Chiu-Hwa Wang

Methylation of the p15INK4B gene in myelodysplastic syndrome: it can be detected early at diagnosis or during disease progression and is highly associated with leukaemic transformation

To investigate the time sequence of occurrence of p15INK4B gene methylation in myelodysplastic syndrome (MDS) and its correlation with leukaemic transformation and survival of patients, the methylation status of the p15INK4B promoter region was analysed in 50 patients and was serially studied in 22 of them. Of the 50 patients, 17 (34%) showed p15INK4B gene methylation, first demonstrated at diagnosis or during follow‐up. When FAB subtypes at the time of study were used in the analysis, the incidence of p15INK4B methylation in each risk group of MDS remained stable throughout the course: 0% for low‐risk MDS [refractory anaemia (RA) and RA with ring sideroblasts] and from 23% at diagnosis to 30% for high‐risk MDS [RA with excess of blasts (RAEB), RAEB in transformation and chronic myelomonocytic leukaemia] respectively. The incidence of p15INK4B methylation rose to 60% at initial study and, finally, to 75% in cases of acute myeloid leukaemia (AML) evolved from MDS. Most patients (69%) with p15INK4B methylation showed disease progression to AML; it could be detected before, at the time or after the diagnosis of leukaemic transformation. p15INK4B methylation in MDS patients implicated a shorter survival time in univariate analyses, but its prognostic significance disappeared in multivariate analyses. In conclusion, p15INK4B methylation can be detected early at the diagnosis of MDS or acquired during disease progression. It may play an important role in the pathogenesis of some high‐risk MDS and is related to leukaemic transformation of MDS.

Hemophagocytic Syndrome in Epstein-Barr Virus-Associated T-Lymphoproliferative Disorders: Disease Spectrum, Pathogenesis, and Management

The Epstein-Barr virus (EBV) has been shown to infect T lymphocytes and is associated with two recently recognized human T-lymphoproliferative disorders: childhood EBV-associated hemophagocytic syndrome (VAHS) representing a primary or active EBV infection of T cells in young children, and the EBV-containing T cell lymphoma in adults predominantly affecting the nose, skin and gastrointestinal tract. In both diseases, hemophagocytic syndrome (HS) accounts for the major cause of mortality. The patients developing HS share common clinicopathologic features such as fever, skin lesions, lung infiltrates, hepatosplenomegaly with jaundice, cytopenias, and coagulopathy. The liver, spleen, lymph nodes, and bone marrow usually show florid histiocytic proliferation with hemophagocytosis in addition to the proliferation of atypical T lymphocytes or immunoblasts. The HS in T cell lymphoma may develop simultaneously with initial lymphoma presentation, at tumor relapse, or even during remission. The cytokines, in particular tumor necrosis factor-alpha, released from the EBV-infected T lymphocytes are presumed to cause the histiocytic activation and the subsequent hemophagocytic process. Chemotherapy or antiviral agents fail to arrest the hemophagocytic process in both diseases. Immunomodulatory treatment incorporating etoposide and intravenous immunoglobulin, however, has been effective in the control of the progression of the hemophagocytic process in a substantial number of VAHS patients. Preliminary data suggest that bone marrow transplantation may be a promising way for eliminating both the virus and the proliferating T cells. Further investigations are mandatory for combating this aggressive hemophagocytic process in EBV-associated T lymphoproliferative disorders.

Acute and chronic arsenic poisoning associated with treatment of acute promyelocytic leukaemia

Seven relapsed and/or refractory acute promyelocytic leukaemia patients were treated by arsenic trioxide (As2O3). Four patients (4/7, 57%) achieved complete remission after one to three cycles of treatment and the most common acute side‐effect was fluid retention (in six patients, 86%), including weight gains and pleuro‐pericardial effusions. Evident polyneuropathy compatible with chronic arsenic toxicity was noted in two of the three patients who received As2O3 maintenance therapy and one of them had marked distal muscular atrophy. We suggest that As2O3 may be a useful salvage therapy for relapsed and refractory APL patients, but the acute or chronic arsenic toxicity should be carefully monitored.

SOCS1 methylation in patients with newly diagnosed acute myeloid leukemia.

