Familial clustering of hypereosinophilic diseases treated with mepolizumab: a case report from Japan.

Summary: We describe a female diagnosed with non-allergic asthma. On March 24, 2016, examination of the skin-biopsy specimen revealed dense eosinophilic infiltration, and the Fip-1-like 1-platelet-derived growth factor receptor a fusion gene in peripheral blood mononuclear cells was negative. She was diagnosed with idiopathic hypereosinophilic syndrome. She was treated with intravenous methylprednisolone (MPSL), and subsequent oral MPSL. Then, she started to receive a monthly mepolizumab in June 2016, and successfully withdrew from daily use of oral MPSL. The patient has a mother diagnosed with non-allergic asthma. In February 2005, she was diagnosed with eosinophilic granulomatosis with polyangitis because of elevated antineutrophil myeloperoxidase antibodies, and the skin-biopsy specimen findings. She started to receive a monthly mepolizumab in June 2016. Corticosteroid therapy was successfully withdrawn. To our knowledge, this is the first case report suggesting mepolizumab may be a useful treatment for familial clustering of hypereosinophilic diseases.

Favorable clinical efficacy of mepolizumab on the upper and lower airways in severe eosinophilic asthma: a 48-week pilot study.

Summary: Objective. Assessing efficacy of mepolizumab on the upper and lower airways in severe eosinophilic asthma patients. Patients and methods. This study was a 48-week prospective open-label analysis of mepolizumab in 11 asthmatics with chronic rhinosinusitis (CRS). It was administered every 4 weeks. Six patients were aspirin-exacerbated respiratory disease (AERD). Results. Blood eosinophil count was reduced after the first administration, and was continued until 48 weeks. The Sino-Nasal Outcome Test scores, the Lund-MacKay CT scoring, and forced expiratory volume in 1 second were improved. Symptom scores of anosmia and nasal congestion were not improved in the patients with AERD. All oral corticosteroid-dependent patients successfully withdrew from corticosteroids. Conclusions. This pilot study showed mepolizumab improved nasal symptoms and lung function in severe eosinophilic asthma patients with CRS, suggesting efficacy of mepolizumab on the upper and lower airway symptoms in eosinophilic asthma.

Prospective Open-Label Study of 48-Week Subcutaneous Administration of Mepolizumab in Japanese Patients With Severe Eosinophilic Asthma.

BACKGROUND: The long-term efficacy and safety of mepolizumab in patients with severe eosinophilic asthma has been evaluated in large-scale double-blind placebo-controlled trials. However, a prospective open-label trial of long-term subcutaneous administration of mepolizumab has not been performed in Japanese patients with severe eosinophilic asthma. METHODS: This study was a prospective, 48-week, open-label trial in 32 Japanese patients with severe eosinophilic asthma who received subcutaneous mepolizumab 100 mg every 4 weeks. Nine patients required oral corticosteroids daily despite receiving high-dose inhaled corticosteroids. Six patients had aspirin-exacerbated respiratory disease. RESULTS: All patients took mepolizumab throughout the study period. No patients experienced adverse events during the treatment. None of the patients experienced asthma exacerbations during the trial. In fact, forced expiratory volume in 1 second increased significantly at 24 weeks (P<.01) and at 48 weeks (P<.05). The peripheral blood eosinophil count in peripheral blood decreased after the first administration of mepolizumab in all patients and remained low until week 48. After starting mepolizumab, all oral corticosteroid-dependent asthmatics successfully withdrew corticosteroids without exacerbations and experienced a sustained reduction in peripheral blood eosinophil count. Blood levels of thymus and activation-regulated chemokine and IgE remained unchanged after 48 weeks of therapy with mepolizumab. CONCLUSION: This first prospective open-label pilot study in Japan demonstrated the long-term efficacy and safety of mepolizumab in patients with severe eosinophilic asthma.

Prospective open-label study of 48-week subcutaneous administration of Mepolizumab in japanese patients with severe eosinophilic asthma

