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Administration of high-dose interleukin-2 (HDIL-2) has durable antitumor effects in 5% to 10% of patients with melanoma and renal cell carcinoma. However, treatment is often limited by side effects, including reversible, multiorgan dysfunction characterized by a cytokine-induced systemic autophagic syndrome. Here, we hypothesized that the autophagy inhibitor chloroquine would enhance IL-2 immunotherapeutic efficacy and limit toxicity. In an advanced murine metastatic liver tumor model, IL-2 inhibited tumor growth in a dose-dependent fashion. These antitumor effects were significantly enhanced upon addition of chloroquine. The combination of IL-2 with chloroquine increased long-term survival, decreased toxicity associated with vascular leakage, and enhanced immune cell proliferation and infiltration in the liver and spleen. HDIL-2 alone increased serum levels of HMGB1, IFN-g, IL-6, and IL-18 and also induced autophagy within the liver and translocation of HMGB1 from the nucleus to the cytosol in hepatocytes, effects that were inhibited by combined administration with chloroquine. In tumor cells, chloroquine increased autophagic vacuoles and LC3-II levels inhibited oxidative phosphorylation and ATP production and promoted apoptosis, which was associated with increased Annexin-V+/propidium iodide (PI)- cells, cleaved PARP, cleaved caspase-3, and cytochrome c release from mitochondria. Taken together, our findings provide a novel clinical strategy to enhance the efficacy of HDIL-2 immunotherapy for patients with cancer. [ABSTRACT FROM AUTHOR]

Presents a study which examined the molecular mechanisms underlying glucocorticoids (GC) downregulation of nitric oxide synthase (iNOS) gene expression in rat hepatocytes. Impact of GC on cytokines and immunomodulatory genes; Methodology used to conduct the study; Results of the study.

The article discusses the contribution of the 2010-2011 Executive Board of periodical in the development of the periodical as a serious academic publication. He says that the primary goal of the Board was to utilize the new electronic media in publishing the periodical and mentions about the creation of periodicals own website in this context. He reflects on his experience of being the Editor-in-Chief of the periodical during 2010-2011.

The article reviews the article related to the recurrence of hepatocellular carcinoma (HCC) after transplant by Richard Kim and coauthors which appeared in the periodical "Oncology" on December 2009 issue.

• Cardiac testing of candidates for liver transplant requires balancing risks and benefits of cardiac procedures. • Framingham Score is a simple algorithm to optimize risk stratification for coronary artery disease before liver transplant. • Patients with Framingham Score ≥35% are triaged toward cardiac catheterization as initial test of coronary artery disease; those with Framingham Score <35% are triaged toward stress testing. • Framingham Score is a streamlined approach that prioritizes testing based on cardiac risk, thereby maximizing diagnostic yield while limiting invasive procedures. Cardiac testing of candidates for liver transplant (LT) requires balancing risks and benefits of cardiac procedures. The goal of this study was to evaluate the utility of the Framingham score (FS) for optimizing preoperative risk stratification for coronary artery disease (CAD). In this single-center retrospective study of 615 adults undergoing LT evaluation from 2016 to 2019, data of preoperative evaluation, post-LT 1-year mortality, and post-LT cardiac events were reviewed. Patients >30 years of age with normal echocardiogram underwent FS calculation. Elevated FS (≥35%) patients were triaged to undergo angiogram for CAD evaluation; FS <35% patients underwent stress testing as initial CAD evaluation. Of 615 patients referred for LT, 481 underwent cardiac testing. Ninety-five were excluded from the FS pathway because of age, abnormal baseline echocardiogram, or known CAD. Of the remaining 386 patients in the FS pathway, 342 had a low FS and 44 had a high FS. In patients with low FS, 90% underwent stress testing as initial test; 16% underwent invasive testing at some time. In those with elevated FS, 59% underwent invasive testing as initial test. Listing rate and posttransplant outcomes were similar between patients with low and high FS. We demonstrated the feasibility of a simple algorithmic evaluation process using FS for optimizing pre-LT risk stratification for CAD. Although exceptions to the protocol occur, the proposed protocol allows for a streamlined approach by prioritizing testing based on cardiac risk. This approach may maximize diagnostic yield while limiting invasive procedures. [ABSTRACT FROM AUTHOR]

