Survival In Osteosarcoma Research Articles

Outcomes of Patients With Maxillofacial Osteosarcoma: A Review of 15 Cases

To assess clinical behavior, response to treatment, and factors affecting survival in maxillofacial osteosarcoma treated at a tertiary referral center. Ethics-approved retrospective review of clinical and pathological records was undertaken for 15 patients managed by the Royal Melbourne Hospital Head and Neck Oncology Tumor Stream. Treatment was a combination of surgery and chemotherapy. Chemotherapy was given as adjuvant, neoadjuvant, or in combination. The overall 2-, 5-, and 15-year disease-free survival rates in this study were 92%, 74%, and 74%, respectively. Using Kaplan-Meier analysis with log rank tests, increasing T stage (P = .01) and positive margins (P = .003) were found to affect survival significantly. Neoadjuvant chemotherapy was not significantly associated with tumor necrosis or improved survival. Tumor size and adequacy of local control were found to be the most important predictors of outcome.

Endothelin-1 Promotes Osteosarcoma Cell Invasion and Survival against Cisplatin-induced Apoptosis

Endothelin-1 (ET-1) participates in a wide range of cancer-relevant processes including cell proliferation, inhibition of apoptosis, matrix remodeling, bone deposition, and metastases. Although ET-1 reportedly promotes osteosarcoma (OS) cell invasion, suggesting an important role of ET-1 in OS metastasis, the role of ET-1 in OS remains unclear. We asked whether (1) ET-1 expression is associated with the malignancy of OS, (2) ET-1 enhances the cell invasion ability of OS, and (3) ET-1 promotes OS cell survival against apoptotic stress. We cultured primary OS specimens from 22 patients with Stages II (OS-II) and III (OS-III) in real-time quantitative RT-PCR and ELISA to compare ET-1 expression. We used Transwell(®) cell invasion assays (in triplicate) to assess the invasion ability of cells in the presence or absence of exogenous ET-1 and/or ET receptor antagonists. We compared cell apoptosis rate among the cells treated with cisplatin in the presence or absence of exogenous ET-1 and/or ET receptor antagonists. We used OS cell line MG-63 in all experiments as a reference. Real-time quantitative RT-PCR and ELISA showed OS-III cells had greater ET-1 expression than OS-II cells at the mRNA and the secreted protein levels. Transwell(®) cell invasion assays showed OS-III cells had a greater migrated cell number than OS-II cells, which could be abrogated by ET(A) receptor antagonist BQ123 (100pmol/L), but not ET(B) receptor antagonist BQ788 (1 μmol/L); exogenous ET-1 dose-dependently promoted OS cell migration, which could be inhibited by BQ123 (100pmol/L). Cisplatin (10nmol/L) induced less apoptosis in OS-III cells than in OS-II cells; exogenous ET-1 dose-dependently promoted OS cell survival against cisplatin-induced apoptosis; both effects were reversed by BQ123 (1 μmol/L), but not BQ788 (1 μmol/L). Increased ET-1 expression appears to be associated with increased malignancy of OS. ET-1 promotes OS cell invasion and survival against cisplatin-induced apoptosis through the ET(A) receptor. The ET-1/ET(A) pathway may represent an important target for treating OS, because blocking the ET(A) receptor with a selective antagonist can inhibit OS cell invasion and potentiate a chemotherapeutic agent's effect on OS.

Influence of prognostic factors in pediatric high-grade osteosarcoma survival.

