Chemokine receptor CXCR4 expression is correlated with VEGF expression and poor survival in soft‐tissue sarcoma

The expression of chemokine receptor CXCR4 has been associated with poor prognosis and VEGF expression in several kinds of human malignancy. We measured CXCR4 expression levels in soft‐tissue sarcoma and compared them with VEGF expression or microvessel density (MVD). We used real‐time quantitative PCR to examine the CXCR4 and VEGF expression levels in a total 176 tumors, including 24 intermediate tumors, 24 malignant round‐cell tumors (MRCTs) and 128 malignant non‐round‐cell tumors (MNRCTs). We also assessed their immunohistochemical expression of CXCR4 and VEGF, MVD and proliferative activities, as measured by the MIB‐1‐labeling index (LI). Furthermore, we evaluated their significance with respect to patient survival rates in MNRCTs, using the Cox regression model. Within the different types of tumor tissue, the expression levels of CXCR4 (p < 0.0001) and VEGF (p < 0.0001) in MNRCTs were significantly higher than those in intermediate tumors or MRCTs. Immunohistochemical expression levels of CXCR4 and VEGF were significantly correlated with their mRNA expression levels (p < 0.0001). Significant positive correlation was found between CXCR4 and VEGF expression in 112 primary MNRCTs (r = 0.434, p < 0.0001). Moreover, both univariate (p < 0.0001) and Cox multivariate analysis (p = 0.0001) revealed that overexpression of CXCR4 was an independent adverse prognostic factor, in addition to high stage according to the American Joint Committee on Cancer and a high MIB‐1‐LI. Determination of the CXCR4 expression level as a novel marker can provide useful prognostic information for patients and it could be a candidate for molecular targeting therapy in MNRCTs of soft‐tissue sarcomas. © 2008 Wiley‐Liss, Inc.     

Expression of nm23 protein in adult soft tissue sarcoma is correlated with histological grade

BACKGROUND: There is controversy about whether expression of nm23 is involved in suppression of metastases or contributes to tumour progression. Few studies have examined the role of nm23 in sarcomas. The aim of this study was to determine if expression of nm23 protein or its H1-subtype correlated with clinicopathological parameters in adult soft tissue sarcomas (STS). MATERIALS AND METHODS: Protein expression was examined by immunohistochemistry on paraffin-embedded sections of 46 STS patients, quantified using a colour video imaging system and correlated to histological grade. The monoclonal antibodies used were anti-nm23 (recognising both nm23-H1 and nm23-H2) and anti-nm23-H1 (recognising nm23-H1 only). RESULTS: High-grade tumours significantly overexpressed nm23 (including both nm23-H1 and nm23-H2) compared with both intermediate and low-grade tumours (ANOVA and Tukey, all p < 0.05). Multiple regression analysis confirmed the significance of the relationship and independence of the nm23 (p = 0.005), but not nm23-H1. CONCLUSION: Expression of nm23 protein, particularly nm23-H2, is an independent predictor of malignant potential of adult STS.     

Prognostic factors for survival in soft tissue sarcoma

Between 1975 and 1984, 125 cases of histologically confirmed soft tissue sarcomata (STS) were registered in the Department of Clinical Oncology in Edinburgh. Of these, 100 were eligible for analysis of prognostic factors. The overall 5-year survival rate was 21.5%. Univariate analysis demonstrated that extent of surgery, radical versus palliative or no radiotherapy, mass as a presenting symptom, metastases at presentation, site, histological type, mitotic activity, grade and UICC stage all had a statistically significant effect on survival. Analysis using the proportional hazard regression model was performed on the 87 patients for whom all variables were recorded. When all histological and clinical features and treatment modalities were included in the model then radiotherapy, surgery, necrosis, sex and mitoses were identified as independent prognostic variables. When symptoms and treatment were excluded then the multivariate analysis identified sex and mitotic activity as independent parameters. For the 33 superficial STS with tumour size recorded multivariate analysis revealed size, necrosis and cellularity as independent prognostic variables. For the 31 deep STS histological type, sex, surgery and radiotherapy were identified as independent prognostic parameters.     

Elevated expression of HABP1 is correlated with metastasis and poor survival in breast cancer patients

Hyaluronan-binding protein 1 (HABP1) is a protein with high affinity for HA, and has been reported to be upregulated in cancer cells. In this study, we show that silencing HABP1 inhibits proliferation, and suppresses the migration and invasion ability of breast cancer cell lines. In addition, silencing HABP1 remarkably slows down tumor growth in mice. We examined the correlation between HABP1 expression and clinicopathological parameters using immunohistochemistry in patients with breast cancer. The results indicate that HABP1 is overexpressed in cancer tissue, and its high levels are related to lymph node metastasis (P = 0.032) and tumor stage (P = 0.041). Moreover, high HABP1 expression is correlated with poor overall survival in breast cancer patients (P = 0.018), and is a signifi cant independent prognostic indicator. Our fi ndings suggest that HABP1 regulates proliferation and migration of breast cancer cells. HABP1 may be a useful independent predictor of outcomes in patients with breast cancer.     

