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Several patients with immune thrombocytopenia show good clinical courses without any major complications. However, severe bleeding complications, such as hemoptysis, gastrointestinal bleeding, and intracranial hemorrhages, are occasionally observed in some patients associated with marked thrombocytopenia; this results in 1.5-fold higher mortality for such patients compared with the general population. We report here the cases of two patients with immune thrombocytopenia whose bone marrow included a prominent cluster of differentiation (CD)10+/ human leukocyte antigen (HLA)-DR+ population and showed good response to steroid therapy. Conversely, two other patients without a CD10+/HLA-DR+ population were refractory to steroids, and one of them had a serious course. Retrospective examination of 30 patients with severe immune thrombocytopenia revealed that they had a higher percentage of CD10+/HLA-DR+ cells compared with patients with other benign hematological diseases. As differential diagnosis of immune thrombocytopenia and aplastic anemia with severe thrombocytopenia is often difficult, it may be helpful to understand whether CD10+/HLA-DR+ cells are increased. We also show the possible correlation of resistance to steroid therapy and lower percentages of CD10+/HLA-DR+ cells. It has been reported that nonresponsiveness to steroid treatment was a high risk factor for intracranial hemorrhage. Lower percentages of CD10+/HLA-DR+ cells may be a useful tool to identify patients with immune thrombocytopenia at a high risk of serious bleeding complications.

Lung cancer is a leading cause of cancer-related death worldwide, and most are non-small cell lung cancers (NSCLC). Since the overall survival remains very poor for NSCLC patients with advanced-stage disease, the development of novel treatments is needed. Previous studies reported a relationship between calpain and tumorigenesis. In this study, we examined the apoptotic effects of calpeptin (Cal), a calpain inhibitor, on A549 NSCLC cells. We assessed whether Cal induced apoptosis in A549 cells. Cal induced apoptosis in A549 cells and also activated p38MAPK. These results suggest a possible clinical use of Cal for the treatment of NSCLC.

Patients with rheumatoid arthritis occasionally develop lymphoproliferative disorders. Methotrexate-associated lymphoproliferative disorders is a lymphoproliferative disease or lymphoma in patients treated with methotrexate for autoimmune diseases, such as rheumatoid arthritis. Here we report two rare cases of highly aggressive plasmablastic lymphoproliferative disorders in rheumatoid arthritis treated with methotrexate. Case 1 is a 68-year-old female patient with leukemic transformation of malignant lymphoma. She received methotrexate therapy for rheumatoid arthritis for >6 years. The patient showed rapid progressive course and died on the 2nd hospital day. After the death, we diagnosed the patient as plasmablastic lymphoma. Case 2 is an 80-year-old female patient with plasmablastic plasma cell myeloma, with a history of methotrexate treatment for rheumatoid arthritis for >5 years. Although M-protein was decreased by chemotherapy, bone marrow examination revealed the further increase of plasmablastic cells and she died 2 months later. The present cases were difficult to diagnose because proliferation of malignant plasmablasts was hardly predicted because neither lymph node enlargement nor an evident M-protein was observed. Both cases showed aggressive features and extremely poor prognosis. Clinicians should be aware of the underlying malignant plasmablastic proliferation when inexplicable inflammatory findings are observed in inactive rheumatoid arthritis patients.

We herein report a unique case of type B2 thymoma-associated myasthenia gravis which was ameliorated by immunosuppressive therapy in combination with chemotherapy. However, the patient subsequently developed pure red cell aplasia and marked lymphocytosis after additional chemotherapy aimed at improvement of thymoma. While a separate immunosuppressive regimen was effective for anemia, lymphocytosis was exacerbated. The biopsied thymoma specimen contained CD4+, CD8+, and CD4+/CD8+ T cells, some of which were CD3−, suggesting immature thymocytes. In contrast, majority of the peripheral lymphocytes were polyclonal CD3+/CD8+/T cell receptor (TCR)αβ+ T cells. The CD4/CD8 ratio in the present patient might be affected by immunosuppressive agents, resulting in CD8+ T cell expansion associated with pure red cell aplasia. Although several cases of thymoma accompanied by peripheral T cell lymphocytosis were reported, marked CD8+ T cell proliferation is extremely rare.

Here, we report a rare case of massive bone marrow necrosis, which – from the clinical findings and images – mimics disseminated bone metastasis. The patient was suffering from severe bone pain with elevated levels of serum alkaline phosphatase (ALP) and lactate dehydrogenase (LDH); moreover, strong incorporation of 18F-fluorodeoxyglucose in multiple bones was observed by positron emission tomography/computed tomography.The underlying disease was Waldenström’s macroglobulinemia, which was thought to transform to cluster of differentiation 5 (CD5)-positive diffuse large B-cell lymphoma (DLBCL). The case showed a highly aggressive course, although the original Waldenström’s macroglobulinemia was in the stable state.Clinicians should be aware of the co-occurrence of non-immunoglobulin-producing immature lymphoma, even with good course of Waldenström’s macroglobulinemia, and should pay attention to accompanying massive bone marrow necrosis, which mimics multiple cancer metastases to the bone. To the best of our knowledge, the present case is the first report of CD5-positive DLBCL transformed from CD5-negative Waldenström’s macroglobulinemia.

