K. Aigner

First Experimental and Clinical Results of Isolated Liver Perfusion with Cytotoxics in Metastases from Colorectal Primary

In two patients suffering from numerous liver metastases in both lobes from colorectal primary isolated liverperfusion with 5-fluorouracil was performed. By means of a special cannulation system the hepatic artery and the portal vein were arterialized. The patients recovered rapidly after the operation. Sonographic measurements, CAT scans, pulse cytophotometry, and second-look operations with histological examinations of metastatic tissue verified extensive tumor regression. No complications occurred within 6 months after the perfusion treatment.

Die isolierte Leberperfusion bei fortgeschrittenen Metastasen kolorektaler Karzinome

Zur Isolierung der Leber in situ und Perfusion im extrakorporalen Kreislauf wurde ein spezielles Kanulierungssystem entwickelt. Bei 32 Patienten mit Lebermetastasen (29 kolorektale Karzinome, 2 Karzin

Die isolierte hypertherme Extremitätenperfusion mit Vindesin, Dacarbazin und Cis-Platin bei der Behandlung maligner Melanome

Zur isolierten Extremitatenperfusion bei malignen Melanomen wurde eine neue Dreierkombination (DVP), bestehend aus Dacarbazin, Vindesin und Cis-Platin, bei 26 Patienten erstmals eingefuhrt. Dosierunge

Die intraarterielle Zytostatikatherapie mit venöser Filtration im halboffenen System

Die Hamofiltration eignet sich zur Elimination von Zytostatika aus dem systemischen Kreislauf. Das Ausmas von systemischen Neben-wirkungen kann dadurch gesteuert werden. Die intraarterielle Infusion mit venoser Zytostatikafiltration nach dem Tumor erlaubt eine hochdosierte Chemotherapie in vorwiegend befallenen Korperarealen unter Reduzierung der systemischen Toxizitat – alternativ unter gleichzeitigen systemischen Wirkspiegeln.Z 1,043 milionu nových nadorů děložniho hrdla, těla a vajecniků ve světě v roce 2008 uvadi databaze Globocan 2008 (IARC) 31 % ve vyspělých a 69 % v meně vyspělých zemich; z 489 tisic zemřelých uvadi 27 % ve vyspělých a 73 % v meně vyspělých zemich. Do roku 2030 mohou nova onemocněni ve světě vzrůst o 550 tisic, tj. 53 %, a umrti o 303 tisic, tj. 62 %. V meně vyspělých zemich může být narůst o 65 % na 1,19 milionu nových připadů, o 80 % na 639 tisic umrti, ve vyspělých zemich o 19 % na 382 tisic nových připadů, o 29 % na 168 tisic umrti. Z odhadu pětilete prevalence 3,203 milionu připadů ve světě se v roce 2008 vyskytlo 67 % v meně vyspělých a 33 % ve vyspělých zemich vcetně 677 tisic v Evropě. Porovnanim hrube incidence 40 zemi Evropy byly ženy CR prvni u nadoru děložniho těla, devate u nadorů vajecniků a jedenacte u nadoru děložniho hrdla. Výzva WHO „Spolecně je to možne” spojuje usili o sniženi budouci incidence a rozdilů v onkologicke peci.

Tissue Toxicity in Experimental Isolated Perfusion with Adriamycin

Adriamycin is known as an antineoplastic agent with a broad spectrum of activity for human malignancies. To determine the highest tolerable concentrations of adriamycin in isolated perfusion of the extremities the hind legs of 12 dogs were isolated in an extracorporeal circuit and perfused under normothermic conditions. Dosages of about 10 mg/l perfused extremity were well tolerated by the animals, and lower concentrations did not result in any side effects. However, in most cases, dosages higher than 10 mg adriamycin/l extremity volume induced severe edema, pain, and histological changes.

Distribution patern of viable tumor residues in liver metastases of colorectal cancer after regional chemotherapy

Tumor regression of liver metastases of colorectal adenocarcinomas was assessed morphometrically without and after high-dose regional chemotherapy using holoptical crosssections. RESULTS: Untreated metastases display extensive necroses which are therefore often difficult to distin -~ guish from therapy induced regression. From this it follows that a definite statement about the therapeutic effect can only be made if the usual extent and distribution pattern of vital tumor tissue are known. The percentage of vital tumor tissue in the untreated metastases decreases logarithmically from the periphery towards the center, the vital tumor tissue amounting to less than 50 % already at an average distance of 2 nm from the tumor margin. The amount of vital tumor tissue is lower in the treated than in the untreated tumors, but the difference between the two groups is not significant. Nevertheless a distinct therapeutic response is detectWole in several cases. The amount of vital tumor tissue is highest in the marginal zone also after therapy. 3 Types of therapy induced tumor regression can be observed in the periphery of the metastases: (]) Broad vital tumor periphery combined with pronounced cellular degeneration. (2) Encapsulated proliferating peripheral tumor seam. (3) Subtotal tumor necroses with small proliferating tumor residues. These three reaction forms of the tumor periphery underline the heterogeneity of the morphological changes seen after therapy. Holoptical cross-sections show that differencies of resistance against therapy in one and the same tumor seem to be due mainly to the vascularisation of the tumor tissue.

