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Using a registration sheet of a prospective registration system for aplastic anemia (AA)/myelodysplastic syndromes (MDS), by the National Research Group on Idiopathic Bone Marrow Failure Syndromes, Japan, we carried out a survey on examinations for diagnosis of bone marrow failure. Bone marrow trephine biopsy was performed in 66 of 105 cases (63%) [Original diagnosis: AA 51 cases (80%), MDS 12 (32%), undiagnosable 3 (75%)]. Bone marrow aspiration was performed in all cases, and aspiration was performed at least twice in 36 cases (34%). The first-line anatomic site for bone marrow aspiration was the posterior iliac crest (62%). Cytogenetic examination was performed in 93%. The concordance rate between the original and the central review diagnosis was 93% among the studied cases: AA, Idiopathic cytopenia of undetermined significance (ICUS) and MDS in total. Flow cytometry analysis to detect paroxysmal nocturnal hemoglobinuria (PNH)-type blood cells was performed in 32%.

The research committee for idiopathic hematopoietic disorders, which has been supported by the government over the past 35 years, has recently worked out a series of reference guide for the management of diseases under investigation to provide aids for better understanding of pathophysiology of diseases and appropriate clinical decision making. Such attempts covered aplastic anemia, Fanconi anemia, pure red cell aplasia, autoimmune hemolytic anemia, paroxysmal nocturnal hemoglobinuria, myelodysplastic syndromes and primary myelofibrosis, and included diagnostic criteria and severity classification as well as clinical pictures derived from nationwide survey studies. Therapeutic measures were evaluated according to the concepts of evidence-based medicine, when applicable. This report presents an overview of these guides and summarizes key issues in each disease entity.

The type of leukemia was defined as HLA-DR(-) non-M3-AML, when HLA antigens were detected by flow cytometry at an incidence of < 20% of the blast population excluding M3-AML. Out of 109 patients with de novo acute myeloid leukemia, 8 patients had HLA-DR(-) non-AML-M3. According to the French-American-British criteria, 7 patients could be subdivided into 3 patients with M1, 4 patients with M2 and 1 patient with M4. The morphological features of bone marrow aspiration demonstrated no dysplasia and peroxidase stain positivity was noted in over 86% of the blast cells in all patients, the blast cells with fine granularity in 7 patients. The cytogenetic analysis revealed a normal karyotype. There was no expression marker of the blast antigens except CD13, CD14, CD33, CD34 and CD56. All of 7 patients who underwent induction therapy attained complete remission. Overall survival and disease-free survival showed no significant differences between the HLA-DR(-) non- M3-AML group and the HLA-DR(+) AML group.

We examined the clinical evaluation of biapenem (BIPM) for febrile neutropenia in patients with hematological disorders. BIPM was administrated by drip infusion when fever developed over 37.5 degrees C with a neutrophil counts lower than 1000/microl. The underlying diseases were acute myelogenous leukemia in 16 cases, acute lymphocytic leukemia in 1, malignant lymphoma in 14, myelodysplastic syndrome in 1, aplastic anemia in 1. Microbiologically documented infections were found in 3 cases (9.1%) before treatment. Clinical effect was excellent in 9 cases, good in 11, fair in 6, poor in 7. Factors associated with efficacy rate were concomitant use of granulocytecolony stimulating factor, duration of neutropenia and neutrophil counts at day 3 of day after start of the therapy. No serious adverse events were observed in all cases, although one case developed exanthema. In conclusion, these results confirmed the efficacy and safety of BIPM for febrile neutropenia in patients with hematological disorders.

A prospective evaluation was carried out on the effect of lamivudine administration as a prophylactic measure to prevent exacerbation of hepatitis in HBV carrier or chronic hepatitis B patients with malignant lymphoma undergoing chemotherapy. Eighteen patients were registered between 1997 and 2002 from institutions of the Research Group for the Treatment of Malignant Lymphoma. The patients' median age was 53 years old (39-73), and consisted of 8 males and 10 females. HBe-seroconversion had already occurred in 13 and liver biopsy had been performed in 8. No adverse effects of lamivudine were noted and the serum HBV-DNA content did not increase during lamivudine administration. Planned treatment courses could be completed in all patients. In 2, however, the viral load increased and the HBe antibody (Ab) value declined after the cessation of lamivudine, which were reversed to the normal ranges following the resumption of lamivudine. As for the overall outcome, 14 of the patients survived, and there were 4 fatalities due to malignant lymphoma. Serum HBeAb status may be regarded as a useful laboratory marker for deciding the safe cessation of lamivudine. An additional case is described, who had recovered from past HBV infection, but eventually succumbed to fulminant hepatitis after the cessation of lamivudine covering prolonged courses of chemotherapy. This illustrates a need for inclusion of such cases for the prophylactic use of lamivudine.

