Kazuho Shimura

B‐cell lymphoma associated with haemophagocytic syndrome: a clinical, immunological and cytogenetic study

B‐cell lymphoma associated with haemophagocytic syndrome (HPS) is extremely rare in Western countries but has recently been increasingly reported in Asian countries. We describe seven patients with B‐cell lymphoma associated with HPS, six males and one female, age range 41–82 years (median 63 years). All patients had fever and splenomegaly, and six of the seven patients had hepatomegaly with no associated lymphadenopathy. The bone marrow showed haemophagocytosis and an infiltration of lymphoma cells. All patients showed increased levels of lactate dehydrogenase, C‐reactive protein, ferritin and soluble interleukin‐2 receptor. Lymphoma cells were positive for CD19, CD20 and surface immunoglobulin in all patients examined, and positive for CD5 in four of seven patients. Cytogenetic analyses of bone marrow cells showed a complex structural abnormality including chromosome 14q32 in two patients, 19q13 in three patients and deletion of the terminal part of 8p21 in six patients. The prognosis was poor; only two of the seven patients have survived in complete remission with a median survival of 11 months. These data suggested that B‐cell lymphoma associated with HPS might constitute a distinct biological and clinical disease entity. Abnormality of chromosome 19q13 and loss of 8p21 might be involved in the pathogenesis of this disease.

Hyperbaric oxygen in addition to antibiotic therapy is effective for bisphosphonate-induced osteonecrosis of the jaw in a patient with multiple myeloma

A 60-year-old man with multiple myeloma (MM) (IgG-κ, stage IIIA) had been treated with minodronate at 6 mg orally as a phase 1 clinical trial for myeloma bone disease for 13 months (total dose, 4032 mg). Then he received incadronate at 10mg intravenously every 1 to 4 weeks (total dose, 350 mg). In July 2005, he complained of mild right mandibular pain, and bone scintigram showed a hot spot at the right side of the mandible. Panoramic radiograph showed osteonecrosis of the jaw (ONJ) and axial and 3-dimensional computed tomography confirmed ONJ. Oral examination showed massive gingival swelling of the right side of the mandible without exposed necrotic bone. He was given clarithromycin in addition to levofloxacin, followed by hyperbaric oxygen (HBO) therapy, which resulted in the complete disappearance of the pain. This is a first reported case of ONJ induced by incadronate. The present case suggests that early detection of ONJ by regular dental check-ups is important in the management of patients with MM who have received bisphosphonate therapy, and HBO in combination with antibiotic therapy is effective in the early stage of ONJ.

Successful peripheral blood stem cell transplantation for myelodysplastic syndrome

Wilms’ tumor (WT1) gene expression is increased in patients with leukemia as well as myelodysplastic syndrome (MDS) and is useful for detection of minimal residual disease (MRD). A 47-year-old man given a diagnosis of refractory anemia with excess of blasts in transformation (RAEB-T) received myeloablative therapy followed by autologous peripheral blood stem cell transplantation (PBSCT). MRD by WT1 expression was not detected in the graft. The patient has been in CR for 25 months after PBSCT. These observations suggest that PBSCT is feasible for patients with RAEB-T and analysis of WT1 expression can be applied for patients with high risk MDS.

Tocilizumab is effective for pulmonary hypertension associated with multicentric Castleman’s disease

A 38-year-old man, diagnosed as having multicentric Castleman’s disease (plasma cell type) in 1995, had been treated with melphalan and prednisolone or prednisolone alone, but there was no remarkable response. In 2002, he was admitted to our hospital with a chief complaint of increasing dyspnea on effort. Laboratory data showed high serum IgG (10050 mg/dl), interleukin-6 (37.9 ng/ml), and vascular endothelial growth factor (VEGF 1920 pg/ml) levels. In addition, serum viscosity was very high (6.0 cp). Electrocardiogram, echocardiogram, and cardiac catheterization demonstrated pulmonary hypertension (PH). There were no other demonstrable causes of PH suggesting that PH was due to hyperviscosity syndrome and high VEGF level. He was treated with plasmapheresis, resulting in a transient improvement of dyspnea. Then, he was given humanized anti-interleukin-6 receptor antibody (tocilizumab), which resulted in the dramatic improvement of dyspnea and PH a few weeks later. PH is a rare complication of MCD, and could be successfully treated with tocilizumab.

