Predictors of adequate ultrasound quality for hepatocellular carcinoma surveillance in patients with cirrhosis.

BACKGROUND: Abdominal ultrasound fails to detect over one-fourth of hepatocellular carcinoma (HCC) at an early stage in patients with cirrhosis. Identifying patients in whom ultrasound is of inadequate quality can inform interventions to improve surveillance effectiveness. AIM: To evaluate and identify predictors of ultrasound quality in patients with cirrhosis. METHODS: We performed a retrospective cohort study among patients who underwent ultrasound examination for a cirrhosis-related indication between April 2015 and October 2015. Three fellowship-trained abdominal radiologists collectively reviewed all ultrasound exams and categorised exam quality as definitely adequate, likely adequate, likely inadequate and definitely inadequate to exclude liver lesions. We performed multivariable logistic regression to determine characteristics associated with inadequate ultrasound quality. RESULTS: Among 941 patients, 191 (20.3%) ultrasounds were inadequate for excluding HCC- 134 definitely inadequate and 57 likely inadequate. In multivariable analysis, inadequate quality was associated with male gender (OR 1.68, 95% CI 1.14-2.48), body mass index category (OR 1.67, 95% CI 1.45-1.93), Child-Pugh B or C cirrhosis (OR 1.93, 95% CI 1.32-2.81), alcohol-related cirrhosis (OR 2.11, 95% CI 1.33-3.37), NASH cirrhosis (OR 2.87, 95% CI 1.71-4.80), and in-patient status (OR 1.55, 95% CI 1.01-2.37). Ultrasounds were inadequate in over one-third of patients with Child-Pugh C cirrhosis, BMI >35, or NASH cirrhosis. CONCLUSIONS: One in five ultrasounds in patients with cirrhosis are inadequate for exclusion of HCC, which can contribute to surveillance failure. Alternative surveillance modalities are needed in subgroups prone to inadequate ultrasounds including obese patients, those with Child Pugh B or C cirrhosis, and those with alcohol- or NASH-related cirrhosis.

Clinical and neuroradiological signs in adults with type 1 neurofibromatosis.

INTRODUCTION: Type 1 neurofibromatosis is the most common neurocutaneous syndrome. Most published case series study the paediatric population. MATERIAL AND METHODS: Cross-sectional study of cases of type 1 neurofibromatosis from neurology departments that were recorded in a database. We analysed the different clinical variables providing the diagnosis as well as demographic and neuroradiological variables. RESULTS: We found a total of 31 patients with type 1 neurofibromatosis. The mean age was 28.9 years and 58.4% were women. Subjects with unidentified bright objects (UBOs) were younger than those without them (22.45±8.22 years vs. 32.5±10.64; P=.011). In contrast, subjects with neurofibromas were older than those without them (30.56±10.68 years vs. 18.25±4.34; P=.032). No sex differences were found in the presentation of clinical or radiological variables. Seven patients (22.6%) had tumours; 3 were optic pathway gliomas (1 bilateral), 3 were plexiform neurofibromas, and 1 was a pilocytic astrocytoma in the brainstem. CONCLUSIONS: Patients with type 1 neurofibromatosis presented both peripheral neurofibromas and tumorous lesions of the central nervous system. Subjects with neurofibromas were older than those who did not present them, while subjects with UBOs were younger than those without such lesions.

First interim analysis of the GIDEON (Global Investigation of therapeutic decisions in hepatocellular carcinoma and of its treatment with sorafeNib) non-interventional study.