A smouldering adult T-cell leukaemia/lymphoma (ATLL) patient was admitted because of multiple erosions in the colon, which were infiltrated by a mixed population of lymphocytes. PET/CT demonstrated diffuse 18F-Fluorodeoxyglucose accumulation in the whole colon accompanied by multiple lymph node swelling. Histological examinations of lymph node suggested aggressive transformation to lymphoma type of ATLL. However, the general condition worsened with extremely elevated LDH, cytomegalovirus pp65 and sIL-2R after the administration of prednisolone. By contrast, subsequent administration of ganciclovir with tapered prednisolone ameliorated the laboratory findings. Differential diagnosis for aggressive ATLL and serious cytomegalovirus infection is needed.

We report a unique case of mediastinal grey zone lymphoma that was considered to originate from CD20 + CD30 + Hodgkin cell–like cells associated with a multilocular thymic cyst that had been completely removed 4 years previously. In the formerly resected thymus, irregular-shaped cysts were observed, and large CD20 + CD30 + Hodgkin cell–like cells proliferated in close association with the proliferating thymic epithelial cells. This case suggests the important role of thymic columnar epithelial cells in the proliferation of thymic B cells and the tumorigenesis of mediastinal grey zone lymphoma. Also, it suggests that mediastinal grey zone lymphoma can proliferate slowly in the very early stage.

We herein report a unique case of type B2 thymoma-associated myasthenia gravis which was ameliorated by immunosuppressive therapy in combination with chemotherapy. However, the patient subsequently developed pure red cell aplasia and marked lymphocytosis after additional chemotherapy aimed at improvement of thymoma. While a separate immunosuppressive regimen was effective for anemia, lymphocytosis was exacerbated. The biopsied thymoma specimen contained CD4

Chronic obstructive pulmonary disease (COPD) is characterized by a progressive airway obstruction that is not completely reversible and is mainly caused by smoking tobacco. COPD is a major cause of morbidity and mortality worldwide and there are currently no proven effective treatments. The pathogenesis of COPD involves several factors such as chronic inflammation, oxidative stress, and apoptosis. Cytokines play important roles in chronic inflammation. Thalidomide (Thal) has been used to treat multiple myeloma due to its inhibitory effects on IL-6-induced cell growth. We recently demonstrated that thalidomide (Thal) played important roles in cytokine-induced lung damage in a bleomycin-induced pulmonary fibrosis model in mice. We herein examined the preventative effects of Thal on cigarette smoke extract (CSE)-induced emphysematous changes in mice. We performed histological examinations and quantitative measurements of the expression of IL-1β and IL-6 mRNA, as well as apoptosis in CSE-induced mouse lung tissues treated with or without Thal. The results of the histological examination showed that Thal ameliorated CSE-induced emphysema in mice. It also inhibited the expression of IL-1β and IL-6 mRNA in mouse lung tissues. Thal decreased apoptosis in the mouse lung. In vitro studies revealed that Thal decreased 1) the expression of IL-1β and IL-6 in human lung epithelial cells, and 2) CSE-induced apoptosis and the inhibition of cell growth, which may be the underlying mechanisms for the preventative effects of Thal on emphysema. These results provide a rationale for exploring the clinical use of Thal for COPD.

Large granular lymphocyte (LGL) leukemia is characterized by a clonal proliferation of large-sized lymphocytes with prominent large azurophilic cytoplasmic granules. Although most cases of T-LGL leukemia are indolent and asymptomatic during the course of the disease, some present with pure red cell aplasia (PRCA) and require therapy. We here reported a case of T-LGL leukemia complicated by PRCA in which anemia was resistant to cyclosporine and had been controlled for several years by cyclophosphamide; however, progressive anemia developed despite the administration of cyclophosphamide, but was ameliorated by the re-administration of cyclosporine. The present case demonstrated the 3 different phases of T-LGL proliferation associated with anemia (1st, T-LGL leukemia; 2nd, polyclonal T-LGL expansion; 3rd, myelodysplastic syndrome). We also showed that cyclophosphamide was effective when PRCA was caused by increased numbers of LGL, whereas cyclosporine was administered when hypoplastic myelodysplastic syndrome was suspected as the main cause of anemia. Repetitive bone marrow examinations should be performed throughout the course of T-LGL in order to monitor combined myelodysplastic syndrome.

Background Diffuse malignant peritoneal mesothelioma (DMPM) is an aggressive malignant tumor of mesothelial origin that shows a limited response to cytoreductive surgery along with intraperitoneal chemotherapy. Therefore, early diagnosis of DMPM is very important. Some researchers have previously reported that high-mobility group box 1 (HMGB1) was correlated with pulmonary fibrosis. DMPM involves the malignant transformation of mesothelial cells, which originate from mesenchymal cells, similar to lung fibroblasts. Here, we investigated serum levels of HMGB1 in patients with MPM and compared them with those of a population that had been exposed to asbestos without developing MPM. Study The serum concentrations of HMGB1 were measured in 13 DMPM patients and 45 individuals with benign asbestos-related diseases. Result We demonstrated that the patients with DMPM had significantly higher serum levels of HMGB1 compared with the population who had been exposed to asbestos but did not develop DMPM. Conclusion Our data suggest that serum HMGB1 concentration is a useful serum marker for DMPM.

