Citations

Liver biopsy remains the gold standard for the histological assessment of the liver. With clear disadvantages and the rise in the incidences of liver disease, the role of neoadjuvant chemotherapy in colorectal liver metastasis (CRLM) and an explosion of surgical management options available, non-invasive serological and imaging markers of liver histopathology have never been more pertinent in order to assess liver health and stratify patients considered for surgical intervention. Liver MRI is a leading modality in the assessment of hepatic malignancy. Recent technological advancements in multiparametric MRI software such as the LiverMultiScanTM offers an attractive non-invasive assay of anatomy and histopathology in the pre-operative setting, especially in the context of CRLM. This narrative review examines the evidence for the LiverMultiScanTM in the assessment of hepatic fibrosis, steatosis/steatohepatitis, and potential applications for chemotherapy-associated hepatic changes. We postulate its future role and the hurdles it must surpass in order to be implemented in the pre-operative management of patients undergoing hepatic resection for colorectal liver metastasis. Such a role likely extends to other hepatic malignancies planned for resection.

Abstract Disclosure: S.H. Johnson: None. C. Zhang: None. P.T. Hangge: None. T.W. Yen: None. T. Shaik: None. K. Doffek: None. J.W. Findling: None. T.B. Carroll: None. D.B. Evans: None. S. Dream: None. T.S. Wang: None. Background: Secondary adrenal insufficiency (SAI) may occur in patients after unilateral adrenalectomy for adrenal-dependent hypercortisolism (HC) and/or primary aldosteronism (PA). Perioperative protocols include routine glucocorticoid replacement (GR) or selective GR based on postoperative day 1 (POD1) basal cortisol levels or cosyntropin stimulation testing (CST). This study aimed to assess if a POD1 basal cortisol level alone was predictive of an abnormal CST and the need for GR in patients following unilateral adrenalectomy for HC and/or PA. Methods: This is a single institution retrospective review of consecutive unilateral adrenalectomies performed for HC and/or PA from 9/2014-10/2022. Patients were grouped as overt hypercortisolism (OH;n=42), mild autonomous cortisol excretion (MACE;n=70), mixed PA/HC (n=22) or PA (n=73); 22 patients with PA did not have preoperative evaluation for HC. Preoperative morning cortisol after low-dose dexamethasone suppression testing (DST), was used to define MACE (1.8-4.9 µg/dL) and OH (≥5.0). POD1 CST was performed for all patients with HC and prior to 2021, all patients with PA. SAI was defined as basal cortisol ≤5 or stimulated ≤14 (≤18 before 4/2017). Receiver operating characteristic (ROC) curves and sensitivity analyses were performed to assess the sensitivity (SN) and specificity (SP) of cutoffs within the range of observed basal cortisol levels in predicting an abnormal CST and need for GR. Results: Of 207 patients, 152 had POD1 CST (93% OH, 96% MACE, 73% PA/HC, 41% PA). Of these, 80 (53%) had SAI (67% OH, 55% MACE, 44% PA/HC, and 33% PA). Of the 10 patients with PA and SAI, 5 did not have preoperative testing for HC. Overall, 81 patients were discharged on GR. Median (interquartile range [IQR]) duration of GR was 246 (127,557), 55 (38,207), 74 (16,185), and 26 (15,36) days in patients with OH, MACE, PA/HC, and PA, respectively. At a median follow-up of 142 days (IQR 42,617), 12 patients (5 OH, 6 MACE, 1 PA/HC) remained on GR. The SN/SP of a basal cortisol ≤10 in predicting GR was 92%/77% in patients with OH and 94%/73% of patients with MACE. Compared to initiation of GR based on basal cortisol ≤10, CST identified 4 patients with SAI in the combined OH and MACE cohorts who would not have received GR, and 11 in the combined cohort who did not require GR. For patients with PA and PA/HC, a basal cortisol ≤10 had SN of 100% and SP of 85% and 67%, respectively. The optimal basal cortisol for predicting SAI in patients with PA/HC was ≤5 (SN,SP 100%). Area under the curve for all ROC curves was >0.9. Conclusion: These results demonstrate that in patients who underwent unilateral adrenalectomy for HC, PA, or mixed PA/HC, POD1 CST improved identification of patients at risk for SAI compared to basal cortisol levels alone. While basal cortisol levels alone may be considered in patients with PA or mixed HC/PA, all other patients with HC should have POD1 CST to determine need for postoperative GR. Presentation: Friday, June 16, 2023

