Citations

Abstract eSource – particularly EHR-to-EDC – is an emerging paradigm in clinical research that enables automated transfer of electronic health record (EHR) data into electronic data capture (EDC) systems, with the potential to reduce site burden, improve data quality and accelerate oncology clinical trial workflows. However, widespread implementation remains limited due to technical, regulatory and operational barriers. To address these challenges, the European Institute for Innovation through Health Data (i~HD) launched the eSource Scale-Up Task Force in 2024. This multi-stakeholder initiative brings together leading oncology centres and pharmaceutical sponsors to establish a consensus-driven roadmap for eSource adoption. Central to this effort are three foundational resources: readiness criteria for early adopters, a performance indicator framework for monitoring success and an operational playbook to guide implementation. This article provides a structured overview of the Task Force’s objectives, collaborative model and outputs, with specific attention to its focus on interoperability, regulatory alignment and real-world validation. While initially developed for oncology, the Task Force’s framework is applicable across therapeutic areas characterized by data-intensive workflows.

OBJECTIVE To evaluate the impact of community paramedic (CP)-delivered, in-home diabetes self-management education and support (DSMES) for adults with poorly managed diabetes. RESEARCH DESIGN AND METHODS In a pragmatic, single-arm pilot trial, adults with HbA1c ≥9% and a recent emergency department or hospital visit received a 1-month CP-led DSMES intervention. Outcomes included HbA1c, health care engagement, and patient-reported satisfaction. RESULTS Seventy participants (median age 61 years, 50% rural, 84% with type 2 diabetes) completed the intervention. HbA1c declined from 9.8% to 8.2% at 4 months (P < 0.001). Engagement with primary care, endocrinology, and DSMES improved. Satisfaction was high (mean rating 9 out of 10). CONCLUSIONS CP-led DSMES improved glycemic management and care engagement in underserved populations. This scalable model warrants further study.

ABSTRACT Light chain multiple myeloma (LCMM) is a subtype of multiple myeloma (MM) characterized by the exclusive production of immunoglobulin light chains and accounts for 15%–20% of newly diagnosed MM. A comprehensive comparison of LCMM with MM producing intact immunoglobulin (non‐LCMM) remains limited. In this retrospective study, we described distinct clinical and cytogenetic features and assessed long‐term outcomes in 852 LCMM patients diagnosed between 01/01/2004 and 12/31/2022, compared with non‐LCMM controls matched for age, sex, and year of diagnosis. On univariable analysis, LCMM patients were more likely to present with elevated creatinine (> 2 mg/dL), beta‐2‐microglobulin ≥ 5.5 mg/L, elevated LDH, hypercalcemia, t(11;14), del(13q), and t(6;14). Conversely, IMS‐IMWG high‐risk disease, hyperdiploidy, t(4;14), and serum albumin < 3.5 g/dL were less common. On multivariable analysis, elevated creatinine (OR: 5.1, 95% CI: 1.2–27, p = 0.04), t(11;14) (OR: 2.6, 95% CI: 1.3–5.2, p = 0.006), and del(13q) (OR: 4.1, 95% CI: 2.1–8.2, p < 0.001) were independently associated with LCMM, while IMS‐IMWG high‐risk disease (OR: 0.3, 95% CI: 0.1–0.8, p = 0.02) and hyperdiploidy (OR: 0.3, 95% CI: 0.1–0.7, p = 0.002) were less frequent. Despite these differences, progression‐free survival with frontline treatment (HR: 0.97, 95% CI: 0.84–1.11, p = 0.63) and overall survival (HR: 0.99, 95% CI: 0.87–1.13, p = 0.94) were similar between LCMM and non‐LCMM patients. This study highlights the distinct clinical and cytogenetic features of LCMM, marked by higher rates of renal failure, t(11;14), and del(13q), lower prevalence of IMS‐IMWG high‐risk disease, and comparable survival outcomes.

