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This study aimed to clarify the attitude of oncologists toward influenza vaccination and the current situation and issues regarding influenza vaccination for patients on chemotherapy in Japan. A web‐based survey of medical oncologists certified by the Japanese Society of Medical Oncology was conducted between November 1 and December 31, 2019. Of the 1369 medical oncologists who were invited to participate, 415 (30.3%) responded to our survey. The questionnaire comprised 4 sections: “oncologist characteristics,” “oncologist attitude toward influenza vaccines and the current status of influenza vaccination for cancer patients undergoing chemotherapy,” “incidence of influenza infection and associated treatment complications,” and “treatment policy for influenza infection.” In total, 153 (36.9%) physicians replied that they did not actively encourage influenza vaccination for patients undergoing chemotherapy. The primary reasons given were lack of evidence (48/153, 31.4%) and uncertainty of appropriate timing (46/153, 30.1%). There was diverse variation in the timing of vaccination and in the levels of encouragement based on the cancer location and medication type. Two hundred eighty‐three (68.2%) oncologists reported that their cancer patients had experienced influenza infection while undergoing chemotherapy, and 169 (40.7%) responded that their patients had experienced an administration delay or discontinuation of medication because of influenza infection. Our surveillance revealed some oncologists considered evidence regarding the administration of influenza vaccine to cancer patients undergoing chemotherapy (particularly the optimal timing and level of recommendation by cancer location and medication) to be lacking. It also exposed the adverse impact of influenza infection in cancer patients., This survey aimed to clarify the current issues regarding influenza vaccination for patients on chemotherapy in Japan. There was a diverse variation in the timing of vaccination and encouragement based on the type of cancer and medication. There was substantial adverse impact of influenza infection such as discontinuation of chemotherapy on patient.

We herein report a case of systemic phaeohyphomycosis by Exophiala dermatitidis (E. dermatitidis) with chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). The patient had been taking oral corticosteroids for years to control the GVHD. Yeast-like fungi were identified in a blood culture, so treatment with micafungin (150 mg/day) was begun, with no improvement. The patient passed away on hospital Day 12. A sequence analysis of rRNA revealed the isolate to be E. dermatitidis. This report brings attention to an emerging mycosis of community-acquired Exophiala species infection in the very-late phase after allogenic HSCT in patients with chronic GVHD.

We observed an emerging resistance to β-lactams in a P. ananatis bacteremia case. Whole genome sequence analysis detected two β-lactamase genes as well as related genes that regulate the β-lactamase genes in the chromosome. The induction experiment resulted in the expression of the class A β-lactamase gene in the isolate.

Background Hypervirulent Klebsiella pneumoniae (HVKp) infections have distinct clinical manifestations from classical K. pneumoniae infections. The hallmark of HVKp infections are liver abscess formation and metastatic infections. Due to the severe sequelae of these complications, method to identify patients at-risk of HVKp infections should be developed. Results A retrospective cohort study of 222 patients with K. pneumoniae bloodstream infections (BSIs) was performed. Patient demographics, clinical manifestations, and bacterial characteristics were investigated. Ten cases of liver abscesses were identified. Characteristics such as community-onset BSIs, hypermucoviscosity phenotype, and capsular serotype K1 were identified as risk factors for HVKp infections. A scoring system was developed based on the risk factors. The area under the receiver operating characteristic curve for the scoring system was 0.90. A score of ≥ 2 points provided sensitivity and specificity of 0.70 and 0.94, respectively. Conclusions Simple scoring system was developed for the diagnosis of HVKp infections. The system allows early identification of patients with K. pneumoniae BSIs in whom hypervirulent infections should be evaluated. Prospective evaluation is expected.

Objective: The objective of this study was to evaluate the effects of earlier intervention by an antimicrobial stewardship team (AST) on antimicrobial use, antimicrobial resistance rates, and the clinical outcomes, without changing the weekly intervention schedule. Methods: A retrospective study was conducted at Fukuoka University Hospital between April 2013 and March 2016. The effects were compared among three study periods (SP): SP1 (patients receiving anti-methicillin-resistant Staphylococcus aureus agents and carbapenems for ≥14 days), SP2 (patients receiving specific antimicrobials for ≥14 days), and SP3 (patients receiving specific antimicrobials regardless of the duration of treatment). Results: The timing of AST intervention was shortened from an average of 15.5 days after administration in SP1 to 4.2 days in SP3. The antimicrobial use density (AUD) of carbapenems and piperacillin–tazobactam decreased significantly (SP2 vs. SP3, p

INTRODUCTION Candidaemia, recognised as a fairly common disease among intensive care unit (ICU) patients, carries a poor prognosis. However, as studies on the prognostic factors associated with candidaemia in ICU patients are limited, this study aimed to establish the best prognostic factor for ICU patients with candidaemia in a tertiary care hospital in Japan. METHODS We conducted a retrospective cohort study of patients with candidaemia in the emergency ICU at Fukuoka University Hospital, Fukuoka, Japan, from April 2010 to March 2015. Demographic and clinical data was collected from the patients' medical records and laboratory databases. RESULTS A total of 25 patients were included in the study. However, 18 patients died during hospitalisation, resulting in an in-hospital mortality rate of 72.0%. The variables of Sequential Organ Failure Assessment (SOFA) score and cumulative number of risk factors for invasive candidiasis showed significant differences between patients in the survivor and non-survivor groups (p < 0.05). The areas under the receiver operating characteristic curves for the SOFA score and cumulative number of risk factors for invasive candidiasis were 0.873 (95% confidence interval [CI] 0.72-1.00) and 0.937 (95% CI 0.84-1.00), respectively. CONCLUSION Our results suggest that the cumulative number of risk factors for invasive candidiasis was the most useful prognostic indicator for candidaemia in ICU patients.