Background: The long-term efficacy and safety of mepolizumab in patients with severe eosinophilic asthma has been evaluated in large-scale double-blind placebo-controlled trials. However, a prospective open-label trial of long-term subcutaneous administration of mepolizumab has not been performed in Japanese patients with severe eosinophilic asthma. Methods: This study was a prospective, 48-week, open-label trial in 32 Japanese patients with severe eosinophilic asthma who received subcutaneous mepolizumab 100 mg every 4 weeks. Nine patients required oral corticosteroids daily despite receiving high-dose inhaled corticosteroids. Six patients had aspirin-exacerbated respiratory disease. Results: All patients took mepolizumab throughout the study period. No patients experienced adverse events during the treatment. None of the patients experienced asthma exacerbations during the trial. In fact, forced expiratory volume in 1 second increased significantly at 24 weeks (P<.01) and at 48 weeks (P<.05). The peripheral blood eosinophil count in peripheral blood decreased after the first administration of mepolizumab in all patients and remained low until week 48. After starting mepolizumab, all oral corticosteroid-dependent asthmatics successfully withdrew corticosteroids without exacerbations and experienced a sustained reduction in peripheral blood eosinophil count. Blood levels of thymus and activation-regulated chemokine and IgE remained unchanged after 48 weeks of therapy with mepolizumab. Conclusion: This first prospective open-label pilot study in Japan demonstrated the long-term efficacy and safety of mepolizumab in patients with severe eosinophilic asthma

Introducción: La eficacia y seguridad a largo plazo de mepolizumab se ha evaluado mediante grandes estudios doble-ciego controlados con placebo. Sin embargo, no hay estudios prospectivos abiertos a largo plazo que analicen la administración de mepolizumab en pacientes japoneses con asma eosinofílica grave. Métodos: Es un estudio prospectivo, abierto, de 48 semanas de duración en 32 pacientes japoneses con asma eosinofílica grave y que recibieron la administración subcutánea de 100 mg de mepolizumab cada 4 semanas. Nueve pacientes necesitaban esteroides orales a diario a pesar del uso de altas dosis de corticoides inhalados. Seis pacientes tenían intolerancia respiratoria a Aspirina. Resultados: Ningún paciente fue retirado del estudio ni tuvo efectos adversos durante el tratamiento. Ningún paciente tuvo exacerbaciones asmáticas durante el periodo del estudio. El volumen expirado máximo en el primer segundo aumentó de forma significativa en la semana 24 (p < 0,01) y en la semana 48 (p < 0,05). El número de eosinófilos en sangre periférica se redujo tras la primera administración de mepolizumab en todos los pacientes y continuó hasta la semana 48. Después del comienzo de la administración de mepolizumab a todos los pacientes con necesidad de esteroides orales se les retiraron sin que tuvieran posteriormente exacerbaciones y en paralelo a la disminución de eosinófilos en sangre periférica. Los niveles séricos de la quemoquina tímica de regulación y activación ni de IgE cambiaron en las 48 semanas del estudio. Conclusión: Es el primer estudio piloto abierto y a largo plazo realizado en Japón que muestra la eficacia y seguridad de mepolizumab en pacientes con asma eosinofílica grave

Longitudinal analysis of antibody profiles against plakins in severe drug eruptions: emphasis on correlation with tissue damage in drug-induced hypersensitivity syndrome and drug reaction with eosinophilia and systemic symptoms.

BACKGROUND: The evidence for severe drug eruption as a trigger for autoimmune disease has recently increased. No information is available on how tissue damage in severe drug eruptions can induce autoimmune responses. OBJECTIVES: To investigate whether the generation of autoantibodies (autoAbs) against plakin family proteins could be the cause or result of tissue damage in patients with severe drug eruptions and whether the generation of autoAbs could be prevented by systemic corticosteroids during the acute stage. METHODS: We retrospectively analysed alterations of serum levels of autoAbs against plakin family proteins in patients with Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) and drug-induced hypersensitivity syndrome (DiHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) during the acute stage and long after resolution over a period of more than 10 years. RESULTS: AutoAbs against plakin family proteins were detected in patients with either SJS/TEN or DiHS/DRESS regardless of the epidermal damage in the acute stage, and were sustained even long after resolution in DiHS/DRESS, indicating that those autoAbs are neither the cause nor the consequence of epidermal damage, at least in DiHS/DRESS. Severe liver damage and noncorticosteroid therapy during the early and acute stages of DiHS/DRESS were associated with the subsequent generation of these autoAbs. CONCLUSIONS: These autoAbs are neither necessarily the cause nor the result of epidermal damage in DiHS/DRESS, because the presence of these autoAbs was not restricted to patients with SJS/TEN but was also observed in those with DiHS/DRESS, which is characterized by lack of epidermal damage. Severe liver damage and/or immune responses that could be prevented by corticosteroids in the acute stage of DiHS/DRESS are among the causal factors contributing to the generation of autoimmune responses.

