Long-term outcome of early steroid withdrawal after kidney transplantation in African American recipients monitored by surveillance biopsy.

Generally chronic steroid therapy is standard care for African American (AA) kidney recipients because of their higher incidence of rejections and lower long-term graft survival. This prospective study evaluated the long-term safety and efficacy of early steroid withdrawal (ESW) in AA recipients. A total of 206 recipients were studied; 103 AA and 103 non-AA recipients monitored by serial surveillance biopsies from 1 to 60 months posttransplantation to evaluate subclinical acute rejections (SCAR) and chronic allograft injury (CAI). Biopsy-proven clinical acute rejections (BPAR) and SCAR were treated. Primary end point was BPAR and secondary end points were 5-year SCAR, CAI and survival. Incidences of BPAR was 16% versus 14% (p = 1.0), prevalence of CAI due to hypertension was 48% versus 30% (p = 0.05) and interstitial fibrosis/tubular atrophy was 47% versus 32% (p = 0.05) and the mean serum creatinine levels were 2.1 versus 1.8 mg/dL (p = 0.05) at 5-years in AA versus non-AA recipients. The incidence of SCAR was 23% versus 11% at 1 month (p = 0.04), 12% versus 3% at 3 years (p = 0.04) and 10% versus 1% at 5 years (p = 0.04) in AA and non-AA recipients, respectively. Five-year patient survivals were 81% and 88% (p = 0.09) and graft survivals were 71% and 73%(p = 0.19) in AA and non-AA groups, respectively. After early steroid withdrawal AA kidney recipients have significantly lower renal function and higher SCAR and CAI but 5-year graft survival are comparable to non-AA recipients.

Rescue of a living donor with liver transplantation.

Postoperative liver failure is a rare complication after living donor liver resection. This is a case report of a 22-year-old healthy donor who was rescued with liver transplantation 11 days after right hemihepatectomy. Nine months later the patient is alive, and has fully recovered from his multiple organ failure. According to a review of the literature, there are four additional living liver donors, who received a liver transplant. Our own patient is the only survivor, so far. This case demonstrates that even in supposedly healthy living donors postoperative complications cannot be completely prevented. Although liver failure is rare in these patients, timely transplantation may need to be considered as the only life-saving treatment.

Comparison of human and rat hepatocyte metabolism and mutagenic activation of 2-acetylaminofluorene.

A method has been developed to assess the metabolism and mutagenic activation of carcinogens using human and rodent hepatocytes in vitro. A slicing technique which was especially useful for nonperfusable biopsy and resected surgical human liver tissue was used to prepare the hepatocytes. Metabolites of the model carcinogen 2-acetylaminofluorene (AAF) produced by human and rat hepatocytes were similar and consisted primarily of 2-aminofluorene with ring hydroxylated products at the 1-, 3-, 5/9-, 7-, and 8-positions produced in addition to N-hydroxy-AAF. Sulphate and glucuronide conjugates of ring-hydroxylated metabolites and 2-aminofluorene were detected. Metabolism and cell-mediated Salmonella mutagenicity illustrated interindividual variation with human hepatocytes. Levels of metabolism and mutagenesis were generally higher with human hepatocytes compared to rat hepatocyte results. The increased levels of metabolism and mutagenesis of AAF by human hepatocytes compared to rat hepatocytes probably indicates a different sensitivity to hepatocarcinogenic effects of AAF on humans as compared to rats. Understanding differences and similarities between human and rodent carcinogen activation capabilities should be useful in the extrapolation of rodent carcinogenesis data to humans.

The hepatic extraction of gastric inhibitory polypeptide and insulin.

