Subpopulation Of Patients Research Articles

Efficacy and Safety of Secukinumab in US Patients with Psoriatic Arthritis: A Subgroup Analysis of the Phase 3 FUTURE Studies.

The aim of this work is to evaluate secukinumab vs. placebo in a challenging-to-treat and smaller US patient subpopulation of the international FUTURE 2-5 studies in patients with psoriatic arthritis (PsA). Data were pooled from US patients enrolled in the phase 3 FUTURE 2-5 studies (NCT01752634, NCT01989468, NCT02294227, and NCT02404350). Patients received secukinumab 300 or 150 mg with subcutaneous loading dose, secukinumab 150 mg without subcutaneous loading dose, or placebo. Categorical efficacy and health-related quality-of-life (QoL) outcomes and safety were evaluated at week 16. Subgroup analyses were performed based on tumor necrosis factor inhibitor (TNFi) status and body mass index (BMI). For hypothesis generation, odds ratios (ORs) for American College of Rheumatology (ACR) 20/50/70 and Psoriasis Area and Severity Index (PASI) 75/90/100 responses by treatment were estimated using logistic regression without adjustment for multiple comparisons. Of 2148 international patients originally randomized, 279 US patients were included in this pooled analysis. Mean BMI was > 30 kg/m2 and 55.2% had prior TNFi treatment. ORs for ACR20/50/70 significantly favored patients receiving secukinumab 300 mg and 150 mg with loading dose vs. placebo (P < 0.05), but not those receiving secukinumab 150 mg without loading dose vs. placebo. For PASI75, ORs favored all secukinumab groups over placebo (P < 0.05); for PASI90 and PASI100, only the secukinumab 300-mg group was significantly favored over placebo (P < 0.05). In this challenging sub-population of US patients with PsA, secukinumab provided rapid improvements in disease activity and QoL. Patients with PsA and active psoriasis might benefit more from secukinumab 300mg than 150mg.

Examining the role of artificial intelligence to advance knowledge and address barriers to research in eating disorders.

To provide a brief overview of artificial intelligence (AI) application within the field of eating disorders (EDs) and propose focused solutions for research. An overview and summary of AI application pertinent to EDs with focus on AI's ability to address issues relating to data sharing and pooling (and associated privacy concerns), data augmentation, as well as bias within datasets is provided. In addition to clinical applications, AI can utilize useful tools to help combat commonly encountered challenges in ED research, including issues relating to low prevalence of specific subpopulations of patients, small overall sample sizes, and bias within datasets. There is tremendous potential to embed and utilize various facets of artificial intelligence (AI) to help improve our understanding of EDs and further evaluate and investigate questions that ultimately seek to improve outcomes. Beyond the technology, issues relating to regulation of AI, establishing ethical guidelines for its application, and the trust of providers and patients are all needed for ultimate adoption and acceptance into ED practice. Artificial intelligence (AI) offers a promise of significant potential within the realm of eating disorders (EDs) and encompasses a broad set of techniques that offer utility in various facets of ED research and by extension delivery of clinical care. Beyond the technology, issues relating to regulation, establishing ethical guidelines for application, and the trust of providers and patients are needed for the ultimate adoption and acceptance of AI into ED practice.

Differences Between Traumatic and Degenerative Medial Meniscus Posterior Root Tears: A Systematic Review.

Intact meniscus roots are a prerequisite for normal meniscal function, including even distribution of compressive forces across the knee joint. An injury to the root disrupts the hoop strength of the meniscus and may lead to its extrusion and the development of osteoarthritis. A medial meniscus posterior root tear (MMPRT) is often thought to have a primary degenerative pathogenesis. However, there is mention of some cases of MMPRTs where the patients have a solely traumatic injury to a previously healthy meniscus. To describe a subpopulation of patients with traumatic MMPRT. Systematic review; Level of evidence, 5. The Web of Science database (www.webofscience.com) was queried using the Medical Subject Headings term "medial root tear." Articles were reviewed, and those evaluated for MMPRTs in a degenerative meniscus were excluded. A total of 25 articles describing cases of acute traumatic causes were included in this study. For these articles, the patient characteristics, injury mechanisms, and concomitant injuries evaluated were recorded and pooled. The search revealed 660 articles, and 25 were selected for inclusion. A total of 113 patients with a traumatic MMPRT were identified and included in this review. The study population had a mean age of 27.1 years and a high share of men (64%). Also, this review displays how most patients with traumatic MMPRTs also suffer concomitant injuries (68%). The findings in this review support our hypothesis that there is a unique subgroup with acute traumatic MMPRTs that have unique patient characteristics, injury mechanisms, and combined injuries, compared with previously published reviews on MMPRTs.

Abstract LB396: The power of NetraAI: Precision medicine in oncology through sub-insight learning from small data sets

