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Unlabelled: Key regulatory components of the BMP-induced osteoblast differentiation cascade remain to be established. Microarray and subsequent expression analyses in mice identified two transcription factors, Hey1 and Tcf7, with in vitro and in vivo expression characteristics very similar to Cbfa1. Transfection studies suggest that Tcf7 modulates BMP2-induced osteoblast differentiation. This study contributes to a better definition of the onset of BMP-induced osteoblast differentiation., Introduction: Elucidation of the genetic cascade guiding mesenchymal stem cells to become osteoblasts is of extreme importance for improving the treatment of bone-related diseases such as osteoporosis. The aim of this study was to identify regulators of the early phases of bone morphogenetic protein (BMP)2-induced osteoblast differentiation., Materials and Methods: Osteoblast differentiation of mouse C2C12 cells was induced by treatment with BMP2, and regulation of gene expression was studied during the subsequent 24 h using high-density microarrays. The regulated genes were grouped by means of model-based clustering, and protein functions were assigned. Real-time quantitative RT-PCR analysis was used to validate BMP2-induced gene expression patterns in C2C12 cells. Osteoblast specificity was studied by comparing these expression patterns with those in C3H10T1/2 and NIH3T3 cells under similar conditions. In situ hybridization of mRNA in embryos at embryonic day (E)14.5 and E16.5 of gestation and on newborn mouse tails were used to study in vivo expression patterns. Cells constitutively expressing the regulated gene Tcf7 were used to investigate its influence on BMP-induced osteoblast differentiation., Results and Conclusions: A total of 184 genes and expressed sequence tags (ESTs) were differentially expressed in the first 24 h after BMP2 treatment and grouped in subsets of immediate early, intermediate early, and late early response genes. Signal transduction regulatory factors mainly represented the subset of immediate early genes. Regulation of expression of these genes was direct, independent of de novo protein synthesis and independent of the cell type studied. The intermediate early and late early genes consisted primarily of genes related to processes that modulate morphology, basement membrane formation, and synthesis of extracellular calcified matrix. The late early genes require de novo protein synthesis and show osteoblast specificity. In vivo and in vitro experiments showed that the transcription factors Hey1 and Tcf7 exhibited expression characteristics and cell type specificity very similar to those of the osteoblast specific transcription factor Cbfa1, and constitutive expression of Tcf7 in C2C12 cells differentially regulated osteoblast differentiation marker genes., (Copyright 2004 American Society for Bone and Mineral Research)

Purpose: To investigate the pattern of catecholamine response in patients undergoing carotid endarterectomy (CEA) or carotid artery stenting (CAS)., Methods: Adrenaline, noradrenaline, and renin levels were measured at 5 time points in 12 patients undergoing 13 CEAs (1 bilateral) and 13 patients undergoing unilateral CAS. Arterial blood samples were taken at the following time points: (1) after induction in CEA patients or 5 minutes following first contrast injection in CAS patients, (2) 5 minutes following ICA clamp release in surgical patients or deflation of the balloon in the CAS cohort, (3) 60 minutes following ICA clamp release in surgical patients or deflation of the balloon in the CAS cohort, and (4) 24 hours following the procedure. Intraoperative blood pressure and heart rate were recorded using radial arterial monitoring. Changes in adrenaline, noradrenaline, and renin levels are expressed as ratios versus baseline., Results: Patterns of adrenaline and noradrenaline release were significantly different in patients undergoing CAS and CEA, with much higher and more variable surges of adrenaline and noradrenaline occurring in CEA patients. Adrenaline and noradrenaline levels increased significantly over baseline following carotid artery clamping in patients undergoing CEA (noradrenaline ratio before clamping: 1.54+/-1.25, 24 hours after unclamping: 8.38+/-16.35 [p<0.001]; adrenaline ratio before clamping: 1.12+/-0.49, 60 minutes after unclamping: 17.59+/-19.14 [p<0.001]). Conversely, in patients undergoing CAS, catecholamine levels remained unchanged (noradrenaline ratio before dilation: 0.96+/-0.23, 24 hours after the procedure: 0.92+/-0.32 [p=NS]; adrenaline ratio before dilation: 0.83+/-0.33, 60 minutes after balloon deflation: 0.56+/-0.32 [p=NS])., Conclusions: CAS is associated with a significantly less marked catecholamine response than CEA, which may reflect down-regulation of the sympathetic nervous system in response to carotid sinus stimulation during carotid angioplasty.

