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This article discusses a study that examined the risk of interstitial lung diseases (ILDs) in patients with myelodysplastic syndrome (MDS) undergoing azacitidine therapy. The study found suggestive findings for ILD in three patients out of 73 with MDS or acute myeloid leukaemia (AML) with myelodysplasia-related changes (MRCs). These patients were diagnosed with ILD based on tests and examinations. The study suggests that patients with MDS and specific chromosomal abnormalities may be at a higher risk of developing ILD during azacitidine therapy, but further research is needed to confirm these findings. Clinicians should exercise caution when considering azacitidine therapy for these patients. [Extracted from the article]

Background: This study evaluated the efficacy and safety of the combination chemotherapy of docetaxel plus S‐1 in patients with previously treated non‐small cell lung cancer (NSCLC) compared to docetaxel alone. Methods: Patients with previously treated NSCLC were randomly assigned to docetaxel alone (arm A) or a combination of docetaxel and S‐1 (arm B) for a maximum of four cycles. The primary endpoint was overall survival (OS). Results: The study was terminated early because of poor accrual. The number of patients evaluated were 74 and 77 in arm A and arm B, respectively. The median OS was 9.8 months (95% confidence interval [CI]: 6.8–15.2) and 12.3 months (95% CI: 9.2–14.5) in arms A and B, respectively. In arms A and B, the median progression‐free survival was 3.5 months (95% CI: 2.7–4.0) and 4.1 months (95% CI: 3.2–4.7), respectively. No statistically significant difference was observed in OS (hazard ratio [HR]: 0.984, 95% CI: 0.682–1.419, p = 0.4569) or progression‐free survival (HR: 0.823, 95% CI: 0.528–1.282, p = 0.0953). The major toxicity was myelosuppression. The incidence of grade 3 or more neutropenia was higher in arm A than in arm B (44.6% vs. 35.1%). However, the incidence of grade 3 or more febrile neutropenia and infection with neutropenia (12.2% vs. 22.1%) was more frequently observed in arm B. Conclusions: The prematurely terminated study did not show the benefit of two cytotoxic agents over single‐agent therapy for previously treated NSCLC patients. [ABSTRACT FROM AUTHOR]

