Transarterial embolization as neo-adjuvant therapy pretransplantation in patients with hepatocellular carcinoma.

BACKGROUND & AIMS: Neo-adjuvant transarterial therapies are commonly used for patients with HCC in the waiting list for liver transplantation (LT) to delay tumour progression, however, their effectiveness is not well-established. We studied the effect of pre-LT transarterial therapies on post-LT HCC recurrence, using the explanted liver histology to assess therapeutic efficacy and the predictors of response to these therapies. METHODS: We included 150 consecutive patients from our prospectively compiled database, listed for liver transplantation using the Milan criteria. Transarterial embolization without chemotherapeutic agents was the transarterial therapy used as standard of care. PVA particles were the embolizing agent of choice. RESULTS: Sixty-seven (45%) patients had TAE as bridging therapy to liver transplantation, of which 60 were transplanted after 2001. The majority of patients (36, 54%) had partial tumour necrosis after transarterial therapy, whereas 22 (33%) had complete tumour necrosis and 9 (13%) had no necrosis. HCC post-transplant recurrence was independently associated with no neo-adjuvant transarterial therapy (OR 5.395, 95% CI 1.289-22.577; P = 0.021) and the total radiological size of HCC nodules (OR 1.037, 95% CI 1.006-1.069; P = 0.020). CONCLUSIONS: Pre-transplant TAE with the more permanently occluding PVA particles significantly reduces post-transplant HCC recurrence in patients within the Milan criteria.

Does the severity of primary sclerosing cholangitis influence the clinical course of associated ulcerative colitis?

BACKGROUND AND AIMS: Ulcerative colitis (UC) associated with primary sclerosing cholangitis (PSC) is usually clinically mild. The aim of the study was to assess whether there is an association between severity of PSC and activity of UC, comparing the course of UC in patients with PSC not needing liver transplantation (LT) and those eventually transplanted. METHODS: Between 1990 and 2009, 96 consecutive patients with PSC/UC were seen in the authors' institution. Data were evaluated from a database regarding UC activity (median follow-up 144 months). Follow-up was censored at time of LT or last clinical review. RESULTS: Patients with PSC/UC were divided into two groups: 46 did not need LT (no-LT) and 50 were transplanted (LT). There were no significant differences concerning duration of UC or PSC and extent of UC. The LT group had significantly (p=0.002) more clinically quiescent UC compared with the no-LT group. The LT group had fewer UC flare-ups (p=0.04) and required fewer steroid courses (p=0.025) with shorter duration (p=0.022) and less use of azathioprine (p=0.003). There was an increased need for surgery in the no-LT group (p=0.006). Colon carcinoma and high grade dysplasia were more frequent in the no-LT group (p=0.004). The no-LT group had increased inflammation in the colonic mucosa at histology (p=0.011), but without visual difference at colonoscopy. CONCLUSIONS: Clinically progressive PSC requiring LT is associated with a milder course of UC (reduced disease activity and less use of steroids, azathioprine and surgery). This is paralleled by less histological activity and reduced incidence of dysplasia and colon carcinoma.

Long-term follow-up of immunosuppressive monotherapy in liver transplantation: tacrolimus and microemulsified cyclosporin.

BACKGROUND: Early withdrawal of steroids after liver transplantation has benefits, but rarely is total avoidance of steroids used. We evaluated long-term results of patients with ab initio monotherapy with cyclosporin (CYA) vs. tacrolimus (TAC), in randomized and cohort studies. METHODS: We evaluated long-term outcomes in 66 adults randomized to TAC or CYA and 94 subsequent patients who received TAC. Protocol liver biopsies were performed. Rejection was treated with three 1 g/d methylprednisolone. Further rejection after two courses of methylprednisolone was defined as monotherapy failure. RESULTS: Actuarial five-yr survival was 68% in TAC and 70% CYA. Monotherapy failed in 8% TAC and 13% CYA patients; no rejection in 24% TAC and 19% CYA patients; 42% TAC and 33% CYA patients were not exposed to any steroids. Rejection episodes were less with TAC, compared to CYA: mean 1.8 vs. 2.5, p = 0.042. Chronic rejection occurred in only 4 (11%) CYA patients. During follow-up of median 97 months (range: 0.06-145), there were 16 (44%) deaths in CYA and 48 (39%) in TAC patients (p > 0.05). CONCLUSIONS: TAC monotherapy ab initio is a viable immunosuppressive strategy in liver transplantation and was associated with lower rejection rates and renal complications, compared to CYA.