Background: The effectiveness of surveillance to identify extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-E) carriers is controversial during a non-outbreak situation. We performed additional stool cultures for ESBL-E among intensive care unit (ICU) patients already under active surveillance by means of sputum and urine cultures. We aimed to assess the efficacy of stool cultures for screening for ESBL-E in a non-outbreak situation. Methods: We conducted a retrospective cohort study in an ICU. Sputum and urine samples were cultured for ESBL-E surveillance purposes from January to September 2013 (phase 1). Stool cultures were routinely performed in addition from January to September 2014 (phase 2). Antimicrobial use density values and clinical outcomes were investigated and compared between phase 1 and 2. Results: We identified 512 and 478 patients in phase 1 and phase 2, respectively. ESBL-E were found in the feces of 65 (13.6%) patients in phase 2. The antimicrobial use density values (expressed as defined daily doses per 1,000 bed-days) were not significantly different between the two phases for fluoroquinolones (7 vs. 10, p = 0.376), third-generation cephalosporins (24.2 vs. 29.5, p = 0.724), tazobac- tam/piperacillin (44.6 vs. 57.3, p = 0.489), and carbapenems (73 vs. 55.5, p = 0.222). Moreover, there were no significant differences in ICU mortality and length of stay (11.5% vs. 9.8%, p = 0.412, and 9 vs. 10 days, p = 0.28, respectively). Conclusions: Stool culture seemed ineffective in improving the antimicrobial use density of broad-spectrum antimicrobials, clinical outcomes, and ICU length of stay, and is not recommended for surveillance of ESBL-E in a non-outbreak situation.

We herein report a case of systemic phaeohyphomycosis by Exophiala dermatitidis (E. dermatitidis) with chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). The patient had been taking oral corticosteroids for years to control the GVHD. Yeast-like fungi were identified in a blood culture, so treatment with micafungin (150 mg/day) was begun, with no improvement. The patient passed away on hospital Day 12. A sequence analysis of rRNA revealed the isolate to be E. dermatitidis. This report brings attention to an emerging mycosis of community-acquired Exophiala species infection in the very-late phase after allogenic HSCT in patients with chronic GVHD.

Linezolid is an antimicrobial agent for the treatment of multiresistant Gram-positive infections. A practical high-performance liquid chromatography method was developed for the determination of linezolid in human plasma and saliva. Linezolid and an internal standard (o-ethoxybenzamide) were extracted from plasma and saliva with ethyl acetate and analyzed on a Capcell Pak C18 MG column with UV detection at 254 nm. The calibration curve was linear through the range 0.5-50 µg/mL using a 200 μL sample volume. The intra- and interday precisions were all

Background Cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) is the standard treatment regimen for malignant lymphoma. CHOP-induced neutropenia is a common clinical complication that often develops into life-threatening febrile neutropenia (FN). The incidence rate of FN in malignant lymphoma patients receiving a CHOP + rituximab regimen is approximately 10%–20% in clinical trials. Assessing FN-related factors in an individual hospital is an important step towards ensuring appropriate treatment. Therefore, we aimed to evaluate the incidence, risk factors, and clinical features related to FN in our institution and to determine the rate of treatment success in FN patients receiving antibiotics. Methods FN-related characteristics were investigated in 182 malignant lymphoma patients who were treated with the CHOP regimen between January 2013 and December 2018. All data were retrospectively collected from the electronic medical record system. Categorical factors were compared using the Fisher’s exact test and Mann-Whitney U test. Logistic regression analysis was used to analyze FN-related risk factors. Results Among 182 patients, 79 (43.4%) were men. Median age was 67 years. Most patients (90.7%) had an Eastern Cooperative Oncology Group performance status (PS) of 0–2. We noted 80 FN episodes in 60 patients (33.0%). On multivariate analysis, lack of granulocyte colony stimulating factor (G-CSF) prophylaxis in cycle 1 and poor PS were significantly associated with FN occurrence. Documented infections were observed in case of 35 FN episodes (43.8%), and median fever duration was 3 days. Treatment was successful without any modifications in case of 64 episodes (80%). No deaths were observed. Conclusion FN incidence was 33.3% at our institution. Lack of G-CSF prophylaxis and poor performance status were risk factors for FN in this setting. Use of G-CSF prophylaxis in patients with poor PS may help in decreasing FN incidence.

