Matrix metalloproteinase-1 contribution to sarcoma cell invasion.

Matrix metalloproteinase-1 (MMP-1) activity has been linked to numerous disease processes from arthritis to ulcer. Its proteolytic activity has been implicated inconsistently in different steps of tumourigenesis and metastasis. The discrepancies may be attributable to our limited understanding of MMP-1 production, cellular trafficking, secretion and local activation. Specifically, regulation of MMP-1 directional delivery versus its general extracellular matrix secretion is largely unknown. Inhibition of prenylation by farnesyl transferase inhibitor (FTI-276) decreased extracellular MMP-1 and subsequently reduced invasiveness by 30%. Parallel, stable cell line RNAi knockdown of MMP-1 confirmed its role in cellular invasiveness. The prenylation agonist farnesyl pyrophosphate (FPP) partially normalized FTI-276 inhibited extracellular MMP-1 levels and invasion capacity while transiently delayed its cellular podia distribution. MMP-1 directional delivery to these structures were confirmed by combination of a MMP-1-specific fluorogenic substrate, a MMP1-Ds-Red fusion protein construct expression and DQ-collagen degradation, which demonstrated coupling of directional delivery and activation. MetaMorph analysis of cellular lamellipodia structures indicated that FTI-276 inhibited formation and delivery to these structures. Farnesyl pyrophosphate partially restored lamellipodia area but not MMP-1 delivery under the time frame investigated. These results indicate that MMP-1 directional delivery to podia structures is involved in the invasive activity of sarcoma cells, and this process is prenylation sensitive.

Malignant sarcoma of the pelvic bones: treatment outcomes and prognostic factors vary by histopathology.

BACKGROUND: Treatment of malignant sarcomas of the pelvis poses a challenge for local disease control and oncologic outcome. Many reports have described the dismal outcomes. Most studies are retrospective series coming out of single centers, thus biased toward patient selection and are of limited statistical power. METHODS: The authors used the Surveillance, Epidemiology, and End Results database to analyze 1185 pelvic sarcoma cases from 1987 to 2006. Kaplan-Meier and Cox regression were used to analyze the significance of prognostic factors. The analysis was repeated for different histopathological subtypes to determine specific prognostic factors in each case. RESULTS: Incidence of pelvic sarcoma in 2006 was 89 per 100,000 persons; it has significantly increased since 1973 (P < .05). The overall 5-year survival for all the patients with pelvic sarcoma was 47%, with osteosarcoma having the worst 5-year survival at 19% and patients with chordoma having the best 5-year survival at 60%. Independent prognostic factors included age, stage, grade, size of primary lesion, histopathology, and treatment-related factors. Comparing the patients only with high-grade lesions, patients with Ewing sarcoma have the best prognosis. CONCLUSIONS: This is an analysis of patients with pelvic sarcomas derived from a population-based registry. Survival and prognostics vary with histopathological diagnoses. Although surgical resection was associated with superior outcomes for osteosarcoma and chondrosarcoma, there was no significant difference in outcomes of patients with Ewing sarcoma treated with surgery and/or radiotherapy.

Osteosarcoma: improvement in survival limited to high-grade patients only.

BACKGROUND: We sought to identify the significant prognostic parameters of patients with osteosarcoma over the past three decades using a population-based registry. METHODS: A total of 3765 patients with osteosarcoma were identified in the SEER database. Information regarding patient demographics, clinical and treatment characteristics, cause of death and survival were extracted. Kaplan-Meier, Log-Rank, and Cox regression were used for analysis. RESULTS: On multivariate analysis only age group '<25 years', 'local' stage and 'low' grade, 'appendicular skeleton' and employment of 'surgical resection' showed a disease-specific survival benefit with a P value < 0.001. The long-term survival improved in the interval from 1973 to 1985 from approximately 55 to 65% but subsequent improvement has been limited only to patients with high-grade disease. CONCLUSION: When comparing survival rates by decade of diagnosis, it appears that improvement in survival since 1985 is limited to patients with high-grade disease only. LEVEL OF EVIDENCE: The level of evidence for this article is 2.

Influence of preoperative cardiovascular risk factor clusters on complications of total joint arthroplasty.