Lymphocytic variant hypereosinophilic syndromes (L-HES) is thought to be caused by the over-production of interleukin (IL)-5 by type 2 helper cells, which leads to reactive eosinophil expansion and activation. Here we demonstrate the effect of cyclosporine in a patient with L-HES. In the present case, the surface markers of cells from resected lymph nodes or peripheral blood were analyzed by flow cytometry. Serum concentrations of IL-4, IL-5, and IL-8 were measured using an enzyme-linked immunosorbent assay. Methyl-prednisolone pulse therapy followed by the administration of 150 mg/day of cyclosporine combined with 15 mg/day of prednisolone ameliorated eosinophilia. However, abnormal CD3-CD4+ T cell clones remained even when the eosinophil count recovered to normal levels. An elevated IL-8 level was observed only when eosinophils increased. On the other hand, serum IL-4 and IL-5 levels were under detectable limits during the course. Cyclosporine was effective in decreasing the eosinophil count without the elimination of abnormal T cell clones in the present case. Cytotoxic agents may be necessary to cure this serious disease. Moreover, target therapy for IL-8 may be a new strategy for L-HES with high IL-8 and low IL-5 concentrations.

Here, we report a rare case of double-hit lymphoma, demonstrating t(6;14;18)(p25;q32;q21), suggesting two independent dual-translocations, c-MYC/BCL-2 and IRF4/BCL-2. The present case had a rare abnormal chromosome, t(6;14;18)(p25;q32;q21), independently, in addition to known dual-hit chromosomal abnormalities, t(14;18)(q32;q21) and t(8;22)(q24;q11.2). Lymph node was characterized by a follicular and diffuse growth pattern with variously sized neoplastic follicles. The intrafollicular area was composed of centrocytes with a few centroblasts and the interfollicular area was occupied by uniformly spread medium- to large-sized lymphocytes. CD23 immunostaining demonstrated a disrupted follicular dendritic cell meshwork. The intrafollicular tumor cells had a germinal center phenotype with the expression of surface IgM, CD10, Bcl-2, Bcl-6, and MUM1/IRF4. However, the interfollicular larger cells showed plasmacytic differentiation with diminished CD20, Bcl-2, Bcl-6, and positive intracytoplasmic IgM, and co-expression of MUM1/IRF4 and CD138 with increased Ki-67-positive cells (> 90%). MUM1/IRF4 has been found to induce c-MYC expression, and in turn, MYC transactivates MUM1/IRF4, creating a positive autoregulatory feedback loop. On the other hand, MUM1/IRF4 functions as a tumor suppressor in c-MYC-induced B-cell leukemia. The present rare case arouses interest in view of the possible "dual" activation of both c-MYC and MUM1/IRF4 through two independent dual-translocations, c-MYC/BCL-2 and IRF4/BCL-2.

Nodal marginal zone B cell lymphoma is a rare type of malignant lymphoma and appears to be heterogeneous. Here we report a 60-year-old woman with stage I splenic type of nodal marginal zone B cell lymphoma with prominent follicular colonization. She was treated only by radiation therapy, and remained free of disease on examination for 4 years. The lymph node cells showed an abnormal chromosome of deletion 13, although neither bone marrow cells nor peripheral blood cells demonstrated the same abnormal chromosome. This type of chromosomal abnormality has not been previously reported and may be related to good prognosis in the present case.

Primary autoimmune neutropenia (AIN) is more common in newborns, and usually benign or self-limiting, so most cases require no specific therapy. In adults, however, for little tendency toward spontaneous remission, they require certain treatments and careful managements. Here we report a successful management of primary AIN patient by estimating the granulopoiesis according to CRP levels without administration of G-CSF or increase of prednisolone when peripheral neutrophil counts dropped down. Transient elevation of CRP associated with severe drop down in neutrophil count, and subsequent dramatic neutrophil increase was occasionally observed during the follow up with minimal dose of prednisolone. Coexistence of decreased neutrophil counts and elevated CRP levels was accompanied by increase of serum levels of IL-6 and IL-8. Although this is the report of only one patient, these elevated CRP levels combined with severe drop down and subsequently spontaneous rapid recovery in neutrophil count, were repetitively observed, suggesting the preceding CRP elevation before neutrophil recovery. We propose the important part of CRP as a predictor of granulopoiesis in patients with neutropenia.

