R. Raab

Arterial chemoembolization before liver transplantation in patients with hepatocellular carcinoma: marked tumor necrosis, but no survival benefit?

BACKGROUND/AIMS Hepatic artery chemoembolization was introduced in the treatment of patients with unresectable hepatocellular carcinoma waiting for liver transplantation. The rationale for this preoperative treatment was to control tumor growth during the waiting period and to improve long-term survival. This study aimed to investigate whether preoperative chemoembolization not only induces marked tumor necrosis but also has a survival benefit. METHODS In this study 21 patients with hepatocellular carcinoma who underwent pretransplant chemoembolization (group I) were compared with 21 historical control patients (group II) without preoperative chemoembolization in a case-control study. The number of pretransplant chemoembolizations in each patient in group I varied between 1 and 5 with a mean of 2.44+/-1.15. In addition, six patients of this group received preoperative systemic chemotherapy. RESULTS Overall, there were no differences in survival between the groups with and without pretransplant chemoembolization at 1 year (60.8% vs 61.5%) and at 3 years (48.4% vs 53.9%). In group I, three patients developed unexplained severe pneumonia, leading to death very early after liver transplantation. Marked tumor necrosis (>50%) was found in 14 cases in group I. In 6 out of these 14 patients, total tumor necrosis was observed. CONCLUSION Although preoperative chemoembolization or chemotherapy induced marked tumor necrosis, these patients showed no benefit in survival compared to historical controls, and appeared to be at higher risk of developing immediate postoperative infective complications.

Hepatic Metastases From Leiomyosarcoma: A Single-Center Experience With 34 Liver Resections During a 15-Year Period

OBJECTIVE To describe a large single-center experience with hepatic resection for metastatic leiomyosarcoma. SUMMARY BACKGROUND DATA Liver resection is the treatment of choice for hepatic metastases from colorectal carcinoma. In contrast, the role of liver resection for hepatic metastases from leiomyosarcoma has not been defined. METHODS The records of 26 patients who between 1982 and 1996 underwent a total of 34 liver resections for hepatic metastases from leiomyosarcoma were reviewed. There were 23 first, 9 second, and 2 third liver resections. The records were analyzed with regard to survival and predictive factors. RESULTS In the 23 first liver resections, there were 15 R0, 3 R1, and 5 R2 resections. Median survival was 32 months after R0 resection and 20.5 months after R1/2 resection. The 5-year survival rate was 13% for all patients and 20% after R0 resection. In 10 patients with extrahepatic tumor at the time of the first liver resection, 6 R0 and 4 R2 resections were achieved. After R0 resection, the median survival was 40 months (range 5-84 months), with a 5-year survival rate of 33%. After repeat liver resection, the median survival was 31 months (range 5-51 months); after R0 resection, median survival was 31 months and after R1/2 resection it was 28 months. There was no 5-year survivor in the overall group after repeat liver resection. CONCLUSIONS Despite frequent tumor recurrence, the long-term outcome after liver resection for hepatic metastases from leiomyosarcoma is superior to that after chemotherapy and chemoembolization. Although survival after tumor debulking also seems to be more favorable than after nonoperative therapy, these data indicate that only an R0 resection offers the chance of long-term survival. The presence of extrahepatic tumor should not be considered a contraindication to liver resection if complete removal of all tumorous masses appears possible. In selected cases of intrahepatic tumor recurrence, even repeated liver resection might be worthwhile. In view of the poor results of chemoembolization and chemotherapy in hepatic metastases from leiomyosarcoma, liver resection should be attempted whenever possible.

Bone density and metabolism in patients with viral hepatitis and cholestatic liver diseases before and after liver transplantation

OBJECTIVE:Osteoporosis is frequently found in patients with cholestatic liver disease (primary biliary cirrhosis/primary sclerosing cholangitis) and chronic viral hepatitis. There is limited information about the long-term effect of liver transplantation (OLT) on bone metabolism. The aim of this study was to investigate the effect of liver transplantation on bone metabolism in patients with cholestatic and viral liver diseases.METHODS:We randomly recruited 193 patients with chronic viral hepatitis or cholestatic liver diseases. Bone density (Z-score) and markers of bone metabolism (intact parathyroid hormone [iPTH], PTH 70–84, osteocalcin, procollagen, telopeptide, and vitamin D) were determined before and at time points (< and > 24 months) post-OLT.RESULTS:Before OLT, bone density (Z-score) was decreased in patients with cholestatic (−1) and viral (−0.4) liver diseases. In both groups bone density continued to decrease in the periods up to and more than 24 months after OLT. In the cholestatic group, bone density decreased significantly compared to pre-OLT (p < 0.05) and to the viral hepatitis group (p < 0,001). Markers of bone metabolism showed that after OLT, bone metabolism was enhanced and shifted versus bone resorption. Immunosuppressive drug therapy (glucocorticoids, cyclosporin, FK 506) directly correlated with increased bone metabolism post-OLT.CONCLUSIONS:Bone loss is a long-term problem after OLT, particularly in patients with cholestatic liver diseases. Drug therapy is a main factor of bone loss. Pre- and post-OLT therapy to reduce bone loss is recommended.

