Management of fever of unknown origin in the neutropenic patient: the Japanese experience.
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Fever of Unknown Origin↗
Biomedical subjects
T Masaoka
Publications and source records attributed to T Masaoka.
[Multiple myeloma with localized tumor].
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Diagnosis, Differential↗
Simple diagnosis of graft-versus-host disease.
BACKGROUND: Among patients undergoing allogeneic bone marrow transplantation, we previously detected an increase of CD8+S6F1+ and CD8+CD57- cells with the onset of acute graft-versus-host disease. OBJECTIVE: This study was an attempt to develop a simple laboratory test for graft-versus-host disease. METHODS: We analyzed the percentage of the two lymphocyte subsets in the peripheral blood mononuclear cells of healthy volunteers, patients with posttransfusion graft-versus-host disease, and recipients of allogeneic bone marrow transplants. RESULTS: Two patients with posttransfusion graft-versus-host disease showed a high percentage of both subsets. When the graft-versus-host disease pattern was defined as 45% or more CD8+S6F1+ cells and 35% or more CD8+CD57- cells, it was found in none of 17 recipients without acute graft-versus-host disease, 9 of 16 recipients with grade I disease, and 8 of 9 recipients with grade II or worse disease had this pattern. CONCLUSIONS: Our test may be useful for the laboratory diagnosis of acute graft-versus-host disease.
Acute Disease↗
Vidarabine therapy for virus-associated cystitis after allogeneic bone marrow transplantation.
We describe a method of diagnosing virus-associated cystitis after allogeneic bone marrow transplantation (BMT) and treatment with vidarabine therapy. At 7-10 days post-BMT when cystitis was suspected, we observed urinary sediments by the Papanicolaou stain to detect virus inclusion bodies. When positive, we examined urinary sediments by transmission electron microscope and measured the diameter of viral particles to determine the families. This process needed only 4 days. Among 16 consecutive cases, adenovirus and polyomavirus were each detected in three. Adenovirus caused hemorrhagic cystitis in two cases and cystitis without macroscopic hematuria in one case. Polyomavirus caused cystitis without macroscopic hematuria in one case. Polyomavirus was also detected in two cases without any symptoms. Vidarabine (10 mg/kg/day i.v.) was administered for 5 days as one course. Soon after one course of vidarabine, most symptoms subsided and virus inclusion bodies disappeared in all cases except for one with severe hemorrhagic cystitis. From these experiences, vidarabine reduces excretion of adenovirus and polyomavirus in the urine of BMT recipients and improves clinical symptoms in some cases of cystitis associated with these viruses.
Adenoviridae Infections↗
Survival of patients with chronic myelogenous leukaemia relapsing after bone marrow transplantation: comparison with patients receiving conventional chemotherapy.
Treatment with busulphan and/or hydroxyurea rarely produces remission in patients with chronic myelogenous leukaemia (CML) in chronic phase. HLA-identical sibling transplants almost always produce remission, and only about 20% of patients relapse post-transplant. The increased anti-leukaemic efficacy of transplants results from intensive pretransplant treatment and immune-mediated anti-leukaemia effects. We studied 433 patients surviving > or = 2 years after diagnosis of CML to determine if patients who have relapsed after a transplant in chronic phase have longer survival from diagnosis than comparable subjects receiving chemotherapy. The chemotherapy cohort included 344 adults < 50 years of age treated on consecutive trials of the Italian Cooperative Study Group on CML between 1973 and 1986. The transplant cohort included 89 patients reported to the International Bone Marrow Transplant Registry who relapsed after an HLA-identical sibling bone marrow transplant carried out between 1978 and 1992. Survivals in the two groups were compared using Cox proportional hazards regression to adjust for prognostic variables. Median survival was 65 months in the chemotherapy cohort and 86 months in the transplant cohort. The 7-year probability (95% confidence interval) of survival was 34% (28-39%) in the chemotherapy cohort and 57% (43-70%) in the transplant cohort (P=0003). There was no difference in survival of patients relapsing after T-cell depleted and non-T-cell-depleted transplants. We conclude that patients who relapse after an HLA-identical sibling bone marrow transplant for CML in chronic phase have longer survival from diagnosis than comparable patients receiving chemotherapy. This effect is most likely to be the result of intensive chemotherapy and/or radiation given for pretransplant conditioning.
Adolescent↗
Second primary cancers following non-Hodgkin's lymphoma in Japan: increased risk of hepatocellular carcinoma.
