Isolated lung perfusion with tumor necrosis factor for pulmonary metastases

BACKGROUND: A phase I trial was initiated to define the feasibility and safety of single-lung isolation perfusion with tumor necrosis factor-alpha, interferon-gamma, and moderate hyperthermia for patients with unresectable pulmonary metastases. METHODS: Twenty patients with lung metastases (Ewing's, 2; sarcoma, 8; melanoma, 6; other, 4) were considered for single-lung isolation perfusion with 0.3 to 6.0 mg of tumor necrosis factor-alpha and 0.2 mg interferon-gamma delivered through an oxygenated pump circuit. Sixteen perfusions were performed in 15 patients (bilateral in 1). Metastases were completely resected (no single-lung isolation perfusion) in 3 patients, 1 patient had extrapulmonary disease, and one single-lung isolation perfusion was aborted for mechanical reasons. RESULTS: There were no significant changes in systemic arterial blood pressure or cardiac output during perfusion. Systolic pulmonary artery pressure increased with isolation, but returned to pre-single-lung isolation perfusion levels after clamp release. The maximum systemic tumor necrosis factor-alpha level was 8 ng/mL, whereas pump-circuit levels ranged from 200 to 10,976 ng/mL. There were no deaths, and the mean hospitalization period was 9 days (range, 5 to 34 days). A short-term (6 to 9 month) unilateral decrease in perfused nodules was noted in 3 patients (melanoma in 1, adenoid cystic carcinoma in 1, renal cell carcinoma in 1). CONCLUSIONS: Future studies using a combination of biologic modifiers, chemotherapy, and hyperthermia should be pursued to define active cytotoxic agents that will preserve underlying pulmonary function.     

Isolated hyperthermic limb perfusion with melphalan and tumor necrosis factor in malignant melanoma

OBJECTIVE: To analyse a personal series of cases of malignant melanoma of a limb with regional metastasis treated by isolated cytostatic perfusion of both recombinant human tumour necrosis factor (rhTNF-alpha) and melphalan, reported to produce a response rate of up to 100%. PATIENTS AND METHODS: 23 isolated hyperthermic regional perfusions were performed between 1993 and 1995 in 21 patients (17 women, four men) with proven regionally metastatic malignant melanoma of the limb, using rhTNF-alpha and melphalan in combination. Perfusion time was 90 min, at a tissue temperature of 38 degrees to 40 degrees C and a perfusion pressure 10-15 mm Hg below mean arterial. RESULTS: All systemic effects of the limb perfusions were easily manageable under intensive care monitoring. There were no severe disturbances (WHO grade 3/4) of cardiovascular or pulmonary functions. One patient, who had sustained a marked leak during the perfusion, died two days after the perfusion of severe pneumonia and pulmonary emboli from a femoral vein thrombosis. Two further perfusions were terminated because of a leakage rate of more than 10%. A rise in bilirubin and the transaminases occurred in 11 of the 23 perfusions up to WHO grade 2 (n = 9) and 3 (n = 2). Renal functions were temporarily impaired in three of the 21 patients (WHO grade 1). Complete tumour regression was obtained in 13 patients, a partial one in three (response rate 80%). After a median follow-up period of 15 months five of the 13 patients developed a regional recurrence. CONCLUSION: The observed response rate is higher than that with melphalan alone as reported in the literature. To clarify this difference a randomized phase III study comparing the two methods has been initiated.     

