Rb-loss is associated with high malignancy in chondrosarcoma

Loss of function of the human retinoblastoma gene (Rb) is a frequent genetic abnormality in human malignancies and causes a disturbance in the cell cycle and loss of normal proliferation and differentiation. We studied the loss of heterozygosity (LOH) of the Rb gene in 31 formalin-fixed, paraffin-embedded cartilaginous tumors using polymerase chain reaction. The tumors were subdivided into 8 cases of dedifferentiated (DD) chondrosarcoma, 17 cases of conventional chondrosarcoma (nine grade 1, seven grade 2 and one grade 3), 4 enchondromas and 2 chondroblastomas. Both components of DD chondrosarcoma, the low-grade and anaplastic components, were separated by a microdissection approach. The genetic data were correlated with the expression of the Rb protein examined by Rb immunohistochemistry. We found Rb-LOH in one grade 3 chondrosarcoma, and in the anaplastic component in 7 of 8 cases of DD chondrosarcoma (89% of all high-grade chondrosarcomas). All tumors with Rb-LOH were immunohistochemically Rb-negative. The only case of DD chondrosarcoma negative for Rb-LOH in both components of the tumor also showed weak expression of the Rb protein in the anaplastic component. All benign cartilaginous tumors, low-grade chondrosarcomas and low-grade tumor components of DD chondrosarcomas were negative regarding Rb-LOH but positive in Rb immunohistostaining. We concluded that Rb-LOH predominantly occurs in high-grade chondrosarcomas. However, it is not a marker for identifying low-grade tumors with a tendency towards progression or local recurrence.     

Endogenous secretory receptor for advanced glycation endproducts as a novel prognostic marker in chondrosarcoma

BACKGROUND: Chondrosarcoma, the second most frequent primary malignant bone tumor, is classified into 3 grades according to histologic criteria of malignancy. However, a low-grade lesion can be difficult to distinguish from a benign enchondroma, whereas some histologically low-grade lesions may carry a poor prognosis. The receptor for advanced glycation endproducts (RAGE) and its ligand, high-mobility group box-1 (HMGB1), was quantified in enchondromas and chondrosarcomas to determine whether these markers were associated with histological malignancy and prognosis. METHODS: Enchondromas (n = 20) and typical chondrosarcomas (n = 39) were evaluated for RAGE, endogenous secretory RAGE (esRAGE, a splice variant form), and HMGB1 protein expression by immunohistochemistry including laser confocal microscopy. The content of esRAGE in resected specimens was measured with an enzyme-linked immunosorbent assay. Associations of these molecules with histology and clinical behavior of tumors were analyzed. RESULTS: Expression of esRAGE and HMGB1 was observed in all specimens. The numbers of cells positive for esRAGE and HMGB1 expression were positively associated with histologic grade. Expression of esRAGE was significantly higher in chondrosarcomas than in enchondromas (P < .001). Tissue esRAGE content was also significantly higher in grade 1 and 2 chondrosarcomas than enchondromas (P = .0255 and P = .008, respectively). High expression of esRAGE in grade 1 chondrosarcoma was associated with subsequent recurrence (P = .0013), lung metastasis (P = .0071), and poor survival (P < .001). CONCLUSIONS: Assessment of esRAGE expression should aid in diagnostic and prognostic determinations in chondrosarcoma.     

