Fernando Rotellar

De Novo neoplasia after liver transplantation: An analysis of risk factors and influence on survival

Immunosuppression increases the risk of posttransplant malignancy and it may increase posttransplant mortality. The finding of factors related to the development of posttransplant malignancy may serve as a guide to avoid those risk factors and to develop strategies of posttransplant surveillance. The incidence and risk factors of malignancy were studied in 187 consecutive liver transplant recipients surviving more than 3 months. None of the 12 patients surviving less than 3 months had de novo neoplasia. The impact of malignancy on survival was studied in a case‐control study. After a median follow‐up of 65 months, 49 patients developed 63 malignancies: 25 patients had 35 cutaneous neoplasias and 27 patients had 28 noncutaneous malignancies. The 5‐ and 10‐year actuarial rates of cutaneous neoplasia were 14 and 24% and the rates of noncutaneous neoplasia were 11 and 22%, respectively. Risk factors for the development of cutaneous malignancy were older age and Child‐Turcotte‐Pugh A status. Risk factors for the development of noncutaneous malignancy were older age, alcoholism, and smoking. Cutaneous neoplasia had no effect on survival, whereas patients with noncutaneous malignancy had a significant reduction of survival. The overall relative risk of cutaneous and noncutaneous neoplasia, as compared with the general population were 16.91 (95% confidence interval: 11.78‐23.51) and 3.23 (95% confidence interval: 2.15‐4.67), respectively. The relative risk of cancer‐related mortality (after excluding recurrent malignancy) was 2.93 (95% confidence interval: 1.56‐5.02). Multivariate analysis showed that noncutaneous malignancy was an independent risk factor for posttransplant mortality. In conclusion, liver transplant recipients have a higher risk of cancer‐related mortality than the general population. This increased risk is due to the development of noncutaneous neoplasia. Older age, alcoholism, and smoking increase the risk of de novo noncutaneous neoplasia. (Liver Transpl 2005;11:89–97.)

Fasting plasma Ghrelin concentrations 6 months after gastric bypass are not determined by weight loss or changes in insulinemia

Background: Ghrelin is a gastric peptide with potent orexigenic effects. Circulating ghrelin concentrations are increased in obese subjects, but increase after weight loss. However, in patients undergoing Roux-en-Y gastric bypass (RYGBP), a decrease in ghrelin levels has been reported. The effect of comparable weight loss induced by either adjustable gastric banding (AGB), RYGBP or conventional dietary treatment (Conv) on ghrelinemia was studied. Methods: 24 matched obese male patients in whom similar weight loss had been achieved by either AGB (n=8), RYGBP (n=8) or Conv (n=8) were studied before and 6 months after treatment start. The independence of ghrelin concentrations from body mass index (BMI) and weight loss was further analyzed in a group of patients with total gastrectomy (TtGx, n=6). Results: Comparable weight loss after 6 months exerted significantly different effects on plasma ghrelin concentrations, depending on the procedure applied (AGB: 424.6 ± 32.8 pg/ml; RYGBP: 131.4 ± 13.5; Conv: 457.3 ± 18.7; P<0.001). Without significant differences in body weight and BMI, patients who had undergone the RYGBP exhibited a statistically significant decrease in fasting ghrelin concentrations, while the other two procedures (AGB and Conv) showed a weight loss-induced increase in ghrelin levels. Despite significant differences in BMI between RYGBP and TtGx patients after 6 months (31.9 ± 2.2 vs 22.0 ± 0.7 kg/m2, respectively; P<0.05), both groups showed similar ghrelin concentrations. Conclusion: The reduction in circulating ghrelin concentrations in RYGBP patients after 6 months of surgery are not determined by an active weight loss or an improved insulin-sensitivity but rather depend on the surgically-induced bypass of the ghrelin-producing cell population of the fundus.

