Citations

Background: Cardiac fibrosis is a central pathological process that leads to worse outcomes in various cardiomyopathies. Recent evidence shows that CDCP1 (CUB domain-containing protein 1) modulates myocardial recovery by attenuating human cardiac fibroblast (HCF) proliferation. This study investigates the hypothesis that selective targeting of the CDCP1 cleavage domain can mitigate fibroblast proliferation, thereby offering a novel therapeutic approach to reducing cardiac fibrosis. Methods: A high-throughput in silico screening was performed using the Enamine compound library, focusing on structural regions that include the cleavage and adjacent sites of CDCP1 . A total of 147 candidate compounds were prioritized based on docking scores and binding stability profiles. Selected compounds were subsequently evaluated in vitro using HCF cultures seeded at 3,000 cells/well in 96-well plates. Each compound was administered at 10 μM concentration, and cell proliferation and viability were assessed by time-lapse imaging in the Incucyte® system at 24 and 96 hours. All experiments were done in triplicate with appropriate DMSO vehicle controls. Results: Compound C3 significantly reduced HCF proliferation (Fig B) to 27.3±2.4% relative to DMSO controls (99.9±0.5%, P <0.001) at 96 hours. Detailed structural modeling indicated that C3 binds to the CDCP1 cleavage site (Fig C) with a favorable Glide XP docking score of -7.66 kcal/mol. The interaction is stabilized by hydrogen bonds with Lys365 and Cys374 (Fig D), and supplementary hydrophobic interactions between aromatic rings and aliphatic groups, which contribute to a strong inhibitory effect. Conclusion: Targeting the CDCP1 cleavage domain with compound C3 effectively diminishes HCF proliferation in vitro. Therefore, these results substantiate the therapeutic potential of CDCP1 inhibition in cardiac fibrosis. Ongoing in vivo studies will explore the translational relevance of these findings.

BACKGROUND The use of Mohs micrographic surgery as a treatment for melanoma is rising, but the reliability of Mohs surgeons in assessing MART-1 melanoma en-face margins has not been evaluated. OBJECTIVE To evaluate interrater and intrarater reliability of Mohs surgeons in interpreting margins of early-stage melanoma. METHODS Twenty Mohs surgeons were asked to independently review images of frozen section MART-1 en-face peripheral margins of in situ or early-stage melanoma. Surgeons determined margins as positive or negative at initial evaluation and 6 weeks later. Primary outcomes were interrater and intrarater reliability. RESULTS Interrater agreement was 84.1% (95% confidence interval [CI]: 75.5%–92.8%) for assessment 1 and 87.5% (95% CI: 78.4%–96.4%) for assessment 2, with kappa values 0.68 (95% CI: 0.50–0.82) and 0.75 (95% CI: 0.57–0.88). Average intrarater percent agreement was 95.0% (95% CI: 70.6%–100.0%) with average kappa 0.90 (95% CI: 0.50–1.00). CONCLUSION Substantial interrater and nearly perfect intrarater agreement was identified among surgeons assessing melanoma margins utilizing MART-1 immunostaining, demonstrating consistent and reproducible assessment of melanoma margins during Mohs cases.

OBJECTIVE The Centers for Medicare & Medicaid Services (CMS) requires a low C-peptide level for insulin pump coverage unless the individual is β-cell autoantibody positive, which precludes coverage of automated insulin delivery (AID) systems for many people with type 2 diabetes. RESEARCH DESIGN AND METHODS In the Randomized Trial Evaluating the Efficacy and Safety of Control-IQ+ Technology in Adults With Type 2 Diabetes Using Basal-Bolus Insulin Therapy study evaluating the t:slim X2 insulin pump with Control-IQ+ technology, adults with insulin-treated type 2 diabetes were categorized into high C-peptide (n = 195) and low C-peptide (n = 59) groups based on CMS criteria. RESULTS In the AID group, mean HbA1c decreased from baseline by 0.8%, which was significantly greater than in the control group with both high (P &lt; 0.001) and low (P = 0.02) C-peptide levels. Results were similar in participants ≥65 years old. CONCLUSIONS The benefit of AID is present with high and low C-peptide levels. Thus, requiring a low C-peptide level as a prerequisite for AID therapy is not warranted.

