EWS-FLI1 fusion type, p53 mutation, and homozygous deletion of p16/p14ARF have each been shown to be prognostically significant in Ewing sarcoma (ES). We provide the first combined prognostic ...analysis of these three molecular parameters in ES.
We studied 60 patients with ES (stage: localized in 54, metastatic in six). All cases were confirmed to contain the EWS-FLI1 (29 type 1, 12 type 2, 14 other types) or EWS-ERG fusions (five cases). Homozygous deletion of p16/p14ARF, and p53 mutations were determined by fluorescent in situ hybridization and Affymetrix (Santa Clara, CA) p53 GeneChip microarray hybridization, respectively.
Eight cases (13.3%) contained point mutations of p53, and eight cases (13.3%) showed p16/p14ARF deletion, including one case with both alterations. Among 32 cases with data on histologic chemoresponse, all 10 with alterations in p53 or p16/p14ARF showed a poor chemoresponse (P = .03). Variables predicting poorer overall survival included p53 mutation alone (P < .001), either p53 or p16/p14ARF alteration (P < .001), and stage (P < .01). In multivariate analysis, alterations of p53 and/or p16/p14ARF as a single variable, was the most adverse prognostic factor (P < .001), followed by stage (P = .04). In a multivariate analysis with alterations of p53 and p16/p14ARF as separate variables, both were significant (P < .001 and P = .03, respectively). Six cases with p16/p14ARF deletion were also studied for co-deletion of the contiguous methylthioadenosine phosphorylase gene, and this was detected in four cases.
Alterations in p53 or p16/p14ARF are found in a fourth of ES cases and define a subset with highly aggressive behavior and poor chemoresponse.
The current study was conducted to identify histologic predictors of survival in patients with localized, lymph node-negative (Stage I, N0M0) primary mucosal melanomas of the head and neck (HNMM).
...The histology of 39 sinonasal, 20 oral, 1 pharyngeal, and 1 laryngeal Stage I HNMM was reviewed by 2 pathologists without knowledge of patient outcome. The invasion was evaluated as Level I: melanoma in situ (without invasion or with microinvasion only); Level II: invasion into the lamina propria only; and Level III: invasion into deep tissue (e.g., skeletal muscle, bone, or cartilage). The tumor architecture was defined as pseudopapillary when tumor cells clustered around blood vessels resembling papillae and sarcomatoid when they resembled high-grade pleomorphic sarcoma. Survival analysis was performed with Kaplan-Meier survival curves using disease-specific survival (DSS) as the endpoint.
The 5-year DSS rate was 43% (median, 41.5 months). The median survival was found to decrease significantly with increasing level of invasion: Level I (n = 4): 138 months; Level II (n = 29): 69 months; and Level III (n = 28): 17 months (P = 0.003). The presence of pseudopapillary and sarcomatoid architecture (n = 20) and undifferentiated cells (n = 16) were found to be associated with a significantly poor DSS (P < 0.05). However, on multivariate analysis, only the level of invasion remained an independent predictor of survival (P = 0.03). Tumor thickness, vascular invasion, and necrosis were found to have no significant influence on survival.
Microstaging according to invasion into three tissue compartments was found to be a significant and independent predictor of poor survival in patients with localized, lymph node-negative, Stage I HNMM. The presence of sarcomatoid and pseudopapillary architecture and undifferentiated cells also appear to be associated with significantly poor DSS.
Purpose: To determine if osteosarcoma cells express chemokine receptors and if their presence or absence relates to clinical features.
Experimental Design: Using fluorescent quantitative real-time ...PCR, the pattern of 17 chemokine receptors in 3 osteosarcoma cell lines and 68 osteosarcoma
patient samples was analyzed.
Results: The expression of the chemokine receptors was generally low among the cell lines. In the high-grade osteosarcoma patient
samples ( n = 47), CXCR4 was the most commonly expressed (63%) and its expression level was inversely correlated to overall survival
( P < 0.0001), event-free survival ( P < 0.001), and metastasis-free survival (MFS; P = 0.002). There was also a correlation between the expression level of CXCR4 and the presence of metastasis at diagnosis
( P = 0.002). CCR7 was expressed in 43% of the samples and its expression level was inversely correlated with overall survival
( P = 0.03) and MFS ( P = 0.007). CCR10 mRNA expression level was inversely correlated with MFS ( P = 0.009). There was no association between the expression of CXCR4, CCR7, and CCR10. Of the 26 samples studied for stromal
cell–derived factor-1 expression, 77% expressed it, but there was no correlation with the clinical variables or CXCR4 expression.
Multivariate analysis revealed that mRNA expression level of CXCR4 was the only significant variable for overall survival
( P = 0.0006), event-free survival ( P = 0.004), and MFS ( P = 0.025).
