Hiroyuki Irisawa

Immunological abnormalities in splenic marginal zone cell lymphoma

The clinical features of patients with splenic marginal zone cell lymphoma (SMZCL) have rarely been reported. In the present study, immunological abnormalities, particularly hematological abnormalities, observed in SMZCL were described. Autoimmune hemolytic anemia, immune thrombocytopenia, and appearance of lupus anticoagulant were observed in 2 of 3 patients with SMZCL. Other abnormal data including monoclonal gammopathy and cold agglutinin were also observed in 2 of the 3 patients. Immunological abnormalities may be characteristic complications in patients with SMZCL and must be followed carefully, since they may be a reliable marker of this type of lymphoma activity. Am. J. Hematol. 56:173–178, 1997.

Prevalence and Clinical Characteristics of Acute Myeloid Leukemia Associated with Disseminated Intravascular Coagulation

Disseminated intravascular coagulation (DIC) is one of the important complications to develop in patients with acute myeloid leukemia (AML). While acute promyelocytic leukemia (APL) is a strong risk factor for DIC, other clinical features have not been fully defined. We retrospectively analyzed 161 consecutive adult patients with de novo non-APL AML. DIC was diagnosed in 52 patients (32%); 28 patients at diagnosis and 24 soon after the initiation of induction chemotherapy. Leukocyte counts, C-reactive protein, and lactate dehydrogenase were significantly higher in the DIC+ group. Negative expressions of CD13, CD19, CD34, and HLA-DR were more prevalent in the DIC+ group. On multivariate logistic-regression analysis, variables that were independently associated with the development of DIC were high C-reactive protein, high leukocyte count, negative expressions of CD13 and HLA-DR, and cytogenetics with a normal karyotype or 11q23 abnormality. Although DIC is considered to be associated with serious morbidity and occasional mortality, we did not find any significant differences in the complete remission rate, overall or disease-free survival between DIC+ and DIC- groups. This study is the first to define the clinical characteristics associated with DIC in patients with non-APL AML, but exactly how and when DIC should be treated remains to be determined.

JAK2-V617F mutation analysis of granulocytes and platelets from patients with chronic myeloproliferative disorders: advantage of studying platelets

There have been conflicting reports over the JAK2‐V617F mutation status of platelets in chronic myeloproliferative diseases (CMPDs). The aim of this study was to analyse JAK2‐V617F status, not only in granulocytes but also in platelets. The JAK2‐V617F mutation was analysed in both granulocytes and platelets in 115 patients with CMPDs using direct sequencing. JAK2‐V617F was detected in granulocytes from 71 of those patients, all 71 of whom also had platelet JAK2‐V617F expression. The remaining 44 patients showed negative JAK2‐V617F expression on granulocytes, but positive JAK2‐V617F expression was detected on the platelets from nine of the 33 essential thrombocythaemia (ET) patients, one of the eight polycythaemia vera patients, and two of the three primary myelofibrosis patients. When ET patients were divided into three groups according to granulocyte and platelet JAK2‐V617F status (both‐positive, platelets‐only positive and both‐negative), the both‐positive and platelets‐only positive groups shared the clinical features of higher white blood cell count and frequent thrombosis. These results suggest that analysis of platelets is a more sensitive approach for detecting JAK2‐V617F in CMPD patients than analysis of granulocytes. They also suggest that previous reports of the incidence of JAK2‐V617F in CMPD patients, obtained using only analysis of granulocytes, could be underestimations.

TCR Vβ repertoire analysis in CD56+ CD16dim/− T-cell large granular lymphocyte leukaemia: association with CD4 single and CD4/CD8 double positive phenotypes

Summary.  We report 10 patients with T‐cell large granular lymphocyte (LGL) leukaemia: four patients had CD16+ CD56− LGL lymphocytes (typical for LGL leukaemia), and six patients had CD56+ CD16dim/− LGL lymphocytes (atypical). Among the CD56+ CD16dim/− patients, LGL lymphocytes were CD4+ CD8− in one patient, CD4/CD8 double positive (DP) in three, and CD4− CD8+ in two. The CD4+ CD8dim DP cells expressed a CD8αα homodimer. T‐cell receptor (TCR) Vβ complementarity‐determining region 3 (CDR3) size distribution analysis and direct sequencing identified at least 1 in‐frame clonal TCR Vβ transcript in each patient; three patients had two or three different clonal sequences. To determine whether these transcripts were translated into cell surface TCR, we performed flow cytometric analysis using Vβ monoclonal antibodies (mAbs). A single Vβ protein was identified in patients, even those with multiple in‐frame transcripts. Previous and present results suggest that CD56+ CD16dim/− LGL leukaemia is more common than previously thought, and is associated with unusual phenotypes. When assessed using only molecular techniques, the monoclonal status of this disease may be misinterpreted as oligoclonal; thus, flow cytometric analysis using Vβ mAb is quite useful. Because mAbs do not cover the entire Vβ repertoire, assessing clonality using a combination of molecular methods and mAbs is preferable.

X-linked agammaglobulinemia diagnosed in adulthood: a case report.

