Miniaturized heart-lung machine.

The miniaturized heart-lung machine consists of commercially available roller pumps, a flexible heat exchanger, a newly devised bubble oxygenator, and polyethylene cannulas and silicone tubes. The minimum and maximal priming volume of the entire system is 4.7 and 16.7 mL, respectively. The efficiency of the system is reflected in an heat transfer coefficient ranging from 0.96 to 0.31 at flow rates between 1 and 20 mL/min, a high value of oxygen uptake in the range of 0.061 mL O2/min mL blood-1, and low blood trauma with plasma hemoglobin concentrations of 47.5 +/- 5.0 mg/dL after 60 min of in vitro perfusion. The system is a simple, reliable, and efficient miniaturized heart-lung machine for use in small animals.

Clinical pharmacokinetics of mitoxantrone in hyperthermic, isolated perfusion of the leg.

The clinical pharmacokinetics of mitoxantrone in hyperthermic, isolated perfusion of the leg were studied in five patients exhibiting solitary, localized malignant melanoma. Mitoxantrone was given as four 1-min infusions at 15-min intervals into the arterial line of the perfusion system at a total dose of up to 14 mg/m2. The mean half-lives for mitoxantrone in the blood circulation of the leg were: t1/2 alpha (distribution phase), 25.5 s, and t1/2 beta (elimination phase), 14.9 min. The mean volume of distribution at steady state in the leg was 25.6 1. In the arterial part of the perfusion, the mean AUC was 155.9 mg min l-1, and that in the corresponding venous part was 91.6 mg min l-1. Leakage of the drug from the leg into the systemic circulation amounted to 1.2% of the total delivered dose; 91% of the delivered dose remained in the leg after the perfusion had been completed. The mean elimination half-life of mitoxantrone in the systemic circulation was 123 min and the corresponding AUC for systemic concentrations was 8.59 mg min l-1. The present data revealed a high uptake of mitoxantrone into the leg and low systemic drug concentrations due to minor leakage, suggesting that mitoxantrone might be a good candidate for use in isolated, hyperthermic limb perfusion.

The value of current staging systems for melanoma of the extremities.

The validity of current staging systems for malignant melanoma was analyzed in a prospective study on 220 patients with extremity melanoma. Patients were followed 2 to 9 years after a wide excision of the primary, regional cytostatic perfusion and dissection of regional lymph nodes. The "original three-stage" system yielded statistically significant differentiation, but with a distinct preference for Stage I. The classification into IA/B, and IIIA/B/C according to the M.D. Anderson system does not distribute the patients into significantly different tumor stages. Using the American Joint Committee of Cancer Staging and End Results Reposting (AJCC) system, 40 patients were classified as Stage I, 95 as Stage II, 53 as Stage III, and 32 patients as Stage IV. The 5-year survival rate was 96% in Stage I, 90% in Stage II, 68% in Stage III, and 30% in Stage IV. According to the UICC staging system there was a numerical preference of Stage II and III. The differentiation of Stage I and II was not significant. It is the authors' opinion that the AJCC staging system allows the best differentiation of melanoma patients into tumor stages that are evenly distributed and significant for prognoses.

Hyperthermic perfusion with chemotherapy for melanoma of the extremities.

A prospective randomized study was carried out to evaluate the effectiveness of additional regional cytostatic perfusion of the extremities in patients with malignant melanoma. In a control group (n = 54), the tumors were widely excised, and regional lymph nodes were dissected. The patients in the perfusion group (n = 53) received additional hyperthermic (42 degrees C) perfusion with Melphalan. The disease-free survival time was chosen as the criterion for evaluation. An intermediate analysis revealed a highly significant difference between the 2 groups (21 recurrences in the control group and 4 recurrences in the perfusion group, p less than 0.001). Therefore, the study was discontinued prematurely. In an analysis of the data performed after a median observation time of 5 years and 11 months, 26 recurrences were diagnosed in the control group, whereas 6 recurrences were noted in the perfusion group (p less than 0.001). The retrospective breakdown into different risk groups according to tumor thickness also demonstrates a significant difference. For patients with a primary tumor of 1.5-3.0-mm in thickness, 2 of 25 in the perfusion group and 10 of 25 in the control group have relapsed. For those with a primary tumor of greater than 3.0-mm in thickness, 4 of 28 in the perfusion group and 16 of 29 in the control group have relapsed. Eleven patients in the control group and 3 patients in the perfusion group have died due to metastatic spread of the melanoma (p less than 0.01). The results most clearly demonstrate the benefits of additional hyperthermic cytostatic perfusion.