Hepatic encephalopathy: a rare cause of focal seizures in chronic liver disease.

Hepatic encephalopathy (HE) is an extremely rare cause of focal seizures and is usually a diagnosis of exclusion when more commoner causes such as infection, autoimmune and malignancy have been discounted. The literature reports patients with generalised cerebral oedema and rarely status epilepticus, but these are often in the context of acute liver failure as opposed to chronic liver disease. Here we discuss a case of HE leading to focal neurological deficits and seizures in a 48-year-old woman with a background of chronic alcoholic liver disease. MRI scan showed extensive left-sided tempo-parietal-occipital cortical oedema and electroencephalogram showed widespread moderate HE with runs of epileptiform discharges. The treatment involves antiepileptic therapy as well as standard management of HE with laxatives, rifaximin and optimisation of nutrition.

Transarterial injection of (131)I-lipiodol, compared with chemoembolization, in the treatment of unresectable hepatocellular cancer.

UNLABELLED: Transarterial chemoembolization (TACE) improves survival in patients with hepatocellular carcinoma (HCC) in whom curative therapies are not suitable. The aim of this study was to assess survival differences in patients with hepatic cirrhosis and unresectable HCC treated by (131)I-lipiodol versus TACE or transarterial embolization (TAE). METHODS: A retrospective study was performed on a cohort of 124 patients undergoing treatment for unresectable HCC between 1997 and 2006. A total of 50 patients (44 men; mean age, 59 y) received (131)I-lipiodol (mean sessions per patient, 1.7), and 74 patients (63 men; mean age, 61 y) received TACE/TAE (mean sessions per patient, 1.8). Although no significant difference between the 2 treatment groups with respect to HCC size and clinical staging was observed, a higher proportion of patients with portal vein thrombosis (PVT) was treated with (131)I-lipiodol than with TACE/TAE (28% vs. 8%, P = 0.003). RESULTS: Actuarial survival was not significantly different between patients treated with (131)I-lipiodol and patients treated with TACE/TAE. Survival at 6 mo, 1 y, 2 y, and 3 y was 86%, 69%, 54%, and 45%, respectively, after (131)I-lipiodol, compared with 77%, 62%, 47%, and 43%, respectively, after TACE/TAE. However, patients with PVT survived a mean of 454 d after (131)I-lipiodol, compared with a mean of 171 d after TACE/TAE (P = 0.025). In addition, patients with more advanced disease (Barcelona Clinic Liver Cancer stage D) lived on average 363 d after (131)I-lipiodol, compared with 36 d after TACE/TAE (P = 0.014). CONCLUSION: In patients with unresectable HCC, there was no difference in survival between (131)I-lipiodol therapy and TACE/TAE treatment. However, in the patients with advanced clinical staging or PVT, there was a significant survival advantage for those treated with (131)I-lipiodol.

Autoimmune hepatitis associated with Kikuchi-Fujimoto's disease.

We describe a 20-year-old woman with autoimmune hepatitis (AIH) with cirrhosis who developed Kikuchi-Fujimoto's disease (KFD) and de novo minor features of systemic lupus erythematosus (SLE). This is the first report of a patient with histologically confirmed AIH developing KFD (histiocytic necrotizing lymphadenitis). One previous case described KFD after AIH (diagnosed clinically but without biopsy). KFD is a rare condition of unknown aetiology, first described in 1972, characterized by fever and cervical adenopathy and has a self-limiting course. KFD is associated with SLE, and SLE in turn can be associated with abnormal liver function tests, which in a minority of cases may be due to AIH. The association of AIH, KFD, and SLE in our patient suggests an autoimmune pathogenesis of KFD.

Well-differentiated bronchial neuroendocrine tumors: Clinical management and outcomes in 105 patients.