Dynamic prediction of overall survival for patients with high-grade extremity soft tissue sarcoma

Purpose

There is increasing interest in personalized prediction of disease progression for soft tissue sarcoma patients. Currently, available prediction models are limited to predictions from time of surgery or diagnosis. This study updates predictions of overall survival at different times during follow-up by using the concept of dynamic prediction.

ErbB2 expression is correlated with increased survival of patients with osteosarcoma

BACKGROUND: Elevated ErbB2 expression and gene amplification have been shown to be associated with poor prognosis in many cancers. Recently, it has been demonstrated that overexpression of ErbB2 protein in osteosarcoma is associated with the presence of pulmonary metastasis and decreased survival. By contrast, a previous study showed that the expression of ErbB2 declines in individual osteosarcomas as they become metastatic. In the current study, the authors determined the relation between ErbB2 status and outcome in a large number of selected patients with high-grade osteosarcoma. METHODS: ErbB2 status was determined immunohistochemically in biopsy specimens of osteosarcoma of the extremities from 81 patients who were treated with surgery and chemotherapy. None of the patients had metastatic disease at presentation (Stage II), and all were followed-up for at least five years. The ErbB2 status was analyzed in relation to the lengths of event-free and overall survival. RESULTS: Of the 81 tumors examined, 51 (61%) demonstrated high levels of ErbB2 expression. The presence of increased levels of ErbB2 in osteosarcoma was significantly associated with the increased probability of event-free (72.2% v. 45.6% at 5 years, P = 0.03) and overall survival (79.7% v. 58.2% at 5 years, P = 0.03). Cox multivariate analysis showed that the risk of adverse events and death was increased substantially (rate ratio: 2.24 and 2.54; 95% confidence interval, 1.07-4.72 and 1.09-5.67, respectively) among patients with decreased levels of ErbB2 protein in tumor cells, as compared with patients who had increased levels of ErbB2 in tumor cells. CONCLUSIONS: In patients with high-grade osteosarcoma without metastatic disease at presentation and treated with surgery and chemotherapy, the presence of increased levels of ErbB2 in tumor cells is associated with a significantly increased probability of event-free and overall survival. Further data are needed before this marker can be used in making clinical decisions.     

MGL ligand expression is correlated to BRAF mutation and associated with poor survival of stage III colon cancer patients

Colorectal cancer (CRC) is the third most prevalent cancer type worldwide with a mortality rate of approximately 50%. Elevated cell-surface expression of truncated carbohydrate structures such as Tn antigen (GalNAcα-Ser/Thr) is frequently observed during tumor progression. We have previously demonstrated that the C-type lectin macrophage galactose-type lectin (MGL), expressed by human antigen presenting cells, can distinguish healthy tissue from CRC through its specific recognition of Tn antigen. Both MGL binding and oncogenic BRAF mutations have been implicated in establishing an immunosuppressive microenvironment. Here we aimed to evaluate whether MGL ligand expression has prognostic value and whether this was correlated to BRAF^V600E mutation status. Using a cohort of 386 colon cancer patients we demonstrate that high MGL binding to stage III tumors is associated with poor disease-free survival, independent of microsatellite instability or adjuvant chemotherapy. In vitro studies using CRC cell lines showed an association between MGL ligand expression and the presence of BRAF^V600E. Administration of specific BRAF^V600E inhibitors resulted in decreased expression of MGL-binding glycans. Moreover, a positive correlation between induction of BRAF^V600E and MGL binding to epithelial cells of the gastrointestinal tract was found in vivo using an inducible BRAF^V600E mouse model. We conclude that the BRAF^V600E mutation induces MGL ligand expression, thereby providing a direct link between oncogenic transformation and aberrant expression of immunosuppressive glycans. The strong prognostic value of MGL ligands in stage III colon cancer patients, i.e. when tumor cells disseminate to lymph nodes, further supports the putative immune evasive role of MGL ligands in metastatic disease.     

