Naoaki Ichikawa

Eosinophilia associated with proliferation of CD3+4−8− αβ+ T cells with chromosome 16 anomalies

We describe a patient with eosinophilia and an abnormal CD3+4−8−αβ+ T‐cell population. Chromosomal analysis of sorted CD3+4−8− cells revealed abnormal karyotypes on chromosome 16. In the presence of IL‐2 the production of IL‐5 from CD3+4−8− cells was higher than that from CD3+4+/8+ cells. Eosinophil survival‐enhancing activity in the patient serum was inhibited by a combination of anti‐IL‐5 and anti‐GM‐CSF monoclonal antibodies. These data suggest that increased production of IL‐5 and GM‐CSF from the abnormal CD3+4−8− cells might cause eosinophilia.

Eosinophilia Associated with Clonal T-Cell Proliferation

Eosinophilia associated with the expansion of cloned T-cells is reviewed in relation to cytokine production. It has been proved that eosinophilopoiesis is caused by eosinophil-stimulating cytokines, including interleukin-5 (IL-5), granulocyte-macrophage colony-stimulating factor and interleukin-3, which are secreted from T-cells. Recently, we and other groups have reported several cases of eosinophilia including hypereosinophilic syndrome (HES) accompanied with proliferation of abnormal T-cells with an unusual phenotype CD3- CD4+ or CD3+ CD4- CD8- in the peripheral blood. The T-cells clonally proliferate, as confirmed by clonal rearrangements of the T-cell receptor (TCR) gene, and produce eosinophil-stimulating cytokines, especially IL-5, with or without stimulation in vitro. Although HES is defined by the combination of unexplained prolonged eosinophilia and evidence of organ involvement, these observations suggest that increased production of eosinophil-stimulating cytokines from the abnormal T-cells with phenotype CD3- CD4+ or CD3+ CD4- CD8- may cause eosinophilia, some of which have been diagnosed as HES.

Changes in serum thrombopoietin levels after splenectomy.

To clarify the role of thrombopoietin (c-Mpl ligand, TPO) in ‘hypersplenic’ thrombocytopenia, we used an enzyme-linked immunosorbent assay to examine changes in serum TPO levels accompanied with splenectomy in 6 patients with liver cirrhosis, 4 patients with gastric cancer, and 2 patients with lymphoid malignancies. We also measured serum levels of other thrombopoietic cytokines such as interleukin-6 (IL-6) and erythropoietin. Platelet counts reached a maximum at day 14 after splenectomy in all subjects. In patients with liver cirrhosis, a lower elevation of platelet counts was observed compared with that in patients with gastric cancer. Serum TPO levels gradually elevated after splenectomy and reached a maximum 3.5 days after splenectomy in noncirrhotic patients, whereas peak serum TPO levels were delayed until day 7 in the cirrhosis group. IL-6 and erythropoietin showed similar kinetics between cirrhotic and noncirrhotic patients. These findings suggest that transient thrombocytosis after splenectomy may be associated with an alteration in the site of TPO catabolism by platelets from spleen to the blood and that deterioration of TPO production may play a role in thrombocytopenia in liver cirrhosis.

Lymphadenopathy of IgG4-related sclerosing disease: three case reports and review of literature

Immunoglobulin (Ig) G4-related sclerosing disease is a recently described syndrome characterized by lymphoplasmacytic infiltration of exocrine glands or extranodal tissues and elevated serum IgG4. We report three cases of lymphadenopathy secondary to IgG4-related sclerosing disease. Histologic features of involved lymph nodes included interfollicular immunoblasts and plasma cells, similar to Castleman’s disease. The percentage of IgG4-/IgG-positive plasma cells in the three patients was markedly elevated (30, 50, and 60%). Administration of prednisolone led to remission in every case. One of three cases was consulted to our hospital due to suspected diagnosis of angioimmunoblastic T cell lymphoma (AITL). The case demonstrates many clinical and pathologic similarities between IgG4-related sclerosing disease and AITL. Pathological similarities between AITL and the lymphoplasmacytic subtype of IgG4-sclerosing disease have recently been reported. It is important to accurately diagnose IgG4-related lymphadenopathy given its ready response to steroid therapy and the potential for misdiagnosing lymphoma on clinical grounds.