9572 Background: Some others prognostic factors are interrelated with the well-known prognostic factors in high-grade Osteosarcoma (HGO), this can result in poor survival and should be considered for appropriate clinical decision making. Methods: Retrospective, longitudinal and clinical study was performed from Jan/1991-Dec/1998, 58 patients younger than 18 years with extremity HGO and no prior chemotherapy treatment were included. All received CDDP, DOX, CFA and VP-16. Prognostic-factors and Cox analysis with odds-ratio (OR) and p<0.05 were calculated. Outcome variables were age, histologic patterns (HP), primary site, tumor size (TS), metastatic disease, soft-tissue involvement (STI), histological response (HR) assessed by Huvos-grades and disease-free survival (DFS). Results: Median age was 12 years (5-18y) with 18 patients (31%) younger than 10 years. Skeletal site (SS) distribution was 59% distal femur, 17% proximal humerus, 14% proximal tibia, 7% fibula and 3% proximal femur. 18 patients (31%) had pulmonary metastases and 3 patients (5%) had multifocal disease at diagnosis. There were 74% osteoblastic tumors, 14% osteoblastic and chondroblastic, and 5% chondroblastic. 15 patients had an amputation procedure and 33 patients undergoing limb salvage of which 5 patients (15%) had eventual local recurrence. The more significant associated prognostic factors (APF) for local recurrence were STI at diagnosis (OR=6), grade-II HR (OR=2.8), grade-III HR (OR=10), TS (p0.0350) and chondroblastic-HP (p0.0089). For amputation procedures were SS (p0.0018) and have microscopic surgical margins (MSM) p0.0075. For development of metastatic disease were TS (p0.0008), MSM (p0.000), pulmonary metastases at diagnosis (p0.000), SS (p0.000) and chondroblastic-HP (p0.000). For death by tumor activity was poor in HR (p0.0013) and TS (p0.0278). 5-years DFS without APF was 68% Vs 43% with APF (p0.021). Conclusions: APF play a very important roll in Osteosarcoma prognosis and should be considered for appropriate clinical decisions making.

Tumor-Infiltrating Macrophages Are Associated with Metastasis Suppression in High-Grade Osteosarcoma: A Rationale for Treatment with Macrophage Activating Agents

High-grade osteosarcoma is a malignant primary bone tumor with a peak incidence in adolescence. Overall survival (OS) of patients with resectable metastatic disease is approximately 20%. The exact mechanisms of development of metastases in osteosarcoma remain unclear. Most studies focus on tumor cells, but it is increasingly evident that stroma plays an important role in tumorigenesis and metastasis. We investigated the development of metastasis by studying tumor cells and their stromal context. To identify gene signatures playing a role in metastasis, we carried out genome-wide gene expression profiling on prechemotherapy biopsies of patients who did (n = 34) and patients who did not (n = 19) develop metastases within 5 years. Immunohistochemistry (IHC) was performed on pretreatment biopsies from 2 additional cohorts (n = 63 and n = 16) and corresponding postchemotherapy resections and metastases. A total of 118/132 differentially expressed genes were upregulated in patients without metastases. Remarkably, almost half of these upregulated genes had immunological functions, particularly related to macrophages. Macrophage-associated genes were expressed by infiltrating cells and not by osteosarcoma cells. Tumor-associated macrophages (TAM) were quantified with IHC and associated with significantly better overall survival (OS) in the additional patient cohorts. Osteosarcoma samples contained both M1- (CD14/HLA-DRα positive) and M2-type TAMs (CD14/CD163 positive and association with angiogenesis). In contrast to most other tumor types, TAMs are associated with reduced metastasis and improved survival in high-grade osteosarcoma. This study provides a biological rationale for the adjuvant treatment of high-grade osteosarcoma patients with macrophage activating agents, such as muramyl tripeptide.

A prognostic evaluation of vascular endothelial growth factor in children and young adults with osteosarcoma

The potential role of VEGF in osteosarcoma has been evaluated in several studies. The majority of them included heterogeneous and limited series of patients, giving conflicting results. The aim of presented study is to evaluate the prognostic role of VEGF-A in biopsy samples of clinically homogeneous group of osteosarcoma patients with at least 5 years of follow up. VEGF-A was assessed immunohistochemically in the pre-treatment biopsy samples of 91 patients (mean age 14 years; range, 4-23 years) with primary, high-grade, non-metastatic osteosarcoma localized in extremities. The survival of each patient was assessed after at least 5-year follow-up period. VEGF-A over 50% of positive tumor cells was observed in 39% of cases and was linked to patients age below 14-year old (P = 0.025) and tumor size more than 8 cm (P = 0.054). VEGF-A was associated with a significantly decreased both overall survival (P = 0.006) and progression-free survival (P = 0.011). In the Cox proportional hazard model it was confirmed that VEGF-A expression in the biopsy samples was an independent prognostic factor of unfavorable survival in osteosarcoma (HR 2.51; 95% CI: 1.12-5.66). The expression of VEGF-A in the biopsy sample is the potential marker for predicting the course and outcome of osteosarcoma.

