Low Baseline Levels Research Articles

Systemic longitudinal immune profiling identifies proliferating Treg cells as predictors of immunotherapy benefit: biomarker analysis from the phase 3 CONTINUUM and DIPPER trials

The identification of predictors for immunotherapy is often hampered by the absence of control groups in many studies, making it difficult to distinguish between prognostic and predictive biomarkers. This study presents biomarker analyses from the phase 3 CONTINUUM trial (NCT03700476), the first to show that adding anti-PD-1 (aPD1) to chemoradiotherapy (CRT) improves event-free survival (EFS) in patients with locoregionally advanced nasopharyngeal carcinoma. A dynamic single-cell atlas was profiled using mass cytometry on peripheral blood mononuclear cell samples from 12 pairs of matched relapsing and non-relapsing patients in the aPD1-CRT arm. Using a supervised representation learning algorithm, we identified a Ki67+ proliferating regulatory T cells (Tregs) population expressing high levels of activated and immunosuppressive molecules including FOXP3, CD38, HLA-DR, CD39, and PD-1, whose abundance correlated with treatment outcome. The frequency of these Ki67+ Tregs was significantly higher at baseline and increased during treatment in patients who relapsed compared to non-relapsers. Further validation through flow cytometry (n = 120) confirmed the predictive value of this Treg subset. Multiplex immunohistochemistry (n = 249) demonstrated that Ki67+ Tregs in tumors could predict immunotherapy benefit, with aPD1 improving EFS only in patients with low baseline levels of Ki67+ Tregs. These findings were further validated in the multicenter phase 3 DIPPER trial (n = 262, NCT03427827) and the phase 3 OAK trial of anti-PD-L1 immunotherapy in NSCLC, underscoring the predictive value of Ki67+ Treg frequency in identifying the beneficiaries of immunotherapy and potentially guiding personalized treatment strategies.

Prognostic role of serum cytokines level in non-small cell lung cancer patients with anti-PD-1 and chemotherapy combined treatment

BackgroundChemotherapy combined with PD-1 inhibitor treatment has revolutionized the standard of care for patients with NSCLC. However, the benefit is not universal, highlighting the need for precise prediction factors. Given their relationship with the immune system and non-invasive nature, serum cytokines are potential candidates for predicting the clinical effects of chemoimmunotherapy. Our study aims to evaluate the association of serum cytokines with the prognosis of patients with NSCLC treated with chemoimmunotherapy.MethodsLevels of 10 serum cytokines were detected in 60 NSCLC patients receiving chemotherapy plus PD-1 inhibitor-based treatment. Of these, dynamic samples from 19 patients were collected at baseline and after two treatment cycles. Their association with patients’ clinicopathological characteristics, PFS and OS was described and investigated using survival analysis, cox regression and time-dependent ROC analysis. Preliminary evaluation of changes in cytokine levels associated with treatment response was conducted.ResultsPatients with lower baseline levels of serum IL-6, IL-5, IL-8, TNF-α and IL-10 had longer PFS, while patients with higher levels of IL-4 had longer PFS. Patients with lower levels of serum IL-6, IL-8, IL-22, TNF-α and IL-10 had longer OS, while patients with higher levels of IL-4 had longer OS. Multivariate analysis suggested that higher IL-6 and IL-5 levels were associated with poorer PFS, and higher IL-6 levels were associated with dismal OS. Additionally, changes in serum cytokine levels could be associated with treatment response.ConclusionOur study suggests that serum cytokines, specifically IL-6, IL-5, IL-8, TNF-α, IL-10, and IL-4, are potential prognostic factors for patients with NSCLC receiving chemotherapy plus PD-1 inhibitor treatment.