Expression of connective tissue growth factor in cartilaginous tumors

BACKGROUND: Connective tissue growth factor (CTGF) predominantly is expressed in hypertrophic chondrocytes and its specific receptors are demonstrated on chondrocytic cells. Therefore, CTGF may be involved in the proliferation and/or differentiation of cartilage cells. In the current study, CTGF expression was examined both in chondrosarcoma and enchondroma to clarify the relation between the expression of CTGF and the grade of malignancy. METHODS: The expression of CTGF and proliferating cell nuclear antigen (PCNA) were analyzed immunohistochemically in 34 cartilaginous tumor specimens. Eighteen tumors were determined to be chondrosarcoma including 8 Grade 1 tumors, 6 Grade 2 tumors, and 4 Grade 3 tumors. The percentage of CTGF positive and PCNA positive cells was quantified using at least 500 cells. RESULTS: CTGF was expressed in 70.1% of enchondroma cells, 84.0% of Grade 1 chondrosarcoma cells, 53.7% of Grade 2 tumor cells, and 26.8% of Grade 3 tumor cells (rho = -0.501; P = 0.0053). In chondrosarcoma cases, CTGF expression was correlated closely with tumor grade (rho = -0.920; P = 0.0001). There was a strong correlation between PCNA expression and tumor grade (rho = 0.907; P < 0.0001) and a strong negative correlation between CTGF and PCNA expression (rho = -0.493; P = 0.0061). In chondrosarcoma cases, patients with high expression of CTGF (>/= 30%) showed higher overall survival compared with those with low expression (< 30%) (P = 0.004). CONCLUSIONS: The current study revealed a correlation between the histologic grade of chondrosarcoma and prognosis, and the concomitant association between CTGF immunostaining and tumor grade and prognosis. Therefore, immunohistochemical staining with CTGF is a useful procedure for assessing the tumor grade and clinical course in patients with chondrosarcoma.     

Sox9 在人普通型与去分化型软骨肉瘤差异表达*

目的:探讨Sox9 在人普通软骨肉瘤,去分化软骨肉瘤和正常软骨中的表达。方法:取12例2003年1 月至2007年1 月在北京大学人民医院经病理切片确诊为软骨肉瘤（普通软骨肉瘤6 例,去分化软骨肉瘤6 例）及正常软骨组织（6 例）的新鲜冰冻标本,利用基因芯片的方法分析后,将Sox9 作为候选基因,而后利用Real-time PCR,Western blot和免疫组化的方法比较其在人普通软骨肉瘤,去分化软骨肉瘤和正常软骨组织中的差异表达。结果:基因芯片结果显示:与正常软骨组织相比,Sox9 在普通软骨肉瘤中上调约1.6 倍,在去分化软骨肉瘤中,其表达水平为正常软骨组织表达水平的0.082 倍;Real-time PCR检测结果显示:Sox9mRNA 在普通软骨肉瘤和去分化软骨肉瘤中表达水平分别为1.68± 0.119 和0.088 ± 0.017;Western blot分析表明Sox9 蛋白在人普通软骨肉瘤的表达量明显高于正常软骨组织,在去分化软骨肉瘤中的表达量显著低于正常软骨组织。免疫组化实验结果表明与正常软骨组织相比,6 例普通软骨肉瘤均有Sox9 表达,细胞染色呈较强的阳性,而去分化软骨肉瘤未发现较强阳性细胞出现,只有可疑的阳性细胞散在出现。结论:Sox9 在普通软骨肉瘤中的表达水平明显高于正常软骨组织,在去分化软骨肉瘤中的表达水平显著低于正常软骨组织。Sox9 在去分化软骨肉瘤中低水平表达与去分化软骨肉瘤疾病进展快,预后差呈正向相关。      

p53 expression in dedifferentiated chondrosarcoma

Background. p53 acts as a tumor suppressor gene because of to its negative control of the cell cycle and its central role in programmed cell death. It frequently is mutated, as observed in a variety of human neoplasms. The mutations inhibit tumor-suppressor activities of p53, which may gain a new function of tumor promotion. In this study, p53 was investigated in various components of dedifferentiated chondrosarcoma and correlated with their proliferative activities. Methods. Immunohistochemical assays for p53, Ki-67, and proliferating cell nuclear antigen (PCNA) were used in a series of eight dedifferentiated chondrosarcomas of bone. The cartilaginous component was low grade (Grade I-II) in five cases. It was predominantly low grade with foci of a high grade (Grade III) chondrosarcoma in the remaining three cases. The noncartilaginous (de-differentiated) high grade component consisted of malignant fibrous histiocytoma in five cases and osteosarcoma in three. Results. Regardless of the histological type, diffuse strong nuclear staining for p53 occurred in the high grade noncartilaginous component of all eight of the tumors. The low grade cartilaginous component of six cases was negative for p53, with focal weak staining in the two remaining cases. The high grade cartilaginous component showed strong positive staining for this protein in all three cases. Ki-67 and PCNA expression were similar to that of p53. Conclusions. The percentage of p53 positive staining roughly was parallel to the proliferating fraction of cells in various components of dedifferentiated chondrosarcoma. Moreover, p53 overexpression was consistently present in the high grade noncartilaginous (dedifferentiated) component of the tumor and was accompanied by increased proliferative activity. Cancer 1995; 76:223-7.     

