CD25 as an adverse prognostic factor in elderly patients with acute myeloid leukemia

Objectives: CD25 has been reported to be highly expressed in leukemia stem cells and correlated with adverse outcomes in young patients with acute myeloid leukemia (AML). However, the significance of CD25 expression in elderly patients with AML has not yet been investigated.

Methods: We retrospectively analyzed 154 newly diagnosed AML patients aged 60 years or over by flow cytometry.

Results: CD25-positive AML was characterized by high white blood cell counts, secondary AML, rare favorable karyotypes, and positivity for CD34 and CD7 antigens, compared with CD25-negative AML. CD25 positivity was significantly correlated with an inferior complete remission (CR), event-free survival (EFS), and overall survival. Multivariate analysis showed CD25 positivity to be a significant prognostic predictor of CR and EFS. A regimen of low-dose cytarabine and aclarubicin combined with granulocyte-colony-stimulating factor (CAG) led to higher CR rates in the CD25-positive AML patients than intensive chemotherapies. CD25 expression was increased at relapse and in the development of leukemic status from myelodysplastic syndrome or myeloproliferative neoplasm.

Discussion: An effective treatment strategy for elderly patients with CD25-positive AML has not been established. Further studies are needed to evaluate the effect of a CAG regimen and allogenic stem cell transplantation in patients.

Conclusion: CD25 is an independent prognostic factor in elderly AML patients. Alternative therapies for CD25-positive elderly AML patients are needed.     

Thymoma-associated pancytopenia: effectiveness of cyclosporine A

 Aplastic anemia is a rare complication of thymoma and is properly documented in only few cases. Here, we report the case of a previously healthy, 65-year-old patient who was found simultaneously to have a spindle-cell thymoma and severe hypoplastic anemia with a mild infiltration of the bone marrow by CD4+ and CD8+ T lymphocytes, CD16+ natural killer cells, and a decrease in blood CD4/CD8 ratio. Cultures of marrow erythroid progenitors demonstrated serum inhibitor. While steroids, cyclophosphamide and antilymphocyte globulin failed to improve hematopoiesis, cyclosporine A (Cy-A) led to a partial, stable remission that was sustained for 4 years. Since Cy-A has been associated with good responses in three cases of thymoma-associated red cell aplasia, we recommend its use in cases of thymoma-associated cytopenias refractory to steroids and cyclophosphamide. Received: February 4, 1998 / Accepted: July 7, 1998     

Expression pattern of CD55 and CD59 on red blood cells in sickle cell disease

Objectives: To investigate the pattern of CD55 and CD59 expression on RBCs of SCD patients, and its association with anemia, biochemical parameters of hemolysis, level of erythropoietin, and pro-inflammatory markers.

Methods: Flow cytometric analysis was performed on RBCs from 71 adult SCD patients and 53 healthy controls, using the commercial REDQUANT kit.

Results: CD59 deficiency was significantly higher among SCD patients than among healthy controls. The proportions of CD55-deficient and CD59-deficient RBCs from SCD patients were significantly higher when compared with those from healthy controls (0.17 vs. 0.09 and 2.1 vs. 1.2, respectively). The MFI of CD55 and CD59 expression on RBCs in SCD was significantly reduced when compared to the expression in healthy controls (5.2 vs. 6.4 and 19.4 vs 20.3, respectively). The pattern of CD55 and CD59 expression was not correlated with anemia, biomarkers of hemolysis, erythropoietin level, or other pro-inflammatory markers.

Discussion: There is an altered pattern of CD55 and CD59 expression on RBCs of SCD Patients; however, it does not seem to play a causal role in the pathophysiology of anemia, and is unlikely to be influenced by the level of erythropoietin or other inflammatory mediators.     