Background The optimal timing of intervention to obtain significant effects with regard to reducing the consumption of antimicrobial agents or antimicrobial-resistant bacteria in facilities that lack the manpower to maintain an antimicrobial stewardship team (AST) is not well-known. Methods An observational retrospective study was performed at Fukuoka University Hospital between April 1, 2013 and March 31, 2016 to evaluate the optimal timing of intervention on appropriate antimicrobial therapy for specific antimicrobial agents, including broad-spectrum antimicrobial agents (piperacillin–tazobactam, carbapenems, fluoroquinolones) and anti-MRSA (vancomycin, teicoplanin, daptomycin, and linezolid) agents. In period 1, interventions were performed for patients using specific antimicrobial agents for >14 days. In period 2, interventions were performed for patients using anti-MRSA agents, and in period 3, interventions were performed for patients using any specific antimicrobial agents, regardless of the days of use, on a weekly basis. The effects on antimicrobial use, the antimicrobial-resistant bacteria, and the clinical outcomes among the three periods were compared. Results The AUDs of piperacillin–tazobactam and carbapenems decreased significantly (10.8 → 9.2 and 15.7 → 14.2; period 2 vs. period 3, P < 0.05). The rates of piperacillin–tazobactam, meropenem and levofloxacin resistance in Pseudomonas aeruginosa isolates decreased from 13.8%, 16.2%, 11.9% in period 1 to 10.4%, 8.7%, 6.5% in period 3, respectively. The annual costs of these antimicrobials decreased according to the period: period 1, US$ 1,080,000; period 2, US$ 944,000; and period 3, US$ 763,000 (period 3 vs. period 1, P 14 days of use to all patients treated with the specific antimicrobial agents was significantly more effective for reducing the consumption of antimicrobials leading to reduction of the related costs and antimicrobial-resistant P. aeruginosa without compromising the patient outcomes. Disclosures T. Takata, Taisho Toyama Pharmaceutical Co. Ltd.: Speaker’s Bureau, Speaker honorarium

Previous studies have shown that Peyer's patches (PP) are not required for intestinal immunoglobulin A (IgA) responses to orally administered soluble protein. However, the roles of PP in regulation of mucosal immune responses against bacterial antigen remain to be clarified. In the present study, we generated several gut-associated lymphoreticular tissue-null mice by treatment with anti-interleukin-7 receptor antibody, the fusion protein of lymphotoxin β receptor and IgG Fc, and/or tumor necrosis factor receptor p55 and IgG Fc. These mice were then immunized with recombinantSalmonellaexpressing the C fragment of the tetanus toxin (rSalmonella-Tox C). Orally immunized PP-null mice as well as isolated lymphoid follicle (ILF)-null, PP/ILF-null, and PP/ILF/mesenteric lymph node-null mice induced identical levels of tetanus toxoid (TT)-specific systemic IgG responses to those of control mice. However, PP-null mice, but not ILF-null mice, failed to induce TT-specific intestinal IgA antibodies. Analysis of TT-specific CD4+T-cell responses showed a reduction of gamma interferon (IFN-γ) synthesis in the intestinal lamina propriae of PP-null mice given oral rSalmonella-Tox C. In contrast, TT-specific IFN-γ responses in the spleen and delayed-type hypersensitivity responses were intact in those immunized mice. Interestingly,Salmonellalipopolysaccharide (LPS)-specific fecal IgA responses were not elicited in PP-null mice, while serum IgG anti-LPS antibodies were identical to those of control mice. These results suggest that while none of the gut-associated lymphoreticular tissues are required for the induction of systemic immune responses, PP are an essential lymphoid tissue for induction and regulation of intestinal IgA immunity against orally administered rSalmonella.

Rho family small GTP-binding proteins, including Rho, Rac, and Cdc42, are key determinants of cell movement and actin-dependent cytoskeletal morphogenesis. Rho GDP-dissociation inhibitor (GDI) α and Rho GDIβ (or D4/Ly-GDI), closely related regulators for Rho proteins, are both expressed in hemopoietic cell lineages. Nevertheless, the functional contributions of Rho GDIs remain poorly understood in vivo. In this study, we report that combined disruption of both the Rho GDIα and Rho GDIβ genes in mice resulted in reduction of marginal zone B cells in the spleen, retention of mature T cells in the thymic medulla, and a marked increase in eosinophil numbers. Furthermore, these mice showed lower CD3 expression and impaired CD3-mediated proliferation of T cells. While B cells showed slightly enhanced chemotactic migration in response to CXCL12, peripheral T cells showed markedly reduced chemotactic migration in response to CCL21 and CCL19 associated with decreased receptor levels of CCR7. Overall, Rho protein levels were reduced in the bone marrow, spleen, and thymus but sustained activation of the residual part of RhoA, Rac1, and Cdc42 was detected mainly in the bone marrow and spleen. Rho GDIα and Rho GDIβ thus play synergistic roles in lymphocyte migration and development by modulating activation cycle of the Rho proteins in a lymphoid organ-specific manner.