Body Adiposity and Type 2 Diabetes: Increased Risk With a High Body Fat Percentage Even Having a Normal BMI

Obesity is the major risk factor for the development of prediabetes and type 2 diabetes. BMI is widely used as a surrogate measure of obesity, but underestimates the prevalence of obesity, defined as an excess of body fat. We assessed the presence of impaired glucose tolerance or impaired fasting glucose (both considered together as prediabetes) or type 2 diabetes in relation to the criteria used for the diagnosis of obesity using BMI as compared to body fat percentage (BF%). We performed a cross‐sectional study including 4,828 (587 lean, 1,320 overweight, and 2,921 obese classified according to BMI) white subjects (66% females), aged 18–80 years. BMI, BF% determined by air‐displacement plethysmography (ADP) and conventional blood markers of glucose metabolism and lipid profile were measured. We found a higher than expected number of subjects with prediabetes or type 2 diabetes in the obese category according to BF% when the sample was globally analyzed (P < 0.0001) and in the lean BMI‐classified subjects (P < 0.0001), but not in the overweight or obese‐classified individuals. Importantly, BF% was significantly higher in lean (by BMI) women with prediabetes or type 2 diabetes as compared to those with normoglycemia (NG) (35.5 ± 7.0 vs. 30.3 ± 7.7%, P < 0.0001), whereas no differences were observed for BMI. Similarly, increased BF% was found in lean BMI‐classified men with prediabetes or type 2 diabetes (25.2 ± 9.0 vs. 19.9 ± 8.0%, P = 0.008), exhibiting no differences in BMI or waist circumference. In conclusion, assessing BF% may help to diagnose disturbed glucose tolerance beyond information provided by BMI and waist circumference in particular in male subjects with BMI <25 kg/m2 and over the age of 40.

Liver transplantation in patients with hepatocellular carcinoma across Milan criteria

Milan criteria are the most frequently used limits for liver transplantation (LT) in patients with hepatocellular carcinoma (HCC), but our previous experience with expanded criteria showed encouraging results. The aim of this study was to investigate whether our expanded Clinica Universitaria de Navarra (CUN) criteria (1 nodule up to 6 cm or 2–3 nodules up to 5 cm each) could be used to select patients with HCC for LT. Eighty‐five patients with HCC fulfilling CUN criteria were included as candidates for LT. Survival of transplanted HCC patients was compared with survival of patients without HCC (n = 180). After the exclusion of 2 patients with tumor seeding of the chest wall due to pre‐LT tumor biopsy, survival and recurrence rates were compared according to tumor staging. Twenty‐six out of 85 (30%) patients exceeded Milan criteria. Twelve patients had tumor progression on the waiting list. Patients exceeding Milan criteria had a higher dropout rate due to tumoral progression. One‐, 3‐, 5‐, 7‐, and 10‐year survival rates of the 73 transplanted HCC patients were 86%, 74%, 70%, 61%, and 50%, respectively. Survival of patients with HCC was significantly lower than that of patients without HCC, but by multivariate analysis, HCC was not associated with lower survival. Tumor recurrence and survival rates were similar for patients fulfilling Milan and CUN criteria. Pathological staging showed 55 patients within Milan criteria, 7 patients exceeding them but within CUN criteria, and 9 patients exceeding CUN criteria. Tumor recurrence rates were 2/55 (4%), 0/7 (0%), and 4/9 (44%) in each of these groups, respectively. In conclusion, following CUN criteria could increase the number of HCC patients who could benefit from LT, without worsening the results. Because of the short number of patients in this series, these data need external validation. Liver Transpl 14:272–278, 2008.

