Improved outcomes of localized diffuse large B-cell lymphoma at the Waldeyer ring in comparison to the sinonasal area in the rituximab era.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) of the head-and-neck area primarily involves the Waldeyer ring (WR) and sinonasal area (SN). However, the differential clinical outcomes between patients with WR-DLBCL and those with SN-DLBCL in the rituximab era remain unclear. METHODS: To avoid confounding factors contributed by advanced DLBCL with WR and SN involvement, we assessed the clinical outcomes of patients with stage I/II WR-DLBCL and SN-DLBCL and compared them with those having corresponding stages of DLBCL in the lymph nodes but without other extranodal involvement (LN-DLBCL) in the same period. We compared the patients' clinical characteristics, treatment modalities, event-free survival (EFS), and overall survival (OS) among the three subgroups. RESULTS: We analyzed 67, 15, and 106 patients with WR-DLBCL, SN-DLBCL, and LN-DLBCL, respectively, between January 2000 and December 2019. All patients received front-line rituximab-based regimens, and > 80% received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone-based regimens. More patients with SN-DLBCL had revised International Prognostic Index (R-IPI) score 3 (27%) when compared with those with WR-DLBCL (7%) and those with LN-DLBCL (10%, p = 0.181). Patients with WR-DLBCL, LN-DLBCL, and SN-DLBCL had 5-year EFS and OS rates of 80.7%, 59.5%, and 41.9% (p = 0.021) and 83.7%, 70.8%, and 55.8% (p = 0.032), respectively. Compared to patients with LN-DLBCL, those with WR-DLBCL also had a significantly favorable 5-year EFS rate (p = 0.021) and 5-year OS rate (p = 0.023). Three of the 15 patients with SN-DLBCL experienced lymphoma recurrence in the brain after front-line treatment. In multivariate analyses, R-IPI scores of 1-2 and 3 served as significantly poor prognostic factors for patients with poor EFS and OS. CONCLUSIONS: Compared to patients with LN-DLBCL, patients with WR-DLBCL receiving front-line rituximab-based treatments had favorable clinical outcomes; however, patients with SN-DLBCL had worse clinical outcomes. Further studies on molecular prognostic factors and treatment strategies for SN-DLBCL are warranted.

First-line antibiotic treatment in patients with localized extragastric mucosa-associated lymphoid tissue lymphoma.

Between January 2010 and December 2015, we enrolled 28 patients with stage IEI/IIE1 extragastric mucosa-associated lymphoid tissue (MALT) lymphoma who received first-line antibiotic treatment, after informing them about the pros and cons of alternative therapies. In addition, during the same period, 64 patients with stage IE/IIE1 disease who received conventional treatment were selected as the control group. The most common primary sites were the ocular adnexal area (17 cases), followed by the salivary glands (four cases), pulmonary (three cases), and thyroid, trachea, larynx, and colon region (one case each). First-line antibiotic treatment resulted in an overall response rate of 57.1%: 12 patients achieved complete remission (CR), while four achieved partial remission (antibiotic-responsive tumors). Monoclonal gammopathy was significantly prevalent in antibiotic-unresponsive tumors than in antibiotic-responsive tumors (50.0% [6/12] vs. 12.5% [2/16], p = 0.044). After a median follow-up of 7 years, all patients with CR remained lymphoma-free, with 7-year event-free survival (EFS) and overall survival (OS) rates of 62.7% and 96.4%, respectively. The 7-year EFS and OS rates of patients who received conventional treatments were 73.1% and 91.1%, respectively. Compared with that noted in patients who received conventional treatment, antibiotic treatment was effective in some patients with localized extragastric MALT lymphoma.

Current Status of the Spectrum and Therapeutics of Helicobacter pylori-Negative Mucosa-Associated Lymphoid Tissue Lymphoma.