X-linked agammaglobulinemia (XLA) is a humoral immunodeficiency caused by mutations in Bruton’s tyrosine kinase (BTK). Patients typically become symptomatic during infancy or early childhood and develop recurrent bacterial infections. We report a Japanese case of XLA diagnosed in a patient who was 27 years of age and who had no history of severe infection. The patient’s serum immunoglobulin (Ig) G, IgA, and IgM levels were 132, 7, and 17 mg/dL, respectively. The percentage of positive cells for CD19 and CD20 was 0.03% and 0.02%, respectively. The patient’s brother and sister had no abnormalities. Flow cytometric analysis showed a partially reduced expression of BTK protein in the patient’s peripheral monocytes. Sequencing of the BTK gene revealed a missense mutation (230C>T,T33I). Given this data, this patient was diagnosed as having rare, late onset XLA with a missense mutation in the BTK gene.

Successful treatment with voriconazole of Aspergillus meningitis in a patient with acute myeloid leukemia

Dear Editor, Aspergillus meningitis is extremely rare and difficult to diagnose among CNS aspergillosis, and many cases have been diagnosed only at autopsy [1, 2]. Voriconazole has recently improved the prognosis in a few patients with CNS aspergillosis compared to amphotericin B [3]. However, the efficacy of voriconazole for Aspergillus meningitis is unclear. In this report, we describe a case of Aspergillus meningitis in a patient with acute myeloid leukemia who was successfully treated with voriconazole. A 33-year-old Japanese man was admitted to our hospital in February 2006 due to abnormal chest computed tomography (CT) findings that showed an anterior mediastinal tumor. Fluorine-18-2-fluoro-2-deoxy-d-glucose PET was also positive for mediastinal tumor. His hemoglobin was 14.2 g/dl, platelets 350×10/l, and WBC 5.3×10/l. Bone marrow showed hypercellularity with 99% blasts positive for myeloperoxidase. The thymus biopsy also showed involvement of immature myeloid cells. He was diagnosed with acute myeloid leukemia with granulocytic sarcoma in the thymus. After treatment with idarubicin and cytarabine he achieved a hematological complete remission and a resolution of the mediastinal enlargement on CT imaging. Subsequently, he was treated with high-dose cytarabine as consolidation therapy. On day 14 postchemotherapy, he developed a sudden fever, severe headache, and a stiff neck. His hemoglobin was 8.3 g/dl, platelets 20×10/l, and WBC 0.1×10/l. C-reactive protein was 9.8 mg/dl. CT of the chest and brain was unremarkable. However, magnetic resonance imaging (MRI) of the brain showed abnormal meningeal enhancement (Fig. 1a,b). Cerebrospinal fluid (CSF) analysis revealed leukocytes 15/μl, glucose 30 mg/dl, and protein 76 mg/dl. Although Aspergillus was not isolated in the CSF, high level of the Aspergillus antigen galactomannan was detected in the CSF by the ELISA test. The galactomannan index was 2.2 in the CSF, compared with 0.1 in serum. Aspergillus DNAwas also detected in the stored CSF samples by PCR assay as described previously [4]. Thus, he was diagnosed with Aspergillus meningitis. We began amphotericin B (1 mg kg day). After 1 week of treatment with amphotericin B, the patient showed no improvement. Treatment with amphotericin B was stopped and voriconazole (3 mg/kg twice daily) treatment was started. The consciousness level and fever dramatically improved within 1 week. After 3 weeks of treatment with voriconazole, Aspergillus antigen and Aspergillus DNA were no longer detected in the CSF. He continued on oral voriconazole (dose 200 mg twice daily, total dose 143 g) for about 1 year. He continues to be in complete recovery and has been for 1 year after allogenic stem cell transplantation. Brain CT is not useful for Aspergillus meningitis, which has no parenchymal lesions. Gadolinium-enhanced MRI of Ann Hematol (2007) 86:697–698 DOI 10.1007/s00277-007-0292-8

Sacroiliitis as an initial manifestation of acute myelogenous leukemia

Sacroiliitis is the most pathognomonic and earliest manifestation of ankylosing spondylitis.We herein report a 28-year-old female patient who presented with sacroiliitis as an initial manifestation of acute myelogenous leukemia (AML). She had a 3-month history of anemia and walking difficulty. Bone marrow findings revealed an increase of blasts with trilineage dysplasia. Although she was initially diagnosed with myelodysplastic syndrome (MDS), blasts rapidly increased and AML developed 1 month after the diagnosis of MDS with sacroiliitis. Induction chemotherapy failed to induce a complete remission of AML, but it did effectively treat the sacroiliitis. However, the sacroiliitis relapsed when the leukemia cells progressed thereafter. Oral corticosteroids helped ameliorate the sacroiliitis. She underwent bone marrow transplantation (BMT) from an HLA-identical sister during a nonremission period; however, the leukemic cells began to rapidly increase from day 30 after BMT. The close relationship between the occurrence of sacroiliitis and AML suggested that autoimmune sacroiliitis was a paraneoplastic phenomenon of AML in this patient. Although autoimmune disorders develop in a substantial number of MDS patients, they are rarely observed in de novo AML. No previous report has described sacroiliitis as the initial manifestation of de novo AML.

