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RANKL (receptor activator of NF-B ligand) induces osteoclastogenesis by activating multiple signaling pathways in osteoclast precursor cells, chief among which is induction of long lasting oscillations in the intracellular concentration ofBone is a dynamic tissue that is constantly being remodeled. The remodeling process is a delicate balance between the activities of osteoblasts and osteoclasts. Interference with this balance results in serious human pathologies that affect bone integrity. Tipping the balance in favor of osteoclasts leads to pathological bone resorption, which is observed in autoimmune arthritis, osteoporosis, and periodontitis (1, 2).Bone marrow-derived monocyte/macrophage precursor cells (BMM) 2 of a hematopoietic origin develop into osteoclasts through cell-to-cell signaling with mesenchymal cells, such as osteoblasts (3, 4). Cell-to-cell interaction between the osteoclast precursors and osteoblastic/stromal cells are also essential for the differentiation of osteoclast progenitor cells into mature osteoclasts (5, 6). RANKL (receptor activator of NF-B ligand) is expressed in osteoblastic/stromal cells and is vital for osteoclast differentiation (7-11). Stimulation of the RANK receptor by RANKL in the presence of the macrophage colonystimulating factor (M-CSF) causes osteoclast differentiation and activation in vitro (6,8,12). Moreover, the binding of RANKL to its receptor results in the recruitment of the TNF receptor-associated factor (TRAF) family of proteins, e.g. TRAF6, which are linked to the NF-B and JNK pathways (13-15). Of particular importance, a series of signals following RANK activation induce oscillations in the free intracellular concentration of Ca 2ϩ ([Ca 2ϩ ] i ), which trigger the late stage of osteoclast differentiation by activating the nuclear factor of activated T cells type c1 (NFATc1) (16). Unique aspects of these RANKL-stimulated Ca 2ϩ oscillations is that they are observed only 24 -48 h post-stimulation, indicating the need for induction of the pathway responsible for the Ca 2ϩ oscillations. The nature of this pathway and how it is induced are not known. Ca 2ϩ is a ubiquitous intracellular messenger that mediates a wide variety of cellular functions and is involved in the fundamental cellular processes of proliferation, differentiation, and programmed cell death (17). In the case of osteoclast differentiation, Ca 2ϩ plays an important role by sequentially activating calcineurin and NFATc1 (16). Members of the NFAT family are among the most strongly induced transcription factors following RANKL stimulation. During osteoclastogenesis, costimulatory signals mediated by the immunoreceptor tyrosine-based

Purpose: To evaluate the usefulness of 3 ¶-deoxy-3 ¶-[18 F]fluorothymidine (FLT)-positron emission tomography (PET) for predicting response and patient outcome of gefitinib therapy in patients with adenocarcinoma of the lung. Experimental Design: Nonsmokers with advanced or recurrent adenocarcinoma of the lung were eligible. FLT-PET images of the thorax were obtained before and 7 days after the start of gefitinib (250 mg/d) therapy, the maximum standardized uptake values (SUVmax) of primary tumors were measured, and the percent changes in SUVmax were calculated. After 6 weeks of therapy, the responses were assessed by computed tomography of the chest. Results: Among 31 patients who were enrolled, we analyzed 28 patients for whom we had complete data. Chest computed tomography revealed partial response in 14 (50%), stable disease in 4 (14%), and progressive disease in 10 (36%) after 6 weeks of treatment. Pretreatment SUVmax of the tumors did not differ between responders and nonresponders. At 7 days after the initiation of therapy, the percent changes in SUVmax were significantly different (-36.0 F 15.4% versus 10.1 F 19.5%; P < 0.001). Decrease of >10.9% in SUVmax was used as the criterion for predicting response. The positive and negative predictive values were both 92.9%. The time to progression was significantly longer in FLT-PET responders than nonresponders (median, 7.9 versus 1.2 months; P = 0.0041). Conclusion: FLT-PETcan predict response to gefitinib 7 days after treatment in nonsmokers with advanced adenocarcinoma of the lung.The change in tumor SUVmax obtained by FLT-PETseems to be a promising predictive variable.Morphologic imaging techniques such as computed tomography (CT) have been standard methods for assessing tumor response to treatment. Changes in size, however, are often delayed; hence, morphologic imaging is usually repeated after at least 6 weeks of therapy. This causes difficulties in assessing the early treatment response and hinders rapid decisions by clinicians regarding a change in therapy for nonresponders. Moreover, in the case of cytostatic agents, tumors may not regress radiologically despite effective treatment. These limitations could be overcome by using functional imaging techniques such as positron emission tomography (PET), because metabolic and physiologic changes in the tumor are likely to precede changes in size (1). The most widely used PET tracer is [18 F]fluorodeoxyglucose (FDG), which reflects cell metabolism. However, FDG is not highly tumor specific and is also taken up by inflammatory cells such as macrophages (2).Recently, 3 ¶-deoxy-3 ¶-[ 18 F]fluorothymidine (FLT) was introduced as a PET tracer for imaging tumor proliferation. FLT is phosphorylated by thymidine kinase 1, the key enzyme of the salvage pathway of DNA synthesis, and then trapped in the cell with little further metabolism (3). Thymidine kinase 1 is selectively up-regulated during the S phase of the cell cycle (4). Therefore, FLT uptake is dependent on cell proliferation. In lung tumors, FLT up...