Malignant pleural mesothelioma (MPM) is an aggressive malignant tumour associated with asbestos exposure that has only a limited response to conventional therapy; therefore, diagnosing MPM early is very important. We have previously reported that angiopoietin (Ang)-1 was correlated with bleomycin-induced pulmonary fibrosis. Here, we investigated the association of Ang-1 with the development of MPM cells, which originate from mesenchymal cells similar to lung fibroblasts, and demonstrated that Ang-1 stimulated the growth and migration of MPM cells in vitro. We also demonstrated that patients with MPM had significantly higher serum levels of Ang-1 in comparison to a population who had been exposed to asbestos but had not developed MPM. The patients with advanced-stage MPM showed higher levels of Ang-1 than the early-stage MPM patients and the Kaplan-Meier method revealed a significant correlation between serum Ang-1 levels and survival. We propose the possibility that Ang-1 plays an important role in MPM tumour growth and our data suggest that the serum concentration of Ang-1 could be useful as prognostic factor.

Malignant pleural mesothelioma (MPM) is an aggressive malignant tumour of mesothelial origin associated with asbestos exposure. Because MPM has limited response to conventional chemotherapy and radiotherapy, the prognosis is very poor. Several researchers have reported that cytokines such as interleukin (IL)-6 play an important role in the growth of MPM. Previously, it was reported that all-trans-retinoic acid (ATRA) inhibited the production and function of IL-6 and transforming growth factor (TGF)-beta1 in experiments using lung fibroblasts. We investigated whether ATRA had an inhibitory effect on the cell growth of MPM, the origin of which was mesenchymal cells similar to lung fibroblasts, using a subcutaneous xenograft mouse model. We estimated the tumour growth and performed quantitative measurements of IL-6, TGF-beta1 and platelet-derived growth factor (PDGF) receptor (PDGFR)-beta mRNA levels both of cultured MPM cells and cells grown in mice with or without the administration of ATRA. ATRA significantly inhibited MPM tumour growth. In vitro studies disclosed that the administration of ATRA reduced 1) mRNA levels of TGF-beta1, TGF-beta1 receptors and PDGFR-beta, and 2) TGF-beta1-dependent proliferation and PDGF-BB-dependent migration of MPM cells. These data may provide a rationale to explore the clinical use of ATRA for the treatment of MPM.

In patients with autoimmune disease-associated hemophagocytic syndrome (AAHS), the clinical features may differ from hemophagocytic syndrome (HPS) of other etiologies, and new criteria for AAHS have been proposed. Since bone marrow (BM) circumstances are changed according to aging, here we reviewed retrospectively our cases with AAHS in elderly patients, including two systemic lupus erythematosus (SLE), three Evans syndrome, one rheumatoid arthritis (RA), one Hashimoto thyroiditis, and one autoimmune pancreatitis. Although only two SLE patients were diagnosed as HPS by the classical criteria, the remaining patients except one RA met the criteria for AAHS. Seven patients except one SLE patient showed good response to therapy and demonstrated positive autoantibodies to blood cells, lower serum ferritin levels, and increased erythroblastic islands in the BM. We consider the diagnosis of AAHS should be carefully made when macrophages phagocytosing blood cells are observed in BM smear without hyperferritinemia in elderly patients with autoimmune diseases.

We report two elderly male patients with hemophagocytic syndrome (HPS) associated with systemic lupus erythematosus (SLE). They were admitted to the hospital because of general malaise. At admission, they showed fever of unknown origin and hematological abnormalities without typical symptoms for SLE such as arthralgia or malar rash. Chest X-rays, computed tomography and cardiac sonogram demonstrated unilateral pleural and pericardial effusions. Bone marrow aspiration revealed hypocellular marrow with increased macrophages phagocytosing blood cells in the both cases. One patient had positive reactivity for direct Coombs's test and high level of platelet-associated antibody, whose symptoms were ameliorated only by 20 mg per day of prednisolone. The other patient, however, progressive worsened and died regardless of intensive treatment containing methyl-prednisolone pulse therapy. Late-onset lupus (LO-SLE) patients tend to have a more insidious onset of disease, and less frequently show typical symptoms of early-onset SLE such as malar rash. So it seems to be important that clinicians make a fast diagnosis and proper treatment for LO-SLE and associated HPS by careful observation for the latent symptoms and laboratory findings.

Background/aims Liver fibrosis with any aetiology, induced by the transdifferentiation and proliferation of hepatic stellate cells (HSCs) to produce collagen, is characterized by progressive worsening in liver function, leading to a high incidence of death. We have recently reported that all-trans-retinoic acid (ATRA) suppresses the transdifferentiation and proliferation of lung fibroblasts and prevents radiation- or bleomycin-induced lung fibrosis. Methods We examined the impact of ATRA on carbon tetrachloride (CCl(4))-induced liver fibrosis. We performed histological examinations and quantitative measurements of transforming growth factor (TGF)-beta1 and interleukin (IL)-6 in CCl(4)-treated mouse liver tissues with or without the administration of ATRA, and investigated the effect of ATRA on the production of the cytokines in quiescent and activated HSCs. Results CCl(4)-induced liver fibrosis was attenuated in histology by intraperitoneal administration of ATRA, and the overall survival rate at 12 weeks was 26.5% without ATRA (n=25), whereas it was 75.0% (n=24) in the treatment group (P=0.0187). In vitro studies disclosed that the administration of ATRA reduced (i) the production of TGF-beta1, IL-6 and collagen from HSCs, (ii) TGF-beta-dependent transdifferentiation of the cells and IL-6-dependent cell proliferation and (iii) the activities of nuclear factor-kappaB p65 and p38mitogen-activated protein kinase, which stimulate the production of TGF-beta1 and IL-6, which could be the mechanism underlying the preventive effect of ATRA on liver fibrosis. Conclusions Our findings indicate that ATRA ameliorates liver fibrosis. As the oral administration of the drug results in good compliance, ATRA could be a novel approach in the treatment of liver fibrosis.

