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Background: This study explores the repurposing of Auranofin (AF), an anti-rheumatic drug, for treating non-small cell lung cancer (NSCLC) adenocarcinoma and pancreatic ductal adenocarcinoma (PDAC). Drug repurposing in oncology offers a cost-effective and time-efficient approach to developing new cancer therapies. Our research focuses on evaluating AF's selective cytotoxicity against cancer cells, identifying RNAseq-based biomarkers to predict AF response, and finding the most effective co-therapeutic agents for combination with AF., Methods: Our investigation employed a comprehensive drug screening of AF in combination with eleven anticancer agents in cancerous PDAC and NSCLC patient-derived organoids (n = 7), and non-cancerous pulmonary organoids (n = 2). Additionally, we conducted RNA sequencing to identify potential biomarkers for AF sensitivity and experimented with various drug combinations to optimize AF's therapeutic efficacy., Results: The results revealed that AF demonstrates a preferential cytotoxic effect on NSCLC and PDAC cancer cells at clinically relevant concentrations below 1 µM, sparing normal epithelial cells. We identified Carbonic Anhydrase 12 (CA12) as a significant RNAseq-based biomarker, closely associated with the NF-κB survival signaling pathway, which is crucial in cancer cell response to oxidative stress. Our findings suggest that cancer cells with low CA12 expression are more susceptible to AF treatment. Furthermore, the combination of AF with the AKT inhibitor MK2206 was found to be particularly effective, exhibiting potent and selective cytotoxic synergy, especially in tumor organoid models classified as intermediate responders to AF, without adverse effects on healthy organoids., Conclusion: Our research offers valuable insights into the use of AF for treating NSCLC and PDAC. It highlights AF's cancer cell selectivity, establishes CA12 as a predictive biomarker for AF sensitivity, and underscores the enhanced efficacy of AF when combined with MK2206 and other therapeutics. These findings pave the way for further exploration of AF in cancer treatment, particularly in identifying patient populations most likely to benefit from its use and in optimizing combination therapies for improved patient outcomes., (© 2024. The Author(s).)

Objectives: The purpose of this study was to assess the quality of video-assisted cervical mediastinoscopy (VACM) in the staging of non-small-cell lung cancer (NSCLC) at the Antwerp University Hospital with a focus on test effectiveness indicators, morbidity and unforeseen pN2 results., Methods: All consecutive VACM workups of cases of NSCLC performed between January 2010 and December 2015 were included to assess overall test quality and effectiveness. Quality assurance was performed in accordance with the recommendations of the European Society of Gastrointestinal Endoscopy and European Society of Thoracic Surgeons (ESTS) where appropriate., Results: A total of 168 video-assisted cervical mediastinoscopies were included. A total of 91.7% of the procedures were performed in accordance with the ESTS guideline. An unforeseen pN2 staging was identified in 10 anatomical lung resections (8.6%). Statistical analysis showed no significant association between VACM performed in accordance with the ESTS guideline and the presence of pN2 positive lymph nodes [χ2 (1) = 0.61; P = 0.57] and no association between VACM performed in accordance with the ESTS guideline and overall futile thoracotomy [χ2 (1) = 0.76; P = 0.50]. Calculations revealed a sensitivity of 81.8 [95% confidence interval (CI) 69.1-90.9], specificity of 100%, positive predictive value of 100%, negative predictive value of 91.9% (95% CI 86.6-95.2) and diagnostic accuracy of 94.1% (95% CI 89.33-97.11)., Conclusions: Overall, 91.7% of the VACM were performed in accordance with the ESTS guideline. This process resulted in a sensitivity of 81.8%, a negative predictive value of 91.9% and an unforeseen pN2 rate of 8.6%., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Opinion Statement: Robotic-assisted videothoracoscopic surgery (R-VATS) has become increasingly popular and widely used since its introduction and is nowadays considered a standard treatment approach in many centres for the treatment of non-small cell lung cancer. R-VATS was initially developed to overcome the drawbacks of VATS by offering surgeons more flexibility and three-dimensional optics during thoracoscopic surgery. The effectiveness of R-VATS lobectomy regarding oncological outcomes, morbidity, mortality, and postoperative quality of life (QoL) has been shown in an increasing number of studies. More recently, these results have also been corroborated for sublobar resections, more specifically for segmentectomy. However, no well-powered, multicentre randomized trials have been performed to demonstrate the superiority of R-VATS compared with open surgery or conventional types of VATS (total VATS, uniportal VATS, etc.). The majority of the evidence currently available is based on non-randomized studies, and many studies report conflicting results when comparing R-VATS and conventional VATS. Moreover, there is a lack of data regarding the cost and the cost-efficiency of robotic surgery compared with VATS and open surgery. Current evidence suggests that R-VATS costs are higher than VATS and that a deficit can only be prevented when up to 150-300 thoracic surgery procedures are performed annually. Finally, robotic-assisted laparoscopic surgery showed better ergonomics and reduced musculoskeletal disorders compared with non-robotic laparoscopic surgery.

