Akiko Hori

Effect of fluconazole prophylaxis on fungal blood cultures: an autopsy-based study involving 720 patients with haematological malignancy

Summary. To investigate the utility of blood culture of invasive fungal infections in patients with haematological malignancies, an autopsy survey was conducted in 720 patients who were treated between 1980 and 1999. We identified 252 patients with invasive mycosis. These included Candida (n = 94), Aspergillus (n = 91), Zygomycetes (n = 34), Cryptococcus (n = 7), Trichosporon (n = 11), Fusarium (n = 1), and unknown fungi (n = 20). Of the 94 patients with invasive candidiasis, 20 had positive blood cultures. Of the 11 patients with invasive trichosporonosis, seven had positive blood cultures. The sensitivities of blood cultures were 1·1%, 0% and 14% for detecting invasive aspergillosis, zygomycosis and cryptococcosis respectively. Multiple regression analysis showed a significant correlation between results of Candida blood cultures and some variables, including prophylactic use of absorbable antifungals (P = 0·0181) and infection by Candida albicans (P = 0·0086). The sensitivity of blood cultures decreased when patients received antifungal chemoprophylaxis. Unless these agents are inactivated in culture bottles, conventional blood cultures might produce false‐negative results.

DOSY Study on Dynamic Catenation: Self-Assembly of a [3]Catenane as a Meta-Stable Compound from Twelve Simple Components

Synthesis of [2]catenane 6 has been successfully achieved by the combination of Pd complex 1 and pyridines 2 and 3 at a molar ratio of 2:1:1 in D20. A mixture of square molecule 4 (prepared from 1 and 2) and macrocycle 5 (obtained from 1 and 3), in which the final ratio of 1, 2, and 3 was kept 2:1:1 reorganizes in D2O/CD3OD (1:1) to form 6 within one day. However, the same mixture in D2O shows the formation of novel [3]catenane 7 along with the [2]catenane. In order to make 7, the theoretical ratio of components 1, 2, and 3 should be 3:1:2. Thus, deliberately maintaining such ratio of the above-mentioned molecules, a higher proportion of the [3]catenane is observed in D2O as found from 1H NMR spectra of the system. Reorganization of the twelve components to form [3]catenane is supported by studies with the DOSY method. This method is a first attempt to separate, from a mixture, either catenanes or any other supramolecular self-assembly structures. CSI-MS studies further support the assigned catenane super structures 6 and 7. All the results indicate that the [2]catenane is thermodynamically the most stable structure, while the [3]catenane is a meta-stable self-assembly.

Antithymocyte globulin affects the occurrence of acute and chronic graft-versus-host disease after a reduced-intensity conditioning regimen by modulating mixed chimerism induction and immune reconstitution

Background. There have been no detailed analyses of the induction of donor cell–type chimerism, the onset and incidence of acute and chronic graft-versus-host disease (GVHD), and the immune recovery kinetics after reduced-intensity stem cell transplantation (RIST). Methods. To address these, with particular emphasis on the impact of the use of antithymocyte globulin (ATG) in RIST, we compared 39 consecutively registered patients who underwent RIST from an HLA-matched related donor and 33 patients who underwent conventional marrow-ablative transplantation. Results. The incidences of grades II to IV acute and chronic GVHD tended to be less in RIST with ATG than in either RIST without ATG or conventional marrow-ablative transplantation. In a multivariate analysis, the predictive factors for acute and chronic GVHD included, respectively, ATG and grades II to IV acute GVHD. In a chimerism analysis, the achievement of complete donor chimera in T-cell lineage was delayed in RIST without ATG compared with RIST with ATG (P =0.038), which might explain the observed delayed onset of acute GVHD in RIST with ATG compared with the other two regimens. The ratio of type 1 and 2 dendritic cells did not affect the development of GVHD, whereas the number of naive CD4+ T cells did. No difference was observed in the incidence of clinically definitive infection, including cytomegalovirus, among the three cohorts, regardless of the use of ATG. Conclusions. We suggest that the conditioning regimen and immunosuppressive strategy after RIST should be carefully balanced against the risk of GVHD and of relapse of the basic disorder caused by the lack of a graft-versus-leukemia benefit.

