Atrial epicardial adipose tissue abundantly secretes myeloperoxidase and activates atrial fibroblasts in patients with atrial fibrillation.

BACKGROUND: Epicardial adipose tissue (EAT) secretome induces fibrosis. Fibrosis, primarily extracellular matrix (ECM) produced by fibroblasts, creates a substrate for atrial fibrillation (AF). Whether the EAT secretome from patients with AF activates human atrial fibroblasts and through which components, remains unexplored. RESEARCH AIMS: (a) To investigate if the EAT secretome from patients with versus without AF increases ECM production in atrial fibroblasts. (b) To identify profibrotic proteins and processes in the EAT secretome and EAT from patients with, who will develop (future onset), and without AF. METHODS: Atrial EAT was obtainded during thoracoscopic ablation (AF, n = 20), or open-heart surgery (future onset and non-AF, n = 35). ECM gene expression of human atrial fibroblasts exposed to the EAT secretome and the proteomes of EAT secretome and EAT were assessed in patients with and without AF. Myeloperoxidase and neutrophil extracellular traps (NETs) were assessed immunohistochemically in patients with paroxysmal, persistent, future onset, and those who remain free of AF (non-AF). RESULTS: The expression of COL1A1 and FN1 in fibroblasts exposed to secretome from patients with AF was 3.7 and 4.7 times higher than in patients without AF (p < 0.05). Myeloperoxidase was the most increased protein in the EAT secretome and EAT from patients with versus without AF (FC 18.07 and 21.57, p < 0.005), as was the gene-set neutrophil degranulation. Immunohistochemically, myeloperoxidase was highest in persistent (FC 13.3, p < 0.0001) and increased in future onset AF (FC 2.4, p = 0.02) versus non-AF. Myeloperoxidase aggregated subepicardially and around fibrofatty infiltrates. NETs were increased in patients with persistent versus non-AF (p = 0.03). CONCLUSION: In AF, the EAT secretome induces ECM gene expression in atrial fibroblasts and contains abundant myeloperoxidase. EAT myeloperoxidase was increased prior to AF onset, and both myeloperoxidase and NETs were highest in persistent AF, highlighting the role of EAT neutrophils in the pathophysiology of AF.

Prosthesis-patient mismatch affects late survival after valve surgery for severe aortic stenosis.

BACKGROUND: The effect of prosthesis-patient mismatch (PPM) on late survival after aortic valve replacement (AVR) in patient with symptomatic severe aortic stenosis (AS) remains unclear. Also, late follow-up in previous studies is confined to only one decade. We aimed to determine the effect of PPM on late survival after isolated AVR for symptomatic severe AS during 25 years of follow-up. METHODS: In this retrospective cohort study, Kaplan-Meier survival analysis was performed to determine late survival in 404 consecutive patients with moderate PPM (N.=86), severe (N.=11), or no/mild PPM (N.=307) after isolated AVR for symptomatic severe AS during a mean follow-up of 25.0±2.9 years. Moderate, severe, and no/mild PPM were defined as indexed effective orifice area of >0.65≤0.85, ≤0.65, and >0.85 cm2/m2, respectively. Multivariable analysis was performed to identify possible independent predictors of decreased late survival, including moderate or severe PPM. RESULTS: Late survival of patients with severe PPM was worse in comparison with those with no/mild PPM: 7.4±2.6 (95% confidence interval 2.2-12.5) vs. 13.6±0.5 (95% confidence interval 12.6-14.6) years, respectively; P=0.020. Late survival of patients with moderate PPM was similar to those with no/mild PPM. Severe PPM was an independent predictor of decreased late survival: hazards ratio 4.002 (95% confidence interval 1.869-8.569); P<0.001. Moderate PPM was not an independent predictor of decreased late survival. CONCLUSIONS: Severe PPM was independently associated with decreased late survival after isolated AVR for symptomatic severe AS during a mean follow-up of 25.0±2.9 years. Therefore, severe PPM should be prevented as much as possible.

Neutrophil degranulation interconnects over-represented biological processes in atrial fibrillation.

