Prevalence and progression of intraductal papillary mucinous neoplasms of the pancreas in solid organ transplant recipients: A systematic review.

Solid organ transplantation (SOT) recipients are known to carry an increased risk of malignancy because of long-term immunosuppression. However, the progression of intraductal papillary mucinous neoplasm of the pancreas (IPMN) in this population remains unclear. We performed a systematic review by searching PubMed, Embase, Scopus, and Google Scholar. All studies containing IPMNs in solid organ transplantation recipients were screened. We included 11 studies in our final analysis, totaling 274 patients with IPMNs of the 8213 SOT recipients. The prevalence from 8 studies was 4.7% (95% CI 2.4%-7.7%) in a random-effects model with median study periods of 24 to 220 months. The median rate for all progressions from 10 studies was 20% (range, 0%-88%) within 13 to 41 months of the median follow-up time. By utilizing the results of 3 case-control studies, the relative risk from a random-effects model for progression (worrisome features and high-risk stigmata) of IPMNs was 0.39 (95% CI 0.12-1.31). No adenocarcinoma derived from IPMN was reported in the included studies. Overall, this study indicates that the progression of pretransplant IPMN does not increase drastically compared with the general nontransplant population. However, considering the limited literature, further studies are required for confirmation.

Favorable Sustained Virologic Response Rates Using Direct-Acting Antiviral Therapies at a Large Safety-Net Hospital.

BACKGROUND: Direct-acting antivirals (DAA) have revolutionized the treatment of chronic hepatitis C virus (HCV) infection. OBJECTIVE: To evaluate the clinical effectiveness of DAA in a safety-net population. METHODS: Retrospective cohort study including patients who received at least one dose of DAA for chronic HCV infection. Primary outcome was sustained virologic response (SVR) defined as undetectable viral load at least 12 weeks after treatment termination. RESULTS: Notable patient (n=174) characteristics included: 58% racial/ethnic minority group members, 34% Medicaid or uninsured, and 51% cirrhosis. Overall, SVR was 87.4%, including 15 patients who were lost to follow-up and deemed treatment failures. Multivariate analysis significantly associated completion of therapy on time (OR 4.55, p=.009) and the presence of insurance (OR 7.25, p=0.008) with SVR. CONCLUSION: A favorable rate of SVR can be obtained in a safety-net population. The majority of treatment failure was due to patients being lost to follow-up.

Pro: Steroids Can Be Withdrawn After Transplant in Recipients With Autoimmune Hepatitis.

Corticosteroids have been a mainstay of immunosuppression following liver transplantation. However, evolution in the field of transplant immunology has produced steroid-free options, resulting in most transplant centers weaning steroids after transplant within days to months-an evidence-based management decision. Patients with autoimmune hepatitis (AIH), however, receive corticosteroids prior to transplant. This raises the question of whether these patients should also be weaned from corticosteroids. In this review, we discuss the benefits of avoiding steroid use in this population of patients-an approach that not only avoids the adverse effects of corticosteroids but does so without risking graft failure from recurrent AIH or from acute cellular rejection.

New paradigms for organ allocation and distribution in liver transplantation.

PURPOSE OF REVIEW: The 'Final Rule,' issued by the Health Resources and Service Administration in 2000, mandated that liver allocation policy should be based on disease severity and probability of death, and - among other factors - should be independent of a candidate's residence or listing. As a result, the Organ Procurement Transplantation Network/United Network for Organ Sharing (UNOS) has explored policy changes addressing geographic disparities without compromising outcomes. RECENT FINDINGS: Major paradigm shifts are underway in U.S. liver allocation policy. New hepatocellular carcinoma exception policy incorporates tumor characteristics associated with posttransplantation outcomes, whereas a National Liver Review Board will promote a standardized process for awarding exception points. Meanwhile, following extensive debate, new allocation policy aims to reduce geographic disparity by broadening sharing to the UNOS region and 150-mile circle around the donor hospital for liver transplant candidates with a calculated model for end-stage liver disease score at least 32. Unnecessary organ travel will be reduced by granting 3 'proximity points' to candidates within the same donation service area (DSA) as a liver donor or within 150 nautical miles of the donor hospital, regardless of DSA or UNOS region. SUMMARY: This review provides an evaluation of major policy changes in liver allocation from 2016 to 2018.

Neutrophil-to-lymphocyte ratio correlates with proinflammatory neutrophils and predicts death in low model for end-stage liver disease patients with cirrhosis.

