Aggressive natural killer-cell leukemia revisited: large granular lymphocyte leukemia of cytotoxic NK cells.

Aggressive natural killer-cell leukemia (ANKL) is a rare form of large granular lymphocyte leukemia, which is characterized by a systemic proliferation of NK cells. The clinical features of 22 ANKL cases were analyzed. Hepatomegaly (64%), splenomegaly (55%) and lymphadenopathy (41%) were also frequently observed. Leukemic cells were identified as CD1-, CD2+, surface CD3-, CD4-, CD5-, CD7+, CD8+/-, CD10-, CD11b+/-, CD13-, CD16+, CD19-, CD20-, CD25-, CD33(-), CD34-, CD38+, CD56+, CD122+, HLA-DR+ and TCR-. Two of the 16 cases examined for CD57 were positive and three of the seven cases examined for cytoplasmic CD3. Epstein-Barr virus was detected in the tumor cells of 11 of the 13 cases examined. No common cytogenetic abnormalities were identified and 6q anomaly was detected in only one. Three of 13 patients treated with chemotherapy containing anthracycline/anthraquinone attained complete remission, in contrast to none of the eight who were treated with regimens without anthracycline. Although the overall prognosis was poor with a median survival of 58 days, those who attained remission showed better prognosis (P=0.005). These findings suggest that ANKL is an entity of mature cytotoxic NK-cell neoplasms with distinct phenotype and disease presentations. Intensive treatment for ANKL may result in a better prognosis.

In vitro expansion of CD34+/CD41+ cells from human peripheral blood CD34+/CD41- cells: role of cytokines for in vitro proliferation and differentiation of megakaryocytic progenitors.

The aim of this study is to clarify the transitional change of the proliferation and differentiation of human peripheral blood CD34+ cells to megakaryocytic lineage, focusing on its clinical application. We developed a rapid system to purify human peripheral blood CD34+ cells from healthy volunteers, which produced CD34+ cells with a 90% purity. The purified CD34+ cells predominantly consisted of CD41- cells, and the rate of coexpression of CD41 was 0.6% +/- 0.5%. When the purified cells were cultured in liquid phase for 10 days in the presence of recombinant human stem cell factor (rSCF: a ligand for c-kit), interleukin-3 (rIL-3), and thrombopoietin (rTPO: a ligand for Mpl), the number of CD34+/CD41+ cells increased to 19% +/- 7% of total expanded cells on day 4 (4 days of liquid culture) and then gradually decreased to 2.2% +/- 0.6% on day 10. The absolute number of CD34+/CD41+ cells increased and reached a plateau on day 6, and 1.7 +/- 0.6 x 10(5) CD34+/CD41+ cells were produced by 1 x 10(5) CD34+/CD41- day 0 cells. The CD34-/CD41+ cells appeared on day 6, continuously increased in number until day 10, and constituted the main population of expanded cells on day 10, with a value of 38% +/- 18%. On day 10, 19.5 +/- 10.6 x 10(5) of CD34-/CD41+ cells were produced by 1 x 10(5) CD34+/CD41- day 0 cells. The deletion of rTPO from this cytokine combination decreased the number of CD34+/CD41+ and CD34-/CD41+ cells, after days 6 and 8, respectively. Day 0 cells required rIL-3 for promoting colonies containing megakaryocytes, whereas rTPO alone promoted almost no megakaryocytic colonies from day 0 cells. Thus, a combination of IL-3 and SCF expands CD34+/CD41+ cells from CD34+/CD41- cells, and TPO mainly acts to increase CD34-/CD41+ cells. This study suggests that if the expansion of CD34+/CD41+ is performed in vitro, the 6 days' culture of peripheral blood CD34+/CD41- cells with a combination of IL-3 and SCF with TPO provides the most rapid and stable products of CD34+/CD41+ cells for the rapid recovery of platelets in patients with peripheral blood stem cell transplantation.

Effective high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation in a patient with the aggressive form of cytophagic histiocytic panniculitis.

