Gary M. Spence

Vascular endothelial growth factor levels in serum and plasma following esophageal cancer resection: relationship to platelet count

In patients with cancer circulating vascular endothelial growth factor (VEGF) may be tumor-derived and have prognostic significance. Activated platelets may also be a source of VEGF, releasing it in serum formation. Debate exists as to whether serum or plasma VEGF (S-VEGF, P-VEGF) is the most appropriate surrogate marker of tumor angiogenesis. As healing wounds produce VEGF that can spill over into the circulation, we aimed to investigate the potential confounding effects of cancer surgery on both perioperative S-VEGF and P-VEGF levels and to evaluate their relationship with platelet count. S-VEGF, P-VEGF and platelet counts were measured in 23 patients undergoing esophageal cancer resection. Samples were taken preoperatively and six weeks following surgery. Seven patients were also sampled on postoperative days 1, 5 and 10. VEGF was assayed using a commercial enzyme linked immunosorbent assay. S-VEGF and P-VEGF both rose after surgery (S-VEGF; day 5: 1017 [446-1224] pg/mL and day 10: 1231 [626-2046] pg/mL versus pre-op: 329 [189-599] pg/mL. P-VEGF; day 1: 55 [46-104] pg/mL and day 10: 58 [20-154] pg/mL versus pre-op: 23 [13-46] pg/mL), falling towards preoperative levels by six weeks. Platelet count correlated with S-VEGF (rho=0.281; p<0.05, Spearmans rank) and P-VEGF (rho=0.330; p<0.01, Spearmans rank). Platelets may contribute to VEGF levels in plasma as well as in serum. The effects of surgery on S-VEGF or P-VEGF levels are mainly transient. Care must be exercised when interpreting circulating VEGF levels in the early postoperative period.

Bone marrow micrometastases in esophageal carcinoma: a 10-year follow-up study.

Detection of bone marrow micrometastases (BMMs) in patients with esophageal carcinoma may indicate a metastatic phenotype. We assessed if the presence of BMMs had adverse prognostic significance in a 10-year follow-up study. Patients undergoing surgery for esophageal cancer were prospectively recruited between February 1999 and August 2000. Bone marrow aspirates were obtained from the iliac crest of patients under general anesthesia at the time of surgery. Immunocytochemical analysis using anticytokeratin antibodies CAM 5.2 and AE1/AE3 was undertaken to determine the presence of BMMs. Union International Contre le Cancer staging was recorded for all patients. Patient follow-up was completed over a 10-year period through analysis of the Northern Ireland Cancer Registry. Forty-two patients (male = 35) were included, with a mean age of 67.2 years (range 39-83). BMMs were detected in 19 patients (45.2%). International Contre le Cancer tumor staging was stage I = 6, stage II = 10, stage III = 24, and stage IV = 2. BMMs were associated with lymphovascular invasion (P= 0.02) and advanced T stage (P= 0.02). Overall, 10-year survival was 21.4% (n= 9), with a median follow-up of 877.5 days (interquartile range 391.5-2546.3). There was no statistically significant difference between the survival of patients with or without BMMs (1451.4 vs. 1431.6 days, P= 0.99). Univariate analysis demonstrated a trend toward decreased survival for patients with positive lymph nodes (P= 0.07), an increased T stage (P= 0.06), and lymphovascular invasion (P= 0.07). Multivariate analysis demonstrated that none of the variables were significant predictors of mortality. Although the presence of BMMs correlates with recognized adverse tumor characteristics in patients with esophageal cancer, micrometastases detected in the bone marrow at time of surgery does not influence long-term survival.

Long-term follow-up of immunocytochemical analysis of vascular endothelial growth factor (VEGF), and its two receptors, VEGF-R1 (Flt-1) and VEGF-R2 (Flk-1/KDR), in oesophagogastric cancer.

Background The prognostic significance of immunocytochemical analysis of tumour vascular endothelial growth factor (VEGF) and its 2 receptors, VEGF-R1 and VEGF-R2, remains incompletely investigated in patients with oesophagogastric cancer. Methods Patients undergoing surgical resection were prospectively recruited between February 1999 and August 2000. Immunocytochemical analysis of VEGF, VEGF-R1 (Flt-1) and VEGF-R2 (Flk-1/KDR) was undertaken using validated techniques. Patients were followed up over a 10-year period using the Northern Ireland Cancer Registry. Results Sixty-one patients were recruited (male=45, 73.8%) with a median age of 66.0 years (range 39-83). Forty-seven (77.0%) adenocarcinomas and 14 (23.0%) squamous cell carcinomas were resected. UICC tumour staging was: stage I=14.7%, II=24.6%, III=54.1% and IV=6.6%. VEGF, VEGF-R1 and VEGF-R2 were over-expressed in tumour epithelial cells. VEGF-R2 expression was decreased in the presence of lymphovascular invasion and higher tumour grade. The 10-year survival rate was 19.7% (n=12) with a median follow-up of 808 (IQR 356-2313) days. On univariate analysis only lymphovascular invasion significantly predicted poor prognosis in this cohort (p=0.05). Conclusion VEGF, VEGF-R1 and VEGF-R2 were over-expressed in tumour epithelial cells. VEGF-R2 expression was decreased in the presence of more aggressive pathological variables. Larger studies are required to assess the prognostic significance of these biomarkers in oesophagogastric cancer.

Quantification of tumour and circulating vascular endothelial growth factor (VEGF) in patients with oesophagogastric cancer: a long-term follow-up study.

ABSTRACT Vascular endothelial growth factor (VEGF) is an angiogenic cytokine that regulates tumour angiogenesis. The prognostic significance of VEGF expression remains incompletely investigated for patients with oesophagogastric cancer. This study assesses the significance of tumour VEGF (T-VEGF) and circulating VEGF (C-VEGF) expression in a 10-year follow-up of patients with oesophagogastric cancer. Patients undergoing surgical resection were prospectively recruited between February 1999 and August 2000. Circulating VEGF, derived both from plasma (P-VEGF) and serum (S-VEGF), and T-VEGF were assessed using a commercial enzyme-linked immunosorbent assay (ELISA). As platelet count may contribute to C-VEGF, pre-operative platelet levels were also recorded to exclude a confounding effect. Patients were followed up over a 10-year period using the Northern Ireland Cancer Registry. Sixty-one patients were recruited (men=45) with a mean age of 65.7 years. The 10-year survival was 19.7% (n= 12) with a median follow-up of 808 days (inter-quartile range [IQR]: 349.5-2358.5). Union for International Cancer Control (UICC) tumour staging was Stage I=9 (14.8%), Stage II=15 (24.6%), Stage III=33 (54.1%) and Stage IV=4 (6.6%). The only significant relationship between clinicopathological features and the study variables was for S-VEGF, which was elevated in patients with advanced T-stage (P=0.05). Circulating VEGF did not correlate with platelet count. Although a trend towards decreased survival was observed for patients who had positive lymph nodes (P=0.08) and advanced UICC stage (P=0.09) on univariate analysis, only lymphovascular invasion significantly predicted poor prognosis in this cohort (P=0.05). Therefore, ELISA quantification of circulatory or tumour VEGF does not appear to be a significant predictor of mortality in patients with oesophagogastric cancer.