Dimitris Kardamakis

X-rays modulate extracellular matrix in vivo

X‐rays have an antiangiogenic effect in the chicken embryo chorioallantoic membrane (CAM) model of in vivo angiogenesis. Our study demonstrates that X‐rays induce an early apoptosis of CAM cells, modulate the synthesis and deposition of extracellular matrix (ECM) proteins involved in regulating angiogenesis and affect angiogenesis induced by tumour cells implanted onto the CAM. Apoptosis was evident within 1–2 hr, but not later than 6 hr after irradiation. Fibronectin, laminin, collagen type I, integrin αvβ3 and MMP‐2 protein amounts were all decreased 6 hr after irradiation. In contrast, collagen type IV, which is restricted to basement membrane, was not affected by irradiation of the CAM. There was a similar decrease of gene expression for fibronectin, laminin, collagen type I and MMP‐2, 6 hr after irradiation. The levels of mRNA for integrin αvβ3 and collagen type IV were unaffected up to 24 hr after irradiation. The decrease in both protein and mRNA levels was reversed at later time points and 48 hr after irradiation, there was a significant increase in the expression of all the genes studied. When C6 glioma tumour cells were implanted on irradiated CAMs, there was a significant increase in the angiogenesis induced by tumour cells, compared to that in non‐irradiated CAMs. Therefore, although X‐rays have an initial inhibitory effect on angiogenesis, their action on the ECM enhances new vessel formation induced by glioma cells implanted on the tissue.

Irradiated C6 glioma cells induce angiogenesis in vivo and activate endothelial cells in vitro

Malignant gliomas are angiogenesis dependent and present a remarkable degree of resistance to radiotherapy. In the present work, we studied the effect of irradiation of C6 glioma cells on their proliferation and activation in vitro and on glioma cell‐induced angiogenesis in vivo and in vitro. Irradiation of C6 glioma cells decreased cell proliferation in a dose‐dependent manner. Interestingly, metalloproteinase‐2 and ‐9 expression and secretion, as well as integrin αv expression, increased with elevated doses of X rays 48 hr after irradiation and was mostly evident at the higher doses used. When pre‐irradiated C6 cells were implanted on nonirradiated chicken embryo chorioallantoic membranes (CAMs), there was a significant dose‐dependent increase in tumor induced angiogenesis, compared to angiogenesis induced by nonirradiated cells. Similar results were obtained when C6 cells were irradiated 48 hr after their inocculation onto nonirradiated CAMs. In the same line, conditioned medium from irradiated C6 cells significantly increased endothelial cell proliferation and migration in vitro, in a manner dependent on the dose of X rays. These results explain at least in part the low effectiveness of radiation therapy of malignant gliomas and support the notion that inhibition of angiogenesis in parallel with radiotherapy may represent a new therapeutic approach.

Management of non resectable malignant esophageal stricture and fistula

OBJECTIVE The palliation of dysphagia caused by esophageal carcinoma and other inoperable tumours obstructing the esophagus presents a challenge for the thoracic surgeon, in particularly when associated with fistula (F). In a prospective study over the last 5 years, we have evaluated the effectiveness of different approaches and types of prostheses to solve the above problem. METHOD Thirty three patients (mean age: 63.5 years, range 42-76, M/F:24/9) with inoperable tumours obstructing the esophagus underwent intubation and/or palliative surgery according to the following protocol: (1) Preoperative esophagography; (2) endoscopy and biopsy; (3) dilatation and insertion of prosthesis usually under general anaesthesia; and (4) re-evaluation the following day, in 30 days and as required thereafter. Prosthesis used were: Atkinson 3, Wilson-Cook (plain) 12, Wilson-Cook (cuffed) 4, Strecker (metallic self-expandable) 13. The patients were divided in three groups according to the extension of the disease: group A (n = 19) plain malignant strictures, group B (n = 5) strictures with respiratory Fs, group C (n = 9) strictures with mediastinal or pleural Fs. RESULTS All patients of group A had successful palliation irrespectively of prosthesis used and site of obstruction. One patient required two stents. There was no death and 50% survival at 6 months was 70%. In group B, a cuffed prosthesis successfully closed two bronchoesophageal Fs, while three patients underwent retrosternal bypass surgery. There was one death on the 26th postoperative day. In group C, one Strecker, two plain Wilson-Cook and two cuffed Wilson-Cook stents, although initially succeeded, in due course, failed to block the Fs in five patients who subsequently underwent bypass surgery with one death. With four patients both leak and dysphagia were significantly improved with the use of self-expandable stents therefore, not requiring surgery. Overall, there were two deaths but no failure in palliating dysphagia. Longer survival was 20 months. Patients with fistulae had poorer prognosis as compared to those suffering from plain malignant stricture (P = 0.01). CONCLUSIONS Plain malignant inoperable oesophageal strictures can be successfully palliated with intubation. Complicated with fistula strictures, however, are difficult to manage and have a poor prognosis. Due to the fact that bypass surgery is associated with an increased mortality, it should be kept for those with late stent failures and fistula recurrences.

