Citations

Abstract Background: Dysregulated Notch signalling contributes to breast cancer development and progression, but validated tools to measure the level of Notch signalling in breast cancer subtypes and in response to systemic therapy are largely lacking. A transcriptomic signature of Notch signalling would thus be warranted, and in this report, we have established such a classifier. Methods: To generate the signature, we first identified Notch-regulated genes from six basal-like breast cancer cell lines subjected to elevated and reduced Notch signalling by culturing on immobilized Notch ligand Jagged1 or blockade of Notch by g-secretase inhibitors, respectively. From this cadre of Notch-regulated genes, we developed candidate transcriptomic signatures that were trained on a breast cancer patient dataset (the TCGA-BRCA cohort) and a broader breast cancer cell line cohort and sought to validate in independent data sets. Results: An optimal 20-gene transcriptomic signature was selected. We validated the signature on two independent patient datasets (METABRIC and Oslo2) and it showed an improved coherence score and tumour specificity compared with previously published signatures. Furthermore, the signature score was particularly high for basal-like breast cancer, indicating an enhanced level of Notch signalling in this subtype. The signature score was increased after neoadjuvant treatment in the PROMIX and BEAUTY patient cohorts, and a lower signature score generally correlated with better clinical outcome. Conclusions: The 20-gene transcriptional signature has the potential to better stratify patients and to evaluate the response of future Notch-based therapies for breast cancer. Citation Format: Eike-Benjamin Braune, Felix Geist, Xiaojia Tang, Krishna Kalari, Judy Boughey, Liewei Wang, Roberto A. Leon-Ferre, Antonino B. D’Assoro, James N. Ingle, Matthew P. Goetz, Kang Wang, Theodoros Foukakis, Anita Seshire, Dirk Wienke, Urban Lendahl. Identification of a Notch transcriptomic signature for breast cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B013.

Abstract Monoclonal gammopathy of undetermined significance (MGUS) is the most common plasma cell dyscrasia, present in ~3% of the population over 50yo. MGUS carries a 1% per year risk of malignant transformation for the rest of the affected individual’s life; long-term followup is recommended for all patients with MGUS. Different risk stratification models exist to evaluate potential for progression to malignancy. The Mayo risk model, published in 2005, uses the presence of 3 risk factors (abnormal free light chain (FLC) kappa/lambda ratio (KLr), M-spike ≥1.5 g/dL, non-IgG isotype) to confer a 3% per year risk of progression instead of the average 1%. For many years, the only FDA-approved measurement of FLC was the FreeLite assay (Binding Site), which uses polyclonal sheep antibodies. Recently, other FLC assays have become available in the US, including the Sebia FLC ELISA, which employs rabbit polyclonal antibodies. The assays have similar reference intervals (RI), however differences in analytical performance between the FreeLite and Sebia were previously reported. The objective of this study was to determine the performance of the Sebia FLC assay in the Mayo risk stratification model of MGUS patients for progression in comparison to FreeLite. Cryopreserved serum samples from a cohort of 923 MGUS patients with available long-term clinical followup (median follow-up time: 7.7years, range: 0.0 to 46.9) was used to measure FLC using Sebia ELISA on a DS2 automated platform (Dynex) and FreeLite on a Siemens BNII nephelometer. Passing-Bablok (P-B) regression and Spearman correlation were used to compare the KLr between assays. Cox proportional hazards models for progression to multiple myeloma or a related plasma cell malignancy were used to estimate the prognostic effect and ability to discriminate low and high risk of abnormal KLr for each assay. Analyses were carried out in R software. Correlation between Sebia and FreeLite KLr had a Spearman r = 0.796; P-B fit: Sebia KLr = 0.825*(FreeLite KLr) – 0.048, 95% CI of slope: 0.810-0.839). With FreeLite, 32.9% of patients had a KLr outside RI for the method. For Sebia, 48.0% of patients had a KLr outside the method specific RI. Despite the individual samples analytical disagreement, both assays showed similar clinical performance for risk stratification: Sebia abnormal KLr was associated with a hazard ratio (HR) of 2.77 (95%CI: 1.79-4.28 c-statistic=0.6505) for progression, while FreeLite abnormal KLr was associated with a HR of 3.31 (95%CI: 2.20-5.00, c-statistic=0.6529), and the difference in c-statistics was not statistically significant (p=0.93). The risk assessment is performed only once per patient, at the initial diagnosis of MGUS. The similarity in clinical performance between FreeLite and Sebia assays support the use of either method as a predictor for risk of progression for MGUS patients.