Helicobacter pylori (HP)-unrelated mucosa-associated lymphoid tissue (MALT) lymphoma includes the majority of extragastric MALT lymphomas and a small proportion of gastric MALT lymphomas. Although the role of first-line antibiotics in treating HP-negative gastric MALT lymphomas remains controversial, HP eradication therapy (HPE)-like regimens may result in approximately 20-30% complete remission (CR) for patients with localized HP-negative gastric MALT lymphoma. In these patients, H. heilmannii, H. bizzozeronii, and H. suis were detected in sporadic gastric biopsy specimens. Extragastric MALT lymphoma is conventionally treated with radiotherapy for localized disease and systemic chemotherapy for advanced and metastatic diseases. However, a proportion of extragastric MALT lymphomas, such as ocular adnexal lesions and small intestinal lesions, were reported to be controlled by antibiotics for Chlamydophila psittaci and Campylobacter jejuni, respectively. Some extragastric MALT lymphomas may even respond to first-line HPE. These findings suggest that some antibiotic-responsive tumors may exist in the family of HP-negative MALT lymphomas. Two mechanisms underlying the antibiotic responsiveness of HP-negative MALT lymphoma have been proposed. First, an HPE-like regimen may eradicate the antigens of unknown bacteria. Second, clarithromycin (the main component of HPE) may have direct or indirect antineoplastic effects, thus contributing to the CR of these tumors. For antibiotic-unresponsive HP-negative MALT lymphoma, high-dose macrolides and immunomodulatory drugs, such as thalidomide and lenalidomide, have reported sporadic success. Further investigation of new treatment regimens is warranted.

miR-155-regulated mTOR and Toll-like receptor 5 in gastric diffuse large B-cell lymphoma.

BACKGROUND: Gastric diffuse large B-cell lymphoma (DLBCL) is often associated with Helicobacter pylori (H. pylori) infection. Those in the early stage could be treated with H. pylori eradication therapy, and are classified into a sensitive group and a resistant group. METHODS: Genome-wide miRNA and miRNA expression profiles were obtained from biopsy specimens of gastric DLBCL. MiRNAs and their targets as predictors of responses to H. pylori eradication therapy were identified through differential expression and pathway enrichment analysis, and further confirmed with transfection experiments in lymphoma cell lines of B-cell origin. RESULTS: Genome-wide miRNA and mRNA profiles showed miR-200 was associated with the sensitive group, and that the resistant group had higher levels of miR-155 and lower levels of DEPTOR (an inhibitor of mTOR) than the sensitive group. BJAB cells transfected with miR-155 also had lower DEPTOR and higher mTOR levels. Therefore, miR-155-mediated inhibition of DEPTOR with secondary activation of mTOR was a potential marker for resistance to H. pylori eradication therapy. In contrast, pathway enrichment analysis showed that Toll-like receptor 5 (TLR5), the receptor for bacterial flagellin, was a potential marker for sensitivity to H. pylori eradication therapy. In an independent series, stronger expression of pS6K1 (a direct target of mTOR) was associated with the resistant group and morphologic evidence of active gastritis was associated with the sensitive group. CONCLUSIONS: These findings showed that activation of the miR-155-DEPTOR pathway is a marker for resistance to H. pylori eradication therapy, and that histological evaluation of active gastritis might be used as a surrogate marker to predict responses to H. pylori eradication therapy in gastric DLBCL.

Comparison of clinicopathological features and treatment outcomes in aggressive primary intestinal B- and T/NK-cell lymphomas.

BACKGROUND: Primary intestinal lymphomas (PILs) are rare, and this study compared the clinical outcomes of aggressive primary intestinal B-cell lymphomas (aB-PILs) and T/natural killer-cell lymphomas (T/NK-PILs). METHODS: The clinical information of patients diagnosed with aggressive PILs at our institution between 1995 and 2015 were retrospectively investigated. Pathological subtypes were confirmed according to the 2016 revision of the World Health Organization classification. The correlation between clinicopathological features and overall survival (OS) was determined using univariate and multivariate analyses. RESULTS: Cases of T/NK-PILs had higher initial bowel perforation incidence (67% vs. 7%, P < 0.001) and lower complete response rate to first-line chemotherapy regimens (22% vs. 69%, P = 0.009) than aB-PILs. Patients with aB-PILs had a better 5-year event-free survival rate (55.8% vs. 13.9%, P = 0.026) and a 5-year OS rate (74.3% vs. 29.6%, P = 0.036) than those with T/NK-cell lymphomas. Multivariate analysis identified that female gender and stage III/IV were unfavorable prognostic factors. Among the 54 patients with diffuse large B-cell lymphoma (DLBCL), those with International Prognostic Index (IPI) scores of 0-2 had a better 5-year OS rate than those with scores of 3-5 (84.2% vs. 46.8%, P = 0.002). IPI scores of 3-5 (P = 0.026) and tumors located in the large intestine (P = 0.015) were poor prognostic factors based on the multivariate analysis. CONCLUSION: The prognosis of T/NK-PILs was less favorable than that of aB-PILs. Female gender, stage III/IV disease, DLBCL with IPI scores of 3-5, or tumors in the large intestine were poor prognostic factors.

