Background:With this study, we sought to characterise the impact of pro-inflammatory cytokines on the outcomes of gemcitabine monotherapy (GEM) in patients with pancreatic cancer (PC).Methods:Treatment-naive patients with advanced PC and no obvious infections were eligible for enrolment. All of the patients were scheduled to undergo systemic chemotherapy. Serum pro-inflammatory cytokines were measured using an electro-chemiluminescence assay method before chemotherapy. High cytokine levels were defined as values greater than the median. Clinical data were collected prospectively.Results:Sixty patients who received GEM were included in the analysis. High IL-6 and IL-1β levels were poor prognostic factors for overall survival in a multivariate analysis (P=0.011 and P=0.048, respectively). Patients with both a high IL-6 level and a high IL-1β level exhibited shortened overall and progression-free survival, a reduction in the tumour control rate, and a high dose intensity of GEM compared with patients with low levels of both IL-6 and IL-1β.Conclusion:The serum levels of IL-6 and IL-1β predict the efficacy of GEM in patients with advanced PC.

The synthesis of prostaglandins (PGs) is regulated by the arachidonic acid release by phospholipase A 2 (PLA 2 ) and its conversion to PGs by cyclooxygenase (COX). In the present study, we examined the regulation of PG synthesis by interleukin (IL)-1␣ in primary mouse osteoblastic cells isolated from mouse calvaria. Although IL-1␣ greatly enhanced cox-2 mRNA expression and its protein levels, PGE 2 was not produced until 24 h. When arachidonic acid was added to osteoblastic cells precultured with IL-1␣ for 24 h, PGE 2 was produced within 10 min. Of several growth factors tested, platelet-derived growth factor (PDGF) specifically initiated the rapid synthesis of PGE 2 , which was markedly suppressed by a selective inhibitor of cox-2 (NS-398). In mouse osteoblastic cells, cytosolic PLA 2 (cPLA 2 ) mRNA and its protein were constitutively expressed and increased approximately 2-fold by IL-1␣, but secretory PLA 2 mRNA was not detected. PDGF rapidly stimulated PLA 2 activity, which was blocked completely by a cPLA 2 inhibitor (arachidonyltrifluoromethyl ketone). The PDGF-induced cPLA 2 activation was accompanied by phosphorylation of its protein. These results indicate that cox-2 induction by IL-1␣ is not sufficient, but cPLA 2 activation by PDGF is crucial for IL-1␣-induced PGE 2 synthesis in mouse osteoblasts. Prostaglandins (PGs)1 are potent regulators of bone metabolism that are produced mainly by osteoblasts in the bone tissue. Among several forms of PG, PGE 2 is the major product of osteoblasts, and its production is regulated by several growth factors and cytokines including interleukin-1 (IL-1), parathyroid hormone, basic fibroblast growth factor (bFGF), and PGE 2 itself (1-6). PGE 2 is a complicated regulator of bone metabolism, potently stimulating bone resorption in vitro (7) and stimulating both bone formation and bone resorption in vivo (8). PGE 2 production is involved in the mechanism of bone resorption induced by IL-1 in vitro (7, 9). PG synthesis is regulated by two successive metabolic steps, the release of arachidonic acid from membranous phospholipids and its conversion to prostanoids. Phospholipase A 2 (PLA 2 ), the enzyme responsible for arachidonic acid release, consists of two forms, secretory PLA 2 (sPLA 2 ) and cytosolic PLA 2 (cPLA 2 ) (10 -13). Secretory PLA 2 requires millimolar levels of calcium for its activation and is divided into several groups, among which pancreatic (type I) and nonpancreatic (type II) subtypes are well characterized (10). Type II sPLA 2 is widely distributed in several tissues and inflammatory exudates. On the other hand, cPLA 2 is an intracellular enzyme that is found in various cells and tissues including macrophages, mast cells, platelets, kidney, and brain (10,14,15). This enzyme preferentially hydrolyzes arachidonic acid at the S n 2 position of membranous phospholipids and requires micromolar levels of calcium for its activation. Both the phosphorylation and Ca 2ϩ -dependent translocation of cPLA 2 to the membranes are essential for its activation (16 -20).C...