Diverse functions have been reported for lipocalin 2. To investigate these functionsin vivo, we generated gene-targeted lipocalin 2-deficient mice (Lcn2−/−mice).In vitrostudies have suggested that lipocalin 2 is important for cellular apoptosis induced by IL-3 withdrawal, and for the induction of kidney differentiation during embryogenesis. Analysis ofLcn2−/−mice showed normal cell death upon IL-3 withdrawal and normal kidney development. However, we found thatLcn2−/−mice exhibited an increased susceptibility to bacterial infections, in keeping with the proposed function of lipocalin 2 in iron sequestration. Neutrophils isolated fromLcn2−/−mice showed significantly less bacteriostatic activity compared with WT controls. The bacteriostatic property of the WT neutrophils was abolished by the addition of exogenous iron, indicating that the main function of lipocalin 2 in the antibacterial innate immune response is to limit this essential element. Another important function ascribed to lipocalin 2 has been its protective role against kidney ischemia-reperfusion injury. We analyzedLcn2−/−mice using a mouse model for severe renal failure and could not detect any significant differences compared with their WT littermates.

We compared the effect of high-dose therapy together with autologous peripheral blood stem cell transplantation (autoPBSCT) in 60 patients with multiple myeloma (MM) with 90 patients who underwent conventional chemotherapy. We scored the prognostic factors according to our reported classification system that includes measurements of serum albumin, serum beta-2-microglobulin, and morphology of myeloma cells selected by multivariate analysis. We separated the patients into three risk groups at stratification level I (low, intermediate and high) and into two risk groups at stratification level II (low and high). AutoPBSCT tended to be as effective for high, as for low-risk patients in level I, and was obviously as helpful for high, as for low-risk patients in stratification II. In conclusion, high-risk patients with MM should be treated with high-dose therapy accompanied with autoPBSCT like low-risk patients.

The formation of lymph nodes (LN) and Peyer's patches (PP) can be distinguished by the requirement of RANK for LN but not IL-7R(alpha), which is essential for PP development. However, lymphotoxin-alphabeta (LT(alpha)beta) signaling is required for both organs. The cellular basis underlying this dichotomy was revealed by the finding that the fetal IL-7R(alpha)(+) population responded equally well to IL-7 and RANKL to express LT(alpha)beta. IL-7R(alpha)(+) cells harvested from TRAF6(-/-) embryos expressed LTalphabeta in response to IL-7 but not RANKL, demonstrating that the RANK-TRAF6 signaling pathway regulates LT(alpha)beta expression in LN but not in PP. Soluble IL-7 administered to TRAF6(-/-) embryos was sufficient to restore LN genesis indicating the functional similarities of the IL-7R(alpha)(+) inducer cells for LN and PP genesis.

Flow cytometry (FC) is widely utilized in the diagnosis of lymphoma and the light chain ratio (LCR) is especially useful in the diagnosis of B-cell malignancy. In this study we analysed, retrospectively, the predictive value of the LCR in the diagnosis of B-cell lymphoma in 105 consecutive patients with persistent lymph node enlargement or extranodal masses who underwent biopsy. We used a receiver-operating characteristic curve to establish a LCR threshold value of 2.0. The specificity, sensitivity, positive and negative predictive values were 92.3%, 73.1%, 90% and 77%, respectively. We concluded that determination of LCR is a useful adjunct to pathological diagnosis.

Background Ocular candidiasis is a major complication of candidemia; however, many remains unknown for the incidence, risk factors, and outcome of eye involvement. Methods We retrospectively reviewed the medical records and obtained information related to fungal infection and its management, and visual outcome at Fukuoka University Hospital from 2000 to 2016. Results Of 143 patients with candidemia for whom an ophthalmology consult was requested, 26 had findings consistent with the diagnosis of ocular candidiasis. Patients with ocular candidiasis were mostly infected with Candida albicans (n = 20), followed by C. glabrata (n = 4), and C. tropicalis (n = 2). In contrast, only one patient infected with C. parapsilosis had ocular involvement although the number of the patients with C. parapsilosis candidemia was second the most among candidemia. No difference was seen for the β-d-glucan in patients with or without ocular candidiasis (128.6 vs. 106.1, P = 0.654). All of the isolates other than C. glabrata were susceptible to fluconazole. In all of 23 patients with existing central venous cathers, CVCs were removed after the diagnosis of candidemia. Four-week mortality rate in patients with ocular candidiasis was 16.7% (three of 18 patients) which was not significantly different from that in patients without ocular manifestations. All treated patients were confirmed for clearance of candidemia, received systemic antifungals, and improved for visual outcome or remained stable, and no patients complicated visual loss without surgical treatment. Therapy with micafungin or caspofungin followed by fluconazole (12 patients) was successful in all patients. Conclusion Ocular involvement occurred in 18% of patients with candidemia, and treatment with echinocandins followed by fluconazole was successful in most cases with follow-up. Disclosures T. Takata, Taisho Toyama Pharma: Speaker’s Bureau, Speaker honorarium

Ninety-four episodes of Klebsiella pneumoniae bloodstream infection were identified at a university hospital in Japan. After excluding extended-spectrum beta lactamase-producing strains, 83 blood isolates from these patients were assayed in terms of their bacterial phenotypes such as the mucoid and hypermucoviscosity phenotypes. Bacterial phenotypes were correlated with the patients' clinical manifestations. The hypermucoviscosity phenotype was significantly associated with septic shock at the onset of infections (odds ratio, 15.92; 95% confidence interval, 1.27-468.12), but was not associated with liver abscess formation. Mortality was determined by the presence of septic shock. RmpA gene was associated with the induction of the hypermucoviscosity phenotype. These results reveal unique roles of bacterial phenotypes on the patient's clinical condition in K. pneumoniae bacteremia.

