CD2+ acute promyelocytic leukemia is associated with leukocytosis, variant morphology and poorer prognosis.

The T cell-lineage marker CD2 is sometimes expressed in acute promyelocytic leukemia (APL), and CD2 expression is reported to correlate with some clinical characteristics. However, the significance of CD2 expression in APL has not been fully elucidated. We evaluated CD2 expression in APL treated by the same treatment strategy in a single institute, and whether it had any special characteristics. Among 29 APL, 6 were positive for CD2. Patients with CD2+ APL tended to have a higher leukocyte count than CD2- APL (34.5 +/- 13.1/l vs. 6.8 +/- 2.1/l), morphological characteristics as variant-APL (50 vs. 0%). They also showed poor clinical prognosis. The CR rate of CD2- APL was 87.0% while that of CD2+ APL was 50 %. The mortality was 13.0 and 66.7%, respectively, and the survival rate was significantly lower in CD2+ APL. CD2 expression was proven to be a risk factor associated with death in addition to the morphological characteristics of variant-APL and leukocytosis. These results indicated that CD2 expression might have a significant impact on the prognosis of APL. Whether CD2+ APL should be characterized as a special clinical entity should be discussed in a larger patient population.

Persistent nucleated red blood cells in peripheral blood is a poor prognostic factor in patients undergoing stem cell transplantation.

We compared detection rates and counts of nucleated red blood cell (NRBC) in the peripheral blood of survivors and nonsurvivors (total 44 patients) of stem cell transplantation. The rate of NRBC detection increased to 79.5% after transplantation. After engraftment, the detection rate of NRBC decreased to 17.0% in survivors, but increased to 100% in nonsurvivors. The NRBC count increased after transplantation in both groups. This increase was transient in survivors, but increased after engraftment in nonsurvivors. The mean NRBC count after engraftment was 872 vs. 40.3 for nonsurvivors vs. survivors, respectively. At postengraftment, all patients who were negative for NRBC survived, but 10 of the 15 patients who were positive for NRBC died (66.7%). The survival rates of patients with a NRBC count >200 x 10(6)/l were significantly lower than those of patients whose counts were <100 x 10(6)/l. These data indicated that persistent NRBC in peripheral blood is a poor prognostic factor, and suggested that monitoring NRBC after SCT might provide useful clinical information.

Secondary polycythemia as a paraneoplastic syndrome of testicular seminoma.

A 45-year-old man was referred to our hospital because of polycythemia. A physical examination revealed a large tumor in his scrotum enlarged to the size of 13 x 10 cm. A laboratory examination revealed severe erythrocytosis with a red blood cell count of 6,820 x 10(9)/L, a hemoglobin concentration of 21.2 g/dL, and a hematocrit of 59.8%. The total red cell volume was increased. A right radical orchidectomy was done with minimum bleeding, and he was diagnosed as having pure seminoma. After the operation, polycythemia improved spontaneously. Polycythemia is a rare complication of seminoma and only two cases have been reported previously. The precise mechanism of polycythemia in our patient could not be clearly evaluated, but clinical course did indicate a close relationship between two distinct disorders.

Adhesion molecule expression by bone marrow CD34-positive cells in aplastic anemia before and after immunosuppressive therapy.

Appropriate adhesion between bone marrow stem cells and the marrow microenvironment is necessary for hematopoiesis, since signals that promote maturation or apoptosis are transmitted from stromal cells to stem cells. In aplastic anemia (AA), interferon-gamma produced by stromal cells has more influence on the pathogenesis of marrow failure than interferon-gamma produced by lymphocytes. We evaluated the expression of cell adhesion molecules, such as very late antigen-4 (CD49d), and -5 (CD49e) or c-kit receptor (CD117), by CD34-positive bone marrow cells in patients with AA who achieved hematological complete remission after immunosuppressive therapy. Before treatment, CD34-positive cells showed markedly higher expression of CD49d and CD49e than cells from healthy controls, indicating the strong adhesion of stem cells to the bone marrow stroma. Expression of CD49d and CD49e was significantly decreased, reaching normal levels, after hematological recovery. These findings suggest that changes in adhesion molecule expression by stem cells are important in the pathology of AA.

