Novel biomarkers for cholangiocarcinoma: how can it enhance diagnosis, prognostication, and investigational drugs? Part-1.

INTRODUCTION: The development of novel biomarkers for cancer has exploded over the last decade with advances in novel technologies. Cholangiocarcinoma (CCA), a cancer of the bile ducts, has a dearth of strong disease and pathophysiology biomarkers, making early detection and prognostication a difficult task. AREAS COVERED: In this comprehensive review, we discuss the spectrum of biomarkers for CCA diagnosis and prognostication. We elaborate on novel biomarker discovery through a comprehensive multi-omics approach. We also cover, how certain biomarkers may also serve as unique and potent targets for therapeutic development. EXPERT OPINION: Despite the relatively poor diagnostic and prognostic performance of existing biomarkers for CCA, there is a vast range of novel biomarkers with exquisite diagnostic and prognostic performance for CCA in the pipeline. Moreover, these biomarkers may serve as potential targets for precision medicine. Existing strategies to target unique biomolecular classes are discussed, within the context of an overall 'omics' focused profiling strategy. Omics profiling will simultaneously allow for enhanced biomarker development and identification of unique subtypes of cholangiocarcinoma and how they are influenced by an individual's unique context. In this manner, patient management strategy and clinical trial design can be optimized to the individual.

Fatty Liver Is an Independent Risk Factor for Delayed Recovery from Anesthesia.

Fatty liver (FL) is associated with altered activity of hepatic drug-metabolizing enzymes, but the clinical significance is unknown. Many anesthetic agents are metabolized in the liver. We aimed to determine whether FL impacts recovery from anesthesia as a surrogate for altered drug metabolism. This was a single-center, retrospective, case-control study of all adults who underwent anesthesia and concurrent abdominal imaging (n = 2,021) in a hospital setting. FL (n = 234) was identified through radiology reports. Anesthesia recovery, the primary endpoint, was defined by Aldrete's recovery score (RS, 0-10), assessed following postanesthesia care unit (PACU) arrival, with RS ≥8 considered discharge eligible. FL and controls were compared using univariate and multivariate analyses, adjusting for confounders. A secondary matched-pairs analysis matched FL and controls 1:1 for confounders. Time from airway removal to discharge eligibility was compared using multivariate Cox regression. On PACU arrival, 54.1% of FL were discharge eligible compared to 61.7% of controls (P = 0.03), with lower activity scores on univariate (P = 0.03) and multivariate analysis (P = 0.03). On matched-pairs analysis, discharge eligibility, activity, consciousness, and total RSs were lower in FL (P ≤ 0.04 for all). Median time from airway removal to discharge eligibility was 43% longer in FL (univariate, P = 0.01; multivariate hazard ratio, 1.32; P = 0.046). To further exclude confounding by obesity, we performed a sensitivity analysis limited to a body mass index <30, where FL was still associated with lower activity (P = 0.03) and total RS (P = 0.03). Conclusion: Patients with FL have delayed recovery from anesthesia, suggesting altered drug metabolism independent of metabolic risk factors.

Lipoprotein Insulin Resistance Index Reflects Liver Fat Content in Patients With Nonalcoholic Fatty Liver Disease.

The recently developed lipoprotein insulin resistance index (LP-IR) incorporates lipoprotein particle numbers and sizes and is considered to reflect both hepatic and peripheral IR. As tissue IR is a strong component of nonalcoholic fatty liver disease (NAFLD) pathogenesis, we aimed to assess the degree by which LP-IR associates with hepatic fat content. This was a single-center retrospective analysis of patients with NAFLD. LP-IR, the homeostasis model assessment of insulin resistance (HOMA-IR), and adipose tissue IR (Adipo-IR) were measured simultaneously. Liver fat content was estimated by FibroScan controlled attenuated parameter. Associations were assessed using Spearman's correlation and multivariate linear regression. The study included 61 patients. LP-IR was correlated with HOMA-IR (ρ = 0.30; P = 0.02), typically thought to reflect hepatic IR, but not with Adipo-IR (ρ = 0.15; P = 0.25). Liver fat content was significantly associated with Adipo-IR (ρ = 0.48; P < 0.001), LP-IR (ρ = 0.35; P = 0.005), and to a lesser degree with HOMA-IR (ρ = 0.25; P = 0.051). The association of liver fat with LP-IR was limited to patients without diabetes (ρ = 0.60; P < 0.0001), whereas no association was seen in those with diabetes. In a multivariate model, Adipo-IR, LP-IR, and diabetes were independently associated with liver fat and together explained 35% of the variability in liver fat. Conclusion: LP-IR is a reasonable measure of IR in non-diabetic patients with NAFLD and is associated with hepatic fat content. Although adipose tissue is the major contributor to liver fat, the additional contribution of nonadipose tissues can be easily estimated using LP-IR.

