Predictors Of Clinical Response Research Articles

Predictors of DAPSA Response in Psoriatic Arthritis Patients Treated with Apremilast in a Retrospective Observational Multi-Centric Study

To date, only a few real-world-setting studies evaluated apremilast effectiveness in psoriatic arthritis (PsA). The aims of this retrospective observational study are to report long-term Disease Activity Index for Psoriatic Arthritis (DAPSA) response of apremilast in PsA patients and to analyze the predictors of clinical response. All PsA consecutive patients treated with apremilast in fifteen Italian rheumatological referral centers were enrolled. Anamnestic data, treatment history, and PsA disease activity (DAPSA) at baseline, 6 months, and 12 months were recorded. The Mann-Whitney test and chi-squared tests assessed the differences between independent groups, whereas the Wilcoxon matched pairs signed-rank test assessed the differences between dependent samples. Logistic regressions verified if there were factors associated with achievement of DAPSA low disease activity or remission at 6 and 12 months. DAPSA low disease activity or remission rates at 6 and 12 months were observed, respectively, in 42.7% (n = 125) and 54.9% (n = 161) patients. Baseline DAPSA was inversely associated with the odds of achieving low disease activity or remission at 6 months (odds ratio (OR) 0.841, 95% confidence interval (CI) 0.804-0.879; p < 0.01) and at 12 months (OR 0.911, 95% CI 0.883-0.939; p < 0.01). Almost half of the PsA patients receiving apremilast achieved DAPSA low disease activity or remission at 6 and 12 months. The only factor associated with achievement of low disease activity or remission at both 6 and 12 months was baseline DAPSA.

Corrigendum for Martínez-Rojas et al., volume 323, 2022, p. F425–F434

CorrigendumCorrigendum for Martínez-Rojas et al., volume 323, 2022, p. F425–F434Published Online:03 Feb 2023https://doi.org/10.1152/ajprenal.00099.2020_COROriginal articleMoreSectionsPDF (101 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Martínez-Rojas MÁ, Sánchez-Navarro A, Mejia-Vilet JM, Pérez-Villalva R, Uribe N, Bobadilla NA. Urinary serpin-A3 is an early predictor of clinical response to therapy in patients with proliferative lupus nephritis. Am J Physiol Renal Physiol 323: F425 − F434, 2022. First published July 14, 2022. doi: 10.1152/ajprenal.00099.2022.In the disclosures section, “Programa de Doctorado en Ciencias Bioquímicas” should be “Programa de Doctorado en Ciencias Biomédicas.” Thus, the full disclosures section should read as follows:This study was performed in partial fulfillment of the requirements for a PhD degree; M.A.M.-R. is a doctoral student from the Programa de Doctorado en Ciencias Biomédicas, Universidad Nacional Autónoma de México, and received a fellowship from CONACYT (961986). No conflicts of interest, financial or otherwise, are declared by the authors.This article has no references to display. Download PDF Previous Back to Top FiguresReferencesRelatedInformation Related ArticlesUrinary serpin-A3 is an early predictor of clinical response to therapy in patients with proliferative lupus nephritis 14 Sep 2022American Journal of Physiology-Renal Physiology More from this issue > Volume 324Issue 2February 2023Pages F225-F225 Crossmark Copyright & PermissionsCopyright © 2023 the American Physiological Society.https://doi.org/10.1152/ajprenal.00099.2020_CORPubMed36734877History Published online 3 February 2023 Published in print 1 February 2023 Metrics

P109 Using baseline Peripheral blood mononuclear cell (PBMC) transcriptomics of Crohn Disease patients receiving Ustekinumab treatment as a tool to assess potential response at 1 year

