Aberrant fragile histidine triad gene transcripts in primary hepatocellular carcinoma and liver cirrhosis.

To determine whether transcriptional alterations of the fragile histidine triad (FHIT) gene play a role in the development and progression of human hepatocellular carcinoma (HCC) we used reverse transcription-PCR to examine mRNA FHIT expression in 28 paired samples of HCC (24 in cirrhotic and 4 in noncirrhotic livers) and matched noncancerous tissue and in 10 normal livers. We also assessed loss of heterozygosity of the polymorphic D3S1300 microsatellite marker in the intron between exons 5 and 6 of the FHIT gene. Abnormal FHIT transcripts were detected in 13 cases (46.4%): 10 in the cancerous tissue only, 1 with the same pattern in both cancerous and matched noncancerous tissue, and 2 in the noncancerous tissue only. The four HCCs that arose in noncirrhotic liver all showed abnormal FHIT transcripts. No alterations were found in normal livers. Sequence analysis of abnormally sized transcripts revealed that they were generated by the fusion of exons 3 or 4 with exons 8 or 9. Among the cancerous specimens, one case showed only an abnormal sized transcript derived from the fusion of exons 4 and 9 in the absence of any normal-sized transcript, and another case showed deletion of a sequence comprised between nucleotides -35 and 399 resulting in an exon 4-9 fusion not respecting the exons' bounds. Loss of heterozygosity was found in two cases with abnormal FHIT transcripts and in only one case with normal transcript. Patients with aberrant FHIT transcripts showed a significantly higher relapse rate and shorter recurrence time (P = 0.001). This could be related to a primary genomic instability affecting particularly susceptible regions like FRA3B and could be associated with an increasing risk of recurrence without involving a causative role.

Intermittent anoxia reduces oxygen free radicals formation during reoxygenation in rat hepatocytes.

The sensitivity of liver cells to anoxia is a major problem afflicting liver preservation and transplantation. Intermittent ischemia has been proposed to reduce reperfusion injury. The aim of the study was to assess oxygen free radical formation and cell injury during continuous or intermittent anoxia/reoxygenation in rat hepatocytes. Anion superoxide was measured by lucigenin-enhanced chemiluminescence and cell damage by LDH release and trypan blue uptake. During anoxia, superoxide generation dropped to background level in both groups; trypan blue uptake and LDH release, which increased progressively, were significantly greater in hepatocytes exposed to continuous compared to intermittent anoxia. During reoxygenation, a massive generation of superoxide anion formation, followed by a sharp increase in LDH release, was observed in both groups. However, both oxyradical generation and cell injury were significantly greater in cells exposed to continuous compared to intermittent anoxia. The data, showing that intermittent oxygen deprivation reduce liver cell injury and oxygen free radical formation determined by anoxia/reoxygenation, suggest a novel possible approach to the reduction of reperfusion injury.

Prosthesis jump graft: an unusual arterial reconstruction in liver transplantation.

The authors present a case of arterial jump graft using a number 9 Goretex prosthesis (FEP ringed vascular graft; W.I. Gore Associates Inc.-Delaware, Flagstaff, AZ) with an excellent outcome 3 years after the transplant. The prosthesis was necessary because of the impossibility of using the donor iliac arterial grafts due to the presence of widespread atherosclerotic damage.

Protease activities, as well as plasminogen activators, contribute to the "lytic" state during orthotopic liver transplantation.

High levels of tissue plasminogen activator (t-PA) have been reported to be the main component of the high fibrinolytic activity measured in patients during orthotopic liver transplantation. However, a previous study of our group suggested that specific t-PA may not completely account for the massive fibrinolytic activities recorded. In the present study we investigated the fibrinolytic patterns in 10 consecutive liver cirrhosis patients undergoing OLT. Euglobulin fibrinolytic activity, measured either on physiologic (fibrin plates) or amidolytic substrates, increased as expected during anhepatic and reperfusion phases, but largely exceeded the specific activity of t-PA, as proved by quenching procedures using anti-t-PA antibodies. The presence of plasmin- and trypsin-like amidolytic activities was detected in native plasmas at the end of anhepatic and reperfusion phases, together with decreased levels of protease inhibitors, especially alpha 1 Antitrypsin. In conclusion, the hyperfibrinolytic pattern recorded in the central OLT phases is not only attributable to an increased t-PA concentration, and is better described as a complex "lytic" state also including the presence of free proteases (plasmin- and trypsin-like), with limited participation of u-PA. Although t-PA increase is probably the main mechanism of stimulation of the fibrinolytic system during OLT, actual and not just potential proteolytic activities can be found in this condition independent of the occurrence of major hemorrhagic complications.