Embolic complications remain the major and unpredictable clinical event during carotid angioplasty and stenting. Cerebral protection devices could play an important role in the prevention of such emboli. Protection devices such as occlusion balloons, filters and reversed flow devices are currently undergoing clinical evaluation and appear to be promising in reducing the incidence of embolic events. This article provides an overview of the three different types of embolic protection devices.

Surgical resection of lung metastases is a widely accepted procedure but long-term results are disappointing with a 5-year survival rate of approximately 40%. Pulmonary metastasectomy is only indicated when complete resection can be achieved. A better survival is reported in patients with a single metastasis or a disease-free survival of more than 3 years. Intravenous chemotherapy has no major impact on survival because high-dose therapy is limited by systemic side-effects. Isolated lung perfusion has the advantage of both selectively delivering an agent into the lung while diverting the venous effluent. This allows the drug to be given in a significantly higher dose compared to intravenous therapy, while drug levels in critical organs are kept low enough to avoid significant morbidity. Isolated lung perfusion has proven to be effective for the treatment of lung metastases in animal models while the procedure is technically safe in humans. However, the real clinical value and survival benefit remain to be determined in ongoing clinical trials.The aim of this paper was to update the literature on isolated lung perfusion for the treatment of lung metastases. Furthermore, some proposals are made in order to improve the ultimate prognosis of these patients.

Background: Isolated lung perfusion (ILuP) proved to be superior for the treatment of lung metastases compared with intravenous (i.v.) injection. However its invasive character limits repetitive treatment. Blood flow occlusion (BFO) as a regional therapy with gemcitabine (GCB) was evaluated in a rat model. Lung levels of GCB were examined with different exposure times and flow rates and compared with ILuP and i.v.. Cell kill was studied in vitro., Methods: In vitro survival of CC531 adenocarcinoma cells was determined after 10, 20, and 40 minutes of exposure to GCB. In vivo 48 Wag/Rij rats underwent BFO with GCB at a rate of 0.2 mL/min and 0.5 mL/min during 10, 20, 30, and 40 minutes. Statistical analysis was performed using Student's t test., Results: In vitro, the dose of GCB resulting in 50% growth inhibition was 9.1 microg/mL, 7.2 microg/mL, and 2.2 microg/mL after 10, 20, and 40 minutes exposure respectively. In vivo, no significant difference in lung levels of GCB was observed between a flow rate of 0.2 mL/min compared with 0.5 mL/min at any exposure time point (p < 0.05). Lung tissue was saturated after 20 minutes. Blood flow occlusion resulted in a lower plasma levels and higher lung levels of GCB compared with i.v. injection of the maximal tolerated dose of 40 mg., Conclusions: Growth inhibition of CC531 cells in vitro increased with exposure time while lung tissue was saturated after 20 minutes of BFO. No difference in GCB lung levels were seen after BFO compared with ILuP. Systemic exposure after i.v. injection was higher compared with BFO but did not result in higher lung levels.

Today, pulmonary resection for lung metastases is a widely accepted treatment if complete resection can be achieved. However, 5-year survival is only 40 %. Many patients develop recurrences, but some reports have demonstrated that salvage operations can result in a long-term survival. A resection of a complete lung or a resection of more than a lung is still controversial since procedure-related morbidity or mortality does not outweigh the survival benefit. We report on a series of 10 consecutive patients who underwent a primary pneumonectomy or an operation on the residual lung after pneumonectomy with curative intent for pulmonary metastases. 5 year survival rates for the 10 patients after pneumonectomy alone or with additional resection was 45 %, which was not significantly different from those who underwent a more minor resection with a 5-year survival of 39 % (p = 0.40). Since there is currently no alternative proven therapy for patients with isolated pulmonary metastases, a primary or completion pneumonectomy may be offered to selected patients as long as sufficient pulmonary reserve is present, and a complete resection can be achieved.