Impact of close surgical margin on local recurrence and survival in osteosarcoma

Whether neoadjuvant chemotherapy safely allows close margins in osteosarcoma patients is still unknown. This study investigates the impact of close margins on local recurrence (LR) and overall survival (OS) for osteosarcoma patients treated with neoadjuvant chemotherapy. We retrospectively reviewed 47 cases of conventional osteosarcoma who were treated at our institution. Patient and treatment factors such as age, gender, MSTS stage, tumour site, surgery type, pathological type, tumour size, surgical margin, tumour necrosis rate, chemotherapy regimens and cycles were recorded. A close margin was defined as tumour present less than 5 mm from the closest resection margin. The average followup was 87.6 months (range, 25-135 months). Twenty-five patients were alive, 22 patients had died, and eight had LR. Twenty-eight patients had wide margins, seven had positive margins and 12 had close margins. Positive margins had a greater risk of LR (57.1%) than wide margins and close margins. There was no difference in LR (8.3% vs 10.7%) between close margins and wide margins. Margin status was not correlated with OS. Compared with wide margins, close margins did not lead to increased local recurrence in our study group. Whether close margins, as defined in our study, are just as acceptable as wide margins in terms of patient outcomes for osteosarcoma patients with neoadjuvant chemotherapy needs to be further confirmed in the future.

Small molecules, LLL12 and FLLL32, inhibit STAT3 and exhibit potent growth suppressive activity in osteosarcoma cells and tumor growth in mice

Constitutive activation of Signal Transducers and Activators of Transcription 3 (STAT3) is frequently detected in osteosarcoma, and hence, may serve as a therapeutic target. In order to target STAT3, we tested two new STAT3 inhibitors, LLL12 and FLLL32. LLL12 and FLLL32 inhibit STAT3 phosphorylation and STAT3 downstream targets. LLL12 and FLLL32 also inhibit IL-6 induced STAT3 phosphorylation. The inhibition of STAT3 by LLL12 and FLLL32 resulted in the induction of apoptosis, reduction of plating efficiency, and migration in osteosarcoma cells. Furthermore, LLL12 and FLLL32 inhibited SJSA osteosarcoma cells and OS-33 tumor growth in murine xenografts. These results provide evidence that constitutive STAT3 signaling is required for osteosarcoma survival and migration in vitro and tumor growth in vivo. Blocking persistent STAT3 signaling by LLL12 and FLLL32 may be a novel therapeutic approach for osteosarcoma.

Preoperative grading scale to predict survival in patients undergoing resection of malignant primary osseous spinal neoplasms

Background context Large population-based studies of malignant primary osseous spinal neoplasms are lacking and are necessary to have sufficient statistical power to determine if various patient-related factors are in fact significant indicators of prognosis. Purpose Using a 30-year US national cancer registry (Surveillance, Epidemiology, and End Results [SEER]), we introduce a preoperative grading scale that is associated with survival in patients undergoing surgical resection for malignant primary osseous spinal neoplasms. Study design Large-scale retrospective study. Patient sample SEER registry. Outcome measure Survival. Methods The SEER registry (1973–2003) was queried to identify adult patients undergoing surgical resection of histologically confirmed primary spinal chordoma, chondrosarcoma, or osteosarcoma via International Classification of Disease for Oncology, Third Edition coding. Variables independently associated with survival were determined via Cox proportional hazards regression analysis for all tumor types. A grading scale comprising these independent survival predictors was then developed and applied to each histology-specific tumor cohort. Results Three hundred forty-two patients who underwent surgical resection of a malignant primary osseous spinal neoplasm (114 chordoma, 156 chondrosarcoma, and 72 osteosarcoma) were identified. Overall median survival after surgical resection was histology specific (osteosarcoma: 22 months; chordoma: 100 months; and chondrosarcoma: 160 months). Increasing age (years) and increasing tumor invasion (confined to periosteum; invasion through periosteum into adjacent tissues; and distal site metastasis) were the only variables independently associated with decreased survival (p<.05) for all tumor types. For spinal chordoma, sacrum/pelvic location (p<.05) and earlier year of surgery (p<.005) were also independently associated with decreased survival. Using variables of patient age, extent of local tumor invasion, and metastasis status in a five-point grading scale, increasing score (1–5) closely correlated (p<.001) with decreased survival for chordoma, chondrosarcoma, and osteosarcoma. Conclusions In our analysis of a US population–based cancer registry (SEER), a grading scale consisting of age, metastasis status, and extent of local tumor invasion was associated with overall survival after surgical resection of chordoma, chondrosarcoma, and osteosarcoma of the spine. Although this analysis could not take into account specific chemotherapy regimens and variations in surgical technique, this grading scale may offer valuable prognostic data based on variables available to the surgeon and patient before surgery and may help guide level of aggressiveness in subsequent treatment strategies.

