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Title: Isolated total lung perfusion as a means to deliver organ-specific chemotherapy: long-term studies in animals

Abstract

The objectives of this study were to develop a surgical procedure that would allow for bilateral isolated lung perfusion in vivo as a means of delivering organ-specific chemotherapy and to evaluate the influence of the procedure on certain pulmonary physiologic parameters. The sterile surgical procedure that was carried out in dogs involved the setting up of two separate perfusion circuits. Once standard systemic cardiopulmonary bypass was established, a second circuit was devised to perfuse the lungs by placing an inflow cannula into the main pulmonary artery and collecting venous effluent in the left atrium. Cross-contamination between perfusion circuits was determined in acute studies with labeled plasma protein or red blood cells and was found to be in an acceptable range if the aorta was cross-clamped and the heart arrested. Only about 0.4 ml/min of pulmonary perfusate leaked into the systemic circulation, indicating that systemic toxicity should not be a major concern when chemotherapy agents are added to the pulmonary perfusate. Chronic studies demonstrated that hemodynamic parameters, lung water, pulmonary endothelial serotonin extraction, and histologic findings all showed minimal changes after 50 minutes of isolated lung perfusion. Five days after perfusion, lung dynamic compliance and peak serotonin extraction showed significant decreases.more » However, all of the measured parameters had returned toward baseline levels by the end of the 8-week postoperative study period. The procedure offers significant advantages over the previously described single lung perfusion and may provide a method of delivering immediate high-concentration adjuvant chemotherapy to coincide with resection of primary or metastatic lung tumors.« less

Authors:
; ; ; ; ; ; ;
Publication Date:
Research Org.:
Medical College of Wisconsin, Milwaukee
OSTI Identifier:
5220224
Resource Type:
Journal Article
Resource Relation:
Journal Name: Surgery; (United States); Journal Volume: 1
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; 59 BASIC BIOLOGICAL SCIENCES; HEART; SURGERY; LUNGS; PERFUSED ORGANS; DYNAMIC FUNCTION STUDIES; BIOPSY; BLOOD CIRCULATION; CHEMOTHERAPY; DOGS; ERYTHROCYTES; IN VIVO; RADIOISOTOPES; SEROTONIN; AMINES; ANIMALS; AROMATICS; AUTONOMIC NERVOUS SYSTEM AGENTS; AZAARENES; AZOLES; BIOLOGICAL MATERIALS; BLOOD; BLOOD CELLS; BODY; BODY FLUIDS; CARDIOVASCULAR SYSTEM; DIAGNOSTIC TECHNIQUES; DRUGS; HETEROCYCLIC COMPOUNDS; HYDROXY COMPOUNDS; INDOLES; ISOTOPES; MAMMALS; MATERIALS; MEDICINE; NEUROREGULATORS; ORGANIC COMPOUNDS; ORGANIC NITROGEN COMPOUNDS; ORGANS; PYRROLES; RADIOPROTECTIVE SUBSTANCES; RESPIRATORY SYSTEM; SYMPATHOMIMETICS; THERAPY; TRYPTAMINES; VERTEBRATES; 550600* - Medicine; 551001 - Physiological Systems- Tracer Techniques