Epigenetic silencing of EphA1 expression in colorectal cancer is correlated with poor survival

Aberrant expression of Eph and ephrin proteins has well-established functions in oncogenesis and tumour progression. We describe EphA1 expression in 6 colorectal cancer (CRC) cell lines, 18 controls and 125 CRC specimens. In addition, a well-characterised cohort of 53 paired normal colon and CRCs was also assessed. Expression of EphA1 mRNA was assessed by quantitative real-time PCR and correlated with protein expression by flow cytometry, immunoprecipitation, western blotting and immunohistochemistry. Significant upregulation (2- to 10-fold) of EphA1 was seen in over 50% of cases (P=0.005) whereas many of the remainder showed downregulation of EphA1. Intriguingly, EphA1 over-expression was more prevalent in stage II compared to stage III CRCs (P=0.02). Low EphA1 expression significantly correlated with poor survival (P=0.02). Epigenetic silencing appeared to explain the loss of EphA1 expression as methylation of the EphA1 CpG island strongly correlated with low EphA1 expression (P<0.01). Furthermore, EphA1 re-expression could be induced by treatment with demethylating agents. Our findings identify EphA1 as a potential prognostic marker in CRC. Although therapies targeting high EphA1 expression seem plausible in CRC, the loss of expression in advanced disease suggests a potential risk that targeted therapy, by selecting for loss of expression, might contribute to disease progression.     

The value of C-reactive protein and comorbidity in predicting survival of patients with high grade soft tissue sarcoma

BackgroundThe aim of this study was to determine whether C-reactive protein (CRP) levels or patient’s comorbidity before treatment predicted the overall disease-specific survival and local tumour control in high grade soft tissue sarcoma patients.MethodsA total of 332 primary adult soft tissue sarcoma patients were retrospectively reviewed. CRP levels were obtained prior to treatment for all patients. The Charlson comorbidity index (CCI) was used for evaluation as a measure of comorbidity. Patients that presented with metastases at diagnosis were excluded from this study.ResultsElevated CRP levels were seen in 152 patients. CCI score varied from 0 to 4. Two-hundred and sixty-five patients had a score of 0 (no identified comorbidity), and 67 patients had a score of 1 or more. Patients with elevated CRP levels prior to initial treatment had a poorer disease-specific survival (42% at 5 years) than patients with normal CRP levels (82% at 5 years) (p < 0.0001). Patients with elevated CRP levels had a poorer local recurrence-free rate after initial treatment (75% at 5 years) than patients with normal CRP levels (89% at 5 years) (p = 0.0004). Multivariate analysis also showed the preoperative CRP level to be an independent predictor of survival and local control. Although age in patients with identified comorbidity was significantly higher than those in patients with no-identified comorbidity, CCI was not a predictive factor for either survival or local control.ConclusionPretreatment elevated CRP levels were found to be a poor prognostic factor for disease-specific survival and local control for soft tissue sarcoma patients.     

Ether à go-go potassium channel expression in soft tissue sarcoma patients

Background  

The expression of the human Eag1 potassium channel (Kv10.1) is normally restricted to the adult brain, but it has been detected in both tumour cell lines and primary tumours. Our purpose was to determine the frequency of expression of Eag1 in soft tissue sarcoma and its potential clinical implications.     

Impact of improved local control on survival in patients with soft tissue sarcoma

An estimate has been made of the gain in survival if the local failure rate for sarcoma of soft tissue was reduced to zero by the application of new treatment methods. The assumption is that the loss, due to distant metastasis and intercurrent disease among patients who achieve local control by the current treatment, would be the same among new local controls. For patients with stage M0 disease at diagnosis (all sites, all histological types), the current local failure rate is approximately 30%. By eliminating these failures, the overall survival rate would be expected to increase by 10-20 percentage points.     

Microsatellite instability and hMLH1 and hMSH2 expression analysis in soft tissue sarcomas

Alterations of the size of microsatellite DNA sequences, namely microsatellite instability (MSI), have been demonstrated in some types of malignancies. We analyzed the MSI of five microsatellite markers in 40 cases of soft tissue sarcoma (STS) using high resolution fluorescent microsatellite analysis. In addition, we examined the expression of hMLH1 and hMSH2 proteins of DNA mismatch repair (MMR) genes by immunohistochemistry, and promoter methylation of the hMLH1 gene by methylation-specific PCR (MSP). MSI was recognized in 10 of 40 STS cases (25%), which consisted of 2 MSH-high (MSI-H) tumors and 8 MSI-low (MSI-L) tumors. A loss of hMLH1 expression was recognized in 7 of 40 STS cases (18%), and loss of hMSH2 expression was recognized in 3 of 40 STS cases (8%). One case showed a loss of both hMLH1 and hMSH2 expression. Promoter hypermethylation of the hMLH1 gene was detected in only 3 of 40 STS cases (8%). Of 10 cases with MSI, 5 (50%) showed a loss of hMLH1 and/or hMSH2 expression. There was a statistically significant correlation between MSI-positive tumors and the loss of hMLH1 and/or hMSH2 expression (p=0.0286). Although the frequency of MSI (25%) or a loss of hMLH1 and/or hMSH2 expression (23%) was relatively low in STS cases, a loss of hMLH1 and/or hMSH2 was recognized in 5 out of 10 MSI-positive cases (50%). These findings suggest that the inactivation of MMR gene expression might be the cause of MSI in STS cases.     

