Epstein-Barr virus-associated post-transplant lymphoproliferative disorder presenting with skin involvement after CD34-selected autologous peripheral blood stem cell transplantation.

We report a case of Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disorder (PTLD) after CD34-selected autologous peripheral blood stem cell transplantation (PBSCT). A 54-year-old woman with multiple myeloma underwent CD34-selected autologous PBSCT. The patient's post-transplantation course was complicated by fever, pancytopenia and CMV antigenemia. On day 128 post PBSCT, a skin biopsy from an erythematous nodule on the right anterior chest revealed a deep dermal infiltrate of atypical CD20 and CD79a-positive B-cells with centroblastic large cell morphology. EBV reactivation was confirmed by immnohistochemistry, in situ hybridization and Southern blot analysis. These findings represent monomorphic PTLD having pathological features of a large cell-type B-cell lymphoma. Bone marrow aspiration also demonstrated hemophagocytic syndrome (HPS), accompanied with infiltration of EBV-positive B-cells. Despite treatment with rituximab and hydroxyurea, the patient died 155 days after transplantation.

Placenta growth factor stimulates the growth of Philadelphia chromosome positive acute lymphoblastic leukemia cells by both autocrine and paracrine pathways.

Vascular endothelial growth factor (VEGF) and its associated molecule, placenta growth factor (PlGF) are now known to support normal hematopoiesis, and leukemia cell growth. In this study, expression of VEGF and PlGF in acute lymphoblastic leukemia (ALL) cells was examined by real time reverse transcription-polymerase chain reaction in 20 patient samples. Expression of PlGF was more intense in Philadelphia chromosome positive (Ph(+)) ALL than in Ph(-) ALL cases. On the other hand, expression level of VEGF was not different between Ph(+) and Ph(-) cases. Then, PlGF was added to the two ALL cell lines, CRL1929 (Ph(+)), and Nalm6 (Ph(-)). The PlGF stimulated the growth of CRL1929 in time- and dose-dependent manners, although the growth of Nalm6 was not affected by PlGF. The growth stimulation of CRL1929 by PlGF was confirmed by the increase of S phase cells. And the growth promoting effect of PlGF on CRL1929 was cancelled by simultaneous addition of VEGFR1/Fc (which binds to PlGF and abrogates its function), but was not cancelled by VEGFR2/Fc (which does not bind to PlGF). Then, addition of VEGFR1/Fc to the simple culture of CRL1929 demonstrated growth inhibitory effect. These observations demonstrated that PlGF stimulates the growth of Ph(+) ALL cells by both autocrine and paracrine pathways. Finally, PlGF-VEGFR1 loop might be a therapeutic target to improve the prognosis of Ph(+) ALL.

Autocrine pathway of angiopoietins-Tie2 system in AML cells: association with phosphatidyl-inositol 3 kinase.

Hematopoietic cells and endothelial cells are mutually correlated in their development and growth. Various angiogenic factors, such as vascular endothelial growth factor (VEGF) and angiopoietins (Angs), are thought to be associated with leukemia cell growth. In this study, we examined if the Angs-Tie2 autocrine pathway works in primary AML cells or not by using soluble Tie2-Fc, which inhibits Angs from binding to Tie2 receptor. After 48 h of culture with Tie2-Fc, nine AML cells from 19 examined samples were not influenced by Tie2-Fc (group A), while AML cells from remaining 10 patients demonstrated remarkable reduction of cell number by Tie2-Fc treatment (group B). Tie2 receptor, upon binding to Angs, are known to activate phosphatidyl-inositol 3 kinase (PI3 kinase). Then, we examined the effect of LY294002, a potent PI3 kinase inhibitor, on primary AML cells. Cell number reduction effect by the treatment of LY294002 was much more prominent in cells of group B than of group A. In addition, extent of cell number reduction by Tie2-Fc and LY294002 was quite well correlated. These observations demonstrated that cells from a part of AML were dependent on autocrine Angs-Tie2 pathway. This notion was further supported by the study of two AML cell lines, KG-1 and HL-60: the growth of KG-1 was suppressed by Tie2-Fc, and also by anti-Tie2 antibody, which inhibits receptor-ligand interaction, while that of HL-60 was not suppressed by Tie2-Fc or anti-Tie2 antibody. Our results will help to explore the angiogenesis-oriented or endothelial cell-mediated therapy for leukemia.

Acute promyelocytic leukemia with drug-induced hypersensitivity syndrome associated with Epstein-Barr virus infection.

We report a case of acute promyelocytic leukemia (APL) with drug-induced hypersensitivity syndrome associated with Epstein-Barr virus (EBV) infection. A 33-year-old woman was admitted because of APL. After complete remission was obtained with the use of all-trans retinoic acid (ATRA), intensive chemotherapy was administered. She developed high grade fever and severe systemic erythematous eruptions followed by cervical lymphoadenopathy, hepatosplenomegaly, hepatitis and hypotension in a state of myelosuppression during consolidation chemotherapy. Systemic corticosteroids alleviated the symptoms. Since an anti-EB VCA IgM antibody titer was continuously positive, persistent infection of EBV was suspected. In this case, EBV infection may have contributed to the development of drug-induced hypersensitivity syndrome.