Background: Toxicity and pharmacokinetics of gemcitabine (GCB) were evaluated in a rat model of isolated lung perfusion (ILuP) and compared to intravenous (iv) infusion., Materials and Methods: CC531S adenocarcinoma cells were incubated in vitro for 24 h with GCB. Cell survival was determined 4 days after GCB treatment with the sulforhodamine B test. In a first in vivo experiment, Wag/Rij rats underwent left ILuP with 20 mg/kg (n = 3), 40 mg/kg (n = 6), 80 mg/kg (n = 6), 160 mg/kg (n = 6), or 320 mg/kg (n = 6) of GCB and a control group (n = 6) with buffered starch. After 3 weeks, right pneumonectomy was performed. Furthermore, survival was determined for rats treated with iv infusion of 40 mg/kg (n = 10), 80 mg/kg (n = 10), 160 mg/kg (n = 10), or 320 mg/kg (n = 6) of GCB and a control group (n = 6) treated with saline (0.9% NaCl). In a second experiment lung and serum GCB levels were determined for rats treated with iv infusion (160 mg/kg, n = 6) and rats which had ILuP (160 mg/kg, n = 6; 320 mg/kg, n = 6)., Results: Incubation of the CC531S adenocarcinoma cells with GCB led to a 50% decrease (P < 0.05) in the number of cells compared to controls at a dose of 23.6 nM. After 90 days, the mortality for rats treated with 320 mg/kg iv GCB was 100% compared to 17% after ILuP for the same dose. ILuP with 160 and 320 mg/kg resulted in significantly higher lung levels of GCB compared to iv therapy without any systemic leakage., Conclusions: GCB ILuP is well-tolerated to a maximum dose of 320 mg/kg and results in significantly higher GCB lung levels with undetectable serum levels compared to iv treatment.

Objective: The influences of flow, perfusion time, and concentration on melphalan (MN) lung levels in a rat model of isolated lung perfusion (ILuP) were studied., Methods: ILuP was performed in WAG/Rij rats by using a single-pass system with 0.5, 0.05, 0.01, and 0.005 mg of MN. Subsequently ILuP with 0.05 mg MN was performed during 30 min with a flow rate of 0.5 ml/min, during 60 min with a flow rate of 0.5 ml/min, and during 30 min with a flow rate of 1.0 ml/min., Results: The lung MN levels of 0.05 mg were significantly lower as compared with 0.5 mg (p = 0.02). In the second experiment, no significant differences were seen in lung levels of MN between the different groups., Conclusion: The final lung MN levels were only determined by the absolute amount administered., (Copyright 2003 S. Karger AG, Basel)

Osteoblasts are cells responsible for matrix deposition during bone development and although temporal expression of many genes has been related to osteoblast differentiation, a complete description of osteoblast-specific gene regulation will lead to a better understanding of osteoblast function. In this study, microarray technology was used to analyze gene expression on a broad scale during osteoblast differentiation. Expression analysis of 9596 sequences revealed 342 genes and expressed sequence tags (ESTs) to be modulated differentially during a time course experiment in which murine C2C12 mesenchymal progenitor cells were induced to differentiate into mature osteoblasts by treatment with bone morphogenetic protein 2 (BMP-2). By means of hierarchical clustering, these genes were grouped by similarities in their expression profiles, resulting in subsets of early, intermediate, and late response genes, which are representative of the distinct stages of osteoblast differentiation. To identify new bone markers, the bone specificity of the late response genes was determined by comparing BMP-induced expression in C2C12 and MC3T3 osteoblasts with that in NIH3T3 fibroblasts. This resulted in the identification of nine novel genes and ESTs that were induced specifically in osteoblasts, in addition to the well-known markers ALP and osteocalcin. For at least one of these novel genes, Wnt inhibitory factor 1, and two of the ESTs, expression in developing bone was verified in vivo by in situ hybridization of E16.5 mouse embryos. In conclusion, by a combination of in vitro and in vivo screening approaches, a set of new genes related to osteoblast differentiation and skeletal development has been identified.

Background: Isolated lung perfusion (ILuP) with melphalan (MN) is superior to intravenous infusion for the treatment of pulmonary carcinoma and sarcoma metastases. However, it is unknown whether a bolus injection of MN into the perfusion circuit or ILuP with a fixed concentration of MN will result in the highest lung levels., Methods: ILuP with 0.5 mg MN was performed in Wag-Rij rats for 30 minutes either by a single-pass system (SP) (fixed concentration) (n = 10) or by reperfusion (RP) (bolus injection) (n = 10). In a separate experiment, rats were perfused with blood as the perfusate. In a third experiment, tumor levels were compared between SP, RP, or intravenous therapy with a dose of 0.5 mg. For induction of pulmonary metastases, 0.5 x 10(6) single adenocarcinoma cells were injected intravenously and therapy was given on day 30. For comparison of drug concentrations, unpaired Student's t test was applied. Statistical significance was accepted at p less than 0.05., Results: Lung perfusion studies were succesfully performed without systemic leakage. Temperature of perfusate and rats was 34 degrees C to 37 degrees C. A significantly higher hematocrit (mean 27.9) compared with buffered starch (mean 2.5) did not result in higher MN lung levels or lower wet-to-dry ratio. Tumor levels were significantly higher after ILuP compared with intravenous therapy. However, no difference in tumor and lung levels was seen between single-pass and reperfusion., Conclusions: Both ILuP techniques resulted in significantly higher MN lung levels than after intravenous therapy. Because no difference was seen between single-pass and recirculating perfusion, MN can be injected as a bolus into the closed perfusion circuit.