Abstract The capabilities of artificial intelligence (AI) and machine learning (ML) are pivotal for refining patient stratification and subtype discrimination in clinical trials. Conventional ML methods often rely on large data sets for meaningful discoveries. NetraAI is a novel ML approach designed and trained to work with smaller data sets. The challenge with smaller data sets is that they do not reflect the totality of the disease that they represent. NetraAI employs a novel approach termed “Sub-Insight Learning”, utilizing validated mathematical methods to analyze even small patient data sets. This allows the system to decompose the data sets into high and low confidence patient subpopulations, enhancing predictive model accuracy and reducing overfitting. Further, the system explains what variables are driving the etiology defining the subpopulations of patients. Using two non-small cell lung cancer (NSCLC) data sets (GSE18842 and GSE10245) consisting of only 104 samples from adenocarcinoma (ADC) and squamous cell carcinoma (SCC), NetraAI distinguished the two subtypes through unique genetic signatures. Notably, nine of the ten variables identified correlate with known NSCLC markers, with PIGX emerging as a novel target. Leveraging protein-protein interaction networks (PPI) revealed connections between PIGX and BACE1. BACE1 has been implicated as a driver of NSCLC brain metastasis. These findings shed light on the biology of membrane proteins and their post-translational modifications, a factor implicated in various diseases, prompting further exploration. NetraAI demonstrates a significant breakthrough in precision medicine for oncology, capable of generating meaningful insights from small data sets. The discovery of novel biomarkers and their implications in cancer and other diseases underline the potential of this AI-driven approach in advancing current research paradigms and patient-specific treatments. Citation Format: Bessi Qorri, Mike J. Tsay, Paul Leonchyk, Larry Alphs, Luca Pani, Joseph Geraci. The power of NetraAI: Precision medicine in oncology through sub-insight learning from small data sets [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB396.

Abstract LB395: NetraAI-driven discovery of novel biomarkers in MSI-high colon cancer for precision immunotherapy

Abstract By leveraging NetraAI, a novel machine learning (ML) approach, we identify potential biomarkers in microsatellite instability-high (MSI-H) colon cancer. MSI, marked by DNA mismatch repair (MMR) defects characterizes 5-20% of colorectal cancers (CRCs). MSI-H tumors harbor higher mutational burdens, produce neoantigens, and enhance immune recognition and responsiveness to immunotherapy. The innovative Sub-Insight Learning approach of NetraAI, allows us to overcome challenges associated with smaller data sets not reflecting the totality of the disease they represent. This approach utilizes a set of validated mathematical methods to identify sub-insights about patients even from small data sets. This allows the system to decompose the data sets into high and low confidence patient subpopulations, enhancing predictive model accuracy and reducing overfitting. Further, the system explains what variables are driving the etiology defining the subpopulations of patients. Utilizing a small data set consisting of 141 RNA expression profiles of CRC samples (E-GEOD-41258) with MSI-H and MSI-low colon cancer, we were able to derive several unique insights into patients’ molecular profiles. NetraAI analysis identified several unique variables, including CATSPERB, FUT8, PLLP, DUSP4, and MLPH that may play significant roles in MSI-H colon cancer pathology. These markers hold potential for personalizing clinical trials as well as potential therapeutic targets. Furthermore, protein-protein interaction (PPI) networks revealed co-expression and co-localizations that exist amongst these genes, suggesting a complex interplay among these genes, particularly in the context of spermatogenesis. The application of NetraAI and its Sub-Insight Learning paradigm has revealed novel insights into the molecular profile of MSI-H colon cancer. These findings pave the way for more targeted and effective precision immunotherapy strategies, demonstrating the power of AI in advancing the understanding and treatment of complex cancers. Citation Format: Bessi Qorri, Mike J. Tsay, Paul Leonchyk, Larry Alphs, Luca Pani, Joseph Geraci. NetraAI-driven discovery of novel biomarkers in MSI-high colon cancer for precision immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB395.

Sustained Improvements in Clinical and Patient-Reported Outcomes and Quality of Life Through 5Years Among Ixekizumab-Treated Patients with Complete Clearance of Scalp Psoriasis by Week 60.

Ixekizumab, a high-affinity monoclonal antibody that selectively targets interleukin-17A, is approved for the treatment of moderate-to-severe plaque psoriasis. Since scalp psoriasis can be burdensome and challenging to treat with non-systemic therapies, this post hoc analysis focused on scalp psoriasis in patients with moderate-to-severe plaque psoriasis and baseline scalp involvement. The analysis considered a holistic concept of clearance through 5years of ixekizumab treatment. Ixekizumab-treated patients with baseline scalp involvement were pooled from three multicenter, randomized, double-blind, placebo-controlled, phase 3 trials (integrated UNCOVER-1/2 and UNCOVER-3). Analyses were performed on a subpopulation of patients who achieved complete resolution of scalp psoriasis at Week 60 (i.e., Week 60 Psoriasis Scalp Severity Index [PSSI-0] responders) and on the overall patient population (i.e., Week 60 PSSI-0 responders and non-responders), which was used as a reference. Clinical outcomes (PSSI), patient-reported outcomes (Itch Numeric Rating Scale [NRS] score, Skin Pain Visual Analogue Scale [VAS]), quality of life (Dermatology Life Quality Index [DLQI]), and concurrent outcomes were assessed from baseline through 5years. Descriptive statistics of observed data were reported. After 60weeks of ixekizumab treatment, 88.4% (UNCOVER-1/2) and 75.9% (UNCOVER-3) of patients with baseline scalp involvement achieved complete clearance (PSSI-0) of scalp psoriasis. Substantial improvements in the clinical outcomes (PSSI), patient-reported outcomes (Itch NRS, Skin Pain VAS), and quality of life (DLQI) were achieved by Week 60 and sustained through Week 264 in the Week 60 PSSI-0 responders and in the overall patient population. Additionally, a significant proportion of Week 60 PSSI-0 responders achieved concurrent complete scalp and skin clearance and quality of life improvement through 5years. Continued treatment with ixekizumab provided long-term sustained scalp clearance over 5years to patients with moderate-to-severe plaque psoriasis and baseline scalp involvement, and holistic improvements occurred across clinical outcomes, patient-reported outcomes, and quality of life. NCT01474512 (UNCOVER-1), NCT01597245 (UNCOVER-2), and NCT01646177 (UNCOVER-3).