Robotic-assisted thoracoscopic surgery has increased in popularity during the past two decades because it offers 3-dimensional optics, increased instrument and wrist flexibility compared to classical video-assisted thoracoscopic surgery, and, for patients, improved quality of life and shorter hospital stays compared to open surgery.  In this video tutorial, we demonstrate a robotic-assisted thoracoscopic surgery lobectomy in a patient with a tumor in the right middle lobe. The patient had an excellent recovery with no perioperative or postoperative complications., (© The Author 2016. Published by MMCTS on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: Up to 66% of patients show local pulmonary disease progression after pulmonary metastasectomy. Regional treatment with isolated lung perfusion (ILuP) may improve local control with minimal systemic adverse effects. The aims of this study were to evaluate local and distant control after ILuP, determine the effect on overall survival compared with historical controls, and confirm the safety and feasibility of ILuP., Methods: A total of 107 patients with resectable pulmonary metastases of colorectal carcinoma, osteosarcoma, and soft-tissue sarcoma were included in a prospective phase II study of pulmonary metastasectomy combined with ILuP with 45 mg melphalan at 37°C. Local and distant control, overall survival, lung function, and 90-day mortality and morbidity were monitored., Results: We report 0% mortality, low morbidity, and no long-term pulmonary toxicity. For colorectal carcinoma, median time to local pulmonary progression, median time to progression, and median survival time were 31, 14, and 78 months, respectively. Median time to local progression was not reached for sarcoma, whereas median time to progression and median survival time were 13 and 39 months, respectively. The 5-year disease-free rate and pulmonary progression-free rate were 26% and 44% for colorectal carcinoma and 29% and 63% for sarcoma, respectively., Conclusions: ILuP with melphalan combined with metastasectomy is feasible and safe. Compared with historical controls, favorable results were obtained in this phase II study for local control. Further evaluation of locoregional lung perfusion techniques with other chemotherapeutic drugs is warranted., (Copyright © 2019 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Malignant pleural mesothelioma (MPM) is a rare but aggressive neoplasm that typically originates from the mesothelial surfaces of the pleural cavity. Exposure to asbestos is the principal etiological agent of MPM. The disease is characterized by difficult stage classification and limited consensus on therapeutic approach. We have evaluated the experience with MPM in the Antwerp University Hospital over the past 15 years., Methods: A database was created with all patients diagnosed with or treated for a MPM between 2001 and 2015. A total of 101 patients were included on which different survival analyses were performed combined with a reproduction of demographic, clinical, histologic and therapeutic data, and these were compared to literature data., Results: Vast majority of our 101 patients were male (80%) with a median age of 66 years at diagnosis with predominantly epitheloid histology (81%). Overall median survival was 18.3 months and overall 1-, 2- and 5-year survival rates were 68%, 37% and 7%, respectively. Kaplan-Meier analysis showed a non-significant difference in survival between the several best (b) TNM-stages (p = .356). A significant difference in survival was observed in patients undergoing surgery versus no surgery (p = .008), between the different histological types (p < .0001) and treatment with chemotherapy alone versus chemotherapy with surgery (p < .0001). Smoking at diagnosis and epitheloid histology have been identified as significant prognostic factors in the multivariate Cox regression model (HR 3.13 and 0.53, respectively)., Conclusion: Descriptive and survival analysis of our patient database confirmed the limitations of the current staging system and were concordant with literature regarding MPM.