Malignant pleural mesothelioma (MPM) is associated with a history of heavy, long-term exposure to asbestos. However, MPM may also be associated with simian virus 40 (SV40), a polyomavirus. The association between SV40 and MPM remains unclear. The present study was conducted in order to investigate the proportion of SV40 presence in the histological specimens of Vietnamese patients with MPM. Histological specimens were obtained from 45 patients (19 men and 26 women) with MPM at the Pham Ngoc Thach Hospital in Ho Chi Minh City, Vietnam. The specimens were processed and examined in order to detect the presence of the SV40 large T antigen (SV40 Tag) expression using immunohistochemistry. Of the 45 patients, 23 (51%) were epithelioid, 7 (16%) were biphasic, 6 (13%) were sarcomatoid, 4 (9%) were desmoplastic, 4 (9%) were well-differentiated papillary and 1 (2%) was the anaplastic subtype. In total, 9/45 patients (20%) demonstrated SV40 Tag expression. The proportion of patients that demonstrated SV40 Tag expression was not significantly different between the epithelioid subtype and the other subtypes (22 vs. 18%; P=1.000) or between the patients with stage IV disease and other stages (20 vs. 20%; P=1.000). The median survival time was not significantly different between the patients with or without SV40 Tag expression (196 vs. 236 days, P=0.8949). In summary, a 5th of the Vietnamese patients with MPM were associated with infection with SV40. SV40 may be a potential cause of MPM in Vietnam and this potential association requires additional studies. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: Carbon monoxide (CO) levels in expired gas are higher in patients with bronchial asthma than in healthy individuals. Heme oxygenase-1 (HO-1) is a rate-limiting enzyme that catalyzes the degradation of heme to yield biliverdin, CO and free iron. Thus, HO-1 is implicated in the pathogenesis of bronchial asthma. However, whether HO-1 expression and activity in lung tissue are related to allergic airway inflammation remains unclear. We investigated whether expression of HO-1 is related to allergic airway inflammation in lungs and whether HO-1 could influence airway hyperresponsiveness and eosinophilia in mice sensitized to ovalbumin (OVA).Methods: C57BL/6 mice immunized with OVA were challenged thrice with an aerosol of OVA every second day for 8 days. HO-1-positive cells were identified by immunostaining in lung tissue, and zinc protoporphyrin (Zn-PP), a competitive inhibitor of HO-1, was administered intraperitoneally to OVA-immunized C57BL/6 mice on day 23 (day before inhalation of OVA) and immediately before inhalation on the subsequent 4 days (total five doses). Mice were analyzed for effects of HO-1 on AHR, inflammatory cell infiltration and cytokine levels in lung tissue. Ethical approval was obtained from the concerned institutional review board.Results: Number of HO-1-positive cells increased in the subepithelium of the bronchi after OVA challenge, and HO-1 localized to alveolar macrophages. Zn-PP clearly inhibited AHR, pulmonary eosinophilia and IL-5 and IL-13 expression in the lung tissue.Conclusion: Expression of HO-1 is induced in lung tissue during attacks of allergic bronchial asthma, and its activity likely amplifies and prolongs allergic airway inflammation. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the diagnostic and prognostic value of circulating tumor cells (CTCs), a potential surrogate of micrometastasis, in malignant pleural mesothelioma (MPM). Methods: We prospectively evaluated CTCs in 7.5 mL of peripheral blood sampled from patients with a suspicion of MPM. A semiautomated system was used to capture CTCs with an antibody against the epithelial cell adhesion molecule. Results: Of 136 eligible patients, 32 were finally diagnosed with nonmalignant diseases (NM), and 104 had MPM. CTCs were detected in 32.7 % (34 of 104) of MPM patients but in only 9.4 % (3 of 32) of NM patients ( P = 0.011). The CTC count was significantly higher in MPM patients than in NM patients ( P = 0.007), and a receiver operating characteristic (ROC) curve analysis showed an insufficient capability of the CTC test in discrimination between MPM and NM, with an area under ROC curve of 0.623 (95 % confidence interval, 0.523-0.723; P = 0.036). Among MPM patients, CTCs were more frequently detected in patients with epithelioid subtype (39.7 %, 31 of 78) than in those with nonepithelioid subtypes (11.5 %, 3 of 26; P = 0.016). Positive CTCs (CTC count ≥1) were a significant factor to predict a poor prognosis among epithelioid patients (median overall survival, 22.3 months for positive CTCs vs. 12.6 months for negative CTCs; P = 0.004) and not in nonepithelioid patients ( P = 0.649). A multivariate analysis showed that positive CTCs were a significant and independent factor to predict a poor prognosis (hazard ratio, 2.904; 95 % confidence interval, 1.530-5.511; P = 0.001) for epithelioid MPM patients. Conclusions: CTC was a promising marker in diagnosis and prediction of prognosis in MPM, especially in epithelioid MPM. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM PUBLISHER]

The newly synthesized naftopidil analogue HUHS1015 reduced cell viability in malignant pleural mesothelioma cell lines MSTO-211H, NCI-H28, NCI-H2052, and NCI-H2452, with the potential greater than that for the anticancer drugs paclitaxel or cisplatin at concentrations higher than 30 μM. HUHS1015 induced both necrosis and apoptosis of MSTO-211H and NCI-H2052 cells. HUHS1015 upregulated expression of mRNAs for Puma, Hrk, and Noxa in MSTO-211H and NCI-H2052 cells, suggesting HUHS1015-induced mitochondrial apoptosis. HUHS1015 clearly suppressed tumor growth in mice inoculated with NCI-H2052 cells. Taken together, the results of the present study indicate that HUHS1015 could be developed as an effective anticancer drug for treatment of malignant pleural mesothelioma. [ABSTRACT FROM AUTHOR]