Purpose: To evaluate the feasibility of endovascular treatment of acute abdominal aortic aneurysm (AAA) with commercially prepared bifurcated systems., Methods: From January through July 2001, 22 patients (17 men; mean age 73.6 years, range 59-89) were referred with an acute (symptomatic/ruptured) AAA. Six patients were treated with emergent open surgery because of hemodynamic instability, but the other 16 patients underwent computed tomographic angiography with multidirectional reconstruction. Six (27%) aneurysms were suitable for endovascular repair (EVR) and were successfully treated. Procedural variables, morbidity, and mortality were compared between the EVR group and 6 patients of equivalent hemodynamic status from among the conventionally treated patients., Results: There was no mortality in either group. The median aneurysm diameter in the EVR group was 63 mm (range 48-84) versus 80 mm (45-82) in the matched surgically treated AAAs (p=0.628). Procedural duration was 193 minutes (150-265) for the EVR group compared to 203 minutes (130-270) for the matched group (p=0.630). Median blood loss was significantly less (p=0.010) in the EVR group (125 versus 3400 mL). Median length of stay (LOS) in intensive care was 8 hours (0-21) versus 62 hours (48-112) for the surgical group (p=0.004). Hospital LOS was significantly reduced (p=0.024) for the EVR patients (7.5 [2-16] versus 15.5 [10-34] days)., Conclusions: Endovascular treatment of acute aneurysm is feasible, and preliminary results are promising.

Between 1990 and 2000, 56 consecutive patients underwent lung resection for removal of metastatic disease. Mortality, disease-free interval, and overall survival were studied. Only patients with a complete follow-up were included and data were collected conform the protocol of the International Registry of Lung Metastases. The primary tumour in our series was an epithelial tumour in 25 patients (45%), sarcoma in 15 (27%), germ cell tumours in 11 (19%) and melanoma in 5. Operative mortality was 1.4% (1 out of 73 procedures). Germ cell tumours had the best survival (76% at 5 years), and melanoma the worst (0% at 5 years). Multivariate analysis showed that survival for patients who underwent 2 or more metastasectomies was surprisingly good with a 5-year survival rate of 46%. Survival was not related to disease-free interval, multiple lung metastases, or pneumonectomy. It is in accordance with some reports that a short disease-free interval, numerous lung metastases, or recurrence after the first metastasectomy should not preclude patients from operation.

The response of cells to ionising radiation has been extensively studied for the past 30 years. When radiation is absorbed in biological material, it can directly ionise a critical site (direct effect) or interact with other molecules to produce reactive free radicals, which can subsequently damage critical biological molecules (indirect effect). DNA is considered the critical target damaged by ionising radiation by both direct and indirect processes. Since radiotherapy had proven to be effective in the treatment of non-malignant proliferative processes, it was assumed that this adjunctive treatment would also inhibit vascular restenosis. The major difference between external and intravascular radiation is dose distribution. Intravascular delivery results in extremely high doses to the lumen with a fall-off in dose as a function of distance from the source; whereas, external beam would deliver a uniform dose over the entire volume of tissue treated. Unlike in the coronary circulation most of the peripheral vessels treated are greater than 3 mm in diameter; in fact many are 7 to 10 mm in diameter. Since beta radiation is related to lower penetration properties and more heterogeneous distribution of radiation in comparison to gamma radiation, it is therefore necessary to use a gamma radiation source because it would be difficult to irradiate the sub-intimal tissue with a beta source centred in a large vessel. Radiation can and does have the potential to destroy blood vessels. The challenge in vascular brachytherapy is to treat blood vessels to a point where restenosis is inhibited; yet the vessel is not irreparably damaged.