Introduction: Stage IIIA-N2 non-small cell lung cancer (NSCLC) represents a heterogeneous group of bronchogenic carcinomas with locoregional involvement. Different categories of N2 disease exist, ranging from unexpectedly encountered N2 involvement after detailed preoperative staging or 'surprise' N2, to potentially resectable disease treated within a combined modality setting, and finally, bulky N2 involvement treated by chemoradiation. Areas covered: Large randomised controlled trials and meta-analyses on stage IIIA-N2 NSCLC have been published but their implications for treatment remain a matter of debate. No definite recommendations can be provided as diagnostic and therapeutic algorithms vary according to local, national or international guidelines. Expert commentary: From the literature, it is clear that patients with stage IIIA-N2 NSCLC should be treated by combined modality therapy including chemotherapy, radiotherapy and surgery. The relative contribution of each modality has not been firmly established. For patients undergoing induction therapy, adequate restaging is important as only down-staged patients will clearly benefit from surgical resection. Each patient should be discussed within a multidisciplinary team to determine the best diagnostic and therapeutic approach according to the specific local expertise. In the near future, it might be expected that targeted therapies and immunotherapy will be incorporated as possible therapeutic options.

Introduction: The 5-year overall survival rate of patients undergoing complete surgical resection of pulmonary metastases (PM) from colorectal cancer (CRC) and sarcoma remains low (20-50%). Local recurrence rate is high (48-66%). Isolated lung perfusion (ILuP) allows the delivery of high-dose locoregional chemotherapy with minimal systemic leakage to improve local control., Methods: From 2006 to 2011, 50 patients, 28 male, median age 57 years (15-76), with PM from CRC (n = 30) or sarcoma (n = 20) were included in a phase II clinical trial conducted in four cardiothoracic surgical centers. In total, 62 ILuP procedures were performed, 12 bilaterally, with 45 mg of melphalan at 37°C, followed by resection of all palpable PM. Survival was calculated according to the Kaplan-Meier method., Results: Operative mortality was 0%, and 90-day morbidity was mainly respiratory (grade 3: 42%, grade 4: 2%). After a median follow-up of 24 months (3-63 mo), 18 patients died, two without recurrence. Thirty patients had recurrent disease. Median time to local pulmonary progression was not reached. The 3-year overall survival and disease-free survival were 57% ± 9% and 36% ± 8%, respectively. Lung function data showed a decrease in forced expiratory volume in 1 second and diffusing capacity of the alveolocapillary membrane of 21.6% and 25.8% after 1 month, and 10.4% and 11.3% after 12 months, compared with preoperative values., Conclusion: Compared with historical series of PM resection without ILuP, favorable results are obtained in terms of local control without long-term adverse effects. These data support the further investigation of ILuP as additional treatment in patients with resectable PM from CRC or sarcoma.

Objectives: Isolated lung perfusion (ILuP) and selective pulmonary artery perfusion (SPAP) are experimental surgical techniques to deliver high-dose chemotherapy selectively to the lung for the treatment of lung metastases. ILuP with melphalan (MN) has shown to be feasible in clinical studies but can only be used once because it is invasive. SPAP as an endovascular technique can be repeated several times, but no results have been reported so far. Pharmacokinetics and efficacy of SPAP with MN were studied in a rodent lung metastasis model and compared it with ILuP and intravenous (IV) therapy., Methods: Pharmacokinetics: forty-five Wag-Rij rats were randomized into three groups: IV 0.5 mg MN, ILuP 0.5 mg MN and SPAP 0.5 mg MN. Every treatment group was again randomized in three groups: 15 min treatment, 30 min treatment and 30 min treatment with 30 min reperfusion. Blood and tissue samples were taken for MN concentrations., Efficacy: twenty-five Wag-Rij rats were randomized into five groups: control, sham thoracotomy, IV 0.5 mg MN, ILuP 0.5 mg MN and SPAP 0.5 mg MN. At day 0, bilateral lung metastases were induced, and treatment followed at day 7. At day 28, rats were sacrificed and pulmonary metastases counted. Survival: thirty Wag-Rij rats were randomized into five groups: control, sham ILuP, IV 0.5 mg MN, ILuP 0.5 mg MN, SPAP 0.5 mg MN. At day 0, left-sided lungmetastases were induced with treatment at day 7. Endpoints were death due to disease or survival up to 90 days., Results: Pharmacokinetics: SPAP and ILuP resulted in significantly higher left lung MN concentrations compared with IV (P = 0.05)., Efficacy: SPAP (30 ± 22 nodules) and ILuP (20 ± 9 nodules) resulted in significantly less nodules compared with IV (113 ± 17 nodules; P < 0.01). Survival: median survival of SPAP (74 ± 8 days) was equal to ILuP MN (71 ± 10 days) but significantly longer compared with IV (54 ± 7 days; P < 0.01 both)., Conclusions: SPAP with MN for the treatment of sarcoma lung metastases in rats is equally effective to ILuP but resulted in a significantly better survival compared with IV MN. As SPAP can be applied as a minimally invasive endovascular procedure, continued research with this technique is warranted.

