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Michael E Burt - One of the best experts on this subject based on the ideXlab platform.
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Toxicity and pharmacokinetics of Isolated Lung perfusion with cisplatin in rat.
The Japanese journal of thoracic and cardiovascular surgery : official publication of the Japanese Association for Thoracic Surgery = Nihon Kyobu Geka, 2001Co-Authors: Yoshikazu Kaneda, Michael E Burt, David Liu, Ari D. Brooks, Amir Abolohda, Daniel M. Labow, Robert J. GinsbergAbstract:Objective: This study was designed to evaluated the toxicity and the pharmacokinetics of cisplatin administered via Isolated Lung perfusion in Fischer 344 rat.Methods: Toxicity study; Cisplatin dosages of 3.3, 5.0, 6.7, and 10.0 mg/kg were injected intravenously in four groups, respectively. Cisplatin dosages of 3.3, 5.0, and 6.7 mg/kg were perfused via Isolated Lung perfusion in a further three groups, respectively. The maximum tolerated dosage of cisplatin was determined by assessing the survival rate on day 21. Pharmacokinetics study; Animals received 6.7 mg/kg of cisplatin intravenously or 3.3 mg/kg of cisplatin via Isolated Lung perfusion. The cisplatin levels of the Lung were measured by flameless atomic spectrometry.Results: Toxicity study; The maximum tolerated dosage of cisplatin via intravenous injection was 6.7 mg/kg, and via Isolated Lung perfusion was 3.3 mg/kg. Pharmacokinetics study; The cisplatin level in the perfused lugn was significantly higher than that in the Lung of the animal treated intravenously (16.6±6.2 μg/g of tissue and 7.5±3.2 μg/g of tissue, respectively) (p=0.0096).Conclusion: Isolated Lung perfusion with 3.3 mg/kg of cisplatin was pharmacokinetically superior to the maximum tolerated intravenous injection of cisplatin.
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Isolated Lung perfusion for patients with unresectable metastases from sarcoma a phase i trial
The Annals of Thoracic Surgery, 2000Co-Authors: Michael E Burt, Howard M Ross, Amir Abolhoda, Yoshikazu Kaneda, Robert J. Ginsberg, Ellen Jara, Ephraim S Casper, Murray F BrennanAbstract:Abstract Background . In patients with unresectable pulmonary metastases from sarcoma, systemic chemotherapy has had limited efficacy possibly because of dose-limiting toxicities. Isolated Lung perfusion is an alternative method of delivering high-dose chemotherapy to the Lungs while minimizing systemic toxicities. We present the results of our Phase I trial of Isolated Lung perfusion with doxorubicin hydrochloride in such a group of patients. Methods . From May 1995 to June 1997, 8 patients with unresectable metastases from sarcoma limited to the Lungs underwent Isolated Lung perfusion with doxorubicin. A dose-escalation schedule starting at 40 mg/m 2 was used. Seven patients were treated with a dose of 40 mg/m 2 or less, and 1 patient received 80 mg/m 2 . Blood, tumor, and normal Lung samples were obtained at various time points during the operation. Patients were evaluated for cardiac, pulmonary, and other toxicities. Results . The doxorubicin concentrations in both normal Lung and tumor correlated directly with the amount of doxorubicin in the perfusate. The tumors took up less doxorubicin than the Lung. All patients had minimal or undetectable systemic levels of doxorubicin at the conclusion of the perfusion. There were no cardiac or other systemic toxicities. In the 7 patients perfused with 40 mg/m 2 or less of doxorubicin, there was a significant decrease in the forced expiratory volume in 1 second and a trend toward a significant decrease in diffusing capacity. The patient who received 80 mg/m 2 underwent Lung scanning postoperatively, and scans showed no ventilation or perfusion in the perfused Lung. There were no perioperative deaths. Two patients are alive with disease, and 6 patients died of disease. The median follow-up is 11 months and the longest, 31 months. There were no partial or complete responses. One patient had stabilization of disease in the perfused Lung, whereas the lesions in the untreated Lung progressed markedly. Conclusion . Isolated Lung perfusion is well tolerated by patients and effectively delivers high doses of doxorubicin to the Lung and tumor tissues while minimizing systemic toxicities. A single dose of 80 mg/m 2 resulted in substantial injury to the Lung. There were no partial or complete responses in patients perfused with doxorubicin at the maximum tolerated dose of 40 mg/m 2 . Isolated Lung perfusion remains a model for testing new and innovative therapies for metastatic sarcoma.