Chondrosarcoma with dedifferentiated foci. A comparative and ultrastructural study.

The light and electron microscopic features of a well-differentiated chondrosarcoma with dedifferentiated foci (CDF) are compared with those of a poorly differentiated chondrosarcoma with spindle cell elements. The differentiation of this lesion from mesenchymal chondrosarcoma and from primitive multipotential primary sarcoma of bone is discussed. Ultrastructurally, the cells of the cartilaginous region of the CDF resembled those of the poorly differentiated chondrosarcoma and of the cartilaginous zones of an extraskeletal mesenchymal chondrosarcoma reported by Fu and Kay, and were characterised by an abundance of dilated endoplasmic reticulum and a scalloped and microvillous cell membrane. The stroma was devoid of mature crossbanded collagen fibers. The dedifferentiated portion was composed of mesenchymal-type cells surrounded by a relatively sparse matrix containing scanty mature collagen fibers; these cells resembled those in the cellular regions of the two previously documented mesenchymal chondrosarcomas but differed from the cartilaginous type cells in the cellular regions of the poorly differentiated chondrosarcoma.     

Prognostic significance of Ki67 (MIB1) proliferation index and p53 over-expression in chondrosarcomas

To investigate the prognostic significance of the Ki67 (MIB1)-proliferation index and p53 over-expression in chondrosarcomas, we retrospectively analyzed a cohort of 29 patients with chondrosarcomas using immunohistochemical assays with MIB1 and p53 monoclonal antibodies on formalin-fixed, paraffin-embedded tissue samples with microwave preparation. We also assessed 19 patients with benign cartilaginous tumors as a control group. There was a significant positive correlation between MIB1 index and tumor grade in chondrosarcomas, while there was no significant difference in the MIB1 index between the grade-I chondrosarcomas and the benign cartilaginous tumors. Patients categorized in the high-MIB1-index group had a significantly lower survival rate than those in the low-index group. Moreover, in analyzing the sub-set of the patients with grade-II chondrosarcomas, it was found that they could be prognostically sub-divided according to MIB1 index. The p53 index also significantly correlated with patient survival, and there was significant correlation between the MIB1 index and the p53 index. However, in multivariate analysis, only the MIB1 index and tumor grade proved to be independent prognostic indicators of chondrosarcomas. These results demonstrate that the MIB1 index can be a useful procedure for assessing tumor grade in chondrosarcomas, especially for determining the prognosis of patients with grade-II chondrosarcoma. © 1996 Wiley-Liss, Inc.     

Prognostic relevance of gene amplifications and coamplifications in breast cancer

Multiple different oncogenes have been described previously to be amplified in breast cancer including HER2, EGFR, MYC, CCND1, and MDM2. Gene amplification results in oncogene overexpression but may also serve as an indicator of genomic instability. As such, presence of one or several gene amplifications may have prognostic significance. To assess the prognostic importance of amplifications and coamplifications of HER2, EGFR, MYC, CCND1, and MDM2 in breast cancer, we analyzed a breast cancer tissue microarray containing samples from 2197 cancers with follow-up information. Fluorescence in situ hybridizations revealed amplifications of CCND1 in 20.1%, HER2 in 17.3%, MDM2 in 5.7%, MYC in 5.3%, and EGFR in 0.8% of the tumors. All gene amplifications were significantly associated with high grade. HER2 (P < 0.001) and MYC amplification (P < 0.001) were also linked to shortened survival. In case of HER2, this was independent of grade, pT, and pN categories. MYC amplification was almost 3 times more frequent in medullary cancer (15.9%), than in the histologic subtype with the second highest frequency (ductal; 5.6%; P = 0.0046). HER2 and MYC amplification were associated with estrogen receptor/progesterone receptor negativity (P < 0.001) whereas CCND1 amplification was linked to estrogen receptor/progesterone receptor positivity (P < 0.001). Coamplifications were more prevalent than expected based on the individual frequencies. Coamplifications of one or several other oncogenes occurred in 29.6% of CCND1, 43% of HER2, 55.7% of MDM2, 65% of MYC, and 72.8% of EGFR-amplified cancers. HER2/MYC-coamplified cancers had a worse prognosis than tumors with only one of these amplifications. Furthermore, a gradual decrease of survival was observed with increasing number of amplifications. In conclusion, these data support a major prognostic impact of genomic instability as determined by a broad gene amplification survey in breast cancer.     