Ex-vivo resection techniques in tissue-preserving surgery for liver malignancies

Abstract Some primary and secondary liver tumours are not absolutely irresectable, but cannot be resected using a conventional approach because of the limited warm ischaemia tolerance of the liver or poor accessibility of the tumour region. In such situations, the techniques of ex vivo liver surgery, pioneered by Rudolf Pichlmayr some 10 years ago, offer new chances for R0 resection. All the three different approaches, namely ”in situ”-, ”ante situm”-, and ”ex situ” resection, require the use of measures originally developed for transplantation, such as hypothermic liver perfusion and veno-venous bypass. They differ mainly in the extent to which major vessels are divided in order to achieve optimal mobility of the organ. The results show that radical resection can be achieved accomplished in many cases. If necessary, complex vascular reconstructions can be performed. Although perioperative morbidity and mortality are high, there are a number of long-term survivors. Tumour recurrence, however, remains the main problem over the long term. In conclusion, ex vivo liver surgery is an important extension of surgical treatment possibilities. However, the procedure is suitable only for a small number of carefully selected patients and should be reserved for use in specialised centres. Furthermore, in view of the fact that the results are not yet optimal, additive and adjuvant treatment modalities are needed.

Dreidimensionale (3-D) Visualisierung der Leber zur Planung erweiterter Leberresektionen

Summary. Preoperative planning of liver resections in patients with liver tumors is based on sonography, computed tomography and magnetic resonance imaging. A new three-dimensional (3D) visualization program was developed based on CT data. This visualization program was used for preoperative planning in 6 patients with liver tumors in problematic intrahepatic localizations. In 5 out of 6 patients the liver resection could be performed as preoperatively planned. The intraoperative findings agreed with the 3D visualization in all these patients. 3D Visualization of the liver allowed clear and interactive planning of liver resections and improved the preparation of complex liver resections.Zusammenfassung. Bei Patienten mit Lebertumoren stellen Sonographie, Computertomographie (CT) und in einigen Fällen die Magnetresonanztomographie (MRT) die Grundlage für die präoperative Planung von Leberresektionen dar. Auf der Basis von CT-Untersuchungen wurde ein dreidimensionales (3-D) Visualisierungsprogramm entwickelt. In dieser Studie wurde das 3-D-Visualisierungsprogramm bei 6 Patienten mit problematischer Lokalisation von Lebertumoren zur Planung des operativen Vorgehens angewendet. Bei 5 von 6 Patienten konnte die Leberresektion – wie präoperativ am Computermodell geplant – durchgeführt werden. Die intraoperativen Befunde entsprachen den 3-D-Visualisierungen. Die 3-D-Visualisierung der Leber erlaubte eine anschauliche und interaktive Planung von Leberresektionen am Computermodell und stellte somit eine verbesserte Vorbereitung für die komplexen Leberresektionen dar.