Reversal of somatostatin inhibition of insulin and glucagon secretion

These studies were designed to elucidate the mechanism of inhibitory action of somatostatin (SRIF) on glucagon (IRG) and insulin (IRI) secretion. Studies were carried out in the unrecirculated isolated rat pancreas perfusion with arginine 19.2 mM and glucose 5.5 mM as stimulus primarily for IRG but also IRI secretion. The effects of excess Ca++ (15.2 mEq./L.) and excess K+ (12.8 mEq./L.) on IRG, IRI, and the SRIF-inhibited pancreas were studied. Ca++ excess in five perfusions strikingly stimulated IRG secretion (+92 per cent) but only stabilized IRI secretion compared with control perfusions. K+ excess (in seven perfusions) markedly inhibited IRG secretion (-39 per cent) while stimulating IRI secretion (+16 per cent). Restoration of normal concentrations of K+ resulted in a rebound of IRG to levels 120 per cent that of controls. SRIF, at concentrations from 0.1-20 ng./ml., produced inhibition of both IRG and IRI. In 11 perfusions, with SRIF at 10 ng./ml., IRG decreased more than IRI (-75.2 per cent IRG and -46.9 per cent IRI). In five perfusions, addition of Ca++ (15.2 mEq./L.) 10 minutes after SRIF was started resulted in a reversal of IRG inhibition to 69.4 per cent and IRI to 73.2 per cent of the arginine controls. The reversal by Ca++ of SRIF effect on IRG was greater at higher concentrations of Ca++, suggesting some form of competition. In four perfusions, excess K+ reversed SRIF-induced IRI inhibition to 79.6 per cent that of controls but had no effect on IRG inhibition. Studies in vitro with isolated islets revealed that SRIF (2 mug./ml.) inhibited 45Ca uptake of islets as did epinephrine (10(-5) M). It was concluded that SRIF-induced inhibition of hormone release appears related to an action on Ca++ uptake.     

Hospital doctors, general practitioners and dentists learning together

BACKGROUND: Recurrent melanoma of the extremity has been treated by local excision, systemic chemotherapy, amputation, or a combination of these approaches. Hyperthermic isolated limb perfusion (HILP) provides a method of limb preservation through isolation, allowing the administration of chemotherapy in higher doses than is possible through systemic treatment. METHODS: An experimental group of 59 HILP patients with melanoma recurrences of the extremity was studied prospectively. A control group of 248 melanoma patients with similar recurrences was excluded from HILP because their recurrences were in non-extremity locations. The experimental group underwent HILP and excision; the control group had excision only. The experimental procedure consisted of vascular isolation of the affected extremity and a 1-hour perfusion with melphalan. Temperatures were maintained at 40 degrees C in the perfusion circuit. RESULTS: The HILP patients had a lower rate of locoregional recurrence (P=.028) and demonstrated increased survival (P=.026) compared to the control group. In multivariate regression analysis, which included age, ulceration and thickness of the primary, and the treatment variable of perfusion, age (P=.02) and perfusion for the treatment of recurrence (P=.006) were significant predictors of survival. CONCLUSIONS: HILP improves prognosis by sterilizing the treated extremity, controlling locoregional disease, and perhaps preventing metastasis, thus having a positive impact on overall survival.     

Total-body and regional bone mineral content and areal bone mineral density in children aged 8-18 y: the Fels Longitudinal Study

We used a modification of the isolated perfused rat heart, in which coronary effluent and interstitial transudate were separately collected, to investigate the localization and production of angiotensin II (Ang II) in the heart. During combined renin (0.7 to 1.5 pmol Ang I/mL per minute) and angiotensinogen (6 to 12 pmol/mL) perfusion (4 to 8 mL/min) for 60 minutes (n=3), the steady-state levels of Ang II in interstitial transudate in two consecutive 10-minute periods were 4.3+/-1.5 and 3.6+/-1.5 fmol/mL compared with 1.1+/-0.4 and 1.1+/-0.6 fmol/mL in coronary effluent (mean+/-half range). During perfusion with Ang II (n=5), steady-state Ang II in interstitial transudate was 32+/-19% of arterial Ang II compared with 65+/-16% in coronary effluent (mean+/-SD, P<.02). During perfusion with Ang I (n=5), Ang II in interstitial transudate was 5.1+/-0.6% of arterial Ang I compared with 2.2+/-0.3% in coronary effluent (P<.05). The tissue concentration of Ang II in the combined renin/angiotensinogen perfusions (per gram) was as high as the concentration in interstitial transudate (per milliliter). Addition of losartan (10(-6) mol/L) to the renin/angiotensinogen perfusion (n=3) had no significant effect on the tissue level of Ang II, whereas losartan in the perfusions with Ang I (n=5) or Ang II (n=5) decreased tissue Ang II to undetectably low levels. The results indicate that the heart is capable of producing Ang II and that this can lead to higher levels in tissue than in blood plasma. Cardiac Ang II does not appear to be restricted to the extracellular fluid. This is in part due to AT1-receptor-mediated cellular uptake of extracellular Ang II, but our results also raise the possibility of intracellular Ang II production.     