INTRODUCTION: Bronchial neuroendocrine tumors (NETs) are rare tumors representing approximately 20%-30% of all neuroendocrine tumors and 2%-3% of all adult lung cancers. Here, they present a large case series of well-differentiated bronchial NETs with the aim of investigating the behavior of these tumors and long-term outcomes. METHODS: A retrospective review was performed of 105 patients with bronchial NETs managed in a tertiary referral center in the period between January 1998 and January 2012. RESULTS: Bronchial NETs are commoner in females and the commonest presenting symptoms were cough (13.9%) and dyspnoea (11.6%). OctreoscanTM and Gallium-68 DOTATATE PET were found to have similar diagnostic sensitivity and FDG PET was more sensitive for higher-grade tumors. Over a median follow-up period of 35.5 months mortality rate was 5.7%. The 5-year survival was 76% and the 10-year survival was 62%. Female patients survived longer but this difference was not statistically significant (P = .59). Older age greater than 50 years (P = .027), higher levels of Chromogranin A (CgA) (P = .034), first-line treatment with surgery (P = .005), ki67 over 10% (P = .037), and tumor stage (P = .036) but not tumor grade (P = .22), were significantly associated with survival. DISCUSSION: Several factors have been identified which are independently associated with survival including CgA levels greater than 100 pmol/L, tumor stage, age greater than 50, ki67 over 10% and having surgery as first-line treatment. There was no difference in survival between typical and atypical carcinoids.

Repeated courses of transarterial embolization with polyvinyl alcohol particles: 'long life elixir' in a cirrhotic patient with unresectable hepatocellular carcinoma.

Chemoembolization improves survival in selected cirrhotic patients with hepatocellular carcinoma, but prolonged survival is unusual. In this study, a 70-year-old cirrhotic patient, who had a histologically proven hepatocellular carcinoma of 5 cm diameter, embolization with polyvinyl alcohol particles alone, without chemotherapeutic agent, has resulted in continued survival, of 5 years to date, with virtual elimination of residual hypervascularity following 10 sessions of embolization, and with continued patency of the injected branch of the hepatic artery. Provided liver function is maintained, embolization alone appears a feasible long term and effective therapy for unresectable hepatocellular carcinoma.

Treatment outcomes for hepatocellular carcinoma using chemoembolization in combination with other therapies.

BACKGROUND: Although transarterial chemoembolization (TACE) improves survival in patients with hepatocellular carcinoma (HCC), it is not known if TACE combined with other treatments is beneficial. AIM: To evaluate the evidence for improved outcomes in HCC with a multimodal treatment approach involving TACE. METHOD: PubMed search for all cohort and randomized trials (n=84) evaluating TACE combined with other therapies; meta-analysis performed where appropriate. RESULTS: A meta-analysis involving 4 RCTs showed a significant decrease in mortality favouring combination treatment (TACE plus percutaneous ablation) compared to monotherapy in patients with either small (<3cm) or large HCC nodules (>3cm) (OR, 0.534; 95% CI, 0.288-0.990; p=0.046). TACE combined with local radiotherapy improved survival in patients with tumour thrombosis of the portal vein in 7 non-randomized studies. Two RCTs and 13 non-randomized studies showed that TACE prior to hepatic resection does not improve survival nor tumour recurrence. Conversely, 2 RCTs and 5 comparative studies showed that transarterial injection of chemotherapeutic drugs mixed with lipiodol (TOCE) following hepatectomy confers survival benefit and less tumour recurrence. TACE before liver transplantation is safe and reduces drop-out rate from the waiting list, but there is no current evidence of improvement in subsequent survival or recurrence rate. CONCLUSIONS: A combined approach involving TACE and percutaneous ablation improves survival. Adjuvant TOCE improves outcome after hepatectomy. TACE is useful to control tumours burden while on the waiting list for OLT. Multimodal treatment seems to be the best way to optimize TACE outcomes in HCC.

Severe venoocclusive disease after liver transplantation treated with transjugular intrahepatic portosystemic shunt.

Venoocclusive disease (VOD) is due to hepatic sinusoidal lining injury leading to portal hypertension; its incidence after liver transplantation is about 2%. When severe, it does not respond to medical therapy and has a high mortality; retransplantation is the only therapeutic option. However, there are no detailed data regarding the use of transjugular intrahepatic portosystemic shunt for VOD after liver transplantation. We describe two patients who developed severe VOD after liver transplantation, failed defibrotide therapy, and were treated by transjugular intrahepatic portosystemic shunt (TIPS). The portal hypertension resolved completely and one had full histological recovery. We believe that TIPS should be attempted as it may resolve progressive portal hypertension and the hepatic congestion, while allowing the clinician time for listing for further liver transplantation if the patient fails to respond.