TRALI after the infusion of marrow cells in a patient with acute lymphoblastic leukemia

BACKGROUND:  TRALI is one of the most serious, life‐threatening complications after blood transfusion. Antibodies against neutrophils or HLA molecules from the donor are thought to be the primary causative agents. Rarely, antibodies in the recipient may react with transfused neutrophils and initiate the same events, which raises the possibility that TRALI may also occur in an allogeneic PBPC transplantation setting.

IL‐15 exacerbates collagen‐induced arthritis with an enhanced CD4+ T cell response to produce IL‐17

IL‐15 is thought to be involved in the pathogenesis of rheumatoid arthritis (RA). We found that IL‐15 plays an important role in the development of murine collagen‐induced arthritis (CIA). The incidence and severity of CIA were slightly decreased in IL‐15 KO mice but were increased in IL‐15 Tg mice compared with wild‐type (WT) mice. The levels of type II collagen (CII)‐specific IL‐17 production were significantly increased in IL‐15 Tg mice compared with WT mice with CIA. Expression of IL‐23R was up‐regulated in CD4+ T cells in IL‐15 Tg mice but down‐regulated in IL‐15 KO mice compared with WT mice. In correlation with the expression levels of IL‐23R, IL‐17 production by CD4+ T cells in response to exogenous IL‐23 was increased in IL‐15 Tg mice compared with WT mice. Furthermore, exogenous IL‐15 synergized with IL‐23 to induce CII‐specific IL‐17 production by CD4+ T cells in vitro. Taken together, these results indicate that IL‐15 plays an important role in the progression of CIA through increasing antigen‐specific IL‐17 production by CD4+ T cells.

A prospective trial to evaluate the safety and efficacy of pravastatin for the treatment of refractory chronic graft-versus-host disease.

This prospective study evaluates the safety and efficacy of pravastatin for the treatment of chronic graft-versus-host disease (GVHD). We included 18 patients with refractory chronic GVHD. Oral pravastatin was started at 10 mg/day, and the dose was increased up to 40 mg/day in 4 weeks. This maximum dose was administered over 8 weeks. There were no severe adverse events caused by pravastatin. A clinical response was observed in the skin score in two patients, mouth score in five patients, eye score in two patients, liver score in three patients, platelet count score in one patient, and weight loss in two patients. The overall response rate was 28%. Immunophenotypic analyses showed that T-helper (Th)1 cells were dominant in all but one patient before treatment and that the Th1/Th2 ratio tended to be lower in the responders than in the nonresponders. A randomized controlled trial is warranted to evaluate the efficacy of pravastatin against chronic GVHD.

Late hemorrhagic cystitis after reduced-intensity hematopoietic stem cell transplantation (RIST)

Summary:We reviewed medical records of 256 patients to investigate the frequency and characteristics of hemorrhagic cystitis (HC) associated with reduced-intensity stem cell transplantation (RIST) as opposed to conventional stem cell transplantation (CST); 137 patients underwent CST and 119 RIST. Diagnosis of HC was made based on two or more episodes of sterile, macroscopic hematuria with normal coagulation profiles, without any evidence of renal stones or genitourinary malignancy. Actuarial frequency of HC development in RIST group was 7.6% (9/119), which gave a cumulative annual incidence of 11.7%. In CST group, 13 of 137 patients (9.5%) developed HC, giving an estimated annual incidence of 9.7%. The probability of developing HC was similar between the two groups (P=0.77). The viral etiologies of HC, adenovirus (n=12) and BK virus (n=2), were documented in eight patients after RIST and in six after CST. HC was milder and of a shorter duration, with less blood transfusion requirements, in RIST group than in CST group. A multivariate analysis revealed that HC was associated with antiadenovirus antibody positivity in the recipients, total dose of busulfan, and chronic GVHD. Although HC following RIST is less severe than that following CST, it is still a significant problem.

