Serum Fractalkine (CX3CL1) and Cardiovascular Outcomes and Diabetes: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study.

BACKGROUND: Cardiometabolic disease is a major cause of morbidity and mortality in persons with chronic kidney disease (CKD). Fractalkine (CX3CL1) is a potential mediator of both atherosclerosis and metabolic disease. Studies of the relationship of CX3CL1 with risk of cardiovascular disease (CVD) events and metabolic traits are lacking, particularly in the high-risk setting of CKD. STUDY DESIGN: Cross-sectional and longitudinal observational analysis. SETTING & PARTICIPANTS: Adults with CKD from 7 US sites participating in the Chronic Renal Insufficiency Cohort (CRIC) Study. PREDICTOR: Quartiles of plasma CX3CL1 levels at baseline. OUTCOMES: Baseline estimated glomerular filtration rate from a creatinine and cystatin C-based equation, prevalent and incident CVD, diabetes, metabolic syndrome and its criteria, homeostatic model assessment of insulin resistance, hemoglobin A1c level, myocardial infarction, all-cause mortality, and the composite outcome of myocardial infarction/all-cause mortality. RESULTS: Among 3,687 participants, baseline CX3CL1 levels were associated positively with several CVD risk factors and metabolic traits, lower estimated glomerular filtration rate, and higher levels of inflammatory cytokines, as well as prevalent CVD (OR, 1.09; 95% CI, 1.01-1.19; P=0.03). Higher CX3CL1 level also was associated with prevalent diabetes (OR, 1.26; 95% CI, 1.16-1.38; P<0.001) in adjusted models. During a mean follow-up of 6 years, there were 352 deaths, 176 myocardial infarctions, and 484 composite outcomes. In fully adjusted models, 1-SD higher CX3CL1 level increased the hazard for all-cause mortality (1.11; 95% CI, 1.00-1.22; P=0.02) and the composite outcome (1.09; 95% CI, 1.00-1.19; P=0.04). LIMITATIONS: Study design did not allow evaluation of changes over time, correlation with progression of phenotypes, or determination of causality of effect. CONCLUSIONS: Circulating CX3CL1 level may contribute to both atherosclerotic CVD and diabetes in a CKD cohort. Further studies are required to establish mechanisms through which CX3CL1 affects the pathogenesis of atherosclerosis and diabetes.

Clinical and functional outcomes of patients with a pathologic fracture in high-grade osteosarcoma.

BACKGROUND AND OBJECTIVES: There have been variable reports of outcomes of patients with osteosarcoma and pathologic fractures. The purpose of this study was to document outcomes after management of this clinical entity at a single large oncology center. METHODS: A retrospective review was undertaken of our database between 1989 and 2006. We compared oncologic and functional outcomes of 201 patients with high-grade osteosarcoma without pathologic fractures to 31 patients with pathologic fractures. RESULTS: The rate of amputation in the group with pathologic fracture was significantly higher than the group without fracture (39% vs. 14%, P = 0.001). There was no difference in the rate of local recurrence between groups. The 5-year survival was superior in the group without pathologic fracture (60% vs. 41%, P = 0.0015). For patients with localized disease, 5-year survival was higher in patients without fracture (68% vs. 52%, P = 0.006). Disability as measured by the Toronto Extremity Salvage Score was no different between the groups. Impairment as measured by the Musculoskeletal Tumor Society scores was lower in the group without fracture. CONCLUSIONS: Presentation with a pathologic fracture in osteosarcoma did not preclude limb salvage surgery in a majority of patients, did not increase the risk of local recurrence, but was associated with poorer overall survival.

Iliosacral resection for primary bone tumors: is pelvic reconstruction necessary?