Ergebnisse der Resektion nichtcolorectaler nichtneuroendokriner Lebermetastasen

Summary. Over a period of 11 years a total of 140 liver resections for non-colorectal, non-neuroendocrine hepatic metastases were performed in 127 patients (73 women, 54 men; median age 53 years). There were 120 first, 14 second and 6 third liver resections. Primary tumors were: breast cancer (n = 34), leiomyosarcoma (n = 20), pancreatic cancer (n = 16), renal cell carcinoma (n = 13), melanoma (n = 9), gastric cancer (n = 9), lung cancer (n = 6) and adrenal cancer (n = 6) and miscellaneous tumors (n = 14). Extrahepatic tumor manifestation (including synchronous primary tumors) was found in 69/140 cases (49 %); 61 of 120 patients with a first liver resection had extrahepatic tumor (51 %). In the 120 first liver resections, 82 (68 %) R0, 13 (11 %) R1 and 25 (21 %) R2 excisions were possible. Median survival after first liver resection was 20 months; after R0 resection a median survival of 28 months and after R1/2 resection of 8 months was achieved. The 5-year survival rate was 16 % for the total group, 24 % in patients with R0 resection and 0 % for R1/2 resections. After a second liver resection (n = 14) there was a median survival of 28 months (5-year-survival-rate of 21 %) for all patients and of 41 months (5-year survival rate 38 %) after R0 resection. Morbidity and mortality after the first liver resection were 32.5 % and 5.8 %, respectively. In patients without extrahepatic tumor at the time of the first liver resection a median survival of 32 months (5-year survival rate 25 %) and 7 months was achieved after R0 resection and R1/2 resection, respectively. In case of extrahepatic tumor the median survival was 24 months (5-year survival rate 23 %) for R0 resection compared to 8 months after R1/2 resection. These data suggest that not the presence of extrahepatic tumor but rather the possibility of a R0 resection is most decisive for the prognosis after liver resection. We conclude that patients with liver metastases of non-colorectal, non-neuroendocrine tumors may benefit from liver resection. Similar to colorectal metastases, a second or third liver resection can be worthwhile in selected cases. Even in more unfavorable tumor entities, several cases of long-term survival were observed after surgical therapy. Therefore, the indication for liver resection should be considered carefully in every single case.Zusammenfassung. In einem Zeitraum von 11 Jahren wurden 140 Leberresektionen bei 127 Patienten (73 Frauen, 54 Männer; medianes Alter: 53 Jahre) wegen nichtcolorectaler nichtneuroendokriner Metastasen vorgenommen, darunter 120 Erst-, 14 Zweit- und 6 Drittresektionen. Bei den Primärtumoren handelte es sich um Mammacarcinome (n = 34), Leiomyosarkome (n = 20), Pankreascarcinome (n = 16), hypernephroide Carcinome (n = 13), Melanome (n = 9), Magencarcinome (n = 9), Bronchial- und Nebennierencarcinome (jeweils n = 6) sowie um 14 sonstige Tumoren. Extrahepatischer Tumorbefall (einschließlich synchroner Primärtumoren) bestand in 69 von 140 (49 %) Fällen, bei den 120 Erstresektionen lag in 51 % (n = 61) ein extrahepatischer Tumor vor. Von den 120 Erstresektionen wurden 82 (68 %) als R0-, 13 (11 %) als R1- und 25 (21 %) als R2-Resektionen eingestuft. Das mediane Überleben lag nach Erstresektion insgesamt bei 20 Monaten, nach R0-Resektionen bei 28 Monaten und nach R1/2-Resektionen bei 8 Monaten. Die entsprechenden 5-Jahres-Prognosen betrugen 16 % für alle Patienten und 24 % bzw. 0 % für Patienten mit R0- und R1/2-Resektionen. Nach Zweitresektion (n = 14) ergab sich ein medianes Überleben von 28 Monaten für alle Patienten und von 41 Monaten nach R0-Resektion. Die entsprechenden 5-Jahres-Prognosen lagen bei 21 % und 38 %. Die perioperative Morbidität lag nach der Erstresektion der Leber bei 32,5 %, die Letalität bei 5,8 %. Bei den Patienten ohne extrahepatischen Tumor zum Zeitpunkt der Erstresektion der Leber betrug das mediane Überleben nach R0-Resektion 32 Monate (5-Jahres-Prognose 25 %) und nach R1/2-Resektion 7 Monate. Im Vergleich hierzu lag das mediane Überleben nach R0-Resektion bei Patienten mit extrahepatischem Tumornachweis (Primärtumor und/oder sonstige Metastasen) bei 24 Monaten (5-Jahres-Prognose: 23 %) sowie nach R1/2-Resektion bei 8 Monaten. Entscheidend war also nicht so sehr, ob extrahepatische Tumormanifestationen vorlagen, sondern ob eine R0-Resektion möglich war. Die vorliegenden Ergebnisse zeigen, daß die Resektion auch nichtcolorectaler nichtneuroendokriner Lebermetastasen durchaus einen prognostischen Gewinn verspricht. Wie auch bei colorectalen Metastasen können Patienten mit hepatischen Rezidiven sogar von Zweit- oder Drittresektionen der Leber profitieren. In einigen Fällen konnten auch bei eher ungünstig eingeschätzter Ausgangssituation beeindruckende Langzeitverläufe beobachtet werden. Daher sollte die Indikation zur operativen Therapie in jedem Einzelfall überprüft werden.

Total hepatectomy and liver transplantation for metastatic neuroendocrine tumors of the pancreas - a single center experience with ten patients.