Identification of preexisting cardiovascular risk factors is important in projecting postoperative outcomes. Using claims data for 16,317 patients who underwent total hip arthroplasty and/or total knee arthroplasty, we performed logistic regression and survival analysis to determine the effects of hypertension, diabetes, dyslipidemia,and obesity (both independently and in clusters) on incidence of myocardial infarction (MI), venous thromboembolism (VTE), and revision arthroplasty. Our results indicated that diabetes (odds ratio [OR],1.55; P<.05) and hypertension (OR, 1.56; P<.05) were independent risk factors for postoperative MI. Risk for MI increased significantly with the addition of each risk factor; there was a 128% increase in risk when all 4 cardiovascular risk factors were present (OR, 2.28; P<.0001). Risk for VTE did not change significantly with 1, 2, or 3 risk factors but reached statistical significance when all 4 risk factors were present (hazard ratio, 3.20; P = .05). There was no association between cardiovascular risk factors and incidence of revision arthroplasty. Our analysis confirmed that diabetes and hypertension are risk factors for postoperative MI, but the respective significant and near significant increased risks for MI and VTE seen with cardiovascular risk factor clustering merit further evaluation of the role of metabolic syndrome in patients who undergo arthroplasty.

Matrix metalloproteinase 1: role in sarcoma biology.

In carcinomas stromal cells participate in cancer progression by producing proteases such as MMPs. The expression MMP1 is a prognostic factor in human chondrosarcoma, however the role in tumor progression is unknown. Laser capture microdissection and In Situ hybridization were used to determine cellular origin of MMP1 in human sarcomas. A xenogenic model of tumor progression was then used and mice were divided in two groups: each harboring either the control or a stably MMP1 silenced cell line. Animals were sacrificed; the neovascularization, primary tumor volumes, and metastatic burden were assessed. LCM and RNA-ISH analysis revealed MMP1 expression was predominantly localized to the tumor cells in all samples of sarcoma (p = 0.05). The percentage lung metastatic volume at 5 weeks (p = 0.08) and number of spontaneous deaths secondary to systemic tumor burden were lower in MMP1 silenced cell bearing mice. Interestingly, this group also demonstrated a larger primary tumor size (p<0.04) and increased angiogenesis (p<0.01). These findings were found to be consistent when experiment was repeated using a second independent MMP1 silencing sequence. Prior clinical trials employing MMP1 inhibitors failed because of a poor understanding of the role of MMPs in tumor progression. The current findings indicating tumor cell production of MMP1 by sarcoma cells is novel and highlights the fundamental differences in MMP biology between carcinomas and sarcomas. The results also emphasize the complex roles of MMP in tumor progression of sarcomas. Not only does metastasis seem to be affected by MMP1 silencing, but also local tumor growth and angiogenesis are affected inversely.

Surgery significantly improves survival in patients with chordoma.

STUDY DESIGN: Retrospective database review using Surveillance, Epidemiology, and End Results database, National Cancer Institute. OBJECTIVE: To determine current treatment outcomes and demographic characteristics and to define the prognostic factors and impact of surgery on survival. SUMMARY OF THE BACKGROUND DATA: Rarity of the disease has limited the number of population-based studies addressing the issues of prognostic factors and the current treatment outcomes. METHODS: A total of 962 patients with chordoma, diagnosed between 1973 and 2005, were identified in the Surveillance, Epidemiology, and End Results database. Patient demographics and clinical characteristics, incidence, year of diagnosis, location, size and stage at diagnosis, treatment(s), and survival were extracted. Kaplan-Meier, log-rank, and Cox regression were used to analyze the significance of prognostic factors. RESULTS: Race specific incidence per 100,000 persons in 2005 shows whites to have the highest (0.473) incidence, followed by Asians/Pacific Islanders (0.091), and Afro-Americans (zero), respectively. The incidence difference between whites and Afro-Americans over time is statistically significant (P < 0.001). The age adjusted incidence reveals a peak in eighth decade of life. Survival was not impacted by race. Age category <59, Hispanic ethnicity, size <8 cm, and surgical resection were all independent predictors of better overall survival. Analysis revealed that survival outcomes were very similar in patients with "in-operable disease" and those in which "surgery was recommended but not performed" suggesting that benefits of resection cannot be solely attributed to selection bias. CONCLUSION: With high local recurrence rates and the significant functional morbidity associated with surgical resections, clinicians are left wondering if surgery constitutes an appropriate treatment option. Our study clearly demonstrates that surgery significantly improves the overall survival for patients with chordoma. We have further identified age <59 and size of primary tumor <8 cm as important prognostic factors determining the outcome with substantial statistical significance.