We report a very rare case of a 45-year-old Japanese male patient with hairy cell leukemia-Japanese variant (HCL-JV) expressing CD27. The patient showed a high number of abnormal peripheral lymphocytes, thrombocytopenia, and severe splenomegaly but no lymphadenopathy. Histology of the resected spleen showed small-sized lymphoma cells diffusely infiltrating the red pulp without follicle formation. By immunohistochemistry, lymphoma cells were negative for CD3, CD5, CD8, CD10, CD34, cyclin-D1, and annexin A1 but positive for CD20 and BCL2. BRAF V600E mutation was not observed. Bone marrow aspirate showed preserved normal hematopoietic cells with invasion of lymphoma cells in an interstitial pattern without obvious nodules. The cells had abundant pale cytoplasm and round nuclei with inconspicuous nucleoli. After natural drying, the cells had unevenly distributed microvilli. Flow cytometric analysis demonstrated positivity for CD11a, CD11c, CD19, CD20, CD22, CD27, surface IgG, and λ but not for CD2, CD3, CD4, CD5, CD7, CD8, CD10, CD21, CD23, CD25, CD30, CD34, CD38, CD43, CD56, CD57, CD103, IgD, IgM, and κ. Monoclonal expansion of B cells was confirmed by an immunoglobulin heavy chain (IgH) rearrangement band as demonstrated by Southern blot hybridization. The lymphoma cells had unevenly distributed long, large, and broad-based microvilli, which resembled splenic diffuse red pulp small B cell lymphoma (SDRPL) cells. CD27 expression is extremely rare in HCL-JV, but the young age of the patient and high peripheral WBC counts were similar to HCL-JV, which suggests, in this case, an intermediate disease between SDRPL and HCL-JV.

We report a patient who had a 4-year history of adult-onset Still's disease (AOSD) and showed a prominent increase in large granular lymphocytes (LGL) when she developed severe Pseudomonas conjunctivitis due to Pseudomonas aeruginosa, skin eruptions, liver damage, and abnormal findings in coagulation studies, without any evidence of active viral activation, hemophagocytosis, or malignancies. The increased LGL cells were CD3(+)CD8(+), and disappeared promptly after the administration of antibiotics combined with prednisolone, with subsequent stabilization of her general condition.

We report a rare primary splenic diffuse large B-cell lymphoma demonstrating CD5(+) and CD23(+) with very low CD20 expression. The only lesion was detected in the spleen, which was extremely enlarged with multiple large white-colored nodules. The lesion was characterized by a diffuse growth pattern of medium- to large-sized lymphoma cells with abundant cytoplasm. Immunohistochemical and flow cytometric study demonstrated that the lymphoma cells were negative for CD2, CD3, CD4, CD8, CD10, CD56, CD138, ALK-1, λ-light chain, and cyclin-D1, and positive for CD5, CD19, CD23, CD25, CD38, CD43, CD79a, IgM, IgD, κ-light chain, BCL2, BCL6, BOB. 1, Oct-2, Pax5, and MUM-1. CD20 was very weakly positive immunohistochemically, and negative by flow cytometric analysis. These findings resembled Richter syndrome, although chronic lymphocytic leukemia was not preexisting. Extremely poor outcome might be supposed because the effect of rituximab might be quite limited since CD20 was very weakly positive, in addition to an inferior prognosis of both CD20(-) and CD5(+) diffuse large B-cell lymphoma. Careful management is thus necessary.

It is well known that some B-cell lymphomas are accompanied by a prominent epithelioid cell response, caused by activated macrophages, such as marginal zone B-cell lymphoma of a mucosa-associated lymphoid tissue. We investigated six bone marrow samples from four cases of Waldenstrom’s macroglobulinemia and report a unique observation that large conjugates of tumor cells around a macrophage were prominent in all cases, particularly in one case, the bone marrow of which contained increased CD163-positive macrophages. Mast cells were increased in all the samples, some of which seemed to be in close contact with tumor cells. We consider that the conjugates represented close interactions of tumor cells, macrophages, and mast cells by cell-to-cell contact. Three of the present cases showed a favorable course. On the other hand, one case suffered from severe anemia and thrombocytopenia due to hemophagocytic syndrome at the second admission and showed a severe clinical course. Clinicians should be aware of the risk of lymphoma-associated hemophagocytic syndrome in this low-grade lymphoma, although many of the patients with hemophagocytic syndrome in Japan have aggressive lymphomas such as diffuse large B-cell lymphoma. 〔J Clin Exp Hematop 54(2): 103-110, 2014〕

