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TPS9607 Background: The majority of 100,000 annual new U.S. cases of mel consist of localized early-stage disease that undergo wide local excision (WLE) +/- SLN biopsy (SLNB). The tumor draining lymph node is the initial site of immune response including formation of tumor mediated immune suppression and pre-metastatic niches. SLN positivity is a key prognostic factor in early stage mel. Thus, the SLN is a target for local immune intervention to boost the antitumor response. Vusolimogene oderparepvec (RP1) is an intratumorally administered oncolytic immunotherapy with unique potential for neo-adjuvant therapeutic application. RP1 is constructed from a high potency HSV1 strain (RH018A) modified to replicate selectively in tumors (deletion of neurovirulence factors ICP34.5 and ICP47). RP1 encodes GM-CSF and a fusogenic GALV-GP R- protein to maximize oncolytic potency and induce immunogenic cell death. Preclinical and clinical data demonstrate robust antitumor efficacy (including non-injected lesions) of RP1 alone and in combination with checkpoint inhibitors in advanced mel. This trial addresses a crucial gap in understanding the impact of RP1 on SLN dynamics and preventing disease recurrence in high-risk patients (pts). We hypothesize that in pts with high risk, clinically node negative mel (pT3b-T4b), RP1 will reduce rates of SLN positivity as compared to a historic control by favorably reshaping the immune landscape of the primary tumor, SLN, and the peripheral blood. Methods: This is an investigator-initiated, single arm phase 1/2 trial (NCT06216938) designed to assess efficacy and safety of neo-adjuvant RP1 in high-risk, clinically node-negative, non-uveal mel. Eligibility criteria: pT3b, T4a, or T4b non-uveal mel with visible residual tumor or positive biopsy margins, ECOG ≤1, and no prior oncolytic virus therapy. Pts receive 3 doses of neo-adjuvant RP1 (10e6 PFU day 1, 10e7 PFU on days 15 and 21), injected at the primary tumor site followed by standard WLE and SLNB within 35 days of dose 1. Biopsy of residual tumor or archival tumor tissue is obtained pre-RP1 and archival tissue from WLE and SLNB is obtained post-RP1. Blood samples are obtained with each RP1 dose and 3 months post-therapy. Pts are followed for 3 years. Primary endpoint: rate of SLN positivity in the overall cohort. Secondary endpoints: treatment related adverse events (per CTCAE), recurrence free survival, and overall survival. Exploratory endpoints: immunophenotype and microenvironment of the primary tumor, SLN and peripheral blood pre- and post- RP1 (via IHC, IF, and flow cytometry). The observed rate of SLN positivity will be compared to the predicted rate (Melanoma Institute of Australia Prediction Tool for SLN metastatic risk) with a one-sided, one-sample proportion test. Kaplan-Meier estimates will be provided for survival endpoints. The trial is active with 13 of 25 pts enrolled in January 2025. Clinical trial information: NCT06216938 .

The gastrointestinal (GI) tract plays a crucial role in nutrient absorption, motility, and metabolism, while serving as a barrier against pathogens. The intestinal epithelial layer, particularly enteroendocrine cells (EEC), is pivotal in sensing luminal stimuli due to its strategic position. Although comprising only 1% of the GI epithelium, in total EEC comprises perhaps the largest endocrine organ that couples GI luminal stimuli with release of hormones and neurotransmitters such as serotonin, glucagon-like peptide-1 (GLP-1), and peptide–tyrosine–tyrosine (PYY), which regulate local and systemic physiology. In this review, we use EECs as a model to explore critical intracellular signaling pathways—centering around calcium (Ca²⁺) and cyclic adenosine monophosphate (cAMP). EECs utilize ionotropic and metabotropic receptors to detect luminal stimuli, leading to increased intracellular cytoplasmic Ca²⁺ and altered intracellular cAMP dynamics. Ca²⁺ influx is critical for the exocytosis of signaling molecules. The interplay between Ca²⁺ and cAMP signaling pathways enhances the release of these molecules, affecting both local and systemic responses. We make a point to discuss the conventional and emerging methodologies for measuring Ca²⁺ and cAMP dynamics in EECs, which is a rapidly expanding toolbox, containing genetically encoded indicators and resonance energy transfer techniques. Understanding these signaling cascades is essential for deciphering the complex roles of EECs in GI physiology and their impact on systemic health.