Five-year survival after pulmonary metastasectomy for adult soft tissue sarcoma.

Determinants of 5-year survival were evaluated after complete resection of pulmonary metastases from adult soft-tissue sarcomas. Fifty-eight patients had complete resection (median survival 25 months, P = 0.0002), with a 25.8% absolute 5-year survival (15 of 58 patients); six patients had unresectable disease (median survival 6 months) and were excluded from additional analysis. Eleven patients remain disease free, with a median follow-up of 76 months. Significant independent prognostic indicators associated with improved survival (P less than 0.05) included metastasis doubling time of 40 days or greater (median survival 37 months versus 15 months if less than 40 days); unilateral disease on preoperative radiography (33 months versus 15 months if bilateral disease); three or fewer nodules on preoperative computed tomography (40 months versus 14 months if 4 or more nodules); two nodules or fewer resected (40 months versus 17 months if 3 or more nodules resected), and tumor histology (33 months for malignant fibrous histiocytoma versus 17 months for all others). Multivariate analysis identified the number of nodules detected by computed tomography preoperatively as having significant prognostic value.     

Failure patterns and survival in pediatric soft tissue sarcoma

We retrospectively analyzed 44 patients with localized soft tissue sarcomas who were seen and treated at the JCRT, DFCI, and TCH between 1970-1984. Patients with rhabdomyosarcoma were excluded. Primary tumors were located in the following sites: extremities 19 (43%), head and neck 9 (20%), and trunk 16 (37%). Median follow-up for survivors was 7.7 years (range 24 mo-16 years). Surgery was the initial aspect of treatment for all patients. All patients also received post-operative irradiation, 43 at presentation and one at local relapse, and 26 received adjuvant chemotherapy. Radiation was delivered to a dose of 4000 cGy (median) followed by a boost to a median dose of 5760 cGy (range 4500-7000 cGy). Actuarial 5- and 10-year disease-free survivals (DFS) were 70% and 59% while the actuarial 5- and 10-year overall survivals (OS) were both 75%. All parameters were assessed for significance by univariate analysis. OS was significantly affected by presenting stage when analyzed according to both the Intergroup Rhabdomyosarcoma Staging System (IRS) and the American Joint Committee on Cancer system (AJCC). For the IRS, OS at 10 years was 100% for Stage I, 72% for Stage II, and 54% for Stage III (p = 0.04). For the AJCC, OS at 10 years was 100% for Stage I and 65% for Stage II and III (p = 0.05). Primary site, histology, and use of adjuvant chemotherapy did not influence OS or DFS. Fourteen patients failed: 8 local, 1 distant, and 5 combined local and distant. There was no LF among the 9 pts. with primary lesions less than 5 cm compared to 11/29 (39%) whose tumor was greater than 5 cm (p = 0.04). Pts. with gross residual disease had a local DFS of 42%, but those with no residual or microscopic residual had a local DFS of 71% (p = 0.02). In conclusion, childhood STS has an excellent OS (75% at 10 years). Tumor size and residual tumor after surgery strongly predicted for local failure. Of interest, the pattern of failure is predominantly local in our series. This suggests that more aggressive local treatment is indicated in management of children with STS. Higher doses of irradiation as used for adult STS are probably indicated for patients with gross residual disease.     

VEGF-C expression is associated with the poor survival in gastric cancer tissue

Vascular endothelial growth factor-C (VEGF-C) is considered as a prime mediator of lymphangiogenesis and has been implicated in carcinogenesis and metastasis. Various studies examined the relationship between VEGF-C overexpression and the clinical outcome in patients with gastric cancer, but yielded conflicting results. Electronic databases updated to July 2013 were searched to find relevant studies. A meta-analysis was conducted with eligible studies which quantitatively evaluated the relationship between VEGF-C overexpression and survival of patients with gastric cancer. Survival data were aggregated and quantitatively analyzed. We performed a meta-analysis of 13 studies that evaluated the correlation between VEGF-C overexpression and survival in patients with gastric cancer. Combined hazard ratios suggested that VEGF-C overexpression had an unfavorable impact on overall survival (OS) (hazard ratio (HR)?=?1.38, 95 % confidence interval (CI)?=?1.08–1.68), but not disease-free survival (DFS) (HR?=?1.25, 95 % CI?=?0.89–1.62) in patients with gastric cancer. No significant heterogeneity (P?=?0.132) was observed among 11 studies for OS and among 5 studies for DFS (P?=?0.105). VEGF-C overexpression indicates a poor prognosis for overall survival, but not disease-free survival in patients with gastric cancer.