Immunosuppressive therapy with antithymocyte globulin and cyclosporine for prolonged marrow failure after hemophagocytic syndrome.

We describe a patient with typical hemophagocytic syndrome (HPS) in whom pancytopenia was refractory to steroid pulse therapy. He was successfully treated with immunosuppressive therapy using antithymocyte globulin (ATG) and cyclosporine (CyA), which is known to be effective for aplastic anemia (AA). Activation of histiocytes occurs in HPS as a response to several cytokines produced by activated T lymphocytes, while apoptosis of hematopoietic stem cells in AA is caused by T lymphocyte-derived cytokines. The response of this patient indicated that both diseases may have some similar immune-mediated conditions involving the activation of T lymphocytes and that intensive immunosuppressive therapy with ATG and CyA might be a useful strategy for steroid-resistant HPS.

Primary central nervous system lymphomas express Vh genes with intermediate to high somatic mutations.

Primary central nervous system lymphoma (PCNSL) is a rare disease, especially among non-AIDS patients. Although almost all PCNSLs belong to the diffuse large B-cell lymphoma (DLBL) category, its clinical course differs from that of other types of DLBL. To elucidate the histogenesis of PCNSL, we analyzed the source of the cells from its variable region (VH) sequences using the polymerase chain reaction (PCR) method to amplify the immunoglobulin heavy chain (IgH) gene of DNA extracted from paraffin sections. Fifteen patients with AIDS-unrelated PCNSL of DLBL type, (7 males and 8 females), were evaluated. Only one case showed positive evidence of EBV infection. The prognosis was very poor with a median survival of 9 months. Analysis of the VH sequences revealed that the VH4 family was used in 4 cases and the VH3 family in 2 cases. The homology with previously published germline sequences was random, ranging from 82.7-93.2%, showing intermediate to high somatic mutations. In 3 of 6 cases, the existence of intraclonal diversity was suspected. These findings suggest that PCNSLs are histogenetically derived from antigen selected B cells in the germinal center (GC) environment.

[Flowcytomeric analysis on neutrophil intracellular enzyme activity in patients on hemodialysis and continuous ambulatory peritoneal dialysis].

To elucidate the mechanism of neutrophil dysfunction in patients with maintenance hemodialysis (HD) and continuous ambulatory peritoneal dialysis (CAPD), intracellular enzyme activity such as oxidative burst, elastase, cathepsin, and collagenase, was investigated. Response of enzyme activity to in vitro addition of TNF-alpha, which is known to have a powerful priming effect on neutrophils, was also evaluated. Peripheral blood from 15 HD and 15 CAPD patients was washed and incubated with Cell Probe, an indicator for intracellular enzyme activity. Mean fluorescent intensity of neutrophils, which represents neutrophil enzyme activity, was measured by flowcytometry. In HD group, unstimulated enzyme activity was similar to that of control, but activity after addition of TNF-alpha was significantly lower than the control. In the group of CAPD, enzyme activity without stimulation was not different from that of control, and in TNF-alpha stimulated neutrophils, only elastase activity was lower than control. Many of the enzyme activities after stimulation were lower in HD than in CAPD. Response to in vitro addition of TNF-alpha was diminished in both dialysis groups, but more prominent in HD neutrophils. Duration of dialysis, serum concentration of beta 2-microglobulin (beta 2-MG) and parathyroid hormone (PTH) was significantly related inversely to intracellular enzyme activity in HD patients. To the contrary, in CAPD group, although beta 2-MG and PTH showed similar negative correlation, duration of dialysis was not related to enzyme activity. These results indicate that neutrophils in patients with maintenance dialysis have diminished intracellular oxidative burst, elastase, and cathepsin activity. Especially, impaired response to TNF-alpha closely related to neutrophil dysfunction in dialysis patients.

Small amount of low-residue diet with parenteral nutrition can prevent decreases in intestinal mucosal integrity.

