Citations

Staphylococcus aureus skin colonization and eosinophil infiltration are associated with many inflammatory skin disorders, including atopic dermatitis, bullous pemphigoid, Netherton’s syndrome, and prurigo nodularis. However, whether there is a relationship between S. aureus and eosinophils and how this interaction influences skin inflammation is largely undefined. We show in a preclinical mouse model that S. aureus epicutaneous exposure induced eosinophil-recruiting chemokines and eosinophil infiltration into the skin. Remarkably, we found that eosinophils had a comparable contribution to the skin inflammation as T cells, in a manner dependent on eosinophil-derived IL-17A and IL-17F production. Importantly, IL-36R signaling induced CCL7-mediated eosinophil recruitment to the inflamed skin. Last, S. aureus proteases induced IL-36α expression in keratinocytes, which promoted infiltration of IL-17-producing eosinophils. Collectively, we uncovered a mechanism for S. aureus proteases to trigger eosinophil-mediated skin inflammation, which has implications in the pathogenesis of inflammatory skin diseases.

216 Background: PCa harbors recurrent FOXA1 alterations, yet distinct alteration types may drive divergent consequences. Here, we established several classes of FOXA1 alterations and evaluated their clinical outcomes, molecular correlates, and immunologic landscape in a large cohort of primary and metastatic PCa samples from Caris Life Sciences. Methods: We interrogated the Caris DNA (592-gene/whole exome) and RNA (whole transcriptome) NGS databases. FOXA1 alterations were annotated based on amino acid (a.a.) location and prior functional studies (Table). Real-world overall survival (OS) was determined from insurance claims data using Kaplan-Meier estimates. Gene set enrichment analyses (GSEA) was used to estimate signaling pathway activity. Immune-cell fractions were inferred from bulk RNA-seq using quanTIseq. All comparisons are made relative to FOXA1 WT cases. Results: The overall prevalence of FOXA1 alterations was 16%, with no enrichment in metastatic PCa samples (15.5%). Class 2 mutations were enriched in histologic NEPC, were associated with a classical NEPC mRNA signature, and showed poor survival with ADT (HR 5.6, 95% CI: 2.5–12.5, p<0.001). Conversely, metastatic PCa patients with Class 1B mutations had numerically improved survival with ADT (HR 0.76, 95% CI: 0.50–1.14, p=0.18). All FOXA1 alterations (except Class 2) resulted in increased FOXA1 transcripts, with 1B and 1C having the greatest effects (q<0.0001). Class 0 and 3 alterations had 2–5 fold higher frequency of TMB-high and MSI-high status (q<0.05). Conversely, Class 1B exhibited lower TMB and markedly fewer TP53 mutations (35.7% vs 20.3%, q<0.001) and TMPRSS2-ERG fusions (34.5% vs 4.6%, q<0.001). Class 1B was depleted of AR transcriptional signatures (q=0.01) but enriched of MYC signaling in GSEA analysis (FDR<0.001), and showed reduced expression of B7-H3. On immune-cell deconvolution analysis, Class 1B showed reduced dendritic cells, but increased B cells and neutrophils (DC: 1.96% vs 0.01%, B cell: 4.27% vs 5.29%, neutrophils: 5.05% vs 8.00%, each q<0.001). Conclusions: Different FOXA1 alterations exhibit divergent molecular and clinical features, and should not be interpreted in aggregate. In particular, Class 1B mutations are associated with a unique molecular and immunological landscape with potentially better outcomes to ADT, while Class 2 mutations are associated with NEPC phenotype with inferior ADT sensitivity. [Table: see text]