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Isolated Lung Perfusion: Single-Pass System Versus Recirculating Blood Perfusion in Pigs
The Annals of thoracic surgery, 1998Co-Authors: Markus Furrer, Didier Lardinois, Wolfgang Thormann, Hans Jörg Altermatt, Daniel Betticher, Thomas Cerny, Antonin Fikrle, Daniel Mettler, Ulrich Althaus, Michael E BurtAbstract:Abstract Background . Cytostatic Isolated Lung perfusion has been advocated for treating pulmonary metastasis of soft tissue sarcoma. Different techniques of Isolated Lung perfusion have been developed. Methods . Isolated Lung perfusion with and without doxorubicin was performed on white pigs during 15 minutes either by a single-pass system (n = 7) or by a recirculating-blood perfusion system (n = 7). Three animals with endovenous drug application served as controls. Leakage was assessed using isotopic tracers. Perfusion-induced Lung tissue injury was determined by postperfusion chest radiographs, by angiotensin-converting enzyme-to-protein ratio in the plasma and in the bronchioalveolar lavage fluid, and by wet-to-dry weight ratio and histologic examination of Lung biopsy specimens at 20 and 50 minutes. Doxorubicin concentration in Lung tissue and plasma was compared between the three study groups. Results . All Isolated Lung perfusion studies were successfully performed without significant systemic leakage ( p p p Conclusions . Both Isolated Lung perfusion techniques resulted in a sixfold to sevenfold higher doxorubicin Lung tissue concentration than after endovenous application. Isolated Lung perfusion-induced Lung injury was similar for both techniques, but recirculating-blood perfusion appeared to result in more acute Lung injury and was technically more demanding than single-pass perfusion.
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Isolated Lung perfusion with antineoplastic agents for pulmonary metastases.
Chest surgery clinics of North America, 1998Co-Authors: Benny Weksler, Michael E BurtAbstract:Lung metastases is a major cause of death in cancer patients. A technique of Isolated Lung perfusion that uses infusions of high doses of local chemotherapy was developed in an attempt to control local disease. This technique prevents systemic side effects. Animal experiments have been encouraging and human trials are pending.
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Characterization of local inflammatory response in an Isolated Lung perfusion model.
Annals of surgical oncology, 1998Co-Authors: Amir Abolhoda, Huiming Cheng, Yoshikazu Kaneda, David Liu, Ari D. Brooks, Modassir Choudhry, Michael E BurtAbstract:Background: Current phase I trials of Isolated Lung perfusion for treatment of pulmonary metastases have an arbitrarily determined length of perfusion. Our objective was to examine the temporal course of the local and distant inflammatory response as a function of the length of perfusion (ischemia) and subsequent reperfusion in an equivalent animal model.
Jeroen M.h. Hendriks - One of the best experts on this subject based on the ideXlab platform.
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phase ii multicenter clinical trial of pulmonary metastasectomy and Isolated Lung perfusion with melphalan in patients with resectable Lung metastases
Journal of Thoracic Oncology, 2014Co-Authors: Willem Den Hengst, Jeroen M.h. Hendriks, Filip Lardon, Jan B. Vermorken, Michel I M Versteegh, Jerry Braun, Inez Rodrigus, Bram Balduyck, Hans Gelderblom, Franz M.n.h. SchramelAbstract: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.