A 20-year-old Japanese man developed generalized, subcutaneous, painless nodules, fever, abnormal liver function, serosal effusions, hepatosplenomegaly, lymphadenopathy and anemia. Skin biopsies revealed lobular panniculitis with a morphologically benign histiocytic infiltration and prominent phagocytosis. Atypical T lymphocytes were also present in the skin and liver. The diagnosis given was aggressive cytophagic histiocytic panniculitis (CHP) or aggressive subcutaneous panniculitic T cell lymphoma (SPTCL). He received cyclophosphamide, doxorubicin, and vincristine on day 1, prednisolone on days 1-5, and etoposide on days 1, 3 and 5 (CHOP-E), with the support of granulocyte colony-stimulating factor. This regimen was repeated every 2 weeks and complete clinical remission (CCR) was attained after three cycles of CHOP-E. As the clinical course of aggressive CHP is recurrent and often fatal, he was given high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation (APBSCT), after five cycles of CHOP-E. He has remained in CCR for 12 months after APBSCT. High-dose chemotherapy followed by APBSCT is considered to be one of the most beneficial therapies for patients with aggressive CHP and aggressive phase SPTCL.

Leukemia cutis in an elderly patient treated with low dose cytosine arabinoside and etoposide.

A 78-year-old man presented with a generalized erythematous papular rash. Such skin lesions were not painful, tender or pruritic, and spread over the truncus. He was admitted to our hospital for examination of the skin lesions. Laboratory tests indicated microcytic hypochromatic anemia and thrombocytopenia, although gave a normal leukocyte count with normal differentiation. His bone marrow showed hypercellularity, with 43% peroxidase positive blasts that displayed positive immunophenotypes for CD4, CD13, CD33, CD41a, KP-1 (CD68), and HLA-DR. His skin specimen revealed infiltration in the dermis and subcutaneous fat tissue by leukemic cells that were positive for the leukocyte common antigen (LCA, CD45), CD15, CD33, CD68, and HLA-DR. He was diagnosed as having M4 subtype of acute myelogeneous leukemia (AML) with leukemia cutis. After three courses of low dose cytosine arabinoside (LDAC), combined with low dose etoposide, he achieved complete remission (CR). He remained well, with no evidence of relapse nine months later. LDAC should be considered as initial treatment for such cases of leukemia cutis with poor general condition.

Subclinical alterations in coagulation and fibrinolysis in patients undergoing autologous peripheral blood stem cell transplantation.

We monitored 30 laboratory hemostatic parameters in an attempt to better comprehend alterations in coagulation and fibrinolysis in 10 patients with hematological malignancies subjected to autologous peripheral blood stem cell transplantation (APBSCT). These parameters were assessed before and just after high-dose conditioning chemotherapy, on days 1, 7, 14 and 28. Although, clinical manifestations associated with fibrino-coagulation disorders never occurred, including veno-occlusive disease, a statistically significant increase was seen in 7 of 30 parameters, compared to values seen before conditioning chemotherapy. These were subdivided into early and late phase parameters. The early phase parameters, which increased during the first day after the conditioning chemotherapy was given, then returned to baseline values, included protein C, plasma tissue factor and tissue-plasminogen activator. The late phase parameters, which increased over baseline values during days 7 to 28, included free-protein S, fibrinogen, plasmin-alpha2-plasmin inhibitor complex and soluble-thrombomodulin. The increase of early phase parameters, as produced by the liver and by endothelial cells, may reflect tissue damage by conditioning chemotherapy. Late phase parameters increased in parallel with C-reactive protein, which suggests a correlation with the degree of inflammation, such as the presence of infective disease during neutropenia. These subclinical alterations in coagulation and fibrinolysis which take on a biphasic pattern during the course of APBSCT should be kept in mind by the attending physicians during therapy.

Coronary artery bypass grafting for spontaneous coronary artery dissection: a case report and a review of the literature.

A 37 year-old woman underwent coronary angiography because of chest pain at rest. Selective coronary angiography demonstrated dissection and stenosis with a filling delay from the left main trunk to the left anterior descending coronary artery. The patient was successfully managed with urgent coronary artery bypass grafting. Spontaneous coronary artery dissection is relatively rare and threatens both elderly and young patients with acute coronary disturbances. Patients can be divided etiologically into three groups. The first was comprised of those in the postpartum period. The second was those with atherosclerotic coronary artery disease, and the third was those associated with coronary vasospasm. Dissections are frequently fatal and most of the known cases have been diagnosed at autopsy. Only a few cases have been documented by coronary angiography, and operative cases of spontaneous coronary artery dissection have rarely been reported.