The Model for End-Stage Liver Disease (MELD) score has reduced accuracy for liver transplantation (LT) wait-list mortality when MELD ≤ 20. Neutrophil-to-lymphocyte ratio (NLR) is a biomarker associated with systemic inflammation and may predict cirrhotic decompensation and death. We aimed to evaluate the prognostic utility of high NLR (≥4) for liver-related death among low MELD patients listed for LT, controlling for stage of cirrhosis. In a nested case-control study of cirrhotic adults awaiting LT (February 2002 to May 2011), cases were LT candidates with a liver-related death and MELD ≤ 20 within 90 days of death. Controls were similar LT candidates who were alive for ≥90 days after LT listing. NLR and other covariates were assessed at the date of lowest MELD, within 90 days of death for cases and within 90 days after listing for controls. There were 41 cases and 66 controls; MELD scores were similar. NLR 25th, 50th, 75th percentile cutoffs were 1.9, 3.1, and 6.8. NLR was ≥ 4 in 25/41 (61%) cases and in 17/66 (26%) controls. In univariate analysis, NLR (continuous ≥ 1.9, ≥ 4, ≥ 6.8), increasing cirrhosis stage, jaundice, encephalopathy, serum sodium, and albumin and nonselective beta-blocker use were significantly (P < 0.01) associated with liver-related death. In multivariate analysis, NLR of ≥1.9, ≥ 4, ≥ 6.8 were each associated with liver-related death. Furthermore, we found that NLR correlated with the frequency of circulating low-density granulocytes, previously identified as displaying proinflammatory properties, as well as monocytes. In conclusion, elevated NLR is associated with liver-related death, independent of MELD and cirrhosis stage. High NLR may aid in determining risk for cirrhotic decompensation, need for increased monitoring, and urgency for expedited LT in candidates with low MELD. Liver Transplantation 23 155-165 2017 AASLD.

Changing prioritization for transplantation: MELD-Na, hepatocellular carcinoma exceptions, and more.

PURPOSE OF REVIEW: This article summarizes the landmark events that shaped current deceased donor liver allocation and distribution policy in the USA and to provide an update on recently approved and anticipated policy changes. RECENT FINDINGS: For liver transplant candidates with model for end-stage liver disease more than 11, the 'MELD-Na' equation incorporating serum sodium will be used for allocation starting January 2016. The 'delay and cap' policy for hepatocellular carcinoma delays the start of model for end-stage liver disease exception by 6 months and subsequently grants 28 points, with increases every 3 months thereafter up to a maximum score at 34 points. There is new guidance for exception petitions for neuroendocrine tumors, polycystic liver disease, and primary sclerosing cholangitis. New guidelines for selecting candidates for simultaneous liver-kidney transplant are being developed that may include a 'safety net' for liver-only recipients with posttransplant renal failure. In an effort to provide broader geographic sharing of livers than in the current distribution system, new larger geographic areas are being considered. SUMMARY: Recent policy changes were designed to reduce waitlist mortality, yet inclusion of outcomes measures in allocation and the use of larger geographic distribution units will likely guide future policy changes.

Early administration of infliximab for severe ipilimumab-related diarrhea in a critically ill patient.

OBJECTIVE: To report a case of ipilimumab-associated life-threatening diarrhea responding quickly to a single dose of infliximab. CASE SUMMARY: A 67-year-old man presented 3 weeks after his second dose of ipilimumab with severe diarrhea, acute kidney injury, and hypotension. After 2 days of high-dose corticosteroids and supportive care, he continued to have 2.8 L of stool output per day (grade 4 National Cancer Institute Common Terminology Criteria for Adverse Events). The patient was transferred to the medical intensive care unit requiring endotracheal intubation because of concerns of worsening mental status, metabolic acidosis, and increased work of breathing, with a serum bicarbonate concentration of <5 mmol/L. Despite aggressive fluid resuscitation and a sodium bicarbonate infusion, he remained hypotensive and hyponatremic with persistent premature ventricular contractions. On the evening of day 3, infliximab (5 mg/kg) was given, resulting in a rapid decrease in diarrhea. After 48 hours, the acidosis was corrected and electrolytes, renal function, and fluid status were improving. At discharge, diarrhea, acute kidney injury, and acidosis had resolved, and he was discharged on a slow steroid taper. DISCUSSION: Autoimmune colitis is a described immune-related adverse event of ipilimumab. Prompt recognition, initiation of steroids, and supportive therapy are key to the management of diarrhea. Infliximab should be considered early in steroid-nonresponsive or life-threatening diarrhea. CONCLUSION: Infliximab is a life-saving intervention in patients with ipilimumab-induced diarrhea.

Feasibility of an interactive voice response tool for adolescent assault victims.

