Trends in indications, complications and outcomes for venous resection during pancreatoduodenectomy.

BACKGROUND: Pancreatoduodenectomy with superior mesenteric-portal vein resection has become a common procedure in pancreatic surgery. The aim of this study was to compare standard pancreatoduodenectomy with pancreatoduodenectomy plus venous resection at a high-volume centre, and to examine trends in management and outcome over a decade for the latter procedure. METHODS: This retrospective observational study included all patients undergoing pancreatoduodenectomy with or without venous resection at Oslo University Hospital between January 2006 and December 2015. Trends were evaluated by assessing preoperative clinical and radiological characteristics, as well as perioperative outcomes in three time intervals (early, intermediate and late). RESULTS: A total of 784 patients had a pancreatoduodenectomy, of whom 127 (16·2 per cent) underwent venous resection. Venous resection resulted in a longer operating time (median 422 versus 312 min; P = 0·001) and greater estimated blood loss (EBL) (median 700 versus 500 ml; P = 0·004) than standard pancreatoduodenectomy. The rate of severe complications was significantly higher for pancreatoduodenectomy with venous resection (37·0 versus 26·3 per cent; P = 0·014). The overall burden of complications, evaluated using the Comprehensive Complication Index (CCI), did not differ (median score 8·7 versus 8·7; P = 0·175). Trends in venous resection over time showed a significant reduction in EBL (median 1050 versus 375 ml; P = 0·001) and duration of hospital stay (median 14 versus 9 days; P = 0·011) between the early and late periods. However, despite an improvement in the intermediate period, severe complication rates returned to baseline in the late period (18 of 43 versus 9 of 42 versus 20 of 42 patients in early, intermediate and late periods respectively; P = 0·032), as did CCI scores (median 20·9 versus 0 versus 20·9; P = 0·041). CONCLUSION: Despite an initial improvement in severe complications for venous resection during pancreatoduodenectomy, this was not maintained over time. Every fourth patient with venous resection needed relaparotomy, most frequently for bleeding.

Reclassification of tumour origin in resected periampullary adenocarcinomas reveals underestimation of distal bile duct cancer.

BACKGROUND: Primary adenocarcinomas removed by pancreatoduodenectomy originate from the duodenum (DC), ampulla (AC), distal bile duct (DBC), or pancreas (PC). Pathobiology, staging, survival, and adjuvant chemotherapy vary among these cancers. The proximity of the structures of possible origin renders it difficult to obtain a correct diagnosis, which might lead to inconsistencies in reported data and inappropriate adjuvant treatment. METHODS: Records of 207 patients undergoing pancreatoduodenectomy (1998-2009) for periampullary adenocarcinoma were reviewed. Routine histopathology reports of tumour origin performed by multiple pathologists were independently re-evaluated based on predetermined criteria by two experienced pancreatic pathologists. RESULTS: Slide review changed the diagnosis in 55 (27%) patients. After reclassification, final distribution was 29 (14%) DC, 52 (25%) AC, 57 (28%) DBC, and 69 (33%) PC. The diagnosis was revised in 4 (14%) DC, 7 (17%) AC, 30 (53%) DBC and 14 (19%) PC. The underestimation of DBC during routine histopathology was caused by misinterpretation of DBC either PC or AC. Misclassification of PC was mainly due to erroneous diagnosis of AC. Reassignment of tumour origin caused no significant changes in survival within cancer type, but resulted in a significant difference in survival between DBC and PC (p = 0.004). CONCLUSION: Specialist slide review resulted in reassignment of tumour origin in 27% of periampullary adenocarcinomas. Distal bile duct cancer was found to be most frequently misdiagnosed (53%). Correct diagnosis of tumour origin is crucial for data quality, appropriate adjuvant therapy, and patient inclusion in clinical trials.

Resection margin involvement and tumour origin in pancreatic head cancer.

