Phase III randomized study of second line ADI-PEG 20 plus best supportive care versus placebo plus best supportive care in patients with advanced hepatocellular carcinoma.

Background: Arginine depletion is a putative target in hepatocellular carcinoma (HCC). HCC often lacks argininosuccinate synthetase, a citrulline to arginine-repleting enzyme. ADI-PEG 20 is a cloned arginine degrading enzyme-arginine deiminase-conjugated with polyethylene glycol. The goal of this study was to evaluate this agent as a potential novel therapeutic for HCC after first line systemic therapy. Methods and patients: Patients with histologically proven advanced HCC and Child-Pugh up to B7 with prior systemic therapy, were randomized 2 : 1 to ADI-PEG 20 18 mg/m2 versus placebo intramuscular injection weekly. The primary end point was overall survival (OS), with 93% power to detect a 4-5.6 months increase in median OS (one-sided α = 0.025). Secondary end points included progression-free survival, safety, and arginine correlatives. Results: A total of 635 patients were enrolled: median age 61, 82% male, 60% Asian, 52% hepatitis B, 26% hepatitis C, 76% stage IV, 91% Child-Pugh A, 70% progressed on sorafenib and 16% were intolerant. Median OS was 7.8 months for ADI-PEG 20 versus 7.4 for placebo (P = 0.88, HR = 1.02) and median progression-free survival 2.6 months versus 2.6 (P = 0.07, HR = 1.17). Grade 3 fatigue and decreased appetite occurred in <5% of patients. Two patients on ADI-PEG 20 had ≥grade 3 anaphylactic reaction. Death rate within 30 days of end of treatment was 15.2% on ADI-PEG 20 versus 10.4% on placebo, none related to therapy. Post hoc analyses of arginine assessment at 4, 8, 12 and 16 weeks, demonstrated a trend of improved OS for those with more prolonged arginine depletion. Conclusion: ADI-PEG 20 monotherapy did not demonstrate an OS benefit in second line setting for HCC. It was well tolerated. Strategies to enhance prolonged arginine depletion and synergize the effect of ADI-PEG 20 are underway. Clinical Trial number: www.clinicaltrials.gov (NCT 01287585).

Randomised controlled trial of doxorubicin-eluting beads vs conventional chemoembolisation for hepatocellular carcinoma.

BACKGROUND: Transcatheter arterial chemoembolisation (TACE) is the treatment of choice for intermediate stage hepatocellular carcinoma (HCC). Doxorubicin-loaded drug-eluting beads (DEB)-TACE is expected to improve the performance of conventional TACE (cTACE). The aim of this study was to compare DEB-TACE with cTACE in terms of time-to-tumour progression (TTP), adverse events (AEs), and 2-year survival. METHODS: Patients were randomised one-to-one to undergo cTACE or DEB-TACE and followed-up for at least 2 years or until death. Transcatheter arterial chemoembolisation was repeated 'on-demand'. RESULTS: We enrolled 177 patients: 89 underwent DEB-TACE and 88 cTACE. The median number of procedures was 2 in each arm, and the in-hospital stay was 3 and 4 days, respectively (P=0.323). No differences were found in local and overall tumour response. The median TTP was 9 months in both arms. The AE incidence and severity did not differ between the arms, except for post-procedural pain, more frequent and severe after cTACE (P<0.001). The 1- and 2-year survival rates were 86.2% and 56.8% after DEB-TACE and 83.5% and 55.4% after cTACE (P=0.949). Eastern Cooperative Oncology Group (ECOG), serum albumin, and tumour number independently predicted survival (P<0.05). CONCLUSIONS: The DEB-TACE and the cTACE are equally effective and safe, with the only advantage of DEB-TACE being less post-procedural abdominal pain.

Characterization of primary and recurrent nodules in liver cirrhosis using contrast-enhanced ultrasound: which vascular criteria should be adopted?

