James O'Beirne

Assessment of Liver Function in Patients With Hepatocellular Carcinoma: A New Evidence-Based Approach—The ALBI Grade

PURPOSE Most patients with hepatocellular carcinoma (HCC) have associated chronic liver disease, the severity of which is currently assessed by the Child-Pugh (C-P) grade. In this international collaboration, we identify objective measures of liver function/dysfunction that independently influence survival in patients with HCC and then combine these into a model that could be compared with the conventional C-P grade. PATIENTS AND METHODS We developed a simple model to assess liver function, based on 1,313 patients with HCC of all stages from Japan, that involved only serum bilirubin and albumin levels. We then tested the model using similar cohorts from other geographical regions (n = 5,097) and other clinical situations (patients undergoing resection [n = 525] or sorafenib treatment for advanced HCC [n = 1,132]). The specificity of the model for liver (dys)function was tested in patients with chronic liver disease but without HCC (n = 501). RESULTS The model, the Albumin-Bilirubin (ALBI) grade, performed at least as well as the C-P grade in all geographic regions. The majority of patients with HCC had C-P grade A disease at presentation, and within this C-P grade, ALBI revealed two classes with clearly different prognoses. Its utility in patients with chronic liver disease alone supported the contention that the ALBI grade was indeed an index of liver (dys)function. CONCLUSION The ALBI grade offers a simple, evidence-based, objective, and discriminatory method of assessing liver function in HCC that has been extensively tested in an international setting. This new model eliminates the need for subjective variables such as ascites and encephalopathy, a requirement in the conventional C-P grade.

Cytomegalovirus glycoprotein-B vaccine with MF59 adjuvant in transplant recipients: a phase 2 randomised placebo-controlled trial

Summary Background Cytomegalovirus end-organ disease can be prevented by giving ganciclovir when viraemia is detected in allograft recipients. Values of viral load correlate with development of end-organ disease and are moderated by pre-existing natural immunity. Our aim was to determine whether vaccine-induced immunity could do likewise. Methods We undertook a phase-2 randomised placebo controlled trial in adults awaiting kidney or liver transplantation at the Royal Free Hospital, London, UK. Exclusion criteria were pregnancy, receipt of blood products (except albumin) in the previous 3 months, and simultaneous multiorgan transplantation. 70 patients seronegative and 70 seropositive for cytomegalovirus were randomly assigned from a scratch-off randomisation code in a 1:1 ratio to receive either cytomegalovirus glycoprotein-B vaccine with MF59 adjuvant or placebo, each given at baseline, 1 month and 6 months later. If a patient was transplanted, no further vaccinations were given and serial blood samples were tested for cytomegalovirus DNA by real-time quantitative PCR (rtqPCR). Any patient with one blood sample containing more than 3000 cytomegalovirus genomes per mL received ganciclovir until two consecutive undetectable cytomegalovirus DNA measurements. Safety and immunogenicity were coprimary endpoints and were assessed by intention to treat in patients who received at least one dose of vaccine or placebo. This trial is registered with ClinicalTrials.gov, NCT00299260. Findings 67 patients received vaccine and 73 placebo, all of whom were evaluable. Glycoprotein-B antibody titres were significantly increased in both seronegative (geometric mean titre 12 537 (95% CI 6593–23 840) versus 86 (63–118) in recipients of placebo recipients; p<0·0001) and seropositive (118 395; 64 503–217 272) versus 24 682 (17 909–34 017); p<0·0001) recipients of vaccine. In those who developed viraemia after transplantation, glycoprotein-B antibody titres correlated inversely with duration of viraemia (p=0·0022). In the seronegative patients with seropositive donors, the duration of viraemia (p=0·0480) and number of days of ganciclovir treatment (p=0·0287) were reduced in vaccine recipients. Interpretation Although cytomegalovirus disease occurs in the context of suppressed cell-mediated immunity post-transplantation, humoral immunity has a role in reduction of cytomegalovirus viraemia. Vaccines containing cytomegalovirus glycoprotein B merit further assessment in transplant recipients. Funding National Institute of Allergy and Infectious Diseases, Grant R01AI051355 and Wellcome Trust, Grant 078332. Sponsor: University College London (UCL).

