Nigel Hacking

Hepatic changes in the failing Fontan circulation

Background: The failing Fontan circulation is associated with hepatic impairment. The nature of this liver injury is poorly defined. Objective: To establish the gross and histological liver changes of patients with Fontan circulation relative to clinical, biochemical and haemodynamic findings. Methods: Patients were retrospectively assessed for extracardiac Fontan conversion between September 2003 and June 2005, according to an established clinical protocol. Twelve patients, mean age 24.6 (range 15.8–43.4) years were identified. The mean duration since the initial Fontan procedure was 14.1 (range 6.9–26.4) years. Results: Zonal enhancement of the liver (4/12) on CT was more common in patients with lower hepatic vein pressures (p = 0.007), and in those with absent cardiac cirrhosis on histological examination (p = 0.033). Gastro-oesophageal varices (4/12) were more common in patients with higher hepatic vein pressure (21 (6.3) vs 12.2 (2.2) mm Hg, p = 0.013) and associated with more advanced cirrhosis (p = 0.037). The extent of cirrhosis (7/12) was positively correlated with the hepatic vein pressure (r = 0.83, p = 0.003). A significant positive correlation was found between the Fontan duration and the degree of hepatic fibrosis (r = 0.75, p = 0.013), as well as presence of broad scars (r = 0.71, p = 0.021). Protein-losing enteropathy (5/12) occurred more frequently in patients with longer Fontan duration (11.7 (3.2) vs 17.9 (6.1) years, p = 0.038). Conclusions: Liver injury, which can be extensive in this patient group, is related to Fontan duration and hepatic vein pressures. CT scan assists non-invasive assessment. Cardiac cirrhosis with the risk of developing gastro-oesophageal varices and regenerative liver nodules, a precursor to hepatocellular carcinoma, is common in this patient group.

Hepatic fibrosis and cirrhosis in the Fontan circulation: a detailed morphological study

Aims: To describe the histological features of the liver in patients with a Fontan circulation. Methods: Specimens from liver biopsies carried out as part of preoperative assessment prior to extracardiac cavopulmonary conversion of an older style Fontan were examined and scored semi-quantitatively for pertinent histological features. To support the use of the scoring, biopsy specimens were also ranked by eye for severity to allow correlation with assigned scores. Results: Liver biopsy specimens from 18 patients with a Fontan circulation were assessed. All specimens showed sinusoidal fibrosis. In 17 cases there was at least fibrous spur formation, with 14 showing bridging fibrosis and 2 showing frank cirrhosis. In 17 cases at least some of the dense or sinusoidal fibrosis was orcein positive, although a larger proportion of the dense fibrous bands were orcein positive compared with the sinusoidal component. All specimens showed marked sinusoidal dilatation, and 14 showed bile ductular proliferation; 1 showed minimal iron deposition, and 1 showed mild lobular lymphocytic inflammation. There was no cholestasis or evidence of hepatocellular damage. Similar appearances were observed in 2 patients with severe tricuspid regurgitation. Discussion: The histological features of the liver in patients with a Fontan circulation are similar to those described in cardiac sclerosis. Sinusoidal dilatation and sinusoidal fibrosis are marked in the Fontan series. The presence of a significant amount of orcein negative sinusoidal fibrosis suggests there may be a remediable component, although the dense fibrous bands are predominantly orcein positive, suggesting chronicity and permanence. No inflammation or hepatocellular damage is evident, suggesting that fibrosis may be mediated by a non-inflammatory mechanism.

Arterialised hepatic nodules in the Fontan circulation: hepatico-cardiac interactions.

Hypervascular nodules occur commonly when there is hepatic venous outlet obstruction. Their nature and determinants in the Fontan circulation is poorly understood. We reviewed the records of 27 consecutive Fontan patients who had computerized tomography scan (CT) over a 4 year period for arterialised nodules and alterations in hepatic flow patterns during contrast enhanced CT scans and related these findings to cardiac characteristics. Mean patient age was 24 ± 5.8 years, (range 16.7-39.8) and mean Fontan duration was 16.8 ± 4.8 years (range 7.3-28.7). Twenty-two patients demonstrated a reticular pattern of enhancement, 4 a zonal pattern and only 1 demonstrated normal enhancement pattern. Seven (26%) patients had a median of 4 (range 1-22) arterialised nodules, mean size 1.8 cm (range 0.5 to 3.2 cm). All nodules were located in the liver periphery, their outer aspect lying within 2 cm of the liver margin. Patients with nodules had higher mean RA pressures (18 mmHg ± 5.6 vs. 13 mmHg ± 4, p=0.025), whereas their mixed venous saturation and aortic saturation was not significantly different (70% ± 11 vs. 67% ± 9 and 92% ± 10 vs. 94% ± 4, p>0.05). Post-mortem histology suggests focal nodular hyperplasia is the underlying pathology. ConclusionsAbnormalities of hepatic blood flow and the presence of arterialised nodules are common in the failing Fontan circulation. They occur especially when central venous pressures are high, and very likely indicate arterialisation of hepatic blood flow and reciprocal portal venous deprivation. The underlying pathology is most likely focal nodular hyperplasia.