Continuous digital cough monitoring during 6-month pulmonary tuberculosis treatment

IntroductionThe recent advances in digital and wearable technologies with artificial intelligence (AI) enable the use of continuous cough monitoring (CCM) to objectively monitor symptoms as surrogate markers of treatment efficacy in pulmonary tuberculosis (PTB). The objectives of this study are to describe the evolution of cough during PTB treatment in adult and to assess the feasibility of community-based CCM.MethodsWe prospectively enrolled PTB adult participants upon treatment initiation. Participants’ coughs were continuously monitored during 6 months with a smartphone loaded with an app able to detect cough by using an AI algorithm.ResultsTwenty-two participants were included. The median age was 28.5 (IQR: 22–42) and 62% were male. The median cough per hour (medCPH) was 11.0 (IQR: 7.0–27.0) at week 1. By the end of the intensive phase of PTB treatment at week 8, the medCPH was 3.5 (IQR: 1.5–7.0), which was significantly lower than the medCPH at week 1 (p=0.002). At week 26 (end of treatment), the medCPH was 1.0 (IQR: 1.0–2.5). The adherence to CCM was high during the first 13 weeks of PTB treatment and then waned over time. The adherence was similar during daytime and nighttime.ConclusionCough counts rapidly drop during the intensive phase of PTB treatment and then slowly decrease to a low baseline level by the end of the treatment. Community-based CCM using digital technology is feasible in low resource settings but requires evaluation of alternative approaches to overcome adherence issues and technical limitations (mobile internet and electricity availability).

9-HODE associates with thalamic atrophy and predicts white matter damage in multiple sclerosis

BackgroundMultiple sclerosis (MS) is characterized by extensive tissue damage leading to a range of complex symptoms, including physical disability and cognitive dysfunction. Recent work has indicated the clinical relevance of bioactive lipid mediators (LMs), which are known to orchestrate inflammation and its resolution and are deregulated in MS. However, it is unknown whether LM profiles relate to white matter (WM) damage. ObjectivesTo investigate the potential association between plasma-derived LMs and MRI-quantified WM damage using fractional anisotropy (FA) and grey matter (GM) atrophy in dimethyl fumarate-treated relapsing remitting MS (RRMS) patients. MethodsSeverity of FA-based WM damage and GM atrophy was determined in RRMS patients (n=28) compared to age- and sex-matched controls (n=31) at treatment initiation (baseline) and after 6 months. Plasma LMs were assessed using HPLC-MS/MS and baseline LMs were correlated to changes in FA and brain volumes. ResultsWe observed significant WM damage in RRMS patients (mean age 41.4 [SD 9.1]) at baseline and follow-up (z-score=-0.33 and 0.31, respectively) compared to controls (mean age 41.9 [SD 9.5]; p<0.001 for both comparisons). Patients with severe WM damage showed a decline of thalamic volume (p=0.02), and this decline correlated (r=0.51, p<0.001) with lower baseline levels of 9-HODE. This LM also predicted FA worsening (beta=0.14, p<0.001) over time at 6 months. ConclusionDespite the relatively small sample size, lower baseline levels of the LM 9-HODE correlated with more thalamic atrophy and predicted subsequent worsening of WM damage in RRMS patients.

Baseline sLAG-3 levels in Caucasian and African-American breast cancer patients.

Worse survival persists for African-Americans (AA) with breast cancer compared to other race/ethnic groups despite recent improvements for all. Unstudied in outcomes disparities to date is soluble LAG-3 (sLAG-3), cleaved from the LAG-3 immune checkpoint receptor which is a proposed target for deactivation in emerging immunotherapies due to its prominent immunosuppressive function in the tumoral microenvironment. A prior study has found that lower sLAG-3 baseline level was associated with poor outcomes. In a cross-sectional study of 95 patients with primary breast cancer (n = 58 Caucasian, n = 37 AA), we measured sLAG-3 (ELISA pg/ml) in pre-treatment blood samples using the non-parametric Mann-Whitney u-Test for independent samples, and, calculated Pearson r correlation coefficients of sLAG-3 with circulating cytokines by race. Mean sLAG-3 level was lower in AA compared to Caucasian patients (1377.6 vs 3690.3, P = .002), and in patients with triple-negative breast cancer (TNBC) compared to those with non-TNBC malignancies (P = .02). When patients with TNBC tumors were excluded from analyses, the difference in sLAG-3 level between AA (n = 21) and Caucasian patients (n = 40) substantially remained (1937.4 vs 4182.4, P = .06). Among Caucasian patients, sLAG-3 was correlated with IL-6, IL-8 and IL-10 (r = .69, P < .001; r = .70, P < .001; and, r = .46, P = .01; respectively). For AA patients, sLAG-3 was correlated only with IL-6 (r = .37, P = .03). We present the first report that African-American breast cancer patients might have comparatively low pre-treatment sLAG-3 levels, independent of TNBC status, along with reduced co-expression with circulating cytokines. The mechanistic and prognostic role of cleaved LAG-3, particularly in disparate outcomes, remains to be elucidated.