OBJECTIVE: To investigate the suitable combination ratio of low-residue diet (LRD) and parenteral nutrition (PN) for nutritional support of surgical patients. SUMMARY BACKGROUND DATA: Bacterial translocation (BT) is a severe complication of total parenteral nutrition (TPN). However, it is sometimes impossible to supply sufficient amounts of nutrients to surgical patients by the enteral route. The authors reported previously that concomitant use of LRD with PN provided preferable nutritional support for patients undergoing surgery for colorectal cancer. METHODS: Ninety male Donryu rats were used for three experiments. In experiment 1, rats were divided into two groups to receive TPN or total enteral nutrition with LRD. In experiment 2, rats were divided into six groups, receiving variable amounts of LRD. In experiment 3, rats were divided into five groups to receive isocaloric nutritional support with variable proportions of PN and LRD. Intestinal permeability was assessed by monitoring urinary excretion of phenolsulfonphthalein. BT was assessed in tissue cultures of mesenteric lymph nodes and spleen. RESULTS: In experiment 1, increases in intestinal permeability and BT were observed in rats maintained on 7-day TPN, but not in those maintained on total enteral nutrition for up to 14 days. In experiment 2, the changes in body weight of rats were correlated with the dose of LRD. However, the intestinal permeability was increased only in rats receiving LRD at 15 kcal/kg per day. In experiment 3, additive LRD corresponding to 15% of total caloric intake prevented increases in intestinal permeability and BT. CONCLUSION: Combined nutritional therapy consisting of PN and small amounts of LRD can provide better nutritional support than TPN for surgical patients.

Severe aplastic anemia associated with chronic natural killer cell lymphocytosis.

Chronic natural killer (NK) lymphocytosis involves a persistent increase in CD56+ large granular lymphocytes (LGLs) that is sometimes associated with immune-mediated complications, such as anemia and neutropenia. However, aplastic anemia (AA) is a rare complication. Here we describe 2 patients with severe AA who presented with persistent increases in NK cells. Their LGLs were positive for CD56, CD16, and intracellular interferon (IFN)-gamma but negative for CD3, Fas-ligand, and T-cell receptor rearrangement, findings that are compatible with NK cells. Not only the number of NK cells, but NK activity as well, was increased in both patients. The number of NK cells changed according to hematologic recovery and relapse in 1 case. Thus, there seemed to be a close relationship between NK cells and the progression of AA, at least in this instance. Further investigation of the clinical course of similar cases and the characteristics of NK cells is necessary.

Long-term administration of G-CSF for aplastic anaemia is closely related to the early evolution of monosomy 7 MDS in adults.

There is an increasing incidence of the evolution of myelodysplastic syndrome (MDS) from aplastic anaemia (AA) with immunosuppressive treatment. In paediatric patients G-CSF is also reported to increase MDS evolution, but this process is not precisely understood in children or in adults. Therefore risk factors of MDS evolution in adults are evaluated here. Of 72 patients, five developed MDS. In 47 patients without cyclosporine (CyA) or antithymocyte globulin (ATG) therapy, only one developed MDS with trisomy 8, 242 months after diagnosis. But of 25 patients treated with either CyA or ATG, four developed monosomy 7 MDS within 3 years. Of these 25 patients, 18 were treated with G-CSF and the four patients (22.2%) who developed MDS were found in this group. The cumulative dose and the duration of G-CSF administration were significantly elevated in patients who developed MDS when compared with those who did not, 822.3 +/- 185.0 v 205.4 +/- 25.5 microg/kg (P<0.05) and 187.5 +/- 52.5 v 72.0 +/- 24.6 d (P<0.002), respectively. However these two values for CyA did not differ significantly. Statistically, treatment with CyA, G-CSF and combined G-CSF and CyA were significantly related to MDS evolution. The administration of G-CSF for more than a year was the most important factor (P=0.00). These results suggested that a close relationship exists between G-CSF and subsequent monosomy 7 MDS from AA in adults who receive immunosuppressive therapy. Long-term administration of G-CSF should be prohibited in order to prevent MDS evolution.