Objective: To study the influence of gentamicin-containing sponges on the healing of colonic anastomoses in a rat model of peritonitis., Design: Controlled laboratory study., Setting: University hospital, Belgium., Materials: 40 male Wistar rats., Interventions: Peritonitis was caused by implantation of a gelatin capsule containing faeces and barium sulphate. The rats then had a colonic anastomosis. They were divided into 4 groups (n = 10 in each). The control group (no additional treatment); a second group in which a plain collagen sponge was wrapped around the anastomosis; a third group in which a gentamicin-containing collagen sponge was wrapped around the anastomosis; the last group in which the animals were given an intramuscular dose of gentamicin., Main Outcome Measures: Operative mortality, weight loss and anastomotic bursting pressure four days after the anastomosis., Results: Seven rats died before necropsy but none in the last group. Peritonitis developed in all rats Weight loss was significantly higher in the plain collagen group. Bursting pressures were similar in the control and two gentamicin groups. In the plain collagen group all the anastomoses but one had broken down., Conclusion: There was no difference in bursting pressure between rats treated with gentamicin sponges or systemically, and controls. Healing was severely compromised when a plain collagen sponge was used.

A 38-year-old patient presented with an anterior mediastinal mass after chemotherapeutic and surgical treatment for lung metastases from a malignant histiocytoma. Because of the risk for tumour recurrence the thymic mass was resected. Thymic hyperplasia was found on pathological examination. In this case thymic hyperplasia is a rebound phenomenon aflcer chemotherapy. It appears to atrophy during the administration of chemotherapy and regrow afterwards. Surgical resection provides the definitive diagnosis and treatment.

Resection of bilateral pulmonary metastases is exceptional. However, in carefully selected patients extensive resections might be successfully performed. We report two patients who underwent a pneumonectomy and excision of pulmonary metastases in the other lung, via a left wedge resection for patient 1 and left segmentectomy for patient 2. Resections were carried out for metastases of a malignant fibrous histyocytoma and for a teratocarcinoma. Both patients are still alive 9 months and 4 years after their last metastasectomy, respectively.

Introduction: The effect of the antiangiogenic agent suramin on the healing of colonic anastomoses was studied in a rat model., Methods: Rats underwent an end-to-end colonic anastomosis and its healing was tested by measuring bursting pressure, hydroxyproline content and number of newly formed vessels. For the bursting pressure experiment suramin was given intraperitoneally in a dose of 200 mg/kg (maximal tolerable dose) and 100 mg/kg. Hydroxyproline content and vessel density were only tested at 100 mg/kg since the toxicity at this dose was lower whereas bursting pressure was still diminished., Results: There were no deaths. On the fourth day after operation bursting pressure in the control group was significantly higher than that in rats treated with suramin 200 mg/kg (P = 0.006) and 100 mg/kg (P = 0.002). Rupture occurred at the anastomotic line. On day 7, this difference was not statistically significant. Four days after the operation, the hydroxyproline content and vessel density were significantly below that in control segments (hydroxyproline: 10.3 versus 7.8 microg per mg dry weight; vessel content: 85.7 versus 49.6 vessels per x 100 field for control and suramin-treated rats respectively). On the seventh day no difference in hydroxyproline levels was seen but the vessel density was still diminished significantly (P = 0.04)., Conclusion: Experimentally, suramin significantly inhibits and delays healing of colonic anastomoses. Presented in part to the XXXII Congress of the European Society for Surgical Research in Corfu, Greece, May 1997

Background: Smoking is the leading cause of both lung cancer and emphysema. Therefore, some patients with stage I and II disease will present with contra-indications to resection including a predicted postoperative FEV1 of less than 0.81 or a VO2max of less than 10 ml/kg/min. Recently, lung volume reduction surgery (LVRS) has re-emerged in the management of emphysema with excellent results., Methods and Patients: 2 patients are reported with lung cancer in the left lower lobe and emphysematous destruction in both upper lobes. They, respectively, had a predicted postoperative FEV1 of 0.9211 and 0.6851. No metastases were present. Pre-operatively, a COPD index of 0.9 and 0.7 was calculated. A left lower lobectomy together with volume reduction of the left upper lobe was performed through a standard posterolateral thoracotomy., Results: Pathological examination showed, respectively, stage IIb and stage Ib disease. The postoperative course was uneventful and 3 months later a FEV1 of 1.441 for patient 1 and 1.041 for patient 2 were recorded., Conclusion: These findings suggest that pulmonary function criteria for pulmonary resection have to be revised when patients can undergo simultaneous lung cancer resection and LVRS. The pre-operatively calculated COPD index can be used to predict which patients may not have a decrease in ventilatory function.