Abstract Background Ustekinumab, a monoclonal antibody to the p40 subunit of interleukin-12 and interleukin-23, is used to treat Crohn Disease (CD) and clinical remission after one year was observed in about 50% of patients. We aimed to identify predictors for clinical response using PBMC transcriptomics obtained from Crohn Disease patients just prior to Ustekinumab treatment initiation. Methods RNA extraction from leukocytes was performed using Qiagen AllPrep RNA/DNA Mini Kit, followed by PolyA-RNA selection, fragmentation, cDNA synthesis, adaptor ligation, TruSeq RNA sample library preparation (Illumina, San Diego, CA), and paired-end 75bp sequencing. mRNA genes with transcripts per million (TPM) values above 1 in at least 20% of the samples were used. Differential gene expression was performed using DESeq2. Results We processed blood samples from 36 CD patients (13 males, [36%], median age 35 [IQR 29-41] years). Samples were obtained at baseline just before starting Ustekinumab treatment. 22/36 (61%) were define as responders and 14/36 (39%) as non-responders after 1 year based on Physician Global Assessment (PGA). Small bowel disease was significantly more common among responders 82% versus 36%, p=0.004. Principal component analysis (PCA) using the 12773 genes that passed expression filtering showed partial separation (Fig. 1). Differential gene expression between responders (n=22) and non-responders (n=14), did not show gene expression signature that passed FDR correction, however the analyses identified 68 genes including CXCL1/2/3 that were induced in non-responders vs. responders with p&amp;lt;0.05 and fold change above 1.5. Functional annotation enrichments of these 68 genes using ToppGene indicated enrichment (Fig. 2) for cytokine activity (FDR=1.98E-05), CXCR chemokine receptor binding (FDR=2.11E-05), Interleukin-10 signaling (FDR=5.03E-07), Genes encoding secreted soluble factors (FDR=1.73E-05), Myeloid Cells, granulocytes CD11b+ (FDR=6.64E-12), and Myeloid Cells Dendritic cells (FDR=1.80E-08). Conclusion No strong differences were found in the blood transcriptomics between responders and non-responders. However, among the non-responders we noted an increased inflammatory response enriched for pathways linked with cytokine activity and chemokine receptor binding and innate granulocytes and Myeloid signature. A larger cohort is required to validate and farther explore these findings. Fig. 1: Principal component analysis (PCA) using the 12773 genes that passed expression filtering showed partial separation.  Fig. 2: Functional annotation enrichments of the 68 genes induced in PBMC. 

P746 Identification of Altered Microbial Genera at Baseline in Adalimumab Clinical Remitters and an Absence of Change in Total Microbial Composition Post Induction Treatment in the SERENE UC Study

Abstract Background The gut microbiome plays an integral role in the pathogenesis of Inflammatory Bowel Disease (IBD). However, there have been a limited number of studies investigating the composition of the gut microbiome in anti-TNF-treated Ulcerative Colitis (UC) patients. The aims of this study were to 1) identify novel microbial baseline predictors of clinical response and remission to Adalimumab treatment, and 2) assess the impact of Adalimumab induction treatment on the gut microbiome of UC patients. Methods The SERENE UC study (NCT02065622) compared the efficacy of higher adalimumab dosing regimens to the standard regimen in patients with moderately to severely active UC. 16S rRNA gene sequencing was performed on 204 stool samples from 107 UC patients at baseline and Week 8. An ANOVA test followed by Tukey HSD was used to compare microbial content within (baseline) or across (baseline vs Week 8) visits between clinical remitters (n=16), clinical responders (n=38), and patients who failed to respond to Adalimumab treatment (n=53). Clinical response was defined as a full Mayo score decrease of ≥3 points and ≥30% from baseline, plus ≥1-point decrease in rectal bleeding score or absolute bleeding score ≤1 at Week 8. Clinical remission was defined as a full Mayo score ≤2 with no sub-score &amp;gt;1 at Week 8. Results There were no differences in alpha diversity in terms of richness and evenness when comparing samples from patients across response categories, or alpha and beta diversity when comparing paired samples from patients pre- and post-treatment. In addition, principal coordinate analysis of the microbiome did not highlight any clustering of the samples between response groups or visits. When stratifying patients by clinical response status at Week 8, we identified 4 genera that were significantly altered at baseline in the clinical remitters compared to the clinical responders and/or non-responders, including Dorea, Ruminococcus torques group, Subdoligranulum, and Collinsella. Unexpectedly, when comparing paired pre- and post-treatment samples within a response group, we failed to detect any significant changes on the total microbiome composition regardless of response status at Week 8. Conclusion These findings suggest that baseline microbial composition is significantly altered in UC patients who achieve clinical remission, but that Adalimumab treatment does not significantly alter the composition of the gut microbiome after 8 weeks of treatment. Future work is focused on achieving a deeper understanding of the gut landscape in UC patients treated with Adalimumab through 1) investigation of bacterial, viral, and fungal composition by metagenomics, and 2) integration of serum metabolomics data.