The lidocaine (MEGX) test as an index of hepatic function: its clinical usefulness in liver surgery.

BACKGROUND: The purpose of this study was to evaluate the clinical usefulness of the lidocaine test, as an index of hepatic function, in the different fields of liver surgery. METHODS: The lidocaine (MEGX [monoethylglycinexylidide]) test, which was performed in 200 patients with different liver diseases and in 23 organ donors, was compared with common laboratory tests. The MEGX value was related to postoperative complications in patients who undergo liver resection and to the survival of patients with cirrhosis who are awaiting transplantation. In organ donors, the test was related to the outcome of patients who underwent transplantation. RESULTS: The MEGX value was significantly higher in patients without cirrhosis compared to patients with cirrhosis (77.8 +/- 25 ng/mL vs 35.6 +/- 30 ng/mL; P < .05); among patients with cirrhosis, there was a significant difference between those patients classified Child A and those classified Child B and C (43.3 +/- 25 ng/mL vs 11.5 +/- 7.1 ng/mL; P < .05). The patients classified Child A who underwent liver resection with MEGX value less than 25 ng/mL had a significantly higher rate of postoperative complications compared with other patients (P < .001). Patients with cirrhosis who were awaiting liver transplantation and who had a MEGX value of less than 10 ng/mL had a life expectancy of no longer than 1 year. CONCLUSIONS: The MEGX test is a reliable index of hepatic function. Patients carrying hepatocellular carcinoma with MEGX value of less than 25 ng/mL have a high risk of liver insufficiency after hepatic resection. Patients with decompensated cirrhosis who have an MEGX value of less than 10 ng/mL should undergo transplantation as soon as possible.

Intraoperative ultrasonography in surgery for liver tumors.

Intraoperative ultrasonography was used in 37 patients during surgery for suspected liver tumors. The size, number, and site of the lesions were determined together with the relationship of the tumor to the intrahepatic vessel, as well as possible small daughter lesions within the liver. Final diagnosis in these patients was hepatocellular carcinoma in 19 cases, metastases from colorectal cancers in 15 cases, and benign lesions in three cases. Previously undetected small tumors were revealed in one patient with sigmoid cancer and in five patients with liver cell carcinoma who had cirrhosis. Vascular tumoral infiltrations were easily displayed and the surgical approach modified accordingly: a more extended resection was performed in two cases of huge central hepatic metastases. Intraoperative ultrasonography revealed seven cases of small (2 to 3 cm) hepatocellular carcinomas in cirrhotic livers that were not visible or palpable, thus allowing a subsegmentary resection. Finally, in three cases of atypical tumors, an intraoperative echo-guided biopsy specimen was required to establish the benign nature of lesions and resection was avoided. Intraoperative ultrasonography facilitates the diagnosis of small liver tumors and can also aid the surgeon in his choice of technique, especially in cases of cirrhosis of the liver. A resection can be avoided altogether when multiple lesions are involved, or echo-guided subsegmentary resections can be performed in cirrhotic livers when a less extended resection is required. This technique makes it possible to establish the relationship between the tumor and intrahepatic vessels, thus preventing vascular injury and making radical hepatic resection safer.

Ultrasonographic study of portal venous system in portal hypertension and after portosystemic shunt operations.