When teicoplanin (TEIC) is injected at the maintenance dose, a long period is required for achievement of the target plasma trough concentration because of its long elimination half-life. An initial loading dose is necessary for rapid achievement of an effective plasma trough concentration. Thus, we proposed that it is necessary for a pharmacist determine the initial loading dose of TEIC to reach an effective plasma trough concentration rapidly after its administration to a patient. In the present study, we evaluated the effectiveness of initial loading dose determination by pharmacists and physicians by comparing the achievement rate of target plasma trough concentrations (>15 μg/mL) and expression of adverse effects. Among 61 patients, 34 were treated according to an initial loading dose determined by a pharmacist (pharmacist intervention) and 27 were treated according to the treating physician's discretion (non-pharmacist intervention). The achievement rate of target concentrations was 91.2% (plasma trough concentration 23.3±5.3 μg/mL) in the pharmacist intervention group and 25.9% (plasma trough concentration 14.0±5.9 μg/mL) in the non-pharmacist intervention group. There was no difference in the incidence of adverse effects between the two groups. Also, we found that systemic inflammatory response syndrome (SIRS) may have a correlation with plasma trough concentrations of TEIC. We suggest that the SIRS score could become a means way of determining initial loading dose. These findings suggest that it is potentially effective for a pharmacist to determine this initial dose in order to rapidly achieve the target plasma trough concentration of TEIC.

Linezolid is an antimicrobial agent for the treatment of multiresistant Gram-positive infections. A practical high-performance liquid chromatography method was developed for the determination of linezolid in human plasma and saliva. Linezolid and an internal standard (o-ethoxybenzamide) were extracted from plasma and saliva with ethyl acetate and analyzed on a Capcell Pak C18 MG column with UV detection at 254 nm. The calibration curve was linear through the range 0.5-50 µg/mL using a 200 μL sample volume. The intra- and interday precisions were all6.44% for plasma and 5.60% for saliva. The accuracies ranged from 98.8 to 110% for both matrices. The mean recoveries of linezolid were 80.8% for plasma and 79.0% for saliva. This method was used to determine the plasma and saliva concentrations of linezolid in healthy volunteers who were orally administered a 600 mg dose of linezolid. Our liquid-liquid extraction procedure is easy and requires a small volume of plasma or saliva (200 μL). This small volume can be advantageous in clinical pharmacokinetic studies, especially if children participate.

The Rab3 small G protein family consists of four members, Rab3A, -3B, -3C, and -3D. Of these members, Rab3A regulates Ca2+-dependent neurotransmitter release. These small G proteins are activated by Rab3 GDP/GTP exchange protein (Rab3 GEP). To determine the function of Rab3 GEP during neurotransmitter release, we have knocked out Rab3 GEP in mice. Rab3 GEP−/− mice developed normally but died immediately after birth. Embryos at E18.5 showed no evoked action potentials of the diaphragm and gastrocnemius muscles in response to electrical stimulation of the phrenic and sciatic nerves, respectively. In contrast, axonal conduction of the spinal cord and the phrenic nerve was not impaired. Total numbers of synaptic vesicles, especially those docked at the presynaptic plasma membrane, were reduced at the neuromuscular junction ∼10-fold compared with controls, whereas postsynaptic structures and functions appeared normal. Thus, Rab3 GEP is essential for neurotransmitter release and probably for formation and trafficking of the synaptic vesicles.

C-reactive protein (CRP) is an acute phase reactant of inflammation. We evaluated the clinical value of serial measurement of CRP in neutropenic patients. CRP was shown to be useful to monitor the response to therapy for febrile episodes in neutropenia. However, we failed to show statistically significant differences in CRP levels between febrile episodes with or without clinically documented infection (p = 0.10) and with or without bacteremia (p = 0.55). Also, we could not predict febrile episodes within three days by the elevation of CRP value. The area under receiver-operating characteristic curve depicting the relationship between CRP levels and forthcoming febrile episodes was only 0.60. In conclusion, serial measurement of CRP was considered to be not useful to predict fever within three days, or to differentiate the types of infection.