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pulmonary adenocarcinoma Isolated Lung perfusion with melphalan and tumor necrosis factor for metastatic
2013Co-Authors: Allan T. Van Oosterom, Jeroen M.h. Hendriks, Paul Van Schil, Erik A. E. Van Marck, E. Eyskens, Patrick LauwersAbstract:Ann Thorac Surg 1998;66:1719-1725 Allan A.T. Van Oosterom, Erik A.E. Van Marck and Erik J.M. Eyskens Jeroen M.H. Hendriks, Paul E.Y. Van Schil, Gert De Boeck, Patrick R.M. Lauwers,pulmonary adenocarcinoma Isolated Lung perfusion with melphalan and tumor necrosis factor for metastatichttp://ats.ctsnetjournals.org/cgi/content/full/66/5/1719 on the World Wide Web at: The online version of this article, along with updated information and services, is located
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selective pulmonary artery perfusion with melphalan is equal to Isolated Lung perfusion but superior to intravenous melphalan for the treatment of sarcoma Lung metastases in a rodent model
European Journal of Cardio-Thoracic Surgery, 2012Co-Authors: Willem Den Hengst, Jeroen M.h. Hendriks, Tom Van Hoof, Karel Heytens, Gunther Guetens, Gert De Boeck, Filip Lardon, Paul Van SchilAbstract: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.
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Isolated Lung perfusion with gemcitabine combined with radiotherapy: no additional Lung toxicity in an experimental model
European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery, 2012Co-Authors: Jana Van Thielen, Jeroen M.h. Hendriks, Willem Den Hengst, Anouk Wittock, Christel De Pooter, Danielle Van Den Weyngaert, Patrick Pauwels, Paul Van SchilAbstract:OBJECTIVES: Isolated Lung perfusion with gemcitabine is an effective technique for the treatment of Lung metastases in an experimental model. In clinical studies, increased toxicity has been observed when combining intravenous gemcitabine with radiotherapy (RT). The goal of our study was to determine whether RT in combination with Isolated Lung perfusion increases Lung toxicity. METHODS: Rodents were randomized into eight groups: sham group, RT, intravenous gemcitabine, intravenous gemcitabine combined with RT, Isolated Lung perfusion with hydroxyethyl starch (HES) or gemcitabine, Isolated Lung perfusion with HES or gemcitabine combined with RT. Gemcitabine was administered in a dose of 40 mg/kg and RT as a single fraction of 8 Gy. The effect on Lung tissue was evaluated by % fibrosis in a haematoxylin–eosin stain and by % alveoli that contained siderophages on Perls stain. A total of 36 slices were made per treatment and per stain. The results of different groups were compared using logistic regression. RESULTS: There were no significant differences between treatment with intravenous gemcitabine and RT. Isolated Lung perfusion with gemcitabine showed significant more histopathologic changes compared with intravenous gemcitabine (P < 0.0001). When RT was added, there was no fibrosis after intravenous gemcitabine and mild-to-moderate haemosiderosis. After Isolated Lung perfusion with gemcitabine combined with RT, there was moderate to severe fibrosis and mild to severe haemosiderosis. Adding RT to Isolated Lung perfusion with gemcitabine showed no significant difference compared to Isolated Lung perfusion alone. CONCLUSIONS: Combination of Isolated Lung perfusion and RT is feasible in an experimental model. No additional toxicity of RT was observed compared to Isolated Lung perfusion alone. Further studies are necessary to determine efficacy of this combined treatment.
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Pharmacokinetics of Isolated Lung perfusion with melphalan for resectable pulmonary metastases, a phase I and extension trial.
Journal of surgical oncology, 2007Co-Authors: Marco J.j.h. Grootenboers, Jeroen M.h. Hendriks, Bart P. Van Putte, Wim J. Van Boven, Jan B. Vermorken, Bernard Stockman, Catherijne A. J. Knibbe, Ernst A. De Bruijn, Paul Van Schil, Franz M.n.h. SchramelAbstract: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 (R2 = 0.578, P = 0.001) and Lung tissue concentrations (R2 = 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. J. Surg. Oncol. 2007;96:583–589. © 2007 Wiley-Liss, Inc.