UNLABELLED: Iliosacral resection for primary bone tumors creates a large unstable pelvic ring defect, the treatment of which remains controversial. We did this study to determine if skeletal reconstruction of such defects is necessary. Sixteen patients whose data were collected prospectively had iliosacral resection with a minimum followup of 12 months. The surgical and functional results of patients who had skeletal reconstruction (n = 4) were compared with the results of patients who did not have iliosacral repair (n = 12) using a case-control design. Function was evaluated by assessing impairment using the Musculoskeletal Tumor Society 1987 and 1993 rating scales, and disability was measured using the Toronto Extremity Salvage Score. Although all four iliosacral arthrodeses initially healed, one allograft used for reconstruction fractured and another was removed because of progressive lumbosacral spinal instability. Patients treated without pelvic reconstruction had fewer operative complications. Although the Toronto Extremity Salvage Score and the Musculoskeletal Tumor Society 1987 and 1993 scores were similar for both patient groups, those patients who were treated without reconstruction were less likely to require the use of an ambulatory assistive device, less likely to require narcotics or have chronic pain, and more likely to return to work. These results suggest that reconstruction of the skeletal defect to restore pelvic stability after iliosacral resection is not mandatory. LEVEL OF EVIDENCE: Therapeutic study, Level III-1 (case-control study). See the Guidelines for Authors for a complete description of levels of evidence.

Outcome in two groups of patients with allograft-prosthetic reconstruction of pelvic tumor defects.

UNLABELLED: To predict the outcomes obtained with allograft-implant composite reconstruction of pelvic defects after bone tumor resection better, a retrospective review of a prospectively collected database was done and two groups of patients were identified. These groups were compared with respect to oncologic and functional outcomes in this investigation. Group 1 included 21 patients with allograft total hip replacement reconstruction for pelvic bone tumors that required Type I and II or Type I, II, and III pelvic resections. Group 2 included five patients who required an acetabular allograft in combination with proximal femoral replacement for reconstruction of Type II pelvic resections done to treat proximal femoral bone sarcomas that invaded or surrounded the hip joint. Functional assessment was measured with three instruments (Toronto Extremity Salvage Score, Musculoskeletal Tumor Society 1987, and the Musculoskeletal Tumor Society 1993 scores). In Group 1, nine of 19 evaluable patients (two patients died in the immediate postoperative period) either retained the allograft until their death or were still alive at last followup with their allograft in place. An additional patient had revision surgery to an allograft-saddle composite that remains intact. The functional results in Group 1 were influenced heavily by the occurrence of deep infection. Nine of 19 evaluable patients developed infection, with seven patients requiring either removal of the graft (three patients) or hindquarter amputation (four patients). Two patients retained their infected allografts with long-term antibiotic suppression. In 10 Group 1 patients who did not develop infection, reasonable functional results were obtained. Group 2 patients had no infections and better functional results. LEVEL OF EVIDENCE: Therapeutic study, Level IV-1 (case series). See the Guidelines for Authors for a complete description of levels of evidence.

Injection of immature dendritic cells into adjuvant-treated skin obviates the need for ex vivo maturation.

A key and limiting step in the process of generating human monocyte-derived dendritic cells (DC) for clinical applications is maturation. In the setting of immunotherapy, DC are matured ex vivo by culturing them with various agents that mimic the conditions encountered at a site of inflammation. This study examined whether the ex vivo DC maturation step could be replaced by maturing DC in situ by injecting immature DC into sites pre-exposed to agents that induce a microenvironment conducive to in situ maturation of the injected DC. The hypothesis was that recapitulation of the physiological conditions occurring during pathogen infection would lead to optimal conditions for DC maturation, migration, and function. Murine immature DC injected into adjuvant (Adjuprime, poly-arginine, or Imiquimod)-pretreated skin exhibited lymph node migratory capacity comparable to and immunostimulatory capacity equal to or exceeding that of ex vivo matured DC. Acquisition of migratory capacity did not always correlate with enhanced immunostimulatory capacity. Immunostimulatory capacity was not enhanced when mature DC were injected into adjuvant-pretreated sites and remained below that seen with immature DC matured in situ. Immature DC injected into adjuvant-pretreated sites were more effective than mature DC in stimulating antitumor immunity in mice. (111)Indium-labeled human monocyte-derived immature DC injected into adjuvant (Imiquimod)-pretreated sites in cancer patients acquired lymph node migratory capacity comparable to ex vivo matured DC. This study shows that in situ maturation offers a simpler and potentially superior method to generate potent immunostimulatory DC for clinical immunotherapy.