We investigated tyrosine phosphorylation of proteins in primary human leukemic cells stimulated by macrophage colony-stimulating factor (M-CSF) in 60 patients with acute myeloid leukemia (AML) and 5 patients with chronic myelomonocytic leukemia and compared the findings for leukemic cells with those of normal human monocytes and bone marrow immature hematopoietic cells. M-CSF induced tyrosine phosphorylation of p140-200, p110, p60, p44, and p42 frequently, and that of p95 and p55 less frequently, in primary myeloid leukemic cells, whereas M-CSF-induced phosphorylation of proteins was not detected in the normal human hematopoietic cells tested. Of these phosphoproteins, p140-200 was phosphorylated in all patients who responded to M-CSF and was considered to be almost identical to Fms, a product of the c-fms proto-oncogene. M-CSF-induced tyrosine phosphorylation was observed frequently (89%) in AML of French-American-British class M4 and infrequently in all other subtypes of AML, including M5. In chronic myelomonocytic leukemia, M-CSF-induced protein phosphorylation was prominent in blast crisis but was not detected in the chronic phase. Both bone marrow immature cells and mature monocytes showed low responsiveness to M-CSF. These findings for responsiveness to M-CSF were correlated with the amount of Fms in each type of cell. We also identified tyrosine phosphorylation of Vav, Shc, and extracellular signal-regulated kinase by M-CSF in some cases. These findings clarified an M-CSF-specific pattern of protein tyrosine phosphorylation and the responsiveness to M-CSF of primary human myeloid cells. Particularly, enhanced phosphorylation responses to M-CSF and increased amounts of Fms protein were observed in restricted human hematopoietic cells with a premature myelomonocytic character.

Rab GDP dissociation inhibitor α (Rab GDIα) is a regulator of the Rab small G proteins implicated in neurotransmission, and mutations of Rab GDIα cause human X-linked mental retardation associated with epileptic seizures. In Rab GDIα-deficient mice, synaptic potentials in the CA1 region of the hippocampus displayed larger enhancement during repetitive stimulation, which was apparently opposite to the phenotype of Rab3A-deficient mice. Furthermore, the Rab GDIα-deficient mice showed hypersensitivity to bicuculline, an inducer of epileptic seizures. These results suggest that Rab GDIα plays a specialized role in Rab3A recycling to suppress hyperexcitability via modulation of presynaptic forms of plasticity.

BACKGROUND Fluconazole is used widely for fungal prophylaxis. Although studies with bone marrow transplantation (BMT) recipients clearly showed the usefulness of oral fluconazole, results of the studies in neutropenic patients other than BMT recipients have been inconsistent. Therefore, the authors performed a meta–analysis to evaluate the efficacy of fluconazole prophylaxis during chemotherapy-induced neutropenia. METHODS The authors identified reports that were not restricted to those in English and not restricted to published trials through MEDLINE, CANCERLIT, or the data base of the Pfizer company. The authors included prospective, randomized studies comparing oral fluconazole with placebo, no treatment, or oral polyenes as prophylaxis for fungal infections in neutropenic patients. Two independent authors extracted data from 16 trials with 3734 patients enrolled. The outcome measures were the development of fungal-related death, systemic and superficial fungal infections, the use of empiric intravenous amphotericin-B, and infections or colonization with fluconazole-resistant fungi. The summarized odds ratios (ORs) were calculated using the Mantel–Haenszel method and the DerSimonian–Laird method. RESULTS Prophylactic fluconazole was not effective in reducing fungal-related death or in reducing proven, systemic fungal infections in non-BMT patients (OR, 0.91; 95% confidence interval [CI], 0.30–2.82 and OR, 0.85; 95% CI, 0.47–1.55, respectively). However, fluconazole was very effective in reducing superficial fungal infections (OR, 0.44; 95% CI, 0.24–0.80), even when it was given in lower doses (50–200 mg per day). There was no increase in proven, systemic infection of fluconazole-resistant fungi, although colonization of those fungi increased. When the results were combined in studies in which the incidence of systemic fungal infections was > 15%, fluconazole was effective in reducing such infections (OR, 0.23; 95% CI, 0.15–0.36). CONCLUSIONS The current analyses failed to find an effect of fluconazole on both fatal fungal infection and systemic fungal infection in non-BMT patients. Further studies on severely neutropenic patients are warranted because prophylactic fluconazole seemed to be effective when the incidence of systemic fungal infection was expected to be > 15%. Cancer 2000;89:1611–25. © 2000 American Cancer Society.

BACKGROUND Although many studies have been performed to evaluate the prognostic significance of CD34 expression in acute myeloid leukemia (AML), the findings have been inconsistent. In this study, the authors reviewed such previous studies to establish a definite conclusion. METHODS Using MEDLINE, the authors identified studies that evaluated the prognostic significance of CD34 expression in AML. The outcome measure was the complete remission rate. They used the random-effect method to combine the results. Results were presented as odds ratios (ORs) with 95% confidence intervals (CIs). The ORs were less than 1 if the complete remission occurred more frequently in the CD34 negative group. RESULTS Twenty-two studies including 2483 patients were reviewed. The combined OR was 0.38 (95% CI, 0.26–0.57), which suggested that CD34 expression was associated with a poor remission rate. However, the authors found statistical evidence of marked heterogeneity among trials (P < 0.001), especially according to time of publication. The combined OR in studies published in or after 1994 was 0.70 (95% CI, 0.47–1.09). The authors divided the studies into several subgroups, but they could not determine the reason for the heterogeneity. CONCLUSIONS At present, CD34 expression should not be considered a marker of poor prognosis because it is not supported by the combined data from recent studies. Further studies should be conducted to investigate the intensity of CD34 expression in specific populations of patients, such as those with t(8;21) or t(15;17) translocations or the AML-M0 subtype. Cancer 2000;88:2529–33. © 2000 American Cancer Society.