Lymphoproliferative disease of granular lymphocytes with T-cell receptor gamma delta-positive phenotype : restricted usage of T-cell receptor gamma and delta subunit genes

Abstract: Lymphoproliferative disease of granular lymphocytes (LDGL) is characterized by more than 0.5 × 109/L of proliferating granular lymphocytes in the peripheral blood. Because of its rarity, the characteristics of LDGL with T‐cell receptor (TCR) γδ phenotype (γδT‐LDGL) have not yet been identified. This report describes the clinical, hematological, and immunological findings of four patients with this disease. In two cases, the clinical course was indolent and the other two patients required various therapies. The cells had a common immunophenotype: CD3+, CD4–, CD16+, CD56–, CD57–, CD122–, TCR‐γδ+, and three were CD8‐positive. The immunopurified TCR‐γδ cells from the patients expressed only Vγ9 and Vδ1. Spectratyping and sequencing showed mono‐ or oligoclonality for TCRγ and TCRδ subunit genes. Soluble Fas ligand in sera was significantly elevated in all patients. These findings suggest that γδT‐LDGL qualifies as a distinct disease entity.

Hairy cell leukemia with translocation (11;20)(q13;q11) and overexpression of cyclin D1

We report on a male Japanese patient with hairy cell leukemia (HCL). A cytogenetic study with lipopolysaccharide stimuli showed a novel translocation (11;20)(q13;q11) in 10% of the analyzed cells. Northern blot analysis and RT-PCR analysis for cyclin D1 revealed the overexpression of cyclin D1, although the southern blot analysis of PRAD1 gene showed no rearrangement. In this particular case, the t(11;20)(q13;q11) might play some role in the oncogenesis of HCL and the overexpression of cyclin D1.

Abnormal proliferation of CD4− CD8+ γδ+ T cells with chromosome 6 anomaly: Role of fas ligand expression in spontaneous regression of the cells

We report a case of granular lymphocyte proliferative disorder accompanied with hemolytic anemia and neutropenia. Phenotypes of the cells were T cell receptor γδ+ CD3+ CD4− CD8+ CD16+ CD56− CD57−. Southern blot analysis of T cell receptor β and γ chains demonstrated rearranged bands in both. Chromosomal analysis after IL‐2 stimulation showed deletion of chromosome 6. Sorted γδ+ T cells showed an increase in Fas ligand expression compared with the levels in sorted αβ+ T cells. The expression of Fas ligand on these γδ+ T cells increased after IL‐2 stimulation. The patients anemia improved along with a decrease in granular lymphocyte count and disappearance of the abnormal karyotype without treatment. The expression of Fas ligand may be involved in spontaneous regression of granular lymphocyte proliferation with hemolytic anemia. Am. J. Hematol. 60:305–308, 1999.

Successful engraftment of cord blood following a one-day reduced-intensity conditioning regimen in two patients suffering primary graft failure and sepsis

Successful engraftment of cord blood following a one-day reduced-intensity conditioning regimen in two patients suffering primary graft failure and sepsis

Use of percutaneous image‐guided coaxial core‐needle biopsy for diagnosis of intraabdominal lymphoma

Although pathological diagnosis is essential for managing malignant lymphoma, intraabdominal lesions are generally difficult to approach due to the invasiveness of abdominal surgery. Here, we report the use of percutaneous image‐guided coaxial core‐needle biopsy (CNB) to obtain intraabdominal specimens for diagnosing intraabdominal lymphomas, which typically requires histopathological and immunohistochemical evaluation. We retrospectively reviewed consecutive cases involving computed tomography (CT)‐ or ultrasonography (US)‐guided CNB to obtain pathological specimens for intraabdominal lesions from 1999 to 2011. Liver, spleen, kidney, and inguinal node biopsies were excluded. We compared CNBs with laparotomic biopsies. A total of 66 CNBs were performed for 59 patients (32 males, 27 females; median age, 63.5), including second or third repeat procedures. Overall diagnostic rate was 88.5%. None of the patients required additional surgical biopsies. Notably, the median interval between recognition of an intraabdominal mass and biopsy was only 1 day. Forty‐five procedures were performed for hematological malignancies. Adequate specimens were obtained for histopathological diagnosis in 86% of cases. Flow cytometry detected lymphoma cells in 79.5% of cases. Twelve patients (nine males, three females; median age, 60) were eligible for surgical biopsy. While every postoperative course was satisfactory, median duration from lesion recognition to therapy initiation for lymphoma cases was significantly shorter for CNB than for surgical biopsy (14 vs. 35 days). While one‐fourth of the patients were not eligible for the procedures, CNB is safe and highly effective for diagnosis of intraabdominal lymphomas. This method significantly improves sampling and potentially helps attain immunohistological distinction, allowing for more timely therapy initiation.