Ab interno minimally invasive glaucoma surgery combined with cataract surgery and cataract surgery alone: IRIS® registry study

PurposeDescribe real-world characteristics and outcomes in patients undergoing Food and Drug Administration (FDA) approved/cleared ab interno Minimally Invasive Glaucoma Surgery (MIGS) combined with cataract surgery or cataract surgery alone. DesignAn observational, retrospective study of glaucomatous disease treated with MIGS (OMNI® Surgical System, Hydrus®, iStent Inject®) combined with cataract surgery or cataract surgery alone, documented in the American Academy of Ophthalmology IRIS® Registry (Intelligent Research in Sight). MethodsThe study period was between 07/01/2017 and 12/31/2022. Eligible patients were identified via Current Procedural Terminology (CPT) codes coupled with electronic health records. Outcomes included intraocular pressure (IOP) and IOP-lowering medication class usage over 24 months stratified by baseline IOP (≤18 and >18 mmHg). Bonferroni testing (p < 0.0125) were applied. ResultsGlaucomatous disease was identified for 77,391 (OMNI: 428, Hydrus: 1,435, iStent Inject: 4,769, cataract surgery alone: 70,759) patients (109,745 eyes). For patients with a baseline IOP >18 mmHg, significant (p < 0.001) change in IOP (OMNI −6.64 [SD 7.59], Hydrus −5.71 [6.30], iStent Inject −4.96 [7.30], cataract surgery alone −5.55 [6.41]) and medication usage (OMNI −1.34 [1.48], Hydrus −1.20 [1.18], iStent Inject −0.86 [1.10], cataract surgery alone −0.67 [1.10]) were observed at 24 months. In the baseline IOP ≤18 mmHg subgroup, all cohorts showed significant medication reductions (p < 0.001), with no change in IOP. ConclusionsMIGS combined with cataract surgery and cataract surgery alone resulted in significant and sustained IOP (baseline IOP >18 mmHg) and medication reductions (both IOP subgroups). As MIGS procedures lead to non-equivalent results, further research will define the role of each in patient subpopulations.

Assessing the Impact of the Different Psychiatric Disorders on the Profiles of Psychiatric Hospitalization: A descriptive study in a Greek Hospital

IntroductionThe prevalence of psychiatric re-admission ranges from 15% to 60%, escalating even more in the first year after admission, affecting the patients’ quality of life. Furthermore, the diagnosis of psychotic or affective disorders represents a risk factor of psychiatric re-admission, highlighting the diagnosis impact to the “profile” of psychiatric hospitalization.ObjectivesTo compare the different “Hospitalization Profiles” in association to the patients’ diagnostic categories.MethodsOverall, 1,633 records of psychiatry inpatients were examined retrospectively throughout the 10-year records of the Psychiatry Department of Papanikolaou General Hospital in northern Greece. The research was conducted between 2013 and August 2023. The sample was divided into subgroups according to gender, diagnoses - according to the International Classification of Diseases (ICD-10)-, and year of hospitalization. A bivariate analysis was performed to examine relationships between the variables: (a.) place of residence; (b.) age; (c.) type of admission; (c.) hospitalization duration; (d.) number of lifetime hospitalizations; (e.) lifetime prosecutor’s orders for coercive examination; (f.) lifetime suicide attempts.Results Developmental disorders (F80-89) stood for the youngest average age of hospitalization (26 years) and lowest average hospitalization duration (7 days). Neurodegenerative disorders (F00-09) represented the diagnostic category with the oldest mean age of hospitalization (66 years). Intellectual disorders (F70-79) yielded the longest average hospitalization duration (21 days). Patients with intellectual disorders were found to be facing homelessness at a higher rate (4.76%) than patients of any other diagnostic entity (p=0.096). Psychotic and substance use disorder patients obtained equivalently (p=0.18) the highest rates of coercive hospitalizations (63% and 71%, respectively); compared to other diagnostic categories (p=0.0008). Dual diagnosis and anxiety disorders projected equivalently (p=0.9) the highest rate of premature voluntary discharge (6.9% and 6.4%, respectively). Dual diagnosis, personality disorders, and affective disorders also recorded the highest rates of suicidality (11-15%; with no significant statistical difference among the three diagnostic entities p&gt;0.1) among hospitalized patients of all diagnostic categories (p&lt;0.05).Conclusions Interestingly, the study’s results reveal the pathologies of the Greek society, with the most representative example being this of patients suffering from intellectual disorders simultaneously presenting the highest risk of homelessness. Further studies are needed, focusing on the sub-populations of psychiatric patients as well as their status in terms of social security, health care providing, quality of life and life expectancy.Disclosure of InterestNone Declared

364 Traumatic Dens Fracture Patients Comprise Distinct Subpopulations Distinguished by Differences in Age, Sex, and Injury Mechanism and Severity

