Effect of related donor availability on outcome of AML in the context of related and unrelated hematopoietic cell transplantation.

Although allogeneic hematopoietic cell transplantation (HCT) from a related donor is effective therapy for younger patients with AML, it remains unknown how the availability of a related donor affects the outcome when unrelated HCT is a treatment option for patients without a related donor. To address this issue, we retrospectively analyzed 605 cytogenetically non-favorable AML patients younger than 50 years for whom a related donor search was performed during first CR (CR1). The 4-year OS was 62% in 253 patients with a related donor and 59% in 352 patients without a related donor (P=0.534). Allogeneic HCT was performed during CR1 in 62% and 41% of patients with and without a related donor, respectively. Among patients transplanted in CR1, the cumulative incidence of non-relapse mortality was significantly higher in patients without a related donor (P=0.022), but there was no difference in post-transplant OS between the groups (P=0.262). These findings show the usefulness of unrelated HCT in younger patients with cytogenetically non-favorable AML who do not have a related donor. The extensive use of unrelated HCT for such patients may minimize the potential disadvantage of lacking a related donor.

Methotrexate-induced acute lung injury in a patient with rheumatoid arthritis.

Methotrexate (MTX)-induced acute lung injury developed in a female patient with rheumatoid arthritis. She was successfully treated with high-dose glucocorticoid therapy. During her hospital stay, the serum concentration of surfactant protein (SP)-D, which was markedly elevated on admission, was finally normalized and the disease resolved. However, the serum concentration of Klebs von den Lungen (KL)-6 remained high. Although the mechanisms of lung injury by MTX have not been well defined, serial measurements of serum SPD might be useful for the clinical evaluation of drug-induced acute lung injury.

Induction of mononuclear cell infiltration into liver by Japanese herbal medicine.

Juzen-Taiho-To (JTT) is a Japanese herbal medicine that has been administered mainly to patients weakened by long illness. Currently, it has also been used for cancer patients and showed antitumor effects that have been reported as phagocytosis enhancement, cytokine induction and antibody production. In this study, we examined the effect of oral administration of JTT in mice on the immunological restoration of the liver, especially focused on natural killer (NK) T-cell induction. Mice were grouped to receive JTT or placebo orally for a period of 1, 3 and 7 days. After sacrifice, the liver tissue was fixed, embedded and stained with hematoxylineosin and some antibodies by common staining methods. Transmission electron microscope (TEM) observation was also carried out. Although the JTT-treated mice had the same appearance as the non-JTT-treated mice, their livers were infiltrated by massive mononuclear cells, some of which were aggregated in clusters. Immunohistochemical staining revealed that there was abundant cytokine expression of interleukin (IL)-12 and massive infiltration of mononuclear cells with large granules in the liver of JTT-treated mice. Oral administration of JTT may induce the expression of IL-12 and be followed by immunological restoration such as NK T-cell induction in liver

Reappraisal of the clinical significance of CD7 expression in association with cytogenetics in de novo acute myeloid leukaemia.

Debate exists over whether CD7 expression indicates an unfavourable prognosis in de novo acute myeloid leukaemia (AML). Meanwhile, the type of cytogenetics is a strong prognostic factor in AML. We analysed 256 de novo adult AML cases and found that the proportion of CD7+ cases increased stepwise from the cases with favourable cytogenetics to the cases with intermediate and unfavourable cytogenetics (3 out of 69 cases, 51 out of 140 cases and 25 out of 47 cases respectively, P < 0.0001). CD7-positivity adversely affected the survival only in the cases with unfavourable cytogenetics (P < 0.03). We recommend that CD7 expression in AML be interpreted in association with the cytogenetics.

Reduced-dose chop therapy for elderly patients with non-Hodgkin's lymphoma.

While CHOP therapy is effective for malignant lymphoma, the optimum schedule for elderly patients remains controversial. The present study investigated the usefulness of reduced-dose CHOP therapy for elderly patients. Previously untreated patients aged 65 years or older with intermediate to high-grade non-Hodgkin's lymphoma were given up to 6 courses of reduced-dose CHOP therapy at 3-week intervals. Group A patients were given (5/6) of the standard dose and Group B received 7/12 of the standard dose. Filgrastim was administered when the white blood cell count fell below 2,000/microL. Fifty-seven patients were evaluable and the scheduled therapy was completed in 37. For patients aged from 65 to 79 years and for patients older than 80 years, the complete response rate was 79.5% and 46.2%, overall 3-year survival was 58.2% and 30.4%, and event-free 3-year survival was 49.3% and 44.4%, respectively. Major toxicities (> or = grade 3) included leukopenia in 42 patients and documented infection in 7 patients. Grade 3 cardiac plus renal failure, grade 3 peritonitis due to small bowel perforation, and grade 3 liver dysfunction occurred in 1 patient each. One patient died of toxicity (grade 4 hematological toxicity and pneumonia). In conclusion, it seems that in the elderly patients with non-Hodgkin's lymphoma, response to reduced-dose ((5/6) dose) CHOP therapy is comparable to that for standard CHOP in younger adults, mainly because of improved dose-intensity.

