Chronic lung hypoxia causes vascular remodeling with pulmonary artery smooth muscle cell (SMCPA) hyperplasia, resulting in pulmonary hypertension and cor pulmonale. We investigated SMCPA and pulmonary artery adventitial fibroblasts (FBPA) for their proliferative response to hypoxia. Strong SMCPA growth occurred under hypoxic conditions in SMCPA/FBPA co-cultures, but not in SMCPA monocultures. SMCPA growth was fully reproduced by transferring serum-free supernatant from hypoxic cultured FBPA to normoxic SMCPA. Hypoxia-inducible-transcription-factor subtypes (HIF-1alpha, HIF-2alpha, HIF-3alpha) and its dependent target genes, carrying the hypoxia-responsive-element as regulatory component, were strongly activated in both hypoxic FBPA and SMCPA. HIF-transcription-factor decoy technique, employed to FBPA during hypoxic culturing, blocked the mitogenic activity of FBPA conditioned medium on SMCPA. The data suggest that hypoxia-driven gene regulation in pulmonary artery fibroblasts results in a mitogenic stimulus on adjacent pulmonary artery smooth muscle cells, and HIF-transcription-decoy may offer a new therapeutic approach to suppress these events.
This clinical study indicates that the intraarterial application of gemcitabine with doses higher than the recommended 1,000 mg/m(2) is well tolerated if combined with microspheres, and yields respectable results in patients who do not respond to systemic chemotherapy.
The aim of the study was to compare prospectively magnetic resonance cholangiography (MRC) and magnetic resonance imaging (MRI) with endoscopic retrograde cholangiography (ERC) in the diagnosis and staging of Klatskin tumours of the biliary tree (hilar cholangiocarcinomas). Forty-six patients with suspected Klatskin tumours of the biliary tract underwent MRI and heavily T2-weighted, non-breathhold, respiratory-triggered fast spin-echo MRC. Forty-two patients underwent ERC within 24 h; in four patients, ERC was not feasible, and percutaneous trans-hepatic cholangiography (PTC) was carried out instead. Two independent investigators evaluated imaging results for the presence of tumour, bile duct dilatation, and stenosis. Clinical and histopathological correlation revealed Klatskin tumours in 33 patients. MRI revealed a slightly hyperintense signal of infiltrated bile ducts in T2-weighted fast spin-echo sequences. The malignant lesion was regularly visualized as a hypointense area in T1-weighted gradient-echo sequences with substantial contrast enhancement along the involved bile duct walls. MRC revealed the location and extension of the tumour in 31 of 33 cases correctly (sensitivity 94%, specificity 100%, diagnostic accuracy 95%). In 27 of 31 cases, ERC enabled accurate staging and diagnosis of Klatskin tumours with a sensitivity of 87%. ERC and PTC combined yielded a sensitivity of 84% and a specificity of 97%. Tumours were grouped according to the Bismuth classification, with MRC allowing correct identification of type I tumour in seven patients, type II tumour in four patients, type III tumour in 12 patients, and type IV tumour in ten patients. MRC provided superior visualization of completely obstructed peripheral systems. MRC in combination with MRI is a reliable non-invasive diagnostic method for the pre-therapeutic staging of Klatskin tumours.
This study aims to evaluate the efficacy and safety of a neoadjuvant treatment protocol with repeated transarterial chemoembolization (TACE) before MR-guided laser-induced thermotherapy (LITT) for large-sized hepatocellular carcinomas (HCC). Repeated TACE (mean, 3.5 treatments per patient) was performed in 48 patients with neoadjuvant intention (the largest lesion was between 50 and 80 mm in diameter, and there were no more than five lesions). For the TACE treatment, we used 10 mg/m(2) mitomycin, 10 ml/m(2) Lipiodol and microspheres. The tumor volume was measured by MRI. Lipiodol retention of the tumors was evaluated with CT. After the diameter of the tumors had decreased to less than 50 mm, the patients were treated with MR-guided LITT 4 to 6 weeks after embolization. Repeated TACE reduced the tumor size in 32 patients (66.7%), forming the basis for performing MR-guided LITT procedures. These patients received one to four laser treatments (mean, 1.9 per patient) for tumor ablation, resulting in a median survival of 36.0 months after the first treatment. For the remaining patients, no reduction in tumor size was achieved in 12 patients and disease progression in 4 patients. Neoadjuvant TACE appears to be an effective treatment of large-sized HCC, which extends the indication for MR-guided LITT.
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