Does Increased Rate of Limb-sparing Surgery Affect Survival in Osteosarcoma?

Does Increased Rate of Limb-sparing Surgery Affect Survival in Osteosarcoma?

Outcome of re‐excision for intralesionally treated parosteal osteosarcoma

The purpose of this study is to evaluate the risk of subsequent local recurrence (LR) and survival of parosteal osteosarcoma (POS) patients who underwent re-excision after intralesional excision. We analyzed clinical outcomes of 11 POS patients referred after intralesional excision. Average follow-up was 86 months (range: 37-190 months). There were 9 Stage IB lesions and 2 Stage IIB lesions. Tumors were located in the femur (3) and in other locations (8). Seven patients showing recurrent tumor at referral received entire segmental excision while remaining four patients without LR underwent hemi-cortical excision. The 5-year metastasis free survival rate of 11 patients was 81.8%. Patients without evident tumor mass did not show further recurrence after re-excision. However, 5 (71.4%) of the 7 patients with recurrent tumor relapsed despite segmental re-excision, and their median interval to subsequent LR was 18.8 months (range: 4-9 months). Two of five patients with re-recurrence developed metastases which were unresponsive to chemotherapy. Following inadvertent intralesional procedure, re-excision should be liberally applied before there is an evidence of recurrence. In patients presenting with gross LR, amputation should not be spared unless wide surgical margin can be achieved.

How can survival be improved in localized osteosarcoma?

Despite numerous chemotherapy trials and the introduction of novel agents, survival in localized osteosarcoma, which plateaued in the mid-1980s, has been recalcitrant to our best efforts. The authors considered that a review of previous and current strategies that target survival might provide a direction for research efforts. Here, the focus is placed mainly on the reappraisal of previous mass chemotherapy trials and prognostic factors, in the hope of contriving a strategy to overcome the current stasis.

The Role of Surgery and Adjuvants to Survival in Pagetic Osteosarcoma

Osteosarcoma is a rare complication of Paget's disease with a very poor prognosis. Treatment is controversial: the older age of the patients affected by Paget's disease may limit the use of chemotherapy and axial involvement may limit the practicality of surgery. The purposes of this study are (1) to report the survival in patients treated for osteosarcoma in Paget's disease; (2) to identify correlations between type of treatment and survival comparing our data with those in the literature; (3) to determine if the extent of Paget's disease and risk of malignant transformation are associated; (4) to assess if prognosis is related with site; and (5) to identify the variations of histologic subtypes of these osteosarcomas. We retrospectively reviewed the medical records of 26 patients treated between 1961 and 2006 who had bone sarcoma arising from a site of Paget's disease. Twenty two of the 26 patients had surgery. In six surgery only was performed; three had surgery, adjuvant chemotherapy, and radiotherapy; one surgery and radiotherapy; 12 underwent surgery and chemotherapy, adjuvant in 10 patients and neoadjuvant in two; two had only radiotherapy and two had only chemotherapy. We performed survival analyses between various combinations of treatment. At last followup four patients had no evidence of disease (NED) at a minimum followup of 42.6 months (mean, 139 months; range, 42.6-257.4 months) and 22 died with disease (DWD) at a minimum time of 1 month (mean, 20.2 months; range, 1-84 months). One of the six patients (11%) treated with surgery only had NED at 10 years; the other five died from disease at a mean of 30 months. Three of 12 patients (25%) treated with surgery and chemotherapy are NED at a mean followup of 12 years; nine died of disease at a mean of 24 months. All patients treated without surgery died at a mean of 7.5 months (range, 1-13.7 months). Despite improvements in surgery and medical treatments the prognosis remains poor in patients with Paget's sarcoma.