Follicular colonization is occasionally observed in marginal zone lymphoma. In rare cases, it has also been associated with mantle cell lymphoma. Chronic lymphocytic leukemia typically involves nodal or extranodal tissues as diffuse proliferation by complete effacement of the normal architecture. The involvement of chronic lymphocytic leukemia may be less frequently limited to the interfollicular areas. Here, we report a case of Richter syndrome of the small intestine that was initially diagnosed as follicular lymphoma of the gastrointestinal tract because of a partial follicular growth pattern in addition to a mainly diffuse proliferation pattern. The follicular pattern mimicking follicular lymphoma was shown to be composed of reactive follicles with follicular colonization of the original chronic lymphocytic leukemia cells. As the prognoses of Richter syndrome and follicular lymphoma of gastrointestinal tract are quite different, clinicians must carefully diagnose these conditions to avoid a misdiagnosis.

We have previously reported that angiopoietin-1 was correlated with pulmonary fibrosis. Here, we investigated the serum levels of angiopoietin-1 in patients with malignant peritoneal mesothelioma, which originate from mesenchymal cells similar to lung fibroblasts. We showed that patients with peritoneal mesothelioma had significantly higher serum levels of angiopoietin-1 in comparison with a population with a history of asbestos exposure without peritoneal mesothelioma, and the Kaplan-Meier method revealed a significant correlation between serum angiopoietin-1 levels and survival. This is the first report about the relationship between angiopoietin-1 and peritoneal mesothelioma.

Here we demonstrate a unique case of CD20-negative low-grade B cell lymphoma showing immunophenotypic and genotypic features resembling multiple myeloma. The female patient had no abnormal masses, splenomegaly, swelled lymph nodes, or bone lesions. Although serum levels of IgG, IgA, and IgM were decreased without M protein, κ-type Bence-Jones protein was observed. In bone marrow, monotonous proliferation of small to medium-sized lymphoid cells was observed without classical myeloma cells, the same histological findings as lymphoplasmacytic lymphoma. The cells were CD38+, CD138+, CD43+, CD44+, CD3-, CD4-, CD5-, CD7-, CD8-, CD10-, CD11b-, CD19-, CD20-, CD21-, CD23-, CD24-, CD25-, CD27-, CD40-, CD45-, and CD56-. Surface or cytoplasmic IgM, κ, or λ were all negative. Chromosomal analysis demonstrated t(11;14)(q13;q32). The present case may belong to a new entity of low-grade B cell lymphoma with the same histological findings as lymphoplasmacytic lymphoma, mainly proliferated in bone marrow whose immunophenotype and genotype are similar to plasma cell myeloma.

Sometimes it is difficult to distinguish anti-phospholipid syndrome (APS) from immune thrombocytopenic purpura (ITP). Here we present successful management of ITP with anti-phospholipid antibodies, complicated by acute coronary syndrome (ACS), using CT coronary angiography (CTCA). The therapy for ITP may be changed for APS if ACS was thromboembolic event. As coronary angiography is thought to be very dangerous for patients with severe thrombocytopenia, noninvasive CTCA was desirable for our patient. Since no occlusion or narrowing was observed in CTCA, she has been safely treated as ITP with immunosuppressive agents throughout the course without antiplatelet or antithrombin therapy.

Malignant pleural mesothelioma (MPM) is an aggressive malignant tumor of mesothelial origin associated with asbestos exposure. MPM has a limited response to conventional chemotherapy and radiotherapy, thus early diagnosis of MPM is extremely critical. CT scans have limited accuracy in the differentiation between benign and malignant pleural disease. Several studies have reported that 18-fluorodeoxyglucose (FDG) positron emission tomography (PET) plays an important role in the assessment of thoracic malignancy such as lung cancer. Here, we investigated the clinical utility of PET in patients with MPM. The maximum SUV (SUVmax) of 18F-FDG was measured in 47 MPM patients and 29 non-MPM patients including those with pleural thickening. We demonstrated that patients with MPM had significantly higher SUVmax levels than a population with non-malignant pleural disease. The Kaplan-Meier method revealed significant differences in overall survival between groups with SUVmax levels lower and higher than the assumed cut-off. Our data suggest that SUVmax levels are useful as an aid for diagnosis and prognosis of MPM.

Diffuse malignant peritoneal mesothelioma (DMPM) is an aggressive malignant tumor of mesothelial origin that shows a limited response to cytoreductive surgery along with intraperitoneal chemotherapy. Therefore, diagnosing DMPM early is very important. Reactive oxygen species play an important role in asbestos toxicity, which is associated with the pathogenesis of DMPM growth. Thioredoxin-1 (TRX) is a small redox-active protein that demonstrates antioxidative activity associated with tumor growth. Here, we investigated the serum levels of TRX in patients with DMPM and compared them with those of a population that had been exposed to asbestos but did not have DMPM.The serum concentrations of TRX were measured in 15 DMPM patients and 34 individuals with benign asbestos-related diseases.We demonstrated that the patients with DMPM had significantly higher serum levels of TRX than the population that had been exposed to asbestos but did not have DMPM.Our data suggest that serum TRX concentration is a useful serum marker for DMPM.