Despite our expanding knowledge about the mechanism underlying atrial fibrillation (AF), the interplay between the biological events underlying AF remains incompletely understood. This study aimed to identify the functionally enriched gene-sets in AF and capture their interconnection via pivotal factors, that may drive or be driven by AF. Global abundance of the proteins in the left atrium of AF patients compared to control patients (n = 3/group), and the functionally enriched biological processes in AF were determined by mass-spectrometry and gene set enrichment analysis, respectively. The data were validated in an independent cohort (n = 19-20/group). In AF, the gene-sets of innate immune system, metabolic process, cellular component disassembly and ion homeostasis were up-regulated, while the gene-set of ciliogenesis was down-regulated. The innate immune system was over-represented by neutrophil degranulation, the components of which were extensively shared by other gene-sets altered in AF. In the independent cohort, an activated form of neutrophils was more present in the left atrium of AF patients with the increased gene expression of neutrophil granules. MYH10, required for ciliogenesis, was decreased in the atrial fibroblasts of AF patients. We report the increased neutrophil degranulation appears to play a pivotal role, and affects multiple biological processes altered in AF.

Outcomes of cardiac surgery after mediastinal radiation therapy: A single-center experience.

BACKGROUND: Mediastinal radiation therapy (MRT) is a widely used therapy for thoracic malignancies. This therapy has the potential to cause cardiovascular injuries, which may require surgery. The primary aim of this study is to identify the perioperative outcomes of cardiac surgery in patients with a history of MRT. Second, potential predictors of mortality and adverse events were identified. METHODS: A retrospective study was conducted among 59 patients with prior MRT who underwent cardiac surgery between December 2009 and March 2015. Included surgeries consisted of procedures through median- and ministernotomy. Baseline, perioperative, and follow-up data were obtained and analyzed. RESULTS: The majority of patients had a history of breast cancer (n = 43), followed by Hodgkin lymphoma (n = 10) and non-Hodgkin lymphoma (n = 3). Preoperative estimated mortality with the Euroscore II was 3.4%. Overall 30-day mortality was 6.8% (n = 4), with a total in-hospital mortality of 10.2% (n = 6). Postoperatively, nine rethoracotomies (15.3%) had to be performed. During a mean follow-up of 53 months, an additional 10 patients (16.9%) died, of which 60% (n = 6) as a result of cancer-related events. Cox proportional modeling showed no differences in mortality between primary malignancies (P > .05). CONCLUSION: This study shows that cardiac surgery after mediastinal radiotherapy is associated with increased short- and long-term mortality when compared to preoperative mortality risks predicted by the Euroscore II. Surgery-related events caused all short-term mortality cases, while malignancy-related events were the main cause of death during the follow-up. Mortality was higher in patients with a previous stroke and a lower estimated glomerular filtration rate.

PREventive left atrial appenDage resection for the predICtion of fuTure atrial fibrillation: design of the PREDICT AF study.

BACKGROUND: Atrial fibrillation is the most common cardiac arrhythmia, posing a heavy burden on patients' wellbeing and healthcare budgets. Patients undergoing cardiac surgery are at risk of developing postoperative atrial fibrillation (POAF), new-onset atrial fibrillation and subsequent atrial fibrillation-related complications, including stroke. Sufficient clinical identification of patients at risk fails while the pathological substrate changes that precede atrial fibrillation remain unknown. Here, we describe the PREDICT AF study design, which will be the first study to associate tissue pathophysiology and blood biomarkers with clinical profiling and follow-up of cardiothoracic surgery patients for the prediction of future atrial fibrillation. METHODS: PREDICT AF will include 150 patients without atrial fibrillation and a CHA2DS2-VASc score of at least 2 undergoing cardiac surgery. The left atrial appendage will be excised during surgery and blood samples will be collected before surgery and at 6 and 12 months' follow-up. Tissue and blood analysis will be used for the discovery of biomarkers including microRNAs and protein biomarkers. The primary study endpoint is atrial fibrillation, which will be objectified by 24 h Holters and ECGs after 30 days for POAF and after 6, 12 and 24 months for new-onset atrial fibrillation. Secondary endpoints include the dynamic changes of blood biomarkers over time and other atrial arrhythmias. PREDICT AF participants may benefit from extensive postoperative care with clinical phenotyping, rhythm monitoring and primary prevention of stroke. CONCLUSION: We here describe the PREDICT AF trial design, which will enable the discovery of biomarkers that truly predict POAF and new-onset atrial fibrillation by combining tissue and plasma-derived biomarkers with comprehensive clinical follow-up data. TRIAL REGISTRATION: Retrospectively registered NCT03130985 27 April 2017.