Advanced chondrosarcomas: role of chemotherapy and survival

BackgroundThere are limited data about the role of chemotherapy in patients withadvanced chondrosarcomas.MethodsThe medical charts of 180 patients with advanced chondrosarcomas having received chemotherapy in 15 participating institutions between 1988 and 2011 were reviewed.ResultsMedian age was 52 years. Sixty-three percent of patients had conventional chondrosarcoma and 88% had metastatic disease. Combination chemotherapy was delivered in 98 cases (54.5%). One hundred and thirty-one patients (73%) received an anthracycline-containing regimen. Using RECIST, the objective response rate was significantly different according to histological subtype, being 31% for mesenchymal chondrosarcoma, 20.5% for dedifferentiated chondrosarcoma, 11.5% for conventional chondrosarcoma and 0% for clear-cell chondrosarcoma (P = 0.04). Median progression-free survival (PFS) was 4.7 months [95% confidence interval (CI) 3–6.5]. Performance status (PS) ≥2, number of metastatic sites ≥1 and single-agent regimen were independently associated with poor PFS. Median overall survival (OS) was 18 months (95% CI 14.5–21.6). PS, number of metastatic sites and palliative surgery were independently associated with OS.ConclusionsConventional chemotherapy have very limited efficacy in patients with advanced chondrosarcoma, the highest benefit being observed in mesenchymal and dedifferentiated chondrosarcoma. These data should be used as a reference for response and outcome in the assessment of investigational drugs in advanced chondrosarcoma.     

Chondrosarcoma of the scapula: long-term oncologic outcome

BACKGROUND: Chondrosarcoma is the second most common primary sarcoma of bone. It often develops within flat bones, such as the pelvis, ribs, and scapula. In the current study, the authors reviewed the surgical experience and long-term oncologic outcomes of patients with chondrosarcoma arising in the scapula. METHODS: The medical records of 29 consecutive patients with chondrosarcoma of the scapula were reviewed. The patients were treated between 1954 and 1994. All patients had localized disease at the time of presentation. The tumors were classified histologically as Grade 1 (10 patients), Grade 2 (10 patients), Grade 3 (7 patients), dedifferentiated (1 patient), and mesenchymal (1 patient) (using the criteria of Evans et al.). The mean maximal dimension of the tumors was 11 cm. Twenty-five patients underwent limb-sparing surgical resection and 4 patients underwent forequarter amputations. The median follow-up was 13 years (range, 1-35 years). RESULTS: At last follow-up, 22 patients (76%) were free of disease and 7 patients (24%) had died of their disease. Local recurrence occurred in 4 patients at 7 months, 16 months, 40 months, and 43 months, respectively. The local recurrence-free survival rate was 86% at 5 years, 10 years, and 20 years. Disease-specific survival was 83% at 5 years, 74% at 10 years, and 74% at 20 years. Patients who had low-grade chondrosarcomas had better survival compared with patients who had high-grade chondrosarcomas (P = 0.07). CONCLUSIONS: Patients who had localized chondrosarcoma of the scapula had a favorable long-term outcome, most likely due to the unique anatomic features that improved the likelihood of achieving wide surgical margins with limb-sparing surgery, despite the frequent presentation of locally advanced disease.     