Bart P. Van Putte - One of the best experts on this subject based on the ideXlab platform.
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multicenter phase ii clinical trial of Isolated Lung perfusion in patients with Lung metastases
The Annals of Thoracic Surgery, 2019Co-Authors: Paul Beckers, Willem Den Hengst, Bart P. Van Putte, Michel I M Versteegh, Thomas J Van Brakel, Jerry Braun, A P W M Maat, Wim Vergauwen, Inez Rodrigus, Filip LardonAbstract: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.
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Isolated Lung perfusion and related techniques for the treatment of pulmonary metastases.
European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery, 2008Co-Authors: Paul Van Schil, Bart P. Van Putte, Marco J.j.h. Grootenboers, Jeroen M. Hendriks, Bernard A Stockman, Patrick R Lauwers, Pieter W Ten Broecke, Franz M.n.h. SchramelAbstract: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.
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Pharmacokinetics of Isolated Lung perfusion with melphalan for resectable pulmonary metastases, a phase I and extension trial.
Journal of surgical oncology, 2007Co-Authors: Marco J.j.h. Grootenboers, Jeroen M.h. Hendriks, Bart P. Van Putte, Wim J. Van Boven, Jan B. Vermorken, Bernard Stockman, Catherijne A. J. Knibbe, Ernst A. De Bruijn, Paul Van Schil, Franz M.n.h. SchramelAbstract: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 (R2 = 0.578, P = 0.001) and Lung tissue concentrations (R2 = 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. J. Surg. Oncol. 2007;96:583–589. © 2007 Wiley-Liss, Inc.
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Isolated Lung perfusion for pulmonary metastases.
Thoracic surgery clinics, 2006Co-Authors: Jeroen M.h. Hendriks, Bart P. Van Putte, Marco J.j.h. Grootenboers, Wim J. Van Boven, Franz M.n.h. Schramel, Paul Van SchilAbstract: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.
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Isolated Lung perfusion for pulmonary metastases, a review and work in progress.
Perfusion, 2006Co-Authors: Marco J.j.h. Grootenboers, Jeroen M.h. Hendriks, Bart P. Van Putte, Wim J. Van Boven, Paul Van Schil, Jos Heeren, Franz M.n.h. SchramelAbstract: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 2540%, 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. Perfusion (2006) 21, 267 276.
Paul Van Schil - One of the best experts on this subject based on the ideXlab platform.
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pulmonary adenocarcinoma Isolated Lung perfusion with melphalan and tumor necrosis factor for metastatic
2013Co-Authors: Allan T. Van Oosterom, Jeroen M.h. Hendriks, Paul Van Schil, Erik A. E. Van Marck, E. Eyskens, Patrick LauwersAbstract:Ann Thorac Surg 1998;66:1719-1725 Allan A.T. Van Oosterom, Erik A.E. Van Marck and Erik J.M. Eyskens Jeroen M.H. Hendriks, Paul E.Y. Van Schil, Gert De Boeck, Patrick R.M. Lauwers,pulmonary adenocarcinoma Isolated Lung perfusion with melphalan and tumor necrosis factor for metastatichttp://ats.ctsnetjournals.org/cgi/content/full/66/5/1719 on the World Wide Web at: The online version of this article, along with updated information and services, is located
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Isolated Lung perfusion with gemcitabine combined with radiotherapy: no additional Lung toxicity in an experimental model