Pharmacological characterization of cepharanthin in chronic idiopathic thrombocytopenic purpura.

Cepharanthin, a bisbenzylisoquinoline (biscolaurine) alkaloid drug, has been reported to improve the symptoms of intractable or steroid-resistant chronic idiopathic thrombocytopenic purpura (ITP). To clarify the mechanism by which the cepharanthin is beneficial to ITP, we examined the effects of cepharanthin on thrombocytopenia in (NZW x BXSB) F1 (W/B F1) mice and on the formation of colony forming unit of megakaryocyte (CFU-MK) derived from human CD34-positive progenitor cells. The decrease in platelet numbers in W/B F1 was diminished by the administration of 5 mg/kg cepharanthin for 6 weeks as well as by 2 mg/kg prednisolone. Furthermore, the administration of over 0.2 mg/kg cepharanthin enhanced the therapeutic effect of prednisolone. From the data in this animal model, it is suggested that cepharanthin may prolong the platelet lifespan. The treatment of CD34-positive progenitor cells isolated from cord blood with cepharanthin (over 5 x 10(-10)g/ml) caused an increase in the formation of CFU-MK induced by the cocktail of thrombopoietin, interleukin (IL)-6 and IL-3. The addition of 0.1% normal human serum dramatically increased the number of CFU-MK. In contrast, the serum isolated from patients with ITP at the same concentration decreased the number of CFU-MK. However, the simultaneous addition of 5 x 10(-8)g/ml cepharanthin recovered the number of CFU-MK to the level induced by normal serum. These findings indicate that cepharanthin has the potent therapeutic activity not only on the platelet destruction process, but also on the platelet production process of thrombocytopenia in chronic ITP.

Diffuse angiodysplasia of the upper gastrointestinal tract in a patient with hypertrophic obstructive cardiomyopathy.

A 64-year-old woman with a known history of hypertrophic obstructive cardiomyopathy presented with severe anemia of unknown origin. She had also suffered from repeated episodes of upper gastrointestinal bleeding for the previous 3 years. Despite bone marrow examination and panendoscopic and angiographic studies, the origin of anemia remained undefined until a small bleeding site was found during a duodenoscopic examination. The lesion proved to be angiodysplasia. This case report is interesting in that angiodysplasia elicited gastrointestinal bleeding and was the cause of anemia. In the international literature, there are very few reported cases of bleeding from gastrointestinal angiodysplasia in association with subvalvular aortic obstruction.

[A randomized trial of conventional dose vs reduced dose in BHAC-DM therapy for acute myelogenous leukemia in elderly patients].

Twenty-nine patients aged 60-75 years with newly diagnosed acute myelogenous leukemia (AML) were randomized to receive BHAC-DM either at a reduced dose (S-1 group, n = 13; BHAC 150 mg/m2 1-7 day, DNR 30 mg/m2 1-3 day, 6MP 70 mg/m2 1-7 day) or the conventional dose (S-2 group, n = 16; BHAC 200 mg/m2 1-7 day, DNR 40 mg/m2 1-3 day, 6MP 70 mg/m2 1-7 day). On day 7, patients were given therapy for 2 more days if the ratio of blasts in their bone marrow was more than 15%. Granulocyte-colony stimulating factor was injected when the leukocyte count decreased below 1,000/microliter. The rates of complete remission were 46.2% in the S-1 group and 43.8% in the S-2 group. No significant differences in response distinguished the 2 groups. The mortality rate during myelosuppression was 1/13 in the S-1 group and 1/16 in the S-2 group. The rate of treatment-related death was 10.1% for all patients. Grade-4 adverse effects were not seen in any of the patients. We concluded that the conventional dose of BHAC-DM was as acceptable as the reduced dose in elderly patients with AML.

Sera from patients with sepsis induce nitric oxide production in vascular smooth muscle cells.