Heterodinuclear MIICuII complexes of a constrained macrocyclic compartmental ligand. EPR studies of spin-coupled MnIICuII (ST=2) and NiIICuII (ST=1/2)

A phenol-based macrocyclic compartmental ligand (L) 2 - , having an N(amine) 2 O 2 metal-binding site with 1,3-trimethylene chain between the two aminic nitrogen atoms and an N(imine) 2 O 2 site with 1,8-naphthalene chain between the two iminic nitrogen atoms, has afforded the following heterodinuclear M I I Cu I I complexes, [MCu(L)(dmf) 2 ](ClO 4 ) 2 (M = Mn (1), Co (2), Ni (3), Zn (4)). X-ray crystallographic studies for 1-4 demonstrate that the M I I resides in the N(amine) 2 O 2 site and the Cu I I in the N(imine) 2 O 2 site of the constrained macrocyclic ligand. The M I I has a six-coordinate geometry together with two dmf molecules at the axial site and the Cu I I has a square-pyramidal geometry with a perchlorate oxygen atom at the apical site. Magnetic, visible spectral and electrochemical properties of the complexes are examined. A frozen dmf solution of 1 at liquid nitrogen temperature shows an EPR signal with a Mn hyperfine structure (A M n = 103 x 10 - 4 cm - 1 ) at ∼ 2400 Ga, which is attributed to the S T = 2 ground state of the spin-coupled Mn I I (S = 5/2)-Cu I I (S = ½). A qualitative analysis is made for the EPR of 1 in comparison with the EPR of the S T = ½ state of spin-coupled Ni I I (S = 1)-Cu I I (S = ½) of 3.

Value of surveillance blood culture for early diagnosis of occult bacteremia in patients on corticosteroid therapy following allogeneic hematopoietic stem cell transplantation

Summary:Bloodstream infection (BSI) is a significant complication following allogeneic hematopoietic stem cell transplantation (allo-SCT). Corticosteroids mask inflammatory responses, delaying the initiation of antibiotics. We reviewed medical records of 69 allo-SCT patients who had been on >0.5 mg/kg prednisolone to investigate the efficacy of weekly surveillance blood cultures. A total of 36 patients (52%) had positive cultures, 25 definitive BSI and 11 probable BSI. Pathogens in definitive BSI were Staphylococcus epidermidis (n=7), S. aureus (n=4), Entrococcus faecalis (n=3), Pseudomonas aeruginosa (n=5), Acenitobacter lwoffii (n=4), and others (n=10). The median interval from the initiation of corticosteroids to the first positive cultures was 24 days (range, 1–70). At the first positive cultures, 15 patients with definitive BSI were afebrile. Four of them remained afebrile throughout the period of positive surveillance cultures. Patients with afebrile BSI tended to be older (P=0.063), and had in-dwelling central venous catheters less frequently than febrile patients (P<0.0001). Bloodstream pathogens were directly responsible for death in two patients with afebrile BSI. This study demonstrates that cortisosteroid frequently masks inflammatory reactions in allo-SCT recipients given conrticosteroids, and that surveillance blood culture is only diagnostic clue for ‘occult’ BSI.

Reduced-intensity stem cell transplantation from an HLA-identical sibling donor in patients with myeloid malignancies

Summary:The purpose of this study was to evaluate the feasibility and efficacy of allogeneic hematopoietic stem cell transplantation with a reduced-intensity regimen (RIST) in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). In all, 36 patients (median age 55 years) underwent RIST from an HLA-matched related donor between September 1999 and December 2002. The diagnoses included AML (n=14), leukemia evolving from MDS (n=10), and MDS (refractory anemia with excess blasts n=6, refractory anemia n=6). The RIST regimen consisted of purine analog (cladribine or fludarabine)/busulfan, with or without antithymocyte globulin. The regimen was well tolerated, and 34 patients achieved durable engraftment and most achieved remission after RIST. A total of 17 patients developed grade II–IV acute GVHD, and 27 developed chronic GVHD. Eight patients relapsed, and five of them received antithymocyte globulin (ATG) as part of the preparative regimen. A total of 12 patients died (four disease progression, six transplantation-related complications, and two others). Estimated 1-year disease-free survival (DFS) in low- and high-risk groups was 85 and 64%, respectively. We conclude that RIST can be performed safely in elderly patients with myeloid malignancies, and has therapeutic potential for those who fail conventional chemotherapy. In view of the significant association between GVHD or ATG and DFS, defined management of GVHD following RIST should become a major target of clinical research.