Vascular endothelial growth factor-mediated signaling has at least two potential roles in diffuse large B cell lymphoma: potentiation of angiogenesis, and potentiation of lymphoma cell proliferation ...and/or survival induced by autocrine vascular endothelial growth factor receptor-mediated signaling. We have recently shown that diffuse large B cell lymphomas expressing high levels of vascular endothelial growth factor protein also express high levels of vascular endothelial growth factor receptor-1 and vascular endothelial growth factor receptor-2. We have now assessed a larger multi-institutional cohort of patients with de novo diffuse large B cell lymphoma treated with anthracycline-based therapy to address whether tumor vascularity, or expression of vascular endothelial growth factor protein and its receptors, contribute to patient outcomes. Our results show that increased tumor vascularity is associated with poor overall survival (P=0.047), and is independent of the international prognostic index. High expression of vascular endothelial growth factor receptor-1 by lymphoma cells by contrast is associated with improved overall survival (P=0.044). The combination of high vascular endothelial growth factor and vascular endothelial growth factor receptor-1 protein expression by lymphoma cells identifies a subgroup of patients with improved overall (P=0.003) and progression-free (P=0.026) survival; these findings are also independent of the international prognostic index. The prognostic significance of overexpression of this ligand-receptor pair suggests that autocrine signaling via vascular endothelial growth factor receptor-1 may represent a survival or proliferation pathway in diffuse large B cell lymphoma. Dependence on autocrine vascular endothelial growth factor receptor-1-mediated signaling may render a subset of diffuse large B-cell lymphomas susceptible to anthracycline-based therapy.
Chronic gastritis is characterized by gastric mucosal inflammation due to autoimmune responses or infection, frequently with Helicobacter pylori. Gastritis with H. pylori background can cause gastric ...mucosa-associated lymphoid tissue lymphoma (MALT-L), which sometimes further transforms into diffuse large B-cell lymphoma (DLBCL). However, gastric DLBCL can also be initiated de novo. The mechanisms underlying transformation into DLBCL are not completely understood. We analyzed immunoglobulin repertoires and clonal trees to investigate whether and how immunoglobulin gene repertoires, clonal diversification, and selection in gastritis, gastric MALT-L, and DLBCL differ from each other and from normal responses. The two gastritis types (positive or negative for H. pylori) had similarly diverse repertoires. MALT-L dominant clones (defined as the largest clones in each sample) presented higher diversification and longer mutational histories compared with all other conditions. DLBCL dominant clones displayed lower clonal diversification, suggesting the transforming events are triggered by similar responses in different patients. These results are surprising, as we expected to find similarities between the dominant clones of gastritis and MALT-L and between those of MALT-L and DLBCL.
Factor XIII (FXIII), a plasma transglutaminase that stabilizes fibrin clots at the final stages of blood coagulation by crosslinking fibrin monomers, is essential for embryo implantation and ...participates in tissue remodeling and wound healing, processes that involve angiogenesis. The aim of our study was to analyze the effect of FXIII on angiogenesis using in vitro and in vivo models and to examine the role of FXIII in the basic steps of angiogenesis, ie, migration, proliferation, and apoptosis/cell survival.
In the Matrigel tube formation model, only FXIIIa caused a dose-dependent enhancement of array formation. This proangiogenic effect was not associated with alterations in vascular endothelial growth factor (VEGF) protein levels nor VEGF or VEGFR2 mRNA levels. FXIIIa, but not nonactivated or transglutaminase-inactivated FXIII, significantly enhanced endothelial cell migration and proliferation and inhibited apoptosis. After treatment of HUVECs with FXIIIa, almost complete disappearance of mRNA of thrombospondin 1 (TSP-1) and a marked reduction in the secretion of TSP-1 protein were observed. A reduction in TSP-1 protein synthesis, although to a lesser extent, was observed on treatment of microvascular endothelial cells with FXIIIa. In a rabbit cornea model, injection of FXIIIa caused neovascularization associated with almost complete disappearance of TSP-1 in the cornea.
These results show that FXIIIa exhibits a novel proangiogenic activity that is associated with downregulation of TSP-1 and also involves stimulation of endothelial cell proliferation and migration and inhibition of apoptosis. These findings might shed light on the mechanism by which FXIII mediates tissue repair and remodeling.