When considering surgical treatment for non-small-cell lung cancer (NSCLC), a distinction is made between early-stage disease (stages IA/B and IIA/B), locoregionally advanced disease (stages IIIA/B) and metastatic disease (stage IV). Complete surgical resection of NSCLC can provide good long-term outcome. Surgery is considered the treatment of choice in patients with early-stage NSCLC or patients with T3N1 disease. Surgery for locoregionally advanced disease remains controversial. In specific cases of T4 disease, surgery can provide long-term survival. In patients with stage IIIA-N2 disease, surgery is only offered to patients who have achieved mediastinal downstaging following induction therapy. Careful preoperative evaluation is clearly important in the staging and selection of patients with NSCLC for surgery.

Objective: Surgical resection of lung metastases is a widely accepted procedure but 5-year survival rates remain low and vary between 20% and 50%. Isolated lung perfusion (ILuP) is an experimental technique to deliver a high dose of chemotherapy to the lung, without systemic toxicity. Long-term survival of ILuP has not been reported yet and was determined in a phase I clinical trial., Methods: From May 2001 to December 2004, a phase I clinical trial was conducted to define the maximum tolerated dose (MTD) of ILuP with melphalan. Twenty-nine procedures were performed in 23 patients. The primary tumour was colorectal in 10 patients, renal in eight, sarcoma in four and salivary gland in one. Toxicity results were previously reported and the MTD of melphalan was determined at 45 mg when given at 37°C. Follow-up was updated and long-term survival is reported., Results: Follow-up was complete, except for one patient who was lost to follow-up after 8 months. After a median follow-up of 62 months, 6 out of 23 patients were alive and free of recurrent disease. One patient died after a subsequent operation. Sixteen patients developed recurrent disease, of whom 11 died. Nine patients had intrathoracic recurrent disease only, one intra- and extrathoracic recurrences each and five extrathoracic only. In one patient, the location of recurrence was not known. Overall- and disease-free 5-year survival rates were 54.8 ± 10.6% and 27.5 ± 9.5%, respectively with an overall median survival time (MST) of 84 months (95% confidence interval (CI): 41-128) and disease-free MST of 19 months (95% CI: 4-34). Lung function and diffusion capacity initially dropped 1 month after perfusion, slightly improving afterwards. Radiographic follow-up with chest computed tomography showed no long-term toxicity from ILuP., Conclusion: ILuP can be applied without major long-term pulmonary toxicity. Five-year survival rate, overall and disease-free MST in this phase I clinical trial are promising. This is another incentive to perform further studies with ILuP., (Copyright © 2010 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.)

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.

In general, patients with additional metastatic nodules or distant metastases of a non-small-cell lung cancer (NSCLC) have a poor prognosis. However, published results suggest that in carefully selected patients with synchronous or metachronous metastatic lesions, long-term survival can be obtained when a complete resection of the primary site and metastasis - mostly single brain or adrenal - is achieved. Different subgroups of patients with metastatic NSCLC exist and a distinction should be made between additional malignant nodules in the ipsilateral and contralateral lung, malignant pleural effusion and extrathoracic, single or multiple metastases. Patients with additional malignant nodules in the same lobe or ipsilateral nonprimary lobe have a better prognosis than suggested by the current tumor-node-metastasis (TNM) classification. The other subgroups have a poor prognosis. In view of recent data from a large, international database, proposals have been made for the new TNM classification that will be introduced in 2009.