INTRODUCTION: Dens fractures are an increasingly common cervical fractures, yet their epidemiology and its implications remain under-examined. METHODS: We retrospectively analyzed all traumatic dens fracture patients managed at our institution over a ten year period with respect to demographic, clinical, and outcomes data. Patient subsets were compared across these parameters. RESULTS: 303 traumatic dens fracture patients were identified, who showed a bimodal age distribution with strong goodness of fit centered at age 22.3 ± 5.7 (R = 0.8781) and at 77.7 ± 13.9 (R = 0.9686). A population pyramid demonstrated a bimodal distribution among male patients, but not among female patients, which was confirmed with a strong goodness of fit for two distinct male patient subpopulations age &lt;35 (R = 0.9791) and age =35 (R = 0.8843), but a weak fit for a second female subpopulation age &lt;35 (24.5 ± 14.2, R = 0.5957). Patients age &lt;35 were more likely to be male (82.4% vs. 46.9%, OR = 5.29 [1.54, 17.57], p = 0.0052). Moreover, patients age &lt;35 were more likely to have MVC as their mechanism of injury (64.7% vs. 14.1%, OR = 11.18 [3.77, 31.77], p &lt; 0.0001), were more likely to have a severe trauma injury severity score (17.6% vs. 2.9%, OR = 7.23 [1.88, 28.88], p = 0.0198). There was no difference with respect to underlying fracture morphology, likelihood of undergoing surgery, having concomitant atlas or subaxial fractures, or Nurick scores at presentation. Patients age &lt;35 were less likely to have fracture nonunion at follow (18.2% vs. 53.7%, OR = 0.19 [0.041, 0.76], p = 0.0288). CONCLUSIONS: The dens fracture patient population comprises two subpopulations, distinguished by differences in age, sex, and injury mechanism and severity, with male dens fracture patients demonstrating a bimodal age distribution. While young patients were more likely to high-energy injury mechanisms leading severe trauma, they were less likely to have fracture nonunion at follow up.

Peripheral T Cell Subpopulations as a Potential Surrogate Biomarker during Atezolizumab plus Bevacizumab Treatment for Hepatocellular Carcinoma.

The therapeutic benefits of the immunotherapeutic combination of atezolizumab and bevacizumab (Atez/Bev) in hepatocellular carcinoma (HCC) vary. Therapeutic biomarkers might help improve outcomes for HCC patients receiving Atez/Bev therapy. The role of systemic immune profiles in HCC progression also remains unclear. This study aimed to evaluate the status and dynamics of peripheral T cell subpopulations in HCC patients receiving Atez/Bev treatment and to explore biomarkers predictive of a therapeutic response. We enrolled 83 unresectable advanced HCC patients who commenced Atez/Bev treatment at our hospital between October 2020 and June 2022. Peripheral T cell subpopulations in peripheral blood mononuclear cells at baseline and 3 weeks post-treatment were investigated using flow cytometry and compared with those in control samples from 18 healthy individuals. We retrospectively analyzed the association between peripheral T cell subpopulation profiles and clinical outcomes. Baseline peripheral T cell subpopulations could be profiled in 70 patients with sufficient cell counts, among whom 3-week subpopulations could be evaluated in 51 patients. Multivariate analysis showed that a high baseline proportion of CD8+ central memory T (TCM) cells was independently associated with longer progression-free survival (PFS). Further, overall survival (OS) was significantly prolonged in patients with increased CD8+ effector memory T (TEM) cell proportions. In conclusion, TCM proportion at baseline might be a good indicator of the efficacy of Atez/Bev therapy. Furthermore, observation of increasing TEM proportions might be an early predictor of the potential clinical benefits of treatment.

Increased glycemic variability results in abnormal differentiation of T cell subpopulation in type 2 diabetes patients

AimsWe aimed to investigate the association between glycemic variability (GV) and the abnormal differentiation of T-cell subpopulations in patients with type 2 diabetes mellitus (T2DM). MethodsIn total, 108 hospitalized patients with T2DM were enrolled and divided into two subgroups (normal glycemic excursion (NGE) and high glycemic excursion (HGE)) according to their mean amplitude of glycemic excursion (MAGE) level. The MAGE was evaluated via continuous glucose monitoring for 72 h consecutively. Flow cytometry was used to determine the proportions of T cell subpopulations. ResultsThe T helper (Th) 1 cell/Th2 cell ratio was significantly higher, and the proportion of regulatory T cells (Tregs) was significantly lower in the NGE group than in the HGE group (all P < 0.05). After fully adjusting for confounders, the MAGE was positively associated with the Th1 cell/Th2 cell ratio (β = 0.370; P = 0.009) and negatively associated with the proportion of Tregs (β = −0.554; P = 0.001). ConclusionThe MAGE was an independent risk factor for abnormally high Th1 cell/Th2 cell ratio and proportion of Tregs. Abnormal differentiation of T cell subpopulations induced by GV may impair β-cell function, aggravate insulin resistance, and contribute to the development of diabetic complications.

Scrutinizing the Role of Venoarterial Extracorporeal Membrane Oxygenation: Has Clinical Practice Outpaced the Evidence?

The use of venoarterial extracorporeal membrane oxygenation (VA-ECMO) for temporary mechanical circulatory support in various clinical scenarios has been increasing consistently, despite the lack of sufficient evidence regarding its benefit and safety from adequately powered randomized controlled trials. Although the ARREST trial (Advanced Reperfusion Strategies for Patients with Out-of-Hospital Cardiac Arrest and Refractory Ventricular Fibrillation) and a secondary analysis of the PRAGUE OHCA trial (Prague Out-of-Hospital Cardiac Arrest) provided some evidence in favor of VA-ECMO in the setting of out-of-hospital cardiac arrest, the INCEPTION trial (Early Initiation of Extracorporeal Life Support in Refractory Out-of-Hospital Cardiac Arrest) has not found a relevant improvement of short-term mortality with extracorporeal cardiopulmonary resuscitation. In addition, the results of the recently published ECLS-SHOCK trial (Extracorporeal Life Support in Cardiogenic Shock) and ECMO-CS trial (Extracorporeal Membrane Oxygenation in the Therapy of Cardiogenic Shock) discourage the routine use of VA-ECMO in patients with infarct-related cardiogenic shock. Ongoing clinical trials (ANCHOR [Assessment of ECMO in Acute Myocardial Infarction Cardiogenic Shock, NCT04184635], REVERSE [Impella CP With VA ECMO for Cardiogenic Shock, NCT03431467], UNLOAD ECMO [Left Ventricular Unloading to Improve Outcome in Cardiogenic Shock Patients on VA-ECMO, NCT05577195], PIONEER [Hemodynamic Support With ECMO and IABP in Elective Complex High-risk PCI, NCT04045873]) may clarify the usefulness of VA-ECMO in specific patient subpopulations and the efficacy of combined mechanical circulatory support strategies. Pending further data to refine patient selection and management recommendations for VA-ECMO, it remains uncertain whether the present usage of this device improves outcomes.