Adult T-cell leukemia/lymphoma (ATL) is a neoplastic disorder of T lymphocytes associated with human T lymphotropic virus type I (HTLV-I). The prognosis of ATL is generally poor. We present here a 79-year-old woman with spontaneous remission of acute type ATL. Spontaneous remission was preceded by surgical biopsy and pneumonia and lasted for two years until she died with pancreas cancer. Monoclonal integration of HTLV-I provirus DNA became undetectable after remission.

Interleukin 2 receptor is expressed not only on the surface of activated T or B lymphocytes, but also on certain lymphoid malignancies. The receptor is released from the cell membrane as soluble form (sIL-2R). Serum sIL-2R level is a sensitive and quantitative marker of circulating peripheral blood mononuclear cell activation or specific tumor cell growth including non-Hodgkin's lymphoma (NHL). However, the relevance of serum sIL-2R levels relating to clinical outcome in adult patients with NHL remains uncertain. Therefore, we investigated the serial serum sIL-2R levels in 28 untreated patients with NHL to evaluate its correlation with clinical characteristics. High serum sIL-2R level (>1000 U/ml) at diagnosis was associated with a high incidence of treatment failure (p=0.03) and poor overall survival (p=0.057). The serum sIL-2R levels decreased significantly after achieving complete remission (p=0.003). Further larger studies are required to evaluate whether serum sIL-2R level is an independent prognostic factor or not. However, adding this parameter to those already employed in the International Prognostic Index would perhaps provide a better prognostic index for adult patients with NHL.

We evaluated possible prognostic factors just before salvage therapy with vincristine, doxorubicin, and dexamethasone (VAD) for 36 patients with refractory multiple myeloma. The median duration from diagnosis to the first VAD salvage was 14 months (range 2-76 months). Among parameters that have been shown to be associated with poor survival, a high serum lactate dehydrogenase (LDH) level was the sole significant predictor of survival. The median survival of patients with high LDH levels was 4 months, whereas that of patients with low LDH levels was 20 months. A multivariate analysis identified high LDH and high age as independent prognostic factors. More aggressive therapies might be indicated for high-LDH patients with refractory myeloma.

This paper proposes an efficient scheduling algorithm for distributed real-time systems with such timing constraints as jitter and end-to-end timing. Conventionally, backtrack searching and annealing methods have been used for scheduling problems when timing constraints are complicated. These methods, however, need a lot of computation. This paper proposes a heuristic scheduling method which solves the problem without backtrack scheduling. The proposed method has the merit that the constraints applied to processor scheduling can also be applied to network scheduling. Furthermore, the proposed method can be applied to a network system which is not provided with real-time communications functions, because the proposed method arbitrates communications at a scheduling time. Computer simulations in this paper show that the proposed method provides flexible scheduling capability and can achieve efficient scheduling. © 1999 Scripta Technica, Syst Comp Jpn, 30(13): 43–51, 1999

In the treatment of severe infections complicated to blood dyscrasia, the efficacy and usefulness of fosfomycin (FOM) in combination with sulbactam (SBT)/cefoperazone (CPZ) were compared between patients receiving FOM in the first followed by SBT/CPZ (Group A) and those receiving both drugs simultaneously (Group B). The following results were obtained. 1. The efficacy rate was 56.3% for Group A and 47.9% for Group B, with no significant difference. 2. The efficacy for patients suspected of the presence of septicemia, the efficacy rate was 57.9% for Group A and 54.3% for Group B, with no significant difference. 3. As for underlying disease, patients with acute myelogenous leukemia were most prevailing. In these patients, the efficacy rate was 57.1% for Group A and 27.3% for Group B, with no statistically significant difference. However, the efficacy rate tended to be higher in Group A. 4. The administration of antibiotics was effective to restore the neutrophil count to 501/microliters or higher in 77.8% and 45.5% of the cases for Groups A and B, respectively, with significantly higher efficacy for Group A. 5. In the safety evaluation a total of 115 cases were included. Side effects and laboratory abnormalities were seen in 3 cases each, but none of them were serious in degree. From these results, it was confirmed that the combination therapy consisting of administration of FOM followed by SBT/CPZ with some interval is effective for severe infections complicated to blood dyscrasia.

Peripheral lymphoid tissues, such as lymph nodes and Peyer’s patches (PPs), are organs required for mounting highly efficient immune responses to small quantities of Ag. The compartmentalization of the cellular components involved in the immune response into distinct zones supports the function of these tissues; however, little is known about how this compartmentalization is achieved. In this study, we analyzed neonatal PP development and present evidence that the CD3−IL-7Rα+ PP inducer cells that initially play a pivotal role in the formation of the PP anlagen are involved in the formation of B and T cell zones in neonatal mice. PP inducer cells migrate between these zones by undergoing chemokine receptor switching.