AIMS: Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib (GIDEON), a global, non-interventional, surveillance study, aims to evaluate the safety of sorafenib in all patients with unresectable hepatocellular carcinoma (uHCC) under real-life practice conditions, particularly Child-Pugh B patients, who were not well represented in clinical trials. METHODS: Treatment decisions are determined by each physician according to local prescribing guidelines and clinical practice. Patients with uHCC who are candidates for systemic therapy, and for whom a decision has been made to treat with sorafenib, are eligible for inclusion. Demographic data and medical and disease history are recorded at entry. Sorafenib dosing and adverse events (AEs) are collected throughout the study. RESULTS: From January 2009 to April 2011, >3000 patients from 39 countries were enrolled. The prespecified first interim analysis was conducted when the initial approximately 500 treated patients had been followed up for ≥4 months; 479 were valid for safety evaluation. Preplanned subgroup analyses indicate differences in patient characteristics, disease aetiology and previous treatments by region. Variation in sorafenib dosing by specialty are also observed; Child-Pugh status did not appear to influence the starting dose of sorafenib. The type and incidence of AEs was consistent with findings from previous clinical studies. AE profiles were comparable between Child-Pugh subgroups. DISCUSSION: The GIDEON study is generating a large, robust database from a broad population of patients with uHCC. First interim analyses have shown global and regional differences in patient characteristics, disease aetiology and practice patterns. Subsequent planned analyses will allow further evaluation of early trends.

The clinical presentation and prognostic factors for intrahepatic and extrahepatic cholangiocarcinoma in a tertiary care centre.

BACKGROUND: The incidence of cholangiocarcinoma is rising. Accurate predictors of survival at diagnosis are not well defined. AIM: To clarify the clinical presentation and prognostic factors of intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma in a contemporary cohort of patients. METHODS: Records for consecutive patients at the University of Michigan hospital diagnosed with cholangiocarcinoma between January 2003 and April 2008 were reviewed. RESULTS: In all, 136 patients had cholangiocarcinoma (79 intra- and 57 extrahepatic cholangiocarcinoma). Median survival was 27.3 months-25.8 months for intrahepatic cholangiocarcinoma and 30.3 months for extrahepatic cholangiocarcinoma. Independent predictors of mortality at presentation on multivariate analysis were elevated bilirubin level (HR 1.04, 95%CI 1.01-1.07), CA 19-9 levels >100 U/mL (HR 1.90, 95%CI 1.17-3.08) and stage of disease (HR 1.51, 95%CI 1.16-1.96). After adjusting for baseline prognostic factors, surgical therapy was associated with improved survival (HR 0.48; 95% CI 0.26-0.88). There were no significant differences regarding clinical presentation, disease stage (P = 0.98), and survival (P = 0.51) between intra- and extrahepatic cholangiocarcinoma. CONCLUSIONS: Survival for cholangiocarcinoma remains poor with no significant difference in outcomes between intra- and extrahepatic cholangiocarcinoma. Stage of disease, bilirubin level and CA 19-9 level are important prognostic factors at presentation. Surgical therapy provides similar efficacy for both tumours when adjusted for other prognostic variables.

Meta-analysis: surveillance with ultrasound for early-stage hepatocellular carcinoma in patients with cirrhosis.

BACKGROUND: A majority of studies investigating the accuracy of ultrasound for detecting hepatocellular carcinoma (HCC) do not reflect how this test is used for surveillance vs. diagnosis. AIM: To determine the performance characteristics of surveillance with ultrasound for the detection of HCC, particularly early HCC as defined by the Milan criteria. METHODS: A systematic literature review using the MEDLINE and SCOPUS databases yielded six studies that evaluated the accuracy of ultrasound for HCC at any stage and 13 studies that were specific to early HCC. RESULTS: Surveillance ultrasound detected the majority of tumours before they presented clinically, with a pooled sensitivity of 94%. However, ultrasound was less effective for detecting early HCC with a sensitivity of 63%. Alpha-fetoprotein provided no additional benefit to ultrasound. Meta-regression analysis demonstrated a significantly higher sensitivity for early HCC with ultrasound every 6 months than with annual surveillance. Current studies have limitations such as verification bias and are of suboptimal quality. CONCLUSIONS: Surveillance with ultrasound demonstrates limited sensitivity for early HCC, although this may be improved by testing at 6-month intervals. Currently available evidence evaluating surveillance ultrasound has significant limitations and future studies are necessary to determine optimal surveillance methods for early HCC.

A novel model measuring the harm of transplanting hepatocellular carcinoma exceeding Milan criteria.