Research Committee for ITP was organized in 1972 under the support of the Government and since then efforts have been concentrated to elucidate pathophysiology of the disease and to establish better management of patients with ITP. A nation-wide epidemiological survey was conducted with estimates for prevalence of 7,500-10,500(5.5-11.5/100,000 population), with annual incidence of 1,700-4,100. Repeated survey after 10 years gave similar values for both parameters. Effectiveness of various treatments including standard modality and other special approaches was evaluated by multicenter collaborative studies, and long-term clinical course and outcome were analyzed to better understand the natural history of ITP. Our insufficient understanding regarding true natural history of ITP was discussed as a problem for the future investigation.

A 40-year-old man was diagnosed as having chronic myeloid leukemia (CML) in December 1990 and received busulfan and hydroxyurea. He developed myeloid blast crisis in February 1996. After DCMP combination chemotherapy, his disease reverted to chronic phase, but right hypochondrial pain developed and low-grade fever persisted. Abdominal CT scan revealed multiple low-density areas in the liver, suggestive of abscess formation. Grocott staining of a liver biopsy sample revealed granuloma and fungus. The patient was treated with intravenous amphotericin B (AMPH-B) without success. AMPH-B was then administered via a catheter placed in the portal vein on January 6, 1997, and an additional catheter placed in the hepatic artery on March 28. AMPH-B was administered through both catheters for more than two months, but later substituted by fluconazole because of renal impairment. On September 10, allogeneic bone marrow transplantation from the patient's HLA-identical brother was performed, despite persistence of the abnormal CT findings. Acute grade III GVHD developed, but there was no evidence of reactivation of the liver abscesses. This case demonstrates that a prior fungal liver abscess is not an absolute contraindication for BMT if prophylactic antifungal drugs are administered and careful observation is conducted.

A 45-year-old man was diagnosed as having Ph1+ acute lymphocytic leukemia (ALL) in February 1997. Complete remission was achieved by chemotherapy. Allogeneic BMT from his HLA-identical sister was performed on June 11, 1997. Engraftment was relatively quick, but acute GVHD (grade I) developed. The patient was discharged on day 113. Seven months after BMT, in January 1998, exertional dyspnea developed gradually. Chest X-ray examination showed diffuse interstitial pneumonia, for which corticosteroid was started immediately. The symptoms and signs gradually improved. However, on the 20th hospital day (February 23), bilateral subcutaneous emphysema developed in the neck and supraclavicular region. Chest X-ray and CT examinations showed pneumomediastinum without pneumothorax. The pneumomediastinum and subcutaneous emphysema gradually subsided after 3 weeks of bed rest. Subcutaneous emphysema and pneumomediastinum are relatively rare complications of allogeneic BMT.

We evaluated efficacy and safety of monotherapy with CZOP (1-2 g x 2/day) and combination therapy with CZOP (1-2 g x 2/day) and AMK (200 mg x 2/day) for infections in patients with hematological diseases. Efficacy was evaluated in 71 patients of monotherapy group and 70 patients of combination therapy group. Underlying diseases were mostly leukemia and lymphoma. Infections included sepsis, suspected sepsis, pneumonia and so on. Efficacy in CZOP monotherapy was excellent in 21 patients (31.3%), good in 23 patients (34.3%), fair in 5 patients (7.5%) and the efficacy rate was 65.7%. On the other hand, in combination therapy, each was 14 patients (21.2%), 23 patients (34.8%), 12 patients (18.2%) and the efficacy rate was 56.1%. Side effects such as eruption were noted in 2 patients. Abnormal laboratory findings were noted in 9 patients. All side effects as well as abnormal laboratory findings were minimal. It was concluded that CZOP monotherapy was effective in the treatment of various infections accompanying hematological diseases.