Novel Insights of Lymphomagenesis of Helicobacter pylori-Dependent Gastric Mucosa-Associated Lymphoid Tissue Lymphoma.

Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is the most common subtype of gastric lymphoma. Most gastric MALT lymphomas are characterized by their association with the Helicobacter pylori (HP) infection and are cured by first-line HP eradication therapy (HPE). Several studies have been conducted to investigate why most gastric MALT lymphomas remain localized, are dependent on HP infection, and show HP-specific intratumoral T-cells (e.g., CD40-mediated signaling, T-helper-2 (Th2)-type cytokines, chemokines, costimulatory molecules, and FOXP3+ regulatory T-cells) and their communication with B-cells. Furthermore, the reason why the antigen stimuli of these intratumoral T-cells with tonic B-cell receptor signaling promote lymphomagenesis of gastric MALT lymphoma has also been investigated. In addition to the aforementioned mechanisms, it has been demonstrated that the translocated HP cytotoxin-associated gene A (CagA) can promote B-cell proliferation through the activation of Src homology-2 domain-containing phosphatase (SHP-2) phosphorylation-dependent signaling, extracellular-signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (MAPK), B-cell lymphoma (Bcl)-2, and Bcl-xL. Furthermore, the expression of CagA and these CagA-signaling molecules is closely associated with the HP-dependence of gastric MALT lymphomas (completely respond to first-line HPE). In this article, we summarize evidence of the classical theory of HP-reactive T-cells and the new paradigm of direct interaction between HP and B-cells that contributes to the HP-dependent lymphomagenesis of gastric MALT lymphomas. Although the role of first-line HPE in the treatment of HP-negative gastric MALT lymphoma remains uncertain, several case series suggest that a proportion of HP-negative gastric MALT lymphomas remains antibiotic-responsive and is cured by HPE. Considering the complicated interaction between microbiomes and the genome/epigenome, further studies on the precise mechanisms of HP- and other bacteria-directed lymphomagenesis in antibiotic-responsive gastric MALT lymphomas are warranted.

Cilostazol Attenuates Retinal Oxidative Stress and Inflammation in a Streptozotocin-Induced Diabetic Animal Model.

PURPOSE: To investigate the anti-oxidative and anti-inflammatory effects of cilostazol in the ocular tissues of streptozotocin (STZ)-induced diabetic rats. MATERIALS AND METHODS: Diabetes was induced in 6-week-old Wistar rats via peritoneal injections of STZ. The treatment group received cilostazol 18 mg/kg/day for 8 weeks (n = 10), and the diabetic group received phosphate buffer solution (n = 20). The expression of oxidative stress and inflammatory mediators in the ocular tissues was then assessed by reverse-transcription polymerase chain reactions, immunohistochemical (IHC) staining, Western blot analysis, and enzyme-linked immunosorbent assay (ELISA). RESULTS: Reverse-transcription polymerase chain reactions, IHC staining, Western blot analysis, and ELISA showed that cilostazol inhibited mRNA and protein expressions of intercellular adhesion molecule-1, monocyte chemoattractant protein-1 and fractalkine in the retina and aqueous humor (AqH). Consistent with these findings, cilostazol attenuated the activation of nuclear factor-κB (NF-κB) in the diabetic rats. The levels of oxidatively modified DNA (8-OHdG), nitrotyrosine and oxidative lipids (acrolein) were also diminished in the cilostazol-treated group. Chemiluminescence analysis showed that reactive oxygen species (ROS) levels in the AqH was significantly higher in the diabetic rats than in the non-diabetic rats. Treatment with cilostazol significantly reduced the ROS levels in the AqH compared to the diabetic rats. CONCLUSIONS: Our results indicated that cilostazol reduced inflammatory reactions and oxidative stress in diabetic eyes. The anti-inflammatory effects of cilostazol may be indirectly via reducing oxidative stress, inhibiting NF-κB activity, and subsequently decreasing inflammatory mediators. Cilostazol may be beneficial to prevent the progression of diabetic retinopathy.

