The adhesion molecule CD44v6 is associated with a high risk for local recurrence in adult soft tissue sarcomas.

In many malignant diseases the expression levels of CD44 and its splice variant v6 (CD44v6) have been associated with the prognosis. The purpose of this study was to investigate the clinical significance of CD44 in adult soft tissue sarcomas (STS). 133 STS patients with a limb or superficial trunk tumour treated at the Helsinki University Central Hospital in 1987-1993 with a median follow-up time of 68 months were included in this study. The expression of CD44 and CD44v6 was determined immunohistochemically on paraffin-embedded tumour samples. 95% of the tumours expressed CD44 and CD44v6 was detected in 57%. Strong CD44 expression was associated with low grade (P = 0.04) and small tumour size (P = 0.02). In diploid tumours the CD44 expression was correlated with low S-phase fraction (P = 0.001). High expression of both, CD44 in general as well as that of CD44v6, predicted a higher risk for local recurrence (CD44: P = 0.01 and CD44v6: P = 0.05). Low CD44v6 content of the primary tumour correlated with poor survival (P = 0.02). Determining the expression of CD44 or CD44v6 in a primary STS could be a valuable tool for selecting the group of patients who might benefit from intensified local tumour treatment.

A high proliferation rate measured by cyclin A predicts a favourable chemotherapy response in soft tissue sarcoma patients.

A small but not insignificant number of patients experience a prolonged survival after treatment of metastatic soft tissue sarcoma. This must be weighed against the majority of the patients who benefit little from the therapy, but nevertheless experience its side-effects. It would therefore be of utmost importance to be able to screen for those patients who respond to the treatment. Since proliferating cells are more sensitive to chemotherapy than non-proliferative cells, we measured the proliferation rate of the primary tumour of 55 soft tissue sarcoma patients with locally advanced or metastatic disease by determining the flow cytometric S phase fraction and immunohistochemical Ki-67 and cyclin A scores. S phase fraction or Ki-67 score did not predict chemotherapy response or progression-free survival. A high cyclin A score, however, correlated with a better chemotherapy response (P = 0.02) and longer progression-free survival time (P = 0.04). Our results suggest that a high cyclin A score predicts chemotherapy sensitivity.

Expression of cyclin A in soft tissue sarcomas correlates with tumor aggressiveness.

Cyclins and cyclin-dependent kinases regulate the cell cycle. Cyclin A has a dual role in cell proliferation. It is essential in the S phase for DNA replication, and it is also involved in G2-M-phase transition, signifying actively dividing cells. The expression of cyclin A was determined by immunohistochemistry in paraffin sections of 126 soft tissue sarcomas. The median cyclin A score was 10.8% (range, 1-54%). Cyclin A expression correlated with the S-phase fraction, Ki-67 score, G2-M phase, and grade. It did not correlate with the size of the tumor. A high cyclin A score predicted a poor metastasis-free survival (P < 0.01) and a poor disease-specific overall survival (P = 0.01). We concluded that the expression of cyclin A is a powerful prognostic factor in soft tissue sarcoma. Moreover, the cyclin A score determines the fraction of tumor cells in the S phase and the G2 phase, which are the most sensitive cell cycle phases for current modalities of cancer treatment.

Comparison of the Ki-67 score and S-phase fraction as prognostic variables in soft-tissue sarcoma.

Immunohistochemically determined Ki-67 scores and flow cytometrically determined S-phase fractions were successfully evaluated from the primary tumours of 123 patients with soft-tissue sarcoma. All patients had either limb or superficial trunk tumours. Ki-67 score correlated strongly with ploidy, S-phase fraction and grade. Ki-67 did not correlate with the size of the primary tumour. When analysed as a continuous variable, Ki-67 was a stronger predictor of both metastasis-free survival and disease-specific overall survival (P = 0.003 and 0.04 respectively) than was the S-phase fraction (P = 0.06 and 0.07 respectively). We tested the relevance of different cut-point values by dividing the whole material into two parts at every 10% (e.g. 10% of patients vs. the remaining 90%, 20% vs. 80%, etc.). We counted the relative risk and confidence interval at all these cut-off points. Ki-67 had good prognostic discriminating power irrespective of the cut-point value, but S-phase fraction lost its prognostic power at higher cut-point values. In conclusion, we found that Ki-67 is a useful prognostic tool in the treatment of soft-tissue sarcoma patients irrespective of the cut-point value. S-phase fraction can be used at lower cut-point values.

S-phase fraction of 155 soft tissue sarcomas: correlation with clinical outcome.

BACKGROUND: Traditionally, grade is considered the most important prognostic factor for soft tissue sarcomas (STS). However, because of the alleged difficulties in reproducibility of grading, new, objectively determined prognostic factors would be of value. The aim of our study was to establish if S-phase fraction (SPF) measured with flow cytometry was of prognostic significance for STS. METHODS: In this study, we included all 193 adult STS patients with superficial trunk or limb tumors who were treated by the Helsinki University Central Hospital (HUCH) STS group between January 1987 and May 1993. One hundred and seventy-two formalin fixed paraffin embedded tumor samples were available. SPF measurement was successful in 155 cases. RESULTS: Eighty-six cases were diploid. Ploidy was found to have no effect on overall survival. The median SPF was 6.8% (diploid tumors, 4% and nondiploid tumors, 12.9%). A high SPF predicted a shorter survival in patients with diploid tumors (P=0.003). The prognostic value was even stronger when we studied disease specific survival and excluded from analysis samples that contained less than 50% tumor cells (P=0.011). However, no prognostic value could be detected in nondiploid tumors or in the material as a whole. CONCLUSIONS: Our results suggest that high SPF is an adverse prognostic factor for survival of patients with diploid STS. However, further studies are needed to confirm these results.