Computer‐assisted image analysis of liver collagen: Relationship to Ishak scoring and hepatic venous pressure gradient

Histopathological scoring of disease stage uses descriptive categories without measuring the amount of fibrosis. Collagen, the major component of fibrous tissue, can be quantified by computer‐assisted digital image analysis (DIA) using histological sections. We determined relationships between DIA, Ishak stage, and hepatic venous pressure gradient (HVPG) reflecting severity of fibrosis. One hundred fifteen patients with hepatitis C virus (HCV) who had undergone transplantation had 250 consecutive transjugular liver biopsies combined with HVPG (median length, 22 mm; median total portal tracts, 12), evaluated using the Ishak system and stained with Sirus red for DIA. Liver collagen was expressed as collagen proportionate area (CPA). Median CPA was 6% (0.2‐45), correlating with Ishak stage (stage 6 range, 13%‐45%), and with HVPG (r = 0.62; P < 0.001). Median CPA was 4.1% when HVPG was less than 6 mm Hg and 13.8% when HVPG was 6 mm Hg or more (P < 0.0001) and 6% when HVPG was less than 10 mm Hg and 17.3% when HVPG was 10 mm Hg or higher (P < 0.0001). Only CPA, not Ishak stage/grade, was independently associated by logistic regression, with HVPG of 6 mm Hg or more [odds ratio, 1.206; 95% confidence interval (CI), 1.094‐1.331; P < 0.001], or HVPG of 10 mm Hg or more (odds ratio, 1.105; 95% CI, 1.026‐1.191; P = 0.009). CPA increased by 50% (3.6%) compared with 20% in HVPG (1 mm Hg) in 38 patients with repeated biopsies. Conclusion: CPA assessed by DIA correlated with Ishak stage scores and HVPG measured contemporaneously. CPA was a better histological correlate with HVPG than Ishak stage, had a greater numerical change when HVPG was low, and resulted in further quantitation of fibrosis in cirrhosis. (HEPATOLOGY 2009.)

Significant small-bowel lesions detected by alternative diagnostic modalities after negative capsule endoscopy

BACKGROUND Capsule endoscopy (CE) is considered a first-line investigation for obscure GI bleeding (OGIB) and small-bowel polyp or tumor detection. The reliability of a negative CE in excluding gross small-bowel pathology remains unclear. New imaging modalities, such as double-balloon enteroscopy (DBE), CT enterography (CTE) or magnetic resonance enterography (MRE) now provide complementary roles to CE for these indications. OBJECTIVE We describe our experience of significant small-bowel pathology missed at CE in 5 patients. The lesions were subsequently detected by DBE, CTE, or MRE. DESIGN A retrospective case series. SETTING Single-center academic endoscopy unit in a tertiary-referral hospital. PATIENTS Five patients were evaluated: 4 with a history of OGIB (transfusion dependent in 2) and 1 patient with Peutz-Jeghers syndrome (PJS) under small-bowel surveillance. INTERVENTIONS CE was performed in all patients. Further evaluation via DBE, CTE, or MRE was performed. Definitive treatment was carried out by enteroscopic polypectomy (1 patient), surgical resection (2 patients), and transjugular intrahepatic portosystemic shunt procedure and embolization (1 patient). MAIN OUTCOME MEASUREMENTS Detection of significant small-bowel pathology by using DBE, CT, or MRE after a negative capsule study. RESULTS Significant small-bowel pathology was missed at CE but was detected by alternative modalities in 5 patients. In 4 patients, the lesions were in the proximal small bowel (adenocarcinoma, malignant melanoma, varices, and stromal tumor). The fifth patient had a large PJS polyp in the proximal ileum. LIMITATIONS Retrospective case series with small numbers. CONCLUSIONS Gross pathology may be missed at CE, especially in the proximal small bowel, and a negative CE study does not exclude significant disease. Alternative imaging modalities, such as DBE, CTE, or MRE, should be considered when clinical suspicion persists.

A self-expanding metal stent for complicated variceal hemorrhage: experience at a single center

BACKGROUND Refractory variceal bleeding is associated with a high mortality. Existing salvage techniques such as transjugular intrahepatic portosystemic shunt (TIPS) and balloon tamponade (BT) have important limitations and may not be appropriate for all patients. OBJECTIVE To evaluate the safety and efficacy of a novel removable self-expanding metal stent in the management of refractory variceal bleeding. DESIGN Case series. SETTING Tertiary referral liver center. PATIENTS Ten patients with variceal hemorrhage with contraindications to TIPS insertion or BT. INTERVENTIONS Insertion of a self-expanding metal stent (SX-Ella DANIS stent). MAIN OUTCOME MEASURES Survival, failure to control bleeding, and complications. RESULTS Stent insertion was successful in 9 of 10 patients. Failure to control bleeding was observed in 3 patients (2 with gastric varices), with control of bleeding in the remainder. Overall survival at 42 days was 50%. Six patients survived the acute bleeding episode and had stents removed endoscopically at a median of 9 days after insertion. One patient had a minor ulceration of the esophagus caused by stent insertion. CONCLUSIONS Insertion of the SX-Ella DANIS stent in patients with refractory variceal bleeding or complications of previous therapy is effective for the control of bleeding. Stent insertion can be achieved in the majority of patients without fluoroscopic control and without major complications. In selected patients, SX-Ella DANIS stent insertion offers an alternative to other methods of salvage such as BT and TIPS and could be considered a substitute for BT after a prospective trial.

Systemic therapy for hepatocellular carcinoma: cytotoxic chemotherapy, targeted therapy and immunotherapy.

Conventional cytotoxic chemotherapy has not provided clinical benefit or prolonged survival for patients with advanced HCC. This review summarizes the results of prospective clinical trials of several categories of systemic therapy, with emphasis on the more promising results from recent trials of biologically targeted therapeutic agents in HCC.

A simple prognostic scoring system for patients receiving transarterial embolisation for hepatocellular cancer

Background The prognosis for patients with hepatocellular cancer (HCC) undergoing transarterial therapy (TACE/TAE) is variable. Methods We carried out Cox regression analysis of prognostic factors using a training dataset of 114 patients treated with TACE/TAE. A simple prognostic score (PS) was developed, validated using an independent dataset of 167 patients and compared with Child–Pugh, CLIP, Okuda, Barcelona Clinic Liver Cancer (BCLC) and MELD. Results Low albumin, high bilirubin or α-fetoprotein (AFP) and large tumour size were associated with a two- to threefold increase in the risk of death. Patients were assigned one point if albumin <36 g/dl, bilirubin >17 μmol/l, AFP >400 ng/ml or size of dominant tumour >7 cm. The Hepatoma arterial-embolisation prognostic (HAP) score was calculated by summing these points. Patients were divided into four risk groups based on their HAP scores; HAP A, B, C and D (scores 0, 1, 2 and >2, respectively). The median survival for the groups A, B, C and D was 27.6, 18.5, 9.0 and 3.6 months, respectively. The HAP score validated well with the independent dataset and performed better than other scoring systems in differentiating high- and low-risk groups. Conclusions The HAP score predicts outcomes in patients with HCC undergoing TACE/TAE and may help guide treatment selection, allow stratification in clinical trials and facilitate meaningful comparisons across reported series.

Cytomegalovirus Replication Kinetics in Solid Organ Transplant Recipients Managed by Preemptive Therapy

After allotransplantation, cytomegalovirus (CMV) may be transmitted from the donor organ, giving rise to primary infection in a CMV negative recipient or reinfection in one who is CMV positive. In addition, latent CMV may reactivate in a CMV positive recipient. In this study, serial blood samples from 689 kidney or liver transplant recipients were tested for CMV DNA by quantitative PCR. CMV was managed using preemptive antiviral therapy and no patient received antiviral prophylaxis. Dynamic and quantitative measures of viremia and treatment were assessed. Median peak viral load, duration of viremia and duration of treatment were highest during primary infection, followed by reinfection then reactivation. In patients who experienced a second episode of viremia, the viral replication rate was significantly slower than in the first episode. Our data provide a clear demonstration of the immune control of CMV in immunosuppressed patients and emphasize the effectiveness of the preemptive approach for prevention of CMV syndrome and end organ disease. Overall, our findings provide quantitative biomarkers which can be used in pharmacodynamic assessments of the ability of novel CMV vaccines or antiviral drugs to reduce or even interrupt such transmission.

Prognostic models in cirrhotics admitted to intensive care units better predict outcome when assessed at 48 h after admission

Background and Aim:  The accuracy of prognostic models in critically ill cirrhotics at admission to intensive care units (ICU) may be unreliable. Predictive accuracy could be improved by evaluating changes over time, but this has not been published. The aim of the present study was to assess the performance of prognostic models in cirrhotics at admission (baseline) and at 48 h to predict mortality in the ICU or within 6 weeks after discharge from the ICU.

RIFLE classification as predictive factor of mortality in patients with cirrhosis admitted to intensive care unit

Background and Aim:  To evaluate the association of the Risk, Injury, Failure, Loss and End‐stage renal failure (RIFLE) score on mortality in patients with decompensated cirrhosis admitted to intensive care unit (ICU).