Intralymphatic Spread is a Rare Finding Associated With Poor Prognosis in Diffuse Large B-Cell Lymphoma With Extranodal Involvements.

Intralymphatic spread is common in solid cancers, but has been rarely studied in lymphomas. Review of 635 extranodal specimens from 475 diffuse large B-cell lymphoma (DLBCL) patients revealed intralymphatic spread in 10 surgical resection specimens from 10 patients including 9 de novo DLBCLs and 1 Richter transformation. The prevalence in de novo DLBCL with extranodal involvements was 1.65%. The most common involved site of intralymphatic spread was the gastrointestinal tract, followed by the female genital tract and breasts. Lymphatic vessels, lined by D2-40-positive endothelial cells, were expanded by lymphoma cells, reminiscent of intravascular lymphoma or tumor emboli. None of the involved lymphatic vessels were located in the mucosa. Patients with intralymphatic spread had a trend of lower overall response rate and a trend of higher progressive disease than those without intralymphatic spread. Compared with patients without intralymphatic spread, those patients with intralymphatic spread had a shorter median overall survival (14.3 vs. 96.2 mo; P=0.004) and a shorter median progression-free survival (11.2 vs. 64.2 mo; P=0.01), respectively. Multivariate analyses showed that intralymphatic spread was an independent poor prognostic factor for overall survival (hazard ratio, 3.029; 95% confidence interval, 1.315-6.978; P=0.009), irrespective of the National Comprehensive Cancer Network-International Prognostic Index, B symptoms, and serum albumin levels. Among patients who underwent surgical resection, intralymphatic spread was still an independent prognostic factor. In conclusion, our study demonstrated extranodal intralymphatic spread in DLBCL. Inspiringly, this rare morphologic finding may serve as a new negative prognostic indicator in DLBCL with extranodal involvements.

FGFR1 translocation with concurrent myeloproliferative neoplasm, systemic mastocytosis, and lymphoblastic lymphoma: a case report.

FGFR1 translocation may cause myeloid or lymphoid neoplasm but rarely systemic mastocytosis (SM). Conversely, SM is associated with myeloproliferative neoplasm (MPN) but rarely lymphoblastic lymphoma (LBL) or FGFR1 translocation. We report the first case of FGFR1 translocation in a patient with concurrent LBL, MPN, and SM. A 21-year-old male patient presented with diffuse lymphadenopathies and leukocytosis. TdT+/cytoCD3+/CD79aweakly+ LBL was identified in the lymph node. Bone marrow had MPN, SM, and TdT+/CD79a+/cytoCD3weakly+ LBL. The cytogenetic study, reverse-transcription polymerase chain reaction, and sequencing revealed t(8;13)(p11;q12) involving FGFR1 and ZMYM2. Under the hyper-cyclophosphamide, vincristine, doxorubicin, and dexamethasone regimen, complete remission of LBL was achieved despite persistent MPN and SM in the bone marrow. This rare case implies FGFR1 translocation in a precursor cell capable of differentiation into mast cells and lymphoblasts, strengthening the relationship between the 2 tumors in the World Health Organization classification: myeloid and lymphoid neoplasms with FGFR1 abnormalities, and SM with an associated hematologic neoplasm.

First-line antibiotic therapy in Helicobacter pylori-negative low-grade gastric mucosa-associated lymphoid tissue lymphoma.