Combination chemotherapy with G-CSF, M-CSF and EPO: successful treatment for acute myelogenous leukemia without blood transfusion at lower medical costs.

A 55-year-old Jehova's Witness was treated for acute myelogenous leukemia (AML) by intensive chemotherapy with enocitabine, 6-mercaptopurine and daunorubicin. G-CSF, M-CSF and EPO were subsequently administered. Even though no blood transfusion was given for religious reasons, complete remission was achieved without serious infection and hemorrhage. The total cost for induction chemotherapy was less expensive than is the case for elderly AML patients. This case indicates that the administration of cytokines might reduce the incidence of infection and the necessity for blood products, which would result in favorable cost effectiveness for the treatment of elderly patients with AML.

[Primary non-Hodgkin's lymphoma of the uterine cervix complicated by acute renal failure due to ureter obstruction].

An 80-year-old woman was referred to our hospital because of irregular genital bleeding. An abnormal mass was found in the uterine cervix, and diagnosed as non-Hodgkin's lymphoma, diffuse large B cell type. Soon after admission, the patient became anuric and was given a diagnosis of acute renal failure due to obstruction of the ureter. She was immediately placed on dose-reduced CHOP and radiotherapy of 15 Gy. As a result, not only did the malignant lymphoma go into remission, but diminished renal function was alleviated. Because malignant lymphoma of the uterus is extremely rare, it exact biocharacteristics are not well understood. We are unaware of any previous report concerning uterine lymphoma complicated by renal failure.

Mesalazine-associated severe aplastic anemia successfully treated with antithymocyte globulin, cyclosporine and granulocyte colony-stimulating factor.

A 20-year-old male with ulcerative colitis complicated by mesalazine-associated severe aplastic anemia is described. The patient developed aplastic anemia four months after the start of mesalazine therapy. He was treated with antithymocyte globulin, cyclosporine, and granulocyte colony-stimulating factor (G-CSF) and responded well. Hematological complications of mesalazine are rare, but if bone marrow suppression is detected, immediate cessation of the drug and intensive immunosuppressive treatment with G-CSF should be considered.

Prognostic factors of hemophagocytic syndrome in adults: analysis of 34 cases.

Hemophagocytic syndrome (HPS) presents with fever, pancytopenia, liver dysfunction and increase in hemophagocytic histiocytes in various organs. Although there are two major classifications of HPS in adults, malignant and reactive histiocytosis, it is often very difficult to distinguish between these disorders. We analyzed the laboratory data of patients with HPS to evaluate prognostic factors. Of 34 patients, 14 survived, and 20 died. The median age of survivors was 29.6+/-11.5 yr significantly younger than those who died (54.7+/-17.8 yr). Twenty patients had no obvious underlying disease, the other 13 had hematological malignancies or viral infections. Comparison of laboratory data revealed that nonsurvivors had significantly lower Hb and platelet values on admission. During treatment, worsening of anemia and thrombocytopenia, increase of transaminase and biliary enzymes were similarly more prominent. Risk factors associated with death were: age over 30 yr, presence of disseminated intravascular coagulation, increased ferritin and beta2-microglobulin, anemia accompanied by thrombocytopenia and jaundice. Our data suggests that patients with HPS and any of these risk factors should be treated aggressively with sufficient chemotherapy and supportive care.

[Erythropoietin improved anemia in a case of multicentric Castleman's disease].

Severe anemia A 37 year-old male with therapy resistant multicentric Castleman's disease (MCD) anemia was treated by subcutaneous injection of erythropoietin. Although immunoglobulin and CRP concentration increased, anemia obviously improved with hemoglobin levels increasing from 4.8 g/dl to 8.5 g/dl without any side effects. Colony assay revealed that the bone marrow mononuclear cells responded to erythropoietin in a dose dependent manner. The mechanism of anemia of MCD is not clearly understood, and treatment is sometimes very difficult. There is no other previous report concerning erythropoietin as a treatment for anemia in MCD.