P663 Post-ustekinumab induction IL12, IL23, and ustekinumab levels are associated with clinical response in a multi-centre prospective cohort study of Crohn’s disease patients: results from the AURORA Study including ANZIBDC Cohort

Abstract Background Ustekinumab (UST) is a monoclonal antibody targeting IL-12 and IL-23 through their shared p40 subunit. This study aimed to determine the clinical outcomes after UST treatment in Crohn’s disease (CD) patients in a real-world setting, and to investigate the association of clinical outcomes with IL-12, IL-23 and UST levels. Methods A multi-centre prospective observational cohort study of UST for moderate to severe CD was conducted. Patients were recruited from 19 Australian centres between Sep 2019 and Apr 2022. Clinical assessments were performed at baseline study visit (SV) 1 and post-induction (SV2). Patients were assessed every 6 months during maintenance therapy to 18 months (SV4). Clinical response and remission rates were determined using PRO2 definitions (STRIDE II guidelines). Logistic regression analyses were performed to identify predictors of clinical response and remission. UST levels were measured post induction and interleukin levels including IL12p40 and IL-23p19 were measured at SV1 and SV2 using ProQuantum ELISA assays. Results A total of 198 patients were recruited: median age 40.7 years, 54.3% male, median duration of disease 90.5 months, 12.8% active smokers, and 49.7% on concomitant immunomodulatory therapy. The majority (58.4%) were biologic-naïve and 82 patients were previously exposed to biologics (51.9%; IFX n=42, ADA n=50, VDZ n=9). Clinical response was achieved in 137 patients (75.7%), and remission in 84 (46.4%) with higher rates of response (85.2% vs 61.6%, p=0.001) and remission (54.6% vs 34.2%, p=0.006) in biologic naïve patients compared to biologic-exposed. For the 114 patients with 18 months (SV4) of follow-up, durable clinical response was maintained in 66.8% and remission in 50.0%. Dose escalation (90mg 4 weekly) was administered to 13 patients (6.6%) during induction, 48 (42.1%) in maintenance, and 15 patients (13.2%) received IV re-induction during maintenance. There was a significant reduction in IL-12 and IL-23 levels from SV1 to SV2 in responders (p=0.0001), but no significant reduction in non-responders (Figure 1). Clinical response at SV4 (n=101) was associated with higher post-induction UST levels (p=0.03) (Table 1). The combination of IL-12. IL-23 and UST level at SV2 predicted long-term response at SV4 (Sn 73%, Sp 71%, AUROC 0.765), but not at SV2 (Figure 2). Conclusion This large real-world study confirms that UST is most effective in bio-naïve CD patients with significantly higher response and remission rates than bio-experienced patients. The combination of post-induction IL-12, IL-23, and UST levels was associated with response at 18 months and could represent a novel predictor of long-term clinical outcomes.

Pediatric Vagus Nerve Stimulation: Case Series Outcomes and Future Directions.

Vagus nerve stimulation (VNS) is a neuromodulatory procedure most extensively studied as an adjunct to medically refractory epilepsy. Despite widespread adoption and decades of clinical experience, clinical predictors of response to VNS remain unclear. To evaluate a retrospective cohort of pediatric patients undergoing VNS at our institution to better understand who may benefit from VNS and identify factors which may predict response to VNS. We conducted a retrospective cohort study examining pediatric patients undergoing VNS over nearly a 20-year span at a single institution. Presurgical evaluation, including demographics, clinical history, and diagnostic electroencephalogram, and imaging findings were examined. Primary outcomes included VNS response. Two hundred ninety-seven subjects were studied. The mean age at surgery was 10.1 (SD = 4.9, range = 0.8-25.3) years; length of follow-up was a mean of 4.6 years (SD = 3.5, median = 3.9 years, range 1 day-16.1 years). There was no association between demographic factors, epilepsy etiology, or genetic basis and VNS outcomes. There was an association between reduction in main seizure type with positive MRI finding. Of all MRI findings analyzed, brain atrophy was significantly associated with worse VNS outcomes, whereas dysplastic hippocampus and chronic periventricular leukomalacia findings were found to be associated with improved outcomes. Increased seizure semiology variability and seizure type were also associated with improved seizure outcomes. Predicting response to VNS remains difficult, leading to incompletely realized benefits and suboptimal resource utilization. Specific MRI findings and increased seizure semiology variability and type can help guide clinical decision making and patient counseling.