First-line antibiotic treatment for eradicating Helicobacter pylori (HP) infection is effective in HP-positive low-grade gastric mucosa-associated lymphoid tissue lymphoma (MALToma), but its role in HP-negative cases is uncertain. In this exploratory retrospective study, we assessed the outcome and potential predictive biomarkers for 25 patients with HP-negative localized gastric MALToma who received first-line HP eradication (HPE) therapy. An HP-negative status was defined as negative results on histology, rapid urease test, 13C urea breath test, and serology. We observed an antibiotic response (complete remission [CR], number = 8; partial remission, number = 1) in 9 (36.0%) out of 25 patients. A t(11;18)(q21;q21) translocation was detected in 7 (43.8%) of 16 antibiotic-unresponsive cases, but in none of the 9 antibiotic-responsive cases (P = 0.027). Nuclear BCL10 expression was significantly higher in antibiotic-unresponsive tumors than in antibiotic-responsive tumors (14/16 [87.5%] vs. 1/9 [11.1%]; P = 0.001). Nuclear NF-κB expression was also significantly higher in antibiotic-unresponsive tumors than in antibiotic-responsive tumors (12/16 [75.0%] vs. 1/9 [11.1%]; P = 0.004). A substantial portion of patients with HP-negative gastric MALToma responded to first-line HPE. In addition to t(11;18)(q21;q21), BCL10 and NF-κB are useful immunohistochemical biomarkers to predict antibiotic-unresponsive status in this group of tumors.

Treatment outcomes of and prognostic factors for definitive radiotherapy with and without chemotherapy for Stage I/II nasal extranodal NK/T-cell lymphoma.

Treatment strategies for nasal extranodal NK/T-cell lymphoma (ENKTL), including sequential chemotherapy followed by radiotherapy (SCRT), concurrent chemoradiotherapy (CCRT), or radiotherapy alone (RT), remain varied. The purpose of this study was to assess the treatment outcome, the toxicity, and the potential prognostic factors for patients with early-stage nasal ENKTL treated using definitive RT (minimum of 50 Gy) with or without chemotherapy. From 1998 to 2014, 37 patients were included in the study. Eight patients were treated with RT alone, 1 with CCRT, and 28 with SCRT. Local regional control (LRC), progression-free survival (PFS), and overall survival (OS) were calculated using the Kaplan-Meier method. RT resulted in an overall response rate of 91.2%, with a complete response rate of 78.4%. After a median follow-up time of 36.8 months, the 3-year LRC, PFS and OS were 87.4%, 64.0% and 76.3%, respectively. Acute severe toxicity (Grade 3) of mucositis was observed in 6 (16.2%) of the 37 patients. In univariate analyses, extensive disease (Stage I/II with local invasiveness) and the presence of B symptoms were significantly associated with a poor PFS, whereas extensive disease was significantly associated with a poor OS. Multivariate analysis identified the presence of extensive disease as an independent predictor of PFS (P < 0.001) and OS (P = 0.015). High-dose RT with or without chemotherapy reported promising locoregional control and a favorable outcome for patients with early-stage nasal ENKTL without local invasiveness. Further investigation of new treatment strategies for patients with local invasiveness is warranted.

Expressions of the CagA protein and CagA-signaling molecules predict Helicobacter pylori dependence of early-stage gastric DLBCL.

