Algorithm for detection of small-bowel metastasis in malignant melanoma of the skin.

BACKGROUND AND STUDY AIM: The aim of this study was to develop an algorithm to detect small-bowel metastasis (SBM) of melanoma by sequential laboratory parameters and pan-intestinal endoscopy (PIE) including video capsule endoscopy (VCE). PATIENTS AND METHODS: A total of 390 melanoma patients (AJCC stage I/II/III/IV, 140/80/121/49) were screened for signs of intestinal blood loss (fecal occult blood test [FOBT] or overt bleeding) in an open, multicenter, prospective study, and those who were positive underwent PIE. Independent of the presence of intestinal bleeding, all stage IV patients were offered PIE. Follow-up was obtained in 357 patients (91.5 %) for a median of 16 months. We undertook to identify possible associations between SBM and clinical and laboratory data. Survival data were analyzed with regard to clinical and laboratory data and small-bowel findings. RESULTS: Intestinal blood loss was suspected in 49 of 390 patients (12.6 %), 38 of whom (77.6 %) agreed to undergo endoscopy. In 10 patients, SBM was detected by VCE (intention-to-diagnose, 20.4 %; AJCC III, n = 2; AJCC IV, n = 8). The SBM was resected in five patients. Total detection rates of SBM were 14 of 49 patients in stage IV (28.6 %, intention-to-diagnose), 2 of 121 in stage III (1.7 %), and 0 in stage I/II. In FOBT-positive patients, SBM detection rates were 72.7 %, 14.3 %, and 0 % in tumor stages IV, III, and I/II, respectively. Positive FOBT proved to be an independent negative prognostic factor for total survival in stage III and IV melanoma. CONCLUSIONS: SBMs are frequent in advanced melanoma. In stage III patients, screening for intestinal blood loss by PIE may help to identify SBMs. In stage IV, indication for PIE should depend on the individual consequences of detecting SBM, but not on bleeding symptoms alone.

Hepatocyte differentiation of mesenchymal stem cells from human adipose tissue in vitro promotes hepatic integration in vivo.

OBJECTIVE: The hepatic integration of human adipose tissue derived mesenchymal stem cells (hAT-MSCs) in vivo with or without prior differentiation to hepatocyte-like cells in vitro was investigated. METHODS AND RESULTS: Cells, isolated either from peritoneal or subcutaneous adipose tissue, expressed mesenchymal stem cell surface markers and featured multiple lineage differentiation. Under conditions favouring hepatocyte differentiation, hAT-MSCs gained hepatocytic functions in vitro including urea formation, glycogen synthesis, cytochrome P450 enzyme activity, and expression of hepatocyte-specific transcripts of carbamoylphosphate synthetase, albumin and cytochrome P450 type 3A4 (CYP3A4). Transgenic expression of green fluorescent protein emerged upon hepatocyte differentiation when driven by the hepatocyte-specific promoter of the cytosolic phosphoenolpyruvate carboxykinase gene but was constitutive from the ubiquitin gene promoter. Human AT-MSCs were transplanted into livers of immunodeficient Pfp/Rag2-/- mice with or without prior hepatocyte differentiation in vitro. Donor-derived human cells engrafted in the mouse host liver predominantly in the periportal region of the liver lobule. They expressed HepPar1 and albumin, typical features of differentiated human hepatocytes, in the otherwise negative mouse liver background. Engraftment was significantly more efficient using hAT-MSCs pre-differentiated to hepatocyte-like cells in vitro as compared with undifferentiated cells. CONCLUSIONS: Pre-differentiation of human MSCs from adipose tissue into hepatocyte-like cells in vitro facilitates long term functional hepatic integration in vivo.

Gemcitabine, oxaliplatin and 5-FU in advanced bile duct and gallbladder carcinoma: two parallel, multicentre phase-II trials.

