Glucocorticoid-induced TNFR-related protein (GITR) ligand modulates cytokine release and NK cell reactivity in chronic lymphocytic leukemia (CLL).

Natural killer (NK) cells play an important role in the immunosurveillance of hematopoietic malignancies. Their reactivity is influenced by activating and inhibitory signals mediated by tumor-expressed ligands for NK receptors. Many members of the tumor necrosis factor (TNF) family modulate differentiation, proliferation, activation and death of both tumor and immune effector cells. The TNF receptor family member glucocorticoid-induced TNFR-related protein (GITR) stimulates anti-tumor immunity in mice, but available data indicate that GITR may mediate different effects in mice and men and impairs the reactivity of human NK cells. Here, we comprehensively studied the expression and function of GITR ligand (GITRL) in leukemia. Among the different leukemia entities, pronounced expression of GITRL on leukemic cells was observed in chronic lymphocytic leukemia (CLL), and the GITR receptor was expressed at significantly higher levels on NK cells of CLL patients compared with healthy controls. Upon GITR-GITRL interaction, signaling via GITRL into the leukemia cells induced the release of interleukin (IL)-6, IL-8 and TNF, which act as growth and survival factors for CLL cells. In addition, GITRL impaired both direct and Rituximab-induced degranulation, cytotoxicity and interferon-γ production of NK cells, which could be restored by GITR blocking antibodies. Thus, GITRL may contribute to disease pathophysiology and resistance to direct and Rituximab-induced NK reactivity in CLL.

Avascular necrosis following distal Chevron osteotomy of the first metatarsal.

The authors present a retrospective study analyzing the radiographic frequency of avascular necrosis following distal Chevron osteotomy of the first metatarsal. A total of 164 procedures performed on 104 patients were evaluated radiographically at a follow-up period of 12 to 91 months, with a mean followup of 30.4 months. Standard anteroposterior radiographs of the foot were taken and evaluated independently by each of the three senior authors and two radiologists. No radiographs revealed evidence of avascular necrosis in the first metatarsal head. While avascular necrosis of the first metatarsal head has been reported to occur with varying frequencies, based on this study the authors believe that avascular necrosis of the first metatarsal head is an infrequent complication following distal Chevron osteotomy.