Sequential high-dose methotrexate, 5-fluorouracil, and doxorubicin for treatment of advanced pancreatic cancer.

A phase II trial of sequential high-dose methotrexate, 1500 mg/m2, and 5-fluorouracil, 1500 mg/m2 intravenously on day 1, plus doxorubicin, 30 mg/m2 i.v. on day 14, has been undertaken in patients with locally advanced or metastatic adenocarcinoma of the pancreas. Of 25 evaluable patients there were 1 complete response and 3 partial responses for an overall response rate of 16% (95% confidence interval 5%-36%). The median survival of all patients was 6.7 months (range 1-17 months). There was one treatment-related death due to pancytopenia and sepsis. In all other patients therapy was generally well-tolerated. We conclude that this combination protocol has only modest activity in the treatment of advanced pancreatic cancer.

Liver amino acids in sepsis.

The metabolic derangement of sepsis leads to changes of the plasma and muscle amino acid (AA) pattern. In this study the influence of a septic process on liver AA pattern was investigated. In seven patients with abdominal sepsis, liver AA concentrations were determined during surgery and compared with those of four patients who had undergone cholecystectomy. In sepsis lowered AA levels were found for most of the AAs. Outstanding decreases exhibited the levels of the gluconeogenetic AAs (especially threonine and alanine), the branched chain AAs, lysine, and taurine. In the patients who did not survive the septic process, the depletion of these AAs was even amplified. Slightly increased AA levels were analyzed for P-ethanolamine, cystathionine, citrulline, beta-alanine, tyrosine, and phenylalanine. The results indicate a disturbed free AA pattern of the septic liver. Despite the increased flux of gluconeogenetic AA from muscle to liver in sepsis, as reported by several authors, no accumulation of these AAs occurs in the liver.

An improved nonsuture method for portacaval anastomosis in the rat.

A nonsuture technique is described for performing portacaval anastomoses in rats. Improvements include reduced clamping time on critical vessels, reduced blood loss, uniformly patent anastomoses, easily manufactured buttons, and decreased mortality rates. The new procedure allows a single operator to perform 25 such operations per day, thus substantially increasing the availability of these animals for studies in hepatic metabolism following portacaval anastomoses.

The role of plasma amino acids in hepatic encephalopathy.

The dog with an end-to-side portacaval shunt has a plasma amino acid pattern similar to that in man with chronic liver disease and encephalopathy. When dogs with end-to-side portacaval shunts manifested symptoms of hepatic encephalopathy, superior caval catheters were placed and one of three solutions was infused. Whereas almost all animals given a commercially available synthetic amino acid mixture died, a special mixture formulated to normalize plasma amino acids was associated with 100 percent survival and few neurological symptoms. The results suggest that manipulation and normalization of plasma amino acids in animals with hepatic failure may be efficacious in providing adequate nutrition while minimizing hepatic encephalopathy. Moreover, these experiments may shed some light on the mechanism of human hepatic encephalopathy.

Free amino acid levels in muscle and liver of a patient with glucagonoma syndrome.

This study set out to measure the amino acid concentrations in the femoral artery, femoral vein, hepatic vein, muscular and hepatic tissue, and urine of a patient with the glucagonoma syndrome. The total plasma amino acid concentration was severely reduced on admission (737 mumol/L, 26% of normal), with only a slight increase during intravenous administration of 200 g of amino acids per day. The total intracellular amino acid levels in the muscle were 86%, and those of the liver were 47% of the normal range. Only 0.62% of the amino acids administered were found in the urine. Arteriovenous amino acid concentration differences across the muscle and splanchnic tissue indicated the release of amino acids (mainly glutamine, glycine, and alanine) from the muscle and the absorption of amino acids by the splanchnic bed. This study shows that the infusion of a high amount of amino acids cannot increase the subnormal plasma AA levels of patients with the glucagonoma syndrome. The low total plasma AA levels are paralleled by decreased intracellular free amino acid levels in the muscle and liver.

Brain tryptophan, plasma free tryptophan and distribution of plasma neutral amino acids.