Intravascular Lipiodol Presenting as an Atrial Mass.

A 68-year-old woman, previously treated with embolization of the thoracic duct with Lipiodol (an ethiodized oil injection) and cyanoacrylate glue (a topical tissue adhesive), was admitted with an asymptomatic mass in the inferior vena cava (IVC) and right atrium. The mass was surgically removed, and pathologic analysis revealed a Lipiodol-containing thrombus. To our knowledge, this is the first clinicopathologic report of Lipiodol-induced thrombus presenting as an intracavitary mass.

Midterm Follow-Up of the Stentless Freedom Solo Bioprosthesis in 350 Patients.

BACKGROUND: The stentless Freedom Solo aortic bioprosthesis is implanted supraannularly using one running suture line in the sinuses of Valsalva. We report our 9-year experience with this bioprosthesis. METHODS: From April 2005 to July 2014, 350 consecutive patients at our institution underwent aortic valve replacement with the Freedom Solo bioprosthesis. Follow-up and echocardiographic data were collected retrospectively from referring cardiology centers. RESULTS: The mean age was 76 ± 6 years, 48% were male, and 46% underwent a concomitant procedure. Median EuroSCORE II was 3.0 (interquartile range, 1.9 to 4.9). Operative mortality was 5.1% for all procedures and 2.1% for isolated aortic valve replacement. The 1-, 5-, and 9-year overall survival was 92%, 74%, and 47%, respectively. At 6 years, freedom from structural valve deterioration and freedom from aortic valve reoperation were 98% and 96%, respectively. Prosthetic valve endocarditis occurred at a rate of 0.8% per patient-year. Permanent pacemaker implantation was necessary in 2.3% (n = 8), and moderate and severe prosthesis-patient mismatch occurred in 30 patients overall (9.6%). Postoperative maximum and mean valvular gradients were 17 mm Hg and 10 mm Hg, respectively, and remained stable during follow-up. CONCLUSIONS: Aortic valve replacement with the Freedom Solo is safe and has a low rate of permanent pacemaker implantations and prosthesis-patient mismatch. Survival is comparable to that with other aortic bioprostheses, and structural valve deterioration and aortic valve reoperation are infrequent during midterm follow-up. Hemodynamic performance is excellent, with low valvular gradients that remain stable during follow-up.

Stentless vs Stented Aortic Valve Bioprostheses in the Small Aortic Root.

In patients with a small aortic root undergoing aortic valve replacement (AVR), the Freedom SOLO bioprosthesis may be the ideal prosthesis because of its stentless design and supra-annular implantation. This study investigated if the stentless Freedom SOLO has an advantage when compared with a stented bioprosthesis in patients with a small aortic root. From April 2005-July 2014, 269 consecutive patients underwent AVR with either a Freedom SOLO (n = 76) or Mitroflow (n = 193) bioprosthesis size 19mm or 21mm, respectively. This retrospective comparison study presents clinical and echocardiographic follow-up data. In results, operative outcome and survival were similar. At 7 years, cumulative incidence of aortic valve reoperation and structural valve deterioration favor the Freedom SOLO (0% vs 7.1%, P = 0.03 and 0% vs 4.5%, P = 0.08, respectively). Additionally, the postoperative peak and mean valvular gradients favor the Freedom SOLO (21 ± 9mmHg vs 32 ± 12mmHg and 12 ± 5mmHg vs 19 ± 8mmHg, both P = <0.001, respectively). During mid-term follow-up this hemodynamic advantage continued in favor of the Freedom SOLO. Also prosthesis-patient mismatch occurred less frequently in the Freedom SOLO (28% vs 52%, P = 0.001). There were no differences in prosthetic valve endocarditis, thromboembolic, or bleeding events. In conclusion, the stentless Freedom SOLO has several significant advantages for AVR in patients with a small aortic root in comparison with a stented Mitroflow bioprosthesis. The Freedom SOLO shows superior hemodynamic performance with significantly lower valvular gradients that remained stable during mid-term follow-up. Additionally, significantly fewer prosthesis-patient mismatch occurred and the Freedom SOLO showed superior durability.