[The prognosis of patients with level V melanomas of the extremities]. / Prognose der Patienten mit Level V Melanomen der Extremitäten.

Patients with level V melanoma have a very bad prognosis on account of their high rate of lymph node and distant metastases. From Jan. 1979 to Dec. 1987, a total of 251 patients suffering from malignant melanoma of the extremities (including 28 patients with level V melanoma = 11.2%) underwent excision of the primary tumor, lymph node dissection, as well as regional hyperthermic perfusion with cytostatics. The prognosis of our patients with level V melanoma could be improved considerably by therapy.

Technical aspects of isolation extremity perfusion: experimental studies and clinical experience.

In experiments with dogs (n = 68), the influence of temperature, flow rate, perfusate, and perfusion duration on the hind leg subjected to an isolation perfusion was studied. The perfusion pressure, the blood gases, and the metabolic status in specimens of skeletal muscle obtained at the end of the perfusion period served as parameters. A perfusion of 1 and 2 h with whole blood, a flow rate of 10 mL/10 g/min, and temperatures of up to 42 degrees C did not result in alterations of the energy metabolism. When the flow rate was lowered to 5 mL/100 g/min, when other perfusates were used, or when the in temperature was raised to 43.5 degrees C, then tissue damage occurred. Knowledge gained in these experiments was utilized in the treatment of 371 patients with malignancies of the extremities, and an extremely low complication rate was observed.

The role of regional hyperthermic cytostatic perfusion in the treatment of extremity melanoma.

To evaluate the effectiveness of regional hyperthermic cytostatic perfusion in patients with malignant melanomas of the extremities, 107 patients were included in a prospective randomized study. In a control group (A, n = 54) the tumors were widely excised, and the regional lymph nodes were dissected. The patients in the perfusion group (B, n = 53) received additional hyperthermic (42 degrees C) perfusion with melphalan. The disease-free survival time was chosen as the criterion for success. An intermediate evaluation (average follow-up observation period of 550 days) revealed a highly significant difference between the groups (P = 0.0001): 21 recurrences in the control group versus four recurrences in the perfusion group. In a second analysis 3 1/2 years after premature discontinuation, 26 recurrences were diagnosed in Group A, whereas only six recurrences were noted in Group B (P = 0.0001). A retrospective analysis of the entire test group revealed the following figures. In Group A seven recurrences in Stage I were diagnosed, seven in Stage II, and 12 in Stage III. In Group B one was observed in Stage I, one in Stage II, and four in Stage III. The level of significance was calculated to be P = 0.05 in Stage I, P = 0.05 in Stage II, and P = 0.01 in Stage III. The results of the study show that additional perfusion in the treatment of extremity melanomas is superior to conventional methods.

[DSA for the imaging of tumor-caused vascular changes and complications during local chemotherapy of the liver via the portal system]. / DSA zur Darstellung tumorbedingter Gefässveränderungen und Komplikationen bei lokaler Chemotherapie der Leber über "Portsysteme".

In 18 patients with primary or secondary liver tumours, 38 digital subtraction angiographies (DSA) of totally implanted catheter systems for liver perfusion were performed during a period of 8 months. The systems had been used for an average of 6.9 months. In 22 out of 38 examinations secondary reactions of liver arteries were observed, in 7 the therapeutic regimen was changed after DSA. Patients with an extensive tumour involvement of the liver showed mural thromboses or obstructions of liver arteries relatively more often (4 of 7) than patients with smaller size tumours (2 of 11). In 7 cases the therapeutic regimen was changed after DSA. DSA of implanted liver catheters is a valuable, well tolerated, easily and rapidly performed method.

[Diagnosis and surgical therapy of lung metastases]. / Diagnostik und operative Therapie von Lungenmetastasen.

Operations for pulmonary metastases were carried out on 33 patients from January 1st 1976 to December 31st 1985 at the Surgical Division, University of Cologne. In six cases each, the primary tumors were hypernephromas, colorectal carcinomas and osteocarcinoma. There were five cases of melanoma, three cases of testicular carcinoma, two cases of corpus carcinoma and two cases of soft-tissue sarcoma as well as one case each of parotid, tonsillar and laryngeal carcinoma. The large number of metastases could be determined in 21 cases (64%) by means of preoperative radiodiagnostics with X-rays of the chest in two planes, conventional tomography and computer tomography of the thorax. Computer tomography was the most efficient single investigation. 17 patients received atypical resection and lobectomy was carried out in 16 cases. For all patients, the cumulative survivals revealed a one-year actuarial survival of around 70% and a three-year actuarial survival of about 20%. Patients with several metastases (two to six) had a very much poorer prognosis than patients with solitary pulmonary metastases. There was no connection between the surgical technique selected and the expected survival time in any case. The tumor-free interval between operation on the primary tumor and resection of the pulmonary metastases only had a slight prognostic significance.