Acute leukemia with the phenotype of a natural killer/T cell bipotential precursor

 An acute leukemia with an unusual immunophenotype developed in a 17-year-old girl. At the initial presentation, extramedullary involvement was not evident, but with advancing disease, massive splenomegaly and an osteolytic rib tumor developed. The disease was aggressive and refractory to intensive chemotherapeutic regimens for myeloid and lymphoid malignancies, and the patient died 3 months after the initial presentation. The leukemic cells were of irregular shape and variable size; they had deeply indented or bi-lobed nuclei and relatively fine, azurophilic granules in their cytoplasm. They were positive for acid phosphatase and β-glucuronidase in granular staining, but they were negative for myeloperoxidase. The leukemic cells had a unique immunophenotype: it was positive for T-cell antigens (CD1a, CD2, cytoplasmic CD3, CD4), myeloid antigens (CD13 and CD33), NK-cell antigen (CD56), CD19 and CD30. DNA analysis revealed no gene rearrangement in the T-cell receptor β, γ and δ, or immunoglobulin heavy chain genes. The leukemic cells of our patient are thought to have arisen from the transformation of a putative precursor cell common to both the T- and NK-cell lineage in the bone marrow. The current literature on precursor NK-cell malignancy is reviewed, and its clinicopathological feature is discussed. Received: 29 April 1998 / Accepted: 28 August 1998     

Genetic and flow cytometry analysis of seronegative celiac disease: a cohort study

Background: Seronegative celiac disease (CD) poses a diagnostic challenge.

Aims: Characterize and identify differences between seronegative and seropositive CD.

Patients and methods: Retrospective cohort study examining adult patients diagnosed with CD (1980–2017). Clinical, analytical, histological, genetic and immunophenotypic data were compiled. Seronegative CD was defined as a anti-tissue transglutaminase type 2 IgA and endomysial antibodies (EMA) negative and HLA-DQ2 and/or DQ8 positive, showing clinical signs of CD plus an abnormal duodenal biopsy, and responding to a gluten-free diet (GFD). Factors associated with seronegative CD were identified through binomial logistic regression.

Results: Of 315?CD patients, 289 were seropositive (91.7%) and 26 seronegative (8.3%). Among the seronegative patients, higher prevalence was observed for autoimmune thyroiditis (26.9% vs. 9.7%, p?=?.016), HLA-DQ8 heterozygosity (23.1% vs. 2.5%, p???.001) and Marsh I lesion (34.6% vs. 3.7%, p???.001). The two groups showed similar flow cytometry-determined duodenal immunophenotypes and rates of refractory CD.

Conclusions: Seronegative CD differs mostly in genetic (more HLA-DQ8) and histologic (milder atrophy) features as compared with seropositive. Intestinal intraepithelial immunophenotype by flow cytometry, similar in both modalities, is a useful tool to diagnose seronegative CD.     

Tentative diagnostic criteria and disease severity classification for Castleman disease: A report of the research group on Castleman disease in Japan

Objectives: To determine the tentative diagnostic criteria and disease severity classification for Castleman disease (CD) and describe the clinical and pathologic features among human herpesvirus 8 (HHV-8) negative idiopathic multicentric CD (iMCD) in the Japanese population.

Methods: We established the working groups for the research of CD in Japan and had meetings to discuss and define the tentative diagnostic criteria and disease severity classification for CD. We subsequently analyzed 142 patients classified into iMCD by using the nationwide Japanese patient registry.

Results: We proposed the preliminary diagnostic criteria and disease severity classification for CD based on our discussion. In addition, we made a proposal for the disease activity score. We identified clinical and pathological features of patients with iMCD diagnosed by these diagnostic criteria. In the disease severity classification, 37, 33 and 30% patients were categorized into mild, moderate and severe diseases, respectively.

Conclusion: This is the first proposal for diagnosis and classification of CD by the Japanese group. Further studies are required to validate whether they can distinguish CD from other inflammatory diseases and to determine their sensitivity and specificity.     

Natural history of HIV infection in the era of combination antiretroviral therapy.