A 66-year-old woman complained of chest discomfort in January 1995. In March the accelerated phase of chronic myeloid leukemia (CML) was diagnosed. Chromosomal analysis demonstrated negative Ph and positive t(9;16) (q34;p11) with positive major BCR/ABL chimeric mRNA. Administration of hydroxycarbamide was initiated, but in May she developed high fever and severe left hypochondralgia. Her WBC was 62,100/microliter (blast 64%), and LDH was 3,590 IU/l. Bone marrow examination showed 78.6% blasts, with a nucleated cell count of 74 x 10(3)/microliter. Blasts were negative for esterase stain and partially positive for both peroxidase stain and PAS reaction. Surface marker analysis revealed that blasts were positive for CD13, CD19, CD33, CD34, and HLA-DR. A diagnosis of blast crisis was made and she was treated with the VDS-CP regimen with heparin for DIC. After temporary improvement her disease recurred rapidly with severe DIC. Treatment with low molecular weight heparin and fresh frozen plasma failed to control DIC and she died of subarachnoid hemorrhage on the 48th hospital day. This is the first veprted of case Ph-negative, M-BCR/ABL-positive CML with t(9;16) accompanied by severe DIC.

A 30-year-old man with a diagnosis of acute promyelocytic leukemia (APL) was admitted. Laboratory findings were as follows: WBC 32,900/microliter with 88% promyelocytes, Hb 10.4 g/dl, platelets 2.6 x 10(4)/microliter. Coagulation tests revealed DIC. Bone marrow was hypercellular with 91.8% promyelocytes which were strongly positive for peroxidase and positive for alpha-naphthyl butyrate esterase. Cytogenetic study revealed 46, XY, t(15;17) (q22:q11). He was treated with all-trans retinoic acid (ATRA) along with hydroxyurea (HU) and low-molecular weight heparin (LMH). Because his WBC increased to 93,700/microliter on day 6 of ATRA therapy, DCMP chemotherapy was given, while ATRA was withheld. He developed enterocolitis due to myelosuppression. ATRA was restarted along with granulocyte-colony stimulating factor (G-CSF). His WBC rose to 10,400/microliter with a marked, but temporary predominance of myelomonocytes both in peripheral blood and in bone marrow. These myelomonocytoid cells were positive for specific and nonspecific esterase double stainings. Then he entered complete remission. It was of interest that myelomonocytoid differentiation of APL cells was induced by ATRA. The etiology was discussed.

Recent advances on the congenital hemolytic anemia due to enzymopathies related to the red cell glycolytic pathway were summarized based on the review articles and reports. A number of investigations has clarified detailed molecular and genetic aspects of the disease, thus facilitating our understanding on the mechanisms of variable clinical expression, as well as the known limitation to the red cell system in some enzymopathies. These findings are expected to be connected with development of the save and rational therapeutic approaches.

We studied the possibility of home care of patients who are unable to swallow. Postsurgical complications during the short term (within a week), medium term (within a month) and long term (more than a month) were recorded along with survival time. We also retrospectively studied the number of patients who were discharged after percutaneous endoscopic gastrostomy from November 1989 to March 1995. The percentage of patients with short-term postsurgical complications was 12.1%. Vomiting was the most frequent complication during the medium term and the long term. The weekly rate of complication development (total complications number/total survival time) was highest in the short term and decreased year by year. It was lower in those who were discharged from the hospital than in those who were not discharged. The average survival time was 460.2 days (544.7 days: home care group, 419.0 days: hospital group). The one-year survival rate was 58%, and the two-year survival rate was 36%. One third (32.8%) of patients were cared for at home after gastrostomy (average duration of care at home: 338.5 days) and the average duration of care at home as a percentage of survival time was 58.8%. We conclude that Percutaneous endoscopic gastrostomy can improve the quality of life of patients who are unable to swallow, and may allow them to be cared for at home.