Arterial morphology and blood volumes of rats following 10-14 weeks of tail suspension

We hypothesized that the structure of systemic arteries would be altered following 10-14 wk of hindlimb unloading (tail suspension) in female Sprague-Dawley rats. Tail suspension resulted in atrophy of the soleus muscle (P < or = 0.01) but no significant differences in the mass of the extensor digitorum muscle, heart, or adrenal glands. In anesthetized rats, there was no difference between groups in arterial pressure (approximately 60 mm Hg). The corresponding maximal (topical papaverine) external diameter (ED) of femoral arteries (N = 5 per group) was reduced (P < or = 0.05) in tail suspended (TS, 511 +/- 47 microm, mean +/- SD) compared with cage sedentary (CS, 615 +/- 89 microm) and food restricted weight-paired (FR, 643 +/- 61 microm) groups. Neither hematocrit, red cell, plasma, nor total blood volume differed among groups. Following systemic vasodilation with papaverine, progressive arterial inflation with liquid silicon rubber (Microfil) revealed a reduction in both ED and distensibility of the femoral artery (P < or = 0.05). To determine the effects of tail suspension on systemic arterial morphology, the vasculature of additional rats was perfusion fixed at 80 mm Hg during vasodilation. Cross sections (thickness, 8 microm) of the carotid, axillary, iliac, and femoral arteries were then evaluated. Whereas the internal diameter of femoral arteries was smaller in TS than in CS (P < 0.05), no differences were observed for other vessels among groups. Further, arterial wall thickness increased systemically (overall, P < 0.05; carotid, 24%, P < 0.01; femoral, 28%, P < 0.01) following tail suspension. These findings illustrate adaptation in the structure of conduit arteries to prolonged tail suspension, with diameter altered regionally and wall thickness increased systemically. We suggest that chronic changes in activity patterns can influence arterial structure.     

Predictive value of the hip flexion test for fractures of the pelvis

In 39 patients with pelvic injury, four clinical tests were performed during physical examination. Of these four tests, the positive and negative hip flexion test (active flexion of the hip with extension of the knee) had the highest predictive value for the presence (95 per cent) or the absence of pelvic fractures (90 per cent), respectively. The predictive values of the other three tests (downward compression on the pubic bone, compression on the iliac rings, and distraction pressure on the iliac crests) were considerably lower.     

The intestinal phase of gastric secretion. Response to liver extract infusion into the proximal jejunum of healthy human subjects

A Levine tube was placed under radiological control in the stomach, and a thin polyethylene tube in the proximal jejunum of 6 healthy volunteers. The stomach and proximal part of jejunum were perfused for 2 hours with 1% acetylcholine, 20% meat extract (Bovril), and 15% liver extract (LE) alone and in combination with simultaneous infusion of different doses of exogenous pentagastrin intravenously. A significant increase in serum gastrin concentration was found with antral perfusion of LE only, whereas perfusion of the proximal jejunum did not change the basal level of the serum gastrin concentration. No change from control values was observed in gastric acid, and pepsin output on perfusing proximal jejunum with LE alone, or in combination with pentagastrin. Reflux to the stomach varied between 0-1.4%, as determined by addition of radioactive B12 to the perfusates. The experiments showed that gastrin was released from the antrum of the stomach by perfusion with 15 per cent LE, but not from the jejunum under the present experimental conditions. In the present experiments Bovril and acetylcholine perfusions did not cause significant responses from the antrum or from the proximal jejunum.     

Isolated hyperthermia chemotherapy perfusion for limb melanoma

Safe techniques for regional chemotherapy of the limbs by perfusion are now available. The method is effective in obtaining regionally confined high levels of toxic drugs or chemotherapeutic agents in the isolated areas. The best responses have been observed in limb melanoma with recurrent or intransit disease. Chemotherapy by perfusion as an adjunct to surgical excision reduces the local recurrence and the regional and lymph node metastases. Our survivals for adjunctive perfusion for Stage I melanomas with Level V and lesions 5 mm thick and thicker are better than usually reported. Regional chemotherapy has had an important role in reduction of major amputations for the control of limb melanoma. Multiple chemotherapeutic limb perfusions can further extent survival in patients with recurring melanoma.     