Ketamine in antidepressant treatment: a revolution?

Thirty percent of depressed patients are treatment resistant (TRD) suggesting the need of new therapeutic strategy. Recently, it has been shown that ketamine, an anesthetic agent with dissociative effects, has potent and rapid antidepressant properties. Ketamine is a ionotropic glutamatergic NMDA antagonist that inhibits gabaergic neurons. Its antidepressant effect peaks at 24 h post-treatment. Several meta-analyses of placebo randomized clinical trials emphasized its efficacy. More recently, a meta-analysis showed its efficiency in real-world population of TRD patients. Although there is no clear biological or clinical predictors of response or remission to ketamine, patients with high level of resistance were found to remit less often. Restoring both the optimism bias and the asymmetry in belief updating mediates the antidepressant ketamine's effect. Consistent with predictive bayesian model and terror management theory, this suggests that dissociation induced by ketamine may contribute to its clinical antidepressant action. Although increasing access to ketamine and esketamine is welcome, legitimate concerns have been raised with respect to long-term safety and abuse risk.

Evaluation of prefrontal cortex volume as a predictor of clinical response to theta-burst stimulation in the treatment of unipolar depression

Evaluation of prefrontal cortex volume as a predictor of clinical response to theta-burst stimulation in the treatment of unipolar depression

Canadian Spine Society

# Abstract 57. Radiographic reporting in adolescent idiopathic scoliosis: Is there a discrepancy comparing radiologists’ reports and surgeons’ assessments? {#article-title-2} Cobb angle measurement is the standard method for quantification of scoliosis in adolescent idiopathic scoliosis (AIS),

First-line biologic therapy with tumor necrosis factor inhibitors for psoriatic arthritis: a prospective observational study

Psoriatic arthritis (PsA) is a chronic inflammatory disease that affects multiple joints. It is associated with psoriasis and treated with synthetic and biologic drugs. The objective of this study was to assess the outcomes of patients who received biologic therapy with tumor necrosis factor (TNF) inhibitors in terms of effectiveness, safety, functionality, and quality of life. A prospective observational study was performed at a single center in Belo Horizonte, Brazil. Patients with PsA who received their first TNF inhibitor treatment were followed up for 12 months. Disease activity was measured using the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Clinical Disease Activity Index (CDAI). Functionality was measured using the Health Questionnaire Assessment (HAQ), and quality of life was evaluated using the European Quality of Life Five Dimensions (EQ-5D). Multiple linear regression was used to identify predictors of the clinical response at 12 months. A total of 143 patients treated with adalimumab or etanercept were evaluated. Most of the clinical measures were significantly improved at 12 months. However, 31%-51% of the patients did not achieve good clinical control. No differences were observed between adalimumab and etanercept, except for poor functionality at 12 months among patients treated with etanercept. The main predictors of a worse clinical response were female sex, etanercept use, poor functionality, or lower quality of life at baseline. The main adverse reactions were alopecia, headache, injection site reaction, sinusitis, flu, dyslipidemia, and infections. TNF inhibitor therapy was effective and safe. However, despite improvements in clinical measures, most patients did not achieve satisfactory control of the disease.

Molecular prediction of clinical response to anti-PD-1/anti-PD-L1 immune checkpoint inhibitors: New perspectives for precision medicine and mass spectrometry-based investigations.

Monoclonal antibodies (mAbs) acting as immune checkpoint inhibitors (ICIs) are among the most frequently used immunotherapies in oncology. However, precision medicine approaches to adapt the treatment to the patient are still poorly exploited. Given the risk of severe adverse reactions, predicting patient eligibility for ICI therapy represents a great asset for precision medicine. Today, the extended panel of mass spectrometric approaches, accompanied by newly developed sample preparation methods is a strategy of choice for responder and non-responder stratification on a molecular basis, and early detection of resistance. In this perspective article, we review the biodisposition of mAbs, the interest in molecular stratification of patients treated with these mAbs, and the possible analytical strategies to achieve this goal, with a major emphasis on mass spectrometric approaches.