Abstract 1059: Biomarkers analysis on samples from patients in EVT801 clinical trial: Patient characterization and immunomonitoring

Abstract Introduction: EVT801 is a highly selective small molecule inhibitor of VEGFR3 that acts by inducing tumor (lymph)-angiogenesis normalization in and around the tumor. EVT801 has shown compelling activity in a wide range of cancer models showing a decrease of tumor hypoxia and an increase of CD8pos T-cells infiltration into the tumor micro-environment. EVT801 was well-tolerated in preclinical toxicology studies. A phase I study is underway focusing primarily on understanding the safety, tolerability, and pharmacokinetics of EVT801 across a range of doses (NCT05114668). Methods: The first stage of the phase I trial aims to determine the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) for EVT801. Clinical samples from enrolled patients have been collected to explore preliminary signals of the biological activity of the drug and characterize tumor phenotypes. Patient characterization includes histology and mRNA signature in archival biopsies. Target engagement and pharmacodynamics effects are investigated by immunomonitoring as well as assessment of a defined set of proteins as markers of inflammation and angiogenesis as identified in preclinical in vivo models. Conclusion: Our first biomarkers analyses on a subpopulation of patients with High Grade Serous Ovarian Cancer (HGS-OC) enrolled in the first stage of the study showed that levels of VEGFR3 expression had a negative correlation with CD8 positive T-cells infiltration in the tumor microenvironment and a tendency to positive correlation with a PD1 mAb resistance signature. VEGFR3 expression also tends to be correlated with higher levels of hypoxia (CAIX labelling). Our working hypothesis is that patients with hypoxic HGS-OC tumors with high VEGFR3 expression may benefit from EVT801 treatment; this will need to be reinforced by inclusion of additional patients in dedicated PD biomarkers cohorts during stage 2 of the clinical trial. Citation Format: Lise Davenne, Michael Fitzgerald, Pierre-Benoit Ancey, Oona Delpuech, Céline Poussereau-Pomié, Michael Esquerre, Michael R. Paillasse, Marie Mandron, Philippe Rochaix, Maha Ayyoub, Clara Maria Scarlata, Christine Caux, Christophe Caux, Philippe Cassier, Carlos Gomez-Roca, Jean-Pierre Delord, John Friend, Pierre Fons. Biomarkers analysis on samples from patients in EVT801 clinical trial: Patient characterization and immunomonitoring [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1059.

Abstract 1446: Gastric cancer with microsatellite instability: Ex vivo generation of syngeneic mouse models

Abstract The DNA mismatch repair (MMR) system is a highly conserved pathway crucial for maintaining the genomic integrity. MMR impairment in sporadic tumors is due to MLH1 epigenetic silencing or mutations in other MMR genes (such as MSH2, MSH6, PMS2) and leads to microsatellite instability (MSI). Two independent molecular classifications reported the existence of a MSI subgroup in gastric cancer (GC), including 22-23% of all cases. GC MSI inter and intra-tumoral heterogeneity represents a significant challenge for precise patient stratification and treatment. Even if MSI status in GC is usually associated with a good prognosis, some reports described a subpopulation of MSI GC patients displaying a worse outcome. Moreover, while clinical trials testing immune checkpoint inhibitors in MSI tumors showed effectiveness across all treatment lines, the outcomes in GC patients were not as remarkable as in other cancer types. From the analysis of MSI GC patients enrolled in phase III clinical trials testing anti-PD1 monotherapy, it emerged that nearly half of the tumors are intrinsically resistant and complete and long-lasting responses are achieved in very few cases. Tumor mouse immunocompetent models allow to mimic the complex interactions between a fully functional immune system and a developing tumor. MSI GC syngeneic mouse models could thus represent a valuable tool to better understand the molecular complexity and predict the clinical behavior of this subgroup. To obtain MSI GC mouse models, we generated non-transformed organoids from normal gastric mucosa of BALB/c mice as a starting point for the induction of a neoplastic transformation ex vivo. To induce MMR deficiency, we inactivated either Mlh1 or Msh2 genes using CRISPR/Cas9 genome editing. Importantly, we did not introduce any other alteration in known oncogenes and tumor suppressor genes, thus allowing the natural emergence of driver mutations in the context of the genetic instability. Over time, MMR deficient models, but not the WT controls, exhibited MSI and increased their mutational burden. Furthermore, when cultured in stringent culture conditions (two-dimensional culture, growth factor deprivation), only MMR deficient cells generated tumor masses upon subcutaneous injection in immunodeficient NOD SCID mice. Importantly, cells retrieved from the tumor masses (n = 8) exhibited mutations in a relevant fraction of genes associated with the MSI subgroup by TCGA (21 out of 35) – including Kras, Arid1a, Erbb3 and Tpr53 – thus offering a good representation of the human MSI GC mutational landscape. Given the immunogenicity of the Cas9 protein, we finalized our models optimizing the genome editing protocol to avoid a persistent Cas9 expression. Cas9-free MMR deficient models were able to generate tumors in immunocompetent BALB/c mice, thus representing a valuable resource to investigate tumor development, progression and responses to immunotherapy in vivo. Citation Format: Daniela Conticelli, Gabriele Picco, Cristina Migliore, Claudia Orrù, Fabrizio Maina, Emanuela Boccuni, Simona Corso, Silvia Giordano. Gastric cancer with microsatellite instability: Ex vivo generation of syngeneic mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1446.