Dedifferentiated peripheral chondrosarcomas. A report of seven cases

Peripheral dedifferentiated chondrosarcoma (CS) is an exceedingly rare variant of the highly malignant entity of dedifferentiated chondrosarcoma. Only five such cases have previously been reported. Seven cases are analyzed and evaluated for the presentation and natural history of this highly malignant lesion when it arises in a tumor that was previously an osteochondroma. Both peripheral and central dedifferentiated chondrosarcomas are high-grade malignant lesions and require wide or radical surgical margins for adequate treatment. Despite adequate resection, survival is poor; five of the seven cases presented herein died of metastatic spread of their disease. These cases of the peripheral variant of dedifferentiated chondrosarcoma occurred in patients who were younger than patients with central dedifferentiated chondrosarcomas and may be present with longer duration of symptoms because they occur in previously long-standing benign osteochondromas. As such, they may be easily overlooked clinically and radiographically. Therefore, careful histologic analysis of all cartilage lesions arising on the surface of bone is essential to prevent overlooking foci of high-grade sarcomatous dedifferentiation.     

Update on chondrosarcomas

PURPOSE OF REVIEW: This paper reviews recent molecular, biologic, developmental therapeutic, and clinical findings in conventional and variant chondrosarcomas. RECENT FINDINGS: The prognosis of chondrosarcomas traditionally correlates with histologic grade and adequacy of surgery. Newer markers of cell differentiation, activation, genetics, and cell signaling may offer important prognostic information. Translational research has validated platelet-derived growth factor receptor, estrogen signaling, matrix metalloproteinase-1, histone deacetylase, methylthioadenosine phosphorylase, and vascular endothelial growth factor-A as potential therapeutic targets. Bisphosphonates may also possess important antitumoral effects. Molecular studies have established that extraskeletal myxoid chondrosarcoma is a unique entity defined by the presence of a fusion gene between the orphan nuclear receptor, CHN/NOR1, and a promiscuous partner, most commonly EWSR1. Clinical studies have shown that development of second malignancies is an uncommon but real risk for chondrosarcoma survivors; the benefit of chemotherapy for dedifferentiated chondrosarcomas remains questionable; and late recurrences of clear cell chondrosarcomas emphasize the need for long-term follow up. SUMMARY: Chondrosarcomas are a heterogeneous group of bone and soft tissue tumors. Recent advances in molecular diagnostics, pathobiology, and developmental therapeutics will aid both scientists and clinicians in improving the classification and therapy of this diverse family of cartilaginous tumors.     

Do pathological fractures influence survival and local recurrence rate in bony sarcomas?

The influence of pathological fracture on surgical management, local recurrence and survival was established in patients with high grade, localised, extremity osteosarcoma (n=484), chondrosarcoma (n=130) and Ewing's sarcoma (n=156). Limb salvage was possible in 79% of patients with a fracture compared to 84% of patients without a fracture (p=0.17). No difference in local recurrence was found between fracture and control groups. In univariate analysis, survival in the fracture group was lower than in the control group for osteosarcoma (34% versus 58%, p<0.01) and chondrosarcoma (35% versus 63%, p=0.04), but not for Ewing's sarcoma (75% versus 64%, p=0.80). In multivariate analysis, fracture remained a significant predictor of survival for osteosarcoma, but not for chondrosarcoma, where dedifferentiated subtype appeared to be decisive. Pathological fracture independently predicts worse survival in osteosarcoma, but not chondrosarcoma and Ewing's sarcoma. Limb saving surgery seems safe, if adequate resection margins are achieved.     

Recurrent gains of 1q, 8 and 12 in the Ewing family of tumours by comparative genomic hybridization.