Macs - a Leukemic Stem Cell- Based Predictor of Clinical Response to Venetoclax and Other BH3 Mimetics for Acute Myeloid Leukemia

Macs - a Leukemic Stem Cell- Based Predictor of Clinical Response to Venetoclax and Other BH3 Mimetics for Acute Myeloid Leukemia

Individual Red Blood Cell Fetal Hemoglobin Concentrations Determined By Imaging Flow Cytometry and the Number of F Cells Are Very Good Predictors of Clinical Response to Increased Level of HbF and Are Associated with Hemolysis, Tricuspid Regurgitant Jet Velocity, and Sickle Retinopathy in Adult Sickle Cell Disease Patients

Sickle cell disease (SCD) patients with similar total fetal hemoglobin (HbF) levels may present with different severity, which is attributed to the heterogeneous distribution of HbF among red blood cells (RBCs) with varying percentages of circulating HbF-containing RBCs (% F cells). Steinberg et al. (2014) proposed that an individual HbF concentration per cell (iHbF) above 10pg inhibits the polymerization of HbS, so the development of precise methods to quantify iHbF and the percentage of F cells may allow clinicians to use those parameters as targets to monitor patient treatment. We devised a novel procedure to very accurately measure and quantify iHbF using imaging flow cytometry (Amnis Imagestream) and investigated its correlations with clinical manifestations. Samples from 54 adult SCD patients (22 [41%] female, 39 [72%] on hydroxyurea) were used to acquire images from RBCs labeled with fluorescent anti-HbF antibody and were analyzed using IDEAS software v 6.2. Along with the hematimetric data and HPLC quantification of total HbF of each sample, we modified the formulas by Maier-Redelsperger et al. (1994) and Horiuchi et al. (1995), with minimization of interference from autofluorescence of non-F cells, correction for area and fluorescence intensity, and analyzed RBC subpopulations with varying levels of HbF expression. Statistical analysis was performed using R considering a p value <0.05 to be statistically significant. We did not find associations of iHbF with alpha thalassemia carrier state or beta globin cluster haplotypes Benin or Bantu, the most common in our population. Perpendicular cutoff correlation studies defined two patient populations: one group with lower mean iHbF (9.9pg) and lower % F cells (28.2%) and another group with a higher mean iHbF (15.8pg) and higher mean % F cells (72.5%). The latter group had a lower frequency of vaso-occlusive crises (p=0.011). That was further validated with our finding that the cutoffs of % F cells>30% and iHbF>10pg were strongly associated with lower absolute reticulocyte counts (p<0.001), LDH (p=0.002), and indirect bilirubin (p<0.001). The association between hemolysis and iHbF was further explored regarding pulmonary hypertension, showing that a value of iHbF>10pg was associated with a lower median tricuspid regurgitant jet velocity than in patients with iHbF<10pg (2.72m/s vs. 2.29m/s, p=0.046). We also found an association of a mean iHbF<8pg with the presence of sickle retinopathy (p=0.002). Patients with retinopathy had a lower mean iHbF and % F cells than those without it (7.08pg vs. 8.75pg, p=0.032; 48.5% vs. 71.0%, p=0.043, respectively), suggesting increments in iHbF and % F cells may be protective against sickle retinopathy, a complication not usually associated with high hemolytic rates. Our results suggest that a percentage of F cells above 30% along with individual RBC HbF concentration of 10pg may be protective against complications in SCD patients and, therefore, should be explored as goals for hydroxyurea therapy in this population. In addition, the data presented here suggest further studies on the efficacy of HbF induction therapy against the development of sickle retinopathy may be performed in a large population of sickle cell disease patients.

CD25, Soluble CD25, and CCL17 As Potential Predictors of Clinical Response to Camidanlumab Tesirine in Patients with Relapsed/Refractory Classical Hodgkin Lymphoma