Abstract BACKGROUND Mirdametinib is the first FDA-approved MEK1/2 inhibitor for both adults and children (≥2 years) with NF1 who have symptomatic PN not amenable to complete resection. We report updated results from the LTFU phase of the pivotal, phase 2b ReNeu trial (NCT03962543) evaluating the efficacy and safety of mirdametinib. MATERIALS AND METHODS In ReNeu, mirdametinib capsules or tablets for oral suspension (2 mg/m2 BID, max 4 mg BID) are administered in 3-weeks-on/1-week-off 28-day cycles. Following the 24-cycle (~2 years) treatment phase, patients could continue mirdametinib in an optional LTFU phase. These analyses are inclusive of the treatment and LTFU phases (data cutoff: June 12, 2024; an additional 9 months of cumulative data following the primary analysis). Exploratory analyses reported here included confirmed objective response rate (ORR; proportion of patients with ≥20% reduction of target PN volume from baseline on consecutive MRI scans within 2 to 6 months, assessed by blinded independent central review), duration of response (DoR), change from baseline in target PN volume, and safety. RESULTS Fifty-eight adults and 56 children were dosed with mirdametinib. Median (range) duration of mirdametinib treatment was 21.8 (0.4, 54.4) months in adults and 25.4 (1.6, 48.5) months in children. Among LTFU-eligible patients, 26/31 (84%) adults and 32/37 (86%) children entered the LTFU. Confirmed ORR was 47% (27/58; 95% CI, 33%, 60%) in adults and 55% (31/56; 95% CI, 42%, 69%) in children. Of patients with a confirmed objective response, 18 adults and 19 children achieved a deep response (best target PN volume reduction from baseline of &gt;50%). Median (range) best percentage change from baseline in target PN volume was -41% (-90%, 13%) in adults and -43% (-98%, 48%) in children. Median DoR was not reached. Treatment-related adverse events (TRAEs) in ≥25% of patients were dermatitis acneiform, diarrhoea, nausea, and vomiting in adults, and diarrhoea, dermatitis acneiform, and paronychia in children. Grade ≥3 TRAEs occurred in 17% of adults and 25% of children. Dose interruptions, dose reductions, and discontinuations due to TRAEs occurred in 9%, 17%, and 22%, respectively, of adults, and in 14%, 14%, and 9%, respectively, of children. CONCLUSIONS An increase in confirmed ORR was observed with longer duration of mirdametinib treatment, with additional deep responses achieved in both adults and children with NF1-PN. Mirdametinib continued to be well tolerated with a manageable safety profile and no new safety signals identified in the LTFU phase. SUPPORTED BY SpringWorks Therapeutics, Inc.

Abstract Background Pathogenic variants in the DMD gene are associated with Duchenne and Becker muscular dystrophy (DMD/BMD). Professional medical societies currently recommend DMD carrier screening for all patients who are pregnant or considering pregnancy. Such testing may identify intragenic duplications of DMD (i.e., involving one or more exons but fully contained with the gene) in patients without a personal or family history of DMD/BMD. These incidentally detected DMD intragenic duplications, however, pose significant challenges for variant interpretation. Pathogenicity of an intragenic duplication depends on its structural configuration. Tandem duplications may cause reading frame disruption and gene loss-of-function; conversely, non-tandem duplications may not disrupt gene function. Current carrier screening assays cannot determine the structural configuration of an intragenic duplication. The current guidelines (e.g., the ClinGen PVS1 decision tree) presume intragenic duplications are in tandem unless proven otherwise. If this presumption of tandem configuration is inaccurate, it may lead to overestimation of variant pathogenicity, potentially resulting in unnecessary invasive procedures (e.g., amniocentesis for prenatal diagnosis) and/or having other negative impacts with regards to prenatal decision-making. This study aims to evaluate the validity of this presumption for incidentally detected DMD intragenic duplications. Methods We performed high-coverage whole-genome long-read sequencing on the PromethION instrument (Oxford Nanopore Technologies) for 15 cases with previously identified DMD intragenic duplications. Among these cases, four had personal or family history of DMD/BMD, while 11 had no known history (i.e., incidentally detected). The structural configurations of the duplications were determined by an in-house bioinformatics tool and manual inspection of the alignment files. Results In all 4 cases with a known personal or family history of DMD/BMD, the DMD intragenic duplications were confirmed to be in tandem, aligning with expectations of their pathogenicity. Interestingly, among the 11 cases with incidentally detected DMD intragenic duplications, seven (64%) were found to involve interspersed duplications. In five of these seven interspersed duplication cases, the involved DMD exons were co-duplicated with distinct segments of the Xp arm located 0.5–30 Mb away, forming complex structural variants. In another case, the duplicated DMD exons have inserted into the Xq arm, about 90 Mb downstream of DMD. The final case involved the duplicated DMD exons inserted into a repetitive region most consistent with 9q12 (i.e., the 9qh region). Conclusions Our study reveals that while DMD intragenic duplications in patients with a personal or family history of DMD/BMD were consistently in tandem, a substantial 64% of incidentally detected DMD intragenic duplications were not in tandem. These findings have important implications for both clinicians and laboratorians. They challenge the presumption of tandem configuration for DMD intragenic duplications in individuals where the variants were identified incidentally, e.g., through carrier screening in those without a family history of DMD/BMD. In these cases, we recommend classifying the DMD intragenic duplications as variants of uncertain significance (VUS), unless there is evidence of tandem configuration.