BACKGROUND: Gemcitabine, oxaliplatin and 5-fluorouracil (5-FU) are active in biliary tract cancer and have a potentially synergistic mode of action and non-overlapping toxicity. The objective of these trials was to determine response, survival and toxicity separately in patients with bile duct cancer (BDC) and gallbladder cancer (GBC) treated with gemcitabine/oxaliplatin/5-FU chemotherapy. METHODS: Eligible patients with histologically proven, advanced or metastatic BDC (n=37) or GBC (n=35) were treated with gemcitabine (900 mg m(-2) over 30 min), oxaliplatin (65 mg m(-2)) and 5-FU (1500 mg m(-2) over 24 h) on days 1 and 8 of a 21-day cycle. Tumour response was the primary outcome measure. RESULTS: Response rates were 19% (95% CI: 6-32%) and 23% (95% CI: 9-37%) for BDC and GBC, respectively. Median survivals were 10.0 months (95% CI: 8.6-12.4) and 9.9 months (95% CI: 7.5-12.2) for BDC and GBC, respectively, and 1- and 2-year survival rates were 40 and 23% in BDC and 34 and 6% in GBC (intention-to-treat analysis). Major grade III and IV adverse events were neutropenia, thrombocytopenia, elevated bilirubin and anorexia. CONCLUSION: Triple-drug chemotherapy achieves comparable results for response and survival to previously reported regimens, but with more toxicity.

Effect of down-regulation and return of insulin receptors on glycogen synthesis in cultured rat hepatocytes.

The dependence of the regulation of insulin receptors by insulin on the time hepatocytes were maintained in culture and the relationship between the return of down-regulated receptors and glycogen synthesis from labelled glucose were investigated in primary cultures of adult rat hepatocytes. Insulin receptor numbers, but not ligand affinity, decreased significantly within the first 24 h of culture, even in the absence of insulin, and then returned to the immediate 'post-attachment' level during 24-48 h. Therefore, down-regulation of insulin receptors by 10 nmol/l insulin was only minor during the 1st day in culture, but amounted to 50% of control levels after the 2nd day, whereas the rate of insulin degradation remained unaltered throughout the entire period of culture. When down-regulated monolayers were switched to insulin-free medium, receptors returned to control levels within 5-10 h. The reduced basal rate of glycogenesis as well as insulin-sensitivity and insulin responsiveness of this metabolic pathway also gradually increased to control levels. However, the time-dependent receptor return was dissociated from the increase in insulin-sensitivity, emphasising the importance of postbinding events. Since the changes both in basal rates and in insulin responsiveness of glycogenesis during the period of receptor return were inversely related to differences in the actual glycogen content between control and down-regulated cells, cellular glycogen content might participate in the regulation of glycogenesis as a 'feedback inhibitor'.

Effects of insulin, glucagon and dexamethasone on pyruvate kinase in cultured hepatocytes.

Long-term (24-48 h) and short-term (10-30 min) regulation by hormones of hepatic pyruvate kinase activity was investigated in adult rat hepatocytes cultured under serum-free conditions. In the absence of hormones, pyruvate kinase total activity decreased to 83%, 67% and 39% of the initial level at 24, 48 and 72 h of culture. Insulin (100 nM) maintained total activity significantly above control levels throughout this period. In contrast, glucagon (100 nM) and dexamethasone (100 nM) accelerated the gradual decrease within 24 h (glucagon) or 48 h (dexamethasone) of culture. In these long-term experiments, activity at non-saturating concentrations of phosphoenolpyruvate was decreased by glucagon and dexamethasone but not directly modulated by insulin. However, insulin increased the cellular content of the pyruvate kinase activator fructose-1,6-diphosphate. In short-term experiments on cells cultured under serum- and hormone-free conditions for 48 h, both glucagon and dexamethasone independently caused a rapid, dose-dependent increase of the K0.5 for phosphoenolpyruvate within 10 min, while Vmax was not affected. Insulin inhibited this action of glucagon and dexamethasone and, in their absence, significantly increased substrate affinity for phosphoenolpyruvate within 30 min. Cellular fructose-1,6-diphosphate contents remained unchanged under these conditions. The data identify glucocorticoids and insulin - in addition to glucagon - as short-term regulators of the catalytic properties of pyruvate kinase. All three hormones are effective in the long-term control of total enzyme activity.

Regulation of insulin binding and glycogenesis by insulin and dexamethasone in cultured rat hepatocytes.