PURPOSE: To assess the impact of different vascular patterns at contrast-enhanced ultrasound (CEUS) on the characterization of small liver nodules (10-30 mm) in cirrhosis and to determine whether primary nodules and recurrent nodules (after a previously treated hepatocellular carcinoma) display variations in enhancement pattern. MATERIALS AND METHODS: A total of 135 cirrhotic patients were evaluated. A diagnosis of hepatocellular carcinoma (HCC) was established according to AASLD Guidelines, based on imaging (computed tomography and/or magnetic resonance) or liver biopsy. All patients underwent CEUS. Different CEUS patterns were evaluated in terms of diagnostic accuracy: HYPER-HYPO: Arterial hyperenhancement followed by washout (hypoechoic appearance compared with surrounding parenchyma) in late phase; HYPER-ISO: Arterial hyperenhancement followed by isoenhancement (isoechoic appearance) in late phase; ISO-ISO: Isoenhancement in all vascular phases. RESULTS: A total of 155 consecutive primary (n = 90) or recurrent (n = 65) nodules were detected. HCC was diagnosed in 127 nodules (71 primary, 56 recurrent). A characteristic HYPER-HYPO CEUS pattern was revealed in 52/127 (40.9%) HCCs (31 primary, 21 recurrent) giving a positive predictive value (PPV) of 98% (97% primary, 100% recurrent) and an accuracy of 51% (54% primary, 46% recurrent). A HYPER-ISO pattern was noted in 46 HCCs (31 primary, 15 recurrent). Assuming this pattern to also be indicative of HCC, the PPV and accuracy were 94% (93% primary, 97% recurrent) and 77% (84% primary, 68% recurrent), respectively. An ISO-ISO pattern was present in 29 HCCs (9 primary, 20 recurrent) and 22 non-HCCs (14 primary, 8 recurrent). CONCLUSION: These data confirm that the HYPER-HYPO pattern at CEUS is definitely diagnostic for HCC in cirrhosis and that the HYPER-ISO pattern has a similar PPV, indicating that this pattern is highly suspicious for HCC. The ISO-ISO pattern was found in > 50% of recurrent nodules and indicates a high risk of HCC.

Early prediction of treatment response to sorafenib with elastosonography in a mice xenograft model of hepatocellular carcinoma: a proof-of-concept study.

PURPOSE: Sorafenib is the reference therapy for advanced hepatocellular carcinoma (HCC). There is no method for predicting in the early period subsequent individual response. Starting from the clinical experience in humans that subcutaneous metastases may rapidly change consistency under sorafenib and that elastosonography allows assessment of tissue elasticity, we investigated the role of this ultrasound-based technique in the early prediction of tumor response to sorafenib in a HCC mice model. MATERIALS AND METHODS: HCC subcutaneous xenografting in mice was utilized. Mice were randomized to vehicle (17 mice) or treatment with sorafenib (19 mice). Strain elastosonography (Esaote, Italy) of the tumor mass was performed at different time points (day 0, + 2 and + 14 from treatment start) until the mice were sacrificed (day + 14). At the same time points, the volume was calculated with ultrasonography. RESULTS: Sorafenib-treated mice showed a smaller increase in tumor size on day + 14 in comparison to vehicle-treated mice (tumor volume increase + 175 % vs. + 382 %, p = 0.009). The median tumor elasticity increased in both groups on day + 2 (+ 5.65 % and + 3.86 %, respectively) and decreased on day + 14 (-3.86 % and -3.63 %, respectively). However, among Sorafenib-treated tumors, 13 mice with a growth percentage delta < 200 % (considered as good treatment response) showed an increase in elasticity on day + 2 (+ 8.9 %, range -12.6 - + 64) while the other 6 with a growth percentage delta > 300 % (considered as poor treatment response) showed a decrease in elasticity (-17 %, range -30.2 - + 15.3) (p = 0.044). CONCLUSION: Elastosonography appears to be a promising noninvasive new technique for the early treatment prediction of HCC tumor response to sorafenib. Specifically, an early increase in tumor elasticity (corresponding to tumors becoming softer) is associated with a good response.

Response rate and clinical outcome of HCC after first and repeated cTACE performed "on demand".

BACKGROUND & AIMS: Aim of the study was to assess the clinical impact of conventional transarterial chemoembolization (cTACE) repeated "on demand" on HCC outcome. Outcome measures were: response rate to first and repeated cTACE, recurrence rates and overall survival. METHODS: The outcome of 151 consecutive HCC patients submitted to a first cTACE from January 2004 to December 2005 was retrospectively analyzed. RESULTS: Complete radiological response (CR) was observed in 72/151 (48%), 34/60 (52%) and 12/22 (55%) patients after first, second and third cTACE, respectively. Recurrence rates at 6 and 12months were 37% and 61% after the first cTACE, and 40% and 59% after the second cTACE, respectively. Patients not achieving CR or with a recurrence after CR not treated with curative therapies were 94 and 84 after first and second cTACE, respectively. Of these, 60/94 (64%) and 22/84 (26%) were submitted to a second and third cTACE, respectively. Median overall survival was 32.0months but 25.0months excluding transplanted patients. Factors at the time of first cTACE associated with overall shorter survival at multivariate analysis were higher bilirubin, higher AFP and not achieving CR. CONCLUSIONS: CR and recurrence rates after first and second cTACE were similar. About 64% of patients were submitted to second cTACE, while only few patients (26%) were submitted to third cTACE using an "on demand" policy. These figures may be also useful for planning trials for the evaluation of the efficacy of repeated TACE vs. TACE combined with adjuvant treatments or vs. systemic treatments.