PURPOSE The Response Assessment in Neuro-Oncology (RANO) criteria for high-grade gliomas (RANO-HGG) and low-grade gliomas (RANO-LGG) were developed to improve reliability of response assessment in glioma trials. Over time, some limitations of these criteria were identified, and challenges emerged regarding integrating features of the modified RANO (mRANO) or the immunotherapy RANO (iRANO) criteria. METHODS Informed by data from studies evaluating the different criteria, updates to the RANO criteria are proposed (RANO 2.0). RESULTS We recommend a standard set of criteria for both high- and low-grade gliomas, to be used for all trials regardless of the treatment modalities being evaluated. In the newly diagnosed setting, the postradiotherapy magnetic resonance imaging (MRI), rather than the postsurgical MRI, will be used as the baseline for comparison with subsequent scans. Since the incidence of pseudoprogression is high in the 12 weeks after radiotherapy, continuation of treatment and confirmation of progression during this period with a repeat MRI, or histopathologic evidence of unequivocal recurrent tumor, are required to define tumor progression. However, confirmation scans are not mandatory after this period nor for the evaluation of treatment for recurrent tumors. For treatments with a high likelihood of pseudoprogression, mandatory confirmation of progression with a repeat MRI is highly recommended. The primary measurement remains the maximum cross-sectional area of tumor (two-dimensional) but volumetric measurements are an option. For IDH wild-type glioblastoma, the nonenhancing disease will no longer be evaluated except when assessing response to antiangiogenic agents. In IDH-mutated tumors with a significant nonenhancing component, clinical trials may require evaluating both the enhancing and nonenhancing tumor components for response assessment. CONCLUSION The revised RANO 2.0 criteria refine response assessment in gliomas.

Abstract Background Analytical and post-analytical errors are a persistent problem, which can be benchmarked using sigma metrics. Manual processes are associated with error rates of 3–4 sigma. Secondary review of manual reporting is meant to reduce/eliminate errors and is widely used, yet the true efficacy of manual secondary review is difficult to assess. Kidney stone analysis is a manually intensive process, requiring personnel to identify stone composition from spectra and to transcribe stone percent composition into an LIS system. Recently, we developed an AI program that allows for quantitative determination of kidney stone composition from spectra. This allows for a unique opportunity to estimate error rates associated with manual reporting and those following secondary review by means of subsequent AI quality assurance analysis. Methods Experienced technologists assessed stone composition and estimated the percent of each component (± 10%), based on Fourier transform infrared (FTIR) spectroscopy. These manual spectral composition assessments are secondarily reviewed by other experienced technologists for identity and percentage composition accuracy. The recently described Kidney stone AI spectral analysis (RokkStar) was implemented to assess reported stone composition identity and percent composition for agreement following secondary review in 159 334 stone reports. AI flagged discrepant reports were reviewed by personnel and reports were revised when appropriate. Secondary reviewer error detection rate was obtained by monitoring detection in a subset of 7440 kidney stones, and was that rate was extrapolated to establish secondary review error detection rate over the entire data set. The sum (total error) of estimated secondary reviewer error detection, and well as AI-mediated error detection, and all client reported errors were used to determine error rates in sigma following manual reporting, secondary review, and AI quality assurance. Results Manual entry led to an estimated 2060 errors in 159 334 stone reports, yielding an initial sigma value of 3.73. Secondary manual review resulted in an estimated 1909 (error detection rate of 92.5%) of these errors being detected over the entire report set, improving the sigma value to 4.61. Post-verification AI caught an additional 138 errors, leading to an improved post-AI sigma value of 5.27. Post-AI quality assurance, there were 13 remaining errors, 9 of which were manual reporting process deviations subsequently caught by laboratory staff, and 4 were reporting errors observed by client physicians. All 13 of these errors involved usual stone constituents or typographical errors that were not assessed by the current AI quality assurance version. Conclusion This study represents a unique large-scale estimate of efficacy of secondary result review by means of AI quality assurance review. While the presence of undetected errors cannot be completely ruled out, in this case the relative paucity of client reported errors, as well the alignment of the estimated rate of manual errors with previous reports may indicate that most errors were detected in this system. Importantly, manual secondary review improved errors rates by ∼0.9 sigma, and the use of AI further improved estimated overall sigma metric by ∼0.7, leading to a “world class” 5+ sigma level for this complex reporting process.