Regulation of insulin-binding and basal (insulin-independent) as well as insulin-stimulated glycogen synthesis from [14C]glucose, net glycogen deposition and glycogen synthase activation by insulin and dexamethasone were studied in primary cultures of adult rat hepatocytes maintained under chemically defined conditions. Insulin receptor number was increased in a dose-dependent fashion by dexamethasone added to the medium between 24 and 48 h of culture and reduced by insulin, whereas ligand affinity remained unaltered. Insulin-induced down-regulation of insulin receptors was not affected by the glucocorticoid. Although the changes in the sensitivity to insulin of glycogen synthesis from glucose and net glycogen deposition paralleled the modulation of the number of insulin receptors, postbinding events appear to be implicated also in the regulation of insulin-sensitivity. Alterations of the responsiveness of glycogen synthesis to insulin caused by the glucocorticoid and/or insulin and by variation between individual rats were inversely related to cellular glycogen contents, suggesting that hepatocellular glycogen content participates in the regulation of insulin-responsiveness of this metabolic pathway. Regulation of insulin-dependent glycogen synthesis were different. Since the effects of this 'physiological' increase in exogenous glucose were small compared to the acute action of insulin, insulin rather than portal venous glucose is considered to represent the prime stimulator of hepatic glycogen synthesis.

Modulation by a sulfonylurea of insulin-dependent glycogenesis, but not of insulin binding, in cultured rat hepatocytes. Evidence for a postreceptor mechanism of action.

To detect potential direct effects of the sulfonylurea glyburide on hepatic carbohydrate metabolism, we tested whether the drug was capable of modulating insulin binding and glycogenesis in primary cultured hepatocytes. After 24-h culture under serum- and hormone-free conditions, cells were incubated with or without 10(-8) M insulin and/or glyburide (0.1-5.0 micrograms/ml) for another 24 h. Then, specific 125I-insulin binding and basal and insulin-stimulated glycogen synthesis were determined. Acute addition of glyburide to previously untreated cells did not modulate any of these parameters. Incubation for 24 h with 2 micrograms/ml of glyburide did not affect the DNA and protein content of the dishes. Cellular glycogen content and basal glycogenesis also remained unchanged by glyburide in hepatocytes incubated in the absence of insulin, but glycogen content was increased and basal glycogen synthesis decreased in insulin-pretreated cells. In contrast, glyburide increased insulin-stimulated glycogenesis in a dose-dependent fashion in both insulin-pretreated and control cells by enhancing responsiveness, but not sensitivity, toward insulin. Pretreating hepatocytes with 10(-8) M insulin caused a 40% reduction in specific insulin binding. Glyburide did not modulate insulin binding or degradation in control cells nor was insulin-induced regulation of insulin receptors affected. These results demonstrate a direct dose-dependent effect of a sulfonylurea on an insulin action toward hepatic carbohydrate metabolism, and suggest that this effect is mediated by a postreceptor mechanism.

Chemotherapy for advanced gastric cancer.

BACKGROUND: Gastric cancer currently ranks second in global cancer mortality. Most patients are either diagnosed at an advanced stage, or develop a relapse after apparently curative operation. Apart from supportive measures, systemic chemotherapy is the only treatment option available in this situation. OBJECTIVES: To assess the effect of chemotherapy versus best supportive care, combination versus single agent chemotherapy and different combination chemotherapy regimens in advanced gastric cancer. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 1, 2004), MEDLINE and EMBASE up to February 2004 and reference lists of articles. We also contacted pharmaceutical companies as well as national and international experts. SELECTION CRITERIA: Randomised controlled trials on systemic intravenous chemotherapy versus best supportive care, combination versus single agent chemotherapy and different combination chemotherapies in advanced gastric cancer. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data. A third investigator was consulted in case of disagreements. We contacted study authors to obtain missing information. MAIN RESULTS: Chemotherapy versus best supportive care consistently demonstrated a significant benefit in terms of overall survival in favour of the group receiving chemotherapy (Hazard Ratios (HR) 0.39; 95% confidence intervals (CI) 0.28 to 0.52). Combination versus single-agent chemotherapy provides evidence for a survival benefit in favour of combination chemotherapy (HR 0.85; 95% CI 0.76 to 0.96). Numbers included in these comparisons were 184 and 1338 participants respectively. This benefit is achieved at the price of increased toxicity in the combination chemotherapy arms. When comparing 5-FU/cisplatin-containing combination therapy regimens with anthracyclines versus those without anthracyclines (HR 0.77; 95% CI 0.62 to 0.95 based on 501 participants) and 5-FU/anthracycline-containing combinations with cisplatin versus those without cisplatin (HR 0.83; 95% CI 0.76 to 0.91 based on 1147 participants), there was a significant survival benefit for regimens including 5-FU, anthracyclines and cisplatin. AUTHORS' CONCLUSIONS: Chemotherapy significantly improves survival in comparison to best supportive care. In addition, combination chemotherapy improves survival compared to single-agent 5-FU, but the effect size is much smaller. Among the combination chemotherapy regimens studied, best survival results are achieved with regimens containing 5-FU, anthracyclines and cisplatin. In this category, ECF (epirubicin, cisplatin and continuous infusion 5-FU) is tolerated best.