A systematic review of the quality of liver biopsy specimens.

Characteristics for an optimal liver biopsy specimen were recently defined as 20 to 25 mm long and/or containing more than 11 complete portal tracts (CPTs). A systematic review of percutaneous liver biopsy (PLB) and transjugular liver biopsy (TJLB) series yielded only 32 PLB studies in which these characteristics were evaluated: mean +/- SD length, 17.7 +/- 5.8 mm and number of CPTs, 7.5 +/- 3.4; and 15 TJLB studies: mean +/- SD length, 13.5 +/- 4.5 mm and number of CPTs, 6.8 +/- 2.3. Studies of sampling heterogeneity and intraobserver and interobserver variability also used inadequate specimens by present standards. Only 11 (5.3%) of 207 therapeutic studies for chronic hepatitis B and C documented length and/or number of CPTs. Of the current 12 studies evaluating noninvasive fibrosis tests, only 8 documented length or number of CPTs, and only 1 documented length and number of CPTs. New studies are needed based on adequate liver biopsy samples to provide reliable estimation of grading and staging in chronic liver disease.

A pilot study comparing ESO-2 capsule endoscopy with conventional upper endoscopy for the assessment of uncomplicated heartburn and dyspepsia.

BACKGROUND: ESO-2 video capsule endoscopy provides images of the oesophageal mucosa and continues to transmit gastric, and often small bowel images, for up to 30 min. This study compares ESO capsule endoscopy capsule oesophago-gastro-duodenoscopy (Cap-OGD) with conventional endoscopy (OGD). METHODS: 50 outpatients with uncomplicated dyspepsia underwent Cap-OGD followed by OGD which was recorded on DVD. Cap-OGD and OGD were each reported independently by two gastroenterologists. A benchmark report was also produced by two gastroenterologists viewing both Cap-OGD and OGD on side-by-side monitors. Major findings included large hiatus hernia, Barrett's oesophagus, oesophagitis, erosive gastritis, tumour and ulceration. Minor findings included histologically-proven superficial gastritis, pouting gastric folds and fundic gland polyps. A questionnaire assessed the patient experience. RESULTS: 49 patients completed the study. In 61%, Cap-OGD transmitted in the duodenum. In the benchmark study, all the major OGD findings were observed on Cap-OGD. Cap-OGD revealed fewer minor findings. When reported independently, Cap-OGD and OGD reports indicated differences in interpretation most marked between the capsule readers with or without previous ESO-2 experience. Patients expressed a clear preference for Cap-OGD. CONCLUSIONS: When compared side-by-side, all the major findings on OGD are seen on Cap-OGD while there is under-reporting of minor findings. Previous experience of ESO-2 capsule reporting improves reading accuracy and indicates the need for training. This pilot study provides a backdrop to explore the possible role of Cap-OGD, especially where patients are reluctant to undergo conventional OGD or where there is risk of prion contamination of the endoscope.

The relationship between transient elastography and histological collagen proportionate area for assessing fibrosis in chronic viral hepatitis.

