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Kappa free light chains (KFLC), a byproduct of immunoglobulin (Ig) synthesis by B-lineage cells, can serve as an indicator for inflammatory activity. In multiple sclerosis (MS), especially the intrathecal KFLC production has gained increasing importance as a biomarker for central nervous system (CNS) inflammation and was included into the proposed 2024 revision of the McDonald criteria. In contrast, studies investigating the significance of KFLC in serum and the effects of disease-modifying therapies (DMT) on KFLC serum concentration in MS are rare. The aim of the present work was to investigate the impact of B cell depletion with ocrelizumab on KFLC concentrations in serum of MS patients and the ability of serum KFLC to monitor disease activity. 50 MS patients were included in the present study- 38 with the diagnosis of relapsing MS (RMS) and 12 with diagnosis of primary-progressive MS (PPMS) -, who were treated with ocrelizumab for two years. Serum concentrations of albumin, immunoglobulins and KFLC as well as lymphocyte subsets were determined at baseline and after two years. Serum Ig and KFLC concentrations were found to be significantly lower after two years of ocrelizumab treatment (mean serum concentrations: KFLC: 9.5mg/l vs. 7.8mg/l, p = 0.0003; IgG: 9g/l vs. 8g/l, p = 0.0002; IgA: 2g/l vs. 1.8g/l, p = 0.0010; IgM: 1.8g/l vs. 0.7g/l, p < 0.0001). Serum KFLC concentration did not correlate with clinical and paraclinical parameters of disease activity. Treatment with ocrelizumab reduces serum KFLC concentration in MS patients. However, serum KFLC concentration is not able to predict disease activity in these MS patients.

IntroductionHealthcare practices providing minimal or no benefit to recipients have been estimated to represent 20% of healthcare costs. However, defining, measuring and monitoring low-value care (LVC) and its downstream consequences remain a major challenge. The purpose of the National Data Stream (LUCID NDS) is to identify and monitor LVC in medical inpatients using routinely collected hospital data.Methods and analysisThis protocol describes a multistep approach to the identification and surveillance of LVC: (1) creating an NDS based on Findable, Accessible, Interoperable, Reusable (FAIR) principles using routinely collected hospital data from medical inpatients who signed a general consent for data reuse from 2014 onwards; (2) selecting recommendations applicable to medical inpatients using data from LUCID NDS to develop a comprehensive and robust set of LVC indicators; (3) establishing expert consensus on the most relevant and actionable recommendations to prevent LVC; (4) applying the Strength of Recommendation Taxonomy methodology to assess the level of evidence of recommendations; (5) involving patients and the public at various stages of LUCID NDS; and (6) designing monitoring rules within the LUCID NDS and validating quality measures.Ethics and disseminationThe ethics committees of all five participating university hospitals (Basel, Bern, Geneva, Lausanne and Zurich) approved LUCID NDS as a national registry on quality of care. We will disseminate our findings in peer-reviewed journals, at professional conferences, and through short reports sent to participating entities and stakeholders; moreover, lay summaries are provided for patients and the broader public on our webpage (www.LUCID-nds.ch).

Purpose To compare image quality, diagnostic performance, and conspicuity between single-energy and multi-energy images for endoleak detection at CT angiography (CTA) after endovascular aortic repair (EVAR). Materials and Methods In this single-center prospective randomized controlled trial, individuals undergoing CTA after EVAR between August 2020 and May 2022 were allocated to imaging using either low-kilovolt single-energy images (SEI; 80 kV, group A) or low-kiloelectron volt virtual monoenergetic images (VMI) at 40 and 50 keV from multi-energy CT (80/Sn150 kV, group B). Scan protocols were dose matched (volume CT dose index: mean, 4.5 mGy ± 1.8 [SD] vs 4.7 mGy ± 1.3, P = .41). Contrast-to-noise ratio (CNR) was measured. Two expert radiologists established the reference standard for the presence of endoleaks. Detection and conspicuity of endoleaks and subjective image quality were assessed by two different blinded radiologists. Interreader agreement was calculated. Nonparametric statistical tests were used. Results A total of 125 participants (mean age, 76 years ± 8; 103 men) were allocated to groups A (n = 64) and B (n = 61). CNR was significantly lower for 40-keV VMI (mean, 19.1; P = .048) and 50-keV VMI (mean, 16.8; P < .001) as compared with SEI (mean, 22.2). In total, 45 endoleaks were present (A: 23 vs B: 22). Sensitivity for endoleak detection was higher for SEI (82.6%, 19 of 23; P = .88) and 50-keV VMI (81.8%, 18 of 22; P = .90) as compared with 40-keV VMI (77.3%, 17 of 22). Specificity was comparable among groups (SEI: 92.7%, 38 of 41; both VMI energies: 92.3%, 35 of 38; P = .99), with an interreader agreement of 1. Conspicuity of endoleaks was comparable between SEI (median, 2.99) and VMI (both energies: median, 2.87; P = .04). Overall subjective image quality was rated significantly higher for SEI (median, 4 [IQR, 4-4) as compared with 40 and 50 keV (both energies: median, 4 [IQR, 3-4]; P < .001). Conclusion SEI demonstrated higher image quality and comparable diagnostic accuracy as compared with 50-keV VMI for endoleak detection at CTA after EVAR. Keywords: Aneurysms, CT, CT Angiography, Vascular, Aorta, Technology Assessment, Multidetector CT, Abdominal Aortic Aneurysms, Endoleaks, Perigraft Leak Supplemental material is available for this article. © RSNA, 2024.