Abstract 6430: Gene expression signature quantifies the cellular contribution of the tumor vs. the microenvironment in determining colorectal cancer prognosis and therapeutic outcome

Abstract Accumulating evidence has suggested that cancer progression and therapeutic response may depend on not only tumor cells but also their tumor microenvironment (TME). However, their contributory roles are complex and not well understood. Here we report an analysis of 2373 human colorectal cancer (CRC) tumors representing all stages, leading to identification of a 20-gene signature capable of quantifying the cellular contribution of the tumor vs. the TME in determining colorectal cancer prognosis and therapeutic outcome. We classified these tumors into the consensus molecular subtypes (CMS1-4) with distinct, variable TME cellular features defined by CIBERSORT deconvolution analysis of bulk gene expression data. Surprisingly, all the 10 positive signature genes (portending worse survival) were strongly correlated with the TME-rich CMS1 and CMS4 tumors. By contrast, all the 10 negative signature genes (portending better survival) were highly related to the TME-poor CMS2 and CMS3 tumors. A single cell expression analysis from an independent database further revealed that strikingly, all the 10 positive genes were principally expressed by the immune/stromal TME whereas all the 10 negative genes were predominantly expressed in epithelial tumor cells. These data suggest that the TME has an equally important role as do tumor cells in determining CRC prognosis and support targeting the TME to improve survival. Moreover, distinct gene expression from tumor cells versus the TME also showed a differential impact on therapeutic outcome. Retrospective analyses on two independent clinical trial datasets show that the 20-gene signature score significantly predicted progression free survival in metastatic CRC patients treated with cetuximab, an FDA-approved EGFR inhibitor therapy. These data suggest a potential for the 20-gene signature as a predictive biomarker to identify “sensitive” versus “resistant” subpopulations of CRC patients to improve outcome of EGFR-targeted therapy. Citation Format: Mingli Yang, Timothy J. Yeatman, Michael V. Nebozhyn, Michael J. Schell, Lance Pflieger, Andrey Loboda, Warren J. Pledger, Ramani Soundararajan, Michelle Maurin, Heiman Wang, Jetsen Rodriguez Silva, Ashley Alden. Gene expression signature quantifies the cellular contribution of the tumor vs. the microenvironment in determining colorectal cancer prognosis and therapeutic outcome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6430.

Abstract 5648: Decoding the non-canonical functions of HO-1 in prostate cancer: A nuclear perspective and its association with a neuroendocrine signature

Abstract Previous studies have demonstrated the non-canonical anti-tumor effect of heme-oxygenase 1 (HO-1) in prostate cancer (PCa). Although HO-1 is crucial for free heme degradation, its nuclear expression unveils non-canonical functions beyond its enzymatic function. Understanding the specifics of its non-canonical role remains a critical unmet need. In this study, we identified nuclear interactors of HO-1 and assessed their association with PCa.PCa cells were treated with hemin (80 µM, 24 h), a specific pharmacological inducer of HO-1. Nuclear HO-1 immunoprecipitation and LC-ESI MS/MS analysis identified 11 differential nuclear associated-HO-1 proteins between control and hemin-treated PCa cells (ILF3, ILF2, BCLAF1, SAFB, DDX17, SLC25A5, CASP14, PRDX1, BRIX1, CCDC175, and GPATCH1). Next, we performed an Ingenuity Pathway Analysis (QIAGEN) showing that ILF3 appears as a master regulator of this signature. To assess the clinical relevance of these factors in PCa, we analyzed overall survival (OS), progression-free survival (PFS), relapse free survival (RFS) in multiple PCa datasets (GSE34312, GSE35988, GSE3933, GSE46602, GSE6956, GSE70768, TCGA-PRAD, GSE70770, GSE16560, GSE24136; n=1064). We performed univariable and multivariable analyses for these factors and identified the ones that significantly and independently affected the OS, RFS, PFS. Next, a risk score model was built based on the expression of 9 genes (∑ni=1(Coefi×Expri)) for the GSE70770 dataset using these factors identifying a subpopulation of PCa patients with high-risk of RFS (HR: 7.39 High vs Low score, p&amp;lt;0.0001); ascertaining the critical role of this signature in PCa. To elucidate the association of these factors with the aggressive phenotype of PCa, we analyzed RNA-seq expression data from the MDA-PCa-PDXs series (PCa Patient Derived Xenografts Program; MD Anderson Cancer Center), capturing PCa heterogeneity. Unsupervised clustering analysis revealed that samples with high expression of HO-1 nuclear interactors corresponded to neuroendocrine tumors, negative for androgen receptor staining. Principal Component Analysis identified ILF3 as the most relevant HO-1 interactor driving PDXs’ samples variance, correlating with a significant decrease in relapse-free survival of PCa patients. Further, we used ChIP-Atlas to assess the epigenomic landscapes for these nuclear HO-1 interactors. Results indicated that 40% of HO-1 nuclear interactors were potential transcription regulators. Strikingly, KEGG pathways analyses revealed that their regulomes were significantly associated with neurodegenerative disorders, highlighting their relevance in neural processes. In conclusion, our findings suggest that HO-1 and its nuclear interactors may play a pivotal role in neuroendocrine PCa, shedding light on potential therapeutic targets for this aggressive form of the disease. Citation Format: Seniuk A. Rocio, Agustina Sabater, Pablo Sanchis, Juan Bizzotto, Gastón Pascual, Estefania Labanca, Nicolas Anselmino, Nora Navone, Elba Vazquez, Pia Valacco, Javier Cotignola, Ayelén Toro, Geraldine Gueron. Decoding the non-canonical functions of HO-1 in prostate cancer: A nuclear perspective and its association with a neuroendocrine signature [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5648.