BACKGROUND: Collagen proportionate area (CPA) has a better correlation with hepatic venous pressure gradient (HVPG) than with Ishak stage. Liver stiffness measurement (LSM) is proposed as non invasive marker of portal hypertension/disease progression. Our aim was to compare LSM and CPA with Ishak staging in chronic viral hepatitis, and HVPG in HCV hepatitis after transplantation. METHODS: One hundred and sixty-nine consecutive patients with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infections pre/post liver transplantation (LT), had a liver biopsy combined with LSM (transient elastography), CPA (biopsies stained with Sirius Red and evaluated by digital image analysis and expressed as CPA) and HVPG (measured contemporaneously with transjugular biopsies in LT HCV patients). RESULTS: LSM was dependent on CPA in HBV (r (2) = 0.61, p < 0.0001), HCV (r (2) = 0.59, p < 0.0001) and LT groups (r (2) = 0.64, p < 0.0001). In all three groups, CPA and Ishak were predictors of LSM, but multivariately CPA was better related to LSM (HBV: r (2) = 0.61, p < 0.0001; HCV: r (2) = 0.59, p < 0.0001; post-LT: r (2) = 0.68, p < 0.0001) than Ishak stage. In the LT group, multiple regression analysis including HVPG, LSM, aspartate aminotransferase to platelet ratio index (APRI) and Ishak stage/grade, showed that only CPA was related to HVPG (r (2) = 0.41, p = 0.01), both for HVPG ≥6 mmHg (OR 1.34, 95 % CI 1.14-1.58; p < 0.0001) or ≥10 mmHg (OR 1.25, 95 % CI 1.06-1.47; p = 0.007). CONCLUSION: CPA was related to LSM in HBV or HCV hepatitis pre/post-LT. CPA was better related to LSM than Ishak stage. In the LT HCV group, CPA was better related to HVPG than Ishak stage/grade, LSM or APRI. CPA may represent a better comparative histological index for LSM, rather than histological stages.

Treatment of hepatocellular carcinoma (HCC) by intra-arterial infusion of radio-emitter compounds: trans-arterial radio-embolisation of HCC.

Traditional radiotherapy is only effective in treating hepatocellular cancer (HCC) in doses above 50 Gy, but this is above the recommended liver radiation exposure of about 35 Gy, which is an important limitation making this treatment unsuitable for routine clinical practice. Trans-arterial radio-embolisation (TARE), consists of delivery of compounds linked to radio-emitter particles which end up in hepatic end-arterioles or show affinity for the neoplasm itself, allowing localised delivery of doses beyond 120 Gy. These are well tolerated in patients treated with this type of internal radiation therapy. TARE for HCC is used for palliative treatment of advanced disease which cannot be treated in other ways, or for tumour down-staging before liver transplantation, or as adjuvant therapy for surgically resected HCC. Tumour response after TARE is between 25% and 60% if assessed by using RECIST criteria, and 80% by EASL criteria. In this review we outline the advantages and limitations of radio-emitter therapy including 131-I, 90-Y and 188-Re. We include several observational, and all comparative studies using these compounds. In particular we compare TARE to trans-arterial chemo-embolisation and other intra-arterial techniques.

Comparison of cystatin C and creatinine-based glomerular filtration rate formulas with 51Cr-EDTA clearance in patients with cirrhosis.

BACKGROUND AND OBJECTIVES: Renal function is an important predictor of survival in cirrhosis and liver transplantation. GFR estimates using serum cystatin C (CysC) are proposed as better predictors of renal function than ones on the basis of serum creatinine (Cr). Our aims were: (1) evaluate correlations between serum CysC and different methods of creatinine measurements; (2) compare CysC and Cr GFR formulas with (51)Cr-EDTA; and (3) evaluate liver-related parameters potentially influencing GFR. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: 254 blood samples in 65 patients with cirrhosis correlating CysC with four Cr methods were used; another 74 patients comparing (51)Cr-EDTA GFR to Modification of Diet in Renal Disease and Larsson and Hoek formulas for CysC were also included. Agreement was assessed using Bland-Altman plots and concordance correlation coefficients. Multivariate linear regression analysis was used for GFR predictors. RESULTS: Serum CysC correlated modestly with O'Leary modified Jaffe, compensated kinetic Jaffe, enzymatic creatinine, and standard kinetic Jaffe 0.72/0.71/0.72/0.72 (all P < 0.001). Bland-Altman agreement with (51)Cr-EDTA GFR was poor; the best agreement was Modification of Diet in Renal Disease (concordance 0.61; 95% CI, 0.47 to 0.71); the worst agreement was the Hoek formula (concordance 0.46; 95% CI, 0.27 to 0.61). A new GFR formula including the Child-Pugh score improved the accuracy of Cr GFR formulas compared with (51)Cr-EDTA GFR. CONCLUSIONS: Estimated GFR in cirrhosis is not better with CysC formulas compared with creatinine ones: specific formulas may be necessary.

Terlipressin therapy for renal failure in cirrhosis.