Pilot phase I/II study of new salvage therapy (CHASE) for refractory or relapsed malignant lymphoma.

A pilot phase I/II study was conducted as a single-institute trial for evaluation of the feasibility and efficacy of a new salvage chemotherapy, CHASE, for patients with refractory or relapsed lymphoma . The CHASE regimen, consisting of cyclophosphamide, cytosine arabinoside, etoposide, and dexamethasone, was administered every 3 weeks in a maximum of 5 courses. A total of 16 patients were eligible and registered for this study. Myelosuppression was the major toxicity. Although grade 4 leukopenia and grade 3 thrombocytopenia were identified in 15 and 16 patients, respectively, duration of the nadir was brief (median, 3 days). Nonhematological grade 4 toxicity was not observed, and transient elevations of bilirubin and grade 3 aspartate aminotransferase/alanine aminotransferase (AST/ALT) were observed in 2 and 3 courses, respectively, in a total of 57 courses. Complete and partial response rates were 71.4% (10/14) and 7.1% (1/14), respectively. The median percentage of maximal CD34+ cells was 6.1% on day 15, and a median number of 1.88 x 10(6) CD34+ cells/kg per apheresis were obtained. Thirteen patients received high-dose chemoradiotherapy followed by autologous peripheral blood stem cell transplantation. With a median follow-up time of 36 months from the start of CHASE, the overall survival rate for the 16 patients was 66.6%. These results indicated that CHASE is a safe and effective salvage regimen for malignant lymphoma, has sufficient mobilizing effect on peripheral blood stem cells, and warrants further phase II study.

Frequent occurrence of CCND1 deregulation in patients with early stages of plasma cell dyscrasia.

Chromosomal translocations involving the immunoglobulin heavy chain gene (IgH) and nonrandom protooncogene loci are the hallmark of genetic alterations found not only in multiple myeloma (MM), but also in premalignant stages of MM, including monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM). We studied the frequency of IgH (14q32) rearrangements and their partner chromosomes in 16 Japanese patients with MGUS (13 cases), and SMM (3 cases) by means of interphase double-color fluorescence in situ hybridization (DCFISH) applied to purified plasma cells and using CD138-bead selection. IgH rearrangement was recognized in nine of the patients (56.3%). Protooncogene loci juxtaposed to IgH were identified in seven cases including CCND1 (11q13) in six cases and FGFR3 (4p16) in one. Four out of the six t(11;14)-positive cases showed nuclear staining of the cyclin D1 protein, whereas none of the seven t(11;14)-negative cases did. Moreover, neither MUM1(6p25)-IgH nor MAFB(20q11)-IgH fusion signals were observed. This suggests to us that cyclin D1 deregulation due to the presence of t(11;14) is involved in the early development of plasma cell neoplasms, and that this event alone is not enough for the development of symptomatic myeloma.

Successful treatment of nasal T-cell lymphoma with a combination of local irradiation and high-dose chemotherapy.

Nasal natural killer (NK)/T-cell lymphoma is characterized by an aggressive clinical course and poor prognosis. The term "NK/T-cell" lymphoma includes both the NK-cell type and the T-cell type, which are classified by immunophenotyping and according to T-cell receptor (TCR) rearrangement. In addition, CD56+ T-cell lymphoma is defined as NK-like T-cell lymphoma. This report concerns a 54-year-old woman with nasal T-cell lymphoma. Its phenotype showed pure T-cell type with CD3+, CD56-, and TCR+ accompanied by Epstein-Barr virus infection. Although the lesions were localized in the nasal mucosa and facial skin (stage IE), local irradiation could not achieve complete remission (CR). We then administered 5 courses of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) regimen followed by high-dose chemotherapy with an autologous peripheral blood stem cell transplantation. This therapy resulted in CR. Our results suggest that this lymphoma subtype may be cured by means of intensive treatment soon after diagnosis.

Superior mesenteric venous thrombosis associated with a familial missense mutation (Pro626Leu) in the SHBG-like domain of the protein S molecule.

A 76-year-old Japanese woman was hospitalized for ileus symptoms caused by extensive thrombosis of the superior mesenteric vein. Because laboratory test results suggested type III protein S (PS) deficiency, molecular changes in PS were investigated. A single-base transition, CCG to CTG at codon 626 in exon XV, resulting in the missense mutation Pro626Leu, was identified in an allele of the patient and in her son. Reverse transcriptase polymerase chain reaction analysis indicated the presence of both normal and mutant types of PS messages in platelet-derived messenger RNAs. Our findings thus suggest that Pro626 in SHBG-like domain 7 may be crucial for in vivo antithrombotic activity of the PS molecule.