ABSTRACTBackgroundRenal medullary carcinoma (RMC) is an aggressive tumor associated with sickle cell trait. Despite treatment advances for other rare renal tumors, RMC survival remains poor. We aimed to describe the contemporary management and survival of children and adults with RMC.ProcedureIn this multicenter retrospective cohort study, Pediatric Surgical Oncology Research Collaborative sites searched their databases for patients diagnosed with RMC (2000–2022). Descriptive statistics were calculated and survival analyses performed using Kaplan–Meier and Cox regression.ResultsThirty‐four patients with RMC were identified. Median age was 19 years (IQR: 15–28; range: 7–52). Most were male (24/34; 71%), Black (27/32; 84%), had sickle cell trait or disease (30/33; 91%), presented with metastatic disease (27/34; 79%), and were symptomatic at presentation (32/34; 94%). Median overall survival (OS) was 24 months from diagnosis (16 months for children, 28 months for adults, p = 0.6). Receipt of platinum‐based chemotherapy (23/34; 68%) was associated with significantly higher OS than other regimens (35 vs. 5 months, p < 0.001). Nephrectomy (24/34; 71%) was associated with significantly improved OS compared with non‐operative management (34 vs. 7 months, p = 0.001). Immunotherapy, targeted therapy, or radiation therapy were not associated with significant differences in OS, nor were age, sex, race, sickle cell status, SMARCB1/INI‐1, stage, nephrectomy approach, retroperitoneal lymph node dissection, gross residual disease, margins, or tumor size.ConclusionsRMC survival remains poor despite newer therapies. Nephrectomy and platinum‐based chemotherapy should be considered in locally advanced and metastatic disease. Coordinated international cooperative group studies are needed to meaningfully improve RMC survival.

Abstract Introduction: Cystic fibrosis (CF) is a genetic disorder characterized by defective chloride ion transport, leading to thick mucus production, chronic respiratory infections, and other multisystem involvement. Although CF is often diagnosed in childhood, the condition can be missed or misdiagnosed in adults. Description of Case: We present the case of a 60-year-old male from India who was diagnosed with CF after a prolonged period of sinopulmonary symptoms. He initially presented in 2014. His medical history was pertinent for asthma, and multiple episodes of clinically and radiographically confirmed pneumonia and polypoid sinusitis requiring IV antibiotics and sinus surgery. He carried a prior diagnosis of allergic bronchopulmonary aspergillosis treated with itraconazole and steroids, as well as elevated IgE levels. His CT chest was notable for extensive bronchiectasis, bronchial wall thickening, and mucus plugging of both lungs. He had no known family history of CF. Sweat chloride testing was in the intermediate range (44, 47 mmol/L; normal &lt;30 mmol/L, intermediate 30 to 59 mmol/L, abnormal &gt;59 mmol/L). Given high suspicion for CF, cystic fibrosis transmembrane conductance regulator (CFTR) full gene analysis was pursued. Sequence analysis and multiplex ligation-dependent probe amplification of the CFTR gene detected heterozygous sequence changes c.1717-2A&gt;T, classified as likely deleterious, and c.1367T&gt;C (p.V456A), variant of uncertain significance. He was thus initially diagnosed as a CF carrier. He re-presented in 2024 with decline in pulmonary function testing and continued sinopulmonary infections. Genetic testing results from 2014 were re-analyzed. Between initial presentation and present, his V456A variant was upgraded to pathogenic. He met diagnostic criteria for CF with two pathogenic CFTR variants, a repeated intermediate sweat chloride (47 mmol/L) suggestive of CFTR protein dysfunction, and disease that could be attributed to CFTR dysfunction. He subsequently started TRIKAFTA® (elexacaftor/tezacaftor/ivacaftor and ivacaftor) and airway clearance therapy. Discussion: The diagnosis of CF in adults can be challenging, particularly in individuals without a known family history, intermediate sweat chloride testing, and with inconclusive genetic testing. Our understanding of CF in Asian populations is limited. CF is suspected to be underreported in patients with Southeast Asian ancestry in part due to genetic heterogeneity. The interpretation of certain genetic variants can evolve over time. A variant of unknown significance may later be reclassified as pathogenic, revealing its true role in disease development. This highlights the critical importance of regularly re-evaluating genetic test results.