The hepatic extractions of gastric inhibitory polypeptide (GIP) and insulin were determined using in vitro and in vivo methods to assess the role of the liver in GIP metabolism and the possible effect of GIP on the hepatic extraction of insulin. During in vitro studies using the isolated perfused rat liver, infusion of GIP (2000 pg/ml) alone and in combination with porcine insulin (200 microU/ml) resulted in negligible hepatic extraction of immunoreactive GIP (IR-GIP) in both fed and fasted animals during either physiologically euglycemic or hyperglycemic perfusions. Hepatic extraction of insulin, however, ranged from 26-36% in fasted animals and from 7-25% in fed animals. Hepatic extraction of insulin and net hepatic glucose appearance were minimally affected by GIP. In vivo studies in awake dogs were then performed, in which simultaneous portal and peripheral venous levels of IR-GIP, immunoreactive insulin (IRI), and glucose were assessed after intraduodenal glucose administration. The portal to peripheral (PORT/PERI) venous ratio of endogenous IRI and IR-GIP reflected the findings of the in vitro studies; the PORT/PERI ratio of IRI levels rose from a basal value of 1.9 +/- 0.3 to a peak of 3.7 +/- 0.9, while the PORT/PERI ratio of IR-GIP levels rose from a basal value of 1.0 +/- 0.1 to a peak of 1.4 +/- 0.2, then rapidly returned to 1.0. The in vivo data are consistent with a continuous hepatic extraction of 40-50% of the insulin entering the liver and a negligible hepatic extraction of IR-GIP. We conclude that hepatic extraction of GIP in vitro or in vivo is minimal. In addition, while the fed state of the animal before infusion can result in changes in the in vitro hepatic extraction of insulin, GIP does not mediate these changes.

Nodular regenerative hyperplasia in partial hepatectomy specimens.

To investigate possible associations of nodular regenerative hyperplasia (NRH) with antitumor chemotherapy, we reviewed 72 partial hepatic resections (55 with metastatic tumor, 12 hepatocellular carcinomas, and five benign neoplasms). Thirty autopsy livers from adults without malignancies served as controls. Studies included hematoxylin and eosin, reticulin, and trichrome stains and immunostaining for proliferating cell nuclear antigen (PCNA). Five of 72 livers (7%) had NRH. All five patients had received chemotherapy, one by intrahepatic artery infusion. Four had received chemotherapy 2 months or less before undergoing partial hepatectomy. These five cases represented 15% of the 33 patients who received chemotherapy. No NRH was seen in autopsy control livers. In contrast to NRH, multiple hyperplastic foci were seen in 28 of 72 livers (39%). This finding did not correlate with chemotherapy. Two of 30 control livers (7%) showed similar mild regenerative changes. In only one case of NRH was PCNA staining increased over controls. A band of PCNA-positive hepatocytes was seen adjacent to the tumor in 21 cases, suggesting that the presence of tumor may cause a local increase in PCNA expression. Mitoses in hepatocytes and assessment of the thickness of liver cell plates were more sensitive indicators of regeneration than PCNA. Vascular changes, such as sinusoidal fibrosis (11 of 72 cases), thickened hepatic arterioles (13 of 72 cases), and mild thickening of central veins (10 of 72 cases), did not correlate with NRH, hyperplastic foci, or chemotherapy. No cases of hepatoportal sclerosis were identified.

The effects of liver denervation on the regulation of hepatic biliary secretion.

Effects of liver denervation on bile formation were studied in eight dogs prepared with chronic biliary fistulas. The animals were studied in the basal state, after feeding, and during infusion of glucagon 50 ng/kg/min, secretin 2 U/kg/hr, or somatostatin 200 ng/kg/min. After this first set of experiments the animals underwent a total hepatic denervation that consisted of section of the hepatic ligaments and a careful dissection of the portal vein, hepatic artery, and common duct with stripping of all the surrounding connective tissue and topical application of phenol. The above experiments were then repeated. Denervation did not modify bile flow, or bile salts, cholesterol, or phospholipid concentration or output. Biliary response to glucagon and secretin was similar before and after denervation. Somatostatin had an anticholerectic effect in both intact and denervated animals, but significantly reduced bile salt output only in the intact dogs. Feeding had a choleretic effect pre- and postdenervation, and the infusion of somatostatin following feeding decreased bile flow to the same degree before and after denervation. In the intact animals the output of all three biliary lipids was reduced by somatostatin after feeding but they were unaffected by somatostatin after denervation. Moreover, cholesterol and phospholipid outputs were stable after feeding in intact animals, but significantly decreased after denervation. 14C-erythritol clearance studies indicated no change in the canalicular component of bile flow with denervation, except again during somatostatin suppression of feeding. These data indicate that basal bile flow is normal after denervation but that innervation may play an important role in the modulation of responses to somatostatin and more complex stimuli such as feeding.