Cytogenetic and morphological analyses were performed on 55 adult patients (34 males, 21 females) with acute non-lymphocytic leukemia (ANLL) diagnosed between 1986 and 1992, and the results were studied with regard to therapeutic response and prognosis. Eleven patients had M1 (20%), 14 had M2 (25.5%), 14 had M3 (25.5%), 7 had M4 (12.7%), 3 had M5 (5.5%), 5 had M6 (9.1%) and one had M7 (1.8%). The overall incidence of chromosomal abnormalities were 65.5% including 10 cases (18.2%) with t (8;21), 12 (21.8%) with t (15;17), 5 (9.1%) with pseudodiploid, 3 (5.5%) with hyperdiploid, 2 (3.6%) with hypodiploid and 4 (7.3%) with abnormalities of 5 or 7 chromosomes. Outcomes were analyzed in 45 patients. 36 patients (80%) achieved complete remission (CR). All 12 patients with M2 entered CR, and they showed a significantly longer median survival than M1. The median survival of 10 patients with t (8;21) was significantly longer than that of patients with t (15;17). However, therapeutic response and prognosis did not correlate with either chromosomal status (NN, AN, or AA) or with age-groups (> or = 60, < 60). These results confirmed that morphological subtypes and certain types of chromosomal abnormality are important variables in determining the prognosis of adult patients with ANLL.

A 55-year-old man was admitted with abdominal pain and nausea. CT-scan and US showed no abnormal findings. On the 5th hospital day, a large mass was palpable on the upper abdomen, and CT-scan (7th hospital day) demonstrated a large, cystic mass below the left lobe. A thoracentesis under ultrasound guidance obtained bile-stained fluid. PTCD revealed choledocholithiasis and severe dilatation of the common bile duct and the left branch. After conservative treatment, cholecystectomy and choledocholithotomy were performed. Biloma occurred mainly traumatically or iatrogenically. This case had a spontaneous biloma, and only 11 cases have been previously reported as spontaneous biloma in Japan.

Eight cases of Philadelphia positive acute leukemia (Ph+AL) were compared with 13 cases of Ph+ chronic myelogenous leukemia in blast crisis (BC) and 10 cases of Ph negative acute lymphoblastic leukemia (Ph-ALL) based on the clinical and molecular biological findings. Distinguishing clinical features were a high leukocyte count (median; 147.9 x 10(3)/microliters) for Ph+AL, and a high incidence of tumor formation and basophilia for BC. A cytogenetic study demonstrated the disappearance or marked reduction of Ph+ metaphases in Ph+AL in remission, while Ph+ cells persisted in BC. The major bcr gene was not rearranged in 4 Ph+AL cases, whereas it was found rearranged in 4 other cases of Ph+ AL and 6 cases of BC. Reverse transcriptase polymerase chain reaction technique demonstrated the presence of minor bcr/abl mRNA in the former three cases, and major bcr/abl mRNA in the latter 4 cases. Remission rates were 63% for Ph+AL, 38% for BC, and 100% for Ph-ALL, and the 50% survival were 12, 5 and 29 months, respectively. It was concluded that Ph+AL can be differentiated from BC by a marked reduction of Ph+ cells at remission, and that the prognosis of Ph+AL is better than BC, but worse than Ph-ALL.

A 76 year old female with atypical leukemia complicated by vitamin B12 deficiency demonstrated marked fluctuation in blast percentage and hemopoiesis over 8 month period. She underwent surgical removal of pancreas head cancer 5.5 years ago. In January 1989 severe pancytopenia and mild increase of bone marrow blast were found. Blood transfusions and inadvertent administration of Vitamin B12 resulted in alleviation of pancytopenia and decrease in blast percentage. Several months later her bone marrow blast exceeded 30%, when serum B12 concentration was below 90 pg/ml. B12 injection and blood transfusion resulted in significant improvement in her hematological condition, but shortly thereafter she died of fulminant hepatitis. Her bone marrow cells showed a polyclonal constitution, as assessed by the RFLP-methylation technique using the PGK gene as a probe. The coexistence of leukemic- and normal clones under Vitamin B12 deficiency conditions and the differing behavior of such clones to B12 supplementation may explain the unusual clinical course observed in this patient.

Treatment results in the 61 adult patients with AML in first relapse were analyzed to establish a better strategy for this group of patients. These patients received reinduction chemotherapy during 1979-1988. Complete remission (CR) was obtained in 57.4% of the cases, and the probability of survival and remaining in CR at five years was 11.9% and 17.9%, respectively. The longer duration of initial remission was favorable factor for achieving second CR. Type of reinduction regimens which were different from those used in the initial induction phase did not influence the second CR rate. The use of different consolidation regimen appeared to favorably affect the survival and probability of remaining in CR.