[Value of magnetic resonance tomography prior to surgery and irradiation of peripheral soft tissue tumors]. / Wert der Kernspintomographie vor chirurgischer Therapie und Radiatio peripherer Weichteiltumoren.

The experience with magnetic resonance imaging (MRI) of 37 patients with peripheral soft tissue tumours and tumour-like lesions is reported. MRI proved to be a highly sensitive method in detecting soft tissue tumours. The main advantages of MRI compared to CT were the high contrast resolution of MRI and the multiplanar display. The anatomic setting of the soft parts tumour could be defined in most cases as either intracompartmental or extracompartmental. The relationship to the major neurovascular bundles and bone could be assessed accurately. Tumour-induced subtle periosteal reactions and cortical erosions are better defined with CT and plain film, especially. An imaging technique using small excitation angles, echoes produced by gradient inversion and extremely fast repetition times ("Fast Field Echo Imaging") is capable of producing MR images in only a few seconds acquisition time. Preliminary experience shows that soft tissue tumours can be evaluated with this rapid pulse sequence.

Miniature equipment for the perfusion of rat limbs.

A simple, reliable and efficient miniaturized extracorporeal circulation system for the use in small animals, especially for the perfusion of rat hind limbs, has been described. The system consists of a newly devised bubble oxygenator and heat exchanger and of commercially available roller pumps, polyethylene cannulas and silicone tubes. The minimal and maximal priming volume of the entire system is 4.7 and 16.7 ml, respectively. The efficiency of the system is reflected in a high value of oxygen uptake in the range of 0.061 ml O2 X min-1 X ml-1 blood, a heat transfer coefficient ranging from 0.96 to 0.31 at flow rates between 1 and 20 ml X min-1, a low pulsation amplitude of the roller pump, a constant flow resistance at the arterial cannula, which implies optimal flow conditions, and in a low blood trauma with plasma hemoglobin concentrations of 47.5 +/- 5 mg dl-1 after 60 min of in vitro perfusion.

[A new model for the regional perfusion of the extremities in rats: metabolism and hemodynamics]. / Ein neues Modell zur regionalen Extremitätenperfusion der Ratte--Stoffwechsel und Hämodynamik.

A pelvic extremity of the rat was recirculatorily perfused by means of a self-developed perfusion equipment in a perfusion pressure of 65 +/- 6 mmHg and a blood temperature of 35 degrees C during one hour. Tissue specimens were taken away in the end of the perfusion and 3 weeks later and the metabolite contents was determined in comparison with control groups. No change of the metabolite status was provable by the perfusion. The technical practicability of the perfusion of rat extremities could be shown, therefore, contrary to hitherto existing assumptions.

[Randomized melanoma study of perfusion of the extremities. Results of treatment 2 1/2 years after premature discontinuation]. / Randomisierte Melanomstudie zur Extremitätenperfusion. Behandlungsergebnisse 2 1/2 Jahre nach vorzeitigem Abbruch.

To evaluate the effectiveness of regional hyperthermic cytostatic perfusion in patients with malignant melanomas of the extremities 107 patients were included in a prospective randomized study. In a control group (A, n = 54) the tumors were excised widely and the regional lymph nodes were dissected. The patients in the perfusion group (B, n = 53) received additional hyperthermic (42 degrees C) perfusion with Melphalan. We chose the disease-free-survival time as the criterion for success. An intermediate evaluation (mean follow-up observation period of 550 days) revealed a highly significant difference between the groups (p = 0.0001) of 21 resp. 4 recurrences. A second evaluation, 2 1/2 years after prematurely discontinuation, also shows a highly significant difference in favour of perfusion (p = 0.0001).

[Malignant melanoma of the anorectum]. / Das maligne Melanom des Anorektums.

Malignant melanoma of the anal canal in stages I, II and III, respectively, was diagnosed in a 58-year-old woman and two men, aged 69 and 73 years. The patients' age was thus above the average reported age of manifestation (60 years) of this tumour. In two patient the tumours had been incorrectly diagnosed because of their proximity to the linea dentata and their similarity to haemorrhoids: operation had been delayed for four and about six months, respectively. Treatment of choice for stages I and II was abdominoperineal amputation of the rectum, while in the patient with stage III a colostomy was performed as a local palliative measure. The patients with stage II and III tumour died after six and 12 months, respectively, a survival time which corresponds to that expected from published series. Radiotherapy did not influence tumour growth in the patient in stage III. The patient in stage I has been free of tumour for six months.