Incomplete seating of a metal-backed alumina liner in ceramic-on-ceramic total hip arthroplasty.

Metal-backed modular ceramic bearing systems using a recessed alumina liner in a titanium sleeve were developed to decrease ceramic chipping or fracture due to femoral neck impingement after total hip arthroplasty (THA). However, malseating of the metal-backed ceramic liner has recently been described. The goal of this study was to assess the prevalence, etiology, and clinical relevance of this event. Between 2005 and 2008, 51 consecutive patients (61 hips) underwent THA with a metal-backed alumina liner housed in a titanium shell. The metal-backed ceramic liner was aligned, seated, and impacted into the shell, and satisfaction in terms of liner stability and seating was confirmed intraoperatively. Postoperative assessment of seating was assessed with standard radiographs. Liner seating was classified as well seated, suspicious, or malseated. Seven liners (11.5%) were found to be malseated and 4 (6.5%) were considered suspicious. Radiographically, there was a gap between the liner and the shell located inferomedially in 4 patients and superolaterally in 3 patients. Two liners subsequently seated at 1 and 3 months postoperatively, respectively. No dislodgement, failures, or adverse events were identified. There were no revision surgeries. The significant percentage of malseated liners were potentially attributed to poor exposure, bony/soft tissue interposition, and surgeon learning curve.

Primary lymphoma of bone in adult patients.

BACKGROUND: The low incidence of primary lymphoma of bone (PLB) has led to discrepancies in classification as well as difficulty in prognostication. The authors of this report used the Surveillance, Epidemiology, and End Results (SEER) database to analyze a large, population-based cohort of adult patients with this disease. The database provides a standardized classification and documentation of outcomes and enables a meaningful evaluation of prognostic factors. METHODS: The SEER database was used to identify all patients who were diagnosed with PLB from 1973 through 2005. Survival was analyzed with the Kaplan-Meier method, and the influence of clinical parameters on survival was analyzed with the log-rank test. A Cox proportional hazards model was used for multivariate analysis. RESULTS: Fifteen hundred adult patients with PLB were analyzed. The 5-year and 10-year survival rates for adult patients were 58% and 45%, respectively. Multivariate analysis revealed that younger age and localized disease were independent predictors of survival. It is noteworthy that the incidence of disease, as determined by the annual percentage change, increased during the study period (P < .05). CONCLUSIONS: This analysis of a large cohort of adults with PLB indicated that the only identifiable prognostic indicators were localized disease and younger age. The authors concluded that future treatment for patients with PLB need to be based on strict staging criteria and adherence to successful published protocols using collaborative clinical trials.

Skeletal Plasmacytoma: progression of disease and impact of local treatment; an analysis of SEER database.

BACKGROUND: Previous reports suggest an as yet unidentifiable subset of patients with plasmacytoma will progress to myeloma. The current study sought to establish the risk of developing myeloma and determine the prognostic factors affecting the progression of disease. METHODS: Patients with plasmacytoma diagnosed between 1973 and 2005 were identified in the SEER database(1164 patients). Patient demographics and clinical characteristics, treatment(s), cause of death, and survival were extracted. Kaplan-Meier, log-rank, and Cox regression were used to analyze prognostic factors. RESULTS: The five year survival among patients initially diagnosed with plasmacytoma that later progressed to multiple myeloma and those initially diagnosed with multiple myeloma were almost identical (25% and 23%; respectively). Five year survival for patients with plasmacytoma that did not progress to multiple myeloma was significantly better (72%). Age > 60 years was the only factor that correlated with progression of disease (p = 0.027). DISCUSSION: Plasmacytoma consists of two cohorts of patients with different overall survival; those patients that do not progress to systemic disease and those that develop myeloma. Age > 60 years is associated with disease progression. Identifying patients with systemic disease early in the treatment will permit aggressive and novel treatment strategies to be implemented.

Ewing sarcoma demonstrates racial disparities in incidence-related and sex-related differences in outcome: an analysis of 1631 cases from the SEER database, 1973-2005.