ADAMTS-13 activity can predict the outcome of disseminated intravascular coagulation in hematologic malignancies treated with recombinant human soluble thrombomodulin.

We conducted a multicenter prospective study for evaluating the utility and prognostic markers of recombinant human soluble thrombomodulin (rTM) treatment for acute disseminated intravascular coagulation (DIC) by various types of hematologic malignancies. The study comprised 30 patients with DIC due to hematologic diseases without severe infection. DIC improved in 15 patients and 20 were alive on day 28. Univariate analyses showed that, in comparison with patients who had survived on day 28, patients who had not survived on day 28 showed significantly higher plasma levels of plasminogen activator inhibitor‐I (PAI‐I) and significantly lower plasma activity of a disintegrin and metalloproteinase with a thrombospondin Type 1 motif, member 13 (ADAMTS‐13). Moreover, multivariate logistic regression analysis identified a significant association between plasma ADAMTS‐13 activity before treatment and survival on day 28 (P = 0.034). In particular, patients with lower ADAMTS‐13 activity (≤65%) had a poorer survival rate than those with a higher activity (P = 0.042). These findings suggest that the plasma ADAMTS‐13 activity at the time of DIC diagnosis might help to predict the prognosis of patients treated with rTM for DIC associated with hematologic malignancies. Am. J. Hematol., 2012.

Toll-like receptors (TLRs) are expressed by myeloid leukaemia cell lines, but fail to trigger differentiation in response to the respective TLR ligands.

reported. In one study (Amoura et al, 2004), two patients with a simultaneous clinical picture of TTP and APS with LA, anticardiolipin, anti ADAMTS13 antibodies and ADAMTS13 low levels, were described. This association is controversial, and recent articles have recommended against the diagnosis of TTP in the presence of aPL antibodies (Porta et al, 2005). Other reports, when aPL antibodies and microangiopathic thrombosis has been observed, have suggested that aPL antibodies could be a consequence of the endothelial damage, but not a cause of the disease. (Asherson et al, 2008). There are isolated findings that could explain a sporadic relationship between APS and TTP. One such finding points out that, although ADAMTS13 deficiency and anti ADAMTS13 antibodies basically cause microcirculation thrombosis, there is a possibility that occasionally large vessel thrombosis in organs, such as the brain, could be a primary manifestation (Downes et al, 2004). In its turn, there is some evidence that the aPL activity creates an increased tissue factor production in extensive vascular regions (catastrophic APS) (Urbanus et al, 2008). It seems probable that systematic testing of ADAMTS13 and anti-ADAMTS13 antibodies in APS patients with neurological symptoms could identify cases of the underdiagnosed TTPAPS combination. Nevertheless, according to the findings of Austin et al (2008), the widespread prevalence of ADAMTS13 low activity and a variety of heterogeneous anti-ADAMTS13 antibodies in aPL positive patients without thrombotic events creates further questions.

Optimized dosage and frequency of cefozopran for patients with febrile neutropenia based on population pharmacokinetic and pharmacodynamic analysis

OBJECTIVES To establish a cefozopran (a fourth-generation cephem) population pharmacokinetic model using patient data and use it to explore alternative dosage regimens that could optimize the currently used dosing regimen to achieve higher likelihood of pharmacodynamic exposure against pathogenic bacteria. METHODS We conducted a prospective clinical trial of cefozopran for haematological patients with febrile neutropenia (FN). Twenty-two patients (30 episodes) were selected to receive intravenous cefozopran every 8 h on a daily basis. We gathered concentration data and performed the NONMEM program. The Monte Carlo simulation was performed to assess the pharmacodynamic exposure based on the population pharmacokinetics and MIC. RESULTS The NONMEM program demonstrated that a two-compartment model provided a best fit for the data, that is, CL of 4.62 (L/h), V1 of 10.3 (L), Q of 4.47 (L/h), and V2 of 4.48 (L). On the basis of the Japanese national surveillance findings for Pseudomonas aeruginosa, methicillin-sensitive Staphylococcus aureus, coagulase-negative Staphylococcus, viridans group streptococci, Escherichia coli and Klebsiella pneumoniae, Monte Carlo simulation data showed that probability of target attainment(T>MIC = 70%) is 67% to 97% for dosing every 8 h, and 48% to 88% for dosing every 12 h. For the patients in whom the efficacy of cefozopran could be evaluated, 17 of 22 patients (77.2%) survived the episode of FN without requiring further antibacterial treatment. CONCLUSIONS Our study proved that Monte Carlo simulation based on population pharmacokinetics can determine optimized dosage and method. The optimal regimen for this cephem was found to be three times daily.