Abstract Background Aortic pseudoaneurysms are complications that arise following cardiac surgery, thoracic trauma, infections, or inflammatory conditions. The mainstay treatment for aortic pseudoaneurysm is surgical management. Given significant morbidity and mortality related to thoracotomy, high-risk patients are not considered for cardiac surgery. Novel percutaneous repair using a variety of devices are being explored, especially in those with prohibitive risk for cardiac surgery. Case summary This case describes the use of an Amplatzer atrial septal defect (ASD) occluder device to manage an aortic pseudoaneurysm in a 69-year-old male who had previously undergone coronary artery bypass graft surgery and pericardial drainage for purulent pericarditis. Following successful implant, there were no complications seen after 2 years of follow-up. Discussion Percutaneous closure of a mycotic pseudoaneurysm with an Amplatzer ASD occluder device can be a safe and efficacious treatment option, especially in patients with prohibitive surgical risk.

ABSTRACT Early COVID-19 convalescent plasma (CCP) transfusion to outpatients with COVID-19 decreases progression to hospitalization, but the mechanism of how CCP reduces severity is unknown. Among 882 COVID-19 participants transfused with CCP or control plasma in a randomized controlled trial, 21 cytokines and chemokines were measured using electrochemiluminescence assays. Wilcoxon rank sum tests were used to evaluate the difference between early (transfused within 5 days of symptom onset) CCP vs early control plasma and late (transfused 6–9 days after symptom onset) CCP vs late control plasma at each visit. Linear mixed-effect models were used to assess the difference in the slope of cytokine change. Median cytokine and chemokine levels were similar between the early CCP and early control groups pre-transfusion. At the day 14 visit, only the median IL-6 ( P = 0.014) and IL-16 ( P = 0.036) levels were lower in the early CCP group compared to the early control group, but these differences were not statistically significant after correcting for multiple comparisons (requiring P < 0.0024). IL-6 levels decreased significantly faster in the early CCP group from screening to the day 14 visit compared to the early control group ( P < 0.001). No difference was observed in the slope of cytokine change from screening to day 90 between early CCP and early control groups. Late control and late CCP arms showed similar cytokine and chemokine levels through study follow-up. One mechanism by which early CCP transfusion reduces hospitalization may be by decreasing IL-6 levels, as the reduction is associated with better recovery from COVID-19. IMPORTANCE This study examined the role that cytokines may have played in the beneficial outcomes found when outpatient individuals infected with SARS-CoV-2 were transfused with COVID-19 convalescent plasma (CCP) early in their infection. We found that the pro-inflammatory cytokine IL-6 decreased significantly faster in patients treated early with CCP. Participants with COVID-19 treated with CCP later in the infection did not have the same effect. This decrease in IL-6 levels after early CCP treatment suggests a possible role of inflammation in COVID-19 progression. The evidence of IL-6 involvement brings insight into the possible mechanisms involved in CCP treatment mitigating SARS-CoV-2 severity.

Abstract Background Optimizing antimicrobial regimens for outpatients with community-acquired pneumonia (CAP) represents an area of opportunity for ambulatory antimicrobial stewardship programs. A pre-populated, antibiotic order panel for outpatient respiratory syndromes was implemented in the Mayo Clinic Enterprise on 1/4/2021. For CAP, it provides national guideline adherent regimens (i.e., selection, dosing, and durations) by patient comorbidity and beta-lactam allergy status. We aimed to assess impacts of panel use on antibiotic prescribing in outpatients with CAP. Methods This retrospective review included Mayo Clinic outpatient encounters from Minnesota in 2021 and 2022. Eligible encounters used a CAP-related primary ICD-10 code, conveyed intention to treat CAP in encounter notes, and were performed by primary care, emergency department, or urgent care clinicians who managed ≥1 CAP patient with the panel and ≥1 without the panel during the study period. Encounters were excluded if patients were already receiving antibiotics at the time of encounter. The primary outcome was adherence (drug and duration) to guideline recommendations. Secondary outcomes included utilization rate by agent and therapy duration. Outcomes were analyzed with Kruskal-Wallis rank sum and Pearson’s chi-squared tests (α level = 0.05). Results 352 encounters (134 panel vs. 218 non-panel) were included. Prescribing was guideline adherent in 61.9% and 29.4% (p&lt; 0.01) of panel and non-panel encounters, respectively. The most common reason for guideline non-adherence during panel use was inappropriate drug selection (n = 45/51, 88.2%). This was predominantly driven by use of the incorrect section of the treatment panel based on patient comorbidity status (n = 30/45, 66.7%). Individual antibiotic utilization rates differed between panel and non-panel cohorts (Table 1), with higher rates of amoxicillin and amoxicillin/clavulanate use and lower rates of azithromycin and doxycycline use in the panel cohort. Durations &gt;5 days were more common in the non-panel as compared to the panel cohort (34.4% vs. 7.5%, p &lt; 0.01). Conclusion Use of a pre-populated antimicrobial order panel in outpatients with CAP resulted in greater adherence to national guideline recommendations. Disclosures Paschalis Vergidis, MD, MSc, AbbVie: Advisor/Consultant|Ansun: Grant/Research Support|Cidara: Grant/Research Support|Scynexis: Grant/Research Support