Chronic pruritus is a classic symptom in patients with primary biliary cholangitis. It affects up to two-thirds of patients in the course of the disease. Efficient therapy consists of topical treatment combined with systemic options such as anion exchangers, rifampicin, bezafibrate, μ-opioid receptor antagonists, selective-serotonin receptor uptake inhibitors, and gabapentinoids. Future therapeutic approaches may contain the selective blockade of the enterohepatic cycle by inhibiting the ileal bile acid transporter, the agonism at κ-opioid receptors, and antagonism of the mas-related G protein-coupled receptor X4. As nondrug treatment, ultraviolet B therapy, albumin dialysis, and biliary drainage are available at specialized centers.

BackgroundImmune checkpoint inhibitors directed against programmed cell death 1 (PDCD1/PD1) receptor and programmed cell death‐ligand 1 (CD274/PD‐L1) have been recently successfully implemented for the treatment of many cancers, but the response rate of tumour patients is still limited due to intrinsic and acquired resistances. However, the underlying molecular mechanisms of this limited response have still to be defined in detail. The aim of this study is to uncover processes inhibiting PDCD1/CD274 expression thereby enhancing anti‐tumour immune responses. The identification and characterization of microRNAs (miRNAs) targeting the 3′‐untranslated region (3′‐UTR) as well as the coding sequence (CDS) of CD274 will provide the basis for a new drug development.MethodsHuman melanoma cell lines and tissue samples were subjected to mRNA and/or protein expression analysis using qPCR, Western blot, flow cytometry, and/or immunohistochemistry. The data were correlated to clinical parameters. MiRNA trapping by RNA in vitro affinity purification (miTRAP) technology in combination with small RNA sequencing and different bioinformatics tools were employed to identify CD274‐regulating miRNAs.ResultsScreening based on miTRAP in combination with RNAseq identified a large number of novel CD274‐regulating candidate miRNAs, from which eight selected miRNAs were functionally validated. Five out of eight miRNAs were able to significantly reduce CD274 surface expression indicating that these miRNAs directly bind to the 3′‐UTR or CDS of the CD274 gene. The miRNA‐mediated inhibition of CD274 expression was accompanied by an increased T cell recognition. Furthermore, an inverse expression of three CD274‐regulating miRNAs and CD274 was demonstrated in melanoma lesions. A CD274 miRNA score was generated, which was associated with disease progression and reduced survival of melanoma patients.ConclusionsThese data revealed a novel mechanism that miRNAs targeting the CDS of immune checkpoint genes are functional, have prognostic relevance, and also the potential for the development of novel miRNA‐based therapies.