The epidemiology of bone cancer in 0 - 39 year olds in northern England, 1981 - 2002.

BackgroundThere is a paucity of recent epidemiological data on bone cancers. The aim of this study was to describe incidence and survival patterns for bone cancers diagnosed during 1981 - 2002.MethodsCases aged 0 - 39 years (236 osteosarcomas, 166 Ewing sarcomas and 73 chondrosarcomas) were analysed using Poisson and Cox regressions.ResultsIncidence rates (per million persons per year) for osteosarcoma were 2.5 at age 0 - 14 years; 4.5 at age 15 - 29 years and 1.0 at age 30 - 39 years. Similarly, for Ewing sarcoma the incidence rates were 2.2; 2.9; 0.4 and for chondrosarcoma rates were 0.1; 1.2; 1.8 respectively. Incidence of osteosarcoma increased at an average annual rate of 2.5% (95% CI 0.4 - 4.7; P = 0.02), but there was no change in incidence of Ewing sarcoma or chondrosarcoma. There was a marginally statistically significant improvement in survival for Ewing sarcoma (hazard ratio (HR) per annum = 0.97; 95% CI 0.94 - 1.00; P = 0.06), although patients aged 15 - 39 years (n = 93) had worse overall survival than those aged 0 - 14 (n = 73; HR = 1.46; 95% CI 0.98 - 2.17; P = 0.06). There was no significant improvement in osteosarcoma survival (HR per annum = 0.98; 95% CI 0.95 - 1.01; P = 0.18).ConclusionsReasons for poorer survival in Ewing sarcoma patients aged 15 - 39 years and failure to significantly improve survival for osteosarcoma patients requires further investigation.

Does Increased Rate of Limb-sparing Surgery Affect Survival in Osteosarcoma?

The emergence of limb salvage surgery as an option for patients with osteosarcoma is attributable to preoperative chemotherapy and advancements in musculoskeletal imaging and surgical technique. While the indications for limb salvage have greatly expanded it is unclear whether limb salvage affects overall survival. We asked whether over the past three decades limb-sparing procedures in high-grade osteosarcoma had increased, and whether this affected survival and ultimate amputation. We retrospectively reviewed 251 patients with high-grade osteosarcoma treated from 1980 to 2004 with a multidisciplinary approach, including neoadjuvant chemotherapy. We compared survival rates, limb-salvage treatment, and amputation after limb-sparing procedure during three different periods of time. Fifty-three patients were treated from 1980 to 1989, 97 from 1990 to 1999, and 101 from 2000 to 2004. Thirty-seven patients were treated with primary amputations and 214 with primary limb salvage. The 5-year survival rate in the first period was 36%, whereas in the 1990 s, it was 60% and 67% from 2000-2004. Limb salvage surgery rate in the 1980s was 53% (28 of 53), whereas in the 1990 s, it was 91% (88 of 97) and 97% from 2000-2004 (98 of 101). In the limb salvage group, 22 of the 214 patients (10%) required secondary amputation; the final limb salvage rate in the first period was 36% (19 of 53), whereas in the 1990 s, it was 81% (79 of 97) and 93% from 2000-2004 (94 of 101). Patients with osteosarcoma treated in the last two periods had higher rates of limb salvage treatment and survival, with lower secondary amputation.

Enhancement of Radiation Response in Osteosarcoma and Rhabomyosarcoma Cell Lines by Histone Deacetylase Inhibition