Abstract 6851: The genomic, transcriptomic, and immunologic landscape of TEM8 (ANTXR1) in neuroendocrine neoplasms (NENs)

Abstract Introduction: TEM8 (coded by ANTXR1) is overexpressed in malignant tissues, with oncolytic viruses such as SVV-01 uniquely binding to this receptor on tumor-associated angiogenic endothelial cells, pericytes, fibroblasts, and immune inflammatory cells. Recent pre-clinical data suggest that TEM8-targeting therapies may convert immunologically “cold” tumor microenvironments (TME) into “hot” milieu more amenable to treatment with immune checkpoint inhibitors (ICIs). Methods: NextGen sequencing of DNA (592 genes or WES) and RNA (WTS) was performed on neuroendocrine neoplasms (NENs; N = 1724), excluding small-cell lung cancer, submitted to Caris Life Sciences (Phoenix, AZ). Mutations were defined as pathogenic SNVs/indels. ANTXR1 expression was divided by ANTXR1-expression quartiles (transcripts per million [TPM];Q4:H;Q1:L). PD-L1 expression (SP142; Positive (+): ≥2+,≥%5) was assessed by IHC. High tumor mutational burden (TMB-H) was defined as ≥10 mutations per MB. Cell infiltration in the TME was estimated by QuantiSEQ. Gene expression profiles were analyzed for transcriptional signatures predictive of response to immunotherapy (T cell-inflamed) and MAPK pathway activation score (MPAS). Overall survival (OS) data was obtained from insurance claims, and Kaplan-Meier estimates were calculated for molecularly defined subpopulations of patients. Mann-Whitney U and X2/Fisher-Exact tests were applied where appropriate, with p-values adjusted for multiple comparisons (p&amp;lt;0.05). Results: NENs from the adrenal gland had the highest median ANTXR1 expression (50 TPM), followed by those from the colon and rectum (43.5), genitourinary organs (43.3), and small bowel (excluding appendix) (39.2). The lowest median ANTXR1 expression was observed in NENs from the pancreas (31.5). No pathogenic mutations were significantly associated with ANTXR1H vs L tumors (p&amp;gt;0.05 for all), along with no differences in the prevalence of TMB-H (8.6% vs 12.6%, p=1) or PD-L1+ (5.8%: vs 3.1%, p=1). A greater proportion of B cells (5.34 % vs 3.78%, p&amp;lt;0.001), M1 (1.46% vs 0.15%, p&amp;lt;0.001) and M2 macrophages (3.92% vs 2.67%, p&amp;lt;0.001), and T-regulatory cells (1.77% vs 1.08%, p&amp;lt;0.001) was observed in ANTXR1H TMEs, which were more frequently classified as T cell-inflamed compared to ANTXR1L (42% vs 8%, p&amp;lt;0.001). ANTXR1H tumors also had higher MPAS compared to ANTXR1L (1.16 vs -1.61 arbitrary units, p&amp;lt;0.001). There was no significant difference in median OS between ANTXR1H vs L tumors (18.8 mo. vs 21.2 months, Hazard Ratio:1.18, p=0.114). Conclusion: The increased immune cell infiltrate and prevalence of T-cell inflamed status among ANTXR1H NENs suggests these tumors might be more responsive to treatment with ICIs. As trials incorporating intratumoral injections of SVV-01 in combination with ICIs are underway, further investigation of clinical and molecular associations with ANTXR1 expression in NENs is warranted. Citation Format: Samuel A. Kareff, Harris Krause, Andrew Elliott, Peter Hosein, Emil Lou, Heloisa Soares, Matthew Oberley, Aman Chauhan. The genomic, transcriptomic, and immunologic landscape of TEM8 (ANTXR1) in neuroendocrine neoplasms (NENs) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6851.

Abstract 1915: A scalable pancancer antigen target discovery platform for precision oncology

Abstract With the emergence of precision oncology as a new paradigm in cancer care, there is an urgent need to develop tools capable of mining the massive amounts of rich omic data generated every year. To support target discovery programs at scale, we developed a pan-cancer bioinformatics platform combining patient data with extensive biological and pharmaceutical knowledge for the identification and prioritization of novel antigen targets. Our pipeline was first validated with the discovery of new antigen targets amenable to CAR-T therapy for relapsed/refractory multiple myeloma. Here, we are exploring AML, a type of leukemia with several unmet needs. First, we identified and integrated 36 relevant microarray datasets from the GEO database using a proprietary data identification and integration pipeline. The clinical data was curated using our proprietary oncology ontology, machine learning models, and domain expert quality control processes. The molecular data was normalized and the datasets aggregated into a virtual patient cohort of unprecedented size and quality, comprising 2,995 AML patients and 220 healthy controls. To both find a clinically relevant patient sub-population and reduce the cohort heterogeneity, AML patients were stratified based on their transcriptomic profile using a consensus clustering analysis, which we interpreted thanks to the curated clinical data. Among multiple others, we identified a highly stable cluster enriched in AML-M3 patients, a very distinct and aggressive subtype of AML caused by a t(15;17) translocation. A differential gene expression analysis was performed comparing this cluster with the control group and 574 genes were found to be overexpressed. We then applied proteomic filters to exclusively focus on cell surface-bound protein targets demonstrating an acceptable level of anticipated cytotoxicity. Finally, the 23 short-listed antigen targets were prioritized with additional multi-omic patient and cell line data to optimize their safety and efficacy profiles as well as expression robustness. Interestingly, well-known targets, such as CD96 and ABCC1, were found in the top targets. Developing scalable pipelines will be instrumental in the advent of precision oncology. Combining unbiased data-driven tools with cancer biology-driven approaches, our state-of-the-art pipeline can be used for any cancer type and antigen-targeting modality, including CAR-T and antibody-based therapies. The present study illustrates the potential of our platform when applied to AML, one of the most heterogeneous groups of neoplastic disorders. Leveraging our large and unique AML patient cohort, we were not only able to detect a relevant subgroup of patients, but also identified novel antigen target candidates for this specific population, which were then prioritized based on domain expertise. A broader study addressing other cancer indications, including solid tumors, is underway. Citation Format: Eleonore Fox, Guillaume Appe, Abdelkader Behdenna, Lea Meunier, Akpeli Nordor, Solene Weill, Camille Marijon. A scalable pancancer antigen target discovery platform for precision oncology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1915.