AimDebridement, antibiotics, and implant retention (DAIR) is a viable treatment option for acute periprosthetic joint infections (PJI). The landmark DATIPO trial of Bernard et al. concluded that six weeks is not non-inferior to 12-week antibiotic therapy for DAIR. However, it is unknown if suppressive antibiotic treatment (SAT) would improve patient outcomes. Therefore, our study aims to evaluate the utility of SAT after 12 weeks of therapy.MethodWe performed a retrospective study of patients with acute hip or knee PJI managed with DAIR at five institutions; in the U.S. (n=1), Netherlands (n=3), and Spain (n=1) from 2005–2020. We analyzed the effect of SAT using a Cox model among patients after 12 weeks of antibiotic treatment. The primary covariate of interest was whether the patient was on antibiotics after week 12, which was coded as a time-varying covariate. We decided a-priori to control for the clinically important risk factors such as age, sex, type of infection, modular exchange, joint, and presence of bacteremia and Staphylococcus aureus. We excluded patients who died, had treatment failure, or were lost to follow-up before 12 weeks. We defined treatment failure as infection recurrence (same or different organism), unexpected reoperation, or death due to infection.ResultsThere were 504 patients included in the study. The majority were female (58%, n=292), with a mean age of 70 years ago (SD 11). Hips and knees were equally proportioned. Primary arthroplasties represented 69% of the total cohort (n=349). Treatment failure was 11.9% in the total cohort (n=60). There was no statistically significant association between SAT after 12 weeks and treatment failure (HR 1.25, p=0.45, 95% CI 0.70–2.24). This finding was consistent across different subgroups, including hip or knee joints, early or late acute infections, cohort, and a subgroup of knee joints after 180 days.ConclusionsSAT after 12 weeks of antibiotic treatment for acute PJI managed with DAIR does not appear to improve patient outcomes.

Local production of growth factors within the airway with autocrine/paracrine effects can promote features of asthma. Here, we show that glial-derived neurotrophic factor (GDNF) is a procontractile and proremodeling factor that contributes to allergen-induced airway hyperreactivity and tissue remodeling in a mouse model of asthma. Blocking GDNF signaling attenuates allergen-induced airway hyperreactivity and remodeling, suggesting a novel approach to alleviating structural and functional changes in the asthmatic airway.

Paediatric trigger finger is rare compared to adult trigger finger or paediatric trigger thumb, and the aetiology is unclear. Proposed causes include local trauma, anatomical anomalies and systemic conditions. The aim of the present study was to detail the anatomical causes of surgically treated paediatric trigger fingers and provide an operative algorithm based on the anatomical findings. A total of 76 trigger fingers in 38 patients were identified retrospectively at our institution between 1975 and 2022. In total, 41 fingers in 26 patients had anatomical variations. A nodular thickening on the tendon, similar to Notta’s nodule in trigger thumbs, was the most common anatomical cause. Abnormal decussation of the flexor digitorum superficialis tendon was the second most common variation. The recurrence rate was significantly lower after resection of one slip of the flexor digitorum superficialis tendon compared to other surgical techniques in these patients. We recommend that surgeons assess for possible anatomical variation during surgery for the trigger finger. Level of evidence: IV

Abstract Although immune checkpoint inhibition (ICI) has produced profound survival benefits in a broad variety of tumors, a proportion of patients do not respond. Treatment failure is in part due to immune suppressive tumor microenvironments (TME), which is particularly true of hepatocellular carcinoma (HCC). Since oncolytic viruses (OV) can generate a highly immune-infiltrated, inflammatory TME, we developed a vesicular stomatitis virus expressing interferon-ß (VSV-IFNß) as a viro-immunotherapy against HCC. Since HCC standard of care atezolizumab/bevacizumab incorporates ICI, we tested the hypothesis that pro-inflammatory VSV-IFNß would recruit, prime, and activate anti-tumor T cells, whose activity anti-PD-L1 ICI would potentiate. However, in a partially anti-PD-L1-responsive model of HCC, addition of VSV-IFNß abolished anti-PD-L1 therapy. Cytometry by Time of Flight showed that VSV-IFNß expanded dominant anti-viral effector CD8 T cells with concomitant, relative disappearance of anti-tumor T cell populations which are the target of anti-PD-L1. However, by expressing a range of HCC tumor antigens within VSV, the potent anti-viral response became amalgamated with an anti-tumor T cell response generating highly significant cures compared to anti-PD-L1 ICI alone. Our data provide a cautionary message for the use of highly immunogenic viruses as tumor-specific immune-therapeutics by showing that dominant anti-viral T cell responses can inhibit sub-dominant anti-tumor T cell responses. However, by chimerizing anti-viral and anti-tumor T cell responses through encoding tumor antigens within the virus, oncolytic virotherapy can be purposed for very effective immune driven tumor clearance and can generate anti-tumor T cell populations upon which immune checkpoint blockade can effectively work.