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Gamma/delta T cell lymphoma is very rare, and usually occurs as an extranodal tumor. We describe the case of a 16-year-old Japanese man with an unusual nodal gamma/delta T cell lymphoma with generalized lymphadenopathy and bone marrow involvement. No tumor involvement was observed in the liver, spleen, or nasal cavity. Examination for surface antigens on lymphoma cells revealed a unique phenotype, positive for CD3 and T cell receptor (TCR) gamma/delta, but negative for CD2. Genotypic analysis revealed the tumor to be of monoclonal origin and characterized by TCR gamma-chain gene rearrangement, but there was no rearrangement of the TCR beta-chain gene. Our patient’s tumor responded to combination chemotherapy and subsequent allogeneic bone marrow transplantation from an HLA-matched unrelated donor. He has remained well and free of disease for 35 months.

A small number of reports have described cases of heparin-induced thrombocytopenia complicating hematological disorders with impaired platelet production. We describe the case of a 66-year-old woman with acute myeloid leukemia who exhibited unexplained refractoriness to platelet transfusion, while receiving heparin flushes, and was found to have anti-platelet factor 4 (PF4)/heparin antibodies with high optical density (OD) values (>2 units) detected by an enzyme-linked immunosorbent assay. After cessation of heparin flushes, her refractoriness to platelet transfusion resolved. We retrospectively confirmed that the OD values for anti-PF4/heparin antibodies declined gradually; refractoriness to platelet transfusion resolved when the OD values fell below 1.0 units. Given the absence of any other evident explanation for this phenomenon, and the correlation between the OD values for anti-PF4/heparin antibodies and the efficacy of platelet transfusions, we conclude that the patient's refractoriness to platelet transfusion was most likely caused by anti-PF4/heparin antibodies that had platelet-activating properties.

Acute graft-versus-host disease (aGVHD) is a serious complication of allogeneic peripheral blood stem cell transplantation (PBSCT). Patients with severe aGVHD not responding to treatment with steroids have a poor prognosis. We treated three patients with severe aGVHD refractory to steroids with infliximab. Patients (MDS 1, NHL 1, ALL 1) developed grade II-IV GVHD at a median of 13 days (range 9-17) after non-myeloablative PBSCT (HLA mismatched). All patients had received treatment with high-dose steroids for a median of 7 days (range 7-10) in addition to mycophenolate mofetil (MMF) (one). Infliximab was given in 3 weekly doses of 5 mg/kg. In one of three patients a partial resolution of diarrhea and minor improvement of skin were observed. One patient died with refractory GVHD. Infliximab is apparently an effective drug for the treatment of aGVHD, but can be more effective at doses of 5 mg/kg or higher and/or by administering it repeatedly every week.

To evaluate the results of high-dose chemotherapy (HDT) and autologous hematopoietic stem cell transplantation (ASCT) in patients with diffuse B-cell aggressive non-Hodgkin's lymphoma(NHL). Between 1991 and 2004, 25 patients who did not achieve complete remission and 26 in complete remission from conventional chemotherapy received HDC-ASCT. Of 25 patients with refractory NHL,14 were chemotherapy-sensitive before HDT-ASCT and 11 were chemotherapy-resistant. CR was achieved after HDC-ASCT in 50% of 14 chemotherapy sensitive patients and in none of 11 chemotherapy-resistant patients. The 5-year probability of event-free survival for chemotherapy-sensitive and chemotherapy-resistant patients was 51.3% and 20.8%, respectively (p0.05, log-rank test). Moreover, the 5-year probability of event-free survival for patients in the low-risk group with International Prognostic Index (IPI) and in the high-risk group with IPI was 75.0% and 16.3%, respectively (p0.05, log-rank test). HDT-ASCT should be considered for patients with refractory aggressive NHL who are chemotherapy-sensitive rather than chemotherapy-resistant. Twenty-six patients in complete remission received consolidation therapy with HDT-ASCT. The 5-year probability of disease-free survival for patients in the low-risk group and in the high-risk group was 68.8% and 60.0%,respectively (p = 0.9 6). HDT-ASCT should be considered for patients at high risk who achieve complete remission after induction treatment. In future, HDT-ASCT combined with rituximab as induction therapy or as consolidation therapy is needed for patients with aggressive NHL in the high-risk group.