Accuracy of VirtualTouch Acoustic Radiation Force Impulse (ARFI) imaging for the diagnosis of cirrhosis during liver ultrasonography.

PURPOSE: VirtualTouch is a new technique recently proposed to evaluate liver stiffness during B-mode ultrasonography. The goal of the present study was to analyze the diagnostic accuracy of VirtualTouch in the diagnosis of cirrhosis and its correlation with transient elastography (Fibroscan). MATERIALS AND METHODS: A total of 133 patients with chronic liver disease were enrolled. 90 of 133 underwent VirtualTouch and transient elastography and 70 patients assessed with VirtualTouch were submitted to liver biopsy. Stiffness was assessed by both techniques in the right liver lobe. The diagnostic accuracy for cirrhosis was first assessed in the 90 patients submitted to transient elastography with > 13 kPa (47 % of patients) as diagnostic for cirrhosis values. The best cut-off for cirrhosis with VirtualTouch was then tested in the 70 patients with biopsy (cirrhosis in 38 % of patients). 41 patients were assessed by VirtualTouch by two different operators. RESULTS: The VirtualTouch values in controls, chronic hepatitis and cirrhosis were respectively 113, 147 and 255 cm/sec. The AUROC of liver VirtualTouch for the diagnosis of cirrhosis (reference Fibroscan) was 0.941 with 175 cm/sec as the best cut-off (sensitivity 93.0 %; specificity 85.1 %). VirtualTouch confirmed good performance also in patients with bioptic diagnosis of cirrhosis (AUROC 0.908, sensitivity 81.5 %, specificity 88.4 %,). The correlation of VirtualTouch with transient elastography was strict (r = 0.891) and the correlation in VirtualTouch measurements between two operators was also good (r = 0.874). CONCLUSION: VirtualTouch is able to identify the presence of cirrhosis with good accuracy, shows good interobserver reproducibility and the correlation of its values with those obtained by transient elastography with Fibroscan is good.

Diagnostic features of real-time contrast-enhanced ultrasound in focal nodular hyperplasia of the liver.

PURPOSE: The typical appearance of focal nodular hyperplasia (FNH) in radiological contrast techniques (helical CT or MRI) includes homogeneous enhancement in the arterial phase, but the exact timing for the best visualization of this pattern is unknown. The aim of the present study was to assess the ultrasound pattern of FNH with special attention to real-time contrast-enhanced ultrasonography (CEUS) appearance and specifically to the timing of perfusion patterns. MATERIALS AND METHODS: 72 patients (60 females, 12 males) with a total of 90 FNH nodules with a diameter ranging from 8 to 100 mm (mean +/- SD, 40.6 +/- 21.5 mm) were examined continuously for at least 4 minutes using CnTI and CPS methods (ESAOTE, Genoa, Italy and Acuson-Siemens) after bolus injection of SonoVue (BRACCO, Milan, Italy). RESULTS: 87 of 90 nodules showed the typical coin-like hyperechogenicity in the arterial phase. The remaining three nodules were all in the same patient and were diagnosed as FNH after resection. Contrast started to appear within the lesions after a mean of 15.7 +/- 4.6 seconds (range 7 - 27 s) and reached peak signal intensity, with the greatest differentiation between the lesion and the surrounding parenchyma, at around 22.6 +/- 7.0 seconds (range 14 - 72 s). In the late phase, 65 lesions (72.2 %) became isoechoic (after a mean of 80.8 +/- 85.7 s, range 20 - 300 s), 22 (24.4 %) slightly hyperechoic and 3 (3.3 %) faintly hypoechoic. CONCLUSION: FNH shows a typical homogeneous hyperechoic pattern during the arterial phase in real-time CEUS which disappears slowly on average but occasionally even as soon as 20 seconds after contrast injection. If the first scans are taken later than 20 seconds after injection (which is still considered to be a full arterial phase), the ultrasound hyperechogenicity may be missed in some cases. Real-time study of these lesions is therefore strongly recommended to avoid possible false-negative results.

