Frequent downregulation of BTB and CNC homology 2 expression in Epstein-Barr virus-positive diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell lymphoma subtype, and the Epstein-Barr virus (EBV)-positive subtype of DLBCL is known to show a more aggressive clinical behavior than the EBV-negative one. BTB and CNC homology 2 (BACH2) has been highlighted as a tumor suppressor in hematopoietic malignancies; however, the role of BACH2 in EBV-positive DLBCL is unclear. In the present study, BACH2 expression and its significance were studied in 23 EBV-positive and 43 EBV-negative patient samples. Immunohistochemistry revealed BACH2 downregulation in EBV-positive cases (P < 0.0001), although biallelic deletion of BACH2 was not detected by FISH. Next, we analyzed the contribution of BACH2 negativity to aggressiveness in EBV-positive B-cell lymphomas using FL-18 (EBV-negative) and FL-18-EB cells (FL-18 sister cell line, EBV-positive). In BACH2-transfected FL-18-EB cells, downregulation of phosphorylated transforming growth factor-ß-activated kinase 1 (pTAK1) and suppression in p65 nuclear fractions were observed by Western blot analysis contrary to non-transfected FL-18-EB cells. In patient samples, pTAK1 expression and significant nuclear p65, p50, and p52 localization were detected immunohistochemically in BACH2-negative DLBCL (P < 0.0001, P = 0.006, and P = 0.001, respectively), suggesting that BACH2 downregulation contributes to constitutive activation of the nuclear factor-κB pathway through TAK1 phosphorylation in BACH2-negative DLBCL (most EBV-positive cases). Although further molecular and pathological studies are warranted to clarify the detailed mechanisms, downregulation of BACH2 may contribute to constitutive activation of the nuclear factor-κB pathway through TAK1 activation.

CD10 down expression in follicular lymphoma correlates with gastrointestinal lesion involving the stomach and large intestine.

Follicular lymphoma (FL) shows co-expression of B-cell lymphoma 2 (BCL2) and CD10, whereas downexpression of CD10 is occasionally experienced in gastrointestinal (GI) FL with unknown significance. Gastrointestinal FL is a rare variant of FL, and its similarity with mucosa-associated lymphoid tissue lymphoma was reported. We investigated the clinicopathological and genetic features of CD10 downexpressed (CD10down ) GI-FL. The diagnosis of CD10down FL was carried out with a combination of pathological and molecular analyses. The incidence of CD10down GI-FL was shown in 35/172 (20.3%) cases, which was more frequent than nodal FL (3.5%, P < 0.001). The difference was additionally significant between GI-FL and nodal FL when the analysis was confined to primary GI-FL (55.2% vs 3.5%, P < 0.001). Compared to CD10+ GI-FL, CD10down GI-FL significantly involved the stomach or large intestine (P = 0.015), and additionally showed the downexpression of BCL6 (P < 0.001). The follicular dendritic cell meshwork often showed a duodenal pattern in the CD10down group (P = 0.12). Furthermore, a lymphoepithelial lesion was observed in 5/12 (40%) gastric FL cases, which indicated caution in the differentiation of mucosa-associated lymphoid tissue lymphoma. Molecular analyses were undertaken in seven cases of CD10down GI-FL, and an identical clone was found between CD10down follicles and CD10+ BCL2+ neoplastic follicles. In the diagnosis of cases with CD10down BCL2+ follicles, careful examination with molecular studies should be carried out.

Clinicopathological features of 49 primary gastrointestinal diffuse large B-cell lymphoma cases; comparison with location, cell-of-origin, and frequency of MYD88 L265P.

The gastrointestinal (GI) tract is the most common primary site of extranodal diffuse large B-cell lymphoma (DLBCL), with approximately one-third of extranodal DLBCL occurring in the GI tract. We investigated the clinicopathological features and immunohistochemically-assessed cell-of-origin of 49 GI DLBCL cases (stomach, 24; small intestine, 10; colon, 15) and also examined the presence of MYD88 L265P as recently this mutation has been frequently identified in ABC-like DLBCL, particularly in extranodal sites. Small intestinal DLBCL was characterized by the preponderance of women (P = 0.041) and elevated LDH (P = 0.002) and soluble interleukin-2 receptor (P = 0.033). Small intestinal DLBCL more frequently showed anemia (P = 0.031) and elevated CRP (P = 0.029) than gastric DLBCL. ABC-like phenotype was seen in 71.4 % cases (stomach, 79 %; small intestine, 70 %; colon, 60 %). MYD88 L265P was detected in 6.1 % cases; all were primary gastric DLBCL with ABC-like phenotype but had no distinct clinicopathological features. In conclusion, GI DLBCL had different clinicopathological features according to the primary site especially in the small intestine. Also, MYD88 L265P had little involvement in GI DLBCL compared with other extranodal DLBCLs, suggesting that its pathogenesis might be different from that of organs with a high frequency of MYD88 L265P.

Impact of chronic kidney disease on left main coronary artery disease and prognosis in Japanese patients.