BACKGROUND: Nitric oxide (NO) is an important physiological mediator of vascular tone and is involved in pathophysiology of septic shock. Although plasma nitrite is a stable end product of NO oxidation derived from endogenous NO, the plasma nitrite level is also easily affected by the intake of various foods, bacterial products and renal functional status. AIMS: We propose an excellent alternative assay technique for measuring endogenous NO production. METHODS: We measured the nitrite level in cultured vascular smooth muscle cells (SMC) treated with serum obtained from patients with sepsis (4 patients), by means of a chemiluminescence detector. RESULTS: The nitrite concentrations in such cells were significantly higher as compared to those in the cells treated with normal serum. Moreover, the increased nitrite levels in the SMC treated with the sera obtained from patients with sepsis were completely inhibited by L-nitroarginine (1 mmol/L), a nitric oxide synthase inhibitor. CONCLUSION: These data suggest that this assay method enable us to know the ability of endogenous NO production in each patient.

[Study of optimal CHOP dose ranges for elderly patients with non-Hodgkin's lymphoma].

Two groups of intermediate-to high-grade non-Hodgkin's lymphoma patients aged 65 years and over were enrolled in a dose-range study of CHOP therapy utilizing 5 doses (1/2, 7/12, 2/3, 5/6, full CHOP): 11 patients 65-79 years of age (group A) and 9 patients 80 years or older (group B). The patients were enrolled consecutively; the study was designed so that if 3 patients completed 3 cycles of CHOP on schedule without major problems, the next highest dose was administered. If 2 patients experienced any major problems during 6 cycles at a given dose, treatment was discontinued and the dose prior to that particular dose was regarded as the optimal dose. The 6 treatment cycles were completed by 3 of 3 (2/3 CHOP), 3 of 4 (5/6 CHOP), and 1 of 4 (full CHOP) group A patients; and by 3 of 3 (1/2 CHOP), 2 of 3 (7/12 CHOP) and 1 of 3 (2/3 CHOP) group B patients. The results indicated that the optimal doses for group A and B were five-sixths and seven-twelfths of the standard CHOP dose, respectively.

[Effective splenectomy in a patient with HIV-associated thrombocytopenia].

A 31-year-old man presented with a 3-month history of petechial hemorrhages. Physical examination revealed no splenomegaly. The patient's platelet count was 1.0 x 10(9)/l and bone marrow aspiration showed an elevated number of megakaryocytes. A diagnosis of HIV-associated thrombocytopenia was made on the basis of HIV seropositive results. The CD4 cell count was 400 x 10(6)/l. No opportunistic infections indicating AIDS were detected. Initially the patient was treated with predonisolone, but showed only a transient response. He also failed to respond to zidovudine, lamivudine, or indinavir. Following splenectomy, however, his platelet count rose above 80 x 10(9)/l (normal level: 150-350 x 10(9)/l).

[Bilateral leg ulcers with pathologic evidence of small vessel vasculitis by skin biopsy during hydroxyurea therapy of chronic myelogenous leukemia].

We report a 45-year-old male with chronic myelogenous leukemia (CML) who experienced skin ulcers of the left lateral malleolus and dorsum of both feet. He had been treated with hydroxyurea (HU) for 2 years. His leg ulcers improved after HU was discontinued. Skin biopsy of the ulcerated lesion revealed that the lesion is compatible with small vessel vasculitis, but circulating immune complexes (C1q, anti-C3d antibody) were negative. Although the precise mechanism of the skin ulcer is unknown, we must take into consideration the skin changes were secondary to hydroxyurea therapy in myeloproliferative disorders.

Effect of vesnarinone, a quinolinone derivative, on the growth of leukemic blasts in acute myelogenous leukemia.

We studied the effects of vesnarinone, a quinolinone derivative used clinically for the treatment of chronic congestive heart failure, on the leukemic blast progenitors in acute myelogenous leukemia (AML) patients and on the normal hematopoietic precursors, colony-forming unit in culture (CFU-C), and colony-forming unit erythroid (CFU-E). Leukemic blast progenitors made blast colonies in the presence of granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF), or interleukin-3 (IL-3). Blast colony-formation was suppressed by vesnarinone in a dose-responsive manner regardless of growth factor added. Vesnarinone suppressed the primary (PE1) and secondary (PE2) colony-formation of leukemic blast progenitors in six AML patients tested. The suppression by vesnarinone did not significantly differ between PE1 and PE2. This finding suggests that vesnarinone exerts an almost equivalent effects on the terminal divisions and the self-renewal of leukemic blast progenitors. Furthermore, this drug suppressed the growth of clonogenic cells of five AML cell lines, OCI/AML1a, OCI/AML2, OCI/AML3, OCI/AML5, and OCI/AML6. Normal hematopoietic precursors CFU-C and CFU-E were also suppressed by vesnarinone, although vesnarinone was less toxic to normal hematopoietic than to leukemic blast progenitors. The possible usefulness of vesnarinone as a new approach to the treatment of AML patients is discussed.