Small (

PURPOSE: We prospectively compared gadoliniumenhanced magnetic resonance imaging (dynamic MRI), superparamagnetic iron oxide (SPIO) (ferucarbotran) MRI and multidetector-row computed tomography (MDCT) and the combination of dynamic MRI plus MDCT vs. dynamic MRI plus SPIO-MRI (double-contrast MRI: DC-MRI) for the detection of small (1 cm and the highest specificity (83.3%) superior to dynamic MRI (p<0.0001). In the per-lesion analysis, SPIO-MRI demonstrated a positive predictive value higher than dynamic MRI (p=0.0059) and than both the combinations dynamic MRI/MDCT and DC-MRI (p=0.0021 and p=0.0087, respectively). DC-MRI showed the highest sensitivity (97.7%) and accuracy (78.9%), detecting hypovascular and atypical HCCs >1 cm. Furthermore its per-patient negative predictive value was the highest (100%), and significantly higher than all the other methods. CONCLUSIONS: DC-MRI is the most sensitive and accurate method and can be confidently used as a single-step procedure for the detection of small HCCs, with the exception of lesions <1 cm.

Liver transplantation for hepatocellular carcinoma: results of down-staging in patients initially outside the Milan selection criteria.

Conventional criteria for liver transplantation for patients with hepatocellular carcinoma are single HCC

Efficacy of doxorubicin coupled to lactosaminated albumin on rat hepatocellular carcinomas evaluated by ultrasound imaging.

BACKGROUND/AIMS: Doxorubicin was conjugated with lactosaminated human albumin, a hepatotropic drug carrier, in order to increase its efficacy in the treatment of hepatocellular carcinoma. In rats bearing hepatocellular carcinomas induced by diethylnitrosamine, lactosaminated human albumin coupled doxorubicin enhanced the drug concentrations in the tumours and lowered those in extrahepatic tissues. The aim of the present study was to investigate the effects of lactosaminated human albumin coupled doxorubicin on the growth of established rat hepatocellular carcinomas induced by diethylnitrosamine. METHODS: Lactosaminated human albumin coupled doxorubicin and the free drug were i.v. administered to rats twice a week for 4 weeks at the single dose of 1 microg/g. Growth of individual tumours was followed through time by ultrasonography. RESULTS: In the control animals injected with saline the mean area of the tracked tumours significantly increased during the whole period of treatment. In the group of rats treated with lactosaminated human albumin coupled doxorubicin the mean area of the followed hepatocellular carcinomas remained practically unchanged. The free drug inhibited tumour growth only in the first period of drug administration. Lactosaminated human albumin coupled doxorubicin also hindered the development of new neoplastic nodules, which was unaffected by the free drug. CONCLUSIONS: The results support lactosaminated human albumin coupled doxorubicin as a promising agent for a systemic chemotherapy of hepatocellular carcinomas to treat noncurable patients.

Mars and Prometheus: our clinical experience in acute chronic liver failure.

INTRODUCTION: In our clinical context, there are two groups that practice blood purification treatments on acute or chronic liver failure (AoCLF) patients: one group used MARS (molecular adsorbent recirculating system) and the other Prometheus. MATERIALS AND METHODS: The MARS group used the lack of response to standard medical treatment after 72 hours of observation as the access criterion. The Prometheus group used the access criteria of the multicenter Helios protocol for patients in AoCLF, as well as those with primary nonfunction (PNF) and secondary liver insufficiency. Both groups performed treatment sessions of at least 6 hours, which were repeated at least every 24 to 36 hours. RESULTS: The 56 treated AoCLF patients underwent 278 treatment sessions; 41 out of 191 procedures with MARS and 16 out of 87 procedures with prometheus, which was also applied in two cases in PNF and four in secondary liver insufficiency. The results showed that both systems accomplished a good purification efficiency and that application to patients enabled reinstatement on the transplant list and grafts in 70% of the cases with either method. CONCLUSION: Treatment led to recovery in dysfunction among patients not destined for transplantation, achieved with a 48.5% 3-month survival in the MARS group and 33.5% in the Prometheus groups. The treatment results were inversely proportional to the MELD at the time of entry; The treatment appeared to be pointless. Among PNF and secondary liver insufficiency cases.