Liver Transplant Recipients Older Than 60 Years Have Lower Survival and Higher Incidence of Malignancy

Older age is not considered a contraindication for liver transplantation, but age‐related morbidity may be a cause of mortality. Survival and the incidence of the main post‐transplant complications were assessed in 111 adult liver transplant recipients. They were divided in two groups according to their age (patients younger than 60 years, n=54; patients older than 60 years, n=57) and both groups were compared. Older patients were more frequently transplanted for hepatitis C (p= 0.03) and hepatocellular carcinoma (p= 0.05) and their liver disease was less advanced (Child‐Pugh and MELD scores were significantly lower; p=0.004 and p=0.05, respectively). After transplantation, older patients had a significantly lower survival (p=0.02). Higher age was independently associated with mortality (hazard ratio for each 10‐year increase: 2.1; 95% confidence interval: 1.1‐ 4.0; p=0.02). The incidence of de novo neoplasia and nonskin neoplasia were higher in older patients (p=0.02 and p =0.007, respectively). Malignancy was the cause of death in one patient younger than 60 years and in 12 patients older than 60 years (p =0.002). In multivariate analysis, a higher age and smoking were independently associated with a higher risk of dying of de novo neoplasia. In conclusion, older liver transplant recipients have a significantly lower survival than younger patients. Malignancy is responsible for this decreased survival.

The l-α-Lysophosphatidylinositol/GPR55 System and Its Potential Role in Human Obesity

GPR55 is a putative cannabinoid receptor, and l-α-lysophosphatidylinositol (LPI) is its only known endogenous ligand. We investigated 1) whether GPR55 is expressed in fat and liver; 2) the correlation of both GPR55 and LPI with several metabolic parameters; and 3) the actions of LPI on human adipocytes. We analyzed CB1, CB2, and GPR55 gene expression and circulating LPI levels in two independent cohorts of obese and lean subjects, with both normal or impaired glucose tolerance and type 2 diabetes. Ex vivo experiments were used to measure intracellular calcium and lipid accumulation. GPR55 levels were augmented in the adipose tissue of obese subjects and further so in obese patients with type 2 diabetes when compared with nonobese subjects. Visceral adipose tissue GPR55 correlated positively with weight, BMI, and percent fat mass, particularly in women. Hepatic GPR55 gene expression was similar in obese and type 2 diabetic subjects. Circulating LPI levels were increased in obese patients and correlated with fat percentage and BMI in women. LPI increased the expression of lipogenic genes in visceral adipose tissue explants and intracellular calcium in differentiated visceral adipocytes. These findings indicate that the LPI/GPR55 system is positively associated with obesity in humans.

Clinical Usefulness of a New Equation for Estimating Body Fat

OBJECTIVE To assess the predictive capacity of a recently described equation that we have termed CUN-BAE (Clínica Universidad de Navarra-Body Adiposity Estimator) based on BMI, sex, and age for estimating body fat percentage (BF%) and to study its clinical usefulness. RESEARCH DESIGN AND METHODS We conducted a comparison study of the developed equation with many other anthropometric indices regarding its correlation with actual BF% in a large cohort of 6,510 white subjects from both sexes (67% female) representing a wide range of ages (18–80 years) and adiposity. Additionally, a validation study in a separate cohort (n = 1,149) and a further analysis of the clinical usefulness of this prediction equation regarding its association with cardiometabolic risk factors (n = 634) was carried out. RESULTS The mean BF% in the cohort of 6,510 subjects determined by air displacement plethysmography was 39.9 ± 10.1%, and the mean BF% estimated by the CUN-BAE was 39.3 ± 8.9% (SE of the estimate, 4.66%). In this group, BF% calculated with the CUN-BAE showed the highest correlation with actual BF% (r = 0.89, P < 0.000001) compared with other anthropometric measures or BF% estimators. Similar agreement was found in the validation sample. Moreover, BF% estimated by the CUN-BAE exhibits, in general, better correlations with cardiometabolic risk factors than BMI as well as waist circumference in the subset of 634 subjects. CONCLUSIONS CUN-BAE is an easy-to-apply predictive equation that may be used as a first screening tool in clinical practice. Furthermore, our equation may be a good tool for identifying patients at cardiovascular and type 2 diabetes risk.