Introduction: Camidanlumab tesirine (Cami), an antibody-drug conjugate targeting CD25, has shown single-agent anti-tumor activity and manageable toxicity in a phase 2 trial in relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL; Carlo-Stella, et al. 2022). In the phase 1 cHL trial, biopsy tumor cell CD25 histoscores (H-scores) were significantly higher in responders vs nonresponders and low baseline soluble CD25 (sCD25) was possibly related to response (Hamadani, et al. 2021). Separately, circulating CCL17 has been correlated with response to therapies for cHL (Plattel, et al. 2016). Objective: To assess CD25, sCD25, and CCL17 as predictive biomarkers of clinical response to Cami in patients (pts) with R/R cHL. Methods: This analysis was based on the open-label, multicenter, phase 2 study in pts with R/R cHL after ≥3 prior lines of therapy (or ≥2 in pts ineligible for SCT; NCT04052997). CD25 expression was assessed by immunohistochemistry (IHC) and H-score in all archival tumor biopsies and a subset of recent biopsies (archival biopsies taken after the last systemic anticancer treatment, including SCT if applicable); serum sCD25 and CCL17 were assessed by qualified immunoassays prior to Cami infusion on day 1 of each cycle. Cami may interfere with the sCD25 assay, underestimating post-baseline (BL) sCD25. CD25 IHC, BL sCD25 and CCL17, and changes in sCD25 and CCL17 from BL were compared between responders and nonresponders. Receiver operating characteristic (ROC) analyses were performed to evaluate the predictive potential of these measures as response biomarkers. Results: Assessments of CD25, sCD25, and CCL17 in pts with a best overall response (BOR) of complete or partial response (responders) and stable disease or PD (nonresponders) were performed for 111 of 117 pts treated with Cami (6 pts were not evaluable for BOR). No significant difference in tumor cell CD25 H-score was observed between responders and nonresponders in all (n=99) or recent biopsies (n=23; p>0.05 for both), despite higher median levels in responders. BL sCD25 (n=108) was significantly higher in nonresponders than responders (p=0.018; Fig 1); though, overlapping values were observed in a substantial number of pts. There was also a significantly greater decrease in sCD25 in nonresponders vs responders from BL to C3D1 (n=79; median 0.53 vs 1.02; p=0.018). While there was no significant difference in BL CCL17 levels (n=106), there was a significantly greater decrease in BL CCL17 in responders vs nonresponders at C2D1 (n=97; median 0.50 vs 0.81; p<0.01 log10 change). In ROC analyses in a subset of 96 pts with CD25 IHC and BL sCD25 results available, sCD25 alone showed a modest predictive potential (area under curve [AUC]=0.65) that was not improved with the addition of tumor cell CD25 H-score (AUC=0.67). In a subset of 76 pts with results available for sCD25 and CCL17 at BL and C2D1, ROC curves of BL sCD25, BL sCD25 plus BL CCL17, sCD25 change from BL, and CCL17 change from BL showed modest predictive potential (AUC<0.7 for all). A better AUC was found in a model including change from BL at C2D1 of sCD25 and CCL17 (AUC=0.74). This AUC was further increased in a model of BL sCD25 and CCL17 plus their change from BL at C2D1 and a model of BL sCD25 plus sCD25 and CCL17 change from BL at C2D1 (AUC=0.76 for both; Fig 2). The latter model had a higher Youden index. Conclusions: Higher median tumor cell CD25 H-score was seen in responders vs nonresponders in all and recent biopsies but the differences did not reach significance. These data warrant further investigations as phase 1 data showed significantly higher tumor CD25 expression in responders (Hamadani, et al. 2021). Nonresponders had significantly higher BL sCD25; however, this parameter alone has insufficient predictive potential for Cami efficacy. Predictive models including BL sCD25 plus sCD25 and CCL17 change from BL at C2D1 (± BL CCL17) showed the best ROC AUCs but need further refining to be clinically relevant. However, given the high overall and early responses in most pts treated with Cami, biomarkers predicting response at C2D1 are suboptimal unless reaching a higher sensitivity and specificity. Investigation of sCD25 in the context of the Cami mode of action and exposure-response and the potential value of sCD25 and CCL17 changes as early indicators of Cami's effect and as biomarkers for disease monitoring and response are ongoing. Funding: ADC Therapeutics SA; writing: CiTRUS Health Group. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clinical Predictors of Response to Rilzabrutinib Therapy in Patients with Immune Thrombocytopenia: Exploratory Analysis of a Phase 1/2 Study

Clinical Predictors of Response to Rilzabrutinib Therapy in Patients with Immune Thrombocytopenia: Exploratory Analysis of a Phase 1/2 Study