Although rat brain tryptophan is strikingly elevated following portacaval shunt, plasma total tryptophan is unchanged and plasma free tryptophan is not elevated to the same degree as brain tryptophan. Investigation of the concentrations of the neutral amino acids (phenylalanine, tyrosine, methionine, threonine, leucine, isoleucine, and valine) revealed that their distribution and the sum of their concentrations were altered following portacaval shunt, and that this pattern was similar to that seen in humans with cirrhosis of the liver. It is suggested that both the elevation in plasma free tryptophan and the decrease in the competing neutral amino acids, act together to increase the transport of tryptophan into brain when portal blood is diverted around the liver. The implications of these findings in therapy of hepatic coma is discussed.

Brain energy metabolism and alterations of transmitter profiles in acute hepatic coma.

Brain energy reserve, tricarboxylic cycle intermediate and some putative neurotransmitters were measured in a devascularisation model with portacaval shunt and hepatic artery ligation done in two interventions. Conditions were standardized in that physiologic parameters, i.e. body temperature, systemic arterial pressure, PO2, PCO2 and pH, were kept constant and brain tissue was obtained with the "freeze-blowing" technique designed for deep freezing brain substance in less than one second. 1. Measured values indicative of the brain energy reserve (glucose, glycogen, ATP and phosphocreatin) were not found to differ from those of sham-operated animals. 2. Of the stimulating neurotransmitters, norepinephrine, dopamine, glutamic acid and aspartic acids were reduced with the exception of acetylcholine among the inhibitory neurotransmitters GABA and cAMP were unchanged, while all others including serotonin, octopamine, and phenylethanolamine were increased. 3. The results of these experiments suggest that an inbalance of amino acids with resultant changes in neurotransmitter profiles rather than an energy deficit constitutes the factor underlying hepatic coma.

Metabolic disorders in severe abdominal sepsis: glutamine deficiency in skeletal muscle.

The metabolic profiles of 14 patients with prolonged abdominal sepsis were analysed on the second day after laparotomy. The profiles of survivors were compared with those of non-survivors who died one to five days after the time of evaluation due to uncontrollable multiple organ failure. In the non-surviving patients plasma glucose and glucagon levels were significantly higher than in surviving patients. The plasma concentrations of phosphoserine, cysteine, valine, phenylalanine, and 3-methylhistidine were found to be significantly increased in non-survivors and their muscle tissue showed significantly decreased concentrations of glutamine, proline and lysine with increases in valine and leucine. A correct classification of non-survivors and survivors could be obtained from the plasma and muscle amino acid concentrations, the highest discriminant power being from muscle glutamine. In severe sepsis metabolic changes correlate with the outcome of the patients, and amino acid metabolism seems to be characterised by low concentrations of muscle glutamine and high levels of the branched chain amino acids possibly indicating an inhibited intracellular glutamine formation in muscle tissue.

Characteristics of release of duodenal gastrin.

Duodenal gastrin release in the dog was studied after mucosal antrectomy with intact duodenal innervation, following which basal gastrin levels fell. Acetylcholine at pH 7 but not at pH 1.5 and insulin hypoglycemia but not 2-deoxyglucose release duodenal gastrin. Glycine (pH7), physiologic saline (pH 7), and balloon distention failed to release duodenal gastrin. These findings suggest differences in release characteristics between canine antral and duodenal gastrin, and point out species differences between man and dog in respect to release of duodenal gastrin.

Effects of nutrition on plasma, liver and muscle amino acids in scalded rats.

This study set out to investigate the effect of three different parenterally administered diets on the free amino acid (AA) levels in the plasma, muscle, and liver of scalded rats. Diet I consisted of AA (1.4 g/100 g weight) and a high glucose dose (6 g/100 g weight), diet II consisted of AA and a low glucose dose (1.4 g/100 g weight) and in diet III only a low glucose dose was infused. Parenteral nutrition was started on the 3rd day posttraumatically. Sampling was performed on the 7th day posttraumatically. Nitrogen balances were significantly different in all three groups, being lowest in group III. Scalded rats fed isonitrogenously, but with different amounts of glucose showed only minor changes in AA concentrations. However scalded rats fed with a nitrogen-free diet exhibited significantly reduced total muscle and liver AA levels. These decreased AA levels were due to a drop of glycine in the muscle tissue (74%) and liver (49%). Contrary to the clinical catabolic situation in scalded and starved rats, it was not intracellular glutamine but glycine which was considerably influenced by catabolism and starvation.