Left ventricular free wall rupture following mitral valve replacement.

During a 10-year period, 110 patients underwent mitral valve replacement (MVR). We experienced three left ventricular ruptures among these patients. Two had a type I immediate rupture, and one had a type III delayed rupture. Two patients (type I, III) survived after repair of the rupture. It was possible to control bleeding by manual compression with oxidized cellulose, collagen mat and fibrin glue with or without external mattress sutures. Following the repair, an intra-aortic balloon pump and sedative agents were used in both patients. In the other patient with a type I early rupture, control of bleeding was attempted by external direct suture using Teflon felt. The bleeding was controlled by this repair and the use of a left ventricular assist device, but the patient died of a brain infarction 5 days after the operation. The manual compression technique using oxidized cellulose, collagen mat and fibrin glue may be useful for minor lacerations, and for reinforcing repairs. The intra-aortic balloon pump and continuous sedation are useful for unloading the ventricle and reducing the tension on repairs.

A case of primary carcinoma of the epididymis.

We present a rare case of primary carcinoma of the left epididymis in a 32-year-old man. Pathological diagnosis was anaplastic carcinoma of epididymis. The patient is alive and free of metastases 2 years after orchidectomy. Clinical and pathological aspects of epididymal carcinomas are discussed with reference to previously reported cases.

[Acute lymphoblastic leukemia with breast infiltration during the second trimester of pregnancy and followed by successful delivery].

A 27-year-old pregnant woman was admitted to a local hospital because of headache, nausea, and general fatigue. Her blood examination showed leukocytosis, anemia, and thrombocytopenia. She was referred to our hospital in March 1998. Her bone marrow was normocellular with an excess of blasts (89.1%, peroxidase stain(-), PAS stain(-)) that displayed a positive immunophenotype for CD2, CD4, CD5, CD7, CD34, CD38, and CD71. Chromosome analysis revealed complex abnormal karyotypes. The patient was given a diagnosis of acute lymphoblastic leukemia associated with central nervous system and breast infiltration, and received induction chemotherapy during the second trimester of her pregnancy. After she achieved complete remission, a cesarean section was performed, and a healthy baby delivered. Our experience in this case demonstrated that combination chemotherapy during the second trimester of pregnancy is feasible.

[CD30-positive anaplastic large cell lymphoma of bone treated with autologous peripheral blood stem cell transplantation].

A 30-year-old man was admitted to our hospital with the chief complaints of fever and pain in the right shoulder, axilla, and inguinocrural region. Computed tomography, magnetic resonance imaging, 67Ga-scintigraphy, and bone-scintigraphy revealed osteolytic lesions in the ribs and right ilium. Biopsy specimens from lesions in the right ilium confirmed the diagnosis of CD 30-positive anaplastic large cell lymphoma. The patient was treated with 6 courses of CHOP therapy followed by high-dose chemotherapy and autologous peripheral blood stem cell transplantation. He achieved and remained in remission with no evidence of relapse 14 months later.

[Perforation of small intestinal during hematologic recovery in an elderly man after induction therapy for acute lymphoblastic leukemia L3].

A 67-year-old man with a 7-month history of dilated cardiomyopathy was admitted to our hospital because of general fatigue, shortness of breath, and anemia on laboratory examination. Increased blasts were observed in the bone marrow. The blasts were characterized by large cells with abundant, intensely basophilic, vacuolated cytoplasm, round nuclei, and prominent nucleoli. Chromosome analysis revealed a nonrandom t(8;22)(q24;q11) chromosomal abnormality, and surface-marker analysis disclosed a positive immunophenotype for CD10, CD19, CD20, CD38, HLA-DR, FMC7, and IgM-lambda. These findings yielded a diagnosis of L3 acute lymphoblastic leukemia. The patient was treated with chemotherapeutic agents. On the 39th hospital day, during hematologic recovery after induction therapy, abdominal pain developed. Abdominal X-ray films disclosed ileus with dilatation of the small bowel and Kerckring's folds. Conservative treatment was begun but the patient died. At autopsy, intestinal perforations were observed at a site 55 cm proximal to the ileocecal junction. A specimen of perforated tissue revealed a diffuse infiltration of leukemic cells through the small bowel wall. However, bone marrow specimens showed no signs of aggravation of leukemia.

