Andrea Pellacani

Height as a Risk Factor for Osteosarcoma

Previous investigations have suggested that osteosarcoma may be associated with a taller stature, but the relationship between height and osteosarcoma remains controversial. Height at diagnosis was evaluated in a continuous series of 962 osteosarcoma subjects treated between 1981 and 2001. Patients diagnosed during growth (group 1) were separated from those diagnosed in adulthood (group 2). Height (H) and final height (FH) were expressed as standard deviation scores (SDS), calculated by national reference data. Group 1 subjects were above the 50th centile and their mean H-SDS values (0.31 ± 1.1) were significantly higher than the mean FH-SDS values (P < 0.0001) of the group 2 subjects, both in males and females. In contrast, the mean FH-SDS (0.01 ± 1.1) of group 2 did not differ from that of the reference population. The highest incidence of osteosarcoma was at 12.5 years in females, 14.5 years in males. These data confirm previous observations of an association between osteosarcoma development and height, at least in growing individuals. The higher incidence during the pubertal spurt, in the anatomic sites of greater growth and in taller individuals, suggests that growth factors play an important role in the pathogenesis of this bone cancer.

In vitro blockade of receptor activator of nuclear factor-κB ligand prevents osteoclastogenesis induced by neuroblastoma cells

Proliferation and differentiation of osteoclasts are regulated by a cytokine system that includes RANKL, which binds 2 receptors: RANK, which activates osteoclast differentiation, and osteoprotegerin (OPG), a decoy receptor that limits RANKL action. We investigated the role of the OPG/RANKL/RANK network in the pathogenesis of skeletal metastasis in neuroblastoma. Four different neuroblastoma cell lines (NB100, CHP212, SH‐SY5Y, SJ‐NK‐P) showed a large amount of OPG and RANKL transcripts. Soluble RANKL was detectable in all cell lines, but poor release of OPG was observed. SH‐SY5Y showed the lowest OPG‐to‐RANKL ratio and promoted osteoclastic differentiation of FLG29.1 and peripheral mononuclear cells, inducing expression of the osteoclast markers RANK, c‐src, c‐fos, cathepsin‐K and TRAP. SJ‐N‐KP, which released both OPG and RANKL, did not show the same capability. OPG, neutralizing anti‐RANKL antibody and antisense oligonucleotides were evaluated for their ability to inhibit RANKL activity. The neutralizing antibody hampered osteoclastic differentiation by blocking both the juxtacrine and the paracrine activity of RANKL. Our findings confirm that neuroblastoma cells induce osteoclastogenesis via RANKL and suggest that the RANKL expression associated with lack of the decoy receptor OPG could be a peculiarity of some tumors that makes them able to induce metastatic osteolysis. Moreover, our results suggest that RANKL could be a relevant target in the adjuvant therapy of bone metastatic neuroblastoma as proper neutralization revokes completely osteoclastic differentiation.

Serum Levels of Osteoprotegerin and Receptor Activator of Nuclear Factor-κB Ligand as Markers of Periprosthetic Osteolysis

BACKGROUNDnPrevious studies have suggested that the balance between receptor activator of nuclear factor-kappaB ligand (RANKL) and its decoy-receptor osteoprotegerin (OPG) in local tissue seems to play a crucial role in the loosening of the total hip replacement. The aim of this study was to evaluate whether the circulating levels of OPG and RANKL, as well as their ratio, could be different in patients with aseptic loosening compared with patients with stable implants.nnnMETHODSnOne hundred and twenty-eight subjects were recruited. They included thirty-nine patients with osteoarthritis who had not yet undergone total hip arthroplasty, thirty-three patients who had undergone total hip arthroplasty and had clinically and radiographically stable implants, thirty-six patients with aseptic loosening of total hip arthroplasty components, and twenty healthy volunteers. Serum levels of OPG and RANKL were measured with use of an immunoenzymatic method, and in each individual the OPG-to-RANKL ratio was calculated.nnnRESULTSnIn every group, a significant correlation was detected between OPG concentration and age (r = 0.58, p < 0.0001), especially in individuals older than fifty years, while gender and underlying disease were not found to influence serum levels of the tested parameters. In comparison with the levels in healthy donors and patients with a stable total hip replacement, the serum levels of OPG were increased in the patients who had not yet had an arthroplasty, those with aseptic loosening of a total hip replacement, and those with a cemented total hip replacement. Moreover, the OPG serum level provided good diagnostic accuracy in detecting the implant failure. A correlation was found between the sum of the osteolytic areas seen radiographically around the femoral stem and the RANKL level (r = 0.38, p = 0.02) and the OPG-to-RANKL ratio (r = -0.29, p = 0.04).nnnCONCLUSIONSnAn increase in OPG levels may reflect a protective mechanism of the skeleton to compensate for the osteolytic activity that occurs in severe osteoarthritis and in aseptic loosening. Prospective studies are needed to determine whether serum OPG levels could be used as markers for monitoring the stability of the implant, as well as for predicting aseptic loosening.nnnLEVEL OF EVIDENCEnDiagnostic study, Level III. See Instructions to Authors for a complete description of levels of evidence.