Bile acids in xenogeneic ex-vivo liver perfusion: function of xenoperfused livers and compatibility with human bile salts and porcine livers.

BACKGROUND: In recent years, hepatic support systems using xenogeneic cells have been developed to support patients in fulminant hepatic failure. The extent to which xenogeneic hepatocytes metabolize and excrete human organic anions is unclear. In these studies we examined the ability of the ex vivo porcine liver to clear human bile acids during extracorporeal liver perfusion (ELP). METHODS: Four patients with fulminant hepatic failure underwent extracorporeal liver perfusion with 9 porcine livers. The venovenous circuit was designed as previously described (NEJM,1994,331:234) as were the immunologic features (Transplantation 1994,58:1162). Bile from the porcine liver and serum samples were collected hourly during perfusion. Three bile acids (glycocholic, glycodeoxycholic, taurodeoxycholic acid) were selected as markers for human bile and three (glycohyocholic, glycohyodeoxycholic, and glyco-3alpha-hydroxy-6-oxo-5beta-cholanoic acid) for markers of pig bile. Bile acids from both serum and bile were processed and analyzed through high performance liquid chromatography. The Students' t test was used for statistical analysis. RESULTS: The mean duration of perfusions was 4.1+/-1.5 hr. The mean total bile acid clearance from serum (243+/-44 micromol/h) was similar to the total bile acid biliary excretion (286+/-84 micromol/hr, P = 0.06). After 1 hr of perfusion, bile samples demonstrated a predominance of pig bile salts (65%). After 3 hr of perfusion, human bile acids made up 85% of total biliary bile acids. Pig bile acids appeared in patients' sera after 1 hr of perfusion, and after 3 hr, 35% of serum bile salts were pig-specific. CONCLUSIONS: Porcine livers perfused with human blood can clear the serum of potentially toxic human bile acids and excrete them into bile. Simultaneously, the percentage of pig-specific bile acids in patient serum increases during xenogeneic perfusion for unknown reasons. The relative hepatic uptake of bile acid from serum is similar to bile acid excretion in bile. Further development of systems using porcine livers or hepatocytes is warranted.

Mechanisms of injury in porcine livers perfused with blood of patients with fulminant hepatic failure.

Hyperacute rejection of renal and cardiac xenografts is initiated by the reaction of recipient natural antibodies and complement with endothelial cell antigens of the donor organ. The liver is thought to be less susceptible to this form of rejection; however, the mechanisms underlying its decreased susceptibility are not known. We investigated the organ injury occurring in porcine livers perfused with blood from 4 human subjects with fulminant hepatic failure. Nine porcine livers were perfused via an extracorporeal circuit in order to provide temporary metabolic support. Each porcine liver exhibited metabolic function, and the duration of xenoperfusion ranged from 2 to 5 hr. Histologic examination of the xenoperfused livers revealed focal hepatocellular necrosis, prominent infiltration of neutrophils, and, in 7 of 9 cases, periportal and centrilobular hemorrhage and thrombosis. Immunopathology demonstrated minimal or no human IgM and IgG along the small vessels and sinusoidal surfaces. Trace deposits of human IgM were observed along the luminal surfaces of large blood vessels in most cases. Trace deposits of C3 were noted in 2 of 9 livers; however, C4, iC3b, C5b, properdin, and the membrane attack complex were not detected. Human anti-porcine natural antibody titers decreased less than expected during the perfusions. Serum CH50, C3, and C4 levels were low before each procedure and decreased slightly with perfusion. One patient perfused 2 porcine livers and a human liver. The human liver had focal hepatocellular necrosis, trace deposits of IgM, no deposits of complement, and an infiltrate consisting of neutrophils; however, the neutrophil influx was less than that observed in the xenoperfused livers. To further evaluate the effects of alloperfusion, venovenous bypass was established in 2 pigs and the extracorporeal circuit was utilized to perfuse 2 porcine livers. The alloperfused porcine livers had focal hepatocellular necrosis and a minimal infiltrate of neutrophils. There were no deposits of porcine IgM, IgG, or complement components. In conclusion, although the porcine livers perfused by human blood sustained structural damage, the time course, the absence of immune deposits, and the findings of similar, albeit less severe, lesions in the alloperfused livers suggest that the pathogenesis of tissue injury in the xenoperfused livers differs from that of hyperacute rejection and may be related to the action of recipient neutrophils.