NIMG-74. RADIOIMMUNOMIC SIGNATURES IN PEDIATRIC LOW-GRADE GLIOMA BASED ON MULTIPARAMETRIC MRI SCANS

Abstract Understanding the immune microenvironment in pediatric low-grade glioma (pLGG) patients may help in identification of the patients who benefit from anti-tumor immunotherapies. However, surgical resection is not feasible for many pLGG tumors in certain anatomical locations. Therefore, developing non-invasive tools that characterize the tumor microenvironment prior to therapeutic interventions could contribute to stratification and enrollment of the patients into relevant clinical trials. In this work, we derived radiomic signatures of immune profiles (radioimmunomics) based on machine learning (ML) analysis of readily available conventional MRI scans. Transcriptomic data for a cohort of 197 subjects was retrospectively collected from Open Pediatric Brain Tumor Atlas (OpenPBTA). The patients were categorized into three groups (Group1-3) based on their immunological profiles using consensus clustering algorithm. This analysis revealed greater immune cell infiltration in non-BRAF mutated pLGGs. Group1 showed more enrichment in M1 macrophages, and microenvironment and immune scores compared to Group2 and Group3. Elevated tumor inflammation score (TIS), as a predictor of clinical response to anti-PD-1 blockade, was observed in Group1 compared to Group2 (p= 1.4e-7) and Group3 (p= 0.0054). Radiomic features, including volumetric, morphologic, histogram, and texture descriptors, were extracted from the segmented tumor regions on multiparametric MRI (mpMRI) scans of 71 (of 197) patients. Multivariate ML models were trained to predict the three immunological groups based on radiomic features using cross-validated random forest classifier along with recursive feature elimination, which yielded AUC of 0.72 for this multi-class classification problem. Our findings indicate the presence of distinct immunological groups in pLGG tumors, with possibly more favorable response to immunotherapies in Group1 tumors. Furthermore, we developed radioimmunomic signatures based on pre-operative conventional mpMRI that can potentially stratify the patients based on their immune tumor microenvironment. Based on these initial promising results, we are exploring additional features to increase the accuracy of radioimmunomics model.

Low FODMAP diet reduces gastrointestinal symptoms in irritable bowel syndrome and clinical response could be predicted by symptom severity: A randomized crossover trial

Fermentable oligo-, di-, monosaccharides and polyols (FODMAPs) can provoke symptoms in patients with irritable bowel syndrome (IBS). We aimed to compare the effects of diets with low vs. moderate FODMAP content on gastrointestinal (GI) symptoms and bowel habits, and to identify possible predictors of clinical response to a low FODMAP diet and FODMAP sensitivity in IBS. Adult participants with IBS (Rome IV criteria, n=29) were included and adhered to two 7-day diet periods, with either low (4 g/day) or moderate (23 g/day) amounts of FODMAPs, in this randomized, double-blind, crossover study. The periods were separated by a wash-out period (≥14 days). IBS-Severity Scoring System (IBS-SSS) and a stool diary (Bristol Stool Form) were completed before and after the diet periods. At baseline, severity of GI symptoms and gut microbial fermentation were assessed (every 15 min, 4 h) during the Lactulose Nutrient Challenge Test (LNCT). Clinical response and FODMAP sensitivity were defined by reduction after low FODMAP period, and increase after moderate FODMAP period in IBS-SSS (≥50 points), respectively. Severity of GI symptoms (P=0.04), stool consistency (P=0.01), and stool frequency (P=0.01) differed between the interventions, with reduced overall GI symptom severity, abdominal pain intensity and frequency, bowel habits dissatisfaction, and daily life interference (P<0.05 for all), as well as more firm (P=0.03) and less frequent (P<0.01) stools after low FODMAP intervention, but not after moderate FODMAP intervention. A third (34%) responded clinically to the low FODMAP diet, and the response could be predicted by higher IBS-SSS at baseline (P=0.02). Although modest associations between FODMAP sensitivity (22%) and GI symptoms during LNCT were observed, no independent predictors could be identified. A diet low in FODMAPs reduces GI symptoms and affects bowel habits in IBS, compared with a moderate FODMAP diet. Assessment of IBS severity before the intervention may be used to predict clinical response to a low FODMAP diet. Trial registry (http://www. gov): Registered under Clinical Trial number NCT05182593.