Background/Aims: Accumulating evidence has suggested that free fatty acids (FFAs) interact with protein kinases and protein phosphatases. The present study examined the effect of FFAs on protein phosphatases and Akt. Methods: Activities of protein phosphatase 1 (PP1), protein phosphatase 2A (PP2A), and protein tyrosine phosphatase 1B (PTP1B) were assayed under the cell-free conditions. Phosphorylation of Akt was monitored in MSTO-211H human malignant pleural mesothelioma cells without and with knocking-down phosphatidylinositol 3 kinase (PI3K) or 3-phosphoinositide-dependent protein kinase-1 (PDK1). Results: In the cell-free assay, unsaturated FFAs (uFFAs) such as oleic, linoleic and linolenic acid and saturated FFAs (sFFAs) such as stearic, palmitic, myristic, and behenic acid markedly reduced PTP1B activity, with the potential for uFFAs greater than that for sFFAs. All the investigated sFFAs inhibited PP2A activity, but otherwise no inhibition was obtained with uFFAs. Both uFFAs and sFFAs had no effect on PP1 activity. Oleic acid phosphorylated Akt both on Thr308 and Ser473, while stearic acid phosphorylated Akt on Thr308 alone. The effects of oleic and stearic acid on Akt phosphorylation were abrogated by the PI3K inhibitor wortmannin or the PDK1 inhibitor BX912 and also by knocking-down PI3K or PDK1. Conclusion: The results of the present study indicate that uFFAs and sFFAs could activate Akt through a pathway along a PI3K/PDK1/Akt axis in association with PTP1B inhibition. © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background/Aims: Our earlier studies suggested crosstalk between IRS/PI3 kinase/PDK1/Akt/Rac1/ROCK and (Shc2/Grb2/SOS)/Ras/Raf/MEK/ERK pathways downstream PDGF-ββ receptor responsible for chemotaxis and proliferation of malignant mesothelioma cells. The present study was conducted to obtain evidence for this. Methods: To assess activation of Akt, MEK, and ERK, Western blotting was carried out on MSTO-211H malignant mesothelioma cells using antibodies against phospho-Thr308-Akt, phopho-Ser473-Akt, Akt, phospho-MEK, MEK, phopho-ERK1/2, and ERK1/2. To knock-down Akt, PI3 kinase, PDK1, and Rac1, siRNAs silencing each-targeted gene were constructed and transfected into cells. To monitor Rac1 activity, FRET monitoring was carried out on living and fixed cells. Results: ERK was activated under the basal conditions in MSTO-211H cells, and the activation was prevented by inhibitors for PI3 kinase, PDK1, Akt, and Rac1 or by knocking-down PI3 kinase, PDK1, Akt, and Rac1. Akt was also activated under the basal conditions, and the activation was suppressed by a MEK inhibitor and an ERK1/2 inhibitor. In the FRET analysis, Rac1 was activated under the basal conditions, and the activation was inhibited by a MEK inhibitor and an ERK1/2 inhibitor. Conclusion: The results of the present study show that ERK could be activated by PI3 kinase, PDK1, Akt, and Rac1 and that alternatively, Akt and Rac1 could be activated by MEK and ERK in MSTO-211H cells. Copyright © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Malignant pleural mesothelioma (MPM) is an aggressive malignant tumor of mesothelial origin that shows a limited response to conventional chemotherapy and radiotherapy. Therefore, diagnosing MPM early is very important. Some researchers have previously reported that high-mobility group box 1 (HMGB1) was correlated with pulmonary fibrosis. MPM 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. Methods: HMGB1 production from MPM cell lines was measured using ELISA. Serum HMGB1 levels were also examined in 61 MPM patients and 45 individuals with benign asbestos-related diseases. Results: HMGB1 concentrations of 2 out of 4 MPM cell lines were higher than that of normal mesothelial cell line, Met-5A. We demonstrated that patients with MPM had significantly higher serum levels of HMGB1 than the population who had been exposed to asbestos but had not developed MPM. The difference in overall survival between groups with serum HMGB1 levels that were lower and higher than assumed cut-off values was significant. Conclusions: Our data suggest that serum HMGB1 concentration is a useful prognostic factor for MPM. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background/Aims:A3 adenosine receptor mediates apoptosis in cancer cells via diverse signaling pathways. The present study examined A3 adenosine receptor-mediated apoptosis in Lu-65 cells, a human giant cell lung carcinoma cell line. Methods: MTT assay, TUNEL staining, real-time RT-PCR, Western blotting, and assay of caspase-3, -8, and -9 activities were carried out in Lu-65 cells, and A3 adenosine receptor or p53 was knocked-down by transfecting each siRNA into cells. Results: Extracellular adenosine induces Lu-65 cell apoptosis in a concentration (0.01-10 mM)-dependent manner, and the effect was inhibited by the A3 adenosine receptor inhibitor MRS1191 or by knocking-down A3 adenosine receptor or p53. Like adenosine, the A3 adenosine receptor agonist 2-Cl-IB-MECA also induced Lu-65 cell apoptosis. Adenosine upregulated expression of p53 and Noxa mRNAs and activated caspase-3 and -9, but not caspase-8. Those adenosine effects were still inhibited by knocking-down A3 adenosine receptor or p53. Conclusion: The results of the present study show that adenosine upregulates p53 expression via A3 adenosine receptor, to promote p53-dependent Noxa gene transcription, causing activation of caspase-9 and the effector caspase-3 to induce Lu-65 cell apoptosis. [ABSTRACT FROM AUTHOR]