[Indole melanogens--useful tumor markers in malignant melanoma?]. / Indolmelanogene--Nützliche Tumormarker beim Malignen Melanom?

The concentrations of indole melanogens have been measured in 24-hour urine samples of 44 patients suffering from malignant melanoma, clinical stages I to IV, and 23 healthy test persons (control group). With regard to the controls, the urinary concentration of indole melanogens amounted to 3.8 +/- 1.329 micrograms/ml; the excretion was 5.41 +/- 1.941 mg daily. In patients with localized malignant melanoma, the concentration of indole melanogens did not differ from the control group. Highly significant levels, however, were measured in patients with generalized disease (7.76 micrograms/ml and 6.85 mg daily). Tyrosin orally given (7 g on the 2nd, 3rd, and 4th day of the collecting period) did not elevate the urinary excretion of indole melanogens in any of the test groups. These results indicate that the applied procedure does not present any fundamental advantage for clinical oncology.

[Current status of therapy of liver metastases of colorectal carcinoma]. / Aktueller Stand der Therapie von Lebermetastasen kolorektaler Karzinome.

Surgical removal of liver metastases stemming from colo-rectal carcinoma is the therapy of choice of this disease. Postoperative mortality is 8%, 5 years survival rate ranges between 22 and 52% and can be considered to be good. However in 85% of patients surgery is not possible because of widespread involvement of the liver. Systemic chemotherapy yields remission rates up to 23% without increase of survival time, and therefore is no real alternative. Infusion of cytostatic drug into the hepatic artery yields better results, e.g. remission rates up to 85% and average survival times up to 26 months.

A prospective randomized study of regional extremity perfusion in patients with malignant melanoma.

One hundred seven patients presenting with malignant melanoma of the extremities were included in a prospective randomized study, which was conducted to evaluate the effectiveness of adjuvant hyperthermic regional cytostatic perfusion. In a control group (A, N = 54) the tumors were excised widely and the regional lymph nodes were dissected. The patients in the second group (B, N = 53) received additional hyperthermic (42 C) perfusion with melphalan. The mean follow-up observation period was 554 days. We chose the disease-free survival time as the criterion for success. The study could be discontinued prematurely, since the intermediate evaluation revealed a highly significant difference between the groups (p = 0.0001). We observed 21 local recurrences in the control group and four recurrences in the perfusion group. The retrospective breakdown by clinical stages also showed significant differences. The recurrence rate in the control group was 27.8% in Stage I, 31.6% in Stage II, and 58.8% in Stage III. In the perfusion group we observed recurrences equaling 5.6% in Stage I, 5.5% in Stage II, and 12.5% in Stage III. The differences between the groups based on the target-criterion of disease-free survival represent significance levels of p = 0.09 in Stage I, p = 0.03 in Stage II, and p = 0.003 in Stage III. We feel that on the evidence provided by our study, shown in the above results, the adjuvant application of regional hyperthermic cytostatic perfusion has proven itself to be superior to conventional procedures alone.

[Regional hyperthermic cytostatic perfusion as an alternative in the treatment of malignant soft tissue tumors of the extremities]. / Die regionale hypertherme Cytostaticaperfusion als Alternative bei der Behandlung von malignen Weichgewebstumoren der Extremitäten.

From March 1979 through December 1983, 15 patients with soft-tissue sarcomas of the extremities were treated by a local excision and an adjuvant regional hyperthermic cytostatic perfusion. Reversible edema in two patients was the only post-operative complication. 14 patients were disease-free after a median follow-up period of 24.2 months. One female patient developed a local recurrence 10 months following surgery. Based on our results and long-term studies of several authors, the adjuvant regional perfusion appears capable of successfully treating patients with soft-tissue sarcomas of the extremities.

[Surgical therapy of malignant soft tissue tumors]. / Chirurgische Therapie maligner Weichteiltumoren.

Soft-tissue sarcomas are rare neoplasms originating from the extraskeletal connective tissues of the body. The GTNM-system is recommended for clinical staging. The most effective treatment are radical surgery and the combination of limited surgical removal and high-dose irradiation. In the management of soft-tissue sarcomas of the extremities the isolated hyperthermic perfusion is a successful adjuvant to excision for saving a tumour bearing limb.