Recent advance in investigation of gene polymorphisms in Japanese patients with aspirin-exacerbated respiratory disease

Aspirin-exacerbated respiratory disease (AERD) is a complex clinical syndrome characterised by severe asthmatic attack upon treatment with aspirin and/or non-steroidal anti-inflammatory drugs (NSAIDs). Genetic predisposition has been considered as a crucial determinant and candidate genes have concentrated especially on cysteinyl leukotrienes (LTs)- related genes as the inhibitory action of aspirin and NSAIDs on cyclooxygenase activity may cause overproduction of cysteinyl LTs. However, conflicting results have been reported, in parallel with replication studies in different ethnic groups. Thus, future areas of investigations need to focus on comprehensive approaches towards the discovery of other genetic biomarkers. Unfortunately, few papers have been reported about gene polymorphisms in Japanese patients with AERD. Here, we described on our recent genetic investigations on B2ADR, IL-13, IL-17A, CYP2C19, TBXA2R, CRTH2 and HSP70. This review indicates potential genetic biomarkers contributing to the early diagnosis of AERD, which may include CYP2C19 and HSP70 gene polymorphisms, and future validation studies in independent population are required to provide reassurance about our findings

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Recent advance in investigation of gene polymorphisms in Japanese patients with aspirin-exacerbated respiratory disease.

Aspirin-exacerbated respiratory disease (AERD) is a complex clinical syndrome characterised by severe asthmatic attack upon treatment with aspirin and/or non-steroidal anti-inflammatory drugs (NSAIDs). Genetic predisposition has been considered as a crucial determinant and candidate genes have concentrated especially on cysteinyl leukotrienes (LTs)-related genes as the inhibitory action of aspirin and NSAIDs on cyclooxygenase activity may cause overproduction of cysteinyl LTs. However, conflicting results have been reported, in parallel with replication studies in different ethnic groups. Thus, future areas of investigations need to focus on comprehensive approaches towards the discovery of other genetic biomarkers. Unfortunately, few papers have been reported about gene polymorphisms in Japanese patients with AERD. Here, we described on our recent genetic investigations on B2ADR, IL-13, IL-17A, CYP2C19, TBXA2R, CRTH2 and HSP70. This review indicates potential genetic biomarkers contributing to the early diagnosis of AERD, which may include CYP2C19 and HSP70 gene polymorphisms, and future validation studies in independent population are required to provide reassurance about our findings.

Etoposide-containing conditioning regimen reduces the occurrence of hemophagocytic lymphohistiocytosis after SCT.

Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening disease of severe hyperinflammation caused by uncontrolled proliferation of activated lymphocytes and macrophages that secrete high amounts of inflammatory cytokines. HLH occurring after SCT is difficult to diagnose. It is characterized by severe clinical manifestations and high mortality. Despite current therapeutic approaches, outcomes remain poor. We analyzed the incidence and risk factors of HLH after SCT and the response to treatment and prognosis of 554 patients with HLH after SCT. The cumulative incidence of HLH after SCT was 4.3% (24/554). Use of etoposide in the conditioning regimen was only factor that reduced HLH after SCT (P=0.027). All patients who received autologous transplantation were successfully treated. Patients with liver dysfunction (for example, high total bilirubin level, prolonged prothrombin time and high level of fibrinogen degradation products) had a poor response to treatment for HLH. Physicians should be cautious of HLH, while not using etoposide for conditioning regimen.

Heritability estimates for racing performance in Japanese Thoroughbred racehorses using linear and non-linear model analyses.

This study evaluated the differences between linear and non-linear modelled heritability estimates of racing performance based on lifetime earnings (LE) and lifetime ranking (LR) in Japanese Thoroughbred racehorses. The heritability estimate (h(2) = 0.25) obtained from a non-linear model based on formal Japan Racing Association ranking was much higher than that obtained from a linear model based on the original trait phenotype (h(2) = 0.11). The linear models showed slightly higher heritability estimates under the trait categorizations than under the original phenotypes, while the non-linear categorical trait models showed much higher heritability estimates than the linear models, especially for binary trait categorizations (h(2) = 0.34) with non-winning and winning horses. The binary trait categorizations were consistent with the case and control classifications in the previous genome-wide association study (GWAS), which identified possible sequence variants on ECA18 that affect racing performance in Japanese Thoroughbred racehorses. Those findings suggested that the different heritability estimates obtained from several trait categorizations would reflect the possible presence of susceptibility gene segregations in the analyzed population, indicating that heritability estimates from non-linear models are useful for the selection of case and control populations in GWAS.

A cohort study of racing performance in Japanese Thoroughbred racehorses using genome information on ECA18.