Histone deacetylase inhibitors (HDACIs) can enhance the sensitivity of cells to photon radiation treatment (XRT) by altering numerous molecular pathways. We investigated the effect of pan-HDACIs such as suberoylanilide hydroxamic acid (SAHA) on radiation response in two osteosarcoma (OS) and two rhabdomyosarcoma (RMS) cell lines. Clonogenic survival, cell cycle analysis, and apoptosis were examined in OS (KHOS-24OS, SAOS2) and RMS (A-204, RD) cell lines treated with HDACI and HDACI plus XRT, respectively. Protein expression was investigated via immunoblot analysis, and cell cycle analysis and measurement of apoptosis were performed using flow cytometry. SAHA induced an inhibition of cell proliferation and clonogenic survival in OS and RMS cell lines and led to a significant radiosensitization of all tumor cell lines. Other HDACI such as M344 and valproate showed similar effects as investigated in one OS cell line. Furthermore, SAHA significantly increased radiation-induced apoptosis in the OS cell lines, whereas in the RMS cell lines radiation-induced apoptosis was insignificant with and without SAHA. In all investigated sarcoma cell lines, SAHA attenuated radiation-induced DNA repair protein expression (Rad51, Ku80). Our results show that HDACIs enhance radiation action in OS and RMS cell lines. Inhibition of DNA repair, as well as increased apoptosis induction after exposure to HDACIs, can be mechanisms of radiosensitization by HDACIs.

Chemoradiotherapy in the treatment of inoperable high-grade osteosarcoma

Radical surgery is not feasible for all osteosarcoma patients. Overall survival for non-extremity osteosarcoma, as well as for patients with metastatic disease at diagnosis remains poor. For such patients, radical radiotherapy combined with chemotherapy may present an effective treatment approach. This report describes the results of conservative treatment for osteosarcoma patients not suitable for surgery. Seven out of 71 consecutive osteosarcoma patients were treated non-surgically at the Helsinki University Central Hospital either due to the inoperability of the tumour or the patient's choice of therapy. Staging procedures and measurement of tumour size were performed using computed tomography and magnetic resonance imaging. Six patients were treated with chemo-radiotherapy, and one patient received radiotherapy alone. Five patients received computer-assisted dose-planned radiotherapy with curative intent (total dose 60-70.5 Gray), and two patients received radiotherapy as palliation. Radiotherapy relieved symptoms efficiently. Median time to local failure was 2.6years (range 0.5-16.9+ years). Five year after treatment termination four patients were alive, and one of them remained disease-free. For selected patients not suitable for surgery, radiotherapy combined with chemotherapy provides an option to reduce symptoms caused by the primary tumour and improve quality of life. For some patients, this approach may (even) produce long-term remission.

Survival in high-grade osteosarcoma: improvement over 21 years at a single institution

BackgroundThe purpose of this study was to analyze improvements in overall survival over 21 years (1982–2002), with a 5-year minimum follow-up, in the largest series from a single center ever reported. Materials and methodsAll diagnoses of high-grade osteosarcoma were included despite histological varieties, age, site and stage. Of the 1656 cases observed, 198 patients were excluded (41 consultation only, 129 low-grade varieties, and 28 lost to follow-up). Within 1458 included patients, 1032 had characteristics to be enrolled in conventional clinical trials (classic histology, age <41, localized, and extremity disease). Data are also analyzed in subgroups to define patients who benefited most. ResultsWith a median follow-up of 12 years (5–25 years), 754 patients (51.7%) are alive, of whom 613 continuously disease free. Survival at 5, 10, and 15 years is 57%, 52%, and 51%, respectively. Patients candidates for clinical trials have a survival rate of 68%, 64%, and 61%, respectively. Survival for the other patients is 30%, 25%, and 24%, respectively. Trend (joinpoint statistical analysis at real 5-year follow-up) shows a yearly statistically significant improvement of 1.31% (95% confidence interval 0.5% to 2.1%) from 51% for patients treated in 1982 to 68% for those treated in 2002. Patients who statistically benefited were those who relapsed or presented with metastatic disease at diagnosis or had axial tumors. ConclusionsDespite the lack of new drugs for osteosarcoma, survival has statistically improved, especially for those patients with the worst outcome. Aggressive treatments are recommended for all patients including those with poor prognosis.

