, P=0.00), a quicker response to IST (2.5 months versus 4.5 months, P=0.018), a lower proportion of bone marrow hematopoietic tissues (20.6% versus 23.6%, P=0.03), and lower white blood cell and absolute neutrophil count (0.8×109/L versus 1.23×109/L and 0.26×109/L versus 0.58×109/L, P=0.026 and P=0.0009, respectively). No significant liver damage or hepatitis B fulminant infection was observed in either group during the follow-up.
The prevalence of SNHAA is 3.01%. SNHAA often presents as severe AA and responds to IST quickly. Neither hepatitis prior to AA nor AA complicating HBV infection have been shown to influence the early efficacy of IST and adverse events, and HBV may not be the causative agent of AA.
PMCID: PMC4166905  PMID: 25246771
hepatitis-associated aplastic anemia; hepatitis B infection; liver injury
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
Patients with severe aplastic anemia (SAA) over 40 years of age are often not offered treatment with hematopoietic cell transplantation (HCT) because of concerns about transplant-related morbidity or mortality. To evaluate this risk, we analyzed outcomes after allogeneic HCT from HLA-identical sibling donors for all older patients with SAA at our center since 1988. The 23 consecutive patients ranged in age from 40 to 68 years. The conditioning regimen was cyclophosphamide (200 mg/kg) and horse anti-thymocyte globulin. Methotrexate and cyclosporine were given for post-grafting immunosuppression. The cumulative incidences of grades II, III and IV acute graft-versus-host-disease (GVHD) were 30%, 4%, and 0%, respectively; that for chronic GVHD was 26%. With a median follow-up of 9.1 years, overall survival was 65%. Documented infections within 1 month before HCT were significantly associated with risk of early transplant-related mortality (p<0.001). The median time to discontinuation of post-transplant immunosuppression was 6.2 (range, 5.9–92.0) months. Three patients developed superficial basal cell carcinoma between 5.5 and 15 years after HCT. Our data favor a practice of extending HLA-identical sibling HCT for treatment of SAA in patients older than 40 years of age who are without significant medical comorbidities.
PMCID: PMC2934906  PMID: 20403449
aplastic anemia; older age; human leukocyte antigen-matched bone marrow transplantation; cyclophosphamide/antithymocyte globulin conditioning
Oncology Letters  2014;8(4):1831-1833.
The outcomes of matched unrelated donor (MUD) hematopoietic stem cell transplantation (HSCT) and immunosuppressive therapy (IST) in patients with severe aplastic anemia (SAA) remain controversial. The clinical outcome in patients that undergo transplantation following failed IST is typically poorer when compared with patients that initially underwent transplantation. Clinical treatment algorithms have been proposed to determine the management of such patients, and account for individual conditions, personal preferences and prognostic risk factors. The present study reports the promising outcome of a 22-year-old patient exhibiting SAA. The patient underwent peripheral blood stem cell transplantation (PBSCT) from an MUD using a fludarabine-based conditioning regimen and low-dose total body irradiation as an alternative method to first-line IST. The patient achieved rapid bone marrow reconstitution and has been in complete remission for 32 months. The aim of the fludarabine-based conditioning regimen with PBSCT was to improve the patient’s therapeutic outcome and provide a convenient treatment strategy. Furthermore, this regimen extends the application of HSCT to patients who are older or those that are without a matched related donor.
PMCID: PMC4156163  PMID: 25202420
unrelated donor; peripheral blood transplants; allogeneic hematopoietic stem cell transplantation; aplastic anemia; bone marrow transplants

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