When Not to Go SOLO? Contraindications Based on Implant Experience.

BACKGROUND AND AIM OF THE STUDY: Because of the design and specific implantation technique of the stentless Freedom SOLO bioprosthesis, patient selection is crucial. The aim of the study was to discuss the contraindications to this prosthesis based on the authors' implant experience. METHODS: Between April 2005 and February 2015, one surgeon at the authors' center performed 292 aortic valve replacements using a bioprosthesis, with the initial intention of implanting a SOLO valve in every patient. A search was conducted for all of these patients and data collected on whether a SOLO valve was used, or not. RESULTS: A SOLO valve was implanted in 238 patients (82%), and a stented bioprosthesis in 54 (18%). The predominant reasons not to implant a SOLO valve were asymmetric commissures (26%) and a large aortic annulus (24%). Only one patient had structural valve deterioration, and none of the patients had to undergo reoperation because of aortic valve insufficiency or paravalvular leakage. CONCLUSIONS: Asymmetric commissures, large aortic annulus (>27 mm), calcified aortic sinuses, dilated sinotubular junction, aberrant location of coronary ostia and whenever the stent of a stented bioprosthesis is useful, were contraindications to implant a SOLO valve. When these contraindications were taken into account, a very good durability could be achieved with the SOLO valve during mid-term follow up.

Navigating the mini-maze: systematic review of the first results and progress of minimally-invasive surgery in the treatment of atrial fibrillation.

BACKGROUND: In this paper we present a systematic literature overview and analysis of the first results and progress made with minimally-invasive surgery using RF energy in the treatment of AF. The minimally-invasive treatment for atrial fibrillation (AF) tries to combine the success rate of surgical treatment with a less invasive approach to surgery. It has the additional potential advantage of ganglion plexus (GP) ablation and left atrial appendage exclusion. Furthermore, additional left atrial ablation lines (ALAL) can be created in non-paroxysmal AF patients. METHODS: For the search query multiple databases were used. Exclusion and inclusion criteria were applied to select the publications to be screened. All remaining articles were critically appraised and only relevant and valid articles were included in our results. RESULTS: Twenty-three studies were included. In 15 studies GPs around the pulmonary veins were ablated. In four studies ALAL were performed. Single procedure success rate was 69% (95% CI, range 58%-78%) without antiarrhythmic drugs (AAD) and 79% (95% CI, range 71%-85%) with AAD at one year follow-up. Mortality was 0.4%, and various complications were reported (3.2% surgical, 3.2% post-surgical, 2.6% cardiac, 2.1% pulmonary, 1.7% other). CONCLUSIONS: Twenty-three studies of minimally-invasive surgery for AF have been reviewed with success rates between that of the standard maze procedure and catheter ablation. These first combined results show promise; however, minimally-invasive surgery is still evolving, for instance by the recent inclusion of electrophysiological endpoints. Furthermore, the type of ALAL and the additional value of GP ablation have to be elucidated.

Epicardial confirmation of conduction block during thoracoscopic surgery for atrial fibrillation--a hybrid surgical-electrophysiological approach.