Response to radioembolization with yttrium-90 resin microspheres may allow surgical treatment with curative intent and prolonged survival in previously unresectable hepatocellular carcinoma

BACKGROUND Occasionally, patients with hepatocellular carcinoma (HCC) who receive radioembolization with palliative intent are downstaged for radical treatments. The aim of this study was to describe and analyze the overall survival (OS) in these patients compared with patients of the same baseline stage (UNOS T3), who were not eligible for radical treatment after radioembolization. METHODS Between September 2003 and August 2010, 118 patients with HCC received radioembolization with yttrium-90 ((90)Y) resin microspheres. Of these, 21 patients with UNOS T3 stage were retrospectively identified and included in this analysis. RESULTS In total, 6 of 21 patients were downstaged and treated radically between 2 and 35 months post-radioembolization. Three patients were resected, 2 received liver transplantation and 1 was ablated and then resected. Patients treated radically were significantly younger (62 vs. 73 years, p = 0.006) and had higher tumor volume (583 mL vs. 137 mL, p = 0.001) than patients who did not achieve radical treatment. There were no differences between the groups in number of lesions, BCLC stage, previous cirrhosis, activity administered per tumor volume, or median levels of alpha-fetoprotein or total bilirubin. Across the whole series, the median OS was 27.0 months (95% CI 5.0-48.9), varying significantly between those treated radically (OS not reached after a median follow-up of 41.5 months since radical therapy) and those who received palliative treatment only (22.0 months; 95% CI 15.0-30.9). CONCLUSIONS Radical therapy following tumor downstaging with radioembolization provides the possibility of long-term survival in a select subgroup (UNOS T3 stage) with otherwise limited options.

Increased Serum Amyloid A Concentrations in Morbid Obesity Decrease after Gastric Bypass

Background: Obesity is considered a state of low-grade chronic inflammation, which may favor the development of cardiovascular diseases. Serum amyloid A (SAA) is an acute phase protein synthesized in response to infection, inflammation, injury, and stress. The aim of the present study was to compare the circulating concentrations of SAA and the mRNA expression in omental adipose tissue between lean and obese individuals and to analyze the effect of weight loss after gastric bypass. Methods: 16 lean volunteers (BMI 20.5 ± 0.6 kg/m2) and 24 obese patients (BMI 47.0 ± 1.2 kg/m2) were included in the study. Serum concentrations of SAA were measured by ELISA. In addition, the concentrations of SAA in 18 morbidly obese patients (7 male/11 female; BMI 44.6 ± 1.9 kg/m2) were measured before and after weight loss following Roux-en-Y gastric bypass (RYGBP). SAA expression in omental adipose tissue was quantified by RT-PCR in biopsies from obese patients undergoing RYGBP and from age-matched lean individuals subjected to Nissen fundoplication. Results: Obese patients exhibited significantly increased circulating SAA concentrations (6.6 ± 0.5 vs 39.3 ± 9.1 μg/ml; P<0.01) compared to lean subjects. A significant positive correlation was found between logSAA and body fat (r=0.631, P<0.0001). Obese patients showed significantly increased (P<0.05) mRNA expression of SAA in omental adipose tissue compared to lean subjects. Weight loss significantly decreased SAA concentrations after RYGBP (final BMI 28.5 ± 0.9 kg/m2, P<0.0001 vs initial) from 47.5 ± 14.5 to 15.7 ± 2.9 μg/ml (P<0.05). Conclusion: It can be concluded that serum SAA and mRNA expression of SAA in omental adipose tissue are increased in obese patients contributing to the obesity-associated cardiovascular disease risk. Moreover, weight loss reduces SAA concentrations, which may contribute to the beneficial effects accompanying weight reduction.

Expression of caveolin‐1 in human adipose tissue is upregulated in obesity and obesity‐associated type 2 diabetes mellitus and related to inflammation

Objective  Caveolin‐1 (CAV‐1) plays important roles in many aspects of cellular biology, including vesicular transport, cholesterol homeostasis and signal transduction. The aim of the present study was to explore gene expression levels of CAV‐1 in human adipose tissue in obesity and obesity‐associated type 2 diabetes mellitus (T2DM) and to analyse its potential implication in the inflammatory state associated with obesity.