Is wear debris responsible for failure in alumina-on-alumina implants?: Clinical, histological, and laboratory investigations of 30 revision cases with a median follow-up time of 8 years

Background and purpose Ceramic-on-ceramic articulation is an attractive alternative to metal-on-polyethylene (PE) bearings, but little is known about the in vivo effects induced by dissemination of alumina wear debris in the periprosthetic tissues. We hypothesized that wear debris is not the main factor responsible for loosening and failure of the implant but that mechanical problems caused by incorrect surgical technique, prosthetic design, or trauma, may cause instability of the implants and result in production of wear debris. Patients and methods Clinical, radiographic, laboratory, and microbiological data from 30 consecutive patients with failed alumina-on-alumina arthroplasties, 19 with screwed socket and 11 with press-fit socket, were systematically collected and evaluated. Retrieved peri-implant tissues and prosthesis wear were also analyzed. Results and Interpretation Loosening was due to malpositioning, primary mechanical instability, trauma, or infection. Bone stock was generally preserved, even if screwed implants showed higher levels of osteolysis. Variable implant wear and tissue macrophage reaction were present but activation of giant cells/osteoclasts was not induced, and no correlation between histocytic reaction and the level of osteolysis was found. These findings indicate that, in contrast to the situation with metal-on-PE bearings, wear debris and occasional osteolysis were the effect rather than the cause of failure of ceramic-on-ceramic implants, and that press-fit socket fixation was the socket fixation design of preference.

Plasma levels of platelet-derived growth factor BB and transforming growth factor in patients with failed hip prostheses

Backgroundu2003The role of growth factors in prosthesis loosening is unclear. We evaluated the levels of plate-let-derived growth factor BB (PDGF-BB), transforming growth factors β1 (TGF-β1) and β2 (TGF-β2), both before and after activation, in patients with aseptic loosening of their hip prosthesis. Patients and methodsu200326 patients with loosened hip implants were compared with 21 patients who had stable hip prostheses, and 28 patients undergoing primary hip replacement. The plasma levels of the growth factors were analyzed by enzyme immunoassay. TGF-β1 and TGF-β2 were determined both before and after activation. Resultsu2003Patients with aseptic loosening had significantly lower PDGF-BB levels than patients undergoing primary hip replacement, and significantly lower TGF-β2 levels than patients with a stable implant. Patients with stable prostheses had significantly higher TGF-β1 and TGF-β2 levels than patients undergoing primary hip replacement. Interpretationu2003It is possible that the prosthetic implant itself causes a local increase in PDGF-BB, TGF-β1 and TGF-β2, released by osteoblasts and other cells in the microenvironment. The plasma PDGF-BB measured does not correspond to local release, which is probably due to local consumption or degradation. The consumption of PDGF-BB is low in stable implants, and TGF-β1 and TGF-β2 levels increase during bone formation. In loosening, PDGF-BB consumption is higher and causes a significant reduction in plasma levels as compared to presurgery. The formation of poor-quality bone may be related to the scarce increase in TGF-β1 and TGF-β2. In conclusion, compared with patients with a stable implant, a reduction in bone-forming growth factors appears to occur in individuals with aseptic loosening.

Xanthoma of bone: first sign of hyperlipidemia type IIB: a case report.

A xanthoma, located in the ulna, not accompanied by the traditional cutaneous and tendinous manifestations (xanthoma and xanthelasma) and with a late onset of alterations in lipid values, was diagnosed in a 56-year-old man. The lesion had a slow but constant growth leading to internal calcifications. Hyperlipidemia Type IIB occurred 15 years after the xanthoma first was detected by radiographs. Therefore, in this patient, xanthoma of bone was the first sign of dyslipidemia.

Immunohistochemical evaluation of bone metastases

Introduction. Metastases are the most common type of malignancy involving the bone, while bone is the third most frequent site for metastases, after the lung and liver. In some patients, medical history, physical and laboratory examixadnation are not conclusive to identify the primary tumor site. In such cases a bone biopsy and immunohistochemical analysis may contribute to the diagnosis, determination of appropriate treatment and evaluation of prognosis. In this study, we tried to evaluate the imunochistochemical expression in bone metastases. Material and methods. We reviewed 125 patients, with a mean age of 63 years, treated for bone metastases in our institution. All patients received palliative orthopaedic surgery for bone metastatic carcinoma. Fifty-eight patients had already an established diagnosis of the primary tumor, while 67 patients presented metastases with an unknown primary tumor origin. Immunohistochemical analysis was performed to intra-operative bone biopsy specimens. The expression of cytokeratine 7, cytokeratin 20 and the expression of a panel of other organ-specific markers were rexadcorded. In patients with a known primary tumor, we examined the relationship between the origin of metastases, as suggested by the cytokeratin phenotype, compared with the one indicated by the initial histological diagnosis. We also recorded the efficacy of organ-specific markers to identify the primary tumor origin in epithelial bone metastases and we evaluated the prognosis between patients with a immunohistologically determined primary tumor origin, with those with an undetermined one. Results. Associations of cytokeratine 7 and cytokeratine 20 expression confirmed diagnosis in 51 out of the 58 patients (88%) with a known primary tumor (Cohen’s K test 0.79 SE 0.80, P < 0.0005). Immunohistochemical analysis also contributed to establish the diagnosis of patients with an unknown primary tumor, yielding diagnosis in 35 out of the 67 cases (52%). Patients with an immunochistologically undetermined primary tumor site presented a statistixadcally significant poorer prognosis. Conclusions. Cytokeratine 7 and cytokeratine20 are useful immunochistochemical markers in determining a prexadliminary evaluation of bone metastases. Organ-specific immunohistochemical markers have a reliable role in either suggesting or confirming the possible origin of metastases. An indeterminate immunohistochemical phenotype seems to relate to a less differentiated lesion, with a worse prognosis.