BACKGROUND: The use of protease inhibitor-containing (PI) combination antiretroviral therapy has led to a reduction in the incidence of opportunistic illness and mortality (events) in HIV infection. We wished to quantify the changing incidence of these events in our clinical practice and delineate the relationship between CD4, HIV-1 RNA, and development of events in patients receiving PI combination therapy. METHODS: We assessed HIV-infected patients with CD4 counts < or =500 cells x10(6)/l. We calculated the incidence of events from 1994 through 1998 and analyzed the association of temporal changes in event incidence and use of antiretroviral therapy. In patients on PI combination therapy, we determined the probability of achieving and maintaining an undetectable HIV-1 RNA response and determined the association of CD4, HIV-1 RNA, and developing an event. RESULTS: The incidence of opportunistic illness declined from 23.7 events/100 person-years in 1994 to 14.0 events/100 person-years in 1998 (P<0.001). Mortality declined from 20.2 deaths/100 person-years in 1994 to 8.4 deaths/ 100 person-years in 1998 (P<0.001). Use of PI combination therapy was associated with a relative rate of opportunistic illness or death of 0.66 [95% confidence interval (CI), 0.51-0.85; P<0.001]. The relative incidence of each of 16 opportunistic illnesses was approximately the same in 1998 as in 1994 except for lymphoma, cervical cancer and wasting syndrome which do not appeared to have declined in incidence. Approximately 60% of patients who received PI therapy achieved an undetectable HIV-1 RNA, and 65% of these patients maintained durable suppression of HIV-1 RNA. Achieving an undetectable HIV-1 RNA was associated with a decreased risk of an event, and was the variable most strongly associated with an increase in CD4 level. By multivariate analysis, the concurrent CD4 level was most strongly associated with developing an event. CONCLUSIONS: We observed a significant decline in the incidence of opportunistic illness and death from 1994 through 1998 associated with combination antiretroviral therapy. Patients who develop events while being treated with PI combination therapy were not likely to have achieved an undetectable HIV-1 RNA and are likely to have a low concurrent CD4 level.     

Functional expression of β1 and β2 integrins on tumor infiltrating lymphocytes (TILs) in colorectal cancer

Integrins play an important role in various lymphocyte functions. In this study, tumor-infiltrating lymphocytes (TIL) were isolated from colorectal cancer tissues and the expression of β1 and β2 integrins on the TIL was quantitatively examined with two-color flow cytometry. In comparison with peripheral blood lymphocytes (PBL), TIL expressed a lower level of common β1 chain (CD29) in both CD4 and CD8 sub-populations. Among the associated α chains, the expressions of α1 (CD49a) and α2 (CD49b) were slightly higher in TIL than in PBL, whereas α4 (CD49d) and α6 (CD49f) were markedly downregulated in TIL. Both αL (CD11a) and β2 (CD18) were reduced in CD8(+) TIL but not in CD4(+) TIL. TIL with the CD8(+) cytotoxic phenotype showed significantly decreased binding to purified intracellular adhesion molecules (ICAM)-1, and vascular adhesion cell molecule (VCAM)-1, and HT29 colon cancer cells, compared with the in counterparts in PBL. The peculiar expression pattern and functional down regulation of these integrins may explain why TIL in colorectal cancer cannot eradicate the malignant cells. Received: August 24, 1998/Accepted: November 27, 1998     

Influenza and risk of later celiac disease: a cohort study of 2.6 million people

Objectives: Influenza has been linked to autoimmune conditions, but its relationship to subsequent celiac disease (CD) is unknown. Our primary aim was to determine the risk of CD after influenza. A secondary analysis examined the risk of CD following pandemic influenza vaccination.

Methods: This nationwide register-based cohort study included 2,637,746 Norwegians (born between 1967–2013) followed during 2006–2014 with information on influenza diagnosed in primary or non-primary care, pandemic vaccination (Pandemrix), and subsequent CD. Cox regression yielded hazard ratios adjusted (HR) for socio-demographic characteristics and earlier healthcare use.

Results: During 13,011,323 person-years of follow-up 7321 individuals were diagnosed with CD (56/100,000 person-years). There were 351,666 individuals diagnosed with influenza, including 82,980 during the 2009–2010 pandemic, and 969,968 individuals were vaccinated. Compared with participants without influenza, who had a CD incidence of 55/100,000 person-years, those diagnosed with seasonal and pandemic influenza had a rate of 68 and 78, per 100,000 person-years, respectively. The HR for CD was 1.29 (95%CI, 1.21–1.38) after seasonal influenza and 1.29 (95%CI, 1.15–1.44) after pandemic influenza; HRs remained significantly increased one year after exposure, when restricted to laboratory-confirmed influenza, and after multivariate adjustments. The reverse association, i.e., risk of influenza after CD, was not significant (HR 1.05; 95%CI, 0.98–1.12). The HR for CD after pandemic vaccination was 1.08 (95%CI, 1.03–1.14).