Although alfacalcidol is widely used in the treatment of osteoporosis, its mechanism of action in bone is not fully understood. Alfacalcidol stimulates intestinal calcium (Ca) absorption, increases urinary Ca excretion and serum Ca levels, and suppresses parathyroid hormone (PTH) secretion. It remains to be clarified, especially under vitamin D-replete conditions, whether alfacalcidol exerts skeletal effects solely via these Ca-related effects, whether the resultant suppression of PTH is a prerequisite for the skeletal actions of alfacalcidol, and, by inference, whether alfacalcidol has an advantage over vitamin D in the treatment of osteoporosis. To address these issues, we (1) compared the effects of alfacalcidol p.o. (0.025-0.1 microg/kg BW) vis-à-vis vitamin D(3) (50-400 microg/kg BW) on bone loss in 8-month-old, ovariectomized (OVX) rats as a function of their Ca-related effects, and (2) examined whether the skeletal effects of alfacalcidol occur independently of suppression of PTH, using parathyroidectomized (PTX) rats continuously infused with hPTH(1-34). The results indicate that (1) in OVX rats, alfacalcidol increases BMD and bone strength more effectively than vitamin D(3) at given urinary and serum Ca levels: larger doses of vitamin D(3) are required to produce a similar BMD-increasing effect, in the face of hypercalcemia and compromised bone quality; (2) at doses that maintain serum Ca below 10 mg/dl, alfacalcidol suppresses urinary deoxypyridinoline excretion more effectively than vitamin D(3); and (3) alfacalcidol is capable of increasing bone mass in PTX rats with continuous infusion of PTH, and therefore acts independently of PTH levels. It is suggested that alfacalcidol exerts bone-protective effects independently of its Ca-related effects, and is in this respect superior to vitamin D(3), and that the skeletal actions of alfacalcidol take place, at least in part, independently of suppression of PTH. Together, these results provide a rationale for the clinical utility of alfacalcidol and its advantage over vitamin D(3) in the treatment of osteoporosis.

High serum IL-6 was related to advanced age, the presence of hepatic metastasis, large tumor burden in liver, severe fatigue, high carcinoembryonic antigen, high C-reactive protein, and anemia in patients with treatment-naive advanced PC.

We conducted this study to evaluate the characteristic effects of alfacalcidol (ALF) and menatetrenone (VK) in preventing bone loss using an ovariectomized rat model of osteoporosis. Bilateral ovariectomy (OVX) or sham operation was performed on 10-month-old female Wistar rats. OVX caused a significant decrease in the bone mass and the mechanical strength of the lumbar vertebra as well as the femur 6 months after surgery. VK treatment (30 mg/kg, food intake) required a 6-month period to prevent the bone loss induced by estrogen deficiency, whereas ALF (0.1 or 0.2 mg/kg, p.o.) increased the bone mass and the mechanical strength of the lumbar vertebra as well as the femur in a 3-month treatment period, far above the level in the sham-operated rats. Neither ALF or VK caused hypercalcemia, despite administration for as long as 6 months. By doing a micro-CT analysis of the vertebral trabecular microstructure, it was revealed that ALF treatment increased the interconnections and the plate-like structures and that VK significantly increased the trabecular number. It was also indicated that the increase in spinal strength by ALF treatment was closely associated with improvement of the microstructure, but not VK. The results of histomorphometric analysis showed that ALF caused a significant suppression of bone resorption yet maintained formation in the endocortical perimeter, and also stimulated bone formation in the periosteal perimeter, thereby causing an increase in cortical area. No marked effect of VK on histomorphometric parameters was observed, whereas VK as well as ALF maintained the material strength at femoral midshaft of the normal level, suggesting that VK affected bone quality and thereby prevented the decrease in mechanical strength of femur caused by OVX. In conclusion, it was demonstrated that the two drugs, ALF and VK, differed markedly in their potency and mechanisms for improving bone strength. These results have important implications in understanding the characteristic actions of vitamin K and active vitamin D on bone metabolism.