Abstract Background While clinical tests are available to aid in the diagnosis of Wilson’s Disease (WD), some such as total copper determination lack sensitivity and specificity, while others such as liver tissue copper assessment are costly and invasive. WD affects copper metabolism and is known to cause low serum copper concentrations. In addition, an elevated percentage of total serum copper exists as non-protein bound or labile bound copper (LBC). Previous studies have shown that measuring the ratio of labile bound copper to total serum copper may aid in the diagnosis of WD. To support the utility of a laboratory developed test using serum LBC ratios to aid in the diagnosis of WD, serum samples from healthy donors were used to establish a reference range for LBC and the ratio of LBC to total copper in adults. Methods Serum samples were collected in trace metal free tubes from 214 donors (n = 110 male, n = 104 female) between the ages of 19–80 years old, selected against pre-determined exclusion criteria including acute hepatitis, chronic hepatitis, renal failure, biliary cirrhosis, celiac disease, and leukemia. Prior to analysis, samples went through a centrifugation-based preparation process to isolate the LBC fraction using molecular weight size exclusion filters and EDTA chelation. Samples were then analyzed via ICP-MS in kinetic energy discrimination (KED) mode to directly measure the LBC and total copper concentrations. LBC ratio values were determined from the LBC/total copper concentrations. Results Preliminary reference ranges were developed for both LBC and the LBC ratio based on the 2.5th and 97.5th percentiles with 95% confidence intervals. Established sex specific reference intervals for total copper were deemed acceptable per CLSI guidelines in document EP28-A3c, with ≤10% of results from this sample set falling outside of the established intervals. No statistically significant relationship was found in the mid-95th percentile between LBC concentration or ratio with age or sex. The reference intervals for LBC concentration were calculated as 13.41–104.66 and 11.69–106.50 ng/mL for females and males respectively. The reference intervals for LBC ratio were calculated as 1.04–8.12 and 1.17–10.48 for females and males respectively. Conclusions A reference range of LBC and LBC ratio has now been determined for the healthy adult population. Further testing can now be done on disease state populations to determine the sensitivity and specificity of LBC ratio in the detection, monitoring, or diagnosis of WD.