Conclusion: A positive association with influenza diagnosis is consistent with the hypothesis that infections may play a role in CD development. We could neither confirm a causal association with pandemic vaccination, nor refute entirely a small excess risk.     

Rising hospitalization rates for inflammatory bowel disease in the United States between 1998 and 2004

BACKGROUND: Recent epidemiological studies suggest that the prevalences of Crohn's disease (CD) and ulcerative colitis (UC) are increasing in the United States. We sought to determine whether nationwide rates of inflammatory bowel disease (IBD) hospitalizations have increased in response to temporal trends in prevalence. METHODS: We identified all admissions with a primary diagnosis of CD or UC, or 1 of their complications in the Nationwide Inpatient Sample between 1998 and 2004. National estimates of hospitalization rates and rates of surgery were determined using the U.S. Census population as the denominator. RESULTS: There were an estimated 359,124 and 214,498 admissions for CD and UC, respectively. The overall hospitalization rate for CD was 18.0 per 100,000 and that for UC was 10.8 per 100,000. There was a 4.3% annual relative increase in hospitalization rate for CD (P < 0.0001) and a 3.0% annual increase for UC (P < 0.0001). Surgery rates were 3.4 bowel resections per 100,000 for CD and 1.2 colectomies per 100,000 for UC and remained stable. There were no temporal patterns for average length of stay for CD (5.8 days) or for UC (6.8 days). The national estimate of total inpatient charges attributable to CD increased from $762 million to $1,330 million between 1998 and 2004, and that for UC increased from $592 million to $945 million.CONCLUSIONS: Hospitalization rates for IBD, particularly CD, have increased within a 7-year period, incurring a substantial rise in inflation-adjusted economic burden. The findings reinforce the need for effective treatment strategies to reduce IBD complications.     

Investigation of the Alveolar Macrophages and T Lymphocytes in 15 Patients with Systemic Sclerosis

The cell distribution and function of alveolar macrophages and T lymphocytes were investigated in the bronchoalveolar lavage (BAL) of 15 patients with systemic sclerosis (SSc). In alveolar macrophages, both spontaneous and PMA-stimulated TNF-α production were increased in SSc. PMA-induced IL-6 production was also elevated. Spontaneous IL-6 excretion of scleroderma alveolar macrophages was similar to the controls. Yeast and C3b-coated yeast (opsonised yeast) phagocytosis, chemotaxis and Fc receptor activity of alveolar macrophages were normal. The proportion of CD3, CD4 and CD8 T-lymphocyte subsets in the BAL was similar to the control values. The lymphocyte blast transformation index of the non-adherent cells deriving from the BAL fluid was markedly decreased. Received: 12 March 1998 / Accepted: 10 December 1998     

Real world data on effectiveness,safety and therapeutic drug monitoring of vedolizumab in patients with inflammatory bowel disease. A single center cohort

Background and aims: The efficacy of vedolizumab (VDZ) has been demonstrated in clinical trials. The aim of this report is to evaluate the long-term effectiveness and safety of VDZ in a real-world cohort and to explore possible associations between concentration measurements of VDZ and treatment effectiveness.

Methods: This is a prospective clinical follow-up including all adult patients with ulcerative colitis (UC) and Crohn’s disease (CD) treated with VDZ from October 2014 until September 2017 at a single center in Norway. The patients were followed for at least 14 weeks or until termination of treatment. Clinical and biochemical activity were obtained at every infusion throughout follow-up. Plasma measurements of VDZ (p-VDZ) were performed before every infusion during maintenance therapy.

Results: In total, 71 patients received VDZ. Improvement of CRP and hemoglobin was observed in CD but not in UC, whereas Partial Mayo Score improved in UC while no change in Harvey Bradshaw Index was revealed in CD. Furthermore, CRP at baseline was negatively correlated with p-VDZ at week 14 in CD but not in UC patients.

Conclusion: Improvement of biochemical markers of inflammation was observed in CD while clinical activity scores improved in UC patients. For CD, baseline CRP was correlated with lower concentrations of p-VDZ at week 14.     