BACKGROUND: Assessment of the origin of adenocarcinoma in pancreatoduodenectomy specimens (pancreatic, ampullary or biliary) and resection margin status is not performed in a consistent manner in different centres. The aim of this review was to identify the impact of such variations on patient outcome. METHODS: A systematic literature search for articles on pancreatic, ampullary, distal bile duct and periampullary cancer was performed, with special attention to data on resection margin status, pathological examination and outcome. RESULTS: The frequent reclassification of tumour origin following slide review, and the wide variation in published incidence of pancreatic (33-89 per cent), ampullary (5-42 per cent) and distal bile duct (5-38 per cent) cancers indicate that the histopathological distinction between the three cancer groups is less accurate than generally believed. Recent studies have shown that the wide range of rates of microscopic margin involvement (R1) in pancreatoduodenectomy specimens (18-85, 0-27 and 0-72 per cent respectively for pancreatic, ampullary and distal bile duct cancers) is mainly caused by differences in pathological assessment rather than surgical practice and patient selection. As a consequence of the existing inconsistency in reporting of these data items, the clinical significance of microscopic margin involvement in each of the three cancer groups remains unclear. CONCLUSION: Inaccurate and inconsistent distinction between pancreatic, ampullary and distal bile duct cancer, combined with inaccuracies in resection margin assessment, results in obfuscation of key clinicopathological data. Specimen dissection technique plays a key role in the quality of the assessment of both tumour origin and margin status. Unless the pathological examination is meticulous and standardized, comparison of results between centres and observations in multicentre trials will remain of limited value.

Hepatic radiofrequency ablation using perfusion electrodes in a pig model: effect of the Pringle manoeuvre.

AIM: To assess the influence of the Pringle manoeuvre on volume and geometry of coagulations close to the portal vein using an impedance-controlled radiofrequency ablation system with perfusion electrodes. METHODS: Twelve pigs were randomly assigned to a control group (n = 6) and a group where the Pringle manoeuvre was applied during ablation (n = 6). One coagulation was made in each animal close to the portal vein. All animals were sacrificed 4 days after ablation, and the livers were removed for gross and histopathologic analysis. RESULTS: Effective coagulation volume in the Pringle group (10.8 +/- 5.0 cm(3)) was significantly increased (p = 0.03) compared to the control group (4.1 +/- 4.1 cm(3)). The efficacy ratio, defined as the effective coagulation volume divided by the coagulation volume, was not significantly different in the Pringle group (0.47 +/- 0.27) compared to the control group (0.33 +/- 0.22). The geometrical centre of the effective coagulation volume did not correspond to the position of the ablation electrode. Thermal damage of the gallbladder was found in three animals, all belonging to the Pringle group. CONCLUSIONS: The Pringle manoeuvre was associated with increased effective coagulation volume, but did not significantly influence the predictability of coagulation volume or geometry.

Cryoablation of colorectal liver metastases: minimally invasive tumour control.

BACKGROUND: Freezing is used for in situ destruction (ablation) of liver tumours not eligible for resection. The procedure is typically done during laparotomy. The objective of this report was to study tumour control at the site of freezing and a minimally invasive approach to cryoablation of colorectal liver metastases. METHODS: A prospective study of 19 patients was conducted between 1999 and 2003. Twenty-five tumours were ablated during 24 procedures (i.e. 5 reablations). Sixteen procedures were performed percutaneously, 5 during laparotomy and 3 laparoscopically. Magnetic resonance imaging (MRI) was used for intraprocedural monitoring during most procedures. Nine patients had concomitant liver resections performed (5 during laparoscopy, 4 during laparotomy). RESULTS: Out of 25 ablations, 18 (72%) were assumed adequate. Total ice-ball volume during percutaneous procedures was median 62 cm (range 32-114). Excellent imaging of the extent of freezing was achieved using MRI. Hospital stay for patients treated percutaneously was median 4 days (range 3-30). No perioperative mortality occurred. Tumour recurrence at the site of ablation occurred in 8 of 18 (44%) tumours adequately ablated. Actuarial 2-year tumour-free survival at site of ablation was 48%. At the time of analyses 12 out of 13 (92%) patients assumed to be adequately ablated were alive. Of all patients, 14 out of 19 (74%) survived. CONCLUSIONS: Short-term tumour control can be achieved following cryoablation of colorectal liver metastases. A minimally invasive approach is feasible but the diameter of metastases considered for percutaneous cryoablation should not exceed 3 cm.

Erroneous diagnosis of pancreatic cancer after radiotherapy of testicular cancer.