Oleanane triterpenoid CDDO-Me induces apoptosis in multidrug resistant osteosarcoma cells through inhibition of Stat3 pathway

BackgroundThe activation of signal transducer and activator of transcription 3 (Stat3) pathway correlates with tumor growth, survival, drug resistance and poor prognosis in osteosarcoma. To explore the potential therapeutic values of this pathway, we assessed both the expression and the activation of Stat3 pathway in several pairs of multidrug resistant (MDR) osteosarcoma cell lines, and tissues. To explore the potential therapeutic values of this pathway, we analyzed the ability of the synthetic oleanane triterpenoid, C-28 methyl ester of 2-cyano-3,12-dioxoolen-1,9-dien-28-oic acid (CDDO-Me), to inhibit Stat3 expression and activation as well as its effects on doxorubicin sensitivity in osteosarcoma cells.MethodsExpression of Stat3, phosphorylated Stat3 (pStat3) and Stat3 targeted proteins, including Bcl-XL, Survivin and MCL-1 were determined in drug sensitive and MDR osteosarcoma cell lines and tissues by Western blot analysis. The effect of CDDO-Me on osteosarcoma cell growth was evaluated by MTT and apoptosis by PARP cleavage assay and caspase-3/7 activity.ResultsStat3 pathway was activated in osteosarcoma tissues and in MDR cell lines. CDDO-Me inhibited growth and induced apoptosis in osteosarcoma cell lines. Treatment with CDDO-Me significantly decreased the level of nuclear translocation and phosphorylation of Stat3. The inhibition of Stat3 pathway correlated with the suppression of the anti-apoptotic Stat3 targeted genes Bcl-XL, survivin, and MCL-1. Furthermore, CDDO-Me increased the cytotoxic effects of doxorubicin in the MDR osteosarcoma cell lines.ConclusionsStat3 pathway is overexpressed in MDR osteosarcoma cells. CDDO-Me significantly inhibited Stat3 phosphorylation, Stat3 nuclear translocation and induced apoptosis in osteosarcoma. This study provides the framework for the clinical evaluation of CDDO-Me, either as monotherapy or perhaps even more effectively in combination with doxorubicin to treat osteosarcoma and overcome drug resistance.

Pelvis and extremity osteosarcoma with similar tumor volume have an equivalent survival

The poor prognosis of pelvic osteosarcoma is well recognized, but the cause of this prognosis has not been well defined. We analyzed the clinicopathologic characteristics of pelvic osteosarcoma, and their prognostic significances in a cohort of 41 patients, treated either surgically by ablation or non-surgically. In a separate case-controlled study, the 20 surgically treated osteosarcoma patients were matched with 38 patients with extremity osteosarcoma by tumor volume and age. The 5-year overall survival rates of the surgically and the non-surgically treated pelvic osteosarcoma were 55.8 +/- 13.0% and 4.8 +/- 4.7%, respectively (P < 0.01). Non-surgically managed pelvic osteosarcoma group were found to have a larger tumor volume (P = 0.02), bladder displacement and sacroiliac joint involvement (P < 0.01). The 5-year metastasis free survival rates in the surgically treated pelvic and extremity osteosarcoma were no different (41.4 +/- 12.8% vs. 48.6 +/- 8.4%), and histologic responses to chemotherapy were similar in two groups. No significant difference in survival or histologic response was found between the surgically treated pelvic and the extremity osteosarcoma with suitable tumor volume. Outcome of pelvis osteosarcoma corresponds to the poor survival of extremity osteosarcoma of high initial tumor burden.

IKKγ protein is a target of BAG3 regulatory activity in human tumor growth

BAG3, a member of the BAG family of heat shock protein (HSP) 70 cochaperones, is expressed in response to stressful stimuli in a number of normal cell types and constitutively in a variety of tumors, including pancreas carcinomas, lymphocytic and myeloblastic leukemias, and thyroid carcinomas. Down-regulation of BAG3 results in cell death, but the underlying molecular mechanisms are still elusive. Here, we investigated the molecular mechanism of BAG3-dependent survival in human osteosarcoma (SAOS-2) and melanoma (M14) cells. We show that bag3 overexpression in tumors promotes survival through the NF-kappaB pathway. Indeed, we demonstrate that BAG3 alters the interaction between HSP70 and IKKgamma, increasing availability of IKKgamma and protecting it from proteasome-dependent degradation; this, in turn, results in increased NF-kappaB activity and survival. These results identify bag3 as a potential target for anticancer therapies in those tumors in which this gene is constitutively expressed. As a proof of principle, we show that treatment of a mouse xenograft tumor model with bag3siRNA-adenovirus that down-regulates bag3 results in reduced tumor growth and increased animal survival.