Abstract Background The diagnosis of monoclonal gammopathies relies on the detection of monoclonal immunoglobulins (M-proteins) in serum or urine. Mass-Fix utilizes matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) to detect and quantify M-proteins. This method employs immunoaffinity enrichment using antibodies against heavy chains (HC) and light chains (LC), followed by MS analysis to determine M-protein isotypes. Mass-Fix has also revealed novel M-protein characteristics, including LC glycosylation and fragmentation, facilitated by measuring the mass of LC. LC glycosylation is as an independent risk factor for disease progression of monoclonal gammopathy of undetermined significance (MGUS), while light chain fragments have been postulated as the origin of amyloid light chain (AL) plaques. Since Mass-Fix enriches intact immunoglobulins before dissociating LCs, it potentially enhances fragment detection. However, the precise nature and clinical significance of these fragments remain to be fully elucidated. Methods Mass-Fix serum results from Mayo Clinic patients tested from September 10, 2018, to October 1, 2024, were reviewed for the presence of M-protein and LC fragments. The frequency and the isotype of fragment LC fragments was determined in the M-protein positive cohort (n=15410). Patients diagnosed with either MGUS (n=6996), AL amyloidosis (n=315), or both (n=32) who had positive M-protein results on Mass-Fix, either prior to or within one month after the diagnosis, were included for a retrospective clinical association study of LC fragments and disease. To validate that these fragments were not artifacts of MS analysis, PAGE gel analysis and Western blots were performed using clinical residual serum from 9 patients: 2 IgG/kappa and 3 IgG/lambda patients with detectable LC fragments and 2 IgG/kappa and 2 IgG/lambda patients without fragments. Samples were purified using antibodies against gamma heavy chains and reduced with TCEP prior to gel electrophoresis and Western blot. Results Of the 15410 patients with monoclonal proteins detected by Mass-Fix, 2896 (18.7%) had detectable LC fragments; kappa fragments in 1533 and lambda fragments in 1363. Most often, the fragments were observed in pairs, with combined molecular weight typically equaled that of the full-length monoclonal LC present in the same sample. LC fragments were observed more frequently among patients diagnosed with AL amyloidosis (118/347=34%) compared to those without the diagnosis (685/6996=10%), with an odds ratio of 4.75 (95% CI, 3.75-6.01). PAGE with Coomassie blue staining revealed bands with sizes representing LC fragments in the five M-protein samples with detectable LC fragments on Mass-Fix, while no such bands observed in those without LC fragments. Western blot using anti-kappa or anti-lambda antibodies confirmed the identity of the bands with higher molecular weight as a fragment of LC in each of the IgG/kappa and IgG/lambda samples. Conclusion Mass-Fix is able to discriminate LC fragments from intact LC based on their sizes. The detection of LC fragments with Western blot without ionization suggests a biological origin rather than analytical artifacts from MS. The clinical association study suggests that LC fragments may have utility in increasing the suspicion of AL amyloidosis in M-protein positive patients with LC fragments, potentially facilitating earlier intervention and improving patient outcomes.

