Effect of multimodality therapy on circulating vascular endothelial growth factor levels in patients with oesophageal cancer

BACKGROUND: Angiogenesis is critical for tumour growth and metastasis. The switch to the angiogenic phenotype depends on the net balance between positive and negative angiogenic factors released by the tumour. It was hypothesized that patients with oesophageal cancer would express raised serum levels of vascular endothelial growth factor (VEGF) which would return to normal values with neoadjuvant chemoradiotherapy. METHODS: Forty-four patients with oesophageal cancer who were selected for treatment with neoadjuvant chemoradiotherapy had blood samples taken before treatment, during chemoradiotherapy, before operation, on days 1, 3 and 5 after surgery, and 3 months after resection. Serum levels of VEGF were measured. Values were correlated with response to treatment. Controls were patients who were undergoing surgery for non-malignant conditions. RESULTS: Serum VEGF levels were raised in patients with oesophageal cancer compared with age-matched controls (mean 247 versus 1157 pg/ml; P < 0.01). VEGF levels were unaffected by neoadjuvant treatment but fell significantly on the first day after operation (652 versus 1057 pg/ml before operation; P < 0.05). No decrease occurred in control patients. VEGF levels had returned to preoperative levels by day 5. A similar postoperative rise in VEGF levels was seen in the control subjects (1194 pg/ml on day 5 versus 71 pg/ml before operation; P = 0.001). There was no correlation between VEGF level and response to treatment or tumour stage. VEGF levels had decreased significantly at 3 months following tumour resection (594 versus 1558 pg/ml on day 5; P = 0.03). CONCLUSION: VEGF levels are raised in patients with oesophageal cancer and are unaltered by neoadjuvant treatment, suggesting an additional source other than tumour cells for this proangiogenic agent.     

A processive versus a distributive mechanism of action correlates with differences in ability of normal and xeroderma pigmentosum group A endonucleases to incise damaged nucleosomal DNA

A DNA endonuclease, isolated from the nuclei of normal human and xeroderma pigmentosum complementation group A (XPA) cells, which recognizes predominately pyrimidine dimers, was examined for the mechanism by which it locates sites of damage on UVC-irradiated DNA. In reaction mixtures with low ionic strengths (i.e. lacking KCl), the normal and XPA endonuclease locate sites of UV damage on both naked and reconstituted nucleosomal DNA by different mechanisms. On both of these substrates, the normal endonuclease acts by a processive mechanism, meaning that it binds non-specifically to DNA and scans the DNA for sites of damage, whereas the XPA endonuclease acts by a distributive one, meaning that it randomly locates sites of damage on DNA. However, while both the normal and XPA endonucleases can incise UVC irradiated naked DNA, they differ in ability to incise damaged nucleosomal DNA. The normal endonuclease showed increased activity on UVC treated nucleosomal DNA compared with naked DNA, whereas the XPA endonuclease showed decreased activity on the damaged nucleosomal substrate. Since a processive mechanism of action is sensitive to the ionic strength of the micro-environment, the KCl concentration of the reaction was increased. At 70 mM KCI, the normal endonuclease switched to a distributive mechanism of action and its ability to incise damaged nucleosomal DNA also decreased. These studies show that there is a correlation between the ability of these endonucleases to act by a processive mechanism and their ability to incise damaged nucleosomal DNA; the normal endonuclease, which acts processively, can incise damaged nucleosomal DNA, whereas the XPA endonuclease, which acts distributively, is defective in ability to incise this substrate.      

A new amino acid mixture permits new approaches to the treatment of phenylketonuria

A new amino acid mixture for incorporation into medical foods for the treatment of hyperphenylalaninemia has been tested in a regular clinic. The mix is designed to be as unobtrusive as possible, consistent with good nutrition. After more than 1 year of trial as a beverage, we have shown that it is safe and well tolerated but that plasma phenylalanine is no better controlled than with some other products. The mix can be incorporated into a large number of different foods without affecting the taste. Occult monitoring of the quantity of medical foods purchased compared with the amounts reported to be consumed in diet histories provides an excellent way to monitor dietary compliance.     

Corneal topographic changes following strabismus surgery in Grave's disease.

A computerized topographic analysis system was used to evaluate corneal changes after strabismus surgery in eight eyes of five patients with Graves' disease. All patients underwent inferior rectus muscle recession; three eyes also had medial rectus recession. Corneal topographic analysis revealed that, postoperatively, corneas steepened inferiorly and inferotemporally at 1.5 mm from corneal apex (p less than 0.05). The opposite effect was observed in the superior quadrant (average flattening of 1.20 +/- 0.32 D at 1.5 mm from corneal apex, and 1.08 +/- 0.39 D at 3.0 mm from corneal apex; p less than 0.05). Superotemporally, the cornea flattened by an average of 0.65 +/- 0.26 D at 3.0 mm from corneal apex, and superonasally 0.72 +/- 0.19 D at 3.0 mm from corneal apex (p less than 0.05). Central, nasal, and temporal cornea did not show statistically significant changes. Spherical equivalent did not change significantly after surgery. The amount of restriction and upgaze measured preoperatively was correlated weakly with inferior corneal steepening (r2 = 0.44; p = 0.046). These results are indicative that corneal topography may be influenced by strabismus surgery for Graves' disease through alteration of extraocular muscle tension or intraocular pressure.     

Electroretinographic findings in macular dystrophy

The flash and pattern electroretinogram were investigated in a group of families with rare forms of inherited macular dystrophy, which included Sorsby's fundus dystrophy, X-linked retinoschisis and macular dystrophy of uncertain classification and variable expression. Flash electroretinograms, under both photopic and scotopic conditions, were attenuated in both Sorsby's fundus dystrophy and X-linked retinoschisis—with some effect on implicit time being noted in the latter condition—but in the unknown group the effect was less demonstrable, only 50% having attenuated flash electroretinograms. Pattern electroretinograms were reduced in all three conditions and in almost all cases. The study demonstrates that some so-called macular dystrophies also have widespread abnormalities affecting the peripheral retina. These findings may contribute to a better understanding of the underlying pathophysiologic mechanisms in these rare forms of retinal dysfunction.     

Lovastatin enhances in vitro radiation-induced apoptosis of rat B-cell lymphoma cells

Our previous demonstration of an antimetastatic effect of lovastatin, both in rat sarcoma and lymphoma tumor-models, as well as the fact that lovastatin and radiation are able to stop the cell cycle in different phases, suggested the feasibility of a combined treatment. We studied the effect of the in vitro combined treatment of a B-cell rat lymphoma (L-TACB) with lovastatin and irradiation. The results herein obtained provide new information about the role of statins as radiosensitizers. The antitumor effect of the combined treatment was higher than that elicited by either treatment alone. This effect could be a consequence, at least in part, of an enhanced apoptosis.