Immune thrombocytopenic purpura associated with multiple myeloma is extremely rare. Here, we present the successful management of an elderly Japanese patient with multiple myeloma complicated by immune thrombocytopenia with low dose cepharanthine - a plant derived alkaloid. A 78-year-old male patient with IgGκ multiple myeloma was repetitively treated with melpharan and prednisolone. In each chemotherapy course, we demonstrated a close relationship between platelet recovery and administration of high dose prednisolone. When further chemotherapy was avoided because of the patient's poor general condition, administration of cepharanthine was effective in halting progressive thrombocytopenia due to abnormal immune mechanisms. We propose the usefulness of cepharanthine in management of this rare disease.

Malignant pleural mesothelioma (MPM) is an aggressive malignant tumor of mesothelial origin associated with asbestos exposure. MPM exhibits a limited response to conventional chemotherapy and radiotherapy. This, early diagnosis of MPM is essential. Malignant tumor progression requires the destruction of the basement membrane, which is constructed from extracellular matrix (ECM) materials. Various types of human tumor cells are reported to produce ECM-degrading proteases that are important in tumor progression. Among this group of proteolytic enzymes, matrix metalloproteinases (MMPs) are thought to be important due to their wide degrading function. We investigated the pleural effusion MMP-3 levels of patients with MPM and compared them with those of a population with non-malignant pleuritis or lung cancer involving malignant pleural effusion. The pleural effusion MMP-3 concentrations of 52 MPM patients and 67 non-MPM patients were measured. The results showed that the MPM patients had significantly higher pleural effusion MMP-3 levels than the population with non-malignant pleuritis. The overall survival of the MPM patients with lower pleural effusion MMP-3 levels was longer than that of patients with higher pleural effusion MMP-3 levels. Our data therefore suggest a clinical role of pleural effusion MMP-3 levels in malignant pleural mesothelioma.

Background Malignant pleural mesothelioma (MPM) is an aggressive malignant tumor of mesothelial origin associated with asbestos exposure. MPM has a limited response to conventional chemotherapy and radiotherapy, so early diagnosis of MPM is very important. This study investigated the pleural effusion mesothelin levels in patients with MPM and compared them to those of a population with a non-malignant pleuritis or lung cancer involving malignant pleural effusion. Methods The pleural effusion mesothelin concentrations were measured in 45 MPM patients and 53 non-MPM individuals (24 individuals with non-malignant pleural effusions and 29 individuals with lung cancer involving malignant pleural effusion). Results This study demonstrated that patients with MPM had significantly higher pleural effusion mesothelin levels than a population with non-malignant pleuritis or lung cancer involving malignant pleural effusion. The difference in overall survival between the groups with pleural effusion mesothelin levels lower and higher than the assumed cut-off of 10 nM was significant. Conclusions The data suggest that the pleural effusion mesothelin concentration could be useful as an aid for the diagnosis of MPM.

Malignant pleural mesothelioma (MPM), an asbestos-related aggressive malignant tumor of mesothelial origin, shows limited response to therapy and overall survival remains very poor. Reactive oxygen species play an important role in asbestos toxicity. Here, we found that the patients with MPM had significantly higher serum levels of thioredoxin-1 (TRX) than control population. The patients with advanced-stage MPM showed higher levels of TRX than those with early-stage MPM. The difference in overall survival between the groups with lower and higher serum TRX levels was significant. Our data suggest that serum TRX concentration could be a useful clinical marker for MPM.

In some instances, because of the lack of mass formation and the absence of prominent lymph node enlargement, diagnosis of lymphoma-associated hemophagocytic syndrome (LAHS) is difficult, which results in the development of progressive disease with unfavorable prognosis. Therefore, in the diagnosis of secondary hemophagocytic syndrome (HPS), markers for underlying malignant lymphoma are required. We reviewed 110 Japanese patients, including 57 LAHS cases and 53 benign disease-associated HPS cases, and demonstrated that the values of the serum sIL-2R level and sIL-2R/ferritin ratio in LAHS patients were both statistically higher than those of patients with benign disease-associated HPS. Most LAHS patients showed high values of both indices. The positive predictive value of patients showing high values of both indices for LAHS was 95.6%. On the other hand, the predictive value of patients showing low values of both indices for benign disease-associated HPS was 92.1%. We propose serum sIL-2R/ferritin ratio as a novel useful marker for predicting underlying malignant lymphoma in HPS patients.