Background/Aims: The present study investigated adenosine-induced apoptosis in human malignant pleural mesothelioma cells. Methods: MTT assay, TUNEL staining, flow cytometry using propidium iodide and annexin V-FITC, real-time RT-PCR, Western blotting, and assay of caspase-3, -8, and -9 activities were carried out using malignant pleural mesothelioma cell lines such as NCI-H28, NCI-H2052, NCI-H2452, and MST0-211H cells, and p53 or A3 adenosine receptor was knocked-down by transfecting each siRNA into cells. Results: Adenosine induced apoptosis in all the malignant pleural mesothelioma cells used here, independently of caspase activation. The adenosine effect was prevented by the adenosine transporter inhibitor dipyridamole, the adenosine kinase inhibitor ABT-702, or the AA3 adenosine receptor inhibitor MRS1191. Adenosine upregulated expression of the p53 mRNA and protein, that is abolished by ABT-702, but not by knocking-down A3 adenosine receptor Adenosine-induced apoptosis in NCI-H28 cells was significantly inhibited by knocking-down p53 and in part by knocking-down A3 adenosine receptor Conclusion: The results of the present study show that AMP converted from intracellularly transported adenosine upregulates p53 expression to induce caspase-independent apoptosis in malignant pleural mesothelioma cells and that A3 adenosine receptor also participates partially in the apoptosis by the different mechanism. [ABSTRACT FROM AUTHOR]