Processing and Handling Cost of Single-use Versus Traditional Instrumentation for 1 Level Lumbar Fusions.

STUDY DESIGN: A single center, observational prospective clinical study. OBJECTIVE: The aim of this study was to compare the instrumentation-related cost and efficiency of single-use instrumentation versus traditional reusable instrument trays. SUMMARY OF BACKGROUND DATA: Single-use instrumentation provides the opportunity to reduce costs associated with cleaning and sterilizing instrumentation after surgery. Although previous studies have shown single-use instrumentation is effective in other orthopedic specialties, it is unclear if single-use instrumentation could provide economic advantages in spine surgery. MATERIALS AND METHODS: A total of 40 (20 reusable instrumentation and 20 single-use instrumentation) lumbar decompression (1-3 level) and fusion (1 level) spine surgeries were collected. Instrument handling, opening, setup, re-stocking, cleaning, sterilization, inspection, packaging, and storage were recorded by direct observation for both reusable and single-use instrumentation. The rate of infection was noted for each group. RESULTS: Mean time of handling instruments by the scrub nurse was 11.6 (±3.9) minutes for reusable instrumentation and 2.1 (±0.5) minutes for single-use instrumentation. Mean cost of handling reusable instruments was estimated to be $8.52 (±$2.96) per case, and the average cost to reprocess a single tray by Sterilization Processing Department (SPD) was $58. Thus, the median cost for sterilizing 2 reusable trays per case was $116, resulting in an average total Costresuable of $124.52 (±$2.96). Mean cost of handling single-use instrumentation was estimated to be $1.57 ($0.38) per case. CONCLUSION: Single-use instrumentation provided greater cost savings and reduced time from the opening of instrumentation to use in surgery when compared with reusable instrumentation.

Disrupting reconsolidation: memory erasure or blunting of emotional/motivational value?

When memories are retrieved they become labile, and subject to alteration by a process known as reconsolidation. Disruption of memory reconsolidation decreases the performance of learned responses, which is often attributed to erasure of the memory; in the case of Pavlovian learning, to a loss of the association between a conditioned stimulus (CS) and unconditioned stimulus (US). However, an alternative interpretation is that disrupting reconsolidation does not erase memories, but blunts their emotional/motivational impact. It is difficult to parse the predictive vs. emotional/motivational value of CSs in non-human animals, but studies on variation in the form of conditioned responses (CRs) in a Pavlovian conditioned approach task suggest a way to do this. In this task a lever-CS paired with a food reward (US) acquires predictive value in all rats, but is attributed with emotional/motivational value to a greater extent in some rats (sign-trackers) than others (goal-trackers). We report that the post-retrieval administration of propranolol selectively attenuates a sign-tracking CR, and the associated neural activation of brain "motive circuits", while having no effect on conditioned orienting behavior in sign-trackers, or on goal-tracking CRs evoked by either a lever-CS or a tone-CS. We conclude that the disruption of reconsolidation by post-retrieval propranolol degrades the emotional/motivational impact of the CS, required for sign-tracking, but leaves the CS-US association intact. The possibility that post-retrieval interventions can reduce the emotional/motivational aspects of memories, without actually erasing them, has important implications for treating maladaptive memories that contribute to some psychiatric disorders.