We have recently demonstrated that granulocyte-colony stimulating factor (G-CSF) delays human neutrophil apoptosis via up-regulation of cellular inhibitor of apoptosis 2 (cIAP2), which is dependent on activation of Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3). Here, we show that type I and type II interferons (IFNs), which bind to the distinct receptors, exert the antiapoptotic effect on human neutrophils through the similar mechanism. IFN-α (type I IFN) and IFN-γ (type II IFN), like G-CSF, delayed human neutrophil apoptosis through the protein synthesis-dependent mechanism. Stimulation of neutrophils with IFN-α or IFN-γ resulted in tyrosine phosphorylation of STAT1 and STAT3 but not phosphorylation of STAT5, Akt, extracellular signal-regulated kinase, and p38 mitogen-activated protein kinase. IFN-α and IFN-γ induced the expression of transcripts of cIAP2 and suppressor of cytokine signaling 1 and 3, but not cIAP1, Mcl-1, and A1. IFN-α- and IFN-γ-induced up-regulation of cIAP2 mRNA and protein, phosphorylation of STAT3, and antiapoptotic effect were inhibited significantly by pretreatment of cells with AG490, a specific inhibitor of JAK2. These findings suggest that cIAP2 expression is up-regulated by IFN-α and IFN-γ through, at least in part, activation of the JAK2-STAT3 pathway, and increased expression of the cIAP2 protein may contribute to an IFN-α- and IFN-γ-mediated antiapoptotic effect on human neutrophils.

We report an 18-year-old woman with acute myelomonocytic leukemia, who developed massive lower intestinal bleeding following induction chemotherapy. Colonoscopy revealed multiple circular ulcers but no infectious colitis or infiltration of leukemia. The biopsy specimen showed mild non-specific inflammatory changes and scattered apoptosis bodies. She took nonsteroidal anti-inflammatory drugs (NASIDs) for pyrexia and pharyngalgia for a long time. We concluded these were signs of ulcers induced by NSAIDs. Despite discontinuance of NSAIDs, melena did not improve. Transarterial embolization therapy using microcoils was tried with unsatisfactory results. Finally, colonoscopic clipping therapy and continuous arterial injection of vasopressin were performed. Subsequently, her condition improved markedly. In conclusion, NSAID-induced intestinal bleeding is not limited to the upper GI tract but may occur in the lower GI tract after long-term NSAID use. The possibility of lower GI tract complications from NSAID should be kept in mind.

A 56-year-old woman noticed soreness and swelling in the right nipple. Two weeks later, she noticed a mass in the outer lower region of the right areolar area, which was excised and the pathology of which was consistent with diffuse large B cell lymphoma (DLBCL). She was admitted when the right nipple mass was noted to be increasing, and was diagnosed as having stage I lymphoma. Her nipple mass was excised, and the pathology was consistent with DLBCL. CHOP therapy was administered three times and she was judged as having complete remission. Malignant lymphoma accounts for 0.15-0.17% of primary breast malignancies. Though the nipple and areolar area seem to be a rare primary site, this should be recognized as a sentinel zone for malignant lymphoma.

Visceral disseminated varicella-zoster virus (VZV) infection occurred with acute graft-versus-host disease in a 33-year-old Japanese male with non-Hodgkin lymphoma who had undergone allogeneic stem cell transplantation from an HLA-identical sibling after reduced intensity conditioning chemotherapy. Although ganciclovir and acyclovir treatment was effective temporarily, the number of VZV-DNA copies in the blood remained at a high level, and the hepatitis was prolonged. The patient was treated with foscarnet, which led to improvement of the VZV viremia and the hepatic dysfunction. Foscarnet therapy should be considered for acyclovir-resistant VZV infection in the setting of allogeneic hematopoietic stem cell transplantation.

We examined the effects of thrombopoietin (TPO) in combination with stem cell factor (SCF), interleukin-3 (IL-3), and granulocyte colony-stimulating factor (G-CSF) on the proliferation and differentiation of human neutrophils. Purified CD34(+) hematopoietic progenitor cells were cultivated with SCF, IL-3, and G-CSF for 7 days (early phase), and thereafter nonadherent cells were further cultivated for 9 days with G-CSF alone (late phase). A large number of highly selected neutrophils (>95%) was obtained on day 16. We compared the expansion capacity in the presence or absence of TPO in each culture phase. The significantly larger number of neutrophils was obtained in the presence of TPO in the early culture phase. The number of expanded cells plateaued at day 16. Ultimately, a 550-fold increase in the number of neutrophils was achieved. These neutrophils gained the ability to respond effectively with chemotaxis and superoxide release, and were appropriately primed by G-CSF, granulocyte-macrophage colony-stimulating factor, tumor necrosis factor-alpha, and IL-1beta for enhanced release of O(2)(-). The responsiveness of these cells was identical to that of peripheral blood neutrophils. However, TPO did not accelerate the maturation of neutrophils supported by G-CSF in the late phase of culture. Furthermore, priming effects and triggering effects of TPO on the production of superoxide metabolites from peripheral blood neutrophils were not observed. These results suggest that TPO regulates the proliferation and differentiation of neutrophils in the early stages, but not the late stages, of differentiation.

