Adenoviral gene transfer of angiostatic ATF-BPTI inhibits tumour growth.

BACKGROUND: The outgrowth of new vessels--angiogenesis--in the tumour mass is considered to be a limiting factor of tumour growth. To inhibit the matrix lysis that is part of the tumour angiogenesis, we employed the chimeric protein mhATF-BPTI, composed of the receptor binding part of the urokinase (ATF) linked to an inhibitor of plasmin (BPTI). METHODS: For delivery, recombinant adenovirus encoding the transgene of interest was injected intravenously or locally into the tumour. The anti tumour effect of this compound was compared to that of human endostatin and of mhATF alone in two different rat bronchial carcinomas growing either as subcutaneous implants or as metastases. RESULTS: Significant inhibition of the tumour growth and decrease of the number of lung metastasis was achieved when the concentration of mhATF-BPTI at the tumour site was above 400 of ng/g tissue. This concentration could be achieved via production by the liver, only if permissive to the recombinant adenovirus. When the tumour cells could be transduced, local delivery of the vector was enough to obtain a response. In the case of metastasis, the capacity of the lung tissue to concentrate the encoded protein was essential to reach the required therapeutic levels. Further, endostatin or mhATF could not reproduce the effects of mhATF-BPTI, at similar concentrations (mhATF) and even at 10-fold higher concentration (endostatin). CONCLUSION: The ATF-BPTI was shown to inhibit tumour growth of different rat lung tumours when critical concentration was reached. In these tumour models, endostatin or ATF induce almost no tumour response.

Multiphase ECG-triggered 3D contrast-enhanced MR angiography: utility for evaluation of hilar and mediastinal invasion of bronchogenic carcinoma.

The purpose of this study was to evaluate the usefulness of cardiac synchronized magnetic resonance angiography [electrocardiographically (ECG)-triggered MRA] for improving image quality and detection of hilar and mediastinal invasion of bronchogenic carcinoma. Fifty patients, suspected of having hilar or mediastinal invasion of bronchogenic carcinoma, underwent contrast-enhanced computed tomography and MR imaging including conventional and ECG-triggered MRA. Twenty patients subsequently also underwent surgical resection. Vascular enhancement-to-background ratio (VBR), vascular enhancement-to-tumor ratio (VTR), signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR) and image quality scores of thoracic vessels obtained with both MRA techniques were determined and compared. In addition, the diagnostic accuracy of tumor invasion of pulmonary vessels was compared. VBRs and VTRs of both MRA techniques were not significantly different. ECG-triggered MRA significantly improved SNRs and CNRs (P < 0.05). Two readers judged that overall image quality of ECG-triggered MRA was better than that of conventional MRA (kappa > or = 0.41). In conclusion, ECG-triggered MRA improves the image quality and the detection of hilar and mediastinal invasion of bronchogenic carcinoma.

Spiral CT angiography of the pulmonary circulation.

Spiral computed tomographic (CT) angiography of the pulmonary circulation has emerged recently as a potential useful diagnostic method for the evaluation of the pulmonary circulation. As a minimally invasive examination, this technique is becoming widely available and has progressively replaced conventional and digital pulmonary angiography as the standard diagnostic imaging modality of the pulmonary circulation. The purpose of this review is to capture the current state of the art of the technical aspects of spiral CT angiography, with special emphasis on the post-processing techniques currently available. As CT is responsible for a considerable part of the medical radiation dose applied to the population, the current trends for dose saving will also be emphasized. With regard to the clinical applications of spiral CT angiography, its introduction into the diagnostic work-up of pulmonary embolism has considerably modified the diagnostic algorithms. Our 8-year review of the literature presented herein is expected to provide the readers with a basis for formulating an informed opinion on this topic. In addition, a large number of congenital and acquired disorders of the pulmonary circulation are also relevant to this technique, and these indications are discussed in the context of the corresponding therapeutic options. Owing to the multiple possibilities inherent to this technique, spiral CT has the potential for cost savings without reduction in image quality or diagnostic accuracy.

The ex-vivo isolated, perfused human lung model: description and potential applications.