Comparative genomic hybridization (CGH) was used to detect copy number changes of DNA sequences in the Ewing family of tumours (ET). We analysed 20 samples from 17 patients. Fifteen tumours (75%) showed copy number changes. Gains of DNA sequences were much more frequent than losses, the majority of the gains affecting whole chromosomes or whole chromosome arms. Recurrent findings included copy number increases for chromosomes 8 (seven out of 20 samples; 35%), 1q (five samples; 25%) and 12 (five samples; 25%). The minimal common regions of these gains were the whole chromosomes 8 and 12, and 1q21-22. High-level amplifications affected 8q13-24, 1q and 1q21-22, each once. Southern blot analysis of the specimen with high-level amplification at 1q21-22 showed an amplification of FLG and SPRR3, both mapped to this region. All cases with a gain of chromosome 12 simultaneously showed a gain of chromosome 8. Comparison of CGH findings with cytogenetic analysis of the same tumours and previous cytogenetic reports of ET showed, in general, concordant results. In conclusion, our findings confirm that secondary changes, which may have prognostic significance in ET, are trisomy 8, trisomy 12 and a gain of DNA sequences in 1q.     

Amplification of the MYC Gene in Osteosarcoma Secondary to Paget's Disease of Bone

Purpose. In a previous series of 25 human osteosarcoma samples studied for MYC gene amplification, we found amplification in two cases (8%), including one arising in association with Paget's disease (pagetic osteosarcoma). Based on this observation, we further investigated the prevalence of MYC gene amplification in pagetic osteosarcomas.Methods. MYC gene amplification was assessed by Southern blot analysis using frozen tissue samples in five cases of pagetic osteosarcoma and 53 cases of primary (non-pagetic) osteosarcoma. Amplification was considered present if the MYC copy number was six or greater.Results. Three out of five patients (60%) with pagetic osteosarcoma showed MYC gene amplification, whereas it was present in only 5/53 patients (9.4%) with primary osteosarcoma. The incidence of MYC amplification in pagetic osteosarcoma was thus significantly higher than that in primary osteosarcoma (p = 0.016).Discussion. The finding that MYC gene amplification may be more common in pagetic than primary osteosarcoma warrants further study and suggests pathogenetic differences between primary osteosarcomas and those arising in the setting of Paget's disease. Three of the four pagetic osteosarcomas from the present study were previously shown to be immunoreactive for p53, suggesting that p53 mutation may also be a frequent genetic lesion in these tumors.     

去分化软骨肉瘤的诊断及治疗进展*

去分化软骨肉瘤（DDCS）约占所有软骨肉瘤的10% ,预后极差,5 年生存率不到10% 。好发于股骨、肱骨和骨盆。DDCS是软骨肉瘤中的一个独特类型。典型的特点是分化良好的软骨样成分和高度恶性的间充质细胞来源的肉瘤成分并存、毗邻。DDCS的诊断非常复杂,需要详细的影像学和病理学检查及准确的活检。DDCS去分化成分可以是骨肉瘤、恶性纤维组织细胞瘤,甚至是任何级别的未分化肉瘤成分。约1/3 的X 光片,1/3 的MR,一多半的CT扫描,DDCS表现为典型的“双态”征。最近利用微阵列- 比较基因组杂交技术,发现反复发生的5q14.2~q21.3,6q16~q25.3,9p24.2~q12和9p21.3。染色体缺失更多见于高度恶性的软骨肉瘤（3 级和DDCS）,该差异具有统计学意义。9 号染色体的缺失是DDCS最常见的染色体缺失。早期研究发现DDCS的去分化成分有p53和p53杂合性的丢失现象,进一步研究发现同时伴随Rb基因杂合性的丢失。DDCS的两种成分可出现p16INK 4,FHIT和E-cadherin（上皮型钙黏附蛋白）甲基化的异常。手术切除包括合适足够的外科切缘或根治性的切除,是目前DDCS最主要的治疗手段。化疗效果目前仍然不确定。最近针对软骨肉瘤（包括DDCS）发现了一些新的药物靶标,有些已经进入临床Ⅱ期试验阶段,其中包括Apomab、Perifosine （哌立福新）、Dasatinib（达沙替尼）和多烯紫杉醇联合吉西他滨的联合化疗。同时几个Ⅰ期药物临床试验报告针对DDCS新的有效药物,如组蛋白去乙酰酶抑制剂和血管内皮生长因子反义寡合甘酸。DDCS患者预后极差,预后主要由DDCS中的去分化成分决定。因此,早期诊断、早手术对改善患者的预后非常关键。      

MYC is amplified in BRCA1-associated breast cancers.