We evaluated the risk of development of second primary cancers, with particular reference to subsequent hepatocellular carcinoma (HCC), in 592 patients diagnosed as non-Hodgkin's lymphoma (NHL), at Osaka Medical Center for Cancer and Cardiovascular Diseases. During 1978-1994, 2,163 person-years of observation were accrued, and 27 of the patients developed a second primary cancer, yielding an observed-to-expected ratio (O/E) of 1.53 [95% confidence interval (CI) = 1.01-2.23]. Significant excess risk was noted for primary liver cancer (PLC; O/E = 4.36, 95% CI = 1.99-8.28; O = 9) and non-lymphocytic leukemia (O/E = 26.17, 95% CI = 5.26-76.46; O = 3). The excess risk of PLC was relatively constant within the first 10 years after the NHL diagnosis. Patients who received chemotherapy as the NHL treatment had a significantly increased risk of PLC (O/E = 5.91, 95% CI = 2.70-11.23; O = 9). Their clinical reports indicated that all nine patients with PLC were diagnosed as HCC, and eight of them had clinical and/or histologic evidence of cirrhosis at the time of HCC diagnosis. None of the nine patients had a history of blood transfusion between the first NHL treatment and the diagnosis of HCC. These findings suggested that Japanese NHL patients might have an increased risk of developing HCC, and they indicated the importance of medical surveillance for liver malignancies, as well as subsequent leukemias. Possible explanations for the excess risk of subsequent HCC are discussed.
Adult↗
[A case of Tsutsugamushi disease as an imported infection].
Tsutsugamushi disease is widely spread throughout Japan. A case of tsutsugamushi disease was seen in October, 1996. A 64-year-old male developed typical symptoms of tsutsugamushi disease with Rickettsia tsutsugamushi, after he returned to Japan from Cheju Island, Korea. Not only in Japan but also in other Asian countries including Korea, China, Taiwan, and Thailand, tsutsugamushi disease is one of the most important rickettsial diseases carried by ticks or mites. If a traveller returning from an Asian country has symptoms such as high fever, skin eruption, and lymphadenitis, we should suspect that he is suffering from tsutsugamushi disease and should search if he has an eschar on any area of his body. We should not forget that tsutsugamushi disease is an imported disease. Patients of tsutsugamushi disease often have hematological disorders. They are sometimes referred to the hematological section of the hospital. Hematologists should be familiar with this disease.
Anti-Bacterial Agents↗
Results of allogeneic bone marrow transplants for leukemia using donors other than HLA-identical siblings.
PURPOSE: To compare outcomes of bone marrow transplants for leukemia from HLA-identical siblings, haploidentical HLA-mismatched relatives, and HLA-matched and mismatched unrelated donors. PATIENTS: A total of 2,055 recipients of allogeneic bone marrow transplants for chronic myelogenous leukemia (CML), acute myelogenous leukemia (AML), and acute lymphoblastic leukemia (ALL) were entered onto the study. Transplants were performed between 1985 and 1991 and reported to the International Bone Marrow Transplant Registry (IBMTR). Donors were HLA-identical siblings (n = 1,224); haploidentical relatives mismatched for one (n = 238) or two (n = 102) HLA-A, -B, or -DR antigens; or unrelated persons who were HLA-matched (n = 383) or mismatched for one HLA-A, -B, or -DR antigen (n = 108). HLA typing was performed using serologic techniques. RESULTS: Transplant-related mortality was significantly higher after alternative donor transplants than after HLA-identical sibling transplants. Among patients with early leukemia (CML in chronic phase or acute leukemia in first remission), 3-year transplant-related mortality (+/-SE) was 21% +/- 2% after HLA-identical sibling transplants and greater than 50% after all types of alternative donor transplants studied. Among patients with early leukemia, relative risks of treatment failure (inverse of leukemia-free survival), using HLA-identical sibling transplants as the reference group, were 2.43 (P < .0001) with 1-HLA-antigen-mismatched related donors, 3.79 (P < .0001) with 2-HLA-antigen-mismatched related donors, 2.11 (P < .0001) with HLA-matched unrelated donors, and 3.33 (P < .0001) with 1-HLA-antigen-mismatched unrelated donors. For patients with more advanced leukemia, differences in treatment failure were less striking: 1-HLA-antigen-mismatched relatives, 1.22 (P = not significant [NS]); 2-HLA-antigen-mismatched relatives, 1.81 (P < .0001); HLA-matched unrelated donors, 1.39 (P = .002); and 1-HLA-antigen-mismatched unrelated donors, 1.63 (P = .002). CONCLUSION: Although transplants from alternative donors are effective in some patients with leukemia, treatment failure is higher than after HLA-identical sibling transplants. Outcome depends on leukemia state, donor-recipient relationship, and degree of HLA matching. In early leukemia, alternative donor transplants have a more than twofold increased risk of treatment failure compared with HLA-identical sibling transplants. This difference is less in advanced leukemia.