The purpose of this study was to identify risk factors that may predict heart failure with reduced ejection fraction (HFrEF) following orthotopic liver transplantation (OLT) and associated mortality. HFrEF following OLT is a poorly understood phenomenon, reported in 3% to 7% of transplanted patients. This is a retrospective analysis of 176 consecutive patients who underwent OLT from 2010 to 2017. Multivariate logistic regression was used to identify associations between cardiovascular risk factors and perioperative variables with post-OLT HFrEF, defined as reduction in left ventricular ejection fraction of at least 10% and left ventricular ejection fraction less than or equal to 40% with acute heart failure symptoms. Multivariate cox proportional hazards regression (with inverse probability weighting by propensity scores) was used to evaluate effects of HFrEF on 1-year mortality. Of the176 patients, 14% developed HFrEF with a median of 5 days. History of heart failure (OR 10.99, 2.15–56.09; P =.04) and intraoperative transfusion of greater than 11 units of packed red blood cells (OR 3.377, 1.025–11.13; P =.045) were associated with increased incidence of HFrEF. Pre-transplant hemoglobin greater than 8.5 g/dL (OR 0.252, CI 0.0954- 0.665; P =.05) was protective against HFrEF. Thirty-three percent of HFrEF group died within 1 year (HR 7.36, 2.57–21.12; P <.001). The incidence of acute HFrEF post-OLT is 14% and is associated with a 7-fold increase in 1-year mortality. Cirrhotic cardiomyopathy and stress-induced cardiomyopathy maybe the underlying mechanisms. Our study identified risk factors associated with post-OLT HFrEF and should provide additional guidance for risk stratification of patients undergoing OLT. [ABSTRACT FROM AUTHOR]

Purpose: To describe results of a planned interim analysis of a prospective, randomized clinical trial developed to compare treatment outcomes among patients with newly diagnosed hepatocellular carcinoma (HCC).Methods and Materials: Eligible subjects had either clinical or pathologic diagnosis of HCC and met either Milan or San Francisco transplant criteria. Patients were randomly assigned to transarterial chemoembolization (TACE) or to proton beam radiation therapy. Patients randomized to TACE received at least 1 TACE with additional TACE for persistent disease. Proton beam radiation therapy was delivered to all areas of gross disease to a total dose of 70.2 Gy in 15 daily fractions over 3 weeks. The primary endpoint was progression-free survival, with secondary endpoints of overall survival, local tumor control, and treatment-related toxicities as represented by posttreatment days of hospitalization.Results: At the time of this analysis 69 subjects were available for analysis. Of these, 36 were randomized to TACE and 33 to proton. Total days of hospitalization within 30 days of TACE/proton was 166 and 24 days, respectively (P<.001). Ten TACE and 12 proton patients underwent liver transplantation after treatment. Viable tumor identified in the explanted livers after TACE/proton averaged 2.4 and 0.9 cm, respectively. Pathologic complete response after TACE/proton was 10%/25% (P=.38). The 2-year overall survival for all patients was 59%, with no difference between treatment groups. Median survival time was 30 months (95% confidence interval 20.7-39.3 months). There was a trend toward improved 2-year local tumor control (88% vs 45%, P=.06) and progression-free survival (48% vs 31%, P=.06) favoring the proton beam treatment group.Conclusions: This interim analysis indicates similar overall survival rates for proton beam radiation therapy and TACE. There is a trend toward improved local tumor control and progression-free survival with proton beam. There are significantly fewer hospitalization days after proton treatment, which may indicate reduced toxicity with proton beam therapy. [ABSTRACT FROM AUTHOR]