V-PYRRO/NO: an hepato-selective nitric oxide donor improves porcine liver hemodynamics and function after ischemia reperfusion.

BACKGROUND: The role of nitric oxide (NO) in ischemia reperfusion (I/R) injury is controversial as both beneficial and harmful effects have been reported. We explored the potential role of a pharmacological agent recently shown to generate NO metabolically in the liver in an animal model of transplantation. METHODS: The effect of a selective hepatic NO donor, O2-vinyl 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (V-PYRRO/NO), on hepatic hemodynamics and biliary function was evaluated in both the in situ and I/R pig liver. RESULTS: V-PYRRO/NO significantly reduced in situ hepatic vascular resistance (HVR) without altering systolic blood pressure. Portal vein flow was essentially unchanged during in situ infusions while hepatic artery flow nearly doubled (P=0.03). After I/R, V-PYRRO/NO infusions significantly reduced both portal vein pressure (PVP) and HVR (P=0.04). Also, serum bile acid clearance increased from 15% when taurocholate (TC) was infused alone to 46% (P=0.007) when infused simultaneously with V-PYRRO/NO. Aqueous bile production tripled with TC and V-PYRRO/NO as compared to TC alone (P=0.04). Analysis of bile outputs revealed a significant increase in biliary cholesterol, biliary phospholipid, and biliary bile acid (P<0.05) with V-PYRRO/NO infusion. CONCLUSIONS: The hepato-selective nitric oxide donor, V-PYRRO/NO, reduced hepatic resistance parameters of the pig liver both before and after I/R and improved the plasma clearance of bile acid and biliary outputs of bile acid-dependent compounds. The augmented function observed after I/R may be due to improvements in hepatic blood flow secondary to altered hepatic hemodynamics.

Protective effects of ischemic preconditioning on the cold-preserved liver are tyrosine kinase dependent.

BACKGROUND: Little data exist regarding the use of ischemic preconditioning before sustained hepatic cold storage. We hypothesized that ischemic preconditioning protects hepatic grafts via a tyrosine kinase-dependent pathway. METHODS: Six porcine livers underwent routine harvest (control). Five other livers underwent 15 min of in situ ischemia followed by 15 min of reflow before harvest (ischemic preconditioning). Another five livers were pretreated with a tyrosine kinase inhibitor (genistein) before preconditioning. Upon reperfusion and after 2 hours of cold storage, graft function, graft circulatory impairment, and markers of cellular damage were analyzed. Tissue cytoplasmic extracts were analyzed for tyrosine phosphorylation with Western blot. Significance was determined with t tests. RESULTS: Ischemic-preconditioned grafts demonstrated enhanced bile production, augmented responses to a bile acid challenge, and elevated O2 consumption (P<0.05) compared to controls. Also, preconditioned grafts demonstrated improved hepatic tissue blood flow and decreased hepatic vascular resistance (P<0.005) compared to controls. Endothelial cell preservation (factor VIII immunostain) was improved in preconditioned graft biopsies compared to controls. With genistein pretreatment, all observed improvements returned to control levels. Analysis of cytoplasmic extracts demonstrated an increase in tyrosine phosphorylation before cold ischemia in preconditioned grafts only, but not in control or genistein-pretreated grafts. CONCLUSIONS: The data indicate that ischemic preconditioning protects the liver from sustained cold ischemia and that tyrosine kinases are involved in preconditioning responses.