Free amino acids in plasma and muscle in fulminant hepatic coma during an extracorporeal liver perfusion.

A 21-year-old female patient suffering from fulminant hepatic failure was treated with extracorporeal normothermic baboon's liver perfusion for 60 hours. The amino acids (AA) uptake of the extracorporeal organ and the ratio of plasma and muscle AA at the end of the perfusion were measured. The AA uptake of the extracorporeal liver was 414 millimoles per 60 hours and even greater during hemodialysis treatment. In spite of this AA uptake, the plasma AA pattern was not normalized. At the end of the perfusion, the free AA concentration in muscle tissue was 86.25 millimoles per liter of intracellular water, an increase of 62% compared to healthy volunteers. In the patient, the ratio of glutamine to glutamine in muscle tissue was 20 to 1 compared to 5 to 1 in normals. It is concluded that (1) the extracorporeal baboon liver cannot extract the quantities of AA released by endogenous protein catabolism in hepatic failure, and (2) the muscular ammonia detoxification system gets overloaded as indicated by the increase ratio of glutamine to glutamate.

[Transhepatic occlusion of bleeding oesophageal varices in cirrhosis of the liver (author's transl)]. / Zur transhepatischen Verödung blutender Osophagusvarizen bei der Leberzirrhose.

The transhepatic method for occluding bleeding oesophageal varices described by Lunderquist and Vang has been carried out in eight patients. The technique, success rate and complications are discussed. In two patients attempt at thrombosis was unsuccessful. One patient suffered a fatal complication. Recurrent bleeding occurred from four days to four months. Bearing in mind the efficiency of the method, its risk, compared with other palliative measures, is acceptable.

Current trends in the management of carcinoma of the pancreatic head.

Between 1965 and 1987, 783 patients were treated for ductal adenocarcinoma. Of these, 59% had carcinoma of the pancreatic head and 22% presented with carcinoma of the body or tail. In 19% of the cases the entire organ was involved. Two hundred and twenty-six patients (25.5%) underwent exploratory laparotomy; 420 patients (55%) had palliative operations, and 137 (18.5%) were resected for cure. In the past 3 years the resection rate increased from an original 18.5% to 28% (43 resective procedures in 153 patients). In 37 of the 137 patients (28%) surgery had to be extended to the portal vein, the superior mesenteric vein, the kidneys, adrenals, colon, stomach, liver and lymph nodes to ensure adequate radicality. At the same time in-hospital mortality (including deaths after extended procedures) dropped to 7%. Of the 137 patients resected for cure, 47% were alive at 1 year, 22% at 2 years, 12% at 3 years, 7% at 4 years, and 5% at 5 years. Mean survival time excluding in-hospital deaths was 18.65 months. In the first 15 months after surgery there was no difference in survival between standard resections and extended resections. Patients undergoing partial pancreaticoduodenectomy fared significantly better (p less than 0.01; Mantel) than those who had total resections, in terms of both median survival (10.8 versus 5.4 months) and mean survival (19.0 versus 7.82 months).(ABSTRACT TRUNCATED AT 250 WORDS)

Primary hepatic cancer--the role of limited resection and total hepatectomy with orthotopic liver replacement.