TPS602 Background: Poorly differentiated neuroendocrine carcinoma (NEC) is an aggressive malignancy comprising both pulmonary and extrapulmonary primary sites. NEC includes both small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC), as well as other neuroendocrine carcinomas arising from any primary organ. A substantial portion (~40%) of NEC arises from gastrointestinal primary sites. The optimal systemic therapy beyond first line platinum and etoposide is not established. There is a critical need to improve upon the median survival in the second line, as most patients do not survive more than 6 months. The efficacy of dual immune checkpoint inhibitor (ICIs) therapy in NEC shows some promise, but most tumors do not respond. One possible explanation for this is that the tumor microenvironment in NEC is non-inflamed. VSV-IFNβ-NIS is a vesicular stomatitis virus (VSV)-based oncolytic virus being tested in multiple early phase clinical trials. Preliminary studies of immune responses in patients receiving VSV-IFNβ-NIS therapy suggest some patients develop T cell responses to viral antigens and known tumor antigens. We hypothesize that VSV-IFNβ-NIS therapy may convert a non-inflamed or immune-excluded phenotype in NEC to a highly inflamed phenotype that sensitizes the tumor to ICIs. Methods: This is a phase 1-2 safety run-in study designed to determine the safety and efficacy of VSV-IFNβ-NIS in combination with dual ICI therapy, ipilimumab and nivolumab, followed by dose expansion in patients with refractory non-small cell lung cancer (NSCLC) or NEC. After a safety run-in, we will be testing the recommended phase 2 dose (RP2D) of VSV-IFNβ-NIS in an expansion cohort of patients with SCLC or NEC of any primary site. Patients must have previously progressed on at least one line of systemic therapy. Prior treatment with checkpoint inhibitors is permitted. Patients are treated with ipilimumab and nivolumab on day 1, followed by one RP2D of 1.0x10^11 TCID50 VSV-IFNβ-NIS on day 4, followed by nivolumab every 3 weeks and ipilimumab every 6 weeks until progression, up to 2 years. The primary objective is to estimate the response rate by RECIST 1.1. Secondary objectives include estimation of disease-control rate, duration or response, progression-free survival, overall survival, and safety signals. The NEC expansion cohort will seek to enroll 10 patients. If at least one objective response is observed, and safety is confirmed, the regimen will be considered for future study. Clinical trial information: NCT03647163 .

AbstractBackgroundWe examined neuropsychiatric symptoms (NPS) and psychotropic medication use at the midway point of data collection of the Longitudinal Early‐onset Alzheimer’s Disease Study (LEADS). We compared amyloid‐positive early‐onset Alzheimer’s disease (EOAD) participants and amyloid‐negative early‐onset non‐Alzheimer’s disease [EOnonAD]) participants across NPS domains and psychotropic medication categories.Method282 participants enrolled in LEADS were compared across diagnostic groups – amyloid‐positive EOAD (n = 212) and amyloid‐negative EOnonAD (n = 70). All participants were between ages 40 and 64 at baseline. NPS were measured with the Neuropsychiatric Inventory – Questionnaire (NPI‐Q) and Geriatric Depression Scale – Short Form (GDS‐SF). Medications were categorized into psychotropic category (e.g., antidepressants, antipsychotics, benzodiazepines). Groups were compared on NPI‐Q using binary logistic regression adjusting for sex and disease severity, on GDS‐SF using linear regression adjusting for sex and disease severity, and on psychotropic medication use using Chi square or Fisher’s exact test.ResultDemographic data are presented in Table 1. Average total NPI‐Q score was higher in EOnonAD than EOAD (p = .002, ŋp 2 = .03). Regardless of diagnostic group, informants endorsed Affective behaviors most frequently (76.2%). EOAD informants endorsed fewer Distress‐Tension behaviors (p = .02, OR = .498) and Impulse Control behaviors (p = .01, OR = .438). EOAD informants also endorsed apathy (p < .001, OR = .316), irritability (p = .02, OR = .498), and disinhibition (p = .04, OR = .476) at lower frequency than EOnonAD. GDS‐SF showed that the EOnonAD participants self‐reported more symptoms of depression than the EOAD group (p = .002, ŋp 2 = .03). (Table 2A). A minority of participants, regardless of diagnostic group, reported psychotropic medication use (35%). There was higher use in EOnonAD (38%) than EOAD (24%) (p = .03, Cohen W = .14) (Table 2B).ConclusionNPS burden and psychotropic medication use were higher in EOnonAD than EOAD participants, despite EOnonAD being less severely impaired. LEADS continues to collect data. Future studies will examine etiologies that may be larger drivers of NPS than AD neuropathology, mediators (e.g., race, ethnicity) in the association between NPS and diagnostic group classication, compare NPS in EOAD vs. LOAD, and examine longitudinal changes in neuropsychiatric profiles.