Age Factors↗
Human urinary macrophage colony-stimulating factor reduces the incidence and duration of febrile neutropenia and shortens the period required to finish three courses of intensive consolidation therapy in acute myeloid leukemia: a double-blind controlled study.
PURPOSE: To determine whether macrophage colony-stimulating factor (M-CSF) reduces the incidence and duration of febrile neutropenia during three courses of intensive consolidation therapy and whether it shortens time to complete consolidation therapy. PATIENTS AND METHODS: In 198 adult patients with acute myeloid leukemia (AML) in complete remission (CR), M-CSF (8 x 10(6) U/d) or placebo was administered from 1 day after the end of each consolidation chemotherapy for 14 days. RESULTS: The duration and incidence of febrile neutropenia was significantly reduced by 34% (P = .00285) and 17% (P = .02065), respectively, in 88 assessable patients in the M-CSF group compared with those in 94 assessable patients in the placebo group. Patients in the M-CSF group had 565 days and 133 episodes of febrile neutropenia during 7,901 days at risk, while patients in the placebo group had 977 days and 185 episodes during 9,077 days at risk. The median period required to finish the three courses of consolidation therapy was 93 days in the M-CSF group, which was significantly shorter than 110 days in placebo group (P = .0050). In the M-CSF group, the recovery of neutrophils and platelets was significantly faster (P = .0348 and P = 0.0364, respectively), the administration of systemic antimicrobial agents tended to be less (P = .0839), and the frequency of platelet transfusion (P = .0259) and the total volume of transfused platelets (P = .0292) were significantly less. However, there was no significant difference in the disease-free survival. CONCLUSION: M-CSF significantly reduced the incidence and duration of febrile neutropenia during the intensive consolidation therapy, and shortened the time to complete consolidation chemotherapy in AML.
Acute Disease↗
Effect of ethylene thiourea on cultured rat embryos in the presence of hepatic microsomal fraction.
To investigate whether teratogenicity of ethylene thiourea (ETU) is due to ETU per se or to its metabolites, rat embryos cultured in vitro were exposed to 10 and 30 micrograms/ml of ETU in the presence or absence of rat liver microsomal fraction (S9mix). In the absence of S9mix, the incidence of morphological abnormalities increased dose-dependently. In the presence of S9mix, abnormal morphogenesis was almost absent in all embryos. These findings suggest that teratogenicity of ETU is due to ETU per se.
Abnormalities, Drug-Induced↗
Effects of fenthion, isoxathion, dichlorvos and propaphos on the serum cholinesterase isoenzyme patterns of dogs.
The serum cholinesterase (ChE) isoenzyme patterns consist of 5 bands for normal beagle dogs. We examined the ChE isoenzyme patterns and ChE activities of 4 groups, each of which consisted of 4 dogs, given the organophosphate (OP) compounds fenthion (P = S type), isoxathion (P = S type), dichlorvos (P = O type) or propaphos (P = O type) po at 220, 75, 120 or 90 mg/kg respectively. Blood samples were collected for 30 d after the OP administrations. ChE isoenzyme bands 4 and 5 were inhibited 12 h after fenthion and isoxathion administration; dichlorvos and propaphos produced suppression of main bands 4 and 5 20 min after administration. This change was effective to differentiate the type of OP administered (P = S and P = O), while the main ChE isoenzyme bands of dog serum reflected inhibition of serum ChE activity.
Animals↗
[Bropirimine (U-54461S) early phase II clinical studies--to investigate the efficacy and safety of bropirimine treatment on various malignant tumors (urological, hematologic, and dermal cancers)].