Drastic genetic instability of tumors and normal tissues in Turcot syndrome.

Turcot syndrome is characterized by an association of malignant brain tumors and colon cancer developing in the patient's teens. Since the mechanism of carcinogenesis in Turcot syndrome is still unclear, we analysed genetic changes in tumors from a Turcot patient with no family history of the condition. All tumors, including one astrocytoma, three colon carcinomas, and two colon adenomas, exhibited severe replication error (RER), and all colon tumors showed somatic mutations at repeated regions of TGFbetaRII, E2F-4, hMSH3, and/or hMSH6 genes. Somatic APC mutations were detected in three of three colon carcinomas, and somatic p53 mutations were detected in the astrocytoma and two of three colon carcinomas, both of which showed two mutations without allele loss. We also found that normal colon mucosa, normal skin fibroblasts and normal brain tissue from this patient showed respective high frequencies of RER, in contrast to usual HNPCC patients in which RER was very rare in normal tissues. These results suggest that extreme DNA instability in normal tissues causes the early development of multiple cancer in Turcot syndrome. A missense mutation (GAG to AAG) at codon 705 of hPMS2 gene was detected in one allele of this patient, which was inherited from his mother without tumors. Additional unknown germline mutation may contribute to the genetic instability in normal tissues.

The effect of basic and acidic fibroblast growth factors (bFGF and aFGF) on the growth of leukemic blast progenitors in acute myelogenous leukemia.

The effect of basic and acidic fibroblast growth factors on leukemic blast progenitors was studied in 14 patients with acute myelogenous leukemia and in one patient with chronic myelocytic leukemia in myeloid crisis. bFGF and aFGF stimulated blast-colony formation by leukemic blast progenitors cultured in methylcellulose in two patients. In the other 13 patients, no significant effect of either FGF on blast-colony formation was noted. The combination of bFGF or a FGF and G-CSF, GM-CSF, interleukin-3, or stem cell factor (SCF) had a synergistic effect on blast-colony formation in three patients. In the other patients, however, synergism between FGF and CSF was not detected. In fact, bFGF was found to suppress the stimulation of blast-colony formation due to GM-CSF in one of 10 patients and that due to SCF in four of eight patients. aFGF suppressed the stimulation of blast-colony formation due to GM-CSF in two of 11 patients and that due to SCF in four of eight patients. The results show that bFGF and aFGF do not directly play a major role in leukemic hematopoiesis but that they may modulate the cytokine network affecting leukemic cell growth.

N-ras and p53 gene mutations are very rare events in multiple myeloma.

The frequencies of p53 and N-ras gene mutations were examined in multiple myeloma. DNA samples of 45 cases of multiple myeloma were obtained from stored bone marrow smears. All samples were analyzed for the N-ras gene at codon 12 by the allele specific restriction analysis method and at codon 61 by direct sequencing. DNA was screened for mutations by single-strand conformation polymorphism analysis for the p53 gene in exons 5 to 8. DNA fragments showing an altered electrophoretic pattern were further studied by direct sequencing to confirm the mutations. Ras mutations were found in two cases at codon 61 (4.4%). A point mutation of the p53 gene was detected in one of 45 cases (2.2%). These 3 cases with mutations were in an advanced stage. In conclusion, N-ras and p53 gene mutations may occur at a late stage of multiple myeloma, but the frequencies of the mutations are very low.

Clinical-study of multiple-myeloma in the elderly.

From January 1989 until December 1992, 120 elderly patients over 65 years old with multiple myeloma (MM) were enrolled with the Elderly Hematology Study Group (EHSG) with 14 institutions participating. Several courses of chemotherapy were conducted in 103 of the 120 patients, 33 patients with alpha-interferon (IFN) and 70 patients without IFN. The response rate (CR+PR) was 24.0% of all 120 cases, 24.2% of the group treated with IFN and 25.7% of those treated without IFN. Similarly, the efficacy rate (CR+PR+MR) of these groups were 78.8%, 81.8% and 78.8%, respectively. The 50% survival time was 31 months in the 120 cases as a whole, 44 months in the group treated with IFN and 38 months in the group treated without IFN. No significant difference was observed either in response rate (p=0.243) or survival time (p=0.262) in the groups treated with or without IFN.