Lung cancer represents a major health problem. Cytostatic and radiotherapeutic treatment is limited because of dose-limiting systemic toxicity and surgery as a result of its invasive nature. Therefore, we developed a catheterization model of selective pulmonary artery perfusion (SPAP) combining the properties of isolated lung perfusion and i.v. treatment to achieve higher local drug levels and equivalent systemic exposure. Sixteen pigs underwent SPAP using a clinically applied dose of gemcitabine (1 g/m(2)). They furthermore underwent thoracotomy for tissue sampling. Three groups were treated with SPAP for 2 min with normal pulmonary blood flow, 50 and 90% flow reduction. Another group had SPAP for 10 min with normal blood flow. All the SPAP groups underwent catheterization of the left pulmonary artery. An additional group (n = 4) was infused i.v. for 30 min using the same dose. Concentrations were analyzed with analysis of variance. Pulmonary peak concentrations (p = 0.01) and areas under the curve (AUC) (p = 0.001) of SPAP for 2 and 10 min were significantly higher compared with i.v., whereas SPAP for 10 min resulted in the highest AUC (p = 0.045) compared with SPAP for 2 min. Flow reduction during SPAP resulted in inhomogeneous distribution. Liver levels, AUC (serum), and wet-to-dry ratios of all the SPAP groups were not significantly different compared with i.v. SPAP resulted in higher lung concentrations, whereas systemic exposure was comparable with i.v. Therefore, we advocate SPAP as a new method to be tested clinically to achieve down-staging of the tumor and lymph node status in lung cancer.

Surgical resection is a widely accepted treatment for pulmonary metastases on the condition that a complete resection can be obtained. However, many patients will develop recurrent disease in the thorax despite the use of systemic chemotherapy, dosage of which is limited because of systemic toxicity. Similar to the basic principles of isolated limb and liver perfusion, isolated lung perfusion is an attractive and promising surgical technique for the delivery of high-dose chemotherapy with minimal systemic toxicity. The use of biological response modifiers, like tumour necrosis factor, is also feasible. Other related methods of delivering high-dose locoregional chemotherapy include embolic trapping (chemo-embolisation) and pulmonary artery infusion without control of the venous effluent. Isolated lung perfusion has proven to be highly effective in experimental models of pulmonary metastases with a clear survival advantage. Lung levels of cytostatic drugs are significantly higher after isolated lung perfusion compared to intravenous therapy without systemic exposure. Phase I human studies have shown that isolated lung perfusion is technically feasible with low morbidity and without compromising the patient's pulmonary function. Further clinical studies are necessary to determine its definitive effect on local recurrence, long-term toxicity, pulmonary function and survival.

Objective: Outcome endpoints are still the most widely used indicators of performance. However, they need to be risk-adjusted in order to be reliable instruments of audit. Recently, the European Society Objective Score (ESOS) was developed from the online European Thoracic Surgery Database as an audit tool. In this study, we applied for the first time the ESOS.01 to assess the performance of three European thoracic surgery units during three successive years of activity., Methods: This study is a retrospective analysis performed on prospective databases. We analysed 695 patients submitted to pneumonectomy (117) or lobectomy (578) for lung neoplasm at three European dedicated thoracic surgery units (unit A 264 patients, unit B 262, unit C 169) from January 2004 through December 2006. Qualified thoracic surgeons performed all the operations. No patients in this series were in the original ESOS development set. ESOS.01 was used to estimate the risk of in-hospital mortality in all patients. Observed and predicted mortality rates were then compared within each unit by the z-test., Results: Cumulative observed mortality rates in units A, B and C were 2.3% (six cases), 2.7% (seven cases) and 4.1% (seven cases), respectively. We were not able to find statistically significant differences between observed and ESOS-predicted mortality rates. The comparison of risk-adjusted mortality rates between units did not show significant differences (unit A 3.9%, unit B 3.3%, unit C 5.6%)., Conclusions: The use of ESOS.01 revealed that the performances of all units were in line with the predicted ones during each period under analysis and did not differ between each other. The results of our study warrant future efforts to refine the ESOS model and to develop other risk-adjusted outcome indicators with the aim to establish European benchmarks of performance.

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.

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.