No empirical studies have defined the posttransplant survival that would justify expansion of the Milan criteria for liver transplantation of hepatocellular carcinoma. We created a Markov model comparing the survival benefit of transplantation for a patient with >Milan HCC, versus the harm caused to other patients on the waiting list. In the base-case analysis, the strategy of transplanting the patient with >Milan HCC resulted in a 44% increased risk of death and a utility loss of 3 quality-adjusted years of life across the pre- and posttransplant periods for a nationally representative cohort of patients on the waiting list. This harm outweighed the benefit of transplantation for a patient with >Milan HCC having a 5-year posttransplant survival of less than 61%. This survival threshold was most sensitive to geographic variations in organ shortage, with the threshold varying from 25% (Region 3) to >72% (Regions 1, 5, 7 and 9). In conclusion, expansion of the Milan criteria will require demonstrating high survival rates for the newly eligible patients-approximately 61% at 5 years after transplantation. In regions with less severe organ shortage, a more aggressive approach to transplanting these patients may be justified.

Relationship between diabetes mellitus and adenocarcinoma of the oesophagus and gastric cardia.

BACKGROUND: Obesity is a risk factor for adenocarcinomas of the oesophagus and gastric cardia. Diabetes mellitus might mediate that association. AIM: To estimate the risk of diabetes mellitus on the development of adenocarcinoma of distal oesophagus and gastric cardia beyond that of gastro-oesophageal reflux disease. METHODS: A case-control study was performed using a national administrative database of the Veterans Administration. RESULTS: A total of 311 cases of cancer and 10,154 controls were identified. Gender, age, and race were risks for cancer. Diabetes was diagnosed in 36% of cases, and 32% of controls (P = 0.15). Diabetic complications were diagnosed in 14% of cases and 13% of controls (P = 0.60). Multiple logistic regression confirmed the absence of an association between cancer and diabetes (odds ratio 1.1, 95% confidence interval 0.8-1.5) or diabetic complications (odds ratio 0.8, 95% confidence interval 0.6-1.3), adjusting for age, gender, and race. CONCLUSIONS: Within the limitations of this case-control study, there is no evidence of an association between diabetes and adenocarcinoma of the oesophagus or gastric cardia among US veterans with gastro-oesophageal reflux disease.

Modification of mediators of immune reaction after general anaesthesia.

UNLABELLED: The adverse reactions that may occur during a surgical intervention are of concern to anesthesiologists and allergists due to the civil responsibility they entail and the increased demand for healthcare in allergology units. The aim of the present study was to determine the prevalence of adverse reactions in our setting (Island of Lanzarote) and modifications to immune response mediators using three types of representative myorelaxants (succinylcholine, cisatracurium and vecuronium) in order to predict and prevent adverse reactions. MATERIAL AND METHODS: We performed a prospective, cross sectional, observational study in a population of 201 patients scheduled to undergo surgery in the Surgery Department of the Lanzarote General Hospital from October 1998. Three groups were retrospectively selected: vecuronium (73 patients), cisatracurium (80 patients), and succinylcholine (48 patients). Blood was extracted from all patients before and after the intervention and the following in vitro variables were evaluated: histaminemia, eosinophil cationic protein, tryptase, IgE to latex, CD4/CD8 fractions, total lymphocytes, total IgE, C3 and C4, and also the histaminuria. CONCLUSIONS: The mean age of the patients was 41 years with a predominance of women. Sixty percent had not previously undergone surgery. The mean operating time was 2 hours. Digestive surgery accounted for the greatest number of interventions (38.8 %) and most of the patients had no personal history of atopy (91.5 %). The greatest number of perioperative reactions was produced by cisatracurium (38.8 %), followed by succinylcholine (27.4 %) and vecuronium (20 %). The reactions observed were immediate type 1 and 2 reactions. All reactions were reversible without sequelae. Histaminuria levels were significantly decreased in the cisatracurium group. Histaminemia and eosinophil cationic protein showed no significant changes in any of the three groups. Tryptase concentrations in blood did not increase in the postoperative period in any of the three groups. On the contrary, concentrations were significantly lower than basal values. In the vecuronium and succinylcholine groups, CD4/CD8 fractions decreased in the postoperative period. Total lymphocytes decreased in all three groups. Total IgE tended to decrease in the cisatracurium and succinylcholine groups. IgE to latex was negative in the three groups. Specific IgE to succinylcholine was unmodified. C3 complement fraction was unmodified in all three groups and C4 fraction was reduced in the vecuronium group. In our setting and in our patients, the three myorelaxants produced immunosuppression of immune response mediators. The present study confirms that tests for allergy to myorelaxants are not indicated in the preoperative period.