Regorafenib for the treatment of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a worldwide problem, with a high prevalence in nonindustrialized countries and a rising incidence in industrialized countries as well. Its close association with chronic liver diseases and liver cirrhosis represents a significant challenge in its treatment. A front-line systemic treatment for unresectable cases of HCC (sorafenib) was identified only in 2007. Following a decade of failed clinical trials with a wide range of drugs for second-line treatment, regorafenib proved its efficacy as a second-line treatment in 2016, when the randomized, placebo-controlled, phase III RESORCE trial demonstrated a meaningful increase in overall survival in the regorafenib treatment arm compared with the placebo arm (10.6 vs. 7.8 months). In this monograph we review the main preclinical and clinical findings in the trials assessing regorafenib for the treatment of HCC patients.

Increased risk of nonalcoholic fatty liver disease in patients with coeliac disease on a gluten-free diet: beyond traditional metabolic factors.

BACKGROUND: A gluten-free diet (GFD) is known to be associated with altered macronutrient intake and metabolic syndrome. Nonalcoholic fatty liver disease (NAFLD) is the hepatic hallmark of metabolic syndrome. The risk of NAFLD in patients with coeliac disease (CD) adhering to a GFD remains to be fully investigated; in particular, data from real-life clinical settings are lacking. AIM: To assess the prevalence and relative risk of NAFLD in CD patients treated with a GFD. METHODS: Case-control study, with prospective enrolment of CD outpatients following a GFD and controls. Patients were matched for demographic characteristics (age and gender) and metabolic risk factors (overweight, diabetes mellitus, total cholesterol, and triglycerides) using a 1:1 ratio. NAFLD was diagnosed according to the European Association for the Study of the Liver criteria. RESULTS: 202 CD patients and 202 controls were compared. The raw prevalence of NAFLD was 34.7% and 21.8% in the CD and control group, respectively (P = 0.006). Binary logistic regression confirmed an increased risk of NAFLD in the CD group (adjusted odds ratio = 2.90, 95% confidence interval: 1.64-5.15, P < 0.001). Additionally, the relative risk for NAFLD was notably higher in non-overweight CD patients (adjusted odds ratio = 5.71, 95% confidence interval: 2.30-14.19, P < 0.001). CONCLUSIONS: More than one-third of CD patients adhering to a GFD had concurrent NAFLD, accounting for a three-fold increased risk compared to the general population. Dietary advice provided using a patient-tailored approach should assist CD patients with NAFLD in achieving an appropriate nutritional intake whilst reducing the risk of long-term liver-related events.

Acute systemic, splanchnic and renal haemodynamic changes induced by molecular adsorbent recirculating system (MARS) treatment in patients with end-stage cirrhosis.

AIM: To evaluate the acute effect of treatment with the molecular adsorbent recirculating system (MARS) on splanchnic, renal and systemic haemodynamics in patients with end-stage cirrhosis. METHODS: Twelve patients with end-stage cirrhosis, undergoing MARS treatment, were enrolled. The following haemodynamic parameters were measured by means of Doppler ultrasonography and thoracic electrical bioimpedance, before and after each session: portal velocity, renal and splenic resistance indices, cardiac output, cardiac stroke volume, heart rate, mean arterial pressure, systemic vascular resistance. RESULTS: Median portal velocity increased significantly after treatment (23.7 vs. 20.3 cm/s, P < 0.05) while renal resistance index (0.72 vs. 0.75, P < 0.05) and splenic resistance index (0.60 vs. 0.65, P < 0.05) decreased significantly. Mean arterial pressure (83 vs. 81 mmHg, P < 0.05) and vascular resistance (899 vs. 749 dyne. s/cm5, P < 0.05) increased significantly, while cardiac output and stroke volume showed no significant changes. CONCLUSIONS: Data emerging from this investigation suggest that MARS treatment improves significantly various haemodynamic alterations in cirrhotic patients in the short term. The observed decrease in renal vascular resistance and improvement in splenic resistance index, a parameter related to portal resistance, which leads us to hypothesize that these haemodynamic effects are probably mediated by clearance of vasoactive substances during MARS treatment.

New perspectives for the use of contrast-enhanced liver ultrasound in clinical practice.