Platelet activation induced by porcine factor VIII (HYATE:C)

We studied the effects of porcine factor VIII (P-FVIII; Hyate:C) and other coagulation products employed in the management of patients with hemophilia A, on platelet activation in vitro. Exposure of normal resting platelets to P-FVIII resulted in platelet activation, as manifested by increased expression of the platelet surface activation markers CD62, CD63, and activated-GPIIbIIIa, and by activation-induced modulation of expression of normal platelet membrane glycoproteins CD41, CD42, and CD36. In contrast, platelet activation was not observed after exposure of the platelets to human FVIII, FEIBA, recombinant FVIIa, or cryosupernatant plasma. As with thrombin, exposure of platelets to P-FVIII resulted in the generation of platelet microparticles, an effect not seen not with the other products. In contrast to the characteristic reduction in expression in the number of CD42 molecules detected on thrombin-activated platelets, P-FVIII-stimulated platelets showed a small increase in CD42 expression. In contrast to thrombin, P-FVIII did not cause platelet dense granule release. The results indicate that therapeutic P-FVIII activates platelets, likely in ways that are different from the platelet activation seen with thrombin. The observed platelet activation and microparticle generation may provide a “hypercoagulable” mechanism for hemostasis with P-FVIII therapy separate from, and additional to, that due to increased circulating FVIII levels. Am. J. Hematol. 57:200–205, 1998. © 1998 Wiley-Liss, Inc.     

Acute myeloid leukemia M2 and t(8;21)(q22;q22) with an unusual phenotype: myeloperoxidase (+), CD13 (–), CD14 (–), and CD33 (–)

 Cases of myeloid surface antigen-negative acute myeloid leukemia (AML) are rare. We describe the morphological, cytochemical, immunologic, and cytogenetic features of two patients with AML with maturation (FAB M2) and the phenotype MPO+, CD13 (–), CD33(–), CD56(+). Cytogenetic studies demonstrated t(8;21)(q22;q22). These findings suggest an association between the lack of CD13 and CD33 in myeloperoxidase-positive AML and the presence of t(8;21). Received: August 8, 1998 / Accepted: January 27, 1999     

Ustekinumab for the treatment of Crohn’s disease

Introduction: Ustekinumab is a human monoclonal antibody directed against the shared p40 subunit of interleukins 12 and 23. Ustekinumab is currently approved for the treatment of psoriatic arthritis (PsA) and moderate to severe plaque psoriasis, and is being evaluated in Crohn’s disease (CD).

Areas covered: The first evidence supporting the efficacy of ustekinumab in the treatment of moderate to severe CD was published in 2008. Results from subsequent phase II and phase III randomized controlled trials (RCTs) have shown promising data on the clinical efficacy of induction and remission of moderate to severe CD. These data and the safety profile of ustekinumab will be reviewed.

Expert commentary: As a significant proportion of individuals with CD have ongoing symptoms and inflammation despite existing therapies, there is a clinical need for new agents like ustekinumab directed at different targets on the inflammatory pathway. Looking forward, more studies are needed to evaluate dosing escalation or de-escalation in addition to timing of therapy switches. In addition, further data is required to gauge the comparative effectiveness of ustekinumab to the biologic agents that are currently used in the treatment of CD.     

Thymic B-cell non-Hodgkin's lymphoma in a child

A 13-year-old male developed thymic non-Hodgkin's lymphoma. Microscopically, the tumor was composed of large cells, resembling centroblasts. Immunohistochemically, the tumor demonstrated leukocyte common antigen⁺, L26 (B-cell)⁺, UCHL1 (T-cell)⁻, suggesting the B-cell phenotype. In contrast to the terminally differentiated phenotype (CD10⁻, surface immunoglobulin⁻) observed in adult cases, flow cytometric analysis showed that they were relatively immature: CD10⁺, CD19⁺, HLA-DR⁻, IgM^+/−, kappa⁺. He was successfully treated with intensive chemotherapy. Since childhood thymic lymphomas are exclusively small non-cleaved cell lymphoma with T-cell phenotype, this case represents a unique entity in children. Am. J. Hematol. 57:48–50, 1998. © 1998 Wiley-Liss, Inc.     