Background: Here we report 2 rare cases of acute myeloid leukemia (AML) complicated with hemolytic anemia limited to the myelodysplastic syndrome (MDS) stage, and disappearing in leukemic transformation. Methods/Results: A 66-year-old man with MDS-RAEB-2 was admitted to hospital for severe anemia with increased reticulocyte counts. Hemolytic anemia was suspected, and it was ameliorated by methylprednisolone pulse therapy. Although anemia grew worse when steroids were tapered off, later improvement coincided with an increase in myeloblasts in the peripheral blood, i.e. with leukemic transformation. In another case, a 68-year-old man was admitted to hospital when laboratory findings showed a white blood cell count of 24,800/µl with increased myeloblasts (62.5%), leading to the diagnosis of AML with multilineage dysplasia. Following a decrease in blasts due to anti-cancer drugs, supporting the MDS-RAEB-2 status, severe anemia with increased reticulocytes and positive direct antiglobulin test was diagnosed, suggesting the existence of autoimmune hemolytic anemia, which was then ameliorated by steroid therapy. Conclusions: The simultaneous loss of autoimmunity and leukemic cell expansion observed in our cases may possibly suggest a common underlying mechanism.

A 65-year-old man with myelodysplastic syndrome (MDS) was admitted for progressive jaundice. Diffuse pancreatic swelling and stricture of the main pancreatic duct were observed with elevated serum levels of direct bilirubin, aspartate transaminase, alanine transaminase, alkaline phosphatase, γGTP and amylase, and impaired glucose tolerance. Serum IgG and IgG4 levels were highly elevated, and both the direct antiglobulin test and platelet-associated IgG were positive. He was diagnosed with autoimmune pancreatitis associated with MDS, and biliary drainage followed by immunosuppressive therapy ameliorated the jaundice and laboratory findings. In addition to diffuse pancreatic FDG accumulation, fine incorporations of FDG to the lachrymal and submandibular glands were demonstrated, suggesting the recently proposed IgG4+ multiorgan lymphoproliferative syndrome (MOLPS). The etiology of IgG4+ MOLPS is still unknown; however, autoantibodies to blood cells in this case suggested that the autoimmune mechanism, which is caused by abnormal immune functions in MDS patients, might be involved in the pathogenesis of IgG4+ MOLPS.

Liver fibrosis with any aetiology, induced by the transdifferentiation and proliferation of hepatic stellate cells (HSCs) to produce collagen, is characterized by progressive worsening in liver function, leading to a high incidence of death. We have recently reported that all-trans-retinoic acid (ATRA) suppresses the transdifferentiation and proliferation of lung fibroblasts and prevents radiation- or bleomycin-induced lung fibrosis.We examined the impact of ATRA on carbon tetrachloride (CCl(4))-induced liver fibrosis. We performed histological examinations and quantitative measurements of transforming growth factor (TGF)-beta1 and interleukin (IL)-6 in CCl(4)-treated mouse liver tissues with or without the administration of ATRA, and investigated the effect of ATRA on the production of the cytokines in quiescent and activated HSCs.CCl(4)-induced liver fibrosis was attenuated in histology by intraperitoneal administration of ATRA, and the overall survival rate at 12 weeks was 26.5% without ATRA (n=25), whereas it was 75.0% (n=24) in the treatment group (P=0.0187). In vitro studies disclosed that the administration of ATRA reduced (i) the production of TGF-beta1, IL-6 and collagen from HSCs, (ii) TGF-beta-dependent transdifferentiation of the cells and IL-6-dependent cell proliferation and (iii) the activities of nuclear factor-kappaB p65 and p38mitogen-activated protein kinase, which stimulate the production of TGF-beta1 and IL-6, which could be the mechanism underlying the preventive effect of ATRA on liver fibrosis.Our findings indicate that ATRA ameliorates liver fibrosis. As the oral administration of the drug results in good compliance, ATRA could be a novel approach in the treatment of liver fibrosis.

Pulmonary fibrosis in humans can occur as a result of a large number of conditions. In idiopathic pulmonary fibrosis (IPF), pulmonary function becomes progressively compromised resulting in a high mortality rate. Currently there are no proven effective treatments for IPF. We have recently reported that IL-6 and TGF-β1 plays an important role in proliferation and differentiation of lung fibroblasts, and all-trans-retinoic acid (ATRA) prevented bleomycin-induced lung fibrosis through the inhibition of these cytokines. Thalidomide (Thal) has been used in the treatment of multiple myeloma through the inhibitory effect on IL-6-dependent cell growth and angiogenesis. In this study, we examined the preventive effect of Thal on bleomycin-induced pulmonary fibrosis in mice. We performed histological examinations and quantitative measurements of IL-6, TGF-β1, collagen type Iα1 (COL1A1), vascular endothelial growth factor (VEGF), angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) in bleomycin-treated mouse lung tissues with or without the administration of Thal. Thal histologically ameliorated bleomycin-induced fibrosis in mouse lung tissues. Thal decreased the expressions of IL-6, TGF-β1, VEGF, Ang-1 Ang-2, and COL1A1 mRNA in mouse lung tissues. In addition, Thal inhibited angiogenesis in the lung. In vitro studies disclosed that Thal reduced 1) production of IL-6, TGF-β1, VEGF, Ang-1, and collagen synthesis from human lung fibroblasts, and 2) both IL-6-dependent proliferation and TGF-β1-dependent transdifferentiation of the cells, which could be the mechanism underlying the preventive effect of Thal on pulmonary fibrosis. These data may provide a rationale to explore clinical use of Thal for the prevention of pulmonary fibrosis.