One hundred sixty patients with portal hypertension were examined by means of ultrasonography in order to evaluate the sensitivity of this technique in the diagnosis of intrahepatic portal hypertension and in the detection of portal vein thrombosis. Thirty-eight of these patients were selected for a portosystemic shunt and were reexamined after operation to assess the value of ultrasonography as a screening test for the patency of surgical portosystemic shunts. In patients with intrahepatic portal hypertension the main ultrasonographic findings observed were dilatation of the portal trunk of more than 1.3 cm (56.6% of cases), patency and dilatation of the umbilical vein (5.8%), presence of intra-abdominal collateral vessels (11.6%), splenomegaly with dilatation of splenic vein radicles at the hilus (91.3%), and disappearance of normal caliber variations during respiration in splenic or mesenteric veins (78.5% and 88.4%, respectively). The disappearance of normal caliber variations proved a highly specific and sensitive finding. Partial or total occlusion of the portal trunk was observed at ultrasonography in 19 of 21 (90.5%) patients with portal vein thrombosis. Surgical portosystemic shunts were displayed in 28 of 37 patients (75.7%). Ultrasonography seems to be the most important noninvasive tool in the diagnosis of portal hypertension. In patients selected for surgical portosystemic shunts ultrasonography supplies morphologic data regarding liver parenchyma and abdominal vascular anatomy, and it should be performed as a routine screening test for assessment of surgical shunt patency.

Plasma amino acid patterns in experimental acute hepatic failure: comparison between hepatectomy and liver devascularization in pigs.

To clarify the physiopathologic mechanism leading to a marked increase in aromatic amino acids (AAA) in acute hepatic failure (AHF), we compared two experimental models of AHF. Ten pigs were submitted to one-stage hepatic devascularization (group A); in eight other pigs total hepatectomy was performed (group B). The animals were maintained under constant glucose infusion. The mean survival time in group A was 23 +/- 2 hours; after hepatectomy it was 30 +/- 4 hours. Hepatic coma progressively deepened from 8 +/- 3 hours in Group A animals and was delayed until 17 +/- 5 hours in the anhepatic pigs. AAA, methionine, and tryptophan immediately increased markedly in pigs with liver ischemia. In group B animals, AAA showed a slight increase only 18 hours after hepatectomy, whereas there were no significant differences in methionine and tryptophan. The different amino acid patterns in the two groups of animals demonstrate that hepatocyte necrosis is a major source of plasma amino acids after liver devascularization. The slight increase in AAA after total hepatectomy suggests that a release mechanism from muscular mass is involved in the later stages of the experiment. The onset of coma is related to the increase in AAA rather than to alterations in blood ammonia that did not differ in either group of animals.

Role of reoperation in recurrence of adrenal cortical carcinoma: results from 188 cases collected in the Italian National Registry for Adrenal Cortical Carcinoma.

BACKGROUND: Recurrence of adrenal cortical carcinoma (ACC) after radical surgery is a common finding. Although successful reoperations have been reported with encouraging results, most published experiences are anecdotal and based on few cases. We report the results of surgical treatment for recurrent ACC in a multiinstitutional series. METHODS: One hundred eighty-eight cases of ACC were collected in a national registry. A complete follow-up was obtained in 179 cases. At initial diagnosis 92 patients had local disease (stage I or II). One hundred seventy patients underwent surgical treatment, considered radical in 140; in this group, recurrent disease was observed in 52 cases (37%) after a mean disease-free interval of 21.7 months. RESULTS: Adjuvant chemotherapy was ineffective in ameliorating the prognosis. The mean survival in 20 patients who underwent reoperation was significantly higher (15.85 +/- 14.9 months) than in nonreoperated cases (3.2 +/- 2.9 months). Five-year actuarial survival in reoperated patients is significantly better than in nonreoperated patients (49.7% versus 8.3%, respectively). CONCLUSIONS: Although the prognosis of this tumor is still poor, surgery is the only effective therapy; reoperation allows survival comparable to that observed in patients without recurrent disease. An aggressive strategy for recurrent ACC is advisable until prospective studies demonstrate a real effectiveness for chemotherapy.

Isolated resection of segment 8 for liver tumors: a new approach for anatomical segmentectomy.