European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery, 2012Co-Authors: Jana Van Thielen, Jeroen M.h. Hendriks, Willem Den Hengst, Anouk Wittock, Christel De Pooter, Danielle Van Den Weyngaert, Patrick Pauwels, Paul Van SchilAbstract:OBJECTIVES: Isolated Lung perfusion with gemcitabine is an effective technique for the treatment of Lung metastases in an experimental model. In clinical studies, increased toxicity has been observed when combining intravenous gemcitabine with radiotherapy (RT). The goal of our study was to determine whether RT in combination with Isolated Lung perfusion increases Lung toxicity. METHODS: Rodents were randomized into eight groups: sham group, RT, intravenous gemcitabine, intravenous gemcitabine combined with RT, Isolated Lung perfusion with hydroxyethyl starch (HES) or gemcitabine, Isolated Lung perfusion with HES or gemcitabine combined with RT. Gemcitabine was administered in a dose of 40 mg/kg and RT as a single fraction of 8 Gy. The effect on Lung tissue was evaluated by % fibrosis in a haematoxylin–eosin stain and by % alveoli that contained siderophages on Perls stain. A total of 36 slices were made per treatment and per stain. The results of different groups were compared using logistic regression. RESULTS: There were no significant differences between treatment with intravenous gemcitabine and RT. Isolated Lung perfusion with gemcitabine showed significant more histopathologic changes compared with intravenous gemcitabine (P < 0.0001). When RT was added, there was no fibrosis after intravenous gemcitabine and mild-to-moderate haemosiderosis. After Isolated Lung perfusion with gemcitabine combined with RT, there was moderate to severe fibrosis and mild to severe haemosiderosis. Adding RT to Isolated Lung perfusion with gemcitabine showed no significant difference compared to Isolated Lung perfusion alone. CONCLUSIONS: Combination of Isolated Lung perfusion and RT is feasible in an experimental model. No additional toxicity of RT was observed compared to Isolated Lung perfusion alone. Further studies are necessary to determine efficacy of this combined treatment.
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Metastatic Cancers in Lung: Isolated Lung Perfusion – Clinical Studies
Induction Chemotherapy, 2011Co-Authors: Paul Van Schil, Willem Den Hengst, Jeroen M. HendriksAbstract: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. Other related methods of delivering high-dose locoregional chemotherapy include embolic trapping (chemo-embolization) 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. 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.
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Isolated Lung perfusion and related techniques for the treatment of pulmonary metastases.
European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery, 2008Co-Authors: Paul Van Schil, Bart P. Van Putte, Marco J.j.h. Grootenboers, Jeroen M. Hendriks, Bernard A Stockman, Patrick R Lauwers, Pieter W Ten Broecke, Franz M.n.h. SchramelAbstract: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.
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Isolated Lung perfusion for pulmonary metastases.
Thoracic surgery clinics, 2006Co-Authors: Jeroen M.h. Hendriks, Bart P. Van Putte, Marco J.j.h. Grootenboers, Wim J. Van Boven, Franz M.n.h. Schramel, Paul Van SchilAbstract: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.
Amir Abolhoda - One of the best experts on this subject based on the ideXlab platform.