Early Phase II clinical studies with bropirimine (U-54461S) having interferon (IFN) inducing and direct antiproliferative activities were conducted in patients with various solid tumors or hematologic neoplasm at 34 institutions nationwide. To investigate the safety and efficacy of the treatment, bropirimine was orally administered to the patients at the dose of 1g every two hours, three times a day for three consecutive days with a four day drug-free interval. Among the 65 patients registered, 60 patients were eligible and 44 patients completed bropirimine treatment in accordance with the respective protocols. Complete response (CR) was observed in 7 cases, and partial response (PR) was observed in 4 cases, so the efficacy rate was 25.0% (7 CRs + 4 PRs/44). Classified by target tumors, the efficacy rates were 12.9% (6 CRs/14) in bladder CIS, 33.3% 1 CR/3) in superficial bladder cancer. 11.1% 1 PR/9) in renal cell carcinoma, and 42.9% (3 PRs/7) in malignant lymphoma, respectively. Adverse drug reactions frequently observed were influenza-like symptoms such as fever (60.0%) and generalized malaise (21.7%), gastrointestinal symptoms like anorexia (56.7%) and nausea/vomiting (43.3%), and adverse effects on the circulatory system such as tachycardia (15.0%) and abnormalities in ECG (11.7%). Most of these symptoms were relieved or improved. Abnormalities in laboratory tests observed frequently were adverse effects on the liver such as elevations in GPT (33.3%), in GOT (31.7%), and in LDH (18.3%) or on the blood system like a decrease in RBC (18.3%), leukopenia (26.7%), or neutropenia (25.0%). In conclusion, bropirimine treatment proved to be effective for bladder CIS in particular, suggesting that it will be promising for use in the treatment of the disease.
Adult↗
[Clinical evaluation of cefpirome sulfate for severe infections in patients with hematological disorders. Hanshin Study Group of Hematopoietic Disorders and Infections].
We investigated the therapeutic efficacy and safety of cefpirome sulfate (CPR) in treatment of hematopoietic disorder-associated infections. A total of 219 patients were admitted to 12 hospitals of Hanshin Study Group of hematopoietic disorders and infections between April 1994 and March 1996 and were enrolled in this study. Most patients received intravenously infused CPR at a dose of 1 or 2 g twice a day for 3 days or more. Twenty nine patients dropped out or were excluded and remaining 190 patients were adopted for the evaluation. A overall response rate was 58.4% (111/190). Among neutropenic patients, the response rate was 50% (8/16) in patients whose peripheral neutrophil counts (PNC) remained less than 100/microliter throughout the observation period and was 53.7% (22/41) in patients with PNC remained less than 500/microliter. In contrast, in patient whose PNC was below 500 before the treatment but exceeded 501/microliter during of at the end of the treatment, the response rate was as high as 78.4% (29/37). When G-CSF was combined, the response rate became significantly (P < 0.05) higher, 68.5% (50/73), as compared with that, 52.1% (61/117), in patients without it. In cases in which the causative organisms could be identified, the organisms were eliminated in 81.8% (9/11) of the patients infected with Gram-positive bacteria, whereas in 100% (12/12) in those infected with Gram-negative bacteria. Skin eruption developed in 6 patients during the treatment with CPR, and vascular pain and parosmia in one each other. These symptoms subsided soon after discontinuation or even without discontinuation of CPR. Abnormal laboratory findings, mainly liver dysfunction, i.e. elevation of slight degree of serum transaminase levels, were observed. The values, however, turned to normal immediately after the cessation or completion of the treatment. In conclusion, CPR is considered to be an antibiotic of value with high efficacy and safety in treatment of hematopoietic disorder-associated infections.
Adolescent↗
ACOS presentations for publication in the Japanese Journal of Cancer and Chemotherapy.
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Adolescent↗
Evaluation of plasma (1-->3)-beta-D-glucan measurement by the kinetic turbidimetric Limulus test, for the clinical diagnosis of mycotic infections.
The present multicentre clinical study was conducted to assess the clinical utility of a new diagnostic method for deep mycosis in which (1-->3)-beta-D-glucan, a fungal cell wall component existing in plasma, was quantitatively measured by the kinetic turbidimetric Limulus test (WB003). Plasma (1-->3)-beta-D-glucan concentrations were 0.57 +/- 0.10 microgram/l in 92 healthy subjects and 0.62 +/- 0.32 microgram/l in 26 patients with non-mycotic diseases (disease control group). In comparison with these healthy subjects and patients with non-mycotic diseases, patients with mycosis had significantly higher plasma (1-->3)-beta-D-glucan concentrations: 19.63 +/- 73.28 micrograms/l in 12 patients with candidaemia, 11.28 +/- 21.42 micrograms/l in 7 patients with urinary Candida infection, 4.84 +/- 12.71 micrograms/l in 5 patients with pulmonary candidiasis, and 12.21 +/- 31.31 micrograms/l in 4 patients with invasive pulmonary aspergillosis. On the statistical analysis of these data, a cut-off value was set at 1.0 microgram/l. Using this cut-off value, 3 patients with pulmonary cryptococcosis and 4 patients (4/6) with pulmonary aspergilloma were all negative with low plasma (1-->3-beta-D-glucan levels. The test WB003 provided equivalent or higher efficiency of diagnosis of candidiasis and aspergillosis, in comparison with commercially available antigen detection kits, demonstrating its utility as a diagnostic reagent. It may also be useful in assessing therapeutic effectiveness when used periodically after treatment.