BACKGROUND: Assault-injured adolescents who are seen in the emergency department (ED) are difficult to follow prospectively using standard research techniques such as telephone calls or mailed questionnaires. Interactive voice response (IVR) is a novel technology that promotes active participation of subjects and allows automated data collection for prospective studies. OBJECTIVES: The objective was to determine the feasibility of IVR technology for collecting prospective information from adolescents who were enrolled in an ED-based study of interpersonal violence. METHODS: A convenience sample of assault-injured 12- to 19-year-olds presenting to an urban, tertiary care ED was enrolled prospectively. Each subject completed a brief questionnaire in the ED and then was randomly assigned to use the IVR system in differently timed schedules over a period of 8 weeks: weekly, biweekly, or monthly calls. Upon discharge, each subject received a gift card incentive and a magnetic calendar with his or her prospective call-in dates circled on it. Each time a subject contacted the toll-free number, he or she used the telephone's keypad to respond to computer-voice questions about retaliation and violence subsequent to the ED visit. Using Internet access, we added $5 to the gift card for each call and $10 if all scheduled calls were completed. The primary outcome was the rate of the first utilization of the IVR system. The numbers of completed calls made for each of the three call-in schedules were also compared. RESULTS: Of the 95 subjects who consented to the follow-up portion of the study, 44.2% (95% confidence interval [CI] = 34.0% to 54.8%) completed at least one IVR call, and 13.7% (95% CI = 7.5% to 22.3%) made all of their scheduled calls. There were no significant differences among groups in the percentage of subjects calling at least once into the system or in the percentage of requested calls made. The enrolled subjects had a high level of exposure to violence. At baseline, 85.3% (95% CI = 76.5% to 91.7%) had heard gunshots fired, and 84.2% (95% CI = 75.3% to 90.9%) had seen someone being assaulted. Twenty-eight adolescents (29.5%, 95% CI = 20.6% to 39.7%) were reached for satisfaction interviews. All of those contacted found the IVR system easy to use and all but one would use it again. CONCLUSIONS: Interactive voice response technology is a feasible means of follow-up among high-risk violently injured adolescents, and this relatively anonymous process allows for the collection of sensitive information. Further research is needed to determine the optimal timing of calls and cost-effectiveness in this population.

pH regulating transporters in neurons from various chemosensitive brainstem regions in neonatal rats.

We studied the membrane transporters that mediate intracellular pH (pH(i)) recovery from acidification in brainstem neurons from chemosensitive regions of neonatal rats. Individual neurons within brainstem slices from the retrotrapezoid nucleus (RTN), the nucleus tractus solitarii (NTS), and the locus coeruleus (LC) were studied using a pH-sensitive fluorescent dye and fluorescence imaging microscopy. The rate of pH(i) recovery from an NH(4)Cl-induced acidification was measured, and the effects of inhibitors of various pH-regulating transporters determined. Hypercapnia (15% CO(2)) resulted in a maintained acidification in neurons from all three regions. Recovery in RTN neurons was nearly entirely eliminated by amiloride, an inhibitor of Na(+)/H(+) exchange (NHE). Recovery in RTN neurons was blocked approximately 50% by inhibitors of isoform 1 of NHE (NHE-1) but very little by an inhibitor of NHE-3 or by DIDS (an inhibitor of HCO(3)-dependent transport). In NTS neurons, amiloride blocked over 80% of the recovery, which was also blocked approximately 65% by inhibitors of NHE-1 and 26% blocked by an inhibitor of NHE-3. Recovery in LC neurons, in contrast, was unaffected by amiloride or blockers of NHE isoforms but was dependent on Na(+) and increased by external HCO(3)(-). On the basis of these findings, pH(i) recovery from acidification appears to be largely mediated by NHE-1 in RTN neurons, by NHE-1 and NHE-3 in NTS neurons, and by a Na- and HCO(3)-dependent transporter in LC neurons. Thus, pH(i) recovery is mediated by different pH-regulating transporters in neurons from different chemosensitive regions, but recovery is suppressed by hypercapnia in all of the neurons.

Comparative approaches to facilitate the discovery of prolongevity interventions: effects of tocopherols on lifespan of three invertebrate species.

Many compounds hold promise for pharmacologic manipulation of aging. However, such claims are difficult to investigate due to time and budget constraints. Here, we took a comparative approach, using short-lived invertebrate species, to directly test the effects of two tocopherols (Vitamin E) on longevity. gamma-Tocopherol represents the most abundant tocopherol in the Western diet, while alpha-tocopherol is selectively enriched in human plasma. Both isoforms demonstrate antioxidant activity and are proposed to have anti-aging activities. We compared the effects of alpha- and gamma-tocopherol supplementation on lifespan in three invertebrate species. gamma-Tocopherol, but not alpha-tocopherol, slightly extended lifespan in nematodes, but neither significantly affected lifespan in two fly species. This study shows that a comparative approach, utilizing multiple invertebrate species, can increase the robustness of invertebrate-based pilot screens for prolongevity interventions.

Resveratrol improves health and survival of mice on a high-calorie diet.

Resveratrol (3,5,4'-trihydroxystilbene) extends the lifespan of diverse species including Saccharomyces cerevisiae, Caenorhabditis elegans and Drosophila melanogaster. In these organisms, lifespan extension is dependent on Sir2, a conserved deacetylase proposed to underlie the beneficial effects of caloric restriction. Here we show that resveratrol shifts the physiology of middle-aged mice on a high-calorie diet towards that of mice on a standard diet and significantly increases their survival. Resveratrol produces changes associated with longer lifespan, including increased insulin sensitivity, reduced insulin-like growth factor-1 (IGF-I) levels, increased AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) activity, increased mitochondrial number, and improved motor function. Parametric analysis of gene set enrichment revealed that resveratrol opposed the effects of the high-calorie diet in 144 out of 153 significantly altered pathways. These data show that improving general health in mammals using small molecules is an attainable goal, and point to new approaches for treating obesity-related disorders and diseases of ageing.