Isolation perfusion in extracorporeal circulation with interleukin-2 and lymphokine-activated killer cells in the treatment of in-transit metastases from limb cutaneous melanoma

BACKGROUND: Therapies of advanced melanoma patients with interleukin-2 (IL-2) and cytotoxic lymphocytes have produced interesting results, but a larger diffusion of these treatments is limited by the severe side effects due to IL-2 systemic infusion. A strictly regional administration of IL-2 and cells by an isolation perfusion (IP) in extracorporeal circulation (ECC) for the treatment of regional melanoma metastases could improve tolerability and efficacy of this specific modality of immunotherapy. METHODS: Ten patients were submitted to adoptive immunotherapy with IL-2 and lymphokine-activated killer (LAK) cells by IP in ECC. The schedule of treatment included the first course of a 5-day systemic administration of IL-2 (Proleukin, EuroCetus 9-12 x 10(6) IU/m2/day continuous infusion); autologous LAK cells were obtained via leukapheresis and after in vitro activation were given (range 8-28 x 10(9)) along with IL-2 (120-2,400 IU/ml of perfusion priming) to the affected limb by IP; IL-2 (9-12 x 10(6) IU/m2/day) was also administered by systemic continuous infusion for 5 days starting on the day after IP. RESULTS: All patients concluded the treatment without any major local or systemic toxicities. Clinical responses included one complete and six partial remissions; three patients had stable disease. All patients are alive. Follow-up after IP ranged from 12 to 35 months (median: 22). The analysis of circulating lymphocytes revealed the rapid disappearance of LAK cells, suggesting their extravasation and/or endothelial adhesion in perfused tissues. CONCLUSIONS: IP with IL-2 and LAK cells is a new approach for the treatment of in-transit metastases due to cutaneous melanoma. The treatment appears to be feasible and reliable. Further biological and immunological studies should permit amelioration of the present modality of treatment.     

The surgical treatment of aneurysms of the abdominal aorta

The sputum specimens from 1363 patients at the age of 16 to 65 years with nonspecific pulmonary diseases and the pleural exudate specimens from 325 patients were tested for fungi in 1989-1994. The etiological significance of Candida was stated at a concentration of > 10(5) GFU per 1 ml of the sputum. The identification was performed by the routine methods. An increase in the rate of the fungi isolation was studied in the time course of the observation: 15.3 +/- 1.9 per cent in 1989 and 31.6 +/- 3.4 per cent in 1994. The fungi were more frequently isolated from the patients with lung abscesses (38.0 +/- 4.1 per cent of the cases). In the patients with pyothorax the fungi were isolated from the pleural exudate specimens only in 6.8 +/- 1.4 per cent of the cases. The groups of risk of the susceptibility to Candida were revealed. They included patients at the age of 21 to 30 years and above 60. Out of 484 Candida isolates 80.7 per cent belonged to C. albicans, 4.2 per cent to C. tropicalis, 2.1 per cent to C. kefyr and 1.8 per cent to C. krusei. The isolates of C. parapsilosis, C. guillermoudii, C. utilis and C. brumptii were rate. The isolates were highly susceptible to nystatin (91,8 per cent) and lowly susceptible to levorin (35.4 per cent), amphoglucamine (24.7 per cent) and ketokonazol (16.8 per cent).     

Changing patterns in aortoiliac reconstruction: a 7-year audit

A prospective vascular audit was performed in this hospital between 1988 and 1994. There was a substantial increase in the number of vascular reconstructions (78 in 1988; 141 in 1994). Aortobifemoral grafts for occlusive disease comprised 18 per cent of the operations in 1988 and 0.7 per cent in 1994 (95 per cent confidence interval 0.086-0.259). There was a corresponding increase in the number of extra-anatomic grafts (from 3 to 20.6 per cent). There was a threefold increase in the number of percutaneous angioplasties performed for iliac occlusive lesions (14 in 1988; 41 plus 13 iliac stent procedures in 1994). This had no impact on the total rate of surgical intervention for aortoiliac disease, although it probably aided the shift to extra-anatomic reconstruction by dilatation of the donor side. To investigate whether this change is national, rather than local, graft sales figures were obtained from two vascular graft companies; these confirmed a national trend away from aortobifemoral grafting and provide some evidence to support an increase in extra-anatomic bypass grafting.     