BACKGROUND: Previous reports of Ewing sarcoma cohorts suggested that there is a difference in incidence according to racial origin. However, to the authors' knowledge, this finding has never been tested in a population-based database, and the impact of race on clinical outcome and the significance of known risk factors stratified to racial groups have not been reported. METHODS: Patients who had Ewing sarcoma diagnosed between 1973 and 2005 were identified in the Surveillance, Epidemiology, and End Results database. Patient demographic and clinical characteristics; incidence; year of diagnosis; tumor location, tumor size, and disease stage at diagnosis; treatment(s); cause of death; and survival were extracted. Kaplan-Meier, log-rank, and Cox regressions were used to analyze the significance of prognostic factors. RESULTS: Race-specific incidence indicated that Caucasians have the highest incidence (0.155), followed by Asians/Pacific Islanders (0.082), and African Americans (0.017). The difference in incidence between Caucasians and African Americans was 9-fold and significant (P<.001). The incidence of Ewing sarcoma increased over the past 3 decades among Caucasians (P<.05). Survival was not impacted by race. Local disease stage, primary tumor location in the appendicular skeleton, and tumor size

Chondrosarcoma in the United States (1973 to 2003): an analysis of 2890 cases from the SEER database.

BACKGROUND: Current demographic, prognostic, and outcomes data on the diagnosis and treatment of chondrosarcoma have been based on case series reported by individual treatment centers. The SEER (Surveillance, Epidemiology and End Results) database is a validated national epidemiological surveillance system and cancer registry that has been used extensively to evaluate treatment outcomes in cases of malignancy. The purpose of the present study was to use this database to identify demographic and prognostic characteristics of chondrosarcoma and to describe the natural history following the treatment of this rare disease in the United States over the last thirty years. METHODS: Two thousand eight hundred and ninety patients with chondrosarcoma were identified in the SEER database, and information regarding the demographic and clinical characteristics of the patients, the histological features and grade of the tumors, the location and size of the tumors, the surgical stage at the time of diagnosis, the use of surgery and radiation treatment, and survival were extracted. RESULTS: Comparison of the overall and disease-specific survival rates revealed that patients who survived for ten years were more likely to die of events that were unrelated to chondrosarcoma. The disease-specific survival rate leveled off at ten years of follow-up. Univariate analysis revealed that female sex, a low histological grade, and local surgical stage were associated with a significant disease-specific survival benefit. An age of fifty years or less and an appendicular location of the tumor were associated with a significant overall survival benefit. On multivariate analysis, only grade and stage had significant association with disease-specific survival. On the basis of a comparison of survival rates according to the decade of diagnosis, it appears that there has been no significant improvement in survival over the last thirty years. CONCLUSIONS: Only grade and stage are independent prognostic factors for survival in cases of chondrosarcoma. Current treatment algorithms have not improved the survival rates of patients with chondrosarcoma over the past thirty years. Routine patient surveillance following treatment should be extended to ten years of follow-up.

Extracellular matrix-induced gene expression in human breast cancer cells.

Extracellular matrix (ECM) molecules modify gene expression through attachment-dependent (focal adhesion-related) integrin receptor signaling. It was previously unknown whether the same molecules acting as soluble peptides could generate signal cascades without the associated mechanical anchoring, a condition that may be encountered during matrix remodeling and degradation and relevant to invasion and metastatic processes. In the current study, the role of ECM ligand-regulated gene expression through this attachment-independent process was examined. It was observed that fibronectin, laminin, and collagen type I and II induce Smad2 activation in MCF-10A and MCF-7 cells. This activation is not caused by transforming growth factor (TGF)-beta ligand contamination or autocrine TGF involvement and is 3- to 5-fold less robust than the TGF-beta1 ligand. The resulting nuclear translocation of Smad4 in response to ECM ligand indicates downstream transcriptional responses occurring. Coimmunoprecipitation experiments determined that collagen type II and laminin act through interaction with integrin alpha(2)beta(1) receptor complex. The ECM ligand-induced Smad activation (termed signaling crosstalk) resulted in cell type and ligand-specific transcriptional changes, which are distinct from the TGF-beta ligand-induced responses. These findings show that cell-matrix communication is more complex than previously thought. Soluble ECM peptides drive transcriptional regulation through corresponding adhesion and non-attachment-related processes. The resultant gene expressional patterns correlate with pathway activity and not by the extent of Smad activation. These results extend the complexity and the existing paradigms of ECM-cell communication to ECM ligand regulation without the necessity of mechanical coupling.