Regional lymph node (LN) metastasis in oral cancer patients is the most significant grave prognostic factor. We evaluated the relationship between clinical outcomes and different histopathological ...changes in tumor-negative LNs (LN0) selected from neck dissections without metastatic disease (pN0). A total of 435 LN0 selected from pN0 neck dissections (up to three nodes in each level) were scored for histopathological parameters of LN areas, capsule thickness, subcapsular and medullary sinus ectasia, lobular architecture and percent of cortical reactive follicles. These were compared to 328 LN0 selected from neck dissections with metastases (pN+) after exclusion of metastatic LNs. Data were presented by maximum scores of each parameter in I–III (close) and in IV–V (distant) levels. Limited data from level V and regression analyses inferred that the values in level IV represented the worst changes for most patients. Cox proportional hazard regression on each parameter in close and distant levels demonstrated that capsule thickness, number of lobules and percent of reactive follicles were significantly associated with time to death from disease. The higher the change in distant levels, the shorter the time to death, while the higher the change in close levels (given a stable change in distant levels), the longer the time to death. After adjustment for gender, age and location, only the effect of the percent of reactive follicles retained their significant effect. Logistic regression of metastases demonstrated that all parameters except for percent of reactive follicles were significantly associated with risk of metastases, with differences between close and distant levels similar to those found for time to death. After adjustment for gender, age and location, only the area and number of lobes retained their significance. The findings of this study suggested that selective histopathological changes in tumor-negative LNs in metastatic-free patients provide new valuable prognostic parameters.
We present a rare case of primary cardiac diffuse large B cell lymphoma with unusual presentation. Our female patient, 34 years old, presented with superior vena cava syndrome that was related to ...thrombophlebitis post breast augmentation. She was treated with anticoagulants but was admitted again, ten months later, due to an aggravation in her state. MRI imaging demonstrated a large mass in her right atrium that was surgically removed. The resected mass was 6 cm in diameter, lobulated and white. Microscopically, the tumor consisted of sheets of large atypical cells, with wide nuclei and prominent nucleoli. Numerous mitotic figures and necrosis were present. On immunostains the tumor cells showed strong diffuse positive staining for CD20, CD30 and vimentin. All other markers for epithelial and muscle tumors, as well as melanoma were negative. Ki67 was positive in 75% of the cells. ALK status was evaluated by both immunohistochemistry and FISH study. The diagnosis was concluded as primary cardiac diffuse large B cell lymphoma. Primary cardiac lymphoma is a very rare entity and its diagnosis is unanticipated by both clinicians and pathologists. We present the case, discuss the differential diagnosis and review the literature.
A 91 year old patient presented with constipation, abdominal distension, weakness and anorexia lasting for two days. Computed tomography revealed multiple peritoneal masses with significant growth ...within days and local invasiveness without regard to anatomical boundaries. No lymphadenopathy or hepatosplenomegaly were found. Abdominal paracentesis showed 60,000 cells/mm3 presumed to be neutrophils. During follow-up, there were no clinical or radiographic signs of peritonitis. Trans-abdominal true-cut biopsy from the peritoneal masses was consistent with diffuse large B cell lymphoma germinal center B cell type, clinically presenting as peritoneal lymphomatosis. FISH cytogenetic study identified single BLC-6 gene in the tumor infiltrating lymphocytes. We speculated that this aberration in the patient's immune system cells contributed to this rare, unusual and aggressive lymphoma presentation in an otherwise non-immune compromised patient.
Extramedullary (EM) organ impairment in patients with multiple myeloma (MM) is a rare event, occurring mostly during disease relapse after high-dose chemotherapy with autologous or allogeneic stem ...cell transplantation. This manifestation is commonly associated with an unfavourable outcome. Previous studies suggested a correlation between the clinical course of patients with MM and EM and the cytogenetic findings, e.g. deletion of TP53 on 17p13.
We investigated patients with these rare plasma cell organ infiltrations (n=17) as well as bone lesions or soft tissue lesions, known to be a common clinical feature of MM (n=14), using a newly established method of fluorescence in situ hybridization in combination with cytoplasmic immunoglobulin staining (cIg-FISH) on paraffin-embedded sections and a specific probe for TP53 on 17p13.
The incidence of del(17)(p13) was similar in both groups but overall it was higher when compared to published data obtained from bone marrow samples and material originating from osteolyses. Further investigations on a larger patient cohort are needed in order to confirm these findings.
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