BACKGROUND: Totally thoracoscopic epicardial pulmonary vein ablation is an emerging treatment of atrial fibrillation (AF). A hybrid surgical-electrophysiological procedure with periprocedural confirmation of conduction block might reduce recurrences of AF or atrial tachycardia and improve surgical success. METHODS AND RESULTS: We report our joint surgical-electrophysiological approach for confirmation of conduction block across pulmonary vein ablation lines and those compartmentalizing the left atrium during totally thoracoscopic surgery. A diagnostic electrophysiology (EP) catheter positioned under the left atrium is used as reference and a custom-made multi-electrode for recording. Determination of conduction block across the pulmonary vein (PV) ablation lines requires measurement of activation time differences of milliseconds. Second, a stable reference electrogram to which to relate local activation time is required. Third, the recording electrode terminals and the inter-electrode distance should be small to prevent recording of far field activity and to allow recording of very small electrograms. We confirm entry and exit block and determine conduction block across linear ablation lines with differential pacing. CONCLUSION: A joint surgical-electrophysiological protocol for confirmation of conduction block across PV isolation lines and left atrial ablation lines is feasible and might prevent recurrences and further improve the success of minimally invasive surgery for AF.

J-shaped versus median sternotomy for aortic valve replacement with minimal extracorporeal circuit.

OBJECTIVES: Minimal access aortic valve replacement (AVR) has been demonstrated to have beneficial effects over median sternotomy. Minimal extracorporeal circulation (MECC) has been shown to have less deleterious effects than conventional cardiopulmonary bypass. We describe for the first time AVR via upper J-shaped partial sternotomy compared to median sternotomy using MECC. METHODS: Prospectively collected pre-operative, intra-operative, post-operative and follow-up data from 104 consecutive patients who underwent minimal access AVR were compared to 72 consecutive patients undergoing median sternotomy using MECC during the same period (January 2007 to December 2009). RESULTS: No significant differences were found in patient's characteristics or intra-operative data with the exception of pre-existing pulmonary disease. The mean cardiopulmonary bypass (86 ± 18 min vs. 78 ± 15 min, p = 0.0079) and cross-clamp times (65 ± 13 min vs. 59 ± 12 min, p = 0.0013) were significantly shorter in the median sternotomy group. Mediastinal blood loss (397 ± 257 ml vs. 614 ± 339 ml, p < 0.0001) and ventilation time (8 ± 6.9 h vs. 11 ± 16.5 h, p = 0.0054) were significantly less in the minimal access group. No differences were seen in transfusion requirements, inotropic support, intensive care unit (ICU) stay, total hospital stay, post-operative haemoglobin drop, major events or mortality. Quality of life scores after discharge demonstrated less pain with a quicker recovery and return to daily activities in patients receiving J-shaped sternotomy. CONCLUSIONS: Minimal access AVR using MECC is feasible and provides excellent clinical results. Less pain and quicker recovery was experienced among patients in this group.

Thoracoscopic video-assisted pulmonary vein antrum isolation, ganglionated plexus ablation, and periprocedural confirmation of ablation lesions: first results of a hybrid surgical-electrophysiological approach for atrial fibrillation.

BACKGROUND: Thoracoscopic pulmonary vein isolation (PVI) and ganglionated plexus ablation is a novel approach in the treatment of atrial fibrillation (AF). We hypothesize that meticulous electrophysiological confirmation of PVI results in fewer recurrences of AF during follow-up. METHODS AND RESULTS: Surgery was performed through 3 ports bilaterally. Ganglionated plexi were localized and subsequently ablated. PVI was performed and entry and exit block was confirmed. Additional left atrial ablation lines were created and conduction block verified in patients with nonparoxysmal AF. The left atrial appendage was removed. Freedom of AF was assessed by ECGs and Holter monitoring every 3 months or during symptoms of arrhythmia. Antiarrhythmic drugs were discontinued after 3 months and oral anticoagulants were discontinued according to the guidelines. Thirty-one patients were treated (16 paroxysmal AF, 13 persistent AF, 2 long-standing persistent AF). Thirteen patients with nonparoxysmal received additional left atrial ablation lines. After 1 year, 19 of 22 patients (86%) had no recurrences of AF, atrial flutter, or atrial tachycardia and were not using antiarrhythmic drugs (11/12 paroxysmal, 7/9 persistent, and 1/1 long-standing persistent). Three patients had a sternotomy because of uncontrolled bleeding during thoracoscopic surgery. Four adverse events were 1 hemothorax, 1 pneumothorax, and 2 pneumonia. No thromboembolic complications or mortality occurred. CONCLUSIONS: Thoracoscopic surgery with PVI and ganglionated plexus ablation for AF is a safe and successful procedure with a single procedure success rate of 86% at 1 year. Electrophysiological guided thorough PVI and additional left atrial ablation line creation presumably contributes in achieving a high success rate in the surgical treatment of AF.