Abstract Bispecific T-cell engagers (TCEs) targeting B-cell maturation antigen (BCMA) and CD3, induce deep hematologic responses in ∼60% of heavily pretreated patients with multiple myeloma (MM). We and others found that high tumor burden leads to resistance to TCE and novel strategies are urgently needed to improve responses in this setting. Ikaros degraders, including immunomodulatory drugs (IMiDs) and cereblon E3 ligase modulatory drugs (CELMoDs), represent logical partners for TCEs due to their direct anti-MM effects and additional immune-stimulatory activity; however, it is unclear how to optimally combine them with TCEs. Taking advantage of the immunocompetent IMiD-sensitive Vk∗MYChCRBN murine model of MM, we optimized strategies to overcome primary resistance to BCMA-TCEs and achieve sustained remission, while maintaining a manageable safety profile. The addition of anti–programmed cell death protein 1 (PD1) and pomalidomide reduced the T-cell exhaustion that occurs in response to TCEs in high tumor burden settings. This allowed for a higher degree of T-cell activation and significant improvement in response rates but also increased risk of lethal cytokine release syndrome (CRS). To moderate the response and prevent CRS, we evaluated Ikaros degraders and dexamethasone (DEX) with step-up–dosed TCEs. Pretreatment with iberdomide and DEX reshaped the bone marrow T-cell compartment, promoted infiltration of naïve T cells, and generated 100% response rates and the longest survival in subjects with high tumor burden. This was accompanied by more favorable T-cell profiling, with limited expansion of regulatory T cells and exhaustion. Overall, administering a TCE after DEX and iberdomide treatments provided deeper and more durable responses with a reduced risk of CRS.

9021 Background: Home call is an expected trainee responsibility in many hematology-oncology (HO) training programs although the specific duties and frequency vary. Home call is associated with sleep deprivation and burnout . The Accreditation Council for Graduate Medical Education (ACGME) outlines that home call should not prevent adequate rest or personal time and that the clinical time spent must be counted toward duty hours. However, little is known about the educational value or impact of home call. We sought to analyze the volume, perceived value, and effects of oncology home call on HO fellows. Methods: We completed a review of the pager log of the outpatient/after hours oncology pager (OP) at a single 2059 bed tertiary medical center from 1/1/23-12/31/24. The HO fellow carries the OP afterhours and on weekends except for 7am-12pm on Saturday/Sunday. The pager receives all consult calls from the emergency department and inpatient teams requesting verbal communication (in addition to the electronic order), critical results, and outpatient patient calls on matters related to oncology (hematology not included). Patient calls are not triaged and are routed through the hospital operator directly to the OP. Overnight home call is maximum 3 times per week without a post call day. An optional survey was distributed to fellows in May 2024 to assess fellows’ experiences with the OP using a 5-point Likert scale and free response. Results: There were 80,672 and 87,605 oncology patient visits in 2023 and 2024 respectively at the analyzed institution. The OP received a total of 7,239 pages over the analyzed period. Fellows received a mean of 5.8 pages per weeknight call shift and 8.8 pages per weekend call shift. The survey response rate was 19/33 (42%) HO fellows. Respondents were 58% male and included first (42%), second (26%), and third year (32%) fellows. 89% of respondents reported that most pages overnight were from outpatients and 0 respondents felt that answering patient calls required a physician. Most fellows (79%) did not report educational value from holding the OP and 63% of fellows felt that holding the OP negatively impacted their performance at work the next day. For nights that received more than 3 calls, 95% fellows reported feeling not well rested. In addition, a majority of negative impact on their wellness including anxiety and inability to exercise or socialize when holding the OP. Conclusions: The results from our single-institution study indicate that home call could represent a major opportunity to improve the wellness of trainees without negatively impacting their education. More research is needed to understand what the primary contributors are for the negative experiences and perceptions while developing sustainable systems and approaches for efficiently handling oncology pager traffic.