Hepatocellular carcinoma.

The number of papers published regarding hepatocellular carcinoma between 1999 and 2001 increased from previous years. This year a study confirmed the increase in incidence in the United States. Also, several studies established for the first time that tobacco smoking was a risk factor for the development of this tumor. Several studies established that the process of angiogenesis is critical for the development of hepatocellular carcinoma, and one paper indicated that inhibiting this process might lead to possible treatment of this tumor. Resection was compared with liver transplantation for the first time in two studies. It was shown that transplantation offered the overall best long-term option, but in a certain group of patients without portal hypertension and well-preserved liver function resection is the best option.

Pathogenic Escherichia coli increase Cl- secretion from intestinal epithelia by upregulating galanin-1 receptor expression.

Galanin is widely distributed in enteric nerve terminals lining the human gastrointestinal (GI) tract. We have shown previously that galanin-1 receptors (Gal1-R) are expressed by epithelial cells lining the human GI tract, and upon activation cause Cl- secretion. Because expression of this receptor is transcriptionally regulated by nuclear factor-kappa B (NF-kappa B), which is activated by enteric pathogens as a part of the host epithelial response to infection, we investigated whether such bacterial pathogens could directly increase Gal1-R expression in the T84-cell model system. Pathogenic Escherichia coli, but not nonpathogenic E. coli, activate a p50/p65 NF-kappa B complex that binds to oligonucleotides corresponding to a recognition site located within the 5' flanking region of the human GAL1R gene. Pathogenic E. coli, but not normal commensal organisms, increase Gal1-R mRNA synthesis and [(125)I]galanin binding sites. Whereas galanin increases short-circuit current (Isc) approximately 5-fold in uninfected T84 cells, exposure to pathogenic, but not nonpathogenic, E. coli results in galanin increasing Isc approximately 20-fold. To confirm the validity of these in vitro observations, we also studied C57BL/6J mice infected with enterohemorrhagic E. coli (EHEC) by gavage. Infection caused a progressive increase in both NF-kappa B activation and Gal1-R expression, with maximal levels of both observed 3 days after gavage. Ussing chamber studies revealed that colons infected with EHEC, but not those exposed to normal colonic flora, markedly increased Isc in response to galanin. These data indicate that pathogen-induced increases in Gal1-R expression by epithelial cells lining the colon may represent a novel unifying pathway responsible for at least a portion of the excessive fluid secretion observed during infectious diarrhea.

Electrophysiological characterization of human distal colon epithelium isolated using a novel technique.

Electrophysiological studies of human colonic epithelia traditionally have been hampered by the lack of tissue availability and by poor tissue quality. Human colonic epithelium is usually obtained surgically from individuals with underlying disease, while surgery itself can injure or alter the resected tissue. As a result, a wide range in electrophysiological parameters is reported in previous studies of human colonic epithelium. Such factors may also account for differences in measurements between humans and the few other species studied. We therefore devised a novel and rapid endoscopic technique, endoscopic mucosal resection (EMR), that allows for the removal and study of intestinal mucosal epithelium from normal volunteers. Using EMR we rapidly (7.2+/-2.4 min) isolated surgical-sized epithelial sheets from the distal colon (1.4+/-0.4 by 1.3+/-0.4 cm) that were readily mounted in a 0.64-cm2 Ussing chamber. We observed stable resistance (289+/-30 omega cm2), potential difference (1.6+/-0.6 mV), and I(SC)(24+/-9 microA/cm2) for at least 90 min, after which all experiments were terminated. Exposure to carbachol increased I(SC)2.2+/-0.5-fold, while forskolin increased I(SC) 4.4+/-0.5-fold. These data show that the electrophysiological characteristics of the human distal colon removed by EMR more closely approximate values reported for other mammals than when removed using other techniques. Thus EMR represents a significant advance over traditional techniques for isolating human tissues and will increase the availability of this tissue for future studies.