An ex-vivo isolated, perfused, and ventilated human lung (IPHL) model is well suited for many kinds of physiological, pharmacological, and surgical studies, when the physiological and biochemical conditions in the lung can be maintained near to those in vivo. The aim of this work was to develop such a model. The lung preparations used were available after resection because of bronchial carcinoma. Since the tumor remains intact in these anatomical preparations, this model is particularly suitable for investigation of the pharmacokinetics and effects of anticancer agents. Carrying out a series of 52 IPHL experiments (with 11 whole-lung preparations and 41 lobe preparations), we have established an IPHL model which allows extracorporeal perfusion and ventilation of the resected lungs in physiological conditions for 2-3 hours. The net weight gain during the experiment, wet-to-dry weight ratio for lung tissue, angiography of the pulmonary artery, pulmonary vascular resistance, color and fluorescence of the lung surface, and alveolar gas diffusion into the perfusate proved to be useful parameters to assess the stability of the preparations and the quality of the experiments. To confirm that an intraparenchymal tumor was perfused via the pulmonary artery, methods to detect avidin and dextran-biotin in tumor tissue after administration into the perfusion solution were employed. Histological examination of bronchial as well as tumor tissue, a computerized histoanalyzation, and a tumor grading program demonstrated that IPHL experiments did not interfere with the grading and staging of the tumors-an important ethical precondition for the use of human preparations in an extracorporeal perfusion model.

Indocyanine green videoangiographic findings in choroidal metastatic tumor.

BACKGROUND: Indocyanine green videoangiography (ICGV) has recently advanced and become widely available as a clinical tool. We tested the efficacy of ICGV in evaluating metastatic choroidal tumors. METHODS: ICGV using Topcon 50-IA was performed in five patients with clinically diagnosed choroidal metastatic tumors. The findings were compared with those of conventional fluorescein angiography (FAG). RESULTS: Compared with FAG, ICGV demonstrated more smooth and regular hypofluorescent lesions, precisely indicating the exact size of the tumor. In all cases, no tumor vessels were found. The choroidal vascular integrity around the tumors was observed. FAG, however, was more sensitive in detecting the tumor development than ICGV when the extent of the hypofluorescent lesion could be seen clearly in the early phase. FAG provided more information regarding retinal pigment epithelial dysfunction in the outer blood retinal barrier overlying the tumor. CONCLUSION: Since ICGV enables visualization of tumors through the retina, it is very useful, particularly in cases of associated secondary retinal detachment around the tumors. ICGV combined with FAG provides more precise assessment of the tumors themselves and their response to treatment than FAG alone.

[Investigation of blood supply of bronchogenic carcinoma deriving from pulmonary artery].

Microfil perfusion technique was used to investigate the blood supply of bronchogenic carcinoma deriving from pulmonary artery on 20 fresh specimens of lung cancer, including 11 squamous carcinoma, 6 adenocarcinoma, 1 alveolar cell carcinoma and 2 undifferentiated carcinoma cases. The results showed that the appearance and quantity of pulmonary blood supply of bronchogenic carcinoma depended on and changed with the site, activity, growth mode as well as the local condition of tumor nodules; pulmonary artery supplied blood to the periphery of the tumor and its innermost part as well; vessels from pulmonary artery in tumor nodules were generally less in number than those in the surrouding normal lung tissues around. The results suggested that the tumor blood supply from pulmonary artery should be evaluated comprehensively and dynamically; during interventional chemotherapy via pulmonary artery, patients should be selected carefully and the catheter for infusion placed in suitable position so as to gain the best therapeutic effect.

[The use of color Doppler flow imaging in diagnosis and differential diagnosis of some pulmonary masses].

The status of blood supply was examined in twenty-nine patients with pulmonary masses with color doppler flow imaging. The results showed that there are no significant blood signals in 5 benign masses. One patient with pulmonary arterio-venous fistula can be diagnosed. Pulmonary inflammatory pseudotumor and 20 lung cancers have rich blood supply. The peak forward velocity and resistance index between them have obvious difference statistically (P < 0.05, P < 0.01). It is concluded that color doppler can be regarded as an useful and noninvasive method before operation in diagnosing some pulmonary masses.

Inhibition of interleukin 8 attenuates angiogenesis in bronchogenic carcinoma.

We investigated the role of interleukin 8 (IL-8) in mediating angiogenesis in human bronchogenic carcinoma. Increased quantities of IL-8 were detected in tumor tissue as compared with normal lung tissue. Immunohistochemical staining of tumors revealed primary localization of IL-8 to individual tumor cells and demonstrated the capacity of tumor to elaborate IL-8. Functional studies that used tissue homogenates of tumors demonstrated the induction of both in vitro endothelial cell chemotaxis and in vivo corneal neovascularization. It is important to note that the addition of neutralizing antisera to IL-8 to these assays resulted in the marked and specific attenuation of these responses. Our observations definitively establish IL-8 as a primary mediator of angiogenesis in bronchogenic carcinoma and offer a potential target for immunotherapies against solid malignancies.

Quantitative single-photon emission tomography for tumour blood flow measurement in bronchial carcinoma.