Between 1977 and 1986, 172 patients with primary hepatic cancer were treated at the Department of Surgery I, University of Vienna Medical School. In 76 cases (80%) males, 20% females), cirrhosis of the liver was also present. Ninety patients underwent curative surgery (hepatic resection in 64, and liver transplantation in 26 cases). There were no early tumor stages. Forty-five large tumors were confined to one lobe, 42 involved both lobes, 3 even invaded adjacent structures, the majority (74%) being hepatocellular carcinomas. Forty-four of the 64 liver resections were performed in patients with otherwise normal livers (mortality 18%), while 20 patients had associated liver cirrhosis. In view of the extremely high mortality rates after extended liver resection, only limited local resections have been performed in cirrhotic malignancies since 1982 (mortality 25%). Perioperative mortality (25% overall) was due mainly to hepatic failure and sepsis; non-fatal complications occurred in 12 patients (26%). Seventeen of the 26 liver transplants were cirrhotic hepatomas. Nine deaths (34%) were caused by technical problems (graft failure, clotting disorder after massive transfusion) and systemic infections. The outcome for the patient after the immediate postoperative period was determined by tumor regrowth (residual liver tissue, graft, distant metastases) in both groups (median life expectancy 18.4 months after radical liver resection and 18.6 months after liver transplantation). Surgery is the only alternative for these patients (50% survival of untreated hepatoma: 2.6 months), improving both their quality of life and survival. We believe that in carefully selected candidates with non-resectable tumors liver replacement may be a useful alternative.

Patency rate of implantable devices during long-term intraarterial chemotherapy.

Intraarterial implantable drug delivery systems have been considered as an alternative method for treating patients with unresectable liver malignancies. However, catheter problems with external implanted devices have resulted in limited application of chemotherapy. The introduction of subcutaneous devices offers an opportunity for long-term locoregional chemotherapy. Twelve external intraarterial catheters were implanted into 12 patients and 52 subcutaneously placed devices into 51 patients, all with various hepatic malignancies. Retrospective analyses comparing those two intraarterial systems were conducted taking into account the function and complication rate (hepatic artery thrombosis, infection, leaking, hemorrhage, and dislocation). The follow-up time for the external system was two to eight months (median five weeks), the thrombosis rate 33.3%, and the infection rate 25%. One instance of severe bleeding from the hepatic artery occurred during chemotherapy. One catheter dislocated. For the subcutaneously implanted intraarterial devices the follow-up time was five to forty-one months (median sixteen months), the thrombotic complication rate 17.3%, and the infection rate 7.6% (all patients with simultaneous bowel surgery). Catheter dislocation one year later required reimplantation; in 1 patient therapy had to be discontinued because of a catheter leak. The overall function rate was 71.3% with a median follow-up time of eight months. Anticoagulation therapy for subcutaneously implanted devices starting from the beginning of intraarterial chemotherapy is recommended to achieve long-term patency. No implantation should be preformed simultaneously with bowel surgery. The subcutaneously placed intraarterial devices had a higher function rate and were available for a longer period as compared with external implanted catheters.

[Liver transplantation--indications and postoperative course]. / Lebertransplantation--Indikation und postoperativer Verlauf.

54 liver transplantations on 53 patients are analysed. Tumor disease was found in 57%, cirrhotic liver disease in 43%. 9 patients had metastatic liver tumors after distal colon surgery. The fatal technical failure rate was 3%, the postoperative mortality for the first 3 month and for 1 year 40% and 52% respectively. Very often jaundice and rejection in the graft were found, independent from the crossmatch (pos. in 16%). There is only one child with 3 years. The main reason for postoperative death are lung and heart diseases, which were not diagnosed preoperatively in 10 patients. We conclude that the postoperative complication rate is to be lowered by applying rigorous selection criteria, raising the replantation rate and improving the donor organisation.

[Resection of intrathoracic oesophageal cancer by blunt dissection without thoracotomy (author's transl)]. / Die Entfernung des Karzinoms im Brustabschnitt der Speiseröhre ohne thorakotomie.

The resection of thoracic oesophageal cancer by blunt finger-dissection and stripping is a further palliative procedure at the disposal of the surgeon. This method represents an alternative to intubation or bypass without resection. The advantages are the better functional results and at least palliative removal of the tumour. This method should be used, however, if there is the possibility of carrying out radical resection from the oncological point of view, with the aim of curing the patient. The technical details are described and the indications and results discussed on the basis of six case reports.

[Liver resection of hematogenous and infiltrating metastases]. / Leberresektionen wegen hämatogener und infiltrierender Metastasen.

