The purpose of this study was to examine predictors of lymph node metastases (LN+) or extrauterine disease (ED) in low grade (FIGO grades 1 or 2) endometrioid carcinoma (LGEC) in a multi institutional setting. For LGEC with and without LNM or ED, each of the 9 participating institutions evaluated patients age, tumor size, myometrial invasion (MI), FIGO grade, % solid component, the presence or absence of papillary architecture, microcystic elongated and fragmented glands (MELF) and single cell/cell cluster invasion (SCI), lymphovascular invasion (LVI), lower uterine segment (LUS) and cervical stromal (CX) involvement and numbers of pelvic (PLN) and para-aortic (PALN) LNs sampled.302 cases were reviewed: LN+ or ED +, 96; LN-/ED-, 208. Patients' ages ranged from 23-91 yrs (median 61). Table 1 summarizes the histopathologic variables that were noted for the LN+ or ED+ group: tumor size ≥2cm, 93/96 (97%), MI >50%, 54/96 (56%), MELF, 67/96 (70%), SCI, 33/96 (34%), LVI, 79/96 (82%), >20% solid, 65/96 (68%), papillary architecture present, 68/96 (72%), LUS involved, 64/96 (67%) and CX involved, 31/96 (32%). For the LN-/ED- group, the results were as follows: tumor size ≥2cm, 152/208 (73%), MI >50%, 56/208 (27%), MELF, 79/208 (38%), single cell invasion, 19/208 (9%) , LVI, 56/208 (27%), >20% solid, 160/208 (77%), papillary architecture present, 122/208 (59%), LUS involved, 77/208 (37%), CX involved, 31/208 (15%). There was no evidence of a difference in the number of pelvic or para-aortic LNs sampled between groups (p=0.9 and 0.1, respectively). Following multivariate analysis, depth of myometrial invasion, cervical stromal involvement, lymphovascular space invasion, and the single cell pattern of invasion emerged as significant predictors of advanced stage disease. Although univariate analysis pointed to LUS involvement, MELF pattern of invasion, and papillary architecture as possible predictors of advanced stage disease, these were not shown to be significant by multivariate analysis. This study validates MI, CX involvement and LV as significant predictors of LN+ or ED. The association of SCI pattern with advanced stage LGEC is a novel finding.

Autoreactive B cells are the source of pathogenic autoantibodies (autoAb) in systemic lupus erythematosus (SLE). Previous studies have demonstrated that anti-small nuclear ribonucleoprotein particles (snRNP) B cells from normal background mice tolerize T cells in the periphery and do not secrete autoAb. In this study, we examined whether these anti-snRNP B cells can be activated for autoAb production by the engagement of Toll-like receptors (TLR). Anti-snRNP B cells proliferated vigorously and secreted abundant anti-snRNP autoAb upon exposure to CpG or polyriboinosinic polyribocytidylic acid [poly (I:C)] in vitro. In addition, the costimulatory molecules CD80 and CD86 were up-regulated. While both anti-snRNP B cells and wild-type B cells produced similar levels of IL-6 and IL-10, anti-snRNP B cells secreted predominately IFN-c in response to CpG or poly (I:C) stimulation. Furthermore, we showed that in vivo engagement of TLR stimulated immature anti-snRNP B cells to further differentiate and produce autoAb and form germinal centers. The activated anti-snRNP B cells became expanded and migrated into the T-B cell interface. Moreover, TLR engagement directly or indirectly activated autoreactive B cells via a CD4 T cell-independent manner. These results provide in vitro and in vivo evidence that BCR/TLR co-engagement promotes the activation of anti-snRNP B cells for autoAb production.

BackgroundNeutrophil infiltration is one of the critical cellular components of an inflammatory response during peritonitis. The adhesion molecules, P-selectin and intercellular adhesion molecule (ICAM)-1, mediate neutrophil-endothelial cell interactions and the subsequent neutrophil transendothelial migration during the inflammatory response. Despite very strong preclinical data, recent clinical trials failed to show a protective effect of anti-adhesion therapy, suggesting that the length of injury might be a critical factor in neutrophil infiltration. Therefore, the objective of this study was to determine the role of P-selectin and ICAM-1 in neutrophil infiltration into the peritoneal cavity during early and late phases of peritonitis.MethodsPeritonitis was induced in both male wild-type and P-selectin/ICAM-1 double deficient (P/I null) mice by cecal ligation-puncture (CLP). Peripheral blood and peritoneal lavage were collected at 6 and 24 hours after CLP. The total leukocyte and neutrophil contents were determined, and neutrophils were identified with the aid of in situ immunohistochemical staining. Comparisons between groups were made by applying ANOVA and student t-test analysis.ResultsCLP induced a severe inflammatory response associated with a significant leukopenia in both wild-type and P/I null mice. Additionally, CLP caused a significant neutrophil infiltration into the peritoneal cavity that was detected in both groups of mice. However, neutrophil infiltration in the P/I null mice at 6 hours of CLP was significantly lower than the corresponding wild-type mice, which reached a similar magnitude at 24 hours of CLP. In contrast, in peritonitis induced by intraperitoneal inoculation of 2% glycogen, no significant difference in neutrophil infiltration was observed between the P/I null and wild-type mice at 6 hours of peritonitis.ConclusionsThe data suggest that alternative adhesion pathway(s) independent of P-selectin and ICAM-1 can participate in neutrophil migration during peritonitis and that the mode of stimuli and duration of the injury modulate the neutrophil infiltration.

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