A single-photon emission tomography (SPET) technique for the absolute measurement of tumour perfusion is described. Phantom studies have shown that source-background ratios are dependent upon source size and radial position within the phantom. A means of correcting source-background count ratios for these variables has been developed and used to correct tumour-lung ratios obtained in 28 patients with bronchial carcinomas who underwent technetium-99m hexamethylpropyleneamine oxime (99mTc-HMPAO) SPET. On SPET images, the normal lung appears as a relatively homogeneous background. The relationship between 99mTc background concentration (kBq/ml) and counts/pixel was determined from phantom studies and the tumour 99mTc concentration from the background 99mTc concentration and corrected tumour-lung ratio. The total activity of the lipophilic 99mTc-HMPAO species injected was measured. The activity reaching the systemic circulation (Asys) was obtained by subtracting the activity trapped in the pulmonary circulation (obtained from background 99mTc concentration and lung volume). Tumour blood flow may then be calculated from fraction of Asys contained in the tumour provided cardiac output and extraction fraction are known. Blood flow through the central region of tumours ranged from zero to 59.0 (mean 14.1) ml min-1 100 g-1 and through the whole tumour from 0.6 to 68.0 (mean 20.6) ml min-1 100 g-1.

[Intra-arterial angio-CT as a perfusion control before intra-arterial chemotherapy in bronchial, breast and liver tumors]. / Intraarterielles Angio-CT als Perfusionskontrolle vor intraarterieller Chemotherapie bei Bronchial-, Mamma- und Lebertumoren.

Intra-arterial angio-CT is used increasingly in the diagnosis of liver metastases since the sensitivity of this method is greater than that of IV-contrast CTs. We carried out this procedure in eight patients with inoperable carcinomas of the bronchus, eight patients with carcinoma of the breast, one patient with an hepatocellular carcinoma and one patient with carcinoma metastases, before starting intra-arterial chemotherapy or tumour embolisation. The procedure permitted optimal placing of the catheter to ensure complete perfusion of the tumour. Perfusion of normal tissue can be reduced to a minimum. Failure of contrast filling on the angio-CT indicates the presence of a second vessel supplying the tumour.

The effects of single dose oral hydralazine on blood flow through human lung tumours.

Hydralazine has been shown to reduce tumour blood flow and to potentiate the cytotoxicity of melphalan and bioreductive agents in mice. In order to determine whether such a strategy might have clinical potential, a study was undertaken to investigate the effects of hydralazine on blood flow through human tumours. Twenty-two patients with carcinoma of the bronchus received a single oral dose of hydralazine in the range 25 to 150 mg (0.37-2.86 mg/kg) according to age and acetylator status. Tumour blood flow was assessed by single photon emission computed tomography (SPECT) performed 10 min following intravenous 99Tcm-HMPAO on two occasions 2-8 days apart, the second being performed 60 min after hydralazine administration. In 20 evaluable patients, hydralazine caused a 38% increase in blood flow through the whole tumour (p = 0.007) and a 28% increase in flow through the tumour centre (p = 0.03) with greater increases occurring in patients sustaining greater falls in peripheral resistance. Tumour vascular resistance fell indicating active vasodilation in arterioles supplying tumours. Side-effects due to hydralazine were reported by eight patients.

[Pericardial and pulmonary vascular involvement]. / L'estensione pericardica e vascolare polmonare.

Over five hundred lung resections were considered, out of a series of 1570 cases of lung cancer. Histology of resected patients resulted squamous (348), adenocarcinoma (107), large cells (21) and small cells carcinoma (37). According to Mountain staging, 41% of patients were related to stage Ist, 12% to the IInd, 40.9% to the IIInd A: in such a group, a special class T3N0M0 was considered, due to the better follow-up observed in such cases. Lobectomies and minor resections were performed in 321 cases, pneumonectomies in 192. An analysis was done of differences in Histology, staging, early mortality, complications and late results after pneumonectomy which was traditional in 117 patients and required an intrapericardial section of great vessels in 68 cases: 16 patients had some pericardial resection, specific ECG disturbances, early mortality and recurrence within five years proved to be higher in the patients who had some pericardial operation: also as far as no connection was recognized with histology, the responsibility of such results can be attributed to the stage, that in those patients required a more aggressive operation.

[Significance of pulmonary DSA for assessing the operability of lung tumors]. / Bedeutung der pulmonalen DSA für die Beurteilung der Operabilität von Lungentumoren.