Introduction: Hemolysis in the emergency department (ED) can significantly delay results and appropriate action. We evaluated the main sources of hemolysis during sample collection, and to evaluate the use of rapid serum tubes (RST) as a transport hemolysis-mitigating measure for high-sensitivity troponin T (hs-cTnT) testing., Methods: We examined the effect of tube type, tube fill, types of sample draw and collection methods on hemolysis and hs-cTnT in samples (n = 158) from ED patients. We also compared hs-cTnT values in paired RST and plasma separate tube (PST) samples that were hemolysis-free., Results: The primary source of hemolysis in samples collected in the ED was underfilling tubes. In both tube types, PST and RST, filled tubes showed a median reduction in hemolysis of 69.1 % (p < 0.0001). Blood collected in RST also experienced less hemolysis compared to PST. In hemolysis-free samples, false positive results in PST were noted in patients with hs-cTnT values < 50 ng/l., Conclusion: We suggest that proper tube filling during sample collection and use of RST tubes can significantly reduce the effects of hemolysis. In addition, laboratories should be aware that PST tubes have a non-trivial rate of false positives when hs-cTnT < 50 ng/l., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Icterus, a phenomenon caused by bilirubin elevation in the blood, is a common endogenous interference in chemistry testing, occurring either spectrally or through chemical reactivity with assay reagents. Often, laboratories have few options other than to dilute or reject samples exceeding icteric thresholds. However, recent studies have optimized in vitro photoisomerization of bilirubin to a 17-minute bilirubin half-life using 500 nm light at 37 °C. Using an enzymatic creatinine assay as a model, due to its prevalence in routine laboratory testing and susceptibility to icteric interference, our study explores the usage of in vitro photoisomerization by replicating these conditions in a device, the Bilibox, as means of resolving icterus in laboratory testing. Left-over icteric and non-icteric clinical samples, collected by lithium heparin vacutainer (n = 10), were analyzed for baseline creatinine, diluted creatinine (1:4 0.9 % NaCl), total bilirubin, direct bilirubin, and hemolysis, icterus and lipemia (HIL) indices. Samples were then placed in the Bilibox in two intervals of 30 min with repeat measurements of the aforementioned analytes. On average, icteric-index, total bilirubin (TBIL), and direct bilirubin (DBIL) decreased by 33.5, 39.1 and 39.9 % respectively following 30 min of Bilibox treatment; and by 47.6 %, 63.7 % and 59.8 % following 60 min. The average percent difference between the pre-exposure diluted and undiluted creatinine was 5.8 %, demonstrating the icterus interference. Following Bilibox treatment, the difference between undiluted (post-exposure) and diluted (pre-exposure) creatinine decreased to 0.02 % (p = 0.0232) and 2.2 % (p = 0.0021) at 30 and 60 min of treatment respectively, demonstrating resolution of interference. Consequently, photoisomerization can be utilized as an additional and reasonably quick method for resolving icterus when dilutional methods cannot be applied., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Background: Urine drug testing (UDT) monitors prescription compliance and/or drug abuse. However, interpretation of UDT results obtained by liquid chromatography-tandem mass spectrometry (LC-MS-MS) can be complicated by the presence of drug impurities that are detected by highly sensitive methods. Hydrocodone is a drug impurity that can be found as high as 1% in oxycodone pills., Objectives: We evaluated the frequency and concentration of hydrocodone and its metabolite, hydromorphone, in patients taking oxycodone to check if the ratio of hydrocodone or hydromorphone to oxycodone could distinguish between oxycodone only use from those consuming additional opiates., Design & Methods: We correlated LC-MS/MS results with medication records of 319 patients with positive oxycodone results over 7 months (4/2021-11/2021)., Results: Fifteen of 319 patients with positive oxycodone results were taking oxycodone only. For these 15 patients, the mean ratio of hydrocodone to oxycodone was 0.57% (range 0.05%-3.35%), and the mean ratio of hydromorphone to oxycodone was 0.81% (range 0.18-3.51%)., Conclusions: Hydrocodone and/or hydromorphone are detectable in patients taking only oxycodone and can likely be identified as an impurity if their calculated ratio to oxycodone is <1 %. Further validation of the ratios in a larger sample size is recommended., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Background: Laboratorians are left unguided by a paucity of literature on how to configure rules for the detection of intravenous (IV) fluid contamination in blood samples. We designed a study to determine the in vitro effect of increasing blood sample contamination from commonly used crystalloid solutions and how these observations can guide the derivation of multianalyte delta checks to detect such pre-analytical error., Methods: In this study, we spiked increasing volumes of commonly used IV fluids (normal saline (NS), lactated ringers (LR), and 5% dextrose) into blood samples that were collected from healthy donors. Routine chemistry analytes were measured and compared between neat and contrived samples. From these observations, we derived several permutations of multianalyte delta checks using the basic metabolic panel framework and