BACKGROUND: Renal insufficiency plays a critical role in the pathogenesis of ischemic heart disease. The aim of the present study was to investigate the prevalence of renal dysfunction and its impact on prognosis in patients with left main coronary artery disease (LMCAD) and stable angina pectoris. METHODS AND RESULTS: A total of 626 consecutive patients with significant coronary artery stenosis were enrolled. Renal insufficiency was graded using estimated glomerular filtration rate (eGFR) before coronary angiography. Chronic kidney disease (CKD) was defined as eGFR <60 ml·min(-1)·1.73 m(-2) and/or proteinuria. Patients with LMCAD (n=95) had a significantly higher prevalence of CKD than those without LMCAD (P=0.02). Multiple logistic regression analysis showed that CKD was independently associated with LMCAD (adjusted odds ratio, 1.74; 95% confidence interval [CI]: 1.09-2.76, P=0.01). A 1-year follow-up of patients with LMCAD showed that the cumulative incidence of major adverse cardiovascular events among patients with eGFR <30 ml·min(-1)·1.73 m(-2) was higher than that among patients with eGFR ≥60 ml·min(-1)·1.73 m(-2) (P=0.03). The hazard ratio for a cardiovascular event was 9.54 (95% CI: 3.15-28.89, P<0.01) when comparing patients with LMCAD and eGFR <30 ml·min(-1)·1.73 m(-2) vs. patients without LMCAD and eGFR ≥60 ml·min(-1)·1.73 m(-2). CONCLUSIONS: Renal insufficiency is a risk factor for LMCAD and predicts poor prognosis in Japanese patients.

Association of serum levels of arachidonic acid and eicosapentaenoic acid with prevalence of major adverse cardiac events after acute myocardial infarction.

We studied the association of serum levels of arachidonic acid (AA) and eicosapentaenoic acid (EPA) with the prevalence of major adverse cardiac events (MACE) after acute myocardial infarction (AMI). We measured serum AA and EPA on admission in 146 consecutive AMI patients. The primary clinical endpoint was occurrence of MACE, defined as cardiac death, occurrence of heart failure, reinfarction, recurrent angina pectoris, and requirement of coronary intervention. Common logarithmic transformed serum levels of AA (logAA) and EPA (logEPA) were used in the analyses. The optimum cutoff point of each fatty acid used to distribute patients into two groups for Kaplan-Meier analysis was determined by receiver operating characteristic curves analysis. MACE occurred in 40 patients (27.4%). Kaplan-Meier analysis disclosed that the group with a logAA above the cutoff point [145.3 µg/mL (logAA 2.162)] showed a higher prevalence of MACE than those with a logAA below the cutoff point (P < 0.01). Conversely, the prevalence of MACE was significantly higher in the group with a logEPA below the cutoff point [52.3 µg/mL (logEPA 1.719)] compared to the group with a logEPA above it (P < 0.01). Similar to logAA, logAA/logEPA showed significant differences in the MACE-free curve between the two groups (cutoff 1.301, P < 0.001). Cox proportional hazards regression analysis suggested that logAA, logEPA, and logAA/logEPA were independently associated with the prevalence of MACE. Although the present study included a limited number of patients with single-time point measurement, the results suggested an association of logAA, logEPA, and logAA/logEPA with the prevalence of MACE after AMI. The present study warrants further studies involving a large number of patients to confirm that the serum levels of these fatty acids and their ratios are predictors of MACE after AMI.

A case of ectopic hamartomatous thymoma: controversy over the designation.

BACKGROUND: Ectopic hamartomatous thymoma, which usually occurs in the lower neck, is a rare benign tumor containing spindle cells, epithelial nests, and adipose tissue. Although the origin of this tumor is still unknown, recent reports suggest that the designation of this tumor is inappropriate. CASE PRESENTATION: A 38-year-old with an anterior cervical mass in the suprasternal region of her neck was referred to our hospital. An ultrasound examination showed that the well-defined oval mass was 31 × 23 × 17 mm in size. A non-enhanced computed tomography scan of the neck revealed that the distinct neck mass in the subcutaneous tissue had a mixture of soft tissue and fatty components. The cervical tumor was clinically diagnosed to be an unusual lipoma with degeneration. The patient underwent the neck mass extirpation. During the surgery, the cervical mass was well demarcated and did not adhere to the surrounding tissues. The postoperative course was uneventful. The gross pathology report showed that the neck mass measured 3.0 × 2.5 × 2.0 cm. Microscopically, the tumor was composed of spindle cells, epithelial nests, and mature adipose tissue. Immunohistochemical examination revealed that both spindle cells and epithelial nests were positive for cytokeratin AE1/AE3. These histopathological findings were consistent with the features of ectopic hamartomatous thymoma. Over a follow-up period of 30 months, this patient exhibited no evidence of recurrence. CONCLUSIONS: Ectopic hamartomatous thymoma should be considered in the differential diagnosis of subcutaneous tumors in the lower neck, when the CT shows the tumor has the mixed components of fat and soft tissues.