BACKGROUND: After radiotherapy with or without chemotherapy radiation-induced normal tissue alteration may mimic cancer and may cause major morbidity. RESULTS: Two patients irradiated for seminoma, in one case combined with cisplatin-based chemotherapy, developed clinical symptoms and radiological signs comparable to pancreatic cancer (stenosis of the ductus choledochus). The non-malignant diagnosis was finally established by revision of the histological specimen (case 1) and per-operatively (case 2). In both patients by-pass operations for biliary tract stenosis resulted in excellent palliation. CONCLUSION: Radiation-induced fibrosis within the upper retroperitoneal space is an important differential diagnosis versus pancreatic cancer in patients with prior radiotherapy for seminoma. Diagnosis based only on clinical and radiological findings may lead to incorrect patient information and registration errors in Cancer Registries.

Laparoscopic resection of the pancreas: a feasibility study of the short-term outcome.

BACKGROUND: Laparoscopic resection is not an established treatment for tumors of the pancreas. We report our preliminary experience with this innovative approach to pancreatic disease. METHODS: Thirty two patients with pancreatic disease were included in the study on an intention-to-treat basis. The preoperative indications for surgery were as follows: neuroendocrine tumors ( n=13), unspecified tumors ( n=11), cysts ( n=2), idiopathic thrombocytopenic purpura with ectopic spleen ( n=2), annular pancreas ( n=1), trauma ( n=1), aneurysm of the splenic artery ( n=1), and adenocarcinoma ( n=1). RESULTS: Enucleations ( n=7) and distal pancreatectomy with ( n=12) and without splenectomy ( n=5) were performed. Three patients underwent laparoscopic exploration only. Four procedures (13%) were converted to an open technique. One resection was converted to a hand-assisted procedure. The mortality rate for patients undergoing laparoscopic resection was 8.3% (two of 24). Complications occurred after resection in nine of 24 procedures (38%). The median hospital stay was 5.5 days (range, 2-22). Postoperatively, opioid medication was given for a median of 2 days (range, 0-13). CONCLUSION: Resection of the pancreas can be performed safely via the laparoscopic approach with all the potential benefits to the patients of minimally invasive surgery.

A comparative study of the short-term outcome following open and laparoscopic liver resection of colorectal metastases.

BACKGROUND: Laparoscopic resection of liver tumors is feasible, but few studies have compared short-term outcome of the laparoscopic approach to that of a conventional technique. METHODS: Eighteen tumor resections performed during 14 procedures (14 patients) by conventional surgery were compared to 21 similar resections performed laparoscopically during 15 procedures (13 patients). All patients had colorectal liver metastases. RESULTS: No perioperative mortality occurred. Surgical time, peroperative bleeding and blood transfusion requirement were similar in the two groups. The resection margin was involved by tumor tissue in one specimen laparoscopically resected and in two specimens conventionally resected (p = 0.58). Patients operated laparoscopically remained in hospital for median 4 days, while patients operated conventionally stayed median 8.5 days (p <0.001). Patients operated laparoscopically required less opioid medication than patients having conventional surgery (median 1 vs 5 days; p = 0.001). CONCLUSIONS: Short-term outcome of laparoscopic liver resection compares to that of conventional surgery, with the additional benefits derived from minimal invasive therapy.

Magnetic-resonance-guided percutaneous cryoablation of hepatic tumours.

OBJECTIVE: To study the feasibility of percutaneous cryoablation of hepatic tumours monitored by magnetic resonance imaging (MRI). DESIGN: Prospective study SETTING: University hospital, Norway PATIENTS: Six patients with hepatic metastases from colorectal cancer. INTERVENTIONS: Percutaneous cryoprobe positioning under general anaesthesia. Positioning and freezing monitored by near-real-time MRI using an open 0.5 Tesla MRI configuration system. MAIN OUTCOME MEASURES: Safety and feasibility of the procedure. Measurement of volumes of cryolesions. RESULTS: One patient developed a biliary leakage that had to be drained. Four patients developed pleural fluid. Two small tumours were adequately cryoablated. In the remaining 4 patients with large (>4 cm) tumours, an adequate cryolesion could not be formed. Cryolesion volumes larger than 105 cm3 were not produced even using 3-4 probes. MRI visualised the growing cryolesion well, but positioning of the cryoprobes was time-consuming. CONCLUSION: MR guided cryoablation is clinically feasible and gives good visualisation of the procedure. Patients with small tumours (<3 cm) seem to be best suited to this percutaneous approach as cryolesion volumes claimed to be adequate for tumour destruction can be produced. Measurement of tumour volume preoperatively may help to select patients who will respond.

Validation of estimated 3D temperature maps during hepatic cryo surgery.