Abstract Background Duplicate measurements can be used to characterize assay imprecision, identify outliers, and estimate error rates. The benefits of duplicate analysis, however, need to be balanced against the increased financial cost. The objective of this study was to evaluate the need for continued replicate measurement in a laboratory developed assay measuring anti-drug antibodies to infliximab (ATI). To this end, duplicate patient sample measurements from the ATI assay over a two-year period were analyzed to calculate outlier and error frequencies. Methods ATI were measured by electrochemiluminescence (ECL) on the MesoScale Discovery (MSD) platform, with a standard curve from 20–1250 U/mL using commercially available monoclonal ATIs. All patient samples tested for ATI over a 27-month period of time (n = 9582) were subject to inclusion in this study. Only patient samples with ATI levels within the analytical measuring range (AMR) of the assay, however, were selected for further analysis. Samples were divided equally into 7 bins across the measuring range based on mean replicate concentration. Within-run imprecision was determined for each bin using the standard deviation (combined from all replicates using sum of squares) and mean concentration derived from all replicates. Outliers were defined as replicate measurements with a percent difference greater than ±3 SD of the calculated assay imprecision. Errors were defined as samples which had replicate values on opposite sides of the clinical cutoff of positive ATI (≥50 U/mL) and a percent difference greater than 3SD of the assay imprecision. Results Of the 9582 total patient samples analyzed, 2467 had ATI values within the AMR and 1655 had levels over the clinical cut-off of 50 U/mL (17.3% positivity rate). Within-run imprecision determined from the mean and combined SD of the duplicate measurements ranged from 15.7% at the lowest concentration bin (20–27.5 U/mL) to 10.0% at the highest concentration bin (358–1243 U/mL). The mean percentage of outliers in each bin ranged from 0.8%–3.4% resulting in an overall outlier frequency of 2.1% when considering all samples within the AMR. There were 66 samples within the AMR which demonstrated qualitative discrepancies between the replicates. However, only 21 (31.8%) of these samples, had a percent agreement greater than 3SD of the assay imprecision resulting in an overall error rate of 0.2% when considering all 9582 samples. Conclusion In this study, the analysis of replicate patient samples enabled the establishment of a precision profile and estimation of error rates for a laboratory developed test measuring ATI. The calculated error rate of 0.2%, however, is well within the reported range of most clinical assays indicating that the continued practice of duplicate measurement may not be necessary. Additionally, updating the laboratory protocol to eliminate replicate testing would have positive impact in laboratory workflow, cost, and turn-around-time for results.

OBJECTIVES: A number of trials related to critical care pharmacotherapy were published in 2022. We aimed to summarize the most influential publications related to the pharmacotherapeutic care of critically ill patients in 2022. DATA SOURCES: PubMed/Medical Literature Analysis and Retrieval System Online and the Clinical Pharmacy and Pharmacology Pharmacotherapy Literature Update. STUDY SELECTION: Randomized controlled trials, prospective studies, or systematic review/meta-analyses of adult critically ill patients assessing a pharmacotherapeutic intervention and reporting clinical endpoints published between January 1, 2022, and December 31, 2022, were included in this article. DATA EXTRACTION: Articles from a systematic search and the Clinical Pharmacy and Pharmacology Pharmacotherapy Literature Update were included and stratified into clinical domains based upon consistent themes. Consensus was obtained on the most influential publication within each clinical domain utilizing an a priori defined three-round modified Delphi process with the following considerations: 1) overall contribution to scientific knowledge and 2) novelty to the literature. DATA SYNTHESIS: The systematic search and Clinical Pharmacy and Pharmacology Pharmacotherapy Literature Update yielded a total of 704 articles, of which 660 were excluded. The remaining 44 articles were stratified into the following clinical domains: emergency/neurology, cardiovascular, gastroenterology/fluids/nutrition, hematology, infectious diseases/immunomodulation, and endocrine/metabolic. The final article selected from each clinical domain was summarized following a three-round modified Delphi process and included three randomized controlled trials and three systematic review/meta-analyses. Article topics summarized included dexmedetomidine versus other sedatives during mechanical ventilation, beta-blocker treatment in the critically ill, restriction of IV fluids in septic shock, venous thromboembolism prophylaxis in critically ill adults, duration of antibiotic therapy for Pseudomonas aeruginosa ventilator-associated pneumonia, and low-dose methylprednisolone treatment in severe community-acquired pneumonia. CONCLUSIONS: This concise review provides a perspective on articles published in 2022 that are relevant to the pharmacotherapeutic care of critically ill patients and their potential impact on clinical practice.