[Chronic cold agglutinin disease accompanied with an increase of CD20+/CD5+ cells; a case report].

A 61-year-old male complained of acrocyanosis and dark urine when exposing to cold temperatures. This had continued for several years. His physical examinations showed neither lymphadenopathy nor hepatosplenomegaly. Laboratory findings were as follows; RBC 305 x 10(4)/microliters, Hb 10.3 g/dl, reticulocytes 4.32%, platelets 27.3 x 10(4)/microliters, WBC 7,400/microliters with 50% lymphocytes, and a high cold agglutinin titer (2,048-fold) with anti-I specificity. Bone marrow smear preparations showed erythroid hyperplasia and increase of lymphocytes (52%). Immunophenotypic analysis showed an increase of CD20+/B-lymphocytes in peripheral blood (32.6%) and in bone marrow, and 94% of these cells co-expressed CD5. Most B-lymphocytes expressed surface IgM-lambda, suggesting a monoclonal proliferation of B-lymphocytes. At this point we diagnosed cold agglutinin disease (CAD) because there was no evidence of lymphoma, and the absolute number of peripheral blood lymphocytes was lower than the criteria of chronic lymphocytic leukemia (CLL) proposed by the International Workshop (1989). However, there still remains the possibility of the transitional form between "idiopathic" CAD and B-CLL or lymphoma.

[A study on antiprothrombin antibodies in antiphospholipid syndrome].

In this study we investigated the frequency and the type of manifestations of antiprothrombin antibodies (aFII) in patients with antiphospholipid syndrome (APS). In 16 (84.2%) of 19 patients with lupus anticoagulant (LA) and either anticardiolipin antibodies or antiphosphatidylserine antibodies, two types of abnormal patterns were shown on a crossed immuno-electrophoresis technique using anti-human prothrombin murine IgG. The slow-moving peak of prothrombin was detected in 8 patients, while a peak in the other patients had the slow-moving shoulder. These slow-moving materials might represent prothrombin-aFII complexes. In 13 patients who were studied on Western blots, IgGs of 11 patients (84. 6%) bound to human purified prothrombin, and the IgGs of 7 (53.8%) of these patients also bound to human purified alpha-thrombin. Our results indicate that aFII detected in patients with APS may explain part of the mechanism of LA.

[Gamma-heavy chain disease associated with MALT lymphoma of the duodenum].

We report a case of a 63-year-old woman with gamma heavy chain disease (HCD) associated with mucosa-associated lymphoid tissue (MALT) lymphoma of the duodenum. She was suffering from drug-resistant tonsillitis with high fever. Examination on admission showed leukocytopenia and thrombocytopenia. Bone marrow aspirate revealed granulocytosis and a hypocellular marrow with no increase in plasma cells or atypical lymphocytes. Serum electrophoresis disclosed, in addition to hypogamma-globulinemia, an abnormal band due to the presence of gamma HCD protein. This abnormal protein was a molecular weight of approximately 40 kd as determined by Western blots technique, and belonged to the IgG1 subclass as determined by ELISA with monoclonal antibodies against IgG. An endoscopic examination of the patient's duodenum found a small tumorous lesion, which was confirmed pathologically to be MALT lymphoma. HCD is known to be associated with lymphoproliferative diseases. In this case, gamma HCD had developed as a secondary complication of MALT lymphoma. gamma HCD associated with MALT lymphoma of the duodenum is rare in the literature.

[A case with AML (M4EO) accompanied by recurrent reactive histiocytosis which showed spontaneous remission].