Small-bowel perforation accompanied by Aspergillus endocarditis in a patient with angioimmunoblastic T-cell lymphoma

Dear Editor:Angioimmunoblastic T cell lymphoma (AITL) is present in1–2% of non-Hodgkin lymphomas, which is associatedwith an aggressive clinical course and infectious complica-tions [1]. Aspergillosis is the most important factor ininfectious mortality among leukemia or lymphoma patientswith neutropenia. We describe a rare case of a patient withAITL who developed small-bowel perforation accompaniedby Aspergillus endocarditis, and who suffered discontinu-ous dull abdominal pain during chemotherapy.A 62-year-old Japanese man was admitted to ourhospital in December 2003 due to acute abdominal painand high fever. A physical examination revealed skin rash,anemia, superficial lymphadenopathy, and hepatospleno-megaly. His peripheral blood counts were hemoglobin,9.8 g/dl; WBC, 7.9×10

X-Linked Lymphoproliferative Disease in an Adult

X-linked lymphoproliferative disease (XLP) is an inherited immunodeficiency characterized by an extreme susceptibility to Epstein-Barr virus (EBV) infection. Patients with XLP mainly present with the 3 clinical manifestations of fulminant infectious mononucleosis, lymphoproliferative disorder, and dysgammaglobulinemia and in rare cases have aplastic anemia and lymphocytic vasculitis.The causative gene for XLP was identified asSH2D1A/DSHP/SLAM-associated protein (SAP) in 1998, and genetic analysis has been used for the definite diagnosis of XLP. Diagnosis for most patients occurs at ages younger than 10 years, and there are few adult patients. Here we describe a 23-year-old man with hypogammaglobulinemia and EBV-associated hemophagocytic lymphohistiocytosis and a diagnosis of XLP. In addition, the patient showed type 1 helper T-cell (Th1) skewing, as has been described inSap knock-out mice. Th1/Th2 imbalance in humans, as well as in mice, may play an important role in the pathogenesis of XLP.

Presentation of extramedullary Philadelphia chromosome-positive biphenotypic acute leukemia as testicular mass: Response to imatinib-combined chemotherapy

Leukemias of ambiguous lineage are uncommon, representing *4% of all leukemias [1] and have been categorized into three sub-types; undifferentiated acute leukemia, bilineal acute leukemia and biphenotypic acute leukemia. Biphenotypic acute leukemia is characterized by blasts which co-express myeloid and T or B lineage specific antigens or concurrent B and T lineage antigens [1,2]. About a third of cases have Philadelphia (Ph) chromosome [1]. The prognosis of biphenotypic acute leukemia is generally unfavorable, especially accompanied with the occurrence of the t(4;11) or Ph chromosome abnormalities [1,3]. We here describe successful treatment for a patient with Ph-positive biphenotypic acute leukemia with testicular involvement who had received allogenic stem cell transplantation after imatinib combined chemotherapy. A 54-year-old Japanese male without a significant past medical history was admitted to the hospital in January 2005 because of enlargement of left testis, leukocytosis, anemia and thrombocytopenia. The blood count was hemoglobin 8.7 g dL (87 g L), platelets 3.5610 mL (35610 L) and WBC 94.3610 mL (94.3610 L) with a differential of 93% blasts, 0% neutrophils, 6% lymphocytes and 1% monocytes. Lactate dehydrogenase (LDH) was 439 IU L (119 – 229 IU L). Bone marrow showed marked hypercellularity with 99% blasts. Flow cytometric analysis revealed that the blast cells were positive for CD13, CD33, CD117, CD79a, CD19 and TdT (Figure 1). Cytogenetic study of the bone marrow cells revealed 46, XY, t(9;22)(q34;q11) in all metaphases. Real-time RT-PCR analysis revealed 950 000 copies per 1 mg RNA of major BCR/ABL. Furthermore, Southern blot analysis revealed IgH rearrangement. Scrotal ultrasound examination revealed a well-circumscribed and hypoechoic mass measuring 6 cm65 cm64 cm. He was diagnosed as having Ph-positive biphenotypic acute leukemia with testicular involvement. At first, the patient was treated with acute myeloid leukemia (AML)-directed therapy [idarubicin (12 mg m per day intravenously) for 3 days (days 1 – 3) and cytarabine (100 mg m per day) by continuous infusion for 7 days (days 1 – 7)], however the response was poor and more than 80% of blasts persisted in the bone marrow cells as well as enlargement of left testis. We started to treat with 600 mg of imatinib orally daily (days 1 – 40) and acute lymphoblastic leukemia (ALL)-directed therapy [cyclophosphamide (1200 mg m per day i.v.) on day 1, daunorubicin (60 mg m per day i.v.) for 3 days (days 1 – 3), vincristine (1.3 mg m per day i.v.) on days 1, 8, 15, 22, prednisolone (60 mg m orally daily on days 1 – 21)]. After this chemotherapy, he achieved hematological complete remission (CR) without testicular mass and we continued 600 mg of