evaluated rule performance using retrospective data., Results: The wet chemistry experiments showed that increasing the volume of crystalloid solution contamination significantly changed several analytes. Subsequently derived multianalyte delta check procedures were applied to retrospective data. For all IV fluids tested, smaller magnitudes of analyte change resulted in more samples flagged., Conclusion: Multianalyte delta checks may be an effective method for the detection of IV fluid contamination., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: In 2017, the American College of Gastroenterology (ACG) and the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition published clinical guidelines recommending the use of alanine aminotransferase (ALT) upper reference limits (URL) of 33, 25, 26, and 22 U/l for men, women, boys, and girls, respectively. This was opposed by laboratory experts who advocated for the use of higher URL of 59, 41, 33, and 24 U/l instead. We suspected that the variable inclusion of individuals who consumed alcohol to be a major contributing source of URL variability and debate., Methods: Outpatient ALT data (n = 7379) were collected from unique individuals ≥13 y with BMIs of ≥19 and ≤25. A total of 222 (3%) were excluded due to suspected liver disease. Patients were split into a pediatric group (age 13-17 y), an alcohol-restricted adult group (age 18-20 y), and adults with access to alcohol by decade (i.e., age 21-29, 30-39, 40-49, 50-59, 60-69, 70-79, and ≥ 80 y). All ALT values were measured on Roche Cobas 8000 with pyridoxal phosphate and traceable to the IFCC-reference measurement procedure., Results: We derived URL similar to CALIPER for our pediatric population, but closer to ACG-proposed URL in our alcohol-restricted adult group. The URL increased significantly in men and women for all other age groups., Conclusions: The discrepancy in ALT URL in clinical laboratories may be attributable in part due to the variable inclusion of individuals who recently consumed alcohol in local population derivation studies., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Heart-type fatty acid binding protein (H-FABP), a low molecular weight protein found primarily in myocardial tissue, has been identified as a potential biomarker in the detection of acute coronary syndrome and acute kidney injury. To further investigate clinical utility, we sought to establish an upper reference limit (URL) of H-FABP within a healthy U.S., Methods: Serum samples of healthy donors were acquired from the AACC Universal Sample Bank. We analyzed 355 samples for H-FABP concentration using the Randox Laboratories immunoturbidimetric assay on the Roche Cobas 8000 series analyzer., Results: The final sample population consisted of individuals aged 18-74 y, with 170 males and 185 females. The distribution of the population exhibited a strong positive skew, affecting outlier analysis and URL determination. The 97.5th-percentile URL was found to be 7.4 ng/ml (95% CI: 6.3-9.2), while the 99th-percentile URL was 12.1 ng/ml (8.6-14.9)., Conclusion: As the URL for H-FABP is highly affected by population distribution and outlier removal, final determination for an assay cutoff should be made in the context of clinical utility, either as a standalone assay or in conjunction with other biomarkers, and the desired clinical sensitivity and specificity., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Pseudohyponatremia describes an artifactual decrease in plasma sodium result in samples with high proteins and/or lipids when measured by an indirect ion-selective electrode (ISE) method. We suspected that Intralipid®-based lipemia cutoffs are inappropriate for detecting interfering lipids in human samples and a major contributing factor to the existence of pseudohyponatremia., Methods: We evaluated 2 approaches to derive a lipemia cutoff for sodium, one in which patient plasma samples were pooled and spiked to simulate hyperlipidemia using Intralipid® (commonly used approach by in-vitro diagnostics manufacturers), and another in which endogenous hyperlipidemic samples (n = 31) were measured by methods not affected by hyperlipidemia (i.e., direct ISE and post-ultracentrifugation indirect ISE). Triglycerides, lipemic index (L-index) and indirect ISE sodium concentrations of samples were measured on Roche Cobas® 8000 and direct ISE on Radiometer® ABL835 Flex analyzers. Endogenous hyperlipidemic samples were also ultracentrifuged on Beckman Coulter® Airfuge to clear excess lipids and re-analyzed for sodium by indirect ISE., Results: We discovered that Intralipid® is not an accurate emulation of the lipemic interference seen in pseudohyponatremia because it showed no effect up to the maximum level of lipemia tested (L-index = 2000). By contrast, endogenous hyperlipidemic samples demonstrated significant deviations in sodium concentration (≥4 mmol/l) when L-index approached or exceeded 700, and a strong positive correlation between L-index and the difference between the indirect and direct methods (i.e., extent of pseudohyponatremia)., Conclusions: Clinical laboratories should lower their tolerance for lipemia from the currently recommended L-index cutoff of 2000 on Roche Cobas 8000®. We recommend reflexing to direct ISE when L-index exceeds 700. Manufacturers and laboratories with other indirect ISE methods should evaluate the effect of lipid interference on their method using hyperlipidemic human samples not Intralipid®., (Copyright © 2021. Published by Elsevier B.V.)