Using 1710 Thoroughbred racehorses in Japan, a cohort study was performed to evaluate the influence of genotypes at four single nucleotide polymorphisms (SNPs) on equine chromosome 18 (ECA18), which were associated in a previous genome-wide association study for racing performance with lifetime earnings and performance rank. In males, both g.65809482T>C and g.65868604G>T were related to performance rank (P= 0.005). In females, g.65809482T>C (P = 1.76E-6), g.65868604G>T (P=6.81E-6) and g.66493737C>T (P=4.42E-5) were strongly related to performance rank and also to lifetime earnings (P < 0.05). When win-race distance (WRD) among all winning racehorses and best race distance (BRD) among elite racehorses were considered as the phenotypes, significant associations (P<0.001) were observed for all four SNPs. The favourable race distance of both elite (BRD) and novice racehorses (WRD) was also associated with genotypes in the ECA18 region, indicating the presence of a gene in this region influencing optimum race distance in Thoroughbred racehorses. Therefore, the association with performance rank is likely due to the bias in the race distances. The location of the SNPs within and proximal to the gene encoding myostatin (MSTN) strongly suggests that regulation of the MSTN gene affects racing performance. In particular, the g.65809482T>C, g.65868604G>T and g.66493737C>T SNPs, or their combinations, may be genetic diagnostic markers for racing performance indicators such as WRD and BRD.

Multiple osteolytic bone lesions with high serum levels of interleukin-6 and CCL chemokines in a patient with adult T cell leukemia.

A 37-year-old woman was diagnosed as having chronic adult T-cell leukemia (ATL) of the skin by a skin biopsy and human T-cell leukemia virus type-1 serology at our hospital in August 1992. The skin lesions of ATL were improved by treatment with psoralen ultraviolet ray A. She complained of severe pain in her bilateral forearms, hands and ankles, and X-ray examination in July 1999 revealed multiple punched-out lesions of the extremities. Serum levels of parathyroid hormone-related peptide, interleukin-1beta (IL-1beta), tumor necrosis factor-alpha and total serum receptor activator of nuclear factor kappaB ligand were not elevated. However, serum levels of IL-6, CCL2 monocyte chemoattractant protein-1 (MCP-1), CCL3 [macrophage inflammatory protein-1alpha (MIP-1alpha)] and CCL4 (MIP-1beta) were markedly elevated. Here, we have discussed the possible mechanism underlying the onset of the osteolytic lesions.

Quantitative analysis of mast cells in benign and malignant colonic lesions: immunohistochemical study on formalin-fixed, paraffin-embedded tissues.

BACKGROUND: Comparison of the number of mast cells in the active stage and that in remission in the same patients with ulcerative colitis with immunohistochemical staining remains to be elucidated, and analysis of the number of mast cells in benign and malignant colonic lesions is insufficient. METHODS: Using immunohistochemical methods, morphological examinations of mast cells were undertaken in colonic tissues from 8 patients with ulcerative colitis and 10 patients with colonic primary cancer, which were formalin-fixed and paraffin-embedded. Changes in the number of mast cells in the active stage and in remission in the same patients with ulcerative colitis were investigated. Then, the number of mast cells in malignant tissues and adjacent healthy tissues obtained from the same patients with colonic primary cancer were compared, and finally the number of mast cells was compared among the samples from benign and malignant colonic lesions. RESULTS: Accumulation of mast cells was found to be significant in the active stage of ulcerative colitis compared with remission in the same patients. The number of mast cells in colonic primary cancer was significantly increased compared with that in adjacent healthy tissues. The number of mast cells in ulcerative colitis was significantly greater than that in adjacent healthy tissues from patients with colonic primary cancer, irrespective of the stages of ulcerative colitis. CONCLUSIONS: We were the first to analyse mast cells in the active stage and in remission in the same patients with ulcerative colitis using immunohisto-chemical methods, and compared the number of mast cells between benign and malignant colonic lesions.

