Daria Zorzi

Increase in Mortality Rate of Liver Transplant Candidates Residing in Specific Geographic Areas: Analysis of UNOS Data

We sought to evaluate survival of liver transplant candidates living in geographic areas with limited access to specialized transplant centers (TxC). We analyzed survival outcome among candidates listed for liver transplant in United Network of Organ Sharing (UNOS) Region 4 from 2004 to 2010. Candidates were stratified into three groups according to the distance from the patients residence to the closest hospital with a liver transplant program: Group 1 (Gr 1) <30 miles (m), Group 2 (Gr 2) 30–60 m and Group 3 (Gr 3) >60 m. Of the 5673 patients included in the study, 49% resided >30 m from a TxC. Eight percent of the cohort experienced death or dropped out of the list due to medical condition deterioration, with worse outcomes for Gr 2 and Gr 3 (8.5% and 9.9%, respectively, vs. 6.5% for Gr 1 [p < 0.001]). Among patients with a MELD score <20, mortality was higher in Gr 2 and Gr 3 compared to Gr 1 (p < 0.001). We conclude that for Region 4, the mortality risk in patients living >30 m from a TxC is higher. We suggest that the variable “distance from a TxC” should be used to improve the estimate of the mortality risk for patients on the waiting list.

Increased Risk of Death for Patients on the Waitlist for Liver Transplant Residing at Greater Distance From Specialized Liver Transplant Centers in the United States

Background We have previously shown that patients listed for orthotopic liver transplantation (OLT) in United Network for Organ Sharing Region 4 (Texas and Oklahoma) have higher waitlist mortality rates when residing more than 30 miles from specialized liver transplant centers (LTC). Considering that findings might only be exclusive for this region with its peculiarities in terms of having the highest land surface extensions, lowest population densities, and largest rural populations. We investigated the entire OLT patient population in the United States to assess if our previous regional findings are nationally validated and if a rural, micropolitan, or metropolitan residence location affects outcome of waitlisted OLT patients in the nation. Methods Patients waiting for OLT in the United States from 2002 to 2012 were stratified by distance from the patients residence to LTC and by Rural Urban Commuting Area (RUCA) codes classification. Statistical analyses were performed to evaluate risk of mortality on the waitlist and the likelihood to receive an OLT using a Cox proportional hazards model and a generalized additive model with a logistic link. Results Survival time and probability of death while on the waitlist for OLT using distance to LTC showed significant increased risk with the distance (P = 0.001 and P < 0.0001, respectively). At the same time, using RUCA classification as the variable did not show significance (P = 0.14 and P = 0.73, respectively). Conclusions Distance from an LTC is a risk factor of mortality on the waitlist for OLT, whereas RUCA classification is not a significant factor.

Impact of islet size on pancreatic islet transplantation and potential interventions to improve outcome.

Better results have been recently reported in clinical pancreatic islet transplantation (ITX) due mostly to improved isolation techniques and immunosuppression; however, some limitations still exist. It is known that following transplantation, 30% to 60% of the islets are lost. In our study, we have investigated 1) the role of size as a factor affecting islet engraftment and 2) potential procedural manipulations to increase the number of smaller functional islets that can be transplanted. C57/BL10 mice were used as donors and recipients in a syngeneic islet transplant model. Isolated islets were divided by size (large, >300 μm; medium 150–300 μm; small, <150 μm). Each size was transplanted in chemically induced diabetic mice as full (600 IEQ), suboptimal (400 IEQ), and marginal mass (200 IEQ). Control animals received all size islets. Engraftment was defined as reversal of diabetes by day 7 posttransplantation. When the superiority of smaller islets was observed, strategies of overdigestion and fragmentation were adopted during islet isolation in the attempt to reduce islet size and improve engraftment. Smaller islets were significantly superior in engraftment compared to medium, large, and control (all sizes) groups. This was more evident when marginal mass data were compared. In all masses, success decreased as islet size increased. Once islets were engrafted, functionality was not affected by size. When larger islets were fragmented, a significant decrease in islet functionality was observed. On the contrary, if pancreata were slightly overdigested, although not as successful as small naive islets, an increase in engraftment was observed when compared to the control group. In conclusion, smaller islets are superior in engraftment following islet transplantation. Fragmentation has a deleterious effect on islet engraftment. Islet isolations can be performed by reducing islet size with slight overdigestion, and it can be safely adopted to improve clinical outcome.