Reduced-intensity cord blood transplantation without prior remission induction therapy induces durable remission in adult patients with relapsed acute leukemia after the first allogeneic transplantation

To the Editor: Leukemia relapse following allogeneic stem cell transplantation (allo-SCT) remains a major cause of treatment failure (1, 2). Among treatment options, second allo-SCT appears to increase disease-free survival compared with other interventions (3). The most important factors influencing outcomes of second allo-SCT may be the length of remission after the first transplantation and age (2). While disease status may also be an important factor, the probability of remission by re-induction therapy is generally low for relapsed acute leukemia after allo-SCT (4, 5). Limited data exist on other factors, such as conditioning regimens or use of different donors (2). Reducedintensity conditioning (RIC) regimens are now widely used in umbilical cord blood transplantation (CBT) (6). However, few reports exist on the use of RIC regimens in second allo-SCT with CB to treat relapsed patients after first allo-SCT (7). We report the outcomes of RIC CBT without prior reinduction chemotherapy for 11 consecutive adult patients from 2007 to 2009 at our institution (Table 1). Seven had acute myeloid leukemia (AML) and four had acute lymphoblastic leukemia (ALL). Median duration between first SCT and relapse was 6 months (3–24). All but one underwent conditioning with fludarabine (125 mg ⁄m), L-PAM (80 mg ⁄m), and total-body irradiation (TBI; 4 Gy). To achieve the maximum graft-versus-leukemia effect, a relatively low concentration of continuous tacrolimus was used as graft-versus-host disease (GVHD) prophylaxis (mean concentrations for each 10-d period spanning days 1 to 40 were 8.9, 8.9, 10.2, and 9.8 ng ⁄mL, respectively). Six patients received minimal cytoreductive chemotherapy prior to or during conditioning to control the rapid increase in leukemic cells in peripheral blood. Median duration between relapse to second SCT was 37 d (22–60). Four were in complete remission (CR) at the last follow-up (15–37 months). Except for three patients who died early after the second SCT, eight achieved longer CR after the second SCT than after the first. According to the definitions for pre-engraftment immune reaction (PIR) (8) and hemophagocytic syndrome (HPS) following SCT (9), PIR was observed in all cases and HPS in seven. In 10 cases, prednisolone (median dose, 1 mg ⁄kg, ranging 0.2–6.9) was introduced for a short period immediately following the diagnosis of PIR to avoid HPS, which may correlate with graft failure of CB. Graft failure was observed in three patients, two of whom underwent further CBTs as salvage treatment. Complications included severe infections (bacterial, n = 4; viral, n = 5). Other toxicities greater than grade 2 included mucositis (n = 3), sinusoidal obstruction syndrome (n = 2), and generalized skin pain (n = 2). While high grade acute GVHD (III or IV) was not observed in the four patients maintaining CR, all had chronic GVHD. To the best of our knowledge, the largest studies of second allo-SCTs using CB included seven relapsed adult leukemia patients (10) and 22 pediatric (11) leukemia patients; none of the adults and 10 of the pediatric patients received RIC regimens. Compared with these two studies, the interval from first SCT to relapse in the surviving four patients maintaining CR was extremely short in our cohort; in three of four patients, it was 5 months. Compared with the first SCT, an extremely high incidence of PIR was observed with the second SCT (one case vs. all cases), whereas no difference was seen in the incidence of acute GVHD (grade II–IV) and chronic GVHD. Although the biological mechanisms are unclear, PIR is assumed to reflect alloimmune reaction and is observed frequently in CBTs. (8). While the use of CB and a relatively low tacrolimus concentration may have caused the high incidence of PIR and HPS, PIR may have contributed to the suppression of leukemic cells that remained in the early phase after the RIC regimen. Graft failure was a devastating complication that has recently been reported to be closely correlated with HPS following CBT (9). As we previously reported, two of three patients who suffered from graft failure and sepsis underwent successful salvage therapy with a one-day regimen using CB (12). However, further studies are needed to clarify how PIR and HPS should be controlled. LETTER TO THE EDITOR doi:10.1111/j.1600-0609.2010.01555.x European Journal of Haematology 86 (268–271)