In lung tumours histological findings, exclusion of metastatic disease and different diagnostic procedures such as bronchoscopy, mediastinoscopy and thoracic CT play an important role for tumour staging to plan the correct therapeutic approach. Selection of patients for thoracotomy depends on results of these examinations. This study was carried out to assess the value of an additionally applied pulmonary DSA in 17 patients with lung tumours (bronchogenic carcinoma n = 14). Our results demonstrate that in 4 cases angiography could prove inoperability of tumours (compression of sup. v. cava, occlusion of a main pulmonary artery): one patient had a negative mediastinoscopy, one patient had a small cell bronchogenic carcinoma; in two patients an additional mediastinoscopy could be omitted. In two other patients with bronchogenic carcinoma who appeared operable in mediastinoscopy and DSA, explorative thoracotomy only could ensure inoperability due to an infiltration of the thoracic wall. As a minimal invasive method applicable in outpatients pulmonary DSA seems to be useful in giving additional important diagnostic information particularly in central bronchogenic carcinomas.

Vascularization of experimental tumours.

At first sight, experimental tumours in observation chambers seem to contain areas with wide vessels showing a sluggish circulation as well as ischaemic areas. Only by careful analysis on cleared specimens can neovascularization be discerned. This process probably occurs primarily in the perimeter of the tumour. It is quite possible that areas of intense vascularization and ischaemic areas in tumours may both result from differences in intensity between the angiogenic stimulus and local tissue pressure.

[Effects of administration of an antineoplastic agent into the bronchial artery].

Morphological observation was performed to see the effect of bronchial arterial infusion therapy (BAI) of mitomycin C (MMC) and also of the ischemia to the transplanted bronchial carcinoma. Single shot of 2mg/kg of MMC showed destructive changes on the tumor. Single shot of 3mg/kg and repeated administration of MMC brought relatively severe intra-arterial inflammatory changes such as intimal edema, thickening and proliferation which suggested ischemic effect on the tumor due to poor perfusion from stenosis or obstruction of the vessels. On the other hand a simple ligation of the artery also brought about more than moderate destructive changes in the tumor. Therefore, mechanisms of the effect of the BAI of MMC to the lung tumor might involve the secondary effect from ischemia in addition to the effect of MMC itself.

Double blood supply of bronchogenic carcinoma from multiple arteries.

Angiography was performed in connection with intra-arterial chemotherapy in 110 patients with bronchogenic carcinoma. All tumors were supplied from at least one ipsilateral bronchial artery. A double systemic arterial supply was found in 12 patients, the additional blood supply coming from a second ipsilateral bronchial artery in 3 patients, from the ipsilateral internal mammary artery in 4, from intercostal arteries in 4 and from the subclavian artery in one patient. All patients with tumor supply from a non-bronchial artery had direct tumor spread to the chest wall or to the mediastinum. A complete angiographic examination may therefore be of prognostic significance and necessary before intra-arterial chemotherapy, which mainly has a local effect.

Bronchial angiography in the staging of bronchogenic carcinoma.

Selective bronchial angiography was performed in 26 patients with bronchogenic carcinoma in connection with intraarterial infusions of cytostatic drugs. The angiographic extension of the tumor was correlated to data obtained at surgery, mediastinoscopy or autopsy. Bronchial angiography is not suitable as a routine procedure in the preoperative evaluation of patients with bronchogenic carcinoma but may contribute to a more precise staging of the tumor.

Bronchial angiography and intraarterial chemotherapy with mitomycin-C in bronchogenic carcinoma. Anatomy, technique, complications.

Bronchial angiography and intraarterial infusion of mitomycin-C were successfully performed in 39 of 47 patients with bronchogenic carcinoma. More than one course was given to several patients. No neurologic complications occurred and the side effects were insignificant. The pertinent anatomy of the bronchial and spinal arteries is summarized and a comprehensive description of the angiography and infusion technique is given. It is important that the infused artery is not occluded by the catheter and that the drug is properly diluted to avoid complications. The method appears to be of therapeutic value in the treatment of pulmonary carcinoma.

Bronchial arteries in various stages of bronchogenic carcinoma.

The vascularization of growing and regressing bronchogenic carcinomas was analyzed by comparison of postmortem angiographic and histologic investigations of bronchial arteries in 20 autopsy lungs with bronchogenic carcinoma. Vascular findings in bronchial arteriograms range from correct orientation of proliferating vessels to convoluted patterns of vascular growth during the early phases of tumor growth. Later spotty or smudgy extravasation may be seen in necrotic tumor areas, and increased vascular anastomoses appear between the nutritive and functional pulmonary circulations. Characteristic findings in angiography may be correlated, to a certain extent, with size and histologic type of the tumors. Our findings emphasize the role of nutritive pulmonary vessels in the vascularization of bronchogenic carcinoma at different stages of its development.