Abstract  Background: Metastatic neuroendocrine pancreatic tumors have a poor prognosis. We have studied retrospectively the efficacy of liver transplantation as ultimate therapy of otherwise untreatable symptomatic neuroendocrine hepatic metastases originating in the pancreas. Methods: We reviewed our experience of liver transplantation (LTx) for hepatic metastases of neuroendocrine pancreatic tumors in ten patients. The indication for liver grafting was seen in cases of irresectable metastases and when patients were suffering from otherwise untreatable tumor-associated symptoms due to massive hormonal release or large intra-abdominal tumor bulk. Results: In four patients, the primary tumors had been removed before LTx, in five patients simultaneously with LTx and in one case 46 months after grafting. There was no operative mortality. After hepatectomy and LTx, all patients had complete relief of symptoms and all preoperatively increased hormonal levels returned to normal. In nine of ten patients, the transplant procedure had the potential for cure, whereas, in one patient, the primary tumor had remained in situ at LTx and was removed 46 months later by an R2-resection. At present, nine patients are alive with a median follow-up of 33 months (range 13.5 months to 117 months). The one patient in whom the primary tumor was removed after transplantation died due to massive intra-abdominal tumor spread 68 months after LTx. Currently, two patients are without evidence of disease, but one of them after re-operation because of lymph-node metastases 8 months after transplantation. The longest disease-free survival is now more than 7 years. In seven of nine patients, tumor recurred between 1.5 months and 48 months after transplantation. Conclusions: Patients with otherwise untreatable symptomatic neuroendocrine hepatic metastases of pancreatic origin may benefit from total hepatectomy and liver transplantation with regard to symptomatic relief and long-term survival, despite frequent recurrence of disease. In some patients, liver transplantation may even offer the chance for cure.

Dreidimensionale Sonographie zur Volumenbestimmung von Lebertumoren – ein erster Erfahrungsbericht

Summary. In a clinical trial the accuracy of volumetry by use of three-dimensional ultrasound (3-D-US) in comparison to three-dimensional computer tomography (3-D-CT) was evaluated. Overall, 42 patients with focal hepatic lesions were investigated with 2-D- and 3-D ultrasound. In 11 patients additional computerized tomographic arterial portography using spiral technique was performed. The volumes of the lesions were calculated using the ellipsoid formula (for 2-D- and 3-D-US) as well as with a planimetric reconstruction for 3-D-US and 3-D-CT. In addition the intra- and inter-investigator variability of 3-D ultrasound was determined. The volume of the investigated liver lesions (planimetric reconstruction with 3-D ultrasound) ranged between 1.5 cm3 and 1231 cm3 with a mean volume of 155 cm3 and a median volume of 68 cm3. The deviation of 2-D-US vs 3-D-CT was − 62 % to + 68 %, in the case of 3-D-US (ellipsoid) vs 3-D-CT it was − 28 % to + 9 %, and for 3-D-US (planimetry) vs 3-D-CT it was − 21 % to + 9 %. The concordance index kappa was 0.886, showing very good agreement between the two investigators. The intra-investigator variability was 5 %. Our data show that volume measurement by use of 3-D-US is independent of the investigator. With regard to accuracy of volume measurements 3-D-US is comparable to 3-D-CT but more precise than 2-D-US. These results indicate that 3-D-US may be applied in the follow-up of tumor patients as an alternative diagnostic procedure to computer tomography. In addition 3-D-US might be useful in planning liver resections by virtue of better evaluation of the volume of the liver tissue remaining after resection and better visualization of the topography of liver tumors and major hepatic vessels.Zusammenfassung. In einer klinischen Studie wurde die Genauigkeit der Volumenbestimmung mittels dreidimensionaler Ultraschalluntersuchung (3-D-US) mit freier Schallkopfführung in vivo im Vergleich zur Computertomographie (3-D-CT) evaluiert. Insgesamt wurden 42 Patienten mit focalen Leberveränderungen mit 2-D- und 3-D-Ultraschall untersucht. Von 11 Patienten lag zusätzlich ein Spiral-CT mit Kontrastmittel vor. Die Volumina wurden einerseits mittels der Ellipsoidformel berechnet (2-D-US und 3-D-US), andererseits planimetrisch an Workstations rekonstruiert (3-D-US und 3-D-CT). Außerdem wurde für die 3-D-Planimetrie die Intra- und Interuntersuchervariabilität bestimmt. Die gemessenen Leberveränderungen hatten bei der planimetrischen Berechnung nach 3-D-Sonographie im Mittelwert ein Volumen von 155 cm3 (Spannweite 1,5–1231 cm3), der Medianwert betrug 68,8 cm3. Die Abweichung des 2-D-US vom 3-D-CT betrug − 62 % bis + 68 %, die des 3-D-US (Ellipsoid) vom 3-D-CT − 28 % bis + 9 %. Für 3-D-US (Planimetrie) lagen die Abweichungen vom 3-D-CT − 21 % bis + 9 %. Der Konkordanzindex kappa betrug 0,886, was einer sehr guten Übereinstimmung der Untersucher entspricht. Die Intrauntersuchervariabilität lag bei 5 %. Unsere Ergebnisse zeigen, daß die 3-D-US-Planimetrie nicht untersucherabhängig ist. In bezug auf die Volumenbestimmung ist 3-D-US wesentlich genauer als die konventionelle Sonographie und vergleichbar der aufwendigeren 3-D-CT-Untersuchung. Diese Ergebnisse deuten darauf hin, daß die 3-D-Sonographie beispielsweise bei Verlaufsuntersuchungen von Tumorerkrankungen als alternatives Verfahren zur Computertomographie eingesetzt werden könnte. Darüber hinaus könnte die 3-D-Sonographie durch Abschätzung des nach Teilentfernung verbleibenden Restlebervolumens sowie durch verbesserte Darstellung der Lagebeziehung von Tumoren zu zentralen Lebergefäßen auch bei der Planung von Leberresektionen hilfreich sein.