HYPOTHESIS: Isolated resection of segment 8 (the right anterosuperior liver segment) is one of the most difficult hepatectomies to perform because of the location of segment 8, the relation between section 8 and the main intrahepatic vessels, and the absence of any anatomical landmarks. The few reports that deal with isolated resection of section 8 generally describe the use of a deep wedge transparenchymal transection. DESIGN: Original surgical technique. PATIENTS AND METHODS: The proposed technique is based on the extraparenchymal isolation and temporary clamping of the right anterior artery and portal branches, causing ischemic demarcation on the liver surface, which corresponds to the anatomical borders of the right paramedian segments (5 and 8). The liver is widely transected along the main hepatic fissure; then the pedicles of segment 8 are selectively ligated inside the parenchyma, and the resection is accomplished. This technique was used in 10 patients: 5 with hepatocellular carcinoma on cirrhosis and 5 with liver metastases. RESULTS: The mean operation time was 253 minutes. Intraoperative blood loss was minimal in all cases, and 7 patients did not require blood transfusion. Slight complications developed in 3 patients, and there was no operative death. The mean hospital stay was 9.3 days. CONCLUSIONS: This operative procedure is safe and ensures a complete anatomical resection of segment 8. The wide opening of the liver parenchyma facilitates hemostasis and makes it possible to obtain a correct resection margin. This technique is recommended for limited metastatic lesions located in segment 8 or for hepatocellular carcinoma arising in a cirrhotic liver.

Total vascular exclusion of the liver during hepatic surgery. Selective use, extensive use, or abuse?

OBJECTIVES: To review our experience with total vascular exclusion of the liver and to assess its role in hepatic resections. DESIGN: Retrospective survey. SETTING: University hospital, a tertiary referring center for surgical liver diseases. PATIENTS: A total of 722 patients who underwent liver resections from November 1, 1981, to March 31, 1996, of whom 19 (2.6%) required total vascular exclusion because of hepatic lesions closely adherent to or infiltrating the retrohepatic vena cava or centrally located in the liver, strictly in contact with the hepatic vein convergence. MAIN OUTCOME MEASURE: chi 2 Test for qualitative data and Student t test for categorical data. RESULTS: Of the 19 resections carried out under total vascular exclusion, 6 had tumoral infiltration of the retrohepatic vena cava: in 4 cases the venous wall was partially resected, while in the remaining 2 it was completely removed and replaced with a prosthetic graft. There were no operative deaths. Of the 722 resections, 227 were major hepatectomies: 74 (32.6%) were performed after ligation of the glissonian elements for the hemiliver to be removed, without clamping of the hepatic pedicle, and a further 36 (15.8%) were performed without any preliminary vascular control. A significant reduction in intraoperative blood transfusions was achieved despite the performance of more extended operations, regardless of the technique used. CONCLUSIONS: Total vascular exclusion is a useful tool in controlling blood inflow to the liver, but true need for it during liver resection is limited. Its performance requires a well-trained team familiar with problems regarding surgical access to the inferior vena cava and prolonged occlusion of the hepatic pedicle and the inferior vena cava.

Interferon-alpha plus ribavirin and amantadine in patients with post-transplant hepatitis C: results of a pilot study.

BACKGROUND: Recurrence of hepatitis C after liver transplantation is almost constant and may lead to graft loss. The results of treatment with interferon and/or other agents have been controversial. AIMS: To evaluate the efficacy and safety of combination therapy with interferon-alpha2b (3 MU, 3 times weekly), ribavirin (600 mg daily) and amantadine (100 mg daily) in post-transplant hepatitis C. PATIENTS AND METHODS: Enrolled in the study were 9 liver transplant recipients with histologically proven recurrent hepatitis C. Patients were treated for 12 months and followed up for 6 months after treatment. RESULTS: Treatment was not tolerated: only one patient completed the planned course, two stopped therapy within the first 3 months and 6 needed a change. However, mean alanine aminotransferase levels significantly decreased during treatment and were significantly lower than baseline at the end of follow-up. One patient out of 9 (11%) achieved a biochemical and virological sustained response. Control liver biopsy showed improvement in 2/7 patients, no change in 3 and worsening in 2. CONCLUSIONS: In recurrent post-transplant hepatitis C, antiviral treatment with interferon, ribavirin and amantadine seems to be poorly tolerated. However further studies are needed before expressing any conclusion on this potentially important option.