Introduction Loss of interferon-γ (IFN-γ) function through the development of neutralizing autoantibodies results in a late-onset immunodeficiency characterized by disseminated opportunistic infection. While rare, there is a higher prevalence in patients of Southeast Asian ancestry. Treatment is aimed at B cell depletion; however, relapse is common. Here we describe two cases of anti–IFN-γ autoantibody-associated immunodeficiency. Case Descriptions Patient 1: A 42-year-old female originally from Laos presented with a 30-lb weight loss and fatigue over the course of 8 months. Cultures grew Mycobacterium hassiacum. Testing by National Jewish was positive for anti–IFN-γ autoantibody via ELISA and for IFN-γ neutralizing ability via pSTAT1 phosphorylation. Autoantibodies were treated with rituximab 375 mg/m2 weekly for 4 weeks. She had subsequent negative autoantibody levels for 6 months until positive autoantibodies were again detected. She was treated with an additional 3 rituximab 375 mg weekly infusions and maintained remission for an additional 15 months until autoantibody levels were again positive without associated symptoms or infection (see table for timeline). She is currently undergoing additional 4 rituximab infusions. Table Patient 2 A 59-year-old female originally from Laos who presented for an immunodeficiency workup with a history of disseminated Mycobacterium avium infection, with pulmonary, lymph node, and parotid gland involvement. Anti–IFN-γ autoantibody testing from National Jewish was positive. She was treated with rituximab 375 mg/m2 weekly for 4 weeks. Autoantibody levels were negative 3 months later, and she has maintained remission since by serial monitoring. Discussion In our experience, anti–IFN-γ autoantibody-associated secondary immunodeficiency should be suspected in middle-aged patients with disseminated opportunistic infection, especially women of Southeast Asian ancestry. Rituximab rapidly depletes autoantibody levels; however, maintenance of remission is variable. The average duration of response in patient 1 was 10.5 months compared with persistent remission in patient 2. Thus, serial monitoring with autoantibody levels, markers of inflammation, and symptom assessments should be performed with consideration for repeated doses of rituximab.

Introduction STAT1 gain-of-function (GOF) mutations result in a broad clinical spectrum characterized by complex phenotypic manifestations. In addition to the hallmark chronic mucocutaneous candidiasis (CMC), patients are predisposed to bacterial and viral infections, autoimmunity, endocrinopathies, lymphoproliferative disorders, and malignancies. Severe complications, including invasive infections, cerebral aneurysms, and malignancies, are significant predictors of poor outcomes. Understanding genotype–phenotype correlations is critical for optimizing management in this challenging patient population. Methods We conducted a retrospective review of electronic medical records for five patients diagnosed with STAT1 GOF mutations at Mayo Clinic, Rochester, MN. This case series included data on demographics, clinical history, immunologic evaluations, genetic testing results, disease manifestations, treatments, and outcomes. Results The cohort included five patients (1 male, 4 females; mean age at diagnosis: 21.7 years) with heterozygous STAT1 GOF mutations. Three patients had c.1154C&gt;T (p.Thr385Met), one had c.1310C&gt;T (p.Thr437Ile) in the DNA-binding domain (DBD), and one had c.856A&gt;G (p.Lys286Glu) in the coiled-coil domain (CCD). Universal features included CMC and recurrent sinopulmonary infections. Patients with c.1154C&gt;T presented with early-onset infections, severe autoimmunity (e.g., pancytopenia and enteropathy), and bronchiectasis, requiring ruxolitinib in all three cases. The patient with c.1310C&gt;T had a late childhood onset of symptoms, later complicated by persistent histoplasmosis. The c.856A&gt;G case experienced severe multidrug-resistant infections, splenomegaly, coagulopathy, neurological complications, poor response to ruxolitinib, and died from complications of MSSA pneumonia and monkeypox. Conclusion Genotype–phenotype correlations in STAT1 GOF mutations highlight a diverse clinical spectrum driven by mutation-specific mechanisms. DBD mutations are associated with more severe outcomes, including early-onset immunodeficiency, invasive infections, and autoimmunity, due to faster nuclear accumulation and impaired dephosphorylation of STAT1. CCD mutations present with multisystem involvement, further emphasizing the heterogeneity of clinical manifestations. These variations underscore the importance of genetic insights for prognostication and tailored management. Early interventions, including hematopoietic stem cell transplantation for severe cases, and emerging therapies like JAK inhibitors show promise; however, ruxolitinib's need for individualized dosing, vigilant monitoring, continuous treatment to maintain benefits, and lack of epigenetic correction warrant further evaluation.