Improved analgesia after the realisation of a pain management programme in ICU patients after cardiac surgery.

BACKGROUND AND OBJECTIVE: Although clinical guidelines recommend systematic evaluation of pain in ICU patients, we know little about the effects from such systematic pain evaluation. This study aims to quantify the effect of a pain management programme in the ICU. METHODS: In this prospective two-phase study, pain levels scored by ICU patients after cardiac surgery through sternotomy were compared before and after the implementation of a pain management programme. The pain management programme consisted of a three-fold strategy; all staff was trained in assessing pain and in providing adequate analgesia, a new patient data management system obliged nurses to ask patients for their pain score three times a day and the preferred analgesic treatment was optimised. The numeric rating scale (NRS 0-10) was used by 190 patients. A NRS at least 4 was considered unacceptable. A generalised linear mixed-effects model was used for analysing repeated measurements data. RESULTS: The occurrence of unacceptable pain (NRS > or = 4) was significantly lower in the intervention group [odds ratio 2.54 (95% confidence interval 1.22-5.65; P = 0.01) for the control group]. Patients in the intervention group received significantly more morphine (29.3 vs. 22.6 mg a day, P<0.01), with higher morphine amounts administered to patients with higher NRS scores (P = 0.01). In the control group, no such relationship was observed (P = 0.66). There was no difference in length of stay in the ICU or in ventilation time. CONCLUSION: The intervention programme successfully reduced the occurrence of unacceptable pain. Further improvement of pain management should focus on the prevention of pain.

Combined coronary artery bypass grafting and aortic valve replacement with minimal extracorporeal closed circuit circulation versus standard cardiopulmonary bypass.

Isolated aortic valve replacement (AVR) or coronary artery bypass grafting (CABG) using minimized extracorporeal circulation (MECC) has been shown to have less deleterious effects than standard cardiopulmonary bypass (CPB). In this prospective cohort study, we evaluated and compared clinical results of combined AVR with CABG using MECC. We prospectively collected preoperative, intraoperative, postoperative and follow-up data of 65 patients who underwent combined AVR with CABG using MECC and compared these with 135 patients undergoing combined AVR with CABG using standard CPB. No significant differences were seen in patients demographic characteristics or intraoperative data. Patients in the MECC group experienced a smaller preoperative haemoglobin drop (4.5±0.8 g/dl vs. 5.0±0.5 g/dl, P=0.002) resulting in higher haemoglobin at discharge (11.3±1.3 g/dl vs. 10.8±1.1 g/dl, P=0.03). They had decreased blood products requirements (P=0.004) compared to patients in the standard CPB group. No differences were noted in pulmonary complications, neurological events or mortality. We present for the first time data showing that combined AVR with CABG using MECC is feasible and provides better clinical results compared to standard CPB with regard to blood products requirements, without compromising operative morbidity or mortality.

Selective pulmonary artery perfusion followed by blood flow occlusion: new challenge for the treatment of pulmonary malignancies.