Citation Formats

Johnston, M.R., Christensen, C.W., Minchin, R.F., Rickaby, D.A., Linehan, J.H., Schuller, H.M., Boyd, M.R., and Dawson, C.A. Isolated total lung perfusion as a means to deliver organ-specific chemotherapy: long-term studies in animals. United States: N. p., 1985. Web.
Johnston, M.R., Christensen, C.W., Minchin, R.F., Rickaby, D.A., Linehan, J.H., Schuller, H.M., Boyd, M.R., & Dawson, C.A. Isolated total lung perfusion as a means to deliver organ-specific chemotherapy: long-term studies in animals. United States.
Johnston, M.R., Christensen, C.W., Minchin, R.F., Rickaby, D.A., Linehan, J.H., Schuller, H.M., Boyd, M.R., and Dawson, C.A. Mon . "Isolated total lung perfusion as a means to deliver organ-specific chemotherapy: long-term studies in animals". United States. doi:.
@article{osti_5220224,
title = {Isolated total lung perfusion as a means to deliver organ-specific chemotherapy: long-term studies in animals},
author = {Johnston, M.R. and Christensen, C.W. and Minchin, R.F. and Rickaby, D.A. and Linehan, J.H. and Schuller, H.M. and Boyd, M.R. and Dawson, C.A.},
abstractNote = {The objectives of this study were to develop a surgical procedure that would allow for bilateral isolated lung perfusion in vivo as a means of delivering organ-specific chemotherapy and to evaluate the influence of the procedure on certain pulmonary physiologic parameters. The sterile surgical procedure that was carried out in dogs involved the setting up of two separate perfusion circuits. Once standard systemic cardiopulmonary bypass was established, a second circuit was devised to perfuse the lungs by placing an inflow cannula into the main pulmonary artery and collecting venous effluent in the left atrium. Cross-contamination between perfusion circuits was determined in acute studies with labeled plasma protein or red blood cells and was found to be in an acceptable range if the aorta was cross-clamped and the heart arrested. Only about 0.4 ml/min of pulmonary perfusate leaked into the systemic circulation, indicating that systemic toxicity should not be a major concern when chemotherapy agents are added to the pulmonary perfusate. Chronic studies demonstrated that hemodynamic parameters, lung water, pulmonary endothelial serotonin extraction, and histologic findings all showed minimal changes after 50 minutes of isolated lung perfusion. Five days after perfusion, lung dynamic compliance and peak serotonin extraction showed significant decreases. However, all of the measured parameters had returned toward baseline levels by the end of the 8-week postoperative study period. The procedure offers significant advantages over the previously described single lung perfusion and may provide a method of delivering immediate high-concentration adjuvant chemotherapy to coincide with resection of primary or metastatic lung tumors.},
doi = {},
journal = {Surgery; (United States)},
number = ,
volume = 1,
place = {United States},
year = {Mon Jul 01 00:00:00 EDT 1985},
month = {Mon Jul 01 00:00:00 EDT 1985}
}
  • Formation of lipids in isolated liver was studied by their incorporation of acetate-1-C/sup 14/ during perfusion of the liver yvith heparinized blood of normal and irradiated rats. Blood was obtained 24 hr after irradiation with a single dose of 3500 r. Synthesis of both cholesterol and fatty acids was significantiy stimulated by blood of irradiated animals. The mean specific activities with normal and irradiated blood, respectively, were 1185 and 2290 cpm/ mg for cholesterol, and 387 and 589 for fatty acids. The incorporation of C/sup 14/ into lipids of the perfusing serum was also greater 4 hr later with lrradiatedmore » blood; the respective values of specific activity were 421 and 1110 cpm/mg for cholesterol, and 65 and 138 fatty acids. The results are in accord with previous findings that irradiation of rats causes accumulation of lipid in the liver in the intact animal. (H.H.D.)« less
  • Purpose: To examine the outcome of patients who developed an isolated locoregional recurrence (LRR) involving the supraclavicular fossa (SCV) after initial treatment with modified radical mastectomy and chemotherapy. Methods and Materials: Records from 140 breast cancer patients treated on five prospective trials with mastectomy and doxorubicin-based chemotherapy, with or without radiation, who developed a LRR were reviewed. Kaplan-Meier survival times were calculated using date of LRR as time zero. Results: The median follow-up after LRR was 2.9 years (N = 140; interquartile range, 1.3-6.6 years). In all, 47 of 140 patients (34%) had an SCV component to their LRR. Thesemore » patients had lower 3-y distant metastasis-free survival (40% vs. 54%, p = 0.003) and overall survival (49% vs. 69%, p = 0.04) than patients without an SCV component. Multivariate analysis revealed that LRR involving an SCV component (hazard ratio, 1.96, p = 0.004) and patients with lymphovascular space invasion in their primary tumors (hazard ratio, 1.65, p = 0.029) were independently associated with a poor distant metastasis-free survival. However, among 23 patients with isolated SCV recurrence, Overall survival was not statistically significantly different between isolated chest wall recurrence and isolated SCV recurrence. Patients with isolated SCV recurrence displayed a median follow-up of 3.3 years (IR, 1.2-5.2). Only 6 LRR of 23 patients were treated with aggressive local therapy, including surgery, chemotherapy, and radiation (alone or in combination). Conclusions: Although breast cancer recurrence with SCV involvement carries a high risk of distant metastasis and death, among women with recurrence limited to the SCV alone, overall survival after isolated SCV recurrence can be long (25% >5 years).« less