We previously reported that early-stage gastric diffuse large B-cell lymphomas (DLBCLs), including DLBCLs with mucosa-associated lymphoid tissue (DLBCL[MALT]) and without ("pure" DLBCL) the features of MALT lymphomas, can achieve long-term complete remission after frontline Helicobacter pylori (HP) eradication (HPE). We recently reported that expression of cytotoxin-associated gene A (CagA) and CagA-signaling molecules (phospho-Src homology-2 domain-containing phosphatase [p-SHP2] and phospho-extracellular signal-regulated kinase [p-ERK]) is associated with HP dependence of gastric MALT lymphoma. However, the significance of CagA and CagA-signaling molecules in gastric DLBCL remains unexplored. The association between expression of CagA, p-SHP-2, and p-ERK in malignant B cells and tumor response to HPE was evaluated in 63 patients with stage IE/IIE1 HP-positive gastric DLBCL who received HPE as frontline treatment. We detected CagA expression in 20 of 42 DLBCL (MALT) cases (47.6%) and in 13 of 21 "pure" DLBCL cases (61.9%). CagA expression was higher in HP-dependent tumors than in HP-independent tumors (74.3% [26 of 35] vs 25.0% [7 of 28]). Patients with CagA expression responded to HPE quicker than those without expression (median time to complete remission, 4.0 months vs 5.0 months). The expression of CagA was closely associated with p-SHP-2 and p-ERK expression. Combined CagA, p-SHP-2, and p-ERK expression showed an increased positive predictive value (81.8% vs 75.9%) and an increased specificity (84.0% vs 75.0%) for HP dependence compared with CagA expression alone. Our results indicated that CagA and its signaling molecules can be detected in the malignant B cells of gastric DLBCL, and the expression of these molecules is clinically and biologically associated with HP dependence.

The B-cell-activating factor signalling pathway is associated with Helicobacter pylori independence in gastric mucosa-associated lymphoid tissue lymphoma without t(11;18)(q21;q21).

We previously reported that activation of the B-cell-activating factor (BAFF) pathway upregulates nuclear factor-κB (NF-κB) and induces BCL3 and BCL10 nuclear translocation in Helicobacter pylori (HP)-independent gastric diffuse large B-cell lymphoma (DLBCL) tumours with evidence of mucosa-associated lymphoid tissue (MALT). However, the significance of BAFF expression in HP independence of gastric low-grade MALT lymphomas without t(11;18)(q21;q21) remains unexplored. Sixty-four patients who underwent successful HP eradication for localized HP-positive gastric MALT lymphomas without t(11;18)(q21;q21) were studied. BAFF expression was significantly higher in the HP-independent group than in the HP-dependent group [22/26 (84.6%) versus 8/38 (21.1%); p < 0.001]. Similarly, BAFF receptor (BAFF-R) expression (p = 0.004) and nuclear BCL3 (p = 0.004), BCL10 (p < 0.001), NF-κB (p65) (p = 0.001) and NF-κB (p52) (p = 0.005) expression were closely correlated with the HP independence of these tumours. Moreover, BAFF overexpression was significantly associated with BAFF-R expression and nuclear BCL3, BCL10, NF-κB (p65) and NF-κB (p52) expression. These findings were further validated in an independent cohort, including 40 HP-dependent cases and 18 HP-independent cases of gastric MALT lymphoma without t(11;18)(q21;q21). The biological significance of BAFF signalling in t(11;18)(q21;q21)-negative lymphoma cells was further studied in two types of lymphoma B cell: OCI-Ly3 [non-germinal centre B-cell origin DLBCL without t(11;18)(q21;q21) cell line] and MA-1 [t(14;18)(q32;q21)/IGH-MALT1-positive DLBCL cell line]. In both cell lines, we found that BAFF activated the canonical NF-κB and AKT pathways, and induced the formation of BCL10-BCL3 complexes, which translocated to the nucleus. BCL10 and BCL3 nuclear translocation and NF-κB (p65) transactivation were inhibited by either LY294002 or by silencing BCL3 or BCL10 with small interfering RNA. BAFF also activated non-canonical NF-κB pathways (p52) through tumour necrosis factor receptor-associated factor 3 degradation, NF-κB-inducing kinase accumulation, inhibitor of κB kinase (IKK) α/ß phosphorylation and NF-κB p100 processing in both cell lines. Our data indicate that the autocrine BAFF signal transduction pathway contributes to HP independence in gastric MALT lymphomas without the t(11;18)(q21;q21) translocation. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Soluble PD-L1: A biomarker to predict progression of autologous transplantation in patients with multiple myeloma.