A simple model for estimating temperature distribution within the frozen region during cryo ablation was tested for accuracy. Freezing experiments were conducted in both ex vivo and in vivo porcine livers. Temperature was measured during freezing using a fiber-optic temperature sensor. Three-dimensional MR images were obtained at the end of each freezing cycle. From the MR image volumes, three-dimensional temperature maps were calculated numerically using a simplified bio-heat model. Estimated temperatures were compared to measured temperatures. The median difference between measured and estimated temperature was 3.03 degrees C. The median distance from a sensor element to the closest point on a isotherm surface with the corresponding estimated temperature was 0.70 mm. The accuracy of this model is acceptable. Temperature maps as outlined here may be used for monitoring of cryotherapy in order to increase clinical effectiveness.

Liver tumors and minimally invasive surgery: a feasibility study.

Laparoscopic liver resection has not yet been established, although recent reports document that liver resection can be performed safely by the laparoscopic approach. Other interventional procedures like cryoablation have also been introduced in treatment of liver metastases. In this report 11 liver resections performed laparoscopically in eight patients are presented. Six patients had colorectal metastases, one a metastases from a malignant melanoma, and one patient had focal nodular hyperplasia. Two patients received synchronous cryoablation of remaining liver metastases. During follow up, two patients received percutaneous cryoablation of liver recurrences monitored by an open configuration magnetic resonance scanner. All except one of the tumors we attempted to remove had free resection margins (re-resection of new metastasis). No complications occurred except an atelectasis of the left lower pulmonary lobe in one patient. Median postoperative hospital stay was 3 days, and median postoperative opioid-dependent days was 1. The report demonstrates that minimally invasive techniques may safely be combined in hepatic intervention, and that the advantages of minimally invasive surgery, such as reduced hospital stay and less patient discomfort, also applies to liver resections.

Intradermal ras peptide vaccination with granulocyte-macrophage colony-stimulating factor as adjuvant: Clinical and immunological responses in patients with pancreatic adenocarcinoma.

K-RAS mutations are frequently found in adenocarcinomas of the pancreas, and induction of immunity against mutant ras can therefore be of possible clinical benefit in patients with pancreatic cancer. We present data from a clinical phase I/II trial involving patients with adenocarcinoma of the pancreas vaccinated by i.d. injection of synthetic mutant ras peptides in combination with granulocyte-macrophage colony-stimulating factor. Forty-eight patients (10 surgically resected and 38 with advanced disease) were treated on an outpatient basis. Peptide-specific immunity was induced in 25 of 43 (58%) evaluable patients, indicating that the protocol used is very potent and capable of eliciting immune responses even in patients with end-stage disease. Patients followed-up for longer periods showed evidence of induction of long-lived immunological memory against the ras mutations. CD4(+) T cells reactive with an Arg12 mutation also present in the tumor could be isolated from a tumor biopsy, demonstrating that activated, ras-specific T cells were able to selectively accumulate in the tumor. Vaccination was well tolerated in all patients. Patients with advanced cancer demonstrating an immune response to the peptide vaccine showed prolonged survival from the start of treatment compared to non-responders (median survival 148 days vs. 61 days, respectively; p = 0.0002). Although a limited number of patients were included in our study, the association between prolonged survival and an immune response against the vaccine suggests that a clinical benefit of ras peptide vaccination may be obtained for this group of patients.

Magnetic resonance imaging-estimated three-dimensional temperature distribution in liver cryolesions: a study of cryolesion characteristics assumed necessary for tumor ablation.

The goal of this study was to estimate the three-dimensional (3D) temperature distribution in liver cryolesions and assess the margin of the transition zone between the tumoricidal core of the lesion and the surrounding unfrozen tissue, using criteria proposed in the literature. Local recurrences after liver tumor cryoablation are frequent. Temperatures below -40 degrees C and a 1-cm zone of normal tissue included in the cryolesion are considered necessary for adequate ablation. The 3D temperature distribution in 10 pig cryolesions was estimated by numerical solution of a simplified bioheat equation using magnetic resonance imaging data to establish cryolesion border conditions. Volumes encompassed by the -20, -40, and -60 degrees C isotherms were estimated. The shortest distance from every voxel on the -40 degrees C isotherm to the cryolesion edge was calculated and the mean and the maximal of these distances were defined for each cryolesion. Median cryolesion volumes with temperatures of -20, -40, and -60 degrees C or colder were 53, 26, and 14% of the total cryolesion volume, respectively. The median cryolesion volume was 12.3 cm(3). The median of the mean distances calculated between the -40 degrees C isotherm and the cryolesion edge was 4.1 mm and increased with increasing cryolesion volume. The median of the largest of these distances calculated for each cryolesion was 8.1 mm. Temperatures claimed to be adequate for tumor destruction were obtained only in parts of the cryolesion. The adequacy of a 1-cm zone of normal liver tissue included in the cryolesion to ensure tumor ablation is questioned.