3-Hydroxy-3-methylglutaryl CoA reductase in cultured hepatocytes. Regulation by heterologous lipoproteins and hormones.

Regulation of the key enzyme of cholesterol synthesis, 3-hydroxy-3-methylglutaryl CoA reductase (EC: 1.1.1.34), by heterologous human lipoproteins and hormones was studied in a maintenance culture of rat hepatocytes. The liver cells were cultured under hormone and serum free conditions and maintained differentiated morphology and specific function. Under control conditions total HMG-CoA reductase increased by 50% after 24 h culture compared to 0 h values immediately after isolation. Thereafter a plateau of enzyme activity was reached lasting until 48 h, with a slight decline at 72 h. Concomitantly the "expressed" enzyme activity increased steadily, probably through dephosphorylation of latent reductase, the activation was largely complete at 48 h. During the steady state period of total reductase VLDL added to the medium at concentrations up to 50 microgram/ml protein had no effect o HMG-CoA reductase activity. In contrast, LDL suppressed the enzyme in a dose-dependent fashion to 40% of controls at 100 microgram/ml. On the other hand, HDL had the opposite effect with a significant induction up to 252% of controls at 50 microgram/ml. Insulin also caused a comparable dose-dependent stimulation of enzyme activity at 10(-8) and 10(-7)M, whereas glucagon inhibited reductase activity. Compared to the insulin action, triiodothyronine and triamcinolone prompted a minor, but still significant increase of reductase activity. Insulin and triamcinolone acted synergistically, but the combination of triamcinolone and tri-iodothyronine was only additive. All hormonal inductions of reductase could be blocked by cycloheximide. The present data establish that HMG-CoA reductase of maintenance cultured hepatocytes is subject to a complex regulation by heterologous lipoproteins as well as pancreatic, adrenal and thyroid hormones.

13C-Methacetin metabolism in patients with cirrhosis: relation to disease severity, haemoglobin content and oxygen supply.

BACKGROUND: Hypoxia may contribute to impairment of liver function and thus interfere with results of liver tests. In patients with cirrhosis, cytochrome P-450 mediated metabolism of substrates is facilitated in the presence of supplemental oxygen. It has not been studied how this relates to liver function and haemoglobin content. AIM: We questioned how oxygen supplementation would influence the hepatic microsomal function as assessed by the 13C-methacetin breath test in patients with cirrhosis of different severity and different degrees of anaemia. METHODS: 13C/12C ratios in exhaled breath assessed by non-dispersive infrared spectrometry were studied in 34 patients with cirrhosis (Child A/B/C 9/17/8) after administration of 75 mg 13C-methacetin p.o. with and without oxygen inhalation (4 L/min). RESULTS: In patients breathing room air the total amount of 13C exhaled weakly correlated both with the Child-Pugh score (r = - 0.41, P < 0.02) and haemoglobin concentrations (r = 0.46; p = 0.006). Oxygen supplementation increased the total amount of 13C exhaled by 68 +/- 90% (P < 0.001). This effect was similar in Child-Pugh classes A (43 +/- 55%), B (83 +/- 80%) and C (66 +/- 123%) and not related to the Child-Pugh score. CONCLUSIONS: Our results suggest that tests of microsomal liver function are independently influenced both by oxygen delivery and the Child-Pugh score.

6-thioguanine--efficacy and safety in chronic active Crohn's disease.