Of a total of 245 resections for hepatic metastases 124 operations were performed for hematogenic metastases and 36 for infiltrating metastases in continuity with the primary tumour. This group of so-called "major hepatic resections" is analysed. The series comprises 83 male and 77 female patients, mean age 62.2 years. There were 85 resections of the right lobe (39 of those with intrahepatic extension to the left), 45 right) and 30 atypical hepatectomies (at least bisegmentectomies). Hematogenic hepatic metastases: 80 resections of hepatic metastases following colorectal carcinoma, 15 following cancer of the stomach and esophagus, 12 after non-gastrointestinal malignant tumours, 4 resections after unknown primary cancer (44% solitary, 32% monolobar multiple, and 24% bilateral metastases); synchronous operations were performed in 32% of the patients, in 19% so-called interval surgery (mean 7.4 weeks), and in 49% metachrone surgery (mean 30 weeks). During 1983 and 1985 our morbidity rate amounted to 10% and the letality rate to 7%, as compared to 17% morbidity and 15% letality in the period 1965-1983. In both periods, septic postoperative complications outnumbered all other causes. The mean survival rate after colorectal carcinoma was 20 months, after non-gastro-intestinal malignant growth 19 months, after carcinoma of the stomach as well as after malignant biliary tract diseases 5 months. The three-year survival rate of colorectal carcinoma amounts to 30%, the five year survival rate to 15% including all metastatic stages. The results of interval and metachrone resections in forms of survival rates are clearly better than the results of synchronous resections with a mean survival time of five months.(ABSTRACT TRUNCATED AT 250 WORDS)

[Regional results of human liver transplantation in Vienna]. / Regionale Ergebnisse der humanen Lebertransplantation in Wien.

21 cases of transplantation of the liver are analysed for indication, anaesthesia, operative management, anhepatic period, immunological therapy and specific post-operative problems (jaundice and rejection episodes). Causes of death are noted and prediction of survival gives a rate of 55%/1st year in the 17 patients operated on since 1982 under a standardised management schedule. The transplantation programme in Vienna provides routine treatment for otherwise untreatable primary (57% cases) and secondary metastatic (14%) tumours of the liver, and, in the second place, for end-stage hepatic cirrhosis (14%) and certain rare liver diseases (14%).

[Measuring cyclosporin in immunosuppressive treatment following liver and heart transplantation]. / Die Messung von Cyclosporin in der immunsuppressiven Behandlung nach Leber- und Herztransplantation.

Selective suppression of the immune system in graft recipients is now achieved in most cases by treatment with cyclosporine A. Due to large individual differences in absorption, utilization and metabolisation of this drug, therapeutic blood levels (immunosuppression/toxicity) can be maintained only by frequent measurements of the cyclosporine concentrations in blood samples and dosage readjustments. In the present study, we measured cyclosporine in whole blood samples from 37 patients (23 liver and 14 heart transplant recipients) using an high pressure liquid chromatographic method for native cyclosporine A which has been developed in our laboratory and a radioimmunoassay method (cyclosporine A + metabolites). By comparison of the results of HPLC and RIA-measurements (n = 520) we found a relatively stable metabolization rate (RIA/HPLC-ratio) of 4.23 +/- 1.30 for heart transplant recipients. In contrast RIA/HPLC ratios were highly variable in liver graft recipients ranging from 1.3-9 for the same patient in the posttransplant period. The liver recipients could be classified into two groups according to their mean RIA/HPLC-ratios: for 11 patients we observed a mean ratio of 2.65 +/- 0.35, for another 12 patients one of 4.35 +/- 0.75. Lower metabolisation rates seem to be associated with low donor age. No direct correlation was found between changes in RIA/HPLC-ratios and liver function, rejection and infection periods. Rejection treatment with high doses of methylprednisolone had no systematic influence on cyclosporine metabolisation in our patients. Since cyclosporine metabolites, at least those ones which are most abundant, have less immunosuppressive and toxic effects we recommend measurements of cyclosporine blood concentrations with any HPLC-method specific for the unchanged drug.(ABSTRACT TRUNCATED AT 250 WORDS)