Background: Isolated lung perfusion (ILuP) is an experimental technique for the treatment of pulmonary metastases. We hypothesized that part of the drug taken up by the lung during ILuP is washed out during the flush procedure. Therefore, we investigated gemcitabine uptake at different inflow concentrations, and the effect of delayed clamp release after ILuP on lung levels was studied., Methods: Thirty rats had ILuP during 30 minutes using gemcitabine perfusate levels of 1.3, 2.7, 4.0, 5.3, and 6.7 mg/mL. Another 37 rats underwent ILuP with gemcitabine perfusate levels of 6.7 mg/mL during 6 minutes followed by a 5-minute flush and 30 or 60 minutes of reperfusion, while two other groups had ILuP and delayed clamp release for 30 or 60 minutes followed by a 5-minute flush. All effluent and lung samples were stored for later analysis. Results were evaluated using Friedmann two-way analysis and two-way analysis of variance., Results: At 6 minutes, steady-state of gemcitabine uptake was achieved for all inflow concentrations and a linear relation (r = 0.933, p < 0.0001) between effluent and lung levels was observed. Delayed clamp release resulted in significantly higher lung levels compared with immediate restoration of blood circulation after ILuP (456% at 30 minutes and 828% at 60 minutes)., Conclusions: Effective gemcitabine lung levels are already achieved after 6 minutes of ILuP with 6.7 mg/mL followed by delayed clamp release during 30 minutes instead of the clinically applied 30 minutes ILuP.

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.

Introduction: Isolated lung perfusion (ILuP) is an experimental surgical technique for the treatment of pulmonary metastases. Phase I trials showed a wide range in drug lung levels. This may be due to the variance of lung size and pulmonary intravascular volume (PIV). Therefore, we developed a method to assess PIV and investigated the relation of PIV and dry lung weight (DLW)., Material and Methods: Thirty-two rats of 555+/-8 and 199+/-5g underwent left ILuP two, four and eight minutes. Venous effluent was analyzed for haemoglobin, red blood cells (RBC), leucocytes, platelets, albumin and creatinine. PIV was calculated by dividing the product of perfusate volume and post-ILuP parameter by the difference between post-ILuP and pre-ILuP parameter., Results: No significant differences in PIV for all perfusion times were noted between the different variables (P=0.14). Based on haemoglobin (P<0.0009), RBC (P=0.006), leucocytes (P=0.0003), platelets (P=0.017) and creatinine (P=0.003) analysis, PIV was significantly smaller in rats of 199g while PIV/DLW ratio was not significantly different., Conclusion: Because PIV/DLW ratio is independent of body weight, we advocate PIV calculation using haemoglobin and RBC as an excellent parameter for drug dose calculation during ILuP intraoperatively in order to achieve more reproducible local drug levels and higher efficacy.

Objective: Isolated lung perfusion is an experimental technique for the treatment of lung metastases. Single-agent isolated lung perfusion does not result in complete remission. We studied the in vivo and in vitro efficacy of combinations of gemcitabine, cisplatin, and melphalan., Methods: In vitro, using the sulforhodamine B assay, CC531s cells were incubated with cisplatin, gemcitabine, or melphalan or with a combination of these drugs. One drug was added at concentrations causing 25% growth inhibition, whereas the second drug was added at variable concentrations. In vivo, left pulmonary metastases were induced in Wag/Rij rats by means of intravenous injection of CC531s adenocarcinoma cells. At day 7, rats underwent left isolated lung perfusion with gemcitabine (n = 7), cisplatin (n = 9), melphalan (n = 7), gemcitabine-cisplatin (n = 6), melphalan-gemcitabine (n = 6), and cisplatin-melphalan (n = 7). Death by means of metastatic disease was the end point. Survival and differences in survival were assessed by using Kaplan-Meier and log-rank testing., Results: In vitro synergistic activity was observed for melphalan-gemcitabine, whereas other combinations showed additive or antagonistic activity. In vivo treated rats lived longer compared with control animals ( P < .0001). In isolated lung perfusion melphalan resulted in longer survival compared with gemcitabine ( P = .0016) and cisplatin ( P = .046). Isolated lung perfusion with melphalan-gemcitabine resulted in 67% survival of the rats after 90 days versus 0% in other groups., Conclusions: Isolated lung perfusion monotherapy or combination therapy with gemcitabine, cisplatin, or melphalan resulted in significantly longer survival compared with that seen in control animals. Isolated lung perfusion combination therapy with melphalan-gemcitabine resulted in the best survival either in vitro or in vivo.