Adolescent↗
[Menogaril (TUT-7) late phase II study for malignant lymphoma, adult T-cell leukemia and lymphoma (ATLL)].
A late Phase II multicenter study with menogaril was conducted nationwide in patients with malignant lymphoma [non-Hodgkin's lymphoma (NHL), Hodgkin's disease (HD)], and ATLL, menogaril was orally administered at 100 mg daily after breakfast, for seven consecutive days with two- or three-week drug withdrawal, then menogaril administration was repeated. For malignant lymphoma, in 81 patients with NHL and 5 patients with HD registered, 70 and 5 patients were evaluable for efficacy, respectively. The efficacy rates were 32.9% (6 CRs + 17 PRs/70) for NHL and 20.0% (1 PR/5) for HD, respectively; that for the NHL patients with prior anthracycline antibiotic chemotherapy was 30.5% (5 CRs and 13 PRs/59). For ATLL, among the 16 patients registered, 15 were evaluable for efficacy, and the efficacy rate was 40.0% (2 CRs and 4 PRs/15). Adverse drug reactions frequently observed in the patients with malignant lymphoma and ATLL included bone-marrow suppression and gastrointestinal symptoms such as anorexia, and nausea/vomiting. With these results, menogaril was considered to be effective for the treatment of non-Hodgkin's lymphoma and ATLL.
Administration, Oral↗
[The development of a consensus on the empiric therapy for fungal infections of patients with leukemia].
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Antifungal Agents↗
Long-term follow-up of minimal residual disease in leukemia patients by monitoring WT1 (Wilms tumor gene) expression levels.
Thirty-one patients (27 with acute myeloid leukemia [AML], 2 with acute lymphocytic leukemia [ALL], and 2 with acute mixed lineage leukemia [AMLL]) treated with conventional chemotherapy (CHT) and 23 patients (13 AML, 5 ALL, and 5 with chronic myeloid leukemia [CML]) treated with allogeneic bone marrow transplantation (BMT) were monitored for WT1 expression levels in BM and peripheral blood (PB) by reverse transcriptase-polymerase chain reaction over a long-term period (mean, 29 months for CHT and 24 months for BMT). Sixteen of the patients in the CHT group and 3 in the BMT group who had achieved complete remission suffered clinical relapse. In 10 of these patients, WT1 expression that had returned to normal BM levels (< 10(-3); the WT1 expression level of K562 cells was defined as 1.0) after complete remission (CR) either gradually or rapidly increased again to abnormal levels 1 to 18 months (mean, 7 months) before clinical relapse became apparent. In another 9 patients, WT1 expression never returned to normal BM levels even after CR and the subsequent relapse was accompanied by a rapid increase in WT1 expression to levels higher than 10(-2) (10(-3) levels in PB). On the other hand, the remaining 35 patients (15 CHT and 20 BMT) maintained their CR. In 29 of these patients (11 CHT and 18 BMT), WT1 expression either gradually or rapidly decreased to normal BM levels, whereas in the other 6 (4 CHT and 2 BMT), low or very low levels of WT1 mRNAs (10(-3) to 10(-2) in BM and 10(-5) to 10(-3) in PB) remain detectable, but without any clinical signs of relapse. A clear correlation was found to exist between the minimal residual disease (MRD) detected in the paired BM and PB samples for all types of leukemias (AML, ALL, and CML), with MRD in PB being approximately one-tenth of that in BM. WT1 quantitation of 168 paired BM and PB samples showed that PB samples were superior to BM samples for the detection of MRD. We conclude that monitoring of WT1 expression levels in BM and PB makes it possible to rapidly assess the effectiveness of individual treatment and diagnose clinical relapse in the early stage for all leukemia patients regardless of the presence or absence of tumor-specific DNA markers.
Bone Marrow↗