9527 Background: Combination of immune checkpoint inhibitors and targeted therapy may produce durable and deep response in a higher proportion of pts with BRAF V600–mutant unresectable or metastatic melanoma. A recent report from the randomized, double-blind, placebo (PBO)-controlled Part 3 of the Phase 3 COMBI-i trial (NCT02967692) failed to show a statistically significant progression-free survival (PFS) benefit (hazard ratio (HR) of 0.82 (95% CI, 0.66‒1.03, p=.042)). Here, we report 3-year OS data from COMBI-i part 3. Methods: Eligible pts were randomized 1:1 to receive either S+D+T (n = 267; S 400 mg IV Q4W + D 150 mg orally BID + T 2 mg orally QD) or PBO+D+T (n = 265), until progression or unacceptable toxicity. Although the primary endpoint of PFS was not met, exploratory OS and safety analyses were performed. OS was summarized descriptively using Kaplan–Meier methods and HR was estimated using a stratified cox regression model. Results: As of October 19, 2021 (median follow-up, 42.8 months), the median OS was not reached in S+D+T arm and was 40.4 months with PBO+D+T (HR 0.796; 95% CI, 0.615‒1.029). There were 113 (42.3%) deaths in the S+D+T and 126 (47.5%) in the PBO+D+T. Estimated 2-year and 3-year OS rates were 67.7% (95% CI 61.6‒73.1) and 60.1% (95% CI 53.8‒65.8) with S+D+T vs 61.9% (95% CI 55.6‒67.5) and 52.9% (95% CI 46.6‒58.9) with PBO+D+T, respectively. An OS benefit was observed with S+D+T in these prespecified subgroups – Eastern Cooperative Oncology Group Performance Status (ECOG PS) 1 (HR 0.50; 95% CI, 0.32‒0.8), age ≥65 years (HR 0.58; 95% CI, 0.36‒0.94), PD-L1 negative ( &lt; 1%) (HR 0.62; 95% CI, 0.42‒0.91), sum of lesion diameters ≥ 66 mm at baseline (HR 0.63; 95% CI, 0.43‒0.91) and metastatic sites ≥ 3 (HR 0.66; 95% CI, 0.47‒0.94). Adverse events (AEs) irrespective of study treatment relationship were observed in 99.3% of pts in S+D+T vs 97.3% in PBO+D+T. The most common AEs (in &gt; 30%; all grades) were pyrexia, diarrhea, and nausea. Grade ≥3 treatment-related AEs (TRAEs) occurred in 56.9% vs 35.2% of pts treated with S+D+T vs PBO+D+T, respectively. Dose reductions of D and T due to AEs were more frequent in the S+D+T arm than PBO+D+T arm (47.2% vs 25.4% and 45.7% vs 25.4%, respectively), contributing to a lower relative dose intensity; the TRAEs leading to discontinuation of all 3 study drugs occurred in 13.5% vs 8% of pts, respectively. Conclusions: Results from this landmark 3-year OS analysis from COMBI-i- part 3 was consistent with the primary analysis, while the PBO+D+T showed a higher OS rate than previously observed for D+T alone in COMBI D/V studies, with a longer median follow-up. Subgroup analyses showed that ECOG PS 1, age ≥65 years, negative PD-L1 status and high tumor burden were associated with better OS in S+D+T in terms of HR. Clinical trial information: NCT02967692.

9575 Background: Both anti-PD-1 antibodies and BRAK/MEK inhibitors (BRAF/MEKi) reduce the risk of recurrence for patients with resected stage III melanoma. For patients with V600 BRAF-mutated melanoma who recur with resectable disease on or after adjuvant, many may be suitable for ‘second adjuvant' treatment after surgery. We sought to examine the efficacy and safety of ‘second adjuvant’ BRAF/MEKi in patients who recurred despite adjuvant PD-1 based immunotherapy. Methods: Patients with V600 BRAF-mutated melanoma treated with adjuvant PD-1 based immunotherapy for resected stage III/IV disease who recurred, underwent resection of recurrence and were then treated with adjuvant BRAF/MEKi were identified retrospectively from 13 centres. Demographics, disease characteristics, treatment details, and outcome data were examined. Results: 55 patients were included; median age at commencement of PD-1 was 53y, most were V600E (91%) and had IIIB (42%) or IIIC (44%) melanoma. PD-1 based adjuvant therapy included nivolumab (71%), nivolumab plus ipilimumab (14%), pembrolizumab (13%) and pembrolizumab plus mRNA-4157 vaccine (2%). Patients had initial recurrence after mean 8.4 months (95% CI 7.4-10.6), mainly while on treatment (65%), in regional nodes (42%), in-transit metastases (ITMs; 38%), both regional nodes and ITMs (7%) and distant metastases (13%). Surgical management included CLND (36%), selected nodal resection (11%), ITM resection (33%) and resection of distant metastasis (13%). A minority had adjuvant radiotherapy (17%). Stage at start of second adjuvant BRAF/MEKi included IIIB (29%), IIIC (53%) IIID (4%) and IV (15%). Patients received dabrafenib and trametinib (95%, N = 52) and encorafenib and binimetinib (5%, N = 3). After a median follow up of 21.4 months (19.7-25.4), 17 (31%) patients have recurred again. Mean duration of treatment was 9 months (95% CI 7.4-10.6); 20% ceased for toxicity, 7% for recurrence and 35% were on treatment at last follow up. The most common toxicity was pyrexia (43%) and 21% patients experienced a severe (G3-4) adverse event. Median RFS was 33.4 months (14.3.7-NR) and median DMFS was not reached. At 12 months, 72% (59-88) of patients were recurrence free and 90% (81-100) were free of distant recurrence. For those whose disease recurred again, most recurred after cessation of second adjuvant BRAF/MEKi (13/17, 76%). 7 (41%) recurred locally and 8 (47%) recurred with new metastatic disease but none had brain metastases. Conclusions: This is the first study examining outcomes of patients receiving second adjuvant targeted therapy for melanoma, after failure of adjuvant PD-1 based immunotherapy. While RFS appears shorter compared to first line trials, second adjuvant treatment with BRAF/MEKi appears safe and active in preventing further recurrence. Further data on sequencing adjuvant therapies are needed.

Ein 54-jähriger Patient stellte sich notfallmässig im Akutspital vor wegen einer seit mehreren Stunden persistierenden Fazialisparese rechts, die nach einem mässigen Schmerz im Bereich des rechten Kieferwinkels auftrat.