Re-appraisal of malignant melanoma diagnosis in the Swedish cancer registry

In many countries the registration of malignant melanoma of the skin shows an increased incidence; this may partially be due to an over-diagnosis. From the group of 3,268 adults and 21 children classified as suffering from malignant melanoma of the skin in the Swedish Cancer Registry between 1959-1968, a one-in-ten systematic sample survey was the object of a retrospective examination. 349 adults and 2 children had a uniform histopathological evaluation performed by one of the authors (B.L.). Slides were not available in 8 cases (2 per cent) and in the remaining 343, the diagnosis was regarded as incorrect in 13 (3.7 per cent). All these 13 cases, (2 children and 11 adults), showed no special predilection as to age, sex, location, or year of registration. In view of such a slight degree of error, the Swedish Cancer registry's melanoma group from 1959-1968 would seem suitable for further epidemiological studies.     

An evaluation of the effect of an alpha hydroxy acid-blend skin cream in the cosmetic improvement of symptoms of moderate to severe xerosis, epidermolytic hyperkeratosis, and ichthyosis

It has been observed that the occurrence of respiratory complications and diarrhoea among measles cases has changed over time but this change has not been quantified. A study was carried out in the city of Gweru, Zimbabwe, to quantify these changes. Rates of respiratory complications and diarrhoea among measles cases were determined in each year for the period 1968-89. It was found that mean rates of respiratory complications and diarrhoea during 1968-78 were 17.2 per cent (95 per cent CI = 11.6-22.8) and 5.2 per cent (95 per cent CI = 0-11) respectively while during 1979-89, mean rates of respiratory complications and diarrhoea were 6.5 per cent (95 per cent CI = 1-12.1) and 16.4 per cent (95 per cent CI = 10.1-22.0) respectively. Analysis of variance (ANOVA) to determine the main effects and the interaction showed that the main effects were not statistically significant (F = 0.01, d.f.1,2 = 1,40, p = 0.935; and F = 0.13, d.f.1,2 = 1,40, p = 0.725 respectively) Meanwhile the interaction term of complications and period was statistically significant (F = 15.7, d.f.1,2 = 1,40, p < 0.001). It was concluded that a change in rates of respiratory complications and diarrhoea had occurred among measles cases. It is suggested that the increase in vaccination coverage in 1979-89 and the shift in age at infection to older age groups in the same period may have brought about this change through selective suppression of respiratory complications among measles cases.     

White blood cell count is a poor predictor of severity of disease in the diagnosis of appendicitis

The white blood cell (WBC) count is considered to be a useful test in the diagnosis of appendicitis. The purpose of this study was to examine the clinical features of patients with normal WBC appendicitis and also to determine whether a higher WBC count correlates with a more advanced stage of appendicitis. Patients with pathologically confirmed appendicitis from January 1989 to December 1994 were included in the study (n = 1919). The age, gender, temperature, length of hospital stay, and severity of disease (1 = acute appendicitis; 2 = gangrenous appendicitis; 3 = perforated appendicitis with abscess formation; 4 = appendicitis with diffuse peritonitis) were compared for patients with a normal WBC count (range, 3.8-10.9) versus those who had an elevated WBC count. A normal WBC count was seen in 11 per cent of patients (n = 209). There was no difference in age, temperature, gender, or severity of disease in the patients with a normal WBC count compared with those with an elevated WBC count (P > 0.05). The severity of disease of patients with a normal WBC count were: 1 = 58 per cent; 2 = 13 per cent; 3 = 7 per cent; and 4 = 22 per cent. For patients with an elevated WBC count the scores were: 1 = 57 per cent; 2 = 17 per cent; 3 = 13 per cent; and 4 = 14 per cent. The proportion of gangrenous and perforated appendicitis in the patients with a normal WBC count is the same as in the patients with an elevated WBC count.     