Distal splenorenal shunt and insulin secretion, plasma glucagon, and glucose homeostasis in cirrhosis.

Over the 1st postoperative yr, distal splenorenal shunt (DSRS) in cirrhotic patients is followed by a reduction in portal perfusion resulting from a spontaneous opening of portal-systemic collaterals. This can influence plasma levels of insulin and glucagon. Fasting plasma glucose, insulin, C-peptide, and glucagon and their 5-h responses to a protein meal (which directly stimulates the hormone secretions) were measured before and 3 and 12 mo after DSRS in 10 cirrhotic patients. Hormone effectiveness and pancreatic alpha- and beta-cell sensitivities to ammonia (NH3), amino acids, and glucose were also calculated. Liver function and portal vein diameter were assessed before each study. Seven cirrhotic patients treated with injection sclerotherapy of esophageal varices served as a control group. Liver function did not deteriorate in either patient group. An increase in fasting glucagon (from 181 +/- 22 to 242 +/- 22 and 255 +/- 22 pg/ml, p = 0.02) and NH3 (from 57 +/- 8 to 84 +/- 11 and 97 +/- 14 micrograms/dl, p = 0.04) and a decrease in glucagon effectiveness (from 0.56 +/- 0.06 to 0.39 +/- 0.05 and 0.035 +/- 0.03, p = 0.047) and portal vein diameter (from 16.0 +/- 1.1 to 11.3 +/- 0.8 and 9.4 +/- 0.6 mm, p < 0.001) was found only in DSRS patients. The elevation in glucagon was correlated with that of NH3 at 3 mo (r = 0.83, p = 0.003) and with the reduction of portal vein diameter at 1 yr (r = -0.81, p = 0.005). In cirrhosis, DSRS does not influence insulin secretion or its plasma level and effectiveness.(ABSTRACT TRUNCATED AT 250 WORDS)

Surgical therapy for undifferentiated (embryonal) sarcomas of the liver in adults.

Undifferentiated (embryonal) sarcoma of the liver is a rare malignant mesenchymal tumor with a poor prognosis. Thirty cases worldwide have been reported over the last 40 years. The absence of specific symptoms, the rapid tumor growth, the normality of the common tumoral markers and the consequential delay in the diagnosis, often allow a significant enlargement of the hepatic mass. Three patients ages 15, 25, and 60 were admitted to our department with such a tumor. In spite of the large dimensions of the neoplasms, all underwent a right hepatectomy without any major surgical complications. Two of them died due to tumor recurrence after 10 and 67 months, respectively. The one case remaining is alive and disease free 62 months postoperatively. The latter one was the only case where a complete tumoral capsule was found in the resected specimen. Surgery is strongly recommended for every case with evidence of a liver-confined tumor even if it is large.

Solitary necrotic nodules of the liver.

An experience is reported with solitary necrotic nodules of the liver, rare benign lesions described for the first time in 1983. Two patients were referred to our department because of the presence of hepatic lesions that radiology showed to be suspected secondary liver tumors. At laparotomy, both patients underwent liver resections because the lesions appeared to be malignant. Subsequent histological examination of the surgical specimens revealed that both were solitary necrotic nodules of the liver. These were the only solitary necrotic nodules found in a total of 840 operations carried out in our department since October 1981. Although they are completely benign, solitary necrotic nodules have a similar ultrasound pattern and radiological features to metastases and have been described in the literature during the follow-up of patients with other tumors. Uncertainty remains as to the etiology of these lesions, which still represent an occasional finding in liver surgery.

Antimicrobial prophylaxis with ceftriaxone for prevention of early postoperative infections after 49 liver transplantations.