Circulating Endothelial Progenitor Cells Decreased in Patients with Sclerodermatous Chronic Graft-versus-Host Disease

Chronic graft-versus-host disease (cGVHD) is a common late complication of allogeneic stem cell transplantation (allo-SCT). Some cGVHD patients develop skin lesions, and the skin lesions in sclerodermatous cGVHD (s-cGVHD) patients resemble those in progressive systemic sclerosis (PSS), which is characterized by impaired production of circulating endothelial progenitor cells (EPCs). We investigated, retrospectively, whether low EPC production may promote the development of sclerodermatous lesions in cGVHD. Peripheral blood (PB) was obtained from 14 healthy volunteers and 27 allo-SCT patients. Five patients developed s-cGVHD. CD34(+) cells were purified by using the magnetic cell-sorting separation system, and the CD34(+)/CD133(+)/vascular endothelial growth factor (VEGF) receptor-2(+) EPCs were quantified. The endothelial cell colony-formation potential was evaluated. Serum VEGF and basic fibroblast growth factor (b-FGF) concentrations were measured by ELISA. The s-cGVHD patients had significantly lower median circulating EPCs frequencies than non-s-cGVHD patients or control (145 of 20 mL [interquartial range-IQR 107-193] versus 1083.5 [IQR 669.3-2151]; P = .0023, and versus 1530.5 [IQR 961.3-2158]; P = .0012, respectively). They also had impaired median endothelial-forming ability compared to non-s-cGVHD patients or controls (3.8 [IQR 1.0-4.3] versus 12.8 [IQR 8.8-28.8], and versus 26.4 [IQR 23.6-30.6], respectively; P = .0012). Their VEGF and b-FGF serum levels were also higher than in controls. In conclusion, s-cGVHD patients show findings consistent with those seen in PSS with impaired vasculogenesis that may limit blood perfusion and may contribute to the development of sclerodermatous lesions.

Close pathogenetic relationship between ocular immunoglobulin G4-related disease (IgG4-RD) and ocular adnexal mucosa-associated lymphoid tissue (MALT) lymphoma

Immmunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a chronic sclerosing inflammatory disease characterized by mass-forming lesions such as swelling, nodules or hypertrophy in one or more organs...

Population pharmacokinetics of itraconazole solution used as prophylaxis for febrile neutropenia

Although administration of antifungal agents, such as itraconazole (ITC) solution, for prophylaxis is the most promising strategy for the treatment of haematological malignancies, little is known about the population pharmacokinetic (PK) parameters. A clinical study was conducted to identify PK parameters for the administration of 200mg/day ITC solution used as prophylaxis for febrile neutropenia in patients undergoing treatment. The study population comprised six patients. NONMEM software was used to estimate PK parameters. Clearance, volume of distribution and the absorption rate constant were 12.7 L/h, 333 L and 1.72 h(-1), respectively. These parameters were different from a previous study to large extent, which may be due to differences in intended patients. These differences strongly suggest that establishment of population pharmacokinetics is essential for planning a prospective clinical trial. Assuming a normal distribution, we predicted the trough concentrations of 94.5% of the patients receiving 200 mg/day ITC solution to be >250 ng/mL, indicating that administration of 200mg/day might be suitable for prophylaxis. This pilot study presents a basic PK model of ITC solution in Japanese haematological patients for the establishment of optimal administration. Large-scale studies will be necessary in the future to determine population PK parameters with covariates.