Rong-Long Chen

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.

Role of breast tumour kinase in the in vitro differentiation of HaCaT cells

Background  Breast tumour kinase (BRK) is a newly identified non‐receptor protein tyrosine kinase from a metastatic breast tumour. Its biological functions are still under extensive investigation. The mouse homologue Sik (Src‐related intestinal kinase) has been implicated in mouse keratinocyte differentiation; however, not much is known about the functions of BRK in human cutaneous biology.

A pathologic study of childhood lymphoma in Taiwan with special reference to peripheral T‐cell lymphoma and the association with Epstein‐Barr viral infection

The authors retrospectively reviewed the clinicopathologic and immunologic features of 65 consecutive cases of childhood lymphoma reported between 1980 and 1989. Southern blot hybridization was also performed in 23 cases to study their association with Epstein‐Barr virus (EBV) and human T‐cell leukemia virus type 1 (HTLV‐1). The 65 cases included 56 non‐Hodgkins lymphoma (NHL) (86%) and 9 Hodgkins disease (HD) (14%). The NHL could be classified into the following groups: Group I, small noncleaved cell lymphoma (20 cases); Group II, lymphoblastic lymphoma (17 cases); Group III, large cell lymphoma (17 cases); and miscellaneous (2 cases). There was no follicular lymphoma case. Immunohistochemical study on paraffin sections and/or frozen specimens in 47 cases of NHL showed that all the Group I cases belonged to B‐cell neoplasm (17 of 17 cases); most of the Group II cases belonged to T‐cell neoplasm (9 of 14 cases); and most of the Group III cases were peripheral T‐cell lymphoma (PTL) (8 of 16 cases), including 2 cases of Ki‐1 lymphoma. The majority of childhood NHL belonged to high‐grade malignancy with an aggressive clinical course (median survival time, 8 months). The EBV DNA could be detected from the tumor tissues in 4 of 6 PTL, but in none of the remaining 19 cases of NHL including 6 Burkitts type lymphomas. HTLV‐1 proviral genome was not detected in all specimens examined. The authors concluded that the distribution pattern and clinicopathologic feature of childhood lymphoma in Taiwan are comparable to that in Japan and western countries. The frequent association of EBV with aggressive PTL was unique and deserves additional investigation.

Cytogenetic characterization of Epstein-Barr virus-associated T-cell malignancies

Recently, Epstein-Barr virus (EBV) infection has been found not only to be associated with Burkitt lymphoma and nasopharyngeal carcinoma but also with some T-cell malignancies. Cytogenetic studies were performed on four Chinese patients with EBV-associated T-cell neoplasms: three peripheral T-cell lymphomas and one large granular lymphocyte leukemia with coexpression of T-cell antigen. Clonal chromosomal abnormalities were detected in all four patients. Rearrangements of chromosome 7 were observed in three patients: one at 7p22, one at 7q35 or 36, and the remaining one at both sites. The last patient also had a chromosomal abnormality involving 14q11. Trisomy of part of the 1q segment was detected in two patients. The results revealed that the chromosomal abnormalities in these patients were similar to those observed in other T-cell lymphomas. Further studies on more patients are necessary to find out whether there are specific chromosomal aberrations in EBV-associated T-cell neoplasms.

Epstein-Barr Virus-Associated Lymphoproliferative Disorder of Granular Lymphocytes Presenting Initially as Cutaneous Vasculitis

Lymphoproliferative disorders of granular lymphocytes (LDGL) represent a family of diseases characterized by persistent granular lymphocytosis with variable prognosis. The Epstein-Barr virus (EBV) has been occasionally linked with the development of LDGL. However, cutaneous manifestations of LDGL have rarely been reported. One patient had cutaneous vasculitis for 10 years before a definite diagnosis of LDGL was made. Chronic EBV infection was documented serologically and EBV DNA was detected in the peripheral blood lymphocytes. EBV RNA was detected in the nuclei of infiltrating lymphoid cells expressing CD43 in a skin biopsy specimen. A cytogenetic study showed clonal chromosomal abnormalities. This is the first report of EBV-associated LDGL of natural killer cells with cutaneous manifestations.