Long-term results of preoperative radiation therapy alone for stage T3 and T4 rectal cancer

BACKGROUND: There has been a resurgence of interest in the use of preoperative radiation therapy, with or without chemotherapy, for locally advanced rectal cancer. The purpose of this study was to analyse the time course and pattern of failure for 74 patients with clinical stage T3 or T4 (cT3-4) rectal cancer treated with preoperative radiation therapy for whom long-term follow-up was available. METHODS: Seventy-four patients with cT3-4 rectal cancer received a median of 45.0 Gy radiation alone followed by surgery 4-8 weeks later. Median follow-up was 90 months; two-thirds of patients were followed for at least 60 months. RESULTS: Following radiation therapy the pathological stage was 4 per cent pT0, 26 per cent pT1-2 and 70 per cent pT3-4. Thirty-two per cent had involved lymph nodes. The actuarial 5-year rates of local control, freedom from distant metastasis and disease-specific survival were 80, 64 and 73 per cent respectively. The corresponding 10-year rates were 73, 51 and 50 per cent. Median times to detection of local and distant recurrence were 34 and 24 months respectively. Eighty per cent of local recurrences were detected within 54 months; 80 per cent of distant recurrences were detected within 57 months. CONCLUSION: In this analysis, the time to detection of both local and distant recurrences following preoperative radiation therapy for advanced rectal cancer was surprisingly long. Almost 5 years (57 months) of follow-up were required to detect 80 per cent of all failures. The 5-year local control rate of 80 per cent compares favourably with that achieved by more aggressive chemoradiation regimens for fixed cancers; however, the high distant failure rate with radiation therapy alone suggests that adjuvant systemic therapy should be investigated.     

2nd revised consensus skin melanoma. De Nederlandse Melanoom Werkgroep]

The 'Guideline melanoma of the skin, second revised consensus' was published in March 1997. Some of the contents are cited: Over 1600 new melanomas are diagnosed in the Netherlands each year; by now the mean 5-year survival amounts to over 80%. In examination of a pigmented lesion a dermatoscope is a valuable tool. The recommended margin of the diagnostic excision was reduced from 5 mm to 2 mm of macroscopically normal skin round the lesion; the margins in definite excision are: 1 cm of normal skin for a Breslow thickness < or = 2 mm; 2 cm for a Breslow thickness > 2 and < or = 4 mm. A margin of at least 2 cm seems also justified for thicker melanomas. Elective (prophylactic) regional lymph node dissection is advised against. Sentinel node biopsy appears to be an attractive method to detect occult metastasis in regional nodes. In lymph node metastasis a (therapeutic) regional lymph node dissection should be performed. In case of inoperable tumourgrowth in an extremity regional isolated perfusion is indicated. Radiotherapy may be applied curatively (e.g. if surgery is not possible), palliatively (if desired in combination with hyperthermia) or postoperatively (if non-radical resection is suspected). Adjuvant systemic therapy in melanoma patients is still experimental; the earliest results of high doses of interferon alpha are encouraging. Atypical (dysplastic) naevi and congenital naevi are important risk factors for melanoma. No consensus was reached regarding prophylactic removal of all congenital naevi. Regarding the duration of the follow-up period, 5 years suffices in patients with a melanoma with a Breslow thickness < or = 1.5 mm (provided there are no histological signs of regression), while 10 years is required for melanomas with a Breslow thickness > 1.5 mm. The patient should be actively involved in the follow-up (inspection, palpation). Routine blood testing, roentgen examination or ultrasonography are considered to be useless. There are no indications that hormonal alterations during pregnancy or use of the pill stimulate the growth of micrometastases that may be present. Excessive exposure to ultraviolet rays is discouraged.     

Isolated lung perfusion: single-pass system versus recirculating blood perfusion in pigs

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 (< 0.6%). Wet-to-dry weight ratio was significantly lower after single-pass as compared with recirculating-blood perfusion and endovenous drug application at both time points (5.0 +/- 1.1 and 5.3 +/- 0.8 for single-pass versus 6.6 +/- 1.1 and 6.9 +/- 0.5 for recirculating-blood versus 6.6 +/- 0.2 and 5.9 +/- 0.7 for the control group, respectively; p < 0.05). Angiotensin-converting enzyme-to-protein plasma ratio in the single-pass group was significantly lower only at 20 minutes (6.3 +/- 2.4 versus 9.3 +/- 1.0 versus 9.7 +/- 1.9, respectively; p < 0.05) but not at 50 minutes. Angiotensin-converting enzyme-to-protein ratio in bronchoalveolar lavage fluid, histology of lung biopsy specimens, and chest radiographs did not differ significantly between the three groups. Doxorubicin lung tissue concentration was not significantly different after single-pass (17.5 micrograms/g) and recirculating-blood perfusion (21.9 micrograms/g), but was significantly higher than after endovenous drug application (3.0 micrograms/g; p < 0.01). 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.