Background Cytokines play an important role in Th1 and Th2 inflammation. Both Th1 and Th2 cytokines can be utilized for evaluation and treatment response in many different disorders, including inborn errors of immunity. The role of broad cytokine panel testing in inborn errors of immunity is not well described. Objective To analyze broad cytokine panel testing in clinical practice. Methods A retrospective review of cytokine panel testing performed at Mayo Clinic was performed. Data were collected from patients at Mayo Clinic Rochester, Mayo Clinic Jacksonville, and Mayo Clinic Health System. Serum cytokine panel testing included the following cytokines: tumor necrosis factor (TNF), IL-6, IFN-β, IL-10, monocyte chemoattractant protein-1 (MCP-1), IL-1β, IFN-γ, macrophage inflammatory protein-1 alpha (MIP-1α), granulocyte-monocyte colony-stimulating factor (GM-CSF), IL-2 receptor α soluble, IFN-α, and IL-18. Data collection ranged from 03/2021 to 09/2024. The study was funded by Mayo CCaTS grant number UL1TR002377. Results A total of 88 cytokine panel tests were performed during the study period on 80 total patients. There was at least 1 elevated cytokine level in 70/88 (80%) tests performed. There was elevation in each individual cytokine level as follows: TNF (49), IL-2 receptor α soluble (40), IFN-α (0), IL-18 (26), IL-6 (33), IFN-β (4), IL-10 (13), MCP-1 (18), IL-1β, IFN-γ (11), MIP-1α (12), and GM-CSF (6). 18 patients that underwent cytokine panel testing had common variable immune deficiency (CVID), and 10 of those patients had granulomatous lymphocytic interstitial lung disease. 6 patients with early onset inflammatory bowel disease, 5 patients with autoimmune lymphoproliferative syndrome, 2 patients with Myhre syndrome, 2 patients with Hyper IgE syndrome, 1 patient with hypereosinophilic syndrome, 1 patient with autoimmune polyglandular syndrome type 1, 1 patient with XIAP deficiency, 1 patient with X-linked chronic granulomatous disease, and 1 patient with STAT 1 gain of function were tested. Other patients tested had other medical diagnoses or were undergoing immunodeficiency evaluation. There was no significant increase noted in any individual cytokine level when compared with the whole cohort. Conclusion Cytokine panel testing could be a potential diagnostic tool in evaluation of inborn errors of immunity. Further research is needed to better characterize the importance of cytokine panel testing in inborn errors of immunity.

Background : Metastatic lung carcinoids (MLCs) represent a rare subset of lung cancers with distinct histologic subtypes. Survival outcomes and prognostic factors have not been well-studied in the real-world setting. This study investigates the impact of various treatments, including chemotherapy, hormonal therapy, and no treatment, on the overall survival (OS) of patients with typical and atypical MLC. Methods: Patients with MLC between 2010 and 2020 were included from the National Cancer Database based on histologic codes ICD-O-3 8240/3 and 8249/3. Kaplan–Meier curves and multivariate Cox proportional hazard regression were used to compare OS and evaluate prognostic factors. Results: The median age at diagnosis was 68 and 69 years for atypical and typical MLC, respectively. The 3-year OS for the atypical MLC cohort was 22.11%, and for typical MLC was 41.94% ( P < 0.001). In the atypical MLC cohort, chemotherapy showed a nonsignificant benefit in OS (hazard ratio [HR], 0.89; 95% confidence interval [CI], 0.73–1.05; P = 0.21), whereas hormonal therapy was associated with significantly improved OS (HR, 0.72; 95% CI, 0.52–0.98; P =0.04). However, in the typical MLC cohort, chemotherapy was associated with adverse OS (HR, 2.15; 95% CI, 1.85–2.49; P < 0.0001), and hormonal treatment showed better, albeit nonsignificant OS (HR, 0.84; 95% CI, 0.67–1.05; P = 0.13). Conclusion: There is a notable difference in survival outcomes between typical and atypical MLC based on the treatment strategies. While hormonal therapy shows improvement in the OS, the effectiveness of chemotherapy varies depending on the histologic subtype. These findings emphasize the necessity for personalized therapeutic approaches based on the specific characteristics of MLC, ultimately contributing to improved patient outcomes in this challenging oncologic group. Further research is warranted to validate and expand upon these observations.

AbstractBackgroundTandem mass spectrometry (MS/MS) has become a common clinical laboratory testing modality has demonstrated success in distinguishing between small protein variations in transthyretin amyloidosis. Since many common clinically significant RBC antigens are also small protein variations, this study aimed to determine if MS/MS could correctly detect common RBC antigens within the Rh, Kell, Duffy, MNS, Kidd, Diego, and Lutheran blood group systems.Study Design and MethodsResidual samples from serotyped/genotyped blood donors at a hospital‐based blood donation center from February to August 2021 were analyzed. RBC membrane protein preparations underwent protease digestion prior to MS/MS analysis for RhD, RhCE, Kell, atypical chemokine receptor 1 (Duffy), glycophorin A (MNS), glycophorin B (MNS), urea transporter 1 (Kidd), band 3 anion transport protein (Diego), and basal cell adhesion molecule (Lutheran). Untargeted liquid chromatography (LC)‐MS/MS detected protein‐specific peptides, while targeted LC‐selected reaction monitoring (LC‐SRM) detected RBC antigen‐containing peptides.ResultsThrough the use of multiple proteases, untargeted LC–MS/MS detected protein‐specific peptides in all but glycophorin B, with band 3 anion transport protein, basal cell adhesion molecule, Kell, and glycophorin A having the greatest protein sequence coverage. Targeted LC‐SRM detected antigen‐specific peptides for Cw, Dia/Dib, Kpb, and Wra/Wrb, which agreed with the donors' previous typing results.DiscussionMS/MS can successfully detect peptides from several blood group systems but only detected a subset of their common RBC antigens. Further sample enrichment and MS/MS detection improvements will need to occur before MS/MS could be considered a clinical RBC phenotyping modality.