Background/Aims: The present study investigated adenosine-induced apoptosis in human malignant pleural mesothelioma cells. Methods: MTT assay, TUNEL staining, flow cytometry using propidium iodide and annexin V-FITC, real-time RT-PCR, Western blotting, and assay of caspase-3, -8, and -9 activities were carried out using malignant pleural mesothelioma cell lines such as NCI-H28, NCI-H2052, NCI-H2452, and MSTO-211H cells, and p53 or A3 adenosine receptor was knocked-down by transfecting each siRNA into cells. Results: Adenosine induced apoptosis in all the malignant pleural mesothelioma cells used here, independently of caspase activation. The adenosine effect was prevented by the adenosine transporter inhibitor dipyridamole, the adenosine kinase inhibitor ABT-702, or the A3 adenosine receptor inhibitor MRS1191. Adenosine upregulated expression of the p53 mRNA and protein, that is abolished by ABT-702, but not by knocking-down A3 adenosine receptor. Adenosine-induced apoptosis in NCI-H28 cells was significantly inhibited by knocking-down p53 and in part by knocking-down A3 adenosine receptor. Conclusion: The results of the present study show that AMP converted from intracellularly transported adenosine upregulates p53 expression to induce caspase-independent apoptosis in malignant pleural mesothelioma cells and that A3 adenosine receptor also participates partially in the apoptosis by the different mechanism. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background/Aims: A3 adenosine receptor mediates apoptosis in cancer cells via diverse signaling pathways. The present study examined A3 adenosine receptor-mediated apoptosis in Lu-65 cells, a human giant cell lung carcinoma cell line. Methods: MTT assay, TUNEL staining, real-time RT-PCR, Western blotting, and assay of caspase-3, -8, and -9 activities were carried out in Lu-65 cells, and A3 adenosine receptor or p53 was knocked-down by transfecting each siRNA into cells. Results: Extracellular adenosine induces Lu-65 cell apoptosis in a concentration (0.01-10 mM)-dependent manner, and the effect was inhibited by the A3 adenosine receptor inhibitor MRS1191 or by knocking-down A3 adenosine receptor or p53. Like adenosine, the A3 adenosine receptor agonist 2-Cl-IB-MECA also induced Lu-65 cell apoptosis. Adenosine upregulated expression of p53 and Noxa mRNAs and activated caspase-3 and -9, but not caspase-8. Those adenosine effects were still inhibited by knocking-down A3 adenosine receptor or p53. Conclusion: The results of the present study show that adenosine upregulates p53 expression via A3 adenosine receptor, to promote p53-dependent Noxa gene transcription, causing activation of caspase-9 and the effector caspase-3 to induce Lu-65 cell apoptosis. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Malignant mesothelioma is an aggressive tumor of serosal surfaces that is closely associated with asbestos exposure which induces oxidative stress. Heme oxygenase (HO)-1, a rate-limiting enzyme of heme degradation, plays a protective role against oxidative stress. The HO-1 gene promoter carries (GT)n repeats whose number is inversely related to transcriptional activity of the HO-1 gene. Methods: To investigate the relationship between the length polymorphism of (GT)n repeats and mesothelioma susceptibility, we analyzed the HO-1 promoter in 44 asbestos-exposed subjects without mesothelioma and 78 asbestos-exposed subjects with mesothelioma using PCR-based genotyping. Results: The number of repeats ranged from 16 to 38, with two peaks at 23 and 30 repeats. Polymorphisms of (GT)n repeats were grouped into two classes of alleles, short (S) (<24) and long (L) (≥24), and three genotypes: L/L, L/S, and S/S. The proportions of allele frequencies in class L as well as genotypic frequencies of L allele carriers (L/L and L/S) were significantly higher in the asbestos-exposed subjects with mesothelioma than in those without mesothelioma. Conclusion: The findings of this study suggest that long (GT)n repeats in the HO-1 gene promoter are associated with a higher risk of malignant mesothelioma in the Japanese population. [ABSTRACT FROM AUTHOR]