Pneumococcal vaccination in celiac disease

Introduction: Celiac disease (CD) is an immune-mediated disorder associated with gluten exposure in genetically predisposed subjects.

Areas covered: Infectious disease is one of the causes of morbidity and mortality in CD patients. Invasive streptococcus pneumoniae (pneumococcus) is a particularly dangerous morbid condition in both the general population and celiac patients. Pneumococcal vaccination is the most effective means for its prevention.

Expert opinion: In CD, evaluation of spleen function should be useful to select patients who may benefit from vaccination to reduce the risk of pneumococcal disease. Different strategies could be employed: physicians could search for signs of hyposplenism on peripheral blood smear or abdominal ultrasound. However, the best strategy to identify which patients will benefit from pneumococcal vaccination has not yet been defined.     

Predictive parameters for mobilized peripheral blood CD34+ progenitor cell collection in patients with hematological malignancies

In order to investigate what is the best single parameter to predict the leukapheretic yield of circulating CD34+ progenitor cells, we retrospectively analyzed data from 68 patients with hematological malignancies who underwent mobilizing therapy. Three main parameters were monitored: total white blood cell (WBC), CD34+ cells, and monocyte counts in peripheral blood (PB) at the same day and at the preceding day of the apheretic procedure. Linear regression analysis revealed a strong correlation between CD34+ cell value in PB just before harvest and the number of CD34+ cells collected (P < 0.0001), but not at the preceding day. Monocyte PB concentration and absolute WBC count did not correlate with CD34+ cells harvested, at the preceding day of leukapheresis as well as at the same day of the procedure. The number of CD34+ cells in mobilized PB at the same day of harvest evidenced a very good capacity of predicting the value of harvested CD34+ cell number after collection, while WBC and monocyte count displayed quite a wide dispersion of results. In particular, an amount greater than 50/μL of circulating CD34+ cells ensured the best collections. Finally, CD34+ and CFU-GM content evaluated for each apheresis showed a strong reciprocal correlation (r 0.78; P < 0.0001). We conclude that the absolute number of CD34+ cells at the day of leukapheresis is the only parameter for identifying the exact timing for apheresis and predicting the amount of peripheral blood progenitor cells (PBPCs) that will be collected. In this setting, WBC and monocyte counts, at the day of collection or at the preceding day, are not useful tools. Am. J. Hematol. 58:255–262, 1998. © 1998 Wiley-Liss, Inc.     

Lymphoid Hyperplasia, CD45RBhigh to CD45RBlow T-cell imbalance, and suppression of Type I diabetes mellitus result from TNF blockade in NOD→NOD-scid adoptive T cell transfer

Summary Sustained antibody-mediated inhibition of tumor necrosis factor (TNF) activity offers protection against Type I (insulin-dependent) diabetes mellitus in non-obese diabetic (NOD) mice. The mechanism of this effect, however, has remained obscure: TNFα might be required for the development of specific immune responses to islet antigens or it could directly participate in destruction of beta cells. In this study, autoimmune destruction of beta cells was initiated in NOD-severe combined immunodeficient (scid) mice by transfer of NOD splenic T-cells to induce diabetes. The blockade of TNFα activity was achieved during a narrow window of time after transfer. Transient inhibition of TNFα greatly reduced the number of islet lymphocytes and the incidence of diabetes in recipients of prediabetic NOD spleen cells. Protection extended beyond the interval of effective TNF blockade. Furthermore, the protective effect was only observed if cells were obtained from 6-week-old donors. The suppression of autoimmunity was reversible in the context of adoptive transfer as indicated by the transfer of splenocytes from the primary recipient to a second NOD-scid host led to a diabetic outcome. The blockade of TNFα was accompanied by a considerable increase in spleen size and doubling of the total splenocyte count, suggesting that TNFα might normally eliminate a transplanted T-cell subset within the recipients. Further analysis showed an increase in the absolute count of CD4 + T cells and pronounced distortion of the CD45RB^high to CD45RB^low ratio, with a relative augmentation in the CD45RB^low count in the spleen. TNFα appears to regulate the number and subtype distribution of a transplanted T cell population. [Diabetologia (1998) 41: 1502–1510] Received: 9 March 1998 and in revised form: 2 June 1998