The proliferation and differentiation of hematopoietic precursor cells depend on various cytokines. The suppressor of cytokine signaling‐1 (SOCS1) down‐regulates Janus kinases/signal transducers and activators of transcription (JAK/STAT) pathway activity and inhibits the biological effects of cytokines. SOCS1 has been shown to have tumor‐suppressor activity, and methylation of this gene, resulting in transcriptional silencing, has been found in 65% of hepatocellular carcinoma and has been suggested to play an important role in the development of the cancer. The methylation status of the SOCS1 gene in acute myeloid leukemia (AML) has not been reported before. In this study, we analyzed SOCS1 methylation in 89 patients with newly diagnosed AML and correlated the result with immunophenotypes, cytogenetics, clinical features, and treatment outcome. SOCS1 methylation was found in the leukemic cells from 53 patients (60%). Thirteen (76%) of the 17 patients with t(15;17) had SOCS1 methylation, whereas this gene was methylated in only one (11%) of the nine patients with t(8;21). The frequencies of SOCS1 methylation among various cytogenetic subgroups differed significantly (P = 0.014). Other clinical and laboratory parameters and the disease‐free survival and overall survival were similar between patients with and without SOCS1 methylation. In conclusion, SOCS1 methylation occurs in more than half of AML cases, correlates with cytogenetic abnormalities, and may play an important role in the development of subsets of AML.

Characteristic clinicopathologic features of epstein-barr virus—associated peripheral T-cell lymphoma

Background. The authors previously reported the existence of a unique subtype of peripheral T‐cell lymphoma (PTCL) characterized by a clonotypical proliferation of Epstein‐Barr virus (EBV) in the tumor cells (Blood 1991; 77:799). Detailed clinicopathologic features of this newly recognized entity remain to be clarified.

Epidemiology of multiple myeloma in Taiwan: increasing incidence for the past 25 years and higher prevalence of extramedullary myeloma in patients younger than 55 years.

The incidence of multiple myeloma (MM) is lower in Asia than in western countries. However, no data are available on descriptive epidemiology of MM in Chinese.

Clinicopathological spectrum of haemophagocytic syndrome in Epstein‐Barr virus‐associated peripheral T‐cell lymphoma

Haemophagocytic syndrome (HS) is frequently observed in Epstein‐Barr virus‐associated peripheral T‐cell lymphoma (EBV‐PTCL) and represents a major cause of death. In this communication we have further analysed the spectrum of HS in 12 patients with EBV‐PTCL. The patients could be divided into three groups according to the time of onset of HS during the clinical course of PTCL. Group I patients (four cases) had HS as the initial clinical manifestation. All four patients were initially suspected to have malignant histiocytosis (MH) but a MH‐like PTCL was later diagnosed. Group II patients (six cases) developed HS at the time of lymphoma relapse. Four of them belonged to the angioinvasive type PTCL. Group III patients (two cases) developed HS at clinical remission; both were angioinvasive type PTCL. Nine patients had serological evidence suggesting active EBV infection. The clinical course after the onset of HS was generally fulminant in each group with a median survival of only 44 d despite combination chemotherapy and/or empirical therapy with high‐dose immunoglobulin and corticosteroids in six patients. In conclusion, HS represents a severe complication of EBV‐PTCL. Although most patients develop HS at a time of active lymphoma, the syndrome may occur when the lymphoma is in remission. Because of the poor outcome, early diagnosis and a new modality of treatment for HS associated with EBV‐PTCL should be pursued in future.

Expression of P-glycoprotein and glutathione-S-transferase in recurrent lymphomas: the possible role of Epstein-Barr virus, immunophenotypes, and other predisposing factors.