Early MOnitoring of REsponse (MORE) to Golimumab Therapy: Results of a Multicentre, Prospective Observational Trial

Background: The therapeutic goal of clinical remission in patients with moderate to severe ulcerative colitis (UC) is achieved after biological therapy only in 16–39%. Individualization of therapeutic intervention would benefit from prediction of early response. Study Objective: The primary objective of our study was to assess golimumab (GLM) trough serum level of ≥2.5 μg/mL in combination with a reduction of faecal calprotectin (FC) of ≥50% at week 6 compared to baseline to predict clinical response at week 26 after regular GLM intake. Methods: Patients with moderate to severe active UC and planned GLM treatment were recruited for a prospective, multicentre, observational study in Germany. Prediction of clinical response was assessed by FC and GLM trough level. Missing data were imputed as therapy failure according to the last observation carried forward method. Results: Fifty nine patients have been enrolled. 54% of patients were anti-TNF naïve. Clinical response at week 6 was a significant predictor for achieving clinical response at week 26 (odds ratio [OR] 10.97, confidence interval [CI], 2.96–40.68; p < 0.001). Moreover, patients with a GLM trough level of ≥2.5 μg/mL and a ≥50% reduction of FC at week 6 had an OR of 5.33 (95% CI, 0.59–47.84) to achieve clinical response at week 26. Conclusion: Clinical response at week 6 is the best predictive marker for achieving clinical response at week 26. Consideration of significant reduction of FC and trough GLM serum levels could improve prediction of response.

Baseline C-reactive protein levels are predictive of treatment response to a neuroimmune modulator in individuals with an alcohol use disorder: a preliminary study

ABSTRACT Background: Inflammation is implicated in alcohol use disorder (AUD). Ibudilast, a neuroimmune modulator, shows promise for the treatment of AUD. Elevated inflammation, indicated by high levels of C-reactive protein (CRP), represents a possible subtype of AUD, which may be associated with treatment response to ibudilast. Objectives: The current study evaluated CRP as a predictor of treatment response to ibudilast; hypothesizing that ibudilast would be more effective at reducing drinking and alcohol cue-reactivity in individuals with higher CRP levels. Methods: This is a secondary analysis of a clinical trial of ibudilast for AUD, which found that ibudilast reduced heavy drinking in individuals with AUD. Fifty-one individuals were randomized to receive ibudilast (n = 24 [16 M/8F]) or placebo (n = 27 [18 M/9F]) for two weeks. Participants provided blood samples at baseline to assess CRP levels, completed daily assessments of alcohol use, and an fMRI alcohol cue-reactivity task at study mid-point. Models tested the effects of medication, CRP levels, and their interaction on drinks per drinking day and alcohol cue-reactivity. Results: There was a significant interaction between medication and CRP (F = 3.80, p = .03), such that the ibudilast high CRP group had fewer drinks per drinking day compared to the ibudilast low CRP group. CRP moderated the effect of medication on brain activation in a cluster extending from the left inferior frontal gyrus to the right-dorsal striatum (Z = 4.55, p < .001). This interaction was driven by attenuated cue-reactivity in the ibudilast high CRP group relative to the ibudilast low CRP and placebo high CRP groups. Conclusions: This study serves as an initial investigation into predictors of clinical response to ibudilast treatment and suggests that a baseline proinflammatory profile may enhance clinical efficacy.

The heterogeneous immune landscape between lung adenocarcinoma and squamous carcinoma revealed by single-cell RNA sequencing

A thorough interrogation of the immune landscape is crucial for immunotherapy strategy selection and prediction of clinical responses in non-small-cell lung cancer (NSCLC) patients. Single-cell RNA sequencing (scRNA-seq) techniques have prompted the opportunity to dissect the distinct immune signatures between lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), the two major subtypes of NSCLC. Here, we performed scRNA-seq on 72,475 immune cells from 40 samples of tumor and matched adjacent normal tissues spanning 19 NSCLC patients, and drew a systematic immune cell transcriptome atlas. Joint analyses of the distinct cellular compositions, differentially expressed genes (DEGs), cell–cell interactions, pseudotime trajectory, transcriptomic factors and prognostic factors based on The Cancer Genome Atlas (TCGA), revealed the central roles of cytotoxic and effector T and NK cells and the distinct functional macrophages (Mφ) subtypes in the immune microenvironment heterogeneity between LUAD and LUSC. The dominant subtype of Mφ was FABP4-Mφ in LUAD and SPP1-Mφ in LUSC. Importantly, we identified a novel lymphocyte-related Mφ cluster, which we named SELENOP-Mφ, and further established its antitumor role in both types, especially in LUAD. Our comprehensive depiction of the immune heterogeneity and definition of Mφ clusters could help design personalized treatment for lung cancer patients in clinical practice.