Infection remains a major problem for individuals who undergo solid organ transplantation and liver transplant recipients are particularly susceptible to infectious complications with a high morbidity and mortality rate. The risk of these infections is determined by previous or future environmental exposures as well as the patient's immune status. We report here the results of an open prospective study involving 49 consecutive liver transplantations, undertaken to evaluate the efficacy of ceftriaxone in the prevention of early postoperative infectious complications. Antimicrobial prophylaxis was done using a single dose of ceftriaxone (2 g i.v.) given at the induction of anesthesia and then 2 further once-daily doses were administered 2 days postoperatively. Early postoperative bacterial infection rate was 43.5% (20/46); this result is comparable or even lower than those documented in other studies. This study, even though open and non-comparative, showed that a once-daily regimen containing ceftriaxone provides adequate antimicrobial prophylaxis and significant cost-savings in comparison with multiple-dose prophylactic regimens in patients undergoing liver transplantation.

Surgical treatment of hepatocellular carcinoma on cirrhosis: a Western experience.

Recent improvements on the therapeutical management of hepatocellular carcinoma (HCC) on cirrhosis have led to further evaluate the role of surgery for this disease. In a 15-year period we have evaluated 532 cirrhotics with HCC on cirrhosis. Contraindications for surgery were founded in 170 (31.9%); 37 of them received a transarterial chemoembolization and 2 a percutaneous ethanol injection. Laparotomy was performed in 315 (59.2%) cases, but in 77 surgical treatment was contraindicated due to unexpected intraoperative findings. A liver resection was performed in 238 (44.7%) patients, representing the 26.1% of all liver resections performed at our Department. Seventy-eight (32.8%) were subsegmentectomies, 143 (60.1%) segmentectomies (including 1 to 3 anatomical segments) and 17 major hepatectomies. Overall 30-day mortality was 4.6%: 9.3% during years 83-91 and 0.8% during following years (P<0.005). Five-year actuarial survival rate was 41.3%. The remaining 47 (8.8%) patients were placed on the waiting list for orthotopic liver transplantation (OLT) and 41 already operated on. Operative mortality was 6.2% and 5-year actuarial survival rate 58.1%. The persistent shortage of organ donor represents the major factor limiting the application of liver transplantation for a larger number of patients carrying HCC on cirrhosis. Liver resection remains the option to be considered for all the patients with such a disease, even if in a large proportion of cases this procedure offers only a limited survival.

Bisegmentectomy 5-8 for the removal of tumors of the 8th hepatic segment--a technical note.

Isolated resection of the 8th segment is a technical challenge. The deep location of the afferent portal pedicle mandates the performance of a wedge resection that leaves a deep and narrow wound in which hemostasis is difficult to achieve. Furthermore the relationships with the middle and right hepatic veins jeopardize the transparenchymal approach. For the removal of tumors located in the 8th segment, we propose a combined resection of the 8th and 5th segments, whose pedicles arise from the anterior right pedicle of the portal vein. The technique permits a safe liver resection and ensures a satisfactory surgical margin.

Reversal of primary liver graft non-function using prostaglandins.

Primary graft non-function remains one of the most life-threatening problems after liver transplantation. Its etiology is still unclear. Liver retransplantation is the only therapeutic alternative to this problem. The PGE1 series of prostaglandins have recently been successfully used in the treatment of transplanted organ dysfunction. In this paper we describe a case of primary graft non-function successfully treated with continuous infusion of prostaglandin PGE1, and we briefly discuss the pathogenetic and therapeutic hypotheses.

Beware of TIPS in liver transplant candidates. Transjugular Intrahepatic Portosystemic Shunt.

Transjugular intrahepatic portosystemic shunt (TIPS) reduce portal pressure and prevent bleeding from esophageal varices in cirrhotic patients. The method is often used in liver transplant candidates. Two cases of TIPS malpositioning in liver transplantation candidates are reported. In the first patient, the caudal end of the TIPS was situated distally in the portal trunk and during transplantation it was necessary to isolate the spleno-portal confluence in order to ensure anastomosis in an area of the wall without endothelial lesions. In the second case, still on the waiting list, the cephalead end of the stent is situated in the right atrium and in this case a more complex trans-diaphragmatic and probably trans-atrial approach is foreseen to allow extraction of the stent. In cirrhotic patients who may be possible transplant candidates, shorter TIPS must be used and positioned with care intrahepatically. Careful radiological evaluation is recommended, together with a CT scan and possibly angiography, in patients with TIPS before liver transplantation is performed, to avoid surprises with detrimental effects during the transplant.