BACKGROUND: : Azathioprine and mercaptopurine are commonly used in chronic active Crohn's disease. They share the disadvantage of a delayed onset of action and potentially serious side-effects, and are metabolized to thioguanine nucleotides which are thought to be the active metabolites. The direct use of 6-thioguanine may offer a more rapid and safer alternative. We conducted an open prospective study to investigate the efficacy and safety of 6-thioguanine in chronic active Crohn's disease. METHODS: : Thirty-seven patients with chronic active Crohn's disease and a Crohn's disease activity index of > 150 were enrolled in this study. Inclusion criteria were steroid dependence (n = 19), steroid refractoriness (n = 9) and/or intolerance (n = 16) or refractoriness (n = 6) to azathioprine. Patients were treated with 40 mg/day of 6-thioguanine for 24 weeks; a dose escalation to 80 mg was allowed at week 12. Remission was defined as a Crohn's disease activity index of < 150 associated with a decrease of > 70 points; response was defined as a decrease of > 70 points in the Crohn's disease activity index. RESULTS: : In the intention-to-treat analysis, 13 of 37 patients achieved remission (35%). Twelve of these 13 patients achieved remission after 4 weeks. Fifty-seven per cent of patients (21/37) achieved a response. The mean Crohn's disease activity index decreased from 284 +/- 74 to 153 +/- 101. 6-Thioguanine was more effective in azathioprine-intolerant than in azathioprine-refractory patients. Twelve of 16 patients intolerant to azathioprine tolerated 6-thioguanine. Adverse events included phototoxicity, pancreatitis, headache, nausea, alopecia, arthralgia, minor infections and reversible elevation of transaminases. Six patients required discontinuation of medication, two because of leucopenia. CONCLUSIONS: : In this patient group with chronic active Crohn's disease, 6-thioguanine appeared to be effective with acceptable short-term toxicity, but long-term controlled trials are clearly needed to further define its role.

Thioguanine-nucleotides do not predict efficacy of tioguanine in Crohn's disease.

BACKGROUND: 6-Thioguanine-nucleotides seem to be the active metabolites of thiopurine therapy, and their monitoring has been considered a useful tool for optimizing response in inflammatory bowel diseases. Tioguanine (thioguanine) therapy results in much higher levels of 6-thioguanine-nucleotide levels when compared with azathioprine or mercaptopurine. AIM: To elucidate the influence of 6-thioguanine-nucleotide and methylated 6-thioguanine-nucleotide levels under tioguanine on efficacy and toxicity in Crohn's disease. METHODS: 6-Thioguanine-nucleotide and methylated 6-tioguanine-nucleotide levels were measured regularly in 26 Crohn's disease patients treated with tioguanine. Nucleotide levels were related to efficacy and toxicity. RESULTS: 6-Thioguanine-nucleotide levels rose very high [median 1241 pmol/8 x 10(8) red blood cells (range 313-1853)]. Methylated 6-thioguanine-nucleotide levels were detected in all patients [491 pmol/8 x 10(8) red blood cells (154-1775)]. 6-Thioguanine-nucleotide and methylated 6-thioguanine-nucleotide concentrations correlated significantly (r = 0.7, P < 0.0001). Nucleotide levels from patients achieving remission (n = 14) did not differ significantly from non-remitters (n = 12) [6-thioguanine-nucleotide: 1077 (599-2160) vs. 1210 (534-4665); methylated 6-thioguanine-nucleotide: 510 (214-1222) vs. 421 (145-1284)]. One patient with intermediate thiopurine S-methyltransferase activity experienced bone marrow toxicity upon dose escalation parallel with excessively high thioguanine-nucleotide levels. CONCLUSIONS: 6-Thioguanine-nucleotide as well as methylated 6-thioguanine-nucleotide levels under tioguanine therapy were not related to efficacy. This suggests that monitoring of 6-thioguanine-nucleotide levels is not a useful tool to predict response to thiopurines.

Prophylactic therapy for variceal hemorrhage revisited.

The high mortality of a first variceal bleed in cirrhotic patients even in very recent studies makes some effective form of primary prophylaxis desirable. Controlled studies of shunt and nonshunting surgery have shown that these operations can prevent variceal hemorrhage only at the expense of increased morbidity and mortality. Therefore, this type of surgery has no place in the primary prophylaxis of variceal bleeding. Liver transplantation, however, is becoming a real therapeutic alternative for many patients with chronic liver disease. Obviously, it will prevent bleeding in many patients, but primary prophylaxis of bleeding itself is not an indication for a transplant. The radically different results of randomized controlled trials of prophylactic sclerotherapy indicate that it is either very helpful and will save many lives or very harmful and will lead to death in patients who would otherwise survive. The cumulative evidence from the trials that took appropriate care of effective treatment for the acute bleed and that had no major problems with complications of the procedure itself suggests that prophylactic sclerotherapy is neither helpful nor very harmful. Thus, there is also no indication for prophylactic sclerotherapy in clinical routine. Personally, I even doubt that it should be used in future controlled trials in the light of the positive results of the prophylactic trials of beta-blockers. If there is an indication for prophylactic treatment, it should be the last invasive treatment available. In the near future, work should focus on the confirmation and further development of endoscopic or other simple and safe means to predict the risk of first bleeding; on the development and characterization of effective drugs; and on development of methods to identify at an early stage responders and nonresponders. If I presently had large varices that had not yet bled, I would like to join one of my senior colleagues and look for admission to the Control group of an ongoing randomized beta-blocker trial.