Abstract 2008: The N6-methyladenine-long noncoding RNA axis promotes drug resistance through PI3k signaling in leukemia

Abstract Disease recurrence characterized by drug resistance remains a major hurdle to the successful cancer treatment. Long noncoding RNAs (lncRNAs) and RNA N⁶-methyladenosine (m6A) have been linked to cancer recurrence. However, if and how lncRNAs and m6A coordinately determine drug resistance in tyrosine kinase (TK)-driven cancers are still unclear. We hypothesize that upon exposure to TK inhibitors (TKI), the dynamic m6A methylation epitransciptomically allows a set of proliferation/anti-apoptosis-relevant lncRNAs bearing m6A motifs to be rapidly upregulated, thus facilitating a subpopulation of cancer cells to evade TKI killing. By performing transcriptomic and epitransciptomic profiling in long-term TKI (nilotinib)-deprived leukemia resistant cells, we show that many differentially expressed lncRNAs enrich m6A, and more lncRNAs tend to have higher m6A content in resistant cells. We further demonstrate a broad clinical relevance of our findings, showing that upregulation of specific top-ranked lncRNAs (e.g., SENCR, PROX1-AS1, LN892) in TKI-resistant cell lines also occurs in leukemia patients at the diagnostic stage, blast crisis phase or in those not-responding to TKI treatment compared to chronic phase or TKI responders, respectively. Some of the upregulated lncRNAs in leukemia patients pre- and post-TKI treatment predict unfavorable outcomes and are associated with shorter survival duration. Through proliferative and clonogenic assays, we demonstrate that knockdown of SENCR, PROX1-AS1 or LN892 impairs resistant cell growth and renders resistant cells sensitive to nilotinib-induced cell death. We further found that this lncRNA upregulation is attributed to FTO-dependent m6A hypomethylation that stabilizes lncRNA transcripts. Using ectopic expression or genetic/pharmacological inhibition, we demonstrate that lncRNA upregulation empowers resistant cell growth through an activated PI3K signaling as supported by overexpression of PI3K signaling mediators (e.g., ITGA2, F2R, COL6A1). Treatment with PI3K inhibitor alpelisib sensitizes TKI-resistant cells to TKI-induced cell death and reduces leukemia burden in mice via downregulation of F2R, ITGA2, and COL6A1. In conclusion, our findings add a new layer to the complexity of mechanisms regulating leukemia cell fate under TKI selection and raise the possibility that the m6A-regulated lncRNAs represents a new non-genetic factor to affect the development and maintenance of TKI resistance; our discoveries identify a promising therapeutic target, the m6A-lncRNAs axis, for specifically the most challenging patient subpopulations who are TKI non-responders/relapsed but do not carry the acquired mutations on top of BCR/ABL; our results also uncover a strong predictor, m6A-regulated lncRNA-PI3K axis, for poorer prognosis and failure in drug response which might be a pan-cancer mechanism. Citation Format: Yanhong Tan, Changli Zhou, Sicheng Bian, Wencke Walter, Jiuxia Pang, Tao Cheng, Gang Huang, Gregor Hoermann, William Tse, Shujun Liu. The N6-methyladenine-long noncoding RNA axis promotes drug resistance through PI3k signaling in leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2008.

CXCL9/10-engineered dendritic cells promote T cell activation and enhance immune checkpoint blockade for lung cancer

Immune checkpoint blockade (ICB) with PD-1/PD-L1 inhibition has revolutionized the treatment of non-small cell lung cancer (NSCLC). Durable responses, however, are observed only in a subpopulation of patients. Defective antigen presentation and an immunosuppressive tumor microenvironment (TME) can lead to deficient Tcell recruitment and ICB resistance. We evaluate intratumoral (IT) vaccination with CXCL9- and CXCL10-engineered dendritic cells (CXCL9/10-DC) as a strategy to overcome resistance. IT CXCL9/10-DC leads to enhanced Tcell infiltration and activation in the TME and tumor inhibition in murine NSCLC models. The antitumor efficacy of IT CXCL9/10-DC is dependent on CD4+ and CD8+ Tcells, as well as CXCR3-dependent Tcell trafficking from the lymph node. IT CXCL9/10-DC, in combination with ICB, overcomes resistance and establishes systemic tumor-specific immunity in murine models. These studies provide a mechanistic understanding of CXCL9/10-DC-mediated host immune activation and support clinical translation of IT CXCL9/10-DC to augment ICB efficacy in NSCLC.