Malignant mesothelioma is an aggressive tumor arising from mesothelial cells of serous membranes. Src family kinases (SFKs) have a pivotal role in cell adhesion, proliferation, survival and apoptosis. Here, we examined the effect of SFK inhibitors in NCI-H2052, ACC-MESO-4 and NCI-H28 cells, mesothelioma cell lines and Met5A, a human non-malignant mesothelial cell line. We found that PP2, a selective SFK inhibitor, inhibited SFK activity and induced apoptosis mediated by caspase-8 in NCI-H28 but not Met5A, NCI-H2052 and ACC-MESO-4 cells. Src, Yes, Fyn and Lyn protein, which are members of the SFK, were expressed in these cell lines, whereas NCI-H28 cells were deficient in Fyn protein. Small interfering RNA (siRNA) targeting Fyn facilitated PP2-induced apoptosis mediated by caspase-8 in NCI-H2052 and ACC-MESO-4 cells. PP2 reduced Lyn protein levels and suppressed SFK activity in all mesothelioma cell lines. Lyn siRNA induced caspase-8 activation and apoptosis in NCI-H28 cells but not in NCI-H2052 and ACC-MESO-4 cells. However, double RNA interference knockdown of Fyn and Lyn induced apoptosis accompanied by caspase-8 activation in NCI-H2052 and ACC-MESO-4 cells. Dasatinib, an inhibitor of multi-tyrosine kinases including SFK, also inhibited SFK activity and induced reduction of Lyn protein levels, caspase-8 activation and apoptosis in NCI-H28 cells but not in other cell lines. Present study suggests that SFK inhibitors induce caspase-8-dependent apoptosis caused by reduction of Lyn protein in Fyn-deficient mesothelioma cells. [ABSTRACT FROM PUBLISHER]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Malignant mesothelioma is an aggressive tumor of serosal surfaces, which is refractory to current treatment options. Arsenic trioxide (AsO) is used clinically to treat acute promyelocytic leukemia, and also to inhibit proliferation of several solid tumors including hepatoma, esophageal, and gastric cancer in vitro. Here we found that AsO inhibited cell viability of a mesothelioma cell line, NCI-H2052. AsO induced apoptosis of NCI-H2052 cells, which was accompanied by activation of c-Jun NH-terminal kinase (JNK)1/2, extracellular signal-regulated kinase (ERK)1/2, and caspase-3. zVAD-fmk, a broad-spectrum caspase inhibitor, inhibited AsO-induced apoptosis and activation of caspase-3, but not that of JNK1/2 and ERK1/2. Small interfering RNAs (siRNAs) targeting JNK1/2 suppressed AsO-induced caspase-3 activation and apoptosis, indicating that JNK1/2 regulate AsO-induced apoptosis though caspase cascade. Furthermore, JNK1 siRNA abrogated AsO-induced JNK2 phosphorylation and JNK2 siRNA abrogated AsO-induced JNK1 phosphorylation, suggesting that JNK1 and JNK2 interact with each other. Moreover, JNK1 siRNA, but not JNK2 siRNA, abrogated AsO-induced ERK1/2 phosphorylation. JNK2 siRNA together with PD98059, a specific MAPK/ERK kinase inhibitor, suppressed AsO-induced apoptosis more significantly than JNK2 siRNA alone. These results indicated that AsO induces apoptosis of NCI-H2052 cells mainly through JNK1/2 activation, and that ERK1/2 is involved in AsO-induced apoptosis when JNK1/2 are inactivated. J. Cell. Physiol. 226: 762-768, 2011. © 2010 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

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. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

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. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 (CCl4)-induced liver fibrosis. We performed histological examinations and quantitative measurements of transforming growth factor (TGF)-β1 and interleukin (IL)-6 in CCl4-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: CCl4-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-β1, IL-6 and collagen from HSCs, (ii) TGF-β-dependent transdifferentiation of the cells and IL-6-dependent cell proliferation and (iii) the activities of nuclear factor-κB p65 and p38mitogen-activated protein kinase, which stimulate the production of TGF-β1 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. [ABSTRACT FROM AUTHOR]