Non-surgical treatment of variceal bleeding.

Variceal bleeding is still one of the key therapeutic problems inpatients with portal hypertension. Vasoactive drugs for the treatment of acute hemmorrhage as well as for the prevention of first and recurrent bleeding have been shown to be effective, in some situations as effective as endoscopic sclerotherapy. In recent years, endoscopic band ligation has replaced sclerotherapy for the prevention of rebleeding and become the new nonsurgical standard in this situation. Furthermore, the transjugular, intrahepatic, portosystemic stent shunt (TIPS) has gained widespread acceptance as a salvage procedure for acute bleeders unresponsive to other treatments as well as the second line approach to failures of chronic endoscopic or drug therapy for prevention of rebleeding. Primary prophylaxis is still the domain of beta-blockers or/and long-acting nitrates.

[Clinical effects of 5-aminosalicylic acid preparations in Crohn disease]. / Klinische Wirkungen von 5-Aminosalicylsäure-Präparaten bei Morbus Crohn.

The antiinflammatory drug 5-aminosalicylic acid is available either as mesalamine in various slightly different galenic preparations or as a prodrug with 5-ASA bound to a carrier molecule as inert as possible, which releases 5-ASA via bacterial degradation in the ileocolon. Data from therapeutic trials in patients with Crohn's disease are only available for mesalamine and sulfasalazine. In active Crohn's disease, high-dose (> 3 g per day) mesalamine only is more effective than placebo, but inferior to systemic steroids. They may be used in patients refusing treatment with classical steroids or not tolerating them if this does not make a case for budesonide. The therapeutic gain of mesalamine over placebo for the prevention recurrence in patients who have reached remission by drug treatment is marginal. Thus, its use in this clinical situation is not appealing. Results for the maintenance of a surgically induced remission appear slightly better so that the use of > 3 g of mesalamine per day may be still justified in this scenario. It is an unresolved question whether the clinical efficacy of different galenic mesalamine prepations in maintaining postoperative remission varies with the preoperative disease location. Present data are not sufficient to support differential drug treatment based on this parameter.

[Non-surgical treatment of portal hypertension]. / Nicht-chirurgische Behandlung der portalen Hypertonie.

The choice of methods for the treatment of acute variceal hemorrhage critically depends on the locally available expertise. Vasoactive drugs or balloon tamponade may bridge the time to more definitive measures such as sclerotherapy or band ligation. Drugs (nonselective beta-adrenergic blockers and long-acting nitrates) are almost equivalent to endoscopic sclerotherapy for the prevention of recurrent bleeding, while band ligation offers both increased efficacy (reduced rate of rebleeding and death) and decreased complication rates when compared to sclerotherapy. Thus, ligation will predominantly be used for the prevention of recurrent bleeding. Alternatively, drugs may be applied when acute bleeding was effectively stopped without the use of endoscopic means. Endoscopic sclerotherapy and surgery have no place in the primary prophylaxis of variceal hemorrhage in patients who have not bled before. Prevention of the first bleed is clearly the field for beta-blockers or nitrates. The role of banding ligation in this situation remains to be defined.

Liver-specific growth factors.

Experimental evidence of the existence of liver-specific growth factors has been collected for more than two decades. Blood-borne growth-promoting activity of hepatocytes may be separated into plasma and platelet-derived factors. Several groups have observed the stimulation of hepatocyte growth in vitro by some platelet-associated activity, which was recently isolated from rat platelets as a 27-kDa protein called platelet growth factor (PGF). There is evidence of at least two different growth factors for hepatocytes derived from platelet-poor rat plasma, 'hepatopoietin' A and B. The partial purification of several other factors has been reported. One of these factors was prepared from the plasma of patients with fulminant hepatic failure. In addition to these 'humoral' factors, cytosolic growth-promoting activity has been partially purified by several groups. While the humoral factors described so far are only active on normal hepatocytes, the cytosolic 'hepatic stimulator substance' (HSS) also promotes the proliferation of differentiated hepatoma cells. In addition, it appears to depend on the permissive action of epidermal growth factor (EGF). None of the liver-specific growth factors except PGF has been purified to homogeneity. Thus, their significance for the control of the proliferation of normal and transformed hepatocytes is still an unsettled issue.