Abstract Background/Introduction Multielectrode mapping catheters enhance the speed and accuracy of 3-dimensional data collection. However, with variable catheter configurations, data acquisition and efficiency may differ. We sought to compare the HD Grid X mapping catheter to a multi linear 8-spline catheter (spline catheter) with respect to chamber modeling speed and accuracy in in-vivo and bench setups. Methods In-vivo: In 6 pigs, 4 physicians used each catheter in a randomized order to create unedited models of the left atrium and ventricle (LA and LV) during coronary sinus atrial pacing. A sensor-enabled ablation catheter marked five locations per chamber while applying 10-15g of force. These markers, which denoted the ‘true’ location of the endocardial surface, were compared to the nearest surface location defined by each mapping catheter. Bench: In a tank setup designed to emulate an LA to pulmonary vein (PV) transition, chamber models were created during robotic manipulation of each mapping catheter. Resulting models were compared to a "gold-standard" model generated using robotic manipulation of sensor-enabled ablation catheters. Additionally, a static shape analysis was performed with each catheter held by a fixture in a deformed (HD Grid X catheter-bent 90o degrees; spline catheter-3 splines bunched) and undeformed state. Images of the physical catheters were captured to determine the true catheter shape and were compared to the renderings from the respective electroanatomical mapping systems (EnSite X v3.1 and Carto v7.2). Results In-Vivo: The mean error between the ablation catheter generated points and the models for HD Grid X trended lower than for the spline catheter by 11.7% (p=0.63; 2.57mm, 2.91mm) in the LA. In the LV, the mean error for HD Grid X was 34.4% (p=0.04; 2.04 mm, 3.67mm) less than for the spline catheter. In the LA, time for model creation for HD Grid X trended higher than for the spline catheter by 14.0% (p=0.34; 524s, 451s). However, in the LV, modeling time for HD Grid X was 22.9% (p=0.05; 368s, 478s) less than for the spline catheter. Bench: Compared to the ablation catheter created models, HD Grid X had a median bloat of 1.70mm (5.91mm max) while the spline catheter had 2.53mm (11.45mm max). The RMS error (mm) for the static shape analysis of electrode positions in an undeformed state was 0.60 for HD Grid X and 2.26 for the spline catheter. In a deformed state, the error was 0.82 for HD Grid X and 2.07 for the spline catheter. Conclusion In this translational model, the HD Grid X catheter created faster and more accurate unedited LV model geometry than the spline catheter, with no statistically significant difference noted in the LA. Bench data further supports the enhanced geometry accuracy seen in-vivo with HD Grid X, which may result in superior anatomical delineation, and faster mapping data acquisition times.

Abstract Background: Targeted agents, such as nanobodies, can be covalently linked to radionuclide chelators for theranostics. Nanobodies are single-domain immunoglobulin variable regions with a short blood half-lives and high specificity. Calreticulin (CALR) is endoplasmic reticular (ER) protein that translocates to the cell surface upon induction with certain agents, namely doxorubicin. We hypothesized surface CALR on tumors could be targeted using a novel nanobody after induction with doxorubicin. Methods: Studies were conducted using in vitro and in vivo models of pancreatic ductal adenocarcinoma (PDAC). Surface CALR expression was determined by western blot on fractionated lysates, flow cytometry, or immunofluorescence (IF). Doxorubicin was administered by intraperitoneal injection to mouse models of PDAC. The anti-CALR nanobody was developed via the panning of a synthetic nanobody phage display library. The top CALR-binding nanobody was confirmed by ELISA, immunohistochemistry (IHC), and flow cytometry. For in vivo studies, the nanobody was conjugated with the chelator NOTA and radiolabeled with 64Cu. PET images were acquired 1-hour after injection. Significance was determined using an independent t-test and p values &lt; 0.05 were considered statistically significant. Results: PDAC cells treated with doxorubicin showed peak surface CALR expression between 24 and 48 hours. Flow cytometry revealed that 61.7% of live PDAC cultured cells treated for 24 hours expressed surface CALR, compared to 2.2% in controls (p &lt; 0.001). In a subcutaneous syngeneic PDAC mouse model, two doses of doxorubicin 48 hours apart significantly increased surface CALR, with 30.4% of live-cells expressing CALR in treated tumors versus 1.5% in controls (p &lt; 0.001). Similarly, doxorubicin-treated tumors from a PDAC patient derived xenograft (PDX) model had a 6.7-fold increase in live-cells expressing surface CALR compared to controls (p &lt; 0.01). IF confirmed a 1.4-fold increase in CALR expression in doxorubicin-treated tumors from the subcutaneous PDAC mouse model (p &lt; 0.01) and a 1.7-fold increase in the PDAC PDX model (p &lt; 0.01). Our anti-CALR nanobody has an apparent 37 nM affinity for recombinant CALR and successfully detected surface CALR by IHC and flow cytometry. In vivo PET imaging showed significant increased uptake of the 64Cu-NOTA-nanobody in tumors from doxorubicin-treated mice over controls, with no significant changes in heart, kidney, or liver accumulation by PET quantification and flow cytometry (p &lt; 0.05). Conclusions: Systemic doxorubicin treatment induces CALR surface translocation in tumors that can be successfully targeted with a radiolabeled nanobody for PET imaging. Targeting chemotherapy-induced surface CALR using our radiolabeled nanobody could provide a theragnostic strategy for the detection and treatment of PDAC. Citation Format: Rachael Guenter, Yuvasri Golivi, Lucinda Hall, Amro Abdelrahman, Chloe La Prairie, Caleb Miller, Tejeshwar C. Rao, Danielle M. Carlson, Mark J. Truty, Benjamin Larimer, J. Bart Rose. Detection of tumor cell surface calreticulin after doxorubicin treatment using a novel radiolabeled nanobody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 574.