Quantitative analysis of mast cells in benign and malignant colonic lesions: immunohistochemical study on formalin-fixed, paraffin-embedded tissues

Background: Comparison of the number of mast cells in the active stage and that in remission in the same patients with ulcerative colitis with immunohistochemical staining remains to be elucidated, and analysis of the number of mast cells in benign and malignant colonic lesions is insufficient. Methods: Using immunohistochemical methods, morphological examinations of mast cells were undertaken in colonic tissues from 8 patients with ulcerative colitis and 10 patients with colonic primary cancer, which were formal in-fixed and paraffin-embedded. Changes in the number of mast cells in the active stage and in remission in the same patients with ulcerative colitis were investigated. Then, the number of mast cells in malignant tissues and adjacent healthy tissues obtained from the same patients with colonic primary cancer were compared, and finally the number of mast cells was compared among the samples from benign and malignant colonic lesions. Results: Accumulation of mast cells was found to be significant in the active stage of ulcerative colitis compared with remission in the same patients. The number of mast cells in colonic primary cancer was significantly increased compared with that in adjacent healthy tissues. The number of mast cells in ulcerative colitis was significantly greater than that inadjacent healthy tissues from patients with colonic primary cancer, irrespective of the stages of ulcerative colitis. Conclusions: We were the first to analyse mast cells in the active stage and in remission in the same patients with ulcerative colitis using immunohistochemical methods, and compared the number of mast cells between benign and malignant colonic lesions

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Cost benefit and clinical efficacy of low-dose granulocyte colony-stimulating factor after standard chemotherapy in patients with non-Hodgkin's lymphoma.

High costs of molecule-targeted drugs, such as rituximab, ibritumomab, and tositumomab have given rise to an economical issue for treating patients with non-Hodgkin's lymphoma (NHL). Granulocyte colony-stimulating factors (G-CSFs), which are also expensive, are widely used for treating neutropenia after chemotherapy. In Japan, lenograstim at 2 microg/kg (about 100 microg/body) or filgrastim at 50 microg/m(2) (about 75 microg/body) is commonly administered for patients with NHL after chemotherapy. Therefore, cost-effectiveness is an important issue in treatment for NHL. Patients with advanced-stage NHL who needed chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or a CHOP-like regimen with or without rituximab were enrolled in this randomized cross-over trial to investigate the efficacy and safety of low-dose G-CSF. Half of the patients were administered 75 microg filgrastim in the first course after neutropenia and 50 microg lenograstim in the second course, and the other half were crossed over. Forty-seven patients were enrolled in this cross-over trial, and 24 patients completed the trial. Frequencies and durations of grade 4 leukocytopenia and neutropenia were similar in the two groups. Severe infection was rare and was observed at similar frequency. Frequencies of antibiotics use were also similar. The total cost of G-CSF (cost/drug x duration of administration) was significantly lower in patients who received 50 microg lenograstim. Hence, a low dose of lenograstim might be safe, effective and pharmaco-economically beneficial in patients with advanced-stage NHL.

Hydrogen analysis for granite using proton-proton elastic recoil coincidence spectrometry.

In an effort to develop DS02, a new radiation dosimetry system for the atomic bomb survivors of Hiroshima and Nagasaki, measurements of neutron-induced activities have provided valuable information to reconstruct the radiation situation at the time of the bombings. In Hiroshima, the depth profile of (152)Eu activity measured in a granite pillar of the Motoyasu Bridge (128 m from the hypocenter) was compared with that calculated using the DS02 methodology. For calculation of the (152)Eu production due to the thermal-neutron activation reaction, (151)Eu(n,gamma)(152)Eu, information on the hydrogen content in granite is important because the transport and slowing-down process of neutrons penetrating into the pillar is strongly affected by collisions with the protons of hydrogen. In this study, proton-proton elastic recoil coincidence spectrometry has been used to deduce the proton density in the Motoyasu pillar granite. Slices of granite samples were irradiated by a 20 MeV proton beam, and the energies of scattered and recoil protons were measured with a coincidence method. The water concentration in the pillar granite was evaluated to be 0.30 +/- 0.07%wt. This result is consistent with earlier data on adsorptive water (II) and bound water obtained by the Karl Fisher method.

Accumulation of mast cells in the interstitium of eosinophilic colitis.

INTRODUCTION: The mechanism of eosinophilic colitis remains unclear, and no case has been reported in which the number of mast cells was examined. CASE REPORT: A 35-year-old man presented to our hospital with chief complaints of chills and consistent watery diarrhea after eating raw fresh-water fish. In blood examination, peripheral blood eosinophilia was found. Histological examination from biopsy specimens of both the ascending colon and rectum showed a prominent eosinophilic infiltration in the intestinal mucosa. Although a provocation test could not be performed due to lack of informed consent, a diagnosis of eosinophilic colitis was made on the basis of other findings. Immunohistochemical staining for human mast cell tryptase using monoclonal antibody against human mast cell tryptase showed an accumulation of mast cells in the colonic interstitium. CONCLUSIONS: We report a case of eosinophilic colitis in which an accumulation of mast cells in the colonic interstitium was demonstrated.