Biliary secretion of extracorporeal porcine livers with single and dual vessel perfusion.

BACKGROUND: Hepatic support systems that provide detoxification without biliary secretion (i.e., isolated hepatocyte systems) are sufficient to improve encephalopathy and bridge patients to transplantation. However, biliary secretion may be critical when hepatic support attempts to restore function and regeneration of the host liver. The purpose of these studies was to optimize the support liver secretory response to bile acid by either single-vessel (portal vein; PV) or dual-vessel (hepatic artery [HA] + PV) perfusions during extracorporeal porcine liver perfusion. METHODS: Extracorporeal porcine liver perfusion of anesthetized pigs was developed using support porcine livers perfused through the PV (n=4) alone and through the HA + PV (n=4) via a venovenous circuit. Support livers were provoked with taurocholate (TC) to enhance bile aqueous and hydrophobic outputs. RESULTS: After cold preservation and reperfusion, both PV and HA + PV livers had initial 1-hr bile aqueous outputs < 15% of in vivo flow, with cholesterol (C) and phospholipid (PC) outputs <25% of in vivo flow. Bile flow was significantly greater for recovered HA + PV livers (3.0+/-0.01 ml/15 min) than PV livers (1.9+/-0.01 ml/15 min). Despite this, PC output was significantly greater for PV than HA + PV livers. The C/PC ratio of PV livers was twice that of HA + PV livers. TC infusion (48 micromol/kg/15 min) of HA + PV livers demonstrated significantly greater increments in bile flow, PC output, and C output than PV livers. CONCLUSION: In the unstimulated state, porcine support livers with dual-vessel perfusion generated greater aqueous and C outputs despite diminished PC output than in those with single-vessel perfusion. TC stimulation increased bile flow, PC output, and C output in dual-perfused livers more than in PV livers. HA + PV perfusion of support livers is the preferred technique for removing hydrophobic compounds that require PC transport for excretion or exist in the aqueous phase.

Gallbladder density and iodine concentration in humans during oral cholecystography. A comparison of iopanoic acid and iopronic acid.

A comparison of two oral cholecystopaques, iopanoic acid (Telepaque) and iopronic acid (Oravue), was performed using normal volunteers. Using a double-blind crossover design, comparisons were made between the degree of gallbladder opacification and the amount of iodine recovered from the gallbladder. Bile was collected via a double lumen intestinal tube before, during, and after stimulating gallbladder contraction. There were no differences between the two agents in terms of opacification or iodine concentration. Only 19% of the administered dose of either agent was recovered, and the maximum iodine concentration in bile was 10 mg I/ml. The results suggest that this technique has merit for future comparative studies of agents concentrated in the gallbladder.

Management of biliary complications after heart transplantation.

BACKGROUND: Immunosuppression increases the risk of biliary complications in heart transplant recipients. METHODS: Patients undergoing heart transplantation since 1986 who were at risk for cholelithiasis (n = 60) were retrospectively studied. RESULTS: Cholestatic jaundice developed in all patients after the operation because of biliary obstruction from cholelithiasis, cyclosporine toxicity, Imuran toxicity, or Gilbert's disease. The incidence of cholelithiasis or sludge was 42% (n = 25 of 60). Gallstones developed within 1.8 +/- 1.1 years in 17% of patients (n = 8 of 48) with a normal pretransplantation ultrasonogram. Biliary colic or gallstone pancreatitis developed 2 +/- 1.2 years after transplantation in 58% of patients (n = 7 of 12) with asymptomatic gallstones diagnosed before transplantation. The overall incidence of cholecystectomy or cholecystectomy with Roux-en-Y cystojejunostomy was 40% (n = 24). Both open cholecystectomy (n = 5) and laparoscopic cholecystectomy (n = 19) were performed without significant complications. Recovery is significantly more rapid (p < 0.05) after laparoscopic cholecystectomy versus open cholecystectomy (1 week versus 3 weeks). CONCLUSIONS: This analysis indicates that transplant candidates who have gallstones on pretransplantation evaluation or in whom gallstones develop after transplantation should undergo laparoscopic cholecystectomy at the earliest time in their posttransplantation course (i.e., 3 months) regardless of their symptomatic status. Removal of the diseased gallbladder not only simplifies the evaluation of cholestatic jaundice by eliminating the need for multiple ultrasonograms to exclude acute cholecystitis or choledocholithiasis but also safely minimizes the risk of the development of severe biliary complications.