Conclusions: These data suggest that CXCR4 could be useful as a prognostic factor and as a predictor of potential metastatic development
in osteosarcoma. If further studies confirm that it is relevant to metastases in this disease, it could represent a new therapeutic
target.
Osteosarcoma is the most common malignant bone tumor in children. Osteosarcoma patients who respond poorly to chemotherapy are at a higher risk of relapse and adverse outcome. Therefore, it was the ...aim of this study to identify prognostic factors at the time of diagnosis to characterize the genes predictive of poor survival outcome and to identify potential novel therapeutic targets. Expression profiling of 30 osteosarcoma diagnostic biopsy samples, 15 with inferior necrosis following induction chemotherapy (Huvos I/II) and 15 with superior necrosis following induction chemotherapy (Huvos III/IV), was conducted using Affymetrix U95Av2 oligonucleotide microarrays. One hundred and four genes were found to be statistically significant and highly differentially expressed between Huvos I/II and III/IV patients. Statistically significant genes were validated on a small independent cohort comprised of osteosarcoma xenograft tumor samples. Markers of Huvos I/II response predominantly were gene products involved in extracellular matrix (ECM) microenvironment remodeling and osteoclast differentiation. A striking finding was the significant decrease in osteoprotegerin, an osteoclastogenesis inhibitory factor. Additional genes involved in osteoclastogenesis and bone resorption, which were statistically different, include annexin 2, SMAD, PLA2G2A, and TGFbeta1. ECM remodeling genes include desmoplakin, SPARCL1, biglycan, and PECAM. Gene expression of select genes involved in tumor progression, ECM remodeling, and osteoclastogenesis were validated via quantitative reverse transcription-PCR in an independent cohort. We propose that osteosarcoma tumor-driven changes in the bone microenvironment contribute to the chemotherapy-resistant phenotype and offer testable hypotheses to potentially enhance therapeutic response.
In osteosarcoma, prognostic factors at diagnosis other than clinical stage have not been clearly identified. The aim of this study was to determine whether human epidermal growth factor receptor 2 ...(HER2)/erbB-2, p-glycoprotein, or p53 expression correlated with histologic response to preoperative chemotherapy or event-free survival.
We performed a retrospective immunohistochemical study on material obtained from patients treated on the Memorial Sloan-Kettering Cancer Center T12 protocol between 1986 and 1993. Paraffin-embedded tissue was identified from 53 patients (73% of patients enrolled onto protocol) and stained for HER2/erbB-2, p53, and p-glycoprotein expression using standard monoclonal antibodies and methods.
At the time of initial biopsy, 20 (42.6%) of 47 samples demonstrated high levels of HER2/erbB-2 expression. Higher frequencies of expression were observed in samples from patients with metastatic disease at presentation and at the time of relapse. Expression of HER2/erbB-2 correlated with a significantly worse histologic response (P =.03). In patients presenting with nonmetastatic disease, expression of HER2/erbB-2 at the time of initial biopsy was associated with a significantly decreased event-free survival (47% v 79% at 5 years, P =.05). p53 and p-glycoprotein expression did not correlate with histologic response or patient event-free survival.
The correlation of HER2/erbB-2 expression with histologic response to preoperative chemotherapy and event-free survival in this study suggests that HER2/erbB-2 should be evaluated prospectively as a prognostic indicator. The correlation also suggests that clinical trials of antibodies that target this receptor, such as recombinant humanized anti-HER2 monoclonal antibody (Herceptin; Genentech, San Francisco, CA), should be considered for the treatment of osteosarcoma.
To improve the long-term event-free survival of patients with Ewing's family of tumors (EFTs) using high-dose, short-term chemotherapy.
P6 was a prospective study of previously untreated patients ...with newly diagnosed EFTs. Patients received seven cycles of chemotherapy. Cycles 1, 2, 3, and 6 consisted of cyclophosphamide 2,100 mg/m2/d on days 1 and 2, and a 72-hour continuous infusion of doxorubicin 75 mg/m2 and vincristine 2 mg/m2 starting day 1. Cycles 4, 5, and 7 consisted of 5 consecutive days of ifosfamide 1,800 mg/m2/d and etoposide 100 mg/m2/d.
Sixty-eight patients were enrolled from 1991 to 2001 (median age, 18.7 years; range, 3.7 to 39.9 years). At diagnosis, 44 patients had local-regional disease, and 24 had distant metastases. The 4-year event-free survival (EFS) rate for patients with local-regional disease is 82%; overall survival (OS) is 89%. The 4-year EFS rate for patients with distant metastases is 12%; the OS rate is 17.8%. All events occurred within 51 months of diagnosis. Four patients with distant metastases had progressive disease during therapy, and no patient with local-regional disease experienced disease progression during therapy.
Sustained EFS and OS can be achieved with intensive chemotherapy in children and young adults with local-regional EFTs. This therapy is relatively ineffective in the treatment of metastatic EFTs.
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