[Liver resection--indications and results]. / Leverreseksjon--indikasjoner og resultater.

BACKGROUND: Liver resection is an established treatment for malignancies like colorectal metastases and hepatocellular carcinoma. MATERIAL AND METHODS: Indications and outcomes of liver resection at the National Hospital, Oslo, Norway was studied retrospectively in 226 patients operated between 1977 and 1999. RESULTS: The main indication for surgery was colorectal metastases (n = 137). The frequency of liver resection for colorectal malignancies was < 1 per 100,000 patients per year in the hospital's catchment area. Other indications included hepatocellular carcinoma (n = 30), benign tumours like hemangioma (n = 14), and various primary and secondary malignant tumours. Reoperation due to postoperative complications was performed in 13 patients (6%). Total perioperative mortality defined as death before hospital discharge or within 30 days after discharge, was 3% (7/226). No perioperative deaths occurred among the 159 patients operated after 1987. Five year survival for patients operated for colorectal metastases and hepatocellular carcinoma were 29% and 24%, respectively. INTERPRETATION: The main indication for liver resection is colorectal metastases. Liver resection is a safe operation with potential curation for selected patients.

[Cryoablation--a treatment option for inoperable liver tumors?]. / Kryoablasjon--aktuell behandling av inoperable leversvulster?

BACKGROUND: Most patients with primary and secondary liver tumours are inoperable by conventional surgery. This has prompted the development of different techniques of local destruction of liver tumours, i.e. cryosurgical ablation radiofrequency, laser, and microwave ablation. MATERIAL AND METHODS: On the basis of relevant literature and our own experience we describe the principles of local destruction by cryoablation of colorectal metastases. RESULTS: Indications for ablation are mainly colorectal metastases and hepatocellular carcinoma. Mechanisms for tumour destruction include intra- and extracellular ice crystal formation, cellular membrane rupture, cellular dehydration and ischaemic damage. Ablation is regularly monitored by ultrasonography, which is suboptimal because of inadequate visualisation of the iceball. Long-term outcome of local destruction of liver tumours is not documented and randomized trials are not ethically acceptable. This complicates analyses of patient outcomes. INTERPRETATION: Local ablation of liver tumours is experimental therapy and should only be performed as a part of prospective trials.

p53 accumulation confers prognostic information in resectable adenocarcinomas with ductal but not with intestinal differentiation in the pancreatic head.

The aim of the study was to examine the relation between p53 protein accumulation, clinicopathological variables and prognosis in resectable adenocarcinomas of the pancreatic head. The clinical records and tissue specimens of 82 consecutive patients resected for adenocarcinomas located in the head of the pancreas were reviewed retrospectively. Formalin-fixed and paraffin-embedded specimens from each tumour were stained with the monoclonal antibody DO7, and the nuclear p53 positivity within each tumour was assessed. Histopathological reclassification showed that 60 tumours exhibited ductal differentiation and 22 tumours intestinal differentiation. Twenty-five percent (15/60) of the ductal tumours and 50% (11/22) of the intestinal tumours were positive for p53 accumulation. p53 immunoreactivity was significantly correlated to a worse prognosis in the tumours of ductal differentiation, with median survival 0.76 years for p53 positive and 1.44 years for p53 negative patients. The p53 positivity of tumours with intestinal differentiation showed no such correlation. No correlation was found between p53 accumulation and other known prognostic factors in either the ductal or the intestinal type of tumours. Our results indicate that the tumour biology of ductal adenocarcinomas differs significantly from that of adenocarcinomas of the intestinal type located in the pancreatic head, and that p53 accumulation confers a worse prognosis only of ductal tumours. Subclassification of these tumours based on type of differentiation is therefore suggested since periampullary tumours include ductally as well as intestinally differentiated adenocarcinomas.