An Ecological Study of the Association between Air Pollution and Hepatocellular Carcinoma Incidence in Texas

Introduction: Primary liver cancer is a significant cause of cancer-related death in both the United States and the world at large. Hepatocellular carcinoma comprises 90% of these primary liver cancers and has numerous known etiologies. Evaluation of these identified etiologies and other traditional risk factors cannot explain the high incidence rates of hepatocellular carcinoma in Texas. Texas is home to the second largest petrochemical industry and agricultural industry in the nation; industrial activity and exposure to pathogenic chemicals have never been assessed as potential links to the states increased incidence rate of hepatocellular carcinoma. Methods: The association between the county-level concentrations of 4 air pollutants known to be linked to liver cancer, vinyl chloride, arsenic, benzene, and 1,3-butadiene, and hepatocellular carcinoma rates was evaluated using nonparametric generalized additive logistic regression and gamma regression models. Hepatocellular carcinoma incidence rates for 2000-2013 were evaluated in comparison to 1996 and 1999 pollution concentrations and hepatocellular carcinoma rates for the subset of 2006-2013 were evaluated in comparison to 2002 and 2005 pollution concentrations, respectively. Results: The analysis indicates that the relationship between the incidence of liver cancer and air pollution and risk factors is nonlinear. There is a consistent significant positive association between the incidence of liver cancer and hepatitis C prevalence rates (gamma all years, p < 0.05) and vinyl chloride concentrations (logistic 2002 and 2005, p < 0.0001; gamma 2002 and 2005, p < 0.05). Conclusions: This study suggests that vinyl chloride is a significant contributor to the incidence of liver cancer in Texas. The relationship is notably nonlinear. Further, the study supports the association between incidence of liver cancer and prevalence of hepatitis B.

Evidence of Absorptive Function in vivo in a Neo-Formed Bio-Artificial Intestinal Segment Using a Rodent Model

A promising therapeutic approach for intestinal failure consists in elongating the intestine with a bio-engineered segment of neo-formed autologous intestine. Using an acellular biologic scaffold (ABS), we, and others, have previously developed an autologous bio-artificial intestinal segment (BIS) that is morphologically similar to normal bowel in rodents. This neo-formed BIS is constructed with the intervention of naïve stem cells that repopulate the scaffold in vivo, and over a period of time, are transformed in different cell populations typical of normal intestinal mucosa. However, no studies are available to demonstrate that such BIS possesses functional absorptive characteristics necessary to render this strategy a possible therapeutic application. The aim of this study was to demonstrate that the BIS generated has functional absorptive capacity. Twenty male Augustu2009×u2009Copenhagen-Irish (ACI) rats were used for the study. Two-centimeter sections of ABS were transplanted in the anti-mesenteric border of the small bowel. Animals were studied at 4, 8, and 12xa0weeks post-engraftment. Segments of intestine with preserved vascular supply and containing the BIS were isolated and compared to intestinal segments of same length in sham control animals (nu2009=u200910). d-Xylose solution was introduced in the lumen of the intestinal segments and after 2xa0h, urine and blood were collected to evaluate d-Xylose levels. Quantitative analysis was performed using ELISA. Morphologic, ultrastructural, and indirect functional absorption analyses were also performed. We observed neo-formed intestinal tissue with near-normal mucosa post-implantation as expected from our previously developed model. Functional characteristics such as morphologically normal enterocytes (and other cell types) with presence of brush borders and preserved microvilli by electron microscopy, preserved water, and ion transporters/channels (by aquaporin and cystic fibrosis transmembrane conductance regulator (CFTR)) were also observed. The capacity of BIS containing neo-formed mucosa to increase absorption of d-Xylose in the blood compared to normal intestine was also confirmed. With this study, we demonstrated for the first time that BIS obtained from ABS has functional characteristics of absorption confirming its potential for therapeutic interventions.