Characteristic Distribution Pattern of CD30-positive Cytotoxic T Cells Aids Diagnosis of Kikuchi-Fujimoto Disease.

INTRODUCTION: Histiocytic necrotizing lymphadenitis (or Kikuchi-Fujimoto disease) frequently occurs in Asian young adult females and typically presents as cervical lymphadenopathy with unknown etiology. Although large immunoblasts frequently appear in Kikuchi-Fujimoto disease, the diffuse infiltration of these cells can cause difficulty in establishing a differential diagnosis from lymphoma. In such cases, CD30 immunostaining may be used; however, the extent or distribution pattern of CD30-positive cells in Kikuchi-Fujimoto disease remains largely unknown. Here we investigated the expression of CD30 and its clinicopathologic significance. MATERIALS AND METHODS: We investigated 30 Kikuchi-Fujimoto disease and 16 control [6, systemic lupus erythematosus (SLE); 10, reactive lymphoid hyperplasia (RLH)] cases. RESULTS: The number of CD30-positive cells in Kikuchi-Fujimoto disease was significantly more than that in SLE and RLH, and majority of these cells were located around necrotic areas. Moreover, double immunohistochemical staining showed these CD30-positive cells to be CD8-positive cytotoxic T cells, suggesting that activated cytotoxic T cells around necrotic areas are a characteristic feature of this disease. Clinicopathologic analysis showed that cases with abundant CD30-positive cells were predominantly female with only mild symptoms and normal laboratory data. CONCLUSIONS: In Kikuchi-Fujimoto disease cases, CD30-positive cytotoxic T cells were abundant around necrotic areas; this histologic feature may be helpful to differentiate this disease from SLE and RLH.

Frequent MYD88 L265P and CD79B Mutations in Primary Breast Diffuse Large B-Cell Lymphoma.

Primary breast diffuse large B-cell lymphoma (PB-DLBCL) is a rare disease comprising <3% of extranodal lymphomas. It frequently reveals an activated B-cell (ABC)-like phenotype. ABC-like DLBCL was reported to have gain-of-function mutations in MYD88, CD79B, CARD11, and TNFAIP3, resulting in constitutive activation of the NFκB pathway. Because of the rare occurrence of PB-DLBCL, the frequency of MYD88 and CD79B mutations is still unknown. We used Sanger sequencing to study these mutations from 46 breast DLBCL cases and also investigated the associated clinicopathologic factors. MYD88 L265P was confirmed by allele-specific polymerase chain reaction and compared with the Sanger sequencing results. MYD88 L265P and CD79B mutations were detected in 27/46 (58.7%) and 11/33 (33.3%) cases, respectively. Twenty-eight of 46 cases met the criteria for PB-DLBCL, and the latter 18 cases were further classified as clinical breast DLBCL (CLB-DLBCL). The frequency of MYD88 L265P and CD79B mutations was 16/28 (57.1%) and 9/23 (39.1%), respectively, in PB-DLBCL and 11/18 (61.1%) and 2/10 (20%), respectively, in CLB-DLBCL. When the cutoff value was set at ΔCt≤1, the result of allele-specific polymerase chain reaction for MYD88 corresponded to those of the Sanger sequence at 92.6% sensitivity and 100% specificity. According to Choi's algorithm, 16/27 (59.3%) demonstrated an ABC-like phenotype in PB-DLBCL, and 15/18 (83.3%) demonstrated an ABC-like phenotype in CLB-DLBCL. In conclusion, MYD88 L265P and CD79B mutations were frequently detected in PB-DLBCL, and they may be key molecules associated with PB-DLBCL lymphomagenesis. Further analysis will be required to clarify the mechanism of its pathogenesis.

Serum N-3 polyunsaturated fatty acid levels correlate with the extent of coronary plaques and calcifications in patients with acute myocardial infarction.

BACKGROUND: The relationship between serum fatty acid levels and the extent of coronary plaques and calcification was examined in patients with acute myocardial infarction (AMI). METHODS AND RESULTS: The serum levels of the n-3 polyunsaturated fatty acids (eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)) and the n-6 polyunsaturated fatty acids (arachidonic acid (AA) and dihomo-gamma-linolenic acid (DGLA)) were determined using gas chromatography on admission of 95 consecutive patients with their first AMI and 17 controls. Using multidetector-row computed tomography, soft plaques and calcification lesions were scored according to the extent of coronary involvement. Serum logarithmic transformed (log) EPA and logDHA levels were inversely correlated with soft plaque scores (r=-0.546, p<0.0001 and r=-0.377, p<0.0001, respectively). Serum logAA and logDGLA levels were not significantly correlated with soft plaque scores. Serum logEPA and logDHA levels were significantly, but weakly, correlated with calcification scores. Multivariate analysis with clinical characteristics and risk factors selected serum n-3 polyunsaturated fatty acid levels as independent factors associated with the extent of coronary soft plaques. CONCLUSION: The present study demonstrates a significant correlation between serum n-3 polyunsaturated fatty acid levels and the extent of coronary soft plaques and calcification in AMI patients.