Immunoglobulin prolongs survival of pig kidneys perfused ex vivo with human blood.

Intravenous immunoglobulin (IVIG) (Octagam), was used to determine the effect on hyperacute rejection in an ex vivo xenograft model. Six pig kidneys were perfused with IVIG and fresh human AB blood, and six control pig kidneys were simultaneously perfused with albumin and blood from the same donation. The survival of the IVIG-perfused xenografts (median, 6.5 h) was significantly (P = 0.03) longer than the albumin-perfused xenografts (median, 3.5 h). Complement was activated in both groups. The administration of IVIG to the perfused blood resulted in immediate and significantly higher complement activation in the fluid phase as compared with the albumin group. At rejection the fluid phase complement activation was higher in the IVIG group than in the albumin group for C1rs/C1inh complexes, C4bc, Bb and TCC. At the time of rejection both the albumin and the IVIG group demonstrated interstitial tubular haemorrhage, vasculitis or necrosis of glomerular capillaries and glomerular microthrombi. IgM, C1q, C3c, C4 and fibrin were located in arteries and glomeruli and IgG in the interstitium in both groups at rejection. The fluid phase findings are consistent with a modulatory effect of IVIG on complement activation by deviating the classical pathway activation towards the fluid phase. The prolonged survival of the IVIG-perfused kidneys suggests that IVIG may be useful to dampen hyperacute rejection.

Regulation of surface expression of high-affinity receptors for epidermal growth factor (EGF) in hepatocytes by hormones, differentiating agents, and phorbol ester.

Freshly isolated adult rat hepatocytes exhibit a nonhomogeneous population of epidermal growth factor (EGF) receptors with about 10,000 high-affinity binding sites (Kd 20 pM) and about 200,000 low-affinity sites (Kd 600 pM) per cell. With culturing as primary monolayers under conditions where the cells show a marked increase in the sensitivity to the growth-stimulatory effect of EGF, a gradual reduction in the number of EGF receptors and an almost complete loss of high-affinity EGF receptors is seen. Insulin, which promotes growth of hepatocytes in concert with EGF, enhances the down-regulation of these high-affinity receptors. The differentiating (and growth-inhibitory) agent n-butyrate counteracts this down-regulation and preserves the high-affinity receptors. This effect of butyrate is synergistic with the glucocorticoid agent dexamethasone. Another differentiating agent, dimethylsulfoxide (DMSO), also counteracts the down-regulation of high-affinity EGF receptors. Moreover, the tumor promoter, tetradecanoylphorbol acetate (TPA), down-regulates the EGF receptor. This effect is particularly evident when studying the high-affinity receptors up-regulated by prior treatment with butyrate plus dexamethasone. Taken together these results provide strong support for the notion that an inverse relationship exists between expression of high-affinity EGF binding and responsiveness to growth activation by EGF.

Dual effects of glucagon and cyclic AMP on DNA synthesis in cultured rat hepatocytes: stimulatory regulation in early G1 and inhibition shortly before the S phase entry.

Although several lines of evidence implicate cyclic AMP in the humoral control of liver growth, its precise role is still not clear. To explore further the role of cyclic AMP in hepatocyte proliferation, we have examined the effects of glucagon and other cyclic AMP-elevating agents on the DNA synthesis in primary cultures of adult rat hepatocytes, with particular focus on the temporal aspects. The cells were cultured in a serum-free, defined medium and treated with epidermal growth factor (EGF), insulin, and dexamethasone. Exposure of the hepatocytes to low concentrations (10 pM-1 nM) of glucagon in the early stages of culturing (usually within 6 h from plating) enhanced the initial rate of S phase entry without affecting the lag time from the plating to the onset of DNA synthesis, whereas higher concentrations inhibited it. In contrast, glucagon addition at later stages (24-45 h after plating) produced only the inhibition. Thus, if glucagon was added at a time when there was a continuous EGF/insulin-induced recruitment of cells to S phase, the rate of G1-S transition was markedly decreased within 1-3 h. This inhibitory effect occurred at low glucagon concentrations (ID50 less than 1 nM) and was mimicked by cholera toxin, forskolin, isobutyl methylxanthine, and 8-bromo cyclic AMP. The results indicate that cyclic AMP has dual effects on hepatocyte proliferation with a stimulatory modulation early in the prereplicative period (G0 or early G1), and a marked inhibition exerted immediately before the transition from G1 to S phase.