A double-blind, placebo-controlled, cross-over clinical trial of recombinant human granulocyte colony-stimulating factor (rG-CSF), produced by Chinese hamster ovary cells, was conducted in 46 patients receiving intensive chemotherapy for non-Hodgkin's lymphoma. Each patient received 2 cycles of CHOP therapy. rG-CSF (2 micrograms/kg/day) or its placebo was given subcutaneously to each patient for 14 days from 2 days after initiation of the chemotherapy, in a cross-over fashion. rG-CSF significantly increased the absolute neutrophil counts (ANC) at nadir, and reduced the number of days with ANC less than 1,000/mm3 and also the number of days for recovery to ANC greater than or equal to 2,000/mm3. Bone marrow examination showed a significant increase in the number of myeloid cells after rG-CSF treatment. 12 infective episodes were observed during placebo cycles, while 6 infective episodes were observed during rG-CSF cycles. No serious side effects were observed. We concluded that rG-CSF was effective in neutropenia induced by intensive chemotherapy for non-Hodgkin's lymphoma.

The effect of recombinant human granulocyte colony-stimulating factor (rhG-CSF) on neutropenia was studied in 30 patients with aplastic anemia (AA). RhG-CSF was administered intravenously daily at a dose of 2, 5, 10, or 20 micrograms/kg/day for more than 7 days. In the patients whose absolute neutrophil counts (ANC) were more than 0.1 X 10(9)/l, the rhG-CSF injections at greater than or equal to 5 micrograms/kg/day caused rapid and selective elevation of ANC which maintained during the injection period. Most of the patients were well tolerated, and minor side effects were observed in only 3 patients. These findings suggest that daily injections of rhG-CSF at a dose of greater than or equal to 5 micrograms/kg/day may be an effective strategy for the treatment of bacterial and/or fungal infections in AA patients.

A clinical trial of recombinant human granulocyte colony-stimulating factor (rG-CSF), produced by Chinese hamster ovary cells, was conducted in 66 patients receiving intensive chemotherapy for non-Hodgkin's lymphoma. Each patient received 2 cycles of CHOP therapy, and one cycle of them was performed with rG-CSF treatment and another one without rG-CSF treatment, in a cross-over fashion. rG-CSF (0.4, 2, 5, 10 micrograms/kg/day) was given intravenously or subcutaneously to each patient for 14 days from 2 days after initiation of the chemotherapy. rG-CSF increased the absolute neutrophil counts (ANC) at nadir, and reduced the period of neutropenia with ANC less than 1,000/mm3 and also the period for restoration to ANC greater than or equal to 2,000/mm3 after initiation of chemotherapy. These effects were remarkable at doses of more than 5 micrograms/kg/day intravenously and 2 micrograms/kg/day subcutaneously. Fourteen infective episodes were observed during the cycles of chemotherapy without rG-CSF treatment, while 7 infective episodes were observed during the cycles with rG-CSF treatment. rG-CSF was well tolerated. These results demonstrated that rG-CSF was effective in neutropenia induced by cancer chemotherapy at a intravenous dose of 5 micrograms/kg/day and a subcutaneous does of 2 micrograms/kg/day.

Clinical investigation of cefotiam and aminoglycosides combination use against infections complicated by acute leukemia was performed, and the results obtained were as follows. 1) Sixteen patients were treated with cefotiam in doses 4--6 grams per day parenterally. The clinical effectiveness were excellent 47.6%, good 14.3%, fair 9.5% and poor 28.6%. No significant differences in therapeutic efficacy was observed between the patients given CTM 4 g/day and CTM 6 g/day. 2) It was considered that the clinical effectiveness of CTM has not been influenced by the difference of a number of maturation granulocyte. CTM has showed a certain, though not distinctive, efficacy compared with CFX. 3) As side effects with CTM, eruption appeared in 1 case, and no remarkable laboratory findings was observed. Cefotiam is thus considered to be a useful drug for the treatment of infections complicated by acute leukemia.