The role of homeobox genes in signaling of recombinant human bone morphogenetic protein-2 (rhBMP-2) was studied in osteoblast-like cells. Expression of several homeobox genes was decreased by rhBMP-2. The finding that this regulation of homeobox gene expression by rhBMP-2 was not dependent on protein synthesis suggests that homeobox proteins can act as direct intermediates in signal transduction of BMPs. Therefore, we studied the regulation of neural cell adhesion molecule (NCAM), which has previously been described as a target gene of both rhBMP-2 and homeobox proteins. We now show that in osteoblast-like cells, rhBMP-2 inhibits NCAM expression, while HOXC6 increases its expression, both acting via the same region of the promoter. As overexpression of HOXC6 could abolish effects of rhBMP-2 on NCAM promoter activity, these data show for the first time that members of the homeobox gene family may form direct functional intermediates in the signaling mechanism of the TGF-beta superfamily.

Introduction: Survival after isolated lung perfusion (ILuP) with melphalan was tested in a model of unilateral pulmonary adenocarcinoma., Methods: On day 0, rats were randomized into four groups: Group 1 (n = 9) received tumor cells intravenously for induction of bilateral lung metastases, whereas groups 2-4 (n = 21) underwent a 10-min occlusion of the right pulmonary artery during tumor cell injection for induction of unilateral left lung metastases. On day 7, groups 1 and 2 received no treatment. Group 3 underwent left ILuP with melphalan (2.0 mg/kg) while group 4 received melphalan intravenously (0.5 mg/kg). The end point of the study was death from metastatic disease., Results: Median survival of ILuP-treated animals (81 +/- 12 days) was significantly longer compared to group 1 (18 +/- 1 days; p = 0.0001), group 2 (28 +/- 3 days; p = 0.0002) and group 4 (37 +/- 6; p = 0.0004)., Conclusions: ILuP with melphalan prolongs survival in the treatment of experimental metastatic pulmonary carcinoma.

Isolated lung perfusion is a novel therapy for the treatment of pulmonary metastases to increase current low survival rates. Due to tumor heterogeneity, perfusion has to be evaluated in different rat species for efficacy and ideal drug regimens. The revised technique of isolated left lung perfusion as described by Wang and originally performed in the Fisher rat resulted in a high morbiditity in the Wag/Rij rat in our laboratory. Therefore, we modified techniques for intubation and anesthesia, and developed a new approach of catheterization with improved results.

Background: Isolated left lung perfusion with melphalan and human tumor necrosis factor-alpha for pulmonary metastatic adenocarcinoma in the WAG/Rij rat was studied., Methods: Survival was determined for melphalan, human tumor necrosis-alpha. Lung, pulmonary effluent, and serum melphalan were analyzed by chromatography after isolated lung perfusion or intravenous injection. On day 0, rats were injected with 2.0 x 10(6) CC531S cells intravenously. On day 7, rats underwent sham thoracotomy, received melphalan intravenously, or underwent isolated left lung perfusion with saline, melphalan, tumor necrosis factor, and a combination of the latter two. On day 14, tumor nodules were counted., Results: For the doses of 400 microg tumor necrosis factor, 1,000 microg tumor necrosis factor, or both melphalan and tumor necrosis factor (2 mg + 200 microg), survival rates after contralateral pneumonectomy were 33%, 17%, and 80%, respectively. Survival in all other groups was 100%. Left lung melphalan level was significantly higher after isolated lung perfusion compared to intravenous administration. Significantly fewer left lung nodules were found for 0.5 mg isolated lung perfusion with melphalan (28+/-17) compared to isolated administration (200+/-0) (p = 0.001), and for 1.0 mg intravenous lung perfusion with melphalan (16+/-10) compared to controls (171+/-65) (p = 0.00047). Tumor necrosis factor showed no significant effect., Conclusions: Isolated lung perfusion with melphalan is an effective treatment for pulmonary metastases from adenocarcinoma in the rat.

Today, pulmonary metastasectomy is the treatment of choice for many patients with lung metastases from various solid tumors. Prognostic factors for a better survival are patients with germ cell tumors, long disease-free intervals and single metastases. Nevertheless, 5-year survival after surgical resection is low due to relative insensitivity to currently available chemotherapy. Isolated lung perfusion as a regional therapy proved to be a technique that can deliver a higher drug level within the tumor mass without apparent systemic toxicity. In addition, isolated lung perfusion in animal models proved to be more effective compared to intravenous therapy. In this way, isolated lung perfusion seems very promising although optimal regimens in patients are still unknown.