Objective: Isolated lung perfusion (ILuP) is an experimental technique currently tested to increase the 5-year survival of 40% after surgical resection of pulmonary metastases from certain solid tumors. The standard technique of anterograde perfusion was compared with retrograde isolated lung perfusion in which the drug is introduced through the pulmonary veins while the effluent is collected from the pulmonary artery. Since the lung has a dual arterial circulation through the pulmonary artery and bronchial circulation, perfusion through the pulmonary veins can result in a more homogeneous distribution throughout the lung with subsequent higher melphalan concentration., Methods: We randomized 20 rats into two groups. Group one underwent anterograde isolated left lung perfusion while group two underwent retrograde isolated left lung perfusion. A dose of 2 mg/kg melphalan (MN) was administered to the lung at a flow of 0.5 mL/min during 30 min, followed by a 5-min washout with buffered hetastarch (BHE). The final melphalan lung concentration (FMLC) was determined in the hilum, at the apex, the mid-periphery and the base of the lung. Statistical analysis was done with an unpaired student's t-test., Results: Retrograde left ILuP resulted in a higher FMLC in the hilum (P<0.0001) and in the base of the lung (P=0.03), while anterograde ILuP induced a higher concentration at the apex of the lung (P=0.04). No difference was seen in the mid-peripheral area of the lung (P=0.92)., Conclusions: In this experimental study, retrograde perfusion seems to increase final melphalan lung concentration in hilar and basal regions of the lung compared to anterograde perfusion.

Background: Efficacy studies of isolated lung perfusion (ILuP) with melphalan showed superior results compared to intravenous therapy. However, the influence of pharmacokinetic parameters on the final melphalan lung concentration (FMLC) is unknown. In this study, we studied the impact of three different perfusion parameters on the FMLC in different areas of the lung., Material and Methods: Fifty-four rats were randomized into nine groups. Each group underwent ILuP with variation of perfusion duration (15, 30, and 60 min), the flow (0.125, 0.25, and 0.5 ml/min), concentration (8.3, 16.7, 33.3, 66.7, and 133.3 microg/ml) and the resulting dose (maximum 4 mg/kg). Lung samples were taken from the hilum and at the periphery of the lung (apex, base). Additional samples were taken to evaluate wet-to-dry ratio (W/D-ratio). Multiple linear regression and Student's t test were used for analysis. Significance was defined as a P

Background: Current 5-year survival after complete resection of pulmonary metastases is 20% to 40%, and many patients develop intrathoracic recurrences. Isolated lung perfusion is an experimental technique to deliver high-dose chemotherapy to the lung without systemic exposure. A phase I trial of isolated lung perfusion with melphalan (MN) combined with pulmonary metastasectomy for resectable lung metastases was conducted to define the dose-limiting toxicity and maximum tolerated dose., Methods: From May 2001 to August 2003, 16 patients underwent isolated lung perfusion with MN, followed by surgical resection of lung metastases. Patients were treated with increasing MN doses (15, 30, 45, and 60 mg). For each dose level, normothermia (37 degrees C) and hyperthermia (42 degrees C) were evaluated (n = 3 per level). Serum samples were obtained during the procedure. Pulmonary, hematologic, and nonhematologic toxicities were recorded. The primary tumor was colorectal in 7 patients, renal in 5, sarcoma in 3, and salivary gland in 1. Isolated lung perfusion was performed unilaterally in 11 patients, and staged bilaterally in 5., Results: In total, 21 procedures of isolated lung perfusion with complete metastasectomy were performed without technical difficulties. Operative mortality was 0%, and no systemic toxicity was encountered. Grade 3 pulmonary toxicity developed at a dose of 60 mg of MN at 37 degrees C in 2 of 3 patients at this dose, terminating the trial., Conclusions: Isolated lung perfusion with MN combined with pulmonary metastasectomy is feasible. Dose-limiting toxicity occurred at a dose of 60 mg of MN at 37 degrees C, and the maximum tolerated dose was set at 45 mg of MN at 42 degrees C.

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: 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.

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.