INTRODUCTION: Selective pulmonary artery perfusion (SPAP) is an experimental endovascular technique for the treatment of pulmonary malignancies. This study evaluated blood flow occlusion (BFO) after SPAP and dose-escalation in order to delay washout of gemcitabine from the lung tissue, to augment pulmonary drug exposure and to maintain plasma concentrations equivalent to intravenous administration. MATERIAL AND METHODS: Six groups of pigs underwent left-sided SPAP using gemcitabine in a clinically applied dose of 1-1.5g/m(2) after balloon catheterisation. BFO experiment: four groups (n=4, each) were treated with SPAP with 1g/m(2) of gemcitabine during 2 min followed by BFO for 0, 10, 20 and 30 min, respectively. Dose-escalation experiment: two more groups (n=3, each) received SPAP with 1.25 and 1.5 g/m(2) of gemcitabine during 2 min followed by 30 min BFO. All pigs underwent left thoracotomy with sampling of lung, liver and blood. The animals were sacrificed after 1h. The lung and plasma areas under the curve (AUC) were calculated for each group and ANOVA and t-test was used for comparison. RESULTS: Thirty minutes BFO resulted in the highest lung AUC compared to 0, 10 and 20 min BFO (p<0.001), while no significant differences in plasma AUC and liver levels were observed. Gemcitabine dose-escalation up to 1.25 g/m(2) resulted in significantly higher lung AUC (p=0.02) compared to 1g/m(2), while plasma AUC was equivalent with intravenous treatment. Further dose-escalation to 1.5g/m(2) did not result in significantly higher lung levels compared to 1.25 g/m(2). CONCLUSION: BFO after SPAP delays the washout of gemcitabine from lung tissue. Dose-escalation resulted in higher lung concentrations, while plasma levels were equivalent with intravenous administration. We advocate 2 min of SPAP with 1.25 g/m(2) of gemcitabine followed by 30 min of BFO to be investigated as a new treatment modality for pulmonary malignancies.

Pharmacokinetics of isolated lung perfusion with melphalan for resectable pulmonary metastases, a phase I and extension trial.

BACKGROUND: Isolated lung perfusion (ILuP) with melphalan was performed under normo- and hyperthermic conditions combined with pulmonary metastasectomy for patients with resectable lung metastases. We present the results of pharmacokinetic analysis of a phase I and extension trial. METHODS: Twenty-one procedures of ILuP with melphalan were performed in the phase I trial according to a dose-escalation schedule under normothermic and hyperthermic conditions followed by surgical resection of pulmonary metastases. In an extension trial 8 additional procedures with 15 and 45 mg melphalan were performed under hyperthermic conditions. Samples of serum, perfusate, lung, and tumor tissue were obtained. RESULTS: High perfusate concentrations of melphalan were recorded in contrast to low systemic concentrations. Marked interindividual variability was observed in melphalan concentrations in perfusate, tumor, and lung tissue. Statistically significant correlation between melphalan dose, and perfusate area under the concentration-time curve (R(2) = 0.578, P = 0.001) and lung tissue concentrations (R(2) = 0.459, P = 0.028) were noted. No significant correlation between melphalan dose and tumor tissue concentrations could be established. CONCLUSION: Isolated lung perfusion effectively delivers high doses of melphalan to the lung and tumor tissues with minimal systemic levels. Significant correlation between perfused melphalan dose, perfusate area under the concentration-time curve and lung tissue melphalan concentrations were observed.

Isolated lung perfusion for pulmonary metastases.

Isolated lung perfusion is an experimental surgical technique evaluated for the delivery of high-dose chemotherapy to improve 5-year survival after pulmonary metastasectomy. Extensive experimental work in animal models has demonstrated superior pharmacokinetics and efficacy compared with systemic therapy. Phase I clinical trials of isolated lung perfusion found a maximum tolerated dose**** of TNF-alpha, doxorubicin, cisplatin, and melphalan, whereas the combination of isolated lung perfusion with a complete metastasectomy was feasible. The combination of isolated lung perfusion and regional lung perfusion techniques needs further investigation.

Isolated lung perfusion for pulmonary metastases, a review and work in progress.

Pulmonary metastasectomy is a widely accepted treatment for many patients with pulmonary metastases from various solid tumors. Nevertheless, 5-year survival is disappointing, with rates of 25-40%, and many patients develop recurrences. Isolated lung perfusion (ILuP) is a promising new technique to deliver high-dose chemotherapy to the lungs, while minimising systemic toxicities. This procedure is technically safe and feasible; however, clinical value and efficacy remain unclear. The aim of this paper is to give a review of literature on ILuP in humans, and to describe the development of the perfusion procedure in our institute.