Spontaneous neutrophil apoptosis during culture was delayed by granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF), or dibutyryl-cyclic adenosine monophosphate (cAMP), whereas apoptosis was accelerated by cycloheximide or actinomycin D. G-CSF-mediated antiapoptosis was completely abolished by cycloheximide or actinomycin D, whereas GM-CSF-mediated antiapoptosis was not completely abolished by these inhibitors. Antiapoptosis induced by dibutyryl-cAMP was highly resistant to cycloheximide, and that induced by benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone was unaffected by cycloheximide. G-CSF- and GM-CSF-mediated antiapoptosis and phosphorylation of signal transducer and activator of transcription 3 (STAT3) and STAT5 were inhibited by AG490, an inhibitor of Janus kinase. The level of Mcl-1 protein was not associated with neutrophil apoptosis. The results suggest that (a) neutrophil survival in the resting state is primarily regulated by the constitutive synthesis of antiapoptotic proteins; (b) the prevention of spontaneous apoptosis is mediated through the protein synthesis-dependent and/or protein synthesis-independent mechanisms according to the stimuli used; and (c) the Janus kinase-STAT pathway is involved in G-CSF- and GM-CSF-mediated antiapoptosis.

Human neutrophils were found to express members of the inhibitor of apoptosis (IAP) family, namely cellular IAP1 (cIAP1), cIAP2, and X-linked IAP. Among these members, cIAP2 expression was selectively up-regulated by stimulation with granulocyte colony-stimulating factor (G-CSF), but not with granulocyte-macrophage CSF. The increased expression of cIAP2 mRNA was detected as early as 30 minutes after in vitro stimulation with G-CSF, and the elevated level of cIAP2 protein was detected at 1 hour. The elevated level of cIAP2 protein was also detected in peripheral blood neutrophils obtained from healthy donors receiving G-CSF administration. G-CSF–induced up-regulation of cIAP2 mRNA and protein, phosphorylation of signal transducer and activator of transcription 3 (STAT3), and the antiapoptotic effects were inhibited by pretreatment of cells with AG490, a specific inhibitor of Janus kinase 2 (JAK2). Mature neutrophils from a patient with chronic neutrophilic leukemia exhibited remarkable overexpression of cIAP2 mRNA and prolongation of survival, whereas cIAP2 mRNA expression and survival in mature neutrophils from patients with chronic myelogenous leukemia were essentially similar to those in normal neutrophils. These findings suggest that cIAP2 expression is up-regulated by G-CSF through activation of the JAK2-STAT3 pathway, and increased expression of cIAP2 protein may contribute to G-CSF–mediated antiapoptosis. In addition, overexpression of cIAP2 may be partly responsible for sustained neutrophilia at least in some cases of chronic neutrophilic leukemia.

Extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) are major signaling molecules activated in human neutrophils stimulated by cytokines. Both molecules were cleaved at the N-terminal portion in neutrophils undergoing apoptosis induced by in vitro culture alone or treatment with TNF and/or cycloheximide. The cleavage of both molecules was inhibited by G-CSF and benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone, a caspase inhibitor, both of which can inhibit neutrophil apoptosis. In a cell-free system, ERK and p38 MAPK were not cleaved by recombinant caspase-3 or caspase-8 while gelsolin was cleaved by caspase-3 under the same condition. The cleavage of both molecules appears to be specific to mature neutrophils, since it was not detected in immature cells (HL-60 and Jurkat) undergoing apoptosis, indicating that proteases responsible for the cleavage of both molecules may develop during differentiation into mature neutrophils. Concomitant with the cleavage of ERK and p38 MAPK, GM-CSF- and TNF-induced superoxide release, adherence, and phosphorylation of ERK and p38 MAPK were decreased in neutrophils undergoing apoptosis. In addition, GM-CSF- and TNF-induced superoxide release and adherence were inhibited by PD98059 MAPK/ERK kinase inhibitor) as well as SB203580 (p38 MAPK inhibitor), suggesting possible involvement of ERK and p38 MAPK in superoxide release and adherence induced by these cytokines. These findings indicate that ERK and p38 MAPK are cleaved and degraded in neutrophils undergoing apoptosis in a caspase-dependent manner and the cleavage of both molecules may be partly responsible for decreased functional responsiveness to inflammatory cytokines.

We report a 26-year-old male patient with acute myelocytic leukemia and hepatosplenic candidiasis during his clinical course. His hepatosplenic candidiasis was refractoty to itraconazole and fluconazol. He developed serious side-effect such as renal dysfunction, when conventional amphotericin B was given. Then he was treated with liposomal amphotericin B (Abelcet). This therapy was safe and effective for him. He was able to be treated with 3075 mg of a liposomal amphotericin B. This was ten times as much as the dose of conventional amphotericin B which was given earlier until amphotericin B was stopped because of renal dysfunction. Liposomal amphotericin B seems to be a safe and effective therapy for systemic fungal infectin and should be considered more in Japan.