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Isolated Lung perfusion for patients with unresectable metastases from sarcoma a phase i trial
The Annals of Thoracic Surgery, 2000Co-Authors: Michael E Burt, Howard M Ross, Amir Abolhoda, Yoshikazu Kaneda, Robert J. Ginsberg, Ellen Jara, Ephraim S Casper, Murray F BrennanAbstract:Abstract Background . In patients with unresectable pulmonary metastases from sarcoma, systemic chemotherapy has had limited efficacy possibly because of dose-limiting toxicities. Isolated Lung perfusion is an alternative method of delivering high-dose chemotherapy to the Lungs while minimizing systemic toxicities. We present the results of our Phase I trial of Isolated Lung perfusion with doxorubicin hydrochloride in such a group of patients. Methods . From May 1995 to June 1997, 8 patients with unresectable metastases from sarcoma limited to the Lungs underwent Isolated Lung perfusion with doxorubicin. A dose-escalation schedule starting at 40 mg/m 2 was used. Seven patients were treated with a dose of 40 mg/m 2 or less, and 1 patient received 80 mg/m 2 . Blood, tumor, and normal Lung samples were obtained at various time points during the operation. Patients were evaluated for cardiac, pulmonary, and other toxicities. Results . The doxorubicin concentrations in both normal Lung and tumor correlated directly with the amount of doxorubicin in the perfusate. The tumors took up less doxorubicin than the Lung. All patients had minimal or undetectable systemic levels of doxorubicin at the conclusion of the perfusion. There were no cardiac or other systemic toxicities. In the 7 patients perfused with 40 mg/m 2 or less of doxorubicin, there was a significant decrease in the forced expiratory volume in 1 second and a trend toward a significant decrease in diffusing capacity. The patient who received 80 mg/m 2 underwent Lung scanning postoperatively, and scans showed no ventilation or perfusion in the perfused Lung. There were no perioperative deaths. Two patients are alive with disease, and 6 patients died of disease. The median follow-up is 11 months and the longest, 31 months. There were no partial or complete responses. One patient had stabilization of disease in the perfused Lung, whereas the lesions in the untreated Lung progressed markedly. Conclusion . Isolated Lung perfusion is well tolerated by patients and effectively delivers high doses of doxorubicin to the Lung and tumor tissues while minimizing systemic toxicities. A single dose of 80 mg/m 2 resulted in substantial injury to the Lung. There were no partial or complete responses in patients perfused with doxorubicin at the maximum tolerated dose of 40 mg/m 2 . Isolated Lung perfusion remains a model for testing new and innovative therapies for metastatic sarcoma.
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Characterization of local inflammatory response in an Isolated Lung perfusion model.
Annals of surgical oncology, 1998Co-Authors: Amir Abolhoda, Huiming Cheng, Yoshikazu Kaneda, David Liu, Ari D. Brooks, Modassir Choudhry, Michael E BurtAbstract:Background: Current phase I trials of Isolated Lung perfusion for treatment of pulmonary metastases have an arbitrarily determined length of perfusion. Our objective was to examine the temporal course of the local and distant inflammatory response as a function of the length of perfusion (ischemia) and subsequent reperfusion in an equivalent animal model.
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Isolated Lung Perfusion With Doxorubicin Prolongs Survival in a Rodent Model of Pulmonary Metastases
The Annals of thoracic surgery, 1997Co-Authors: Amir Abolhoda, Sumihiko Nawata, Huiming Cheng, Yoshikazu Kaneda, Ari D. Brooks, Michael E BurtAbstract:Abstract Background . We developed a rodent model of unilateral pulmonary metastases to evaluate long-term survival after Isolated Lung perfusion with doxorubicin. Methods . In the model development study, on day 0, two groups of F344 rats (n = 15) underwent transient right pulmonary artery occlusion for either 5 or 10 minutes at the time of intravenous injection of methylcholantrene-induced sarcoma cells. On day 14, all animals were sacrificed and Lung nodules counted. In the survival study, on day 0, 21 rats received intravenous injection of sarcoma cells with concomitant 10-minute right pulmonary artery occlusion. On day 7, eight rats underwent left Isolated Lung perfusion with doxorubicin (6.4 mg/kg); five rats underwent perfusion with buffered Hespan; six untreated rats were studied as controls. Results . Ten of fifteen animals (67%) in the model study with 5-minute pulmonary artery occlusion had right-sided tumor nodules. Ten-minute occlusion resulted in a tumor-free right Lung in all animals. In the survival study, all animals in the Hespan and control groups died of massive tumor replacement of the left Lung, with median survival times of 20 and 18 days, respectively. The median survival time of 36 days for the animals undergoing Isolated Lung perfusion with doxorubicin was significantly longer ( p Conclusions . Isolated Lung perfusion with doxorubicin results in a durable response and prolongs survival in the treatment of experimental sarcoma pulmonary metastases.