Purpose To investigate the gliding resistance dynamics between the supraspinatus (SSP) tendon and the coracoacromial arch, both before and after subacromial decompression (anterolateral acromioplasty) and acromion resection (acromionectomy). Methods Using 4 fresh‐frozen cadaveric shoulders, acromion shapes were classified (2 type I and 2 type III according to Bigliani). Subacromial bursa and coracoacromial ligament maintenance replicated physiologic sliding conditions. Gliding resistance was measured during glenohumeral abduction (0° to 60°) in internal rotation (IR) and external rotation (ER). Peak gliding resistance between the SSP tendon and the coracoacromial arch was determined and compared between intact, anterolateral acromioplasty, and acromionectomy. Results Peak SSP gliding resistance during abduction in an intact shoulder was significantly higher in IR than in ER (4.1 vs 2.1 N, P < .001). The mean peak SSP gliding resistance during 0° to 60° glenohumeral abduction in IR in the intact condition was significantly higher compared with the subacromial decompression condition (4.1 vs 2.8 N, P = .021) and with the acromionectomy condition (4.1 vs 0.9 N, P < .001). During 0° to 60° glenohumeral abduction in ER, mean peak SSP gliding resistance in the intact condition was not significantly different compared with the subacromial decompression condition (2.1 vs 2.0 N, P = .999). The 2 specimens with a hooked (i.e. type III) acromion showed significantly higher mean peak SSP gliding resistance during glenohumeral abduction in IR and ER when compared with the 2 specimens with a flat (i.e. type I) acromion (IR: 5.8 vs 3.0 N, P = .006; ER: 2.8 vs 1.4 N, P = .001). Conclusions In this cadaveric study, peak gliding resistance between the SSP tendon and the coracoacromial arch during combined abduction and IR was significantly reduced after anterolateral acromioplasty and was significantly higher in specimens with a hooked acromion. Clinical Relevance The clinical benefit of subacromial decompression remains unclear. This study suggests that anterolateral acromioplasty might reduce supraspinatus gliding resistance in those with a hooked acromion and in the typical “impingement” position.

Primary cardiac tumors (CTs) are exceptionally rare, and are predominantly benign masses. Myxomas make up more than 60% of these lesions and most frequently develop in the left atrium (LA), followed by the right atrium (RA). Carney complex (CNC) is a rare, typically autosomal dominant, multiple endocrine neoplasia characterized by cutaneous findings, myxomas, endocrine and/or nonendocrine neoplasms. We report a rare case of CNC involving biatrial and recurrent myxomas. A 36-year-old female presented to Cardiology Clinic at our center for management of CNC. Three years prior, she was evaluated at a local hospital for acute stroke where TTE showed a myxoma (2 x 2 x 2.5cm) attached to the left atrial septum, prompting resection. On followup TTE 2 years later, she had a mass in the LA, prolapsing through the mitral valve into the left ventricle. She underwent resection of the myxoma (2.9 x 3.9 cm) and left atrial appendage, which was complicated by recurrent stroke. She was found to have a PRKAR1A gene mutation (c.97 deletion) suggestive of CNC and was referred to our center. At Cardiology Clinic, she denied chest pain, dyspnea, presyncope, and syncope. Her father and children did not have the gene mutation. Exam revealed lentigines on her lower lip and pigmentation of an inner canthus. She was diagnosed with primary pigmented nodular adrenal disease by Endocrinology. On TEE, she was found to have a recurrent LA mass (1 x 1 x 0.8 cm) attached to the interatrial septum, but no right-to-left atrial shunt. This prompted surgery consultation. Numerous intracardiac myxomas were removed during surgery; one in the LA attached to the septum, 3-4 smaller ones, and one 2 cm myxoma located in the RA. The interatrial septum was also resected given recurrent myxoma in this region. She underwent cryoablation to prevent recurrence and did well post-surgery. CTs, which includes primary CTs and secondary metastatic disease, are uncommon where the former has an incidence of 0.001-0.3%. We presented a case of recurrent and biatrial cardiac myxomas in the setting of CNC, which is seldomly reported in the literature. Taken together, given the rarity of primary CTs, genetic predispositions or syndromes should be considered especially in the setting of recurrence and/or multiple masses.

Abstract Mpox, caused by infection with Monkeypox virus, usually presents as a mild, self-limited illness in immunocompetent persons that resolves within 2–4 weeks. Serious complications have been reported when mpox lesions involve vulnerable anatomic sites, such as the eye, and in those with substantial immunosuppression. We describe a patient with advanced human immunodeficiency virus infection and sustained viral shedding of mpox with ocular involvement, which resulted in vision loss.