PURPOSE: Germ-line mutations in the BRCA1 tumor suppressor gene predispose to early onset breast cancers with a distinct phenotype characterized by high tumor grade, aneuploidy, high proliferation rate, and estrogen receptor-negativity. The molecular mechanisms and cooperative oncogenes contributing to multistep tumor progression in cells lacking BRCA1 are not well defined. To examine whether C-MYC (MYC), a transforming oncogene associated with genetic instability, contributes to multistep tumor progression in BRCA1-associated breast cancer, we have analyzed tumors from women with hereditary BRCA1-mutated and sporadic breast cancers. EXPERIMENTAL DESIGN: We performed fluorescence in situ hybridization using a MYC:CEP8 assay on formalin-fixed paraffin-embedded tumor tissues from 40 women with known deleterious germ-line BRCA1 mutations and 62 sporadic cases, including 20 cases with hypermethylation of the BRCA1 gene promoter. RESULTS: We observed a MYC:CEP8 amplification ratio >/=2 in 21 of 40 (53%) BRCA1-mutated tumors compared with 14 of 62 (23%) sporadic tumors (P = 0.003). Of the 14 sporadic cases with MYC amplification, 8 (57%) were BRCA1-methylated. In total, MYC amplification was found in a significantly higher proportion of tumors with BRCA1 dysfunction (29 of 60, 48% versus 6 of 42, 14%; P = 0.0003). In a multivariable regression model controlling for age, tumor size, and estrogen receptor status, BRCA1-mutated tumors demonstrated significantly greater mean MYC:CEP8 ratio than sporadic tumors (P = 0.02). CONCLUSIONS: Our data indicate that MYC oncogene amplification contributes to tumor progression in BRCA1-associated breast cancers. Thus, we conclude that the aggressive histopathological features of BRCA1-associated tumors are in part due to dysregulated MYC activity.     

Breast cancer in young women (< or = 35 years): Genomic aberrations detected by comparative genomic hybridization

Sporadic breast cancer in young women is different from the one in older patients regarding pathological features and aggressiveness of the tumors, but the spectrum of genetic alterations are largely unknown. We used comparative genomic hybridization (CGH) to analyze DNA copy number changes in 88 tumor samples from women 相似文献   

Prognostic factors and outcome of pelvic, sacral, and spinal chondrosarcomas: a center-based study of 69 cases

BACKGROUND: The surgical treatment of chondrosarcoma of the pelvis, sacrum, and spine is complex and technically demanding. As such, adequate surgical margins have been difficult to achieve, resulting in poor local control and survival. The objective of this study was to assess the outcome of patients with chondrosarcomas in these sites who were treated at a tumor center by using modern, aggressive surgical techniques and to identify prognostic factors. METHODS: Sixty-nine consecutive patients with chondrosarcoma of the pelvis (46 cases), sacrum (11 cases), and mobile spine (12 cases) who were treated at Sahlgrenska University Hospital from 1967 to 1999 were included in this study. Demographic information and follow-up data were obtained and statistically analyzed. RESULTS: There were 53 men and 16 women with a mean age of 45 years and a mean tumor size of 12 cm. There were 61 conventional chondrosarcomas, Grades 1-3 (with 13 arising in a preexisting osteochondroma) and 8 Grade 4 chondrosarcomas (7 dedifferentiated and one mesenchymal). The overall local recurrence rate was 27%, and the estimated overall 5- and 10-year survival rates were 72% and 67%, respectively. In contrast, the observed local recurrence rate was 3% (1 patient) in 31 patients whose conventional chondrosarcomas were resected with adequate surgical margins; 90% of these patients survived and most of them (26 of 31 or 84%) were continuously disease free. Significant factors associated with a worse prognosis with respect to local control and/or survival were high histologic tumor grade, increasing patient age, primary surgery outside of a tumor center, incisional biopsy versus a noninvasive diagnostic procedure, and inadequate surgical margins. CONCLUSIONS: Center-based diagnosis and treatment using modern aggressive surgical techniques significantly improve the prognosis of patients with chondrosarcoma of the pelvis, sacrum, and spine.