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Sequential Bilateral Isolated Lung Perfusion in the Rat: An Experimental Model
The Annals of thoracic surgery, 1997Co-Authors: Sumihiko Nawata, Howard M Ross, Amir Abolhoda, Ari D. Brooks, Michael E BurtAbstract:Abstract Background . A model of Isolated single-Lung perfusion in the rat has been established in our laboratory to study the chemotherapeutic treatment of pulmonary metastases. A sequential bilateral Isolated Lung perfusion model was designed to investigate the feasibility of staged perfusions in the rat. Methods . Twenty-four Fischer rats were randomized into three experimental groups of 8 rats each. All rats underwent left Isolated Lung perfusion. One, 2, or 3 weeks later, the rats in groups I, II, and III, respectively, underwent contralateral (right) perfusion. Five control animals (group IV) underwent sequential bilateral sham thoracotomies 1 week apart. Arterial blood gas analysis was performed 1 week after the second operation in the rats in groups I and IV. Results . All animals survived the first operation, with 100% (8/8), 75% (6/8), and 100% (8/8) of the animals in perfusion groups I, II, and III, respectively, surviving the second operation. All control animals (group IV) survived the second sham thoracotomy. Arterial blood gas analysis did not show a significant difference in the oxygen or carbon dioxide partial pressure or the pH between group I and IV ( p = 0.32, 0.96, and 0.76, respectively). Conclusions . Our experiments demonstrate that sequential bilateral Isolated Lung perfusion is safe in and well tolerated by the rat. This model can be used to investigate the safety and efficacy of staged perfusions with chemotherapeutic agents in the treatment of bilateral pulmonary metastases in the rat.
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Isolated Lung perfusion with melphalan for the treatment of metastatic pulmonary sarcoma
The Journal of Thoracic and Cardiovascular Surgery, 1996Co-Authors: Sumihiko Nawata, Nuno Abecasis, Howard M Ross, Amir Abolhoda, Huiming Cheng, Komal S Sachar, Michael E BurtAbstract:Abstract Objective: Isolated Lung perfusion allows the delivery of high-dose chemotherapy to the perfused Lung and is an efficacious modality in the treatment of pulmonary metastases in the rat. Melphalan activity in this model was investigated. Methods: Toxicity study: Maximum tolerated dose of melphalan delivered by means of Isolated Lung perfusion was determined by survival after contralateral pneumonectomy. Pharmacokinetics study: Nineteen rats were treated with melphalan administered either by Isolated Lung perfusion (2 mg) or intravenously (2 mg or 1 mg). Lung, pulmonary effluent, and serum melphalan were analyzed by high-pressure liquid chromatography. Efficacy study: On day 0, 41 rats received an intravenous injection of 5 × 10 6 methylcholanthrene induced sarcoma cells. On day 7, rats either received intravenous melphalan (2 mg [ n = 10]; 1 mg [ n = 8]) or underwent left Isolated Lung perfusion with 2 mg of melphalan ( n = 12). Isolated Lung perfusion with buffered hetastarch in sodium chloride (Hespan, n = 11) was used as control. On day 14, pulmonary nodules were counted. Results: Toxicity: Maximum tolerated dose of melphalan delivered buy means of Isolated Lung perfusion was 2 mg. Pharmacokinetics: Left Lung melphalan level was significantly higher in the Isolated Lung perfusion group (62.2 ± 34.3 μg/gm Lung) than in the intravenous treatment groups (6.9 ± 1.9 μg/gm Lung and 3.3 ± 0.9 μ g/gm Lung, respectively) ( p = 0.0002). Efficacy: Significantly fewer left Lung nodules were found in animals receiving melphalan by means of Isolated Lung perfusion (7 ± 10) than in the groups receiving intravenous melphalan (60 ± 21) or buffered hetastarch by Isolated Lung perfusion (84 ± 52) ( p = 0.01 and p = 0.0001, respectively). Conclusion: Isolated Lung perfusion with melphalan is safe and effective in the treatment of pulmonary sarcoma metastases in the rat. (J Thorac Cardiovasc Surg 1996;112:1542-8)