Sorafenib in combination with transarterial chemoembolisation in patients with unresectable hepatocellular carcinoma (TACE 2): a randomised placebo-controlled, double-blind, phase 3 trial.

BACKGROUND Transarterial chemoembolisation (TACE) is the standard of care for patients with intermediate stage hepatocellular carcinoma, while the multikinase inhibitor sorafenib improves survival in patients with advanced disease. We aimed to determine whether TACE with sorafenib improves progression-free survival versus TACE with placebo. METHODS We did a multicentre, randomised, placebo-controlled, phase 3 trial (TACE 2) in 20 hospitals in the UK for patients with unresectable, liver-confined hepatocellular carcinoma. Patients were eligible if they were at least aged 18 years, had Eastern Cooperative Oncology Group performance status of 1 or less, and had Child-Pugh A liver disease. Patients were randomised 1:1 by computerised minimisation algorithm to continuous oral sorafenib (400 mg twice-daily) or matching placebo combined with TACE using drug-eluting beads (DEB-TACE), which was given via the hepatic artery 2-5 weeks after randomisation and according to radiological response and patient tolerance thereafter. Patients were stratified according to randomising centre and serum α-fetoprotein concentration (<400 ng/mL and ≥400 ng/mL). Only the trial coordinator was unmasked to treatment allocation before patient progression during the study. The primary endpoint was progression-free survival defined as the interval between randomisation and progression according to Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1) or death due to any cause, and was analysed by intention-to-treat. Safety was analysed by intention-to-treat. The trial has been completed and the final results are reported. The trial is registered at EudraCT, number 2008-005073-36, and ISRCTN, number ISRCTN93375053. FINDINGS Between Nov 4, 2010, and Dec 7, 2015, the trial enrolled 399 patients and was terminated after a planned interim futility analysis. 86 patients failed screening and 313 remaining patients were randomly assigned: 157 to sorafenib and 156 to placebo. The median daily dose was 660 mg (IQR 389·2-800·0) sorafenib versus 800 mg (758·2-800·0) placebo, and median duration of therapy was 120·0 days (IQR 43·0-266·0) for sorafenib versus 162·0 days (70·0-323·5) for placebo. There was no evidence of difference in progression-free survival between the sorafenib group and the placebo group (hazard ratio [HR] 0·99 [95% CI 0·77-1·27], p=0·94); median progression-free survival was 238·0 days (95% CI 221·0-281·0) in the sorafenib group and 235·0 days (209·0-322·0) in the placebo group. The most common grade 3-4 adverse events were fatigue (29 [18%] of 157 patients in the sorafenib group vs 21 [13%] of 156 patients in the placebo group), abdominal pain (20 [13%] vs 12 [8%]), diarrhoea (16 [10%] vs four [3%]), gastrointestinal disorders (18 [11%] vs 12 [8%]), and hand-foot skin reaction (12 [8%] and none). At least one serious adverse event was reported in 65 (41%) of 157 patients in the sorafenib group and 50 (32%) of 156 in the placebo group, and 181 serious adverse events were reported in total, 95 (52%) in the sorafenib group and 86 (48%) in the placebo group. Three deaths occurred in each group that were attributed to DEB-TACE. Four deaths were attributed to study drug; three in the sorafenib group and one in the placebo group. INTERPRETATION The addition of sorafenib to DEB-TACE does not improve progression-free survival in European patients with hepatocellular carcinoma. Alternative systemic therapies need to be assessed in combination with TACE to improve patient outcomes. FUNDING Bayer PLC and BTG PLC.

Prostate artery embolization (PAE) for benign prostatic hyperplasia (BPH)

Introduction Prostate artery embolization (PAE) for LUTS is a potential minimally invasive alternative treatment for BPH [1–4]. The first step for PAE is a clinical assessment of the urinary symptoms by a urologist [5]. Men with confirmed BOO, who have either failed to respond adequately to medical therapy or have experienced intolerable side-effects can consider entering trials of PAE as an alternative to proceeding to surgical treatment.

TACE 2: A randomized placebo-controlled, double-blinded, phase III trial evaluating sorafenib in combination with transarterial chemoembolisation (TACE) in patients with unresectable hepatocellular carcinoma (HCC)—Background.