Autologous hematopoietic stem cell transplantation (AuHSCT) is standard in treating eligible multiple myeloma (MM) patients. However, the outcome after treatment is highly variable. We used ELISA to analyze the levels of soluble PD-L1 (suPD-L1) in bone marrow (BM) plasma from 61 patients with MM at 100 days after AuHSCT. Patients were classified into high (H) and normal-to-low (NL) groups depending on their suPD-L1 levels. Among patients who had a very good partial response (VGPR) or better after AuHSCT, those in the H-group had a shorter response period (RpSCT) as well as shorter overall survival (OS) than those in the NL-group. Multivariate analyses confirmed that a high suPD-L1 level and high-risk cytogenetic abnormalities are independent factors for RpSCT. Our data suggest that suPD-L1 in the BM plasma of MM patients who have VGPR or better after AuHSCT could be used as a biomarker to predict outcome.

Regulation of EBV LMP1-triggered EphA4 downregulation in EBV-associated B lymphoma and its impact on patients' survival.

Epstein-Barr virus (EBV), an oncogenic human virus, is associated with several lymphoproliferative disorders, including Burkitt lymphoma, Hodgkin disease, diffuse large B-cell lymphoma (DLBCL), and posttransplant lymphoproliferative disorder (PTLD). In vitro, EBV transforms primary B cells into lymphoblastoid cell lines (LCLs). Recently, several studies have shown that receptor tyrosine kinases (RTKs) play important roles in EBV-associated neoplasia. However, details of the involvement of RTKs in EBV-regulated B-cell neoplasia and malignancies remain largely unclear. Here, we found that erythropoietin-producing hepatocellular receptor A4 (EphA4), which belongs to the largest RTK Eph family, was downregulated in primary B cells post-EBV infection at the transcriptional and translational levels. Overexpression and knockdown experiments confirmed that EBV-encoded latent membrane protein 1 (LMP1) was responsible for this EphA4 suppression. Mechanistically, LMP1 triggered the extracellular signal-regulated kinase (ERK) pathway and promoted Sp1 to suppress EphA4 promoter activity. Functionally, overexpression of EphA4 prevented LCLs from proliferation. Pathologically, the expression of EphA4 was detected in EBV(-) tonsils but not in EBV(+) PTLD. In addition, an inverse correlation of EphA4 expression and EBV presence was verified by immunochemical staining of EBV(+) and EBV(-) DLBCL, suggesting EBV infection was associated with reduced EphA4 expression. Analysis of a public data set showed that lower EphA4 expression was correlated with a poor survival rate of DLBCL patients. Our findings provide a novel mechanism by which EphA4 can be regulated by an oncogenic LMP1 protein and explore its possible function in B cells. The results provide new insights into the role of EphA4 in EBV(+) PTLD and DLBCL.

Tunical Outer Layer Plays an Essential Role in Penile Veno-occlusive Mechanism Evidenced from Electrocautery Effects to the Corpora Cavernosa in Defrosted Human Cadavers.

OBJECTIVE: To determine the exact anatomical structure for establishing penile veno-occlusive function, we sought to conduct a hemodynamic study on defrosted human cadavers. MATERIALS AND METHODS: Thirteen penises were used for this experiment, and 11 intact penises were allocated into the electrocautery group (EG, n = 6) and the ligation group (LG, n = 5). A circumcision was made on the penis to access the veins. Two #19 scalp needles were fixed in the 3 and 9 o'clock positions in the distal penis for colloid infusion and intracavernous pressure (ICP) monitoring, respectively. For the EG, the deep dorsal vein and cavernosal vein trunks were freed for 3-5 cm where at least 3 emissary veins were identified via opening Buck's fascia; these veins underwent electrocautery at 45 watts, while the ICP was maintained at 0, 50, 75, 100, 125, and 150 mmHg, respectively. For control, venous ligation was made but at the ICP of 150 mmHg. A tissue block including the emissary vein was then obtained for histological analysis. RESULTS: Except all in the EG and those whose ICP exceed 125 mmHg in the EG, the sinusoids of the corpora cavernosa sustained varied fulgurated fibrosis in every specimen and the severity appeared reversely commensurate with the ICP regarding sinusoidal clumping and darkish bands (P <.02 and .01 respectively). CONCLUSION: We conclude that the tunica albuginea can prevent the electrocautery damage to intracavernous sinusoids once the ICP reached a level corresponding to a rigid erection. The outer tunica plays an essential role in fulfilling the veno-occlusive mechanism.