PURPOSE We previously have reported the poor prognoses of recurrent peripheral T-cell lymphoma (PTCL) and Epstein-Barr virus (EBV)-associated PTCL (J Clin Oncol 7:725-731, 1989; Blood 77:799-808, 1991). To study the role that drug resistance plays in this scenario, we conducted a retrospective study of 23 adult patients. PATIENTS AND METHODS All patients had recurrent lymphoma tissue available for immunophenotyping and screening for the existence of EBV DNA in tumor cells by Southern blot analysis and in situ hybridization. Expression of a multidrug resistance P-glycoprotein ([P-gp]mdr-1) and a glutathione redox cycle-related glutathione-S-transferase pi (GST-pi) was determined by an immunohistochemistry method. RESULTS Expression of mdr-1 or GST-pi was found in 11 (48%) and 12 (52%) cases, respectively. Most (11 of 12) of the GST-pi expression occurred simultaneously with mdr-1. Prechemotherapy tumor tissues were available in 11 cases; only two (18.2%) of these cases expressed mdr-1. Four (36%) of 11 cases that expressed mdr-1 (mdr-1(+)) and nine (90%) of 10 cases that did not express mdr-1 (mdr-1(-)) responded to second-line chemotherapy (P < .05). The survival-after-recurrence (SAR) curves significantly favored mdr-1(-) recurrent lymphoma (P < .05). The mdr-1 expression was further correlated with the immunophenotype and EBV association. All six cases of EBV-associated lymphoma (PTCL, five cases; Hodgkins disease, one case) had significant simultaneous expression of mdr-1 and GST-pi in their recurrent tumor tissues. CONCLUSION (1) mdr-1 expression is a significant prognostic factor in recurrent lymphomas; (2) high expression of mdr-1 is observed in recurrent EBV-associated PTCL; and (3) GST-pi usually expresses simultaneously with mdr-1 in recurrent lymphomas. The role of EBV in the development of mdr-1 and the biologic significance of the simultaneous expression of mdr-1 and GST-pi in recurrent lymphomas are well worth further exploration.

A subset of acute nonlymphocytic leukemia with expression of surface antigen CD7— morphologic, cytochemical, immunocytochemical and t cell receptor gene analysis on 13 patients

An increasing number of acute leukemias coexpressed markers normally believed to be restricted to a single lineage have been found recently. This special subgroup of leukemias have drawn a lot of attention because of their biologic and clinical significance. In a study of 100 consecutive de novo ANLL patients diagnosed by FAB criteria, T-cell antigen CD7 was identified on the leukemic blasts of 13 patients, ten of whom had M1 subtype of leukemia, myeloblastic leukemia without maturation. All the patients showed positive staining with myeloperoxidase and expressed myeloid markers CD13 and/or CD33, but lacked CD11b, a marker of more mature myeloid cells. Combined staining with myeloperoxidase and CD7 of the cells from four patients revealed coexpression of both markers on the same cells. None of the patients expressed the two other T-cell antigens CD2 or CD5. All ten patients who had DNA analysis showed germline configuration of TCR beta and gamma chain genes. One patient had chromosomal translocation involving 11q23, t(11; 19) (q23; p13), which is the site frequently associated with both myeloid and lymphoid malignancies. The clinical implications of this subgroup of patients need further study on more patients, and need longer follow-up.

Clinical, haematological and molecular studies in patients with chromosome translocation t(7;11): a study of four Chinese patients in Taiwan

Translocation t(7;11)(p15;p15) is an uncommon but recurrent chromosome aberration in acute myeloid leukaemia (AML), which occurs mostly in oriental patients and in AML M2 or, occasionally, M4 subtype. Recently, a consistent chimaeric fusion transcript NUP98‐HOXA9 was found in several cases of t(7;11). Four AML cases with the chromosome abnormality in Taiwan are described. They were all adults with ages ranging from 30 to 41 years (median 36 years). Three of them were diagnosed as having AML M2; the remaining one as M4. Marked dyserythropoiesis was demonstrated in two patients. All four patients showed pan‐myeloid antigen CD13 on the leukaemic cells, but none coexpressed lymphocyte‐associated antigens and neither of the two patients studied for CD34 expression had positive staining. NUP98‐HOXA9 fusion transcript was detected in both patients who had molecular analysis and the breakpoints on chromosome 11 and 7 respectively were similar to those previously reported. They all received conventional induction chemotherapy, but only one achieved a complete remission (CR) with short duration. This study and others reported in the literature suggest a racial or geographical predisposition among oriental patients to AML with t(7;11) and that this is associated with a poor prognosis. The molecular detection of NUP98‐HOXA9 fusion transcript would be a useful method for the diagnosis of t(7;11) and also for monitoring disease status after treatment.