  • Tumor angiogenesis is necessary for solid tumor progression and metastasis. Increasing evidence indicates that tumor endothelial cells (TECs) are more relevant to the study of tumor angiogenesis than normal endothelial cells (NECs) because their morphologies and gene expression are different from NECs. However, it is challenging to isolate and culture large numbers of pure ECs from tumor tissue since the percentage of ECs is only about 1-2% and tumor cells and fibroblasts easily overgrow them. In addition, there has been concern that isolated TECs may lose their special phenotype once they are dissociated from tumor cells. In this study, wemore » have successfully purified murine TECs from four different human tumor xenografts and NECs from murine dermal tissue. Isolated ECs expressed endothelial markers, such as CD31, VE-cadherin (CD144), and endoglin (CD105), for more than 3 months after isolation. TECs maintained tumor endothelial-specific markers, such as tumor endothelial marker 8 (TEM8) and aminopeptidase N (APN), as in tumor blood vessels in vivo. In addition, TECs were more proliferative and motile than NECs. TECs showed a higher response to VEGF and higher expression of VEGF receptors-1 and -2 than NECs did. Stem cell antigen-1 was up-regulated in all four TECs, suggesting that they have a kind of stemness. Cultured TECs maintain distinct biological differences from NECs as in vivo. In conclusion, it was suggested that TECs are relevant material for tumor angiogenesis research.« less
  • Purpose: We analyzed variables associated with long-term toxicity using three-dimensional conformal external beam radiation therapy (3D-CRT) to deliver accelerated partial breast irradiation. Methods and Materials: One hundred patients treated with 3D-CRT accelerated partial breast irradiation were evaluated using Common Terminology Criteria for Adverse Events version 4.0 scale. Cosmesis was scored using Harvard criteria. Multiple dosimetric and volumetric parameters were analyzed for their association with worst and last (W/L) toxicity outcomes. Results: Sixty-two patients had a minimum of 36 months of toxicity follow-up (median follow-up, 4.8 years). The W/L incidence of poor-fair cosmesis, any telangiectasia, and grade {>=}2 induration, volume reduction,more » and pain were 16.4%/11.5%, 24.2%/14.5%, 16.1%/9.7%, 17.7%/12.9%, and 11.3%/3.2%, respectively. Only the incidence of any telangiectasia was found to be predicted by any dosimetric parameter, with the absolute breast volume receiving 5% to 50% of the prescription dose (192.5 cGy-1925 cGy) being significant. No associations with maximum dose, volumes of lumpectomy cavity, breast, modified planning target volume, and PTV, dose homogeneity index, number of fields, and photon energy used were identified with any of the aforementioned toxicities. Non-upper outer quadrant location was associated with grade {>=}2 volume reduction (p = 0.02 W/p = 0.04 L). A small cavity-to-skin distance was associated with a grade {>=}2 induration (p = 0.03 W/p = 0.01 L), a borderline significant association with grade {>=}2 volume reduction (p = 0.06 W/p = 0.06 L) and poor-fair cosmesis (p = 0.08 W/p = 0.09 L), with threshold distances ranging from 5 to 8 mm. Conclusions: No dose--volume relationships associated with long-term toxicity were identified in this large patient cohort with extended follow-up. Cosmetic results were good-to-excellent in 88% of patients at 5 years.« less
  • Purpose: Long-term androgen suppression plus radiotherapy (AS+RT) is standard treatment of high-risk prostate cancer. A randomized trial, Radiation Therapy Oncology Group trial 9902, was undertaken to determine whether adjuvant chemotherapy with paclitaxel, estramustine, and etoposide (TEE) plus AS+RT would improve disease outcomes with acceptable toxicity. Methods and Materials: High-risk (prostate-specific antigen 20-100 ng/mL and Gleason score {>=}7; or Stage T2 or greater, Gleason score 8, prostate-specific antigen level <100 ng/mL) nonmetastatic prostate cancer patients were randomized to AS+RT (Arm 1) vs. AS+RT plus four cycles of TEE (Arm 2). TEE was delivered 4 weeks after RT. AS continued for 2more » years for both treatment arms. RT began after 8 weeks of AS began. Results: The Radiation Therapy Oncology Group 9902 trial opened January 11, 2000. Excess thromboembolic toxicity was noted, leading to study closure October 4, 2004. A total of 397 patients were accrued, and the data for 381 were analyzable. An acute and long-term toxicity analysis was performed. The worst overall toxicities during treatment were increased for Arm 2. Of the 192 patients, 136 (71%) on Arm 2 had RTOG Grade 3 or greater toxicity compared with 70 (37%) of 189 patients on Arm 1. Statistically significant increases in hematologic toxicity (p < 0.0001) and gastrointestinal toxicity (p = 0.017) but not genitourinary toxicity (p = 0.07) were noted during treatment. Two Grade 5 complications related to neutropenic infection occurred in Arm 2. Three cases of myelodysplasia/acute myelogenous leukemia were noted in Arm 2. At 2 and 3 years after therapy completion, excess long-term toxicity was not observed in Arm 2. Conclusion: TEE was associated with significantly increased toxicity during treatment. The toxicity profiles did not differ at 2 and 3 years after therapy. Toxicity is an important consideration in the design of trials using adjuvant chemotherapy for prostate cancer.« less