Response to the Comments on Cicalese et al.: “An Ecological Study of the Association between Air Pollution and Hepatocellular Carcinoma Incidence in Texas”

Dear Editor In response to the comments [1, 2] regarding the article by Cicalese et al., “An Ecological Study of the Association between Air Pollution and Hepatocellular Carcinoma Incidence in Texas” [3], the authors acknowledge minor editorial errors but stand behind the methodology and conclusions of the paper. There appears to be a misunderstanding concerning what these data and results suggest; we aim to clarify these points and respond to critiques that the authors knowingly published results based on limited assumptions. First of all, no cause-effect relationship is stated or implied by the authors. When done properly, statistical control for lurking and confounding variables aims to focus simply on the correlation between 2 random variables. After controlling for as many variables as possible, significant relationships discovered through correlation alone do not imply causation; this requires further exploration. By carefully excluding other common causes of hepatocellular carcinoma (HCC) in Texas, the authors explore a previously unstudied (but toxicologically well-known) cause of liver cancer – airborne toxics, such as 1,3-butadiene, arsenic, benzene, and vinyl chloride. Two kinds of regression were performed on the data for distinct reasons. Logistic regression tests the association of a positive HCC rate with risk factors (including vinyl chloride), while gamma regression tests the association of the magnitude of positive HCC rates with these factors. It should also be noted that the logistic regression included all data from the Texas Cancer Registry and National Air Toxics Assessment (NATA), while the gamma regression only included the subset of these data with a non-zero HCC incidence rate. The authors acknowledge some inconsistencies between the results of the 2 regressions, though they generally measure different relationships. Below, each claim of the commenter is numbered, with the authors’ responses following each claim. Quoted material is reproduced from either the comments submitted to the editor [1, 2] (numbered) or the published paper [3] (bulleted). To the many claims by Krock [1] of the Vinyl Institute, the authors provide the following responses: 1. “The latency period for angiosarcoma of the liver and HCC is much longer than the 7to 13-year duration used in the study (36–48 years)” [1]. − The cited latency periods account for a latency period between exposure and death from HCC, not between exposure and cancer incidence. Published online: April 12, 2018

381 How Distance From Specialized Transplant Centers and Residence in Rural and Urban Setting Affects Outcome of Liver Transplant Patients on Waitlist in the USA

A S L D A b st ra ct s AIC optimization. Results: This cohort was 40% female with an average age of 58±9 years and average MELD score of 12±5. The etiology of liver disease was due to HCV in 78, alcohol in 49, and NASH in 66 patients. Of 193 patients, 75% reported pain-related disability based on any positive response. The median score on individual items ranging in severity from 0-10 was 3.0 (0.17, 5.83). In univariate testing, disability was strongly correlated with age, depression and anxiety symptoms, MELD score, pain severity, and levels of CRP, TNFα, and IL-6. Disability was also strongly related to the use of prescription opioids, with non-opioid users having median disability scores of 1.7 (iqr=0.0,4.7) on a scale of 0-10 and opioid users having median scores of 6.5 (iqr=4.5,7.8). Factors associated with higher levels of disability in the final model included MELD score (IRR for each point=1.03, 95% CI= 1.003,1.05), prescription opioid use (IRR=1.58, 95% CI=1.23,2.05), HADS score (IRR= 1.05, 95%CI=1.03,1.06), CRP (IRR=1.13 95%CI=1.04,1.24), and severity of pain (IRR=1.01, 95% CI=1.004,1.02). Conclusion: Self-reported pain-related disability is nearly universal in outpatients with cirrhosis, even in a group with relatively low MELD scores. Disability is most strongly related to opioid use, inflammation, mental health, pain, and severity of liver disease in this group. Interestingly, opioid use and inflammation appears to be more strongly associated with pain-related disability than severity of pain. This corresponds with prior publications demonstrating that opioid use is driven by factors other than pain and may decrease pain without improving overall function. Longitudinal studies are needed to determine whether opioid use marks or drives disability and whether the common use of these agents actually contributes to dysfunction.