Can severe neonatal jaundice be prevented by neonatal screening for glucose-6-phosphate dehydrogenase deficiency : A review of evidence

An evidence-based approach is used to evaluate the neonatal screening program for glucose-6-phosphate dehydrogenase (G-6-PD) deficiency. The primary consideration to include G-6-PD deficiency (G-6-PDD) in neonatal screening program was the public health burden of G-6-PDD-associated neonatal jaundice (G-6-PDDANJ) in the target population. However, the prevalence of G-6-PDD per se cannot be the sole index of the public health burden of G-6-PDDANJ. In more developed areas, G-6-PDDANJ is no longer a major public health problem. Further, most cases with G-6-PDDANJ in more developed areas are not precipitated by any identifiable icterogenic agents, and therefore not preventable by avoidance education. In less developed areas, however, G-6-PDDANJ is still a big public health burden and requires intervention. In this study, the effectiveness of neonatal screening programs for G-6-PDD to prevent severe neonatal jaundice(NJ) has been shown based on historical comparison, but the results may be confounded by other temporal factors. G-6-PDDANJ usually occurs in the first week after birth. Prompt need for G-6-PD screening results precludes it from incorporation into other existent neonatal screening programs (i.e., for PKU), and from centralization of laboratory work. The efficacy, adverse effects and cost-effectiveness of this mass screening program need further study.

Bone Marrow Transplantation for Childhood Acute Myelogenous Leukemia

Six consecutive patients with acute myelogenous leukemia (AML) underwent 7 allogeneic bone marrow transplants at National Taiwan University Hospital. Marrow ablation for 4 patients consisted of busulfan 16 mg/kg and cyclophosphamide 120 mg/kg (BUCY 2). Two patients had busulfan 16 mg/kg and cyclophosphamide 200 mg/kg (BUCY 4) as marrow ablation. One had a second transplant following cytosine arabinoside 3 gm/m2/dose x 10 doses plus total body irradiation 12 Gy. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and short course methotrexate. Four patients received marrow from their HLA compatible siblings and two from their HLA-haplotype-matched fathers. Four transplants were performed during first remission and the other three during subsequent remission or relapse. All patients except one engrafted and achieved a complete remission (CR). Three of 4 patients transplanted in first CR are alive for over 10, 20 and 59 months respectively after transplant. One of the two patients who each received marrow from their fathers during 2nd CR and relapse, developed relapse 5 months later and the other developed aplasia 3 months later. Acute GVHD occurred in two of six patients. Localized chronic GVHD occurred in one of these two patients. Toxicities of BUCY 2 were minimal except veno-occlusive disease. One patient who received BUCY 4 developed hemorrhagic cystitis. There were no treatment related deaths except one patient who received 2nd transplant. These results demonstrate that BUCY 2 should be considered as a preparative regimen for allogeneic bone marrow transplantation for patients with AML in first remission.(ABSTRACT TRUNCATED AT 250 WORDS)

Allogeneic bone marrow transplantation for children with acute lymphoblastic leukemia in second remission or relapse.

Most children with acute lymphoblastic leukemia (ALL) are successfully treated by chemotherapy. For those patients, who relapse on therapy, bone marrow transplantation (BMT) is considered most appropriate after a subsequent remission is achieved. Three boys with ALL aged from 9 to 13 years met these criteria and received BMT from their HLA-compatible sisters after marrow ablation with total body irradiation 12 Gy plus high dose cytosine arabinoside 3 gm/m2/12h x 12 doses and graft-versus-host disease (GVHD) prophylaxis with cyclosporine plus short course methotrexate from March 10, 1989 to May 23, 1992. Filgrastim (rhG-CSF) was used to hasten the recovery of granulocyte in one patient. All three patients got full engraftment and two had grade 1 acute GVHD. None of them developed chronic GVHD. Two patients have disease-free survival over 51 and 12 months respectively post BMT without further chemotherapy. One patient died of recurrent refractory leukemia 5 months after BMT. The toxicity of this conditioning regimen included photophobia, conjunctivitis and erythematous skin rashes. One patient who received filgrastim from day 1 to 21 developed severe bone pain. However, this patient had faster recovery of granulocyte count than the other two patients. The preliminary results of this work favors BMT for children with recurrent ALL whose ultimate survival is usually poor when treated with chemotherapy. Further efforts are necessary to investigate new methods for reducing leukemic relapse in ALL patients undergoing BMT.

Cytomegalovirus-induced persistent mononucleosis in an infant

Chronic mononucleosis has recently gained much attention in the literature. Almost all cases of this new syndrome have been ascribed to persistent Epstein-Barr virus infection. However, a case presented with infantile chronic mononucleosis syndrome caused by persistent cytomegalovirus infection. Transient clonal chromosomal change was noted during follow-up.