Pre-treatment plasma retinol binding protein 4 level and its change after treatments predict systemic treatment response in psoriasis patients

BackgroundRetinol binding protein 4 (RBP4) is a mediator of inflammation and related to skin lesion formation, which suggests its engagement in psoriasis pathology and progression. This study intended to explore the change in RBP4 after systemic treatments, and its ability to predict treatment response in psoriasis patients.MethodsThis prospective study enrolled 85 psoriasis patients and 20 healthy subjects. Plasma RBP4 was detected by enzyme-linked immunosorbent assay at baseline and 12th week (W12) after systemic treatments in psoriasis patients, as well as after enrollment in healthy subjects. Psoriasis Area and Severity Index (PASI) 75 and PASI 90 were evaluated at W12 in psoriasis patients.ResultsRBP4 at baseline was higher in psoriasis patients than in healthy subjects [median (interquartile range): 13.39 (9.71–22.92) versus 9.59 (6.57–13.72) µg/mL] (P = 0.003). In psoriasis patients, 50 (58.8%) patients achieved PASI 75 at W12, and 25 (29.4%) patients achieved PASI 90 at W12. RBP4 was decreased at W12 compared to its level at baseline (P < 0.001). Lower RBP4 at baseline predicted achieving PASI 75 at W12 (P = 0.038). Greater RBP4 change (baseline-W12) precited achieving PASI 75 (P = 0.036) and PASI 90 (P = 0.045) at W12. Receiver operating characteristic curves suggested that after adjustment for all clinical features, RBP4 at baseline and RBP4 change (baseline-W12) had an acceptable ability to predict PASI 75 and PASI 90 at W12 with all area under curve values > 0.7.ConclusionPlasma RBP4 is decreased after systemic treatments, and its low baseline level and greater decline after treatments predict good treatment response in psoriasis patients.

Trajectory of Irisin as a Predictor of Kidney-Related Outcomes in Patients with Asymptomatic Heart Failure.

The purpose of the study is to elucidate whether irisin is a promising predictive biomarker for kidney-related events in patients with T2DM and concomitant asymptomatic HF. We prospectively enrolled 146 T2DM patients who had either evidence of structural cardiac abnormality or elevated levels of N-terminal brain natriuretic pro-peptide (NT-proBNP) > 125 pmol/mL and followed them for 52 weeks. Structural cardiac abnormalities were used as the minimum from the following criteria: abnormal left ventricular (LV) global longitudinal strain (GLS) < -16%, LV hypertrophy, left atrial volume index > 34 mL/m2, abnormal ratio of early transmitral diastolic filling velocity/early mitral annular velocity ≥ 13 units. All the patients underwent echocardiographic and Doppler examinations by two blinded, highly experienced echocardiographers. NT-proBNP, irisin, TNF-alpha, and hs-CRP were quantified in the serum at baseline, at 26 weeks, and at the end of the study. The kidney-related outcomes consisted of an eGFR reduction by 40% from baseline, or end-stage kidney disease, or kidney replacement therapy. We found that levels of irisin at baseline < 4.15 ng/mL and/or its decrease > 20% from baseline in T2DM patients predicted kidney-related events better than baseline levels/dynamic NT-proBNP and the use of SGLT2 inhibitors. In conclusion, we established that a low baseline level of irisin and its 20% decrease correlated with newly kidney-related events in T2DM patients with asymptomatic HFpEF/HFmrEF.

Analysis of proliferating Treg cells as a predictor for immunotherapy response using systemic longitudinal immune profiling: Biomarker analysis of the phase 3 CONTINUUM trial.