We report a male patient with adult T-cell lymphoma, who was initially diagnosed clinically as having Henoch–Schönlein purpura (HSP) with abdominal pain and specific purpura. Adult T-cell lymphoma-like cells were minimal and abdominal lymph nodes were transiently swollen, and the symptoms were improved by supportive management. Although the clinical course was compatible with HSP, the histological examination revealed infiltration of lymphocytes rather than neutrophils. Later he developed lymphoma and was treated with chemotherapy. This rare case suggests the importance of skin biopsies to seek the underlying pathology in adult HSP. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Although high-dose thoracic radiotherapy is an effective strategy for some malignancies including lung cancers and malignant lymphomas, it often causes complications of radiation fibrosis. To study the mechanism initiating tissue fibrosis, we investigated irradiation-induced cytokine production from human lung fibroblastic cells and found that IL-6 production was stimulated by irradiation. IL-6 is an autocrine growth factor for human myeloma cells, and retinoic acid is reported to inhibit their growth. Thus we evaluated the effect of all-trans retinoic acid (ATRA) on cell proliferation of lung fibroblasts along with the cytokine/receptor system. Irradiation-dependent stimulation of IL-6 production was correlated with increased NF-KB activity, and ATRA reduced this effect. Irradiation also increased the levels of mRNA for IL-6R and gp130, which were blocked by coexisting ATRA. Furthermore, IL-6 stimulated cell proliferation in dose-dependent manner but was overcome by pharmacological concentration of ATRA. These effects of ATRA were inhibited by rottlerin, which suggests ATRA abolished irradiation-induced stimulation through a PKCδ-dependent pathway. Finally, we demonstrated that IL-6 transcripts in the lung were upregulated at 2 mo after irradiation, and the effect was inhibited by the intraperitoneal administration of ATRA. ATRA is expected to have an advantage for radiotherapy in its antitumor effects, as reported previously, and to prevent radiotherapy-induced pulmonary injury. [ABSTRACT FROM AUTHOR]

A case study of 66-year-old woman is presented, who was admitted to the hospital for progressive anemia. It informs that the patient had hypoplastic bone marrow after immunosuppressive therapy in malignant lymphoma cases. It also discusses the administration of prednisolone and azathioprine ameliorated neutropenia and anemia.

A letter to the editor is presented related to growth of diffuse large B cell lymphoma and angioimmunoblastic T cell lymphoma from composite lymphoma, that was published in the previous issue.

A letter to the editor is presented related to complications of CD2-positive follicular lymphoma developed due to venous thrombosis in surface vein.

A letter to the editor on follicular lymphoma with prominent fibrosis is presented.

A letter to the editor is presented which discusses a case of a 87-year-old woman with prominent granulomas in bone marrow associated hemophagocytic syndrome.

A letter to the editor is presented about a study on extranodal follicular lymphoma.

Background: Malignant pleural mesothelioma (MPM) is an aggressive malignant tumor of mesothelial origin that shows a limited response to conventional chemotherapy and radiotherapy. Therefore, diagnosing MPM early is very important. Some researchers have previously reported that high-mobility group box 1 (HMGB1) was correlated with pulmonary fibrosis. MPM 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.Methods: HMGB1 production from MPM cell lines was measured using ELISA. Serum HMGB1 levels were also examined in 61 MPM patients and 45 individuals with benign asbestos-related diseases.Results: HMGB1 concentrations of 2 out of 4 MPM cell lines were higher than that of normal mesothelial cell line, Met-5A. We demonstrated that patients with MPM had significantly higher serum levels of HMGB1 than the population who had been exposed to asbestos but had not developed MPM. The difference in overall survival between groups with serum HMGB1 levels that were lower and higher than assumed cut-off values was significant.Conclusions: Our data suggest that serum HMGB1 concentration is a useful prognostic factor for MPM. [ABSTRACT FROM AUTHOR]

An abstract of the article "The Calpain Inhibitor Calpeptin Prevents Bleomycin-Induced Pulmonary Fibrosis in Mice" by Chiharu Tabata and colleagues is presented.

An abstract of the article "Is Serum Thioredoxin-1 a Useful Clinical Marker for Malignant Pleural Mesothelioma?" by Risa Maeda, Chiharu Tabata, Rie Tabata, Kazuya Fukuoka, Takashi Nakano is presented.