Prognostic factors for survival in patients with epithelioid sarcoma: 441 cases from the SEER database.

UNLABELLED: Current stratification of prognosis in patients with epithelioid sarcoma (ES) is based largely on data reported by individual centers with a limited number of patients. We sought to identify the important prognostic parameters using the Surveillance, Epidemiology, and End Results (SEER) database. We identified 441 patients with ES in the database and extracted information regarding patient demographics and clinical characteristics. Kaplan-Meier, log-rank, and Cox regression were used for analysis. Disease-specific survival declined until 100 months after diagnosis after which survival was unrelated to epithelioid sarcoma. The overall incidence of ES during 2005 was 0.041 per 100,000. The reported incidence has increased since 1973, with an annual percentage change of 5.217%. On multivariate analysis, only age younger than 16 years, local stage of disease, or negative nodes and surgical resection of the tumor predicted better disease-specific survival. We observed no increase in survival by comparing decades of diagnosis since 1986. The SEER database shows only age younger than 16 years, negative nodes, or local stage of disease and operability of primary disease independently predict survival in patients with ES. LEVEL OF EVIDENCE: Level II, prognostic study. See Guidelines for Authors for a complete description of levels of evidence.

Surgical management of conventional grade I chondrosarcoma of long bones.

We retrospectively reviewed 70 patients with low-grade (Grade I) chondrosarcoma of the appendicular skeleton treated at the Mayo Clinic from 1980 to 2001. Fifty-four patients underwent wide resections and three patients underwent marginal excision for radiographically aggressive lesions. Thirteen patients were treated with intralesional curettage for more indolent lesions. The mean age of the patients was 43 years (range, 5-85 years) and the minimum followup was 0.2 year (mean, 8.5 years; range, 0.2-22.8 years). Of the patients who had wide resection, one experienced local recurrence and one had metastasis develop. One patient in the group treated with intralesional curettage had local recurrence and metastasis. We observed no difference in overall survival rate between the intralesional curettage group and the wide resection group. Although there was no difference in the treatment outcome between the two groups, patients with more radiographically aggressive lesions underwent more extensive surgery. The data suggest in selected patients less radiographically aggressive Grade I chondrosarcoma can be safely treated with intralesional curettage without compromising patient outcome.

Direct tendon attachment and healing to porous tantalum: an experimental animal study.

BACKGROUND: The ability to directly attach soft-tissue to metal would have broad clinical application. Previous attempts to obtain normal tendon-to-bone attachment strength have been unsuccessful. In the present study, we hypothesized that when the initial interface mechanical environment is carefully controlled, a highly porous form of tantalum metal would allow the ingrowth of tendon tissue with clinically relevant tendon-to-implant fixation strength approaching that of an intact tendon-to-bone insertion. METHODS: Supraspinatus tendons from forty skeletally mature dogs were reattached to the greater tuberosity between two custom-designed porous tantalum washers. Clinical function as judged on the basis of gait analysis, reattachment fixation strength and stiffness, and tendon function as seen through muscle volume were evaluated preoperatively, immediately postoperatively, and at three, six, and twelve weeks after surgery. Qualitative and quantitative histomorphologic evaluation was performed at three, six, and twelve weeks after surgery. RESULTS: Gait analysis with use of force-plate measurements demonstrated return to a normal gait pattern by three weeks after surgery. Tendon-implant strength as a percentage of normal, contralateral controls increased significantly, from 39% at the time of surgery to 67% at three weeks, 99% at six weeks, and 140% at twelve weeks (p < 0.0014). The stiffness of the construct also increased and approached that of normal tendon, measuring 47% at the time of surgery, 62% at three weeks, 94% at six weeks, and 130% at twelve weeks (p < 0.0299). Supraspinatus muscle volume initially decreased by 33% but recovered to 92% of normal by twelve weeks (p < 0.01). Histomorphologic evaluation showed Sharpey-like fibers inserting onto the surface of the porous tantalum. Quantitative histomorphometric analysis revealed a time-dependent increase in the density of the collagen tissue filling the metal voids below the implant surface of first the bottom washer and then the top washer. CONCLUSIONS: Robust biologic ingrowth of tendon into a porous tantalum implant surface can be achieved under conditions of secure initial mechanical fixation. The strength and stiffness of the tendon-implant construct reached normal levels by six to twelve weeks in this animal model.