140 Background: The discovery of predictive biomarkers for immunotherapy is hindered by the lack of control groups in most translational studies, making it impossible to discern whether the identified biomarkers are merely prognostic or truly predictive for treatment outcomes. This study reported on prospectively designed biomarker analyses of the phase 3 CONTINNUUM trial (NCT03700476), the first trial that demonstrated prolonged event-free survival (EFS) with the addition of anti-PD-1 (aPD1) to chemoradiotherapy (CRT) in locoregionally-advanced nasopharyngeal carcinoma (LA-NPC). Methods: Mass cytometry was performed to generate a dynamic single-cell atlas on longitudinal peripheral blood mononuclear cell (PBMC) samples from 12 pairs of matched patients with or without relapse in the aPD1-CRT arm. The machine-learning algorithm CellCnn was applied to identify a cell subset that was most strongly associated with disease relapse, which was further confirmed by flow cytometry (n = 120). Single-cell RNA sequencing data from matched PBMC and tumor samples were analyzed and multiplex immunohistochemistry was performed on baseline tumor samples (n = 249) to verify the predictive value of the cell subset within tumors. Results: Baseline circulating regulatory T cells (Tregs), with a Ki67+ proliferating phenotype, were found to display a higher frequency in LA-NPC patients who developed posttreatment relapse ( P &lt; 0.001), which was further validated by flow cytometry. The intratumoral Ki67+ Tregs were also identified and correlated with an immunosuppressive tumor microenvironment. In patients with a low baseline level of Ki67+ Tregs, additional aPD1 significantly improved EFS compared with CRT alone (log-rank P = 0.011, HR = 0.22, 95% CI: 0.06−0.79), while EFS was almost identical in both treatment arms in patients with high Ki67+ Treg levels (log-rank P = 0.995, HR = 1.00, 95% CI: 0.49−2.05; interaction P = 0.047). This predictive value was further validated in datasets from two independent randomized trials in renal cancer. Conclusions: The frequency of Ki67+ Tregs can serve as a reliable predictive tool in selecting patients who are more likely to benefit from immunotherapy, potentially informing individualized immunotherapy strategies.

Sex differences in motor learning flexibility are accompanied by sex differences in mushroom spine pruning of the mouse primary motor cortex during adolescence.

Although males excel at motor tasks requiring strength, females exhibit greater motor learning flexibility. Cognitive flexibility is associated with low baseline mushroom spine densities achieved by pruning which can be triggered by α4βδ GABAA receptors (GABARs); defective synaptic pruning impairs this process. We investigated sex differences in adolescent pruning of mushroom spine pruning of layer 5 pyramidal cells of primary motor cortex (L5M1), a site essential for motor learning, using microscopic evaluation of Golgi stained sections. We assessed α4GABAR expression using immunohistochemical and electrophysiological techniques (whole cell patch clamp responses to 100 nM gaboxadol, selective for α4βδ GABARs). We then compared performance of groups with different post-pubertal mushroom spine densities on motor learning (constant speed) and learning flexibility (accelerating speed following constant speed) rotarod tasks. Mushroom spines in proximal L5M1 of female mice decreased >60% from PND35 (puberty onset) to PND56 (Pubertal: 2.23 ± 0.21 spines/10 μm; post-pubertal: 0.81 ± 0.14 spines/10 μm, P < 0.001); male mushroom spine density was unchanged. This was due to greater α4βδ GABAR expression in the female (P < 0.0001) because α4 -/- mice did not exhibit mushroom spine pruning. Although motor learning was similar for all groups, only female wild-type mice (low mushroom spine density) learned the accelerating rotarod task after the constant speed task (P = 0.006), a measure of motor learning flexibility. These results suggest that optimal motor learning flexibility of female mice is associated with low baseline levels of post-pubertal mushroom spine density in L5M1 compared to male and female α4 -/- mice.

Prognostic significance of baseline low-density lipoprotein cholesterol in patients undergoing coronary revascularization; a report from the CREDO-Kyoto registry