Eleven patients with hairy cell leukemia (HCL) were treated with YK-176 (2'-deoxycoformycin) at a dose of 5 mg/m2 by intravenous injection every week or every other week. Patients received a median of eight (range 4-19) injections of YK-176. Five patients had previously been untreated, four of whom had massive splenomegaly. Six patients had previously been treated, four with interferon-alpha (IFN-alpha) or IFN-alpha and chemotherapy and two with prednisolone. Two patients had had splenectomies. Five patients achieved complete remission (CR) and six, partial remission (PR) according to WHO criteria (remission rate 100%, 95% confidence interval (CI) 74-100%). All six neutropenic patients recovered > 1,500/microliters neutrophils, six of seven anemic patients recovered > 12.0 g/dl hemoglobin and five of nine thrombocytopenic patients recovered > 100,000/microliters platelets following the treatment. According to the response criteria for HLC, five patients achieved CR, two PR and four minor response. The overall remission (CR + PR) rate was 64% (95% CI 35-85%). The CR and PR have lasted from > 30 to > 718 days (median, > 281 days) so far with no relapses. Of four patients previously treated with IFN-alpha, two achieved CR and one, PR. All patients were alive with a median survival time of > 290 days from treatment (range > 50- > 763 days). The treatment was generally well tolerated. Mild to moderate nausea, vomiting, appetite loss and general fatigue were experienced in two patients, skin rash in one and a transient fever in three. YK-176 was a highly active agent in the treatment of HCL.

Miconazole (400-1200 mg/day) was administered to patients with deep mycosis and suspected deep mycosis, and the efficacy evaluated. beta-Glucan was determined as the early diagnostic parameter of deep mycosis, and the relationships between the clinical efficacy of miconazole and the titers of beta-glucan were also evaluated. Forty-nine cases were evaluated, including 2 cases of deep mycosis and 47 cases of suspected deep mycosis. Most of the patients had hematological malignancies. The rate of efficacy was 100% (2/2) in deep mycosis, 66.0% (31/47) in suspected deep mycosis, and 67.3% (33/49) in total. beta-Glucan was determined in 39 cases before the administration of miconazole. The rate of beta-glucan positivity was 100% (1/1) in deep mycosis and 44.7% (17/38) in suspected deep mycosis. beta-Glucan was also determined before and after the administration of miconazole in 11 cases. The titers of beta-glucan became negative in 6 cases, decreased in 2 cases and increased in 3 cases. Thus, the beta-glucan titers became negative or decreased in 72.7% (8/11) of the cases. Efficacy of miconazole was 83.3% (5/6) in the cases in which beta-glucan became negative, 50.0% (1/2) in the cases in which the titers of beta-glucan decreased, and 33.3% (1/3) in the cases in which the titers of beta-glucan increased. Miconazole was effective in the treatment of deep mycosis, and the titers of beta-glucan correlated well with the clinical efficacy of miconazole. The determination of beta-glucan appears to be useful for the diagnosis of deep mycosis.

Mesenchymal stromal cells are crucial components of secondary lymphoid organs (SLOs). Organogenesis of SLOs involves specialized stromal cells, designated lymphoid tissue organizer (LTo) in the embryonic anlagen; in the adult, several distinct stromal lineages construct elaborate tissue architecture and regulate lymphocyte compartmentalization. The relationship between the LTo and adult stromal cells, however, remains unclear, as does the precise number of stromal cell types that constitute mature SLOs are unclear. From mouse lymph nodes, we established a VCAM-1+ICAM-1+MAdCAM-1+ reticular cell line that can produce CXCL13 upon LTβR stimulation and support primary B cell adhesion and migration in vitro. A similar stromal population sharing many characteristics with the LTo, designated marginal reticular cells (MRCs), was found in the outer follicular region immediately underneath the subcapsular sinus of lymph nodes. Moreover, MRCs were commonly observed at particular sites in various SLOs even in Rag2−/− mice, but were not found in ectopic lymphoid tissues, suggesting that MRCs are a developmentally determined element. These findings lead to a comprehensive view of the stromal composition and architecture of SLOs.

Death rates due to multiple myeloma are increasing by every year in Japan since 1970. 1,896 men and 1,889 women were died, during 2005. Crude mortality rates are also rising since 1970 and reach 3.04 per 100,000 and 2.89 per 100,000 among men and women, respectively in 2005. Age-adjusted mortality rates (using the 1985 Japan Standard) reach 1.5-1.6 per 100,000 in 1995 and persist its value till now.

It is now well established that the interaction between “inducer” cells of hemopoietic origin and “organizer” cells of mesenchymal lineage is involved in the organogenesis of lymph node (LN) and Peyer’s patch (PP). Organizer cells are defined by the expression of VCAM-1 and ICAM-1 and the production of homeostatic chemokines. However, several studies suggested the presence of a diversity among these cells from different lymphoid tissues. Thus, we attempted to define the difference of organizer cells of LN and PP in terms of gene expression profile. Microarray analyses of organizer cells revealed that these cells isolated from embryonic mesenteric LN expressed higher levels of genes that are related to inflammation, tissue remodeling, and development of mesenchymal lineage compared with those from PP. Several transcription factors related to epithelial-mesenchymal interactions were also up-regulated in organizer cells from LN. These results indicate that organizer cells in LN and PP are indeed distinct and suggest that the organizer cells in LN are at a more activated stage than those in PP.