Isolated Hyperthermic Liver Perfusion with High Dose Tumor Necrosis Factor Alpha in Pigs: An Experimental Study in Preparation of Clinical Use

Isolated hyperthermic perfusion of the liver was performed for 45 min in 27 pigs via hepatic artery and portal vein at mean inflow temperatures between 40.7 and 41.2°C. In two study groups B and C (n = 9 pigs each) 50 μg recombinant human tumor necrosis factor-α (rhTNFα) per kg body weight were added to the perfusate, whereas in a control group A liver perfusion was done without rhTNFα. Before reperfusion the livers were washed out with Ringer’s solution in all groups followed by a protein solution in group C. At 30 and 60 min after reperfusion the maximum systemic rhTNFα concentrations were significantly higher in group B with 68 and 61 ng/ml compared to 14.5 and 14.9 ng/ml in group C (p < 0.05). Mean systemic porcine TNFα concentration was significantly higher in group B (217 pg/ml) compared to group C (50 pg/ml) 30 min after reperfusion (p = 0.012). Survival was 7/9 in group A and C and only 2/9 in group B with 6/7 pigs dying due to severe cardiopulmonary failure within 12 h after operation. In surviving pigs of group A and C only mild and transient hepatotoxicity was registered. The presented study underlines the feasibility of high dose rhTNFα application in an isolated hyperthermic liver perfusion system. Washout of the liver with a protein solution before reperfusion reduces systemic TNFα levels as well as associated lethal cardiocirculatory and hepatotoxic side effects.

Chirurgische Therapie maligner Lebertumoren: Resektion und Transplantation

Zum ThemaDie Leberchirurgie hat in den letzten Dekaden große Fortschritte erzielen können, nicht zuletzt dadurch, daß Operationstechniken und Organkonservierung wie bei der Lebertransplantation auch bei Resektionsverfahren zur Anwendung kommen. Durch verfeinerte Funktionstests, prädiktive Scoringsysteme und ein immer exakteres Tumorstaging stehen bessere Selektionskriterien zur Verfügung. So können die Indikationsstellungen für die entsprechenden Operationsmethoden präzisiert und günstigere Langzeitüberlebensraten erzielt werden.An den hier dargestellten Ergebnissen der Chirurgie primärer und sekundärer Lebertumoren mittels Resektion oder Transplantation (unter Einbeziehung der Ergebnisse des großen Krankenguts der Autoren) zeigt sich, wie immens besonders der Aufwand der Transplantation unter vielfältigen Gesichtspunkten ist, z.B. auch unter organisatorischen und logistischen. Zunächst stehen viel zu wenige Spenderorgane zur Verfügung, ferner muß zusätzlich zum Tumorpatienten ein anderer mit Transplantationsindikation bei einem benignen Leberleiden einbestellt und vorbereitet werden, falls der Tumorbefall eine Lebertransplantation ausschließt. Auf diese Weise geht kein Spenderorgan verloren.Diese Schwierigkeiten zeigen, daß unter den gegebenen Umständen die Resektionstechniken und die prä-, peri- und postoperativen multimodalen Behandlungsverfahren weiter verbessert werden müssen, also hier der künftige therapeutische Fortschritt chirurgischer Intervention bei malignen Lebertumoren zu suchen sein wird.