Ultrastructural Changes in the Dog Liver Cell After Isolated Liver Perfusion with Various Cytotoxins

Following isolated liver perfusion with different cytotoxins - 5-fluorouracil (5-FU), methotrexate (MTX), dacarbazine (DTIC) cis-platinum (cis-PT) - liver tissue of dogs was examined with the electron microscope (a) directly after the perfusion and (b) after a survival time of 4 weeks (5-FU and DTIC). Acute disintegration of the granular endoplasmic reticulum and depletion of the glycogen stores occurred after perfusion with 5-FU, MTX, and DTIC, while cis-PT induced disintegration of the granular endoplasmic reticulum accompanied by an accumulation of glycogen. Four weeks after perfusion with DTIC signs of remarkably increased cellular activity were observed, while 4 weeks after perfusion with 5-FU the parenchymal liver cells revealed a well-balanced and moderate recovery of the cellular structures.

Systemisch applizierte regionale Tumortherapie

Da die systemische Applikation einer Hochdosischemotherapie durch das Ausmas intolerabler Nebenwirkungen begrenzt wird und zudem die Ansprechraten bislang nur ungenugend sind, gilt die systemische Chemotherapie in der Melanombehandlung als nur begrenzt geeignet. Andererseits weisen die Resultate der isolierten Extremitatenperfusion zur Behandlung von Satellitose und In-Transit-Metastasierung auf ausgepragte Dosis-Wirkungs-Beziehungen geeigneter zytotoxisch wirksamer Chemotherapeutika hin. Dieser Umstand war Grundlage fur den experimentellen Ansatz, die Wirksamkeit einer Hochdosischemotherapie zu untersuchen, die auf eine topographische Halbkorperregion beschrankt wird. Nach Standardisierung der operativen Technik bot sich die Moglichkeit, diese Vorgabe dadurch zu realisieren, das das regional behandelte Kompartiment ausgedehnt und gleichzeitig im nicht behandelten zur Absenkung toxischer Plasmaspiegel eine Zytostatikafiltration durchgefuhrt wird. Bei zwei hier vorgestellten Patienten, deren Behandlung einer kontrollierten Studie bei verschiedenen soliden Tumoren vorangestellt war, liesen sich mit diesem Behandlungsansatz eindrucksvolle Tumorregressionen erzielen.

Drug testing in regional chemotherapy (RC)

Tox ic i t y and ef f icacy of at least a dozen most commonly used cytotox ic drugs vary predictably depending upon the time of day when they are given (W. Hrushesky, Science 228,73-75,1985). In a series of murine experiments inv-oTving more than 700 CD~F. mice and F344 rats, we have repeatedly shown that the:s~fest time for FUDR adminis t ra t ion is the midto l a t e a c t i v i t y span. An implantable, programmable drug administrat ion device (Medtronic, Inc . ) , al lowing automatic dose modif icat ions of continuous longterm infusion, was implanted in 19 patients (p t ) , while 26 pt received an Infusaid pump for continuous f l a t infusion. 31 pt with metastatic adenocarcinomas confined to the l i v e r received i n t r a a r t e r i a l hepatic (IA) FUDR infusions. Tox ic i t y of the same da i l y dose of f l a t vs t ime-modified infusion patterns (6-hourly port ions of 68% (3-9 p.m.),15%,2%,15%) was compared. IA-FUDR Infusion (monthly O.2-O.3mg/kg/dxl4) f l a t timed X 2 p No. of patients 22 8 Hepat i t i s /cho lang i t i s (%) 46 25 2.8 <.05 Gastrointest inal tox. (%) 67 0 9.9 <.01 Dose reductions (%) 20 0 14 patients with widely spread cancer received central venous (IV) FUDR e i ther as f l a t or time modified continous infusion as above. IV-FUDR Infusion (monthly 0.15 mg/kg/day x14) f l a t timed X z p No. of courses 13 7 Severe diarrhea 8 0 10.1 <.03 Hospital admissions 5 0 Dose reductions 4 0 This time qua l i f i ed infusion-chemotherapy is less tox ic .