BackgroundThe impact of very low baseline levels of low-density lipoprotein cholesterol (LDL-C) on patients with coronary artery disease remains unclear. MethodWe enrolled 39,439 patients of the pooled population from the CREDO-Kyoto registries Cohorts 1, 2, and 3. The study population consisted of 33,133 patients who had undergone their first coronary revascularization. We assessed the risk for mortality and cardiovascular events according to quintiles of the baseline LDL-C levels. ResultsPatients in the very low LDL-C quintile (<85 mg/dL) had more comorbidities than those in the other quintiles. Lower LDL-C levels were strongly associated with anemia, thrombocytopenia, and end-stage renal disease. The cumulative 4-year incidence of all-cause death increased as LDL-C levels decreased (very low: 19.4 %, low: 14.5 %, intermediate: 11.1 %, high: 10.0 %, and very high: 9.2 %; p < 0.001), which was driven by both the early and late events. After adjusting for baseline characteristics, the adjusted risks of the very low and low LDL-C quintiles relative to the intermediate LDL-C quintile remained significant for all-cause death (very low: HR 1.29, 95 % CI 1.16–1.44, p < 0.001; low: HR 1.15, 95 % CI 1.03–1.29, p = 0.01). The excess adjusted risks of the lowest LDL-C quintile relative to the intermediate LDL-C quintile were significant for clinical outcomes such as cardiovascular death (HR 1.17, 95 % CI 1.01–1.35), non-cardiovascular death (HR 1.35, 95 % CI 1.15–1.60), sudden death (HR 1.44, 95 % CI 1.01–2.06), and heart failure admission (HR 1.11 95 % CI 1.01–1.22), while there was no excess risk for the lowest LDL-C quintile relative to the intermediate LDL-C quintile for myocardial infarction and stroke. ConclusionsLower baseline LDL-C levels were associated with more comorbidities and a significantly higher risk of death, regardless of cardiovascular or non-cardiovascular causes, in patients who underwent coronary revascularization.

Are Dutch adults equally susceptible to nudging and pricing strategies? Secondary analyses of the Supreme Nudge parallel cluster-randomised controlled supermarket trial

BackgroundSupermarket interventions are promising to promote healthier dietary patterns, but not all individuals may be equally susceptible. We explored whether the effectiveness of nudging and pricing strategies on diet quality differs by psychological and grocery shopping characteristics.MethodsWe used data of the 12-month Supreme Nudge parallel cluster-randomised controlled supermarket trial, testing nudging and pricing strategies to promote healthier diets. Participants were Dutch speaking adults aged 30–80 years and regular shoppers of participating supermarkets (n = 12) in socially disadvantaged neighbourhoods. Data on psychological characteristics (food-related behaviours; price sensitivity; food decision styles; social cognitive factors; self-control) and grocery shopping characteristics (time spent in the supermarket; moment of the day; average supermarket visits; shopping at other retailers; supermarket proximity) were self-reported at baseline. These characteristics were tested for their moderating effects of the intervention on diet quality (scored 0–150) in linear mixed models.ResultsWe included 162 participants from intervention supermarkets and 199 from control supermarkets (73% female, 58 (± 10.8) years old, 42% highly educated). The interventions had no overall effect on diet quality. Only five out of 23 potential moderators were statistically significant. Yet, stratified analyses of these significant moderators showed no significant effects on diet quality for one of the subgroups and statistically non-significant negative effects for the other. Negative effects were suggested for individuals with lower baseline levels of meal planning (β − 2.6, 95% CI − 5.9; 0.8), healthy shopping convenience (β − 3.0, 95% CI − 7.2; 1.3), and healthy food attractiveness (β − 3.5, 95% CI − 8.3; 1.3), and with higher levels of price consciousness (β − 2.6, 95% CI − 6.2; 1.0) and weekly supermarket visits (β − 2.4, 95% CI − 6.8; 1.9).ConclusionsAdults with varying psychological and grocery shopping characteristics largely seem equally (un)susceptible to nudging and pricing strategies. It might be that certain characteristics lead to adverse effects, but this is not plausible, and the observed negative effects were small and statistically non-significant and may be explained by chance findings. Verification of these findings is needed in real-world trials based on larger sample sizes and with the use of more comprehensive interventions.Trial registrationDutch Trial Register ID NL7064, 30th of May, 2018, https://onderzoekmetmensen.nl/en/trial/20990

Long-term survival follow-up for tebentafusp in previously treated metastatic uveal melanoma

BackgroundTebentafusp, a bispecific (gp100×CD3) ImmTAC, significantly improved overall survival (OS) outcomes for HLA-A*02:01+ adult patients with untreated metastatic uveal melanoma (mUM) and showed promising survival in previously treated mUM with...

Biomarker analysis of zanzalintinib in clear cell renal cell carcinoma from STELLAR-001.

4545 Background: Zanzalintinib (zanza