OBJECTIVES: Renal failure is common in cirrhosis frequently due to hepatorenal syndrome (HRS). Terlipressin and albumin improve renal function with a trend to prolong survival in HRS, but prognostic factors with therapy have been poorly studied. METHODS: Forty-five cirrhotics seen consecutively in a single centre with renal failure defined as oliguria/anuria and/or rising creatinine and no response to volume loading, without intrinsic renal disease, sepsis, gastrointestinal bleeding [median Child-Pugh score 12(8-14)/Model for End-Stage Liver Disease 29(10-40)], had intravenous terlipressin and albumin and were audited retrospectively classified into three groups: group 1 HRS type 1 (15), group 2 HRS type 2 (11) and group 3(19): not fulfilling HRS 1 or 2 criteria. Baseline median creatinine was 1.7 (0.9-5.46) mg/dl and 30 (67%) had creatinine greater than 1.5 mg/dl. All 45 patients had initial colloid/albumin and 31 continued terlipressin (2-4 mg/day) for a median 8 (2-76) days. RESULTS: Improvement in serum creatinine occurred in 23 (51%) [(1.3 mg/dl (0.6-3.9)] compared with baseline [1.7 mg/dl (0.92-3.75)] (P<0.001). In the multivariate analysis a greater reduction in creatinine between baseline and day 4 (95% confidence interval, odds ratio: 0.25) was associated with improved survival at 6 weeks. CONCLUSION: Albumin and terlipressin improve renal failure in the absence of sepsis in cirrhosis independently of whether HRS criteria are fulfilled or not. Improvement at 4 days of therapy is associated with better survival. Randomized studies are needed for oliguria and rising creatinine in cirrhotics even if HRS criteria are not fulfilled.

Expression of the HER-1-4 family of receptor tyrosine kinases in neuroendocrine tumours.

The type I receptor tyrosine kinase family comprises four homologous members: Epidermal growth factor receptor (EGFR), HER-2, HER-3 and HER-4. Studies have shown that EGFR and HER-2 play a critical role in oncogenesis. In this study we sought to determine the pattern of expression and the prognostic significance of EGFR, HER-2, HER-3 and HER-4 in a variety of neuroendocrine tumours using immunohistochemistry. HER family receptor expression in 82 paraffin-embedded specimens of neuroendocrine tumours using immunohistochemistry was examined. The pattern and protein expression levels for each receptor were correlated with clinical and pathological parameters. EGFR expression was identified in 86.6% samples, HER-2 was not expressed in any samples, HER-3 was expressed in 8.5% samples and HER-4 was expressed 91.5%. EGFR and HER-4 were co-expressed in 79.3% of cases. HER-3 was correlated with better survival. EGFR was not associated with poor prognosis. This study has demonstrated EGFR, HER-2 and HER-4 expression is not associated with poorer survival. HER-3 expression is correlated with better prognosis. Overexpression of EGFR and HER-4 may offer potential new therapeutic targets.

A comparison of four- versus three-pass transjugular biopsy using a 19-G Tru-Cut needle and a randomized study using a cassette to prevent biopsy fragmentation.

Recently, it has been shown that transjugular liver biopsy (TJLB) with three passes gives comparable specimens to percutaneous liver biopsy (PLB). The aim of this study was to evaluate the adequacy of TJLB using four passes in a consecutive series of patients, and whether using a supportive cassette can prevent fragmentation. One hundred consecutive TJLBs in 92 patients (48 transplanted), always using four passes (19-G Tru-Cut), were compared to three-pass TJLBs. The four-pass TJLB specimens were randomized at a 1:1 ratio of liver cores placed in a cassette versus not. The four-pass TJLBs, compared to three-pass TJLBs, resulted in better specimens for length (>or=25 mm: 50% vs. 35%; p = 0.026) and number of complete portal tracts (CPTs) (>or=11: 40% vs. 26%; p = 0.027), without a higher complication rate. The four-pass TJLB with >or=11 CPTs had a median length of 27 mm, and 57% of them longer than 28 mm contained >or=11 CPTs. Putting the liver biopsy cores into a cassette did not improve the fragmentation rate or adequacy of the specimen (length and number of CPTs) of TJLB. We conclude that at least four passes with TJLB should be performed when liver specimens are needed for grading and staging. Using a supportive cassette did not reduce fragmentation.