The introduction of second-generation microbubble ultrasound contrast agents and the development of contrast specific ultrasound techniques have improved the ability of contrast enhanced ultrasound in detecting and characterising liver lesions, offering new perspectives for its exploitation in clinical hepatology. Indeed, several studies have demonstrated a high diagnostic accuracy in focal lesion characterisation (85-96%) in patients either with or without underlying chronic liver disease. This review article describes the basic principles of contrast enhanced ultrasound, defines the different vascular features of benign and malignant liver lesions, and assesses its clinical impact in different clinical scenarios, according to the guidelines of the European Federation of Societies for Ultrasound in Medicine and Biology, contrast enhanced ultrasound enables the characterisation of focal liver lesions, regardless of the presence or absence of underlying chronic liver disease. Contrast enhanced ultrasound is also useful in staging and follow-up of cancer patients and in monitoring local ablative treatment. Contrast enhanced ultrasound is expected to be considerably increased and replace many computed tomography and magnetic resonance imaging examinations in near future, according to the European Federation of Societies for Ultrasound in Medicine and Biology guidelines. Therefore, it is necessary to take measures in order to meet the demand for an increasing number of these procedures.

Analysis of risk factors for early hepatic artery thrombosis after liver transplantation. Possible contribution of reperfusion in the early morning.

BACKGROUND: Since the incidence of myocardial infarction and other cardiovascular ischaemic events is highest in early morning, on account of a relative hypercoagulable state occurring in this time period, an attempt was made to test whether reperfusion of the hepatic artery at this time of the day, at liver transplantation, produces an increased risk of early thrombosis. METHODS: The records of 255 consecutive patients receiving a first transplant for chronic liver disease were retrospectively analysed. As possible risk factors, for early post-operative thrombosis (<30 days from transplantation), several medical and surgical parameters were taken into consideration. Arterial reperfusion was considered to have taken place at a time of high coagulability when occurred between 6.00 a.m. and 10.00 a.m. on the basis of previous reports. RESULTS: Logistic regression identified donor age (OR for age >60: P=0.017), bench reconstruction of the artery (OR: 5.06, P=0.013) and time of high coagulability at reperfusion (OR 2.93, P=0.087), as independently associated with early hepatic artery thrombosis. CONCLUSIONS: The present findings identified three independent predictors of early hepatic thrombosis, warranting stricter post-surgical follow-up of patients presenting such conditions. Interestingly, these factors are consistent with arterial reperfusion in the early morning being associated with an increased risk of early hepatic artery thrombosis, suggesting relative coagulative imbalances to provide a contribution in the pathogenesis of this severe complication of liver transplantation.

Molecular adsorbent recirculating system (MARS) application in liver failure: clinical and hemodepurative results in 22 patients.

PURPOSE: Acute liver failure (ALF) and acute on chronic liver failure (ACLF) still show a poor prognosis. MARS was used in 22 patients with ALF or ACLF to prolong patient survival for liver function recovery or as a bridge to transplantation. DESIGN: Evaluation of depurative efficiency, biocompatibility, hemodynamics, encephalopathy (HE) and clinical outcome. PROCEDURES: During 71 five-hour sessions we evaluated (0', 60', 120', 180', 240', 300'): bilirubin, ammonia, cholic acid (CCA), chenodeoxycholic acid (CCDCA), leukocytes, platelets, hemoglobin and mean arterial pressure (MAP). Serum creatinine, electrolytes, cardiac output, cardiac index (bioimpedence) and HE (West Haven Criteria score) were evaluated at 0' and 300'. STATISTICAL METHODS AND OUTCOME MEASURES: Student's t-test for pre- vs. end-session values was used. For bilirubin and ammonia the correlation test was made between pre- and end-session values and between pre-session values and removal rates (RRS). MAIN FINDINGS: Survival was 90.9% at 7 days, 40.9% at 30 days. Pre- vs. end-session: bilirubin from 37.2 +/- 12.5 mg/dL to 24.9 +/- 8.9 mg/dL (p < 0.01), ammonia from 88.0 +/- 60.4 micromol/L to 43.6 +/- 32.9 micromol/L (p < 0.01), CCA from 42.8 +/- 21.0 micromol/L 18.2 +/- 9.8 micromol/L (p < 0.01), CCDCA from 26.3 +/- 6.3 micromol/L to 15.7+/-7.6 micromol/L (p<0.01). The correlation test between pre-session values of bilirubin and ammonia vs. RR S was respectively 0.32 (p = 0.01) and 0.30 (p = 0.04). Leukocytes, platelets and hemoglobin remained stable. MAP increased from 82.0 +/- 12.0 mmHg to 87.0 +/- 13.0 mmHg (p < 0.05), West Haven Criteria score decreased from 2.7 +/- 0.7 to 0.7 +/- 0.7 (p < 0.001). CONCLUSION: MARS treatment led in all patients to an improvement of clinical, hemodynamic and neurological conditions, with significant reduction in the hepatic toxins blood level. Treatment biocompatibility and tolerance were satisfactory.

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.