Inhibition of bile flow by intravenous arginine hydrochloride.

One proposed mechanism for the cholestasis associated with total parenteral nutrition is infusion of amino acids. Arginine, 19 mumol/kg/min, was infused for a short time in healthy dogs with a biliary fistula to test the effect of endogenous hormone release on bile flow and composition. Both plasma glucagon and blood glucose levels increased. Despite the release of the choleretic hormone, glucagon, bile flow decreased 30%. The suppression of bile flow was attributed to a decrease in the bile acid-dependent fraction of bile flow. Bile acid, cholesterol, and phospholipid output were all depressed.

Inhibition of basal and meal-stimulated choleresis by somatostatin.

The effect of somatostatin, an inhibitor of release of a number of gastrointestinal and other hormones, on choleresis was investigated in chronic, bile fistula dogs with taurocholate-stabilized bile flow. Somatostatin inhibited both fasting and meal-stimulated choleresis, and bile flows during somatostatin inhibition of both fasting and fed dogs were similar, suggesting a complete suppression of factors causing feeding choleresis. Although a transient decrease in bile salt output was observed, bile salt output was unaffected during most of the period of bile flow inhibition. Hormone suppression by somatostatin, indicated by measurement of serum insulin, occurred over a similar time course as inhibition of choleresis. These observations provide further evidence for physiological humoral regulation of choleresis.

Successful management of late-onset primary lymphatic hypoplasia.

Primary lymphedema of the extremities, abdomen, or chest is an unusual and difficult clinical problem with few guidelines for management. A case is reported of lymphedema acquired at the age of 61 years, with associated massive chylous ascites and chylothorax. No underlying condition was discovered and the patient was found to have hypoplastic lymphatics by lymphangiography. Initial management consisted of extremity elevation, diuresis, and repeated paracenteses and thoracenteses. A peritoneojugular shunt provided temporary relief. Surgical pleurodesis combined with intensive diuresis has given prolonged relief of his symptoms allowing him to return to a functional life. Diagnostic and therapeutic guidelines for the management of this unusual condition are suggested.

Effects of serotonin on canine bile formation.

Long-term studies were performed on dogs previously prepared by cholecystectomy, ligation of the lesser pancreatic duct, and insertion of a duodenal cannula. After an overnight fast, bile duct cannulation and stabilization of bile flow with intravenous (IV) sodium taurocholate, serotonin, 10 micrograms/kg/min, or 0.15 N NaCl was infused. In similar experiments, animals were fed a standard meal, and serotonin or 0.15 N NaCl was infused IV beginning simultaneously with or 30 minutes after the meal. Short-term experiments were performed on dogs anesthetized with pentobarbital and prepared by abdominal evisceration, cholecystectomy, and bile duct cannulation. Serotonin caused significant inhibition of fasting bile formation (3.8 +/- 0.3 ml/15 min to 3.2 +/- 0.3 ml/15 min), meal-stimulated choleresis (4.0 +/- 0.3 ml/15 min to 3.5 +/- 0.3 ml/15 min), and bile flow in eviscerated animals (1.6 +/- 0.1 ml/15 min to 1.1 +/- 0.2 ml/15 min). Bile acid output and 14C erythritol clearance were stable while bile bicarbonate output was decreased during serotonin infusion. A similar inhibitory effect was demonstrated with serotonin, 5 micrograms/kg/min, but the inhibition was not statistically significant with 2.5 micrograms/kg/min. These studies demonstrate that serotonin inhibits bile acid-independent bile formation, possibly at the ductular level, and the inhibition occurs independently of endogenous gastrointestinal tract hormone secretion.