Abstract Background The Freelite serum free light chain (FLC) assay has been widely used for detecting and monitoring monoclonal gammopathies. Reference intervals (RIs) established by Katzmann et al. in 2002 have served as the standard values for interpreting kappa/lambda FLC ratios. However, multiple reports suggested an assay drift and clinical laboratories started to move towards locally established RIs given the challenge in verifying original RIs. The assay drift over time increased kappa concentration measurements and was attributed to an interaction between the kappa FLC calibrator and serum proteins, including alpha-1-antitrypsin. A stabilized calibrator was developed to improve consistency of results with original RI. The objective of this study was to assess whether the new updated kappa calibrator would warrant a RI update. Methods Healthy adult donors’ serum samples were selected from the institution quality unit. Exclusion criteria included autoimmune diseases, cancers and renal disease. FLC measurements were obtained on the Optilite by turbidimetry using routine reagents for kappa (old lot); the new lot of reformulated kappa calibrator, and a single measurement for lambda FLC. FLC ratios were calculated with the old lot and new lot. All samples were tested by MASS-FIX to confirm absence of a monoclonal protein. Bootstrap resampling (10,000 replicates) estimated standard errors, with statistical significance defined as p &lt; 0.05. Clinical significance was assessed per CLSI EP28-A3 guidelines. A RI was considered for partitioning by sex if the mean difference between males and females exceeded 25% of the RI width or if &gt;4% of either sex had values beyond RI limits. Similar tests were applied to age groups (&lt;60 and =60 years). Results 465 donors (48.2% male, 51.8% female) aged 30-89 years were used. Sixteen donors with incidental monoclonal proteins identified by MASS-FIX were excluded, for a final n=449. No clinically significant relationships of results were found with sex or age. The updated kappa calibrator resulted in a measurable shift down in FLC values with the new lot of reagents. The kappa FLC concentration and corresponding FLC ratio decreased by a median -12.1%, see table 1 for absolute values When reviewing Optilite results of the new lot, 98/449 samples were outside the kappa concentration original RI (21%). Lambda concentration RI was shifted up on Optilite when compared to original RI but passes verification (1.6% of samples, acceptance criteria &lt; or =10%). 19 samples (4.2%) were outside the original RI for the FLC ratio of 0.26 to 1.65 (all &gt;1.65), which was originally established as a 100% diagnostic range. The calibrator reformulation, while decreasing test results by &gt;10%, was not sufficient to verify the original RI for kappa and still left a few cases outside the original diagnostic range for the FLC ratio. Conclusion This study assessed the impact of the stabilized calibrator on RIs for the Optilite Freelite assay. These findings suggest revisiting existing RIs to ensure continued accuracy in clinical interpretation and should be further evaluated with additional lots of reagents for robustness.

Abstract Background The use of autonomous mobile robots (AMRs) to move materials/supplies is long-standing in manufacturing/warehouse settings and is expanding into hospitals and clinical laboratories. The recently launched Proxie robot (Collaborative Robotics i.e. Cobot) is an AMR that can autonomously move existing carts between defined locations. However, AMRs pose new challenges compared to traditional lab automation. The aims of this study were to: i) perform functional validation to verify Proxie*s manufacturer performance specifications within the laboratory, ii) assess the risk of using Proxie to deliver laboratory specimens, and iii) pilot the use of the Proxie robot to autonomously deliver loaded carts from the Pathology case intake area to the sorting station at Mayo Clinic Laboratories. Methods Functional validation of Proxie consisted of verifying manufacturer’s performance specifications for the following robot parameters (5 test runs): maximum speed, emergency-stop, and ability to maintain localization, travel autonomously, stop and/or avoid moving/fixed objects, and park/unpark. Risk assessment for the robotic use case was performed by a multi-disciplinary team utilizing an AMR risk assessment tool developed by the institutional robotics group. Hazards were categorized as mechanical, electrical, noise, ergonomic, environmental, material/substance or combination risks. Injury severity, exposure(frequency), and avoidance scores were assigned to each hazard to determine negligible-, low-, medium-, high- or very high-risk levels. Proxie’s workstream was evaluated weekly over four weeks by measuring number of cart deliveries, total time/miles traveled, % autonomous deliveries(goal &gt;80%), % on-time deliveries, average±standard deviation(SD) time (min:sec±min:sec) for delivery/return trips, and dwell times at intake/sorting stations. Results Manufacturer’s performance specifications were verified in 100% of test runs. Proxie traveled at human walking speed, stopped within 1 second of emergency stop being enabled, maintained localization, and traveled autonomously for =5 consecutive workflow cycles. Proxie navigated through spaces =4’ wide along fixed pathways and stopped safely when encountering obstacles. Proxie navigated around people and carts in the main 6’ hallway if they were blocking &lt;2’ hallway width. For objects blocking &gt;2’, Proxie stopped and resumed motion after the object moved. After task completion, Proxie side-shifted into the AMR parking space stopping no closer than 7.8” from any object. Twenty-four potential hazards were identified through the risk assessment tool with all risk levels scored as negligible or low. Proxie completed 304 cart deliveries/returns operating 17:35 hours and traveling 11.5 miles during the pilot. The % autonomous deliveries for week 1-4 was 82%,88%,91% and 88%, respectively with =99% on-time deliveries. Delivery from pathology case intake to sorting station averaged 5:43±0:25 min and return trips averaged 3:32±0:34. Proxie dwell times were 13:10±0:33 and 37:34±0:23 min at the pathology intake and sorting stations, respectively. Conclusions The Proxie AMR was capable of successfully and autonomously moving carts with laboratory specimens between the pathology intake and sorting stations of the laboratory during the pilot study. Adding Proxie to this workstream translated to eliminating 5,800 steps and 4 hours 24 min of human cart-pushing per week. Incorporating Proxie into laboratory operations as a cart-moving AMR would increase efficiency and allow laboratory staff to focus on technical, non-repetitive work.

Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with limited treatment options and poor survival. This study explores how a medically supervised ketogenic diet (MSKD) impacts the gut microbiome and treatment response in patients with newly diagnosed metastatic PDAC receiving gemcitabine, nab-paclitaxel, and cisplatin chemotherapy. Methods: As part of a randomized Phase II trial, 32 evaluable patients (median age 65.9 years; 53% male), 16 were randomized to either MSKD or standard diet (SD) combined with chemotherapy. Stool samples were collected from 4 patients in the MSKD group (13 samples) and 8 patients in the SD group (23 samples). Deep shotgun metagenomic sequencing was conducted using NovaSeq (Illumina). Taxonomical and functional microbiome characterization was performed using MetaPhlAn 4.0 and HUMAnN 3.6 (The Huttenhower Lab, Harvard). Comprehensive bioinformatics analyses, using QIIME2, were performed to analyze microbiome composition and function over time. Results: Patients in the MSKD group showed better treatment responses overall. Microbiome profiles between the two groups remained distinct throughout therapy. Though not statistically significant due to sample size, MSKD patients showed lower alpha diversity (Shannon diversity; p-value=0.1339), likely reflecting reduced intake of fermentable fiber. Differential abundance analysis using the ANCOM-BC method revealed a significant enrichment of beneficial taxa in the MSKD group compared to the SD group (p&lt;0.05, log-fold change [lfc]≥2), including Akkermansia muciniphila (linked to improved response to immune checkpoint inhibitors; p=0.017931, q=1), Intestinimonas butyriciproducens (a short-chain fatty acid [SCFA] and butyrate producer; p=3.09E-05, q=0.017), and Streptococcus thermophilus (a supporter of gut mucosal health; p=1.15E-05, q=0.006). During the course of the study, only MSKD patients showed sustained increases in Roseburia hominis (SFCA/butyrate producer; p=3.94E-05, q=0.021) and Lacticaseibacillus rhamnosus (with anti-inflammatory and immune-modulating properties; p=7.28E-19, q=3.98E-16), along with a marked reduction in potentially pro-inflammatory Actinomyces spp.(p≤4.47E-05, q≤0.024). Functional profiling showed increased abundance of cancer-relevant microbial pathways in MSKD patients, including phosphatidate metabolism (PWY-7039; involved in lipid signaling and immune regulation; p=4.36E-04, q=0.20) and allantoin degradation (PWY-5705; linked to redox balance; p=9.16E-06, q=0.004). Conversely, L-ascorbate biosynthesis V (PWY-6415) was reduced (p=3.80E-04, q=0.17), likely due to decreased D-galacturonate substrate availability from fiber restriction. Conclusion: These findings suggest that an MSKD may beneficially modulate the gut microbiome in ways that support and enhance therapeutic response in patients with PDAC. Further validation in a larger cohort is warranted to confirm these results and improve analytical resolution. Citation Format: Keehoon Lee, Derek Cridebring, Gayle S. Jameson, Denis J. Roe, Erkut Borazanci, Diana L. Hanna, Caroline G.P. Roberts, Meredith S. Pelster, Richard C. Frank, Angela T. Alistar, Alan M. Miller, J. Erin Wiedmeier-Nutor, Sandra D. Algaze, Alison R. Zoller, Sarah J. Hallberg, Betsy C. Wertheim, Joshua D. Rabinowitz, Stephen Gately, Jennifer Keppler, Sunil Sharma, Drew W. Rasco, Daniel D. Von Hoff. Ketogenic Diet Modulates Gut Microbiome Composition and Enhances Treatment Response in Patients with Advanced Pancreatic Cancer: A Phase II Study [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr B094.