A 30-year-old female was admitted to our hospital complaining of high fever and fatigue. Laboratory findings showed as follows; WBC 41,500/microliter (40% of blasts), Hb 8.5g/dl, platelets 4.4 x 10(4)/microliter. Cytochemical staining of blasts was positive for peroxidase and non-specific esterase with NaF inhibition. Chromosome analysis showed 46, XX, inv (16p+,q-). AML with eosinophilia was diagnosed. During myelosuppression after remission induction therapy, she developed high fever, and did not respond to transfusions. Marrow smears showed the presence of phagocytic histiocytes consisting of 18% total nuclear cells. A diagnosis of reactive histiocytosis (RH) was made. She recovered spontaneously, but suffered two episode of recurrence during subsequent chemotherapy. Reactive histiocytosis is characterized by proliferation of histiocytes which phagocyte blood cells in immunodeficient cases, e.g. a myelosuppressive state after chemotherapy. RH causes high fever and prolonged myelosuppression. It is considered to be one of the poor prognostic factors in AML during chemotherapy, and spontaneous recovery is rare. In this report, the effect of hydrocortisone on histiocytes derived from patient marrow was also investigated in vitro.

[Effect of ulinastatin on microcirculation under excessive hemorrhage and fluid therapy].

Microcirculation during excessive hemorrhage and fluid therapy under anesthesia with or without associated treatment by ulinastatin (urinary trypsin inhibitor) was studied by using the rabbit ear chamber. Sixteen rabbits were divided into 2 groups; 8 rabbits without ulinastatin treatment (C group) and rabbits treated with ulinastatin (U group). After blood withdrawal, hemodynamic disturbance appeared in both groups. But the catecholamine concentration showed no increase in either groups. Significant differences between the groups were found only in urinary output and microcirculation. These were well maintained during hemorrhage in the ulinastatin treated group. It is concluded that ulinastatin is effective in maintaining microcirculation during excessive hemorrhage and fluid therapy.

[Mediastinitis treated by an omental transfer following CABG using the right gastroepiploic arterial graft].

We treated four cases with mediastinitis after coronary artery bypass grafting using the right gastroepiploic artery. These four patients were treated with the pedicled omentum. Omental transfer was successful in three cases. After the harvest of the right gastroepiploic arterial graft, the residual omentum was viable. The residual omentum was applicable for the treatment of mediastinitis.

[Two cases of classical polyarteritis nodosa associated with a low titre of MPO-ANCA].

We studied two autopsy cases, each with a low titre of myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA) associated with systemic vasculitis. It was difficult to distinguish these cases from classic polyarteritis nodosa. The patients had suffered from continuous fever, malaise, and weight loss: however, their renal insufficiency was clinically mild over the course of their disease. The patients were diagnosed initially as having MPO-ANCA-associated vasculitis and were treated with prednisolone. Their clinical status improved, but unfortunately, they died of an infectious disease. Autopsies revealed systemic vasculitis in small arteries with no signs of necrotizing and crescentic glomerulonephritis. Our pathologist subsequently diagnosed both cases as classic polyarteritis nodosa. Systemic vasculitis associated with MPO-ANCA is usually considered to be a microscopic polyarteritis. However, classic polyarteritis nodosa should always be considered as a possibility for those patients with mild renal insufficiency and a low titre of MPO-ANCA.

Thrombotic thrombocytopenic purpura in a patient with rapidly progressive scleroderma.

Abstract A 57-year-old man presented with palpitations, shortage of breath on exertion, and rapidly progressive scleroderma. On admission, a computed tomographic scan of his lung showed active interstitial pneumonia. We treated him with d-penicillamine and intravenous pulse methylprednisolone. After this treatment, severe abdominal pain, microangiopathic hemolytic anemia, thrombocytopenia, and progressive renal involvement appeared. We diagnosed him as having systemic sclerosis (SSc) complicated by thrombotic thrombocytopenic purpura. At postmortem, thromboses of capillaries, arterioles, and small arteries were found in several organs. As well as the differential diagnosis of SSc with thrombocytopenia, microangiopathic hemolytic anemia (MAHA), and renal involvement, we diagnosed scleroderma renal crisis (SRC), normotensive renal crisis (NRC), and SSc complicated by TTP. Typical SRC and NRC were excluded because his blood pressure was in the normal range without elevation of plasma renin activity or azotemia over his clinical course. Although distinguishing TTP from renal crisis is difficult, an evaluation of ultra-large multimers of von Willebrand factor (UL-vWF) concentration may be helpful in these situations.