Liver metastases from breast cancer: long-term survival after curative resection.

BACKGROUND: Liver metastases from breast cancer are associated with a poor prognosis (median survival < 6 months). A subgroup of these patients with no dissemination in other organs may benefit from surgery. Available data in the literature suggest that only in exceptional cases do these patients survive more than 2 years when given chemohormonal therapy or supportive care alone. We report the results of liver resection in patients with isolated hepatic metastases from breast cancer and evaluate the rate of long-term survival, prognostic factors, and the role of neoadjuvant high-dose chemotherapy. PATIENTS AND METHODS: Over the past decade, 17 women underwent hepatic metastectomy with curative intent for metastatic breast cancer. The follow-up was complete in each patient. The median age at the time breast cancer was diagnosed was 48 years. Neoadjuvant high-dose chemotherapy (HDC) with hematopoietic progenitor support was used in 10 patients before liver resection. Perioperative complications, long-term outcome, and prognostic factors were evaluated. RESULTS: Seven of the 17 patients are currently alive, with follow-up of up to 12 years. Four of these patients are free of tumors after 6 and 17 months and 6 and 12 years. The actuarial 5-year survival rate is 22%. One patient died postoperatively (mortality rate, 6%) of carmustine-induced fibrosing pneumonitis. There was no further major morbidity in the other patients. The liver was the primary site of recurrent disease after liver resection in 67% of the patients. Patients in whom liver metastases were found more than 1 year after resection of the primary breast cancer had a significantly better outcome than those with early (< 1 year) metastatic disease (P = .04). The type of liver resection, the lymph node status at the time of the primary breast cancer resection, and HDC had no significant impact on patient survival in this series. CONCLUSIONS: Favorable 22% long-term survival can be achieved with metastasectomy in this selected group of patients. Careful evaluation of pulmonary toxicity from carmustine and exclusion of patients with extrahepatic disease are critical. Improved survival might be achieved with better selection of patients and the use of liver-directed adjuvant therapy.

Selective biliary secretion of basal and glucagon-inhibited neutral sterol after triparanol administration.

Biliary cholesterol secretion was studied in dogs with chronic bile fistulas, using glucagon, an inhibitor of biliary cholesterol secretion, and triparanol, an inhibitor of cholesterol synthesis. Glucagon inhibited neutral sterol secretion before and after triparanol administration. Triparanol caused a significant accumulation in bile of the cholesterol precursor desmosterol which comprised a significant portion of the neutral sterol in bile but not in blood. Glucagon inhibited both biliary desmosterol and cholesterol secretions to a similar degree. These findings suggest that biliary cholesterol is derived from newly synthesized hepatic sterol as well as from equilibrated sources. Furthermore, glucagon suppressed biliary secretion of both equilibrated as well as newly synthesized neutral sterol, suggesting that glucagon inhibits the movement of neutral sterol to or through the canalicular membrane.

Somatostatin-induced cholestasis can be independent of portal blood flow.

Short-term experiments were performed on adult mongrel dogs (15 to 25 kg) anesthetized with sodium pentobarbital. The operative procedure included cholecystectomy, side-to-side mesocaval shunt with ligation of the portal vein, and cannulation of the common bile duct. Intravenous sodium taurocholate (500 mg/hr) was administered to prevent depletion of bile salts. Somatostatin (125 micrograms over 30 minutes) was given to six dogs after 2 hours of bile salt infusion, while six additional dogs received saline to serve as control. Bile flow decreased significantly during administration of somatostatin (206 +/- 28 to 150 +/- 21 microliters kg-1 15 min-1, P less than 0.001) and was unchanged during administration of saline (216 +/- 45 to 216 +/- 46 microliters kg-1 15 min-1). This decrease persisted for 1/2 hour after cessation of the somatostatin infusion. Bile salt outputs were similar for both groups throughout the experiment. The data demonstrate that somatostatin-induced cholestasis can be independent of portal blood flow.