Angiogenesis and metastatic potential in breast carcinoma

Abstract We studied tumour specimens from 106 patients with primary breast tumours seen at the University Hospital of Patras, Greece, with a follow-up period of 3–10 years, focusing on the role of breast cancer angiogenesis as a prognostic factor. Angiogenesis was assessed in the primary tumour using an immunohistochemical stain for the CD31 antigen assay for quantitation of microvessel counts. Multiple regression analysis using microvessel count and other clinical-histological findings (age, tumour size, grade and lymphnode metastases) showed that only microvessel counts were significantly predictive of haematogenous metastases to lung, bones, liver and brain ( χ 2 test, P = 0.022). This study shows that angiogenesis is significantly predictive of haematogenous metastases.

Simulation studies on the effect of absorbers on dose distribution in rotational radiotherapy

The effect of cylindrical protector dimensions, material and distance from the source on the dose distribution in rotational radiotherapy was studied to assess the potential protection possibilities of small-sized radiosensitive structures, such as spinal cord. The dose distributions were evaluated in terms of dose at the protected region and surface dose, ratio of the dose at the protected region to the maximum dose, and dose gradient. High-density materials, such as lead, tungsten, gold and cerrobend, along with new polymer-metal composite ones were used in simulation studies, performed by an in-house developed Monte Carlo Radiotherapy Simulator. To ensure correct modeling of the composite materials, simulated attenuation data were verified against experimentally measured data. The dependence of the dose at the protected region from the protector diameter and the field size was established. Protectors of higher density and larger diameter provide not only lower dose at the protected region, but also steeper dose gradient and lower ratio of the dose at the protected region to the treatment dose. For the protection of small structures, high-density protectors placed further from the source allow thicker protectors to be used. The surface dose increases insignificantly for the studied protector-surface distances. The results have shown that shielding properties of composite materials are close to those of lead.

Studies on the attenuating properties of various materials used for protection in radiotherapy and their effect of on the dose distribution in rotational therapy

Protection of vital organs within a radiation field is one of the major concepts in radiotherapy. Measurements of beam attenuation by materials commonly used for protection in radiotherapy, such as lead, cerrobend and brass, as well as by three new materials for radiation shielding, which are polymers filled with tungsten powder, were carried out. The results of measurements were compared with the results of simulations for the same experimental setup to verify some aspects of the in-house developed Monte Carlo Radiotherapy Simulator. The later was also used for simulation studies on the effect of cylindrical protectors on the dose distributions in the rotational radiotherapy. The experimental and simulated data were found to be in a good agreement with a RMS error not higher than 2.1%. The metal-polymer composites can rival the lead in the protection of vital organs if the density provided is high. The results of studies in rotational therapy have shown that a protector of high density and bigger diameter offers more extensive protection of the organ at risk. In the case of cylindrical protector, however, increase in diameter leads to an increase of the attenuated field width, which is not always desirable.

An integrated system for the production of field shaping devices in radiotherapy

A system has been developed in our department that simplifies the production processes of field shaping devices in radiotherapy, integrating an image grabbing and processing facility at a radiotherapy simulator and an automated block cutter. The data acquisition subsystem captures images, processes and corrects them for pincushion distortions, creates a composite radiograph, records user defined contours of blocks and exports data to the block cutter controller. A robotic subsystem drives and controls the polystyrene cutting unit. The system has been experimentally evaluated. Errors in contour definition were found to be less than 1 mm for a broad range of gantry angles and not exceeding 1.5 mm for those gantry orientations that present maximum magnetic field related image intensifier distortion, while the automated block cutter is capable of cutting out contours in polystyrene with an accuracy comparable to that of commercially available systems. The system is expected to contribute to the overall improvement of radiotherapy processes, particularly in low budget radiotherapy departments, introducing improvements in accuracy and efficiency at minimum costs.

Management of Malignant Esophageal Strictures Complicated by Fistula

Malignant esophageal fistula is a devastating complication presenting a challenging problem in terms of occluding the fistula and restoring esophageal patency. Among 29 patients with unresectable esop