1 UCL Cancer Institute, University College London, UK 2 Royal Free London NHS Foundation Trust, London, UK 3 Cancer Research UK Clinical Trials Unit (CRCTU), University of Birmingham, UK 4 Queen Elizabeth Hospital Birmingham, UK 5 Guys Hospital, London, UK 6 University of Nottingham, Nottingham, UK 7 Aintree University Hospital, Liverpool, UK 8 Newcastle Clinical Trials Unit, Newcastle, UK 9 Western General Hospital, Edinburgh, UK 10 The Royal Devon and Exeter Hospital, Exeter, UK 11 Southampton University Hospitals NHS Trust, Southampton, UK 12 ,University of Glasgow, Glasgow UK 13 Bristol Royal Infirmary, Bristol, UK 14 Christie Hospital NHS Foundation Trust, Manchester, UK 15 The Royal Marsden NHS Foundation Trust, Sutton and London Hospital, Surrey,

Direct measurement of porto-systemic gradient in a failing Fontan circulation.

We describe the case history of a 42-year-old man with cardiac cirrhosis, portal hypertension, and life-threatening variceal bleeding after Fontan revision surgery. Direct pressure measurements in the portal vein, though high, demonstrated only a modest portosystemic gradient (PSG), 9 mm Hg. A transjugular intrahepatic portosystemic shunt procedure was performed. This reduced the PSG (3 mm Hg). His bleeding was controlled. The patients histopathological findings were identical to that previously documented in Fontan patients, raising the question of whether these subdiaphragmatic hemodynamics are representative of the broader failing Fontan population.

Transarterial Embolization and Doxorubicin Eluting Beads- Transarterial Chemoembolization (DEB-TACE) of Malignant Extra-Adrenal Pheochromocytoma

Extra-adrenal pheochromocytomas (EAPs) are neuroendocrine tumors that arise from paraganglion cells of the sympathetic component of the autonomic nervous system. The paraganglia are chromaffin tissue complexes that extend along the paravertebral axis [1]. As part of the autonomic nervous system, these paraganglia are the dominant source of catecholamine production during early childhood [2]. Failure of involution of these paraganglia leads to the development of extra-adrenal pheochromocytomas. The majority of intra-abdominal paragangliomas present at the organ of Zuckerkandl (to the left of the aorta near the inferior mesenteric artery takeoff). Tumors below the diaphragm are typically functional with symptoms relating to excess catecholamine secretion. Generally, patients report nonspecific symptoms, such as headaches, sweating, palpitation, anxiety, and tremors. Biochemical workup demonstrates elevated levels of plasma and urinary catecholamines and their metabolites. Provided there is no contraindication, a contrastenhanced CT should be the initial imaging modality because it is readily available and highly sensitive. Scintigraphy with I-labelled metaiodobenzylguanidine (I-MIBG) is the most common functional study used. The treatment traditionally consists of open or laparoscopic exploration and resection with preoperative a and b blockade [3]. It is now known that EAPs demonstrate potential malignant change in up to 50% of patients, far greater than the 10% reported for pheochromocytomas [4]. Because there are no pathognomonic histological findings that distinguish benignity from malignancy, the diagnosis of malignant transformation is made on the basis of the development of recurrence or metastases and presence of lymph nodes.

Prostate artery embolization: a new, minimally invasive treatment for lower urinary tract symptoms secondary to prostate enlargement:

Prostate artery embolization (PAE) is emerging as a safe and efficacious treatment which approaches benign prostatic obstruction (BPO) from a unique perspective. This brings with it distinct advantages and solutions, which we discuss along with cost, evidence, complications and disadvantages.

Trans-jugular intrahepatic porto-systemic shunt placement for refractory ascites: a ‘real-world’ UK health economic evaluation

Objective To assess the benefit of trans-jugular intrahepatic porto-systemic shunt (TIPS) placement for refractory ascites. Design A retrospective observational study of all patients undergoing TIPS for refractory ascites in our hospital between 2003 and 2012. Setting Secondary care. Patients Cirrhotic patients with refractory ascites. Main outcome measures We examined direct real-world (National Health Service) health related costs in the year before and after the TIPS procedure took place. Data were collected relating to the need for reintervention and hepatic encephalopathy. Results Data were available for 24 patients who underwent TIPS for refractory ascites (86% of eligible patients). TIPS was technically successful in all cases. Mean number of bed days in the year prior to TIPS was 30.3 and 14.3 in the year following (p=0.005). No patient had ascites at the end of the year after the TIPS with less requirement for paracentesis over the course of the year (p<0.001). Mean reduction in cost was £2759 per patient. TIPS was especially cost-effective in patients requiring between 6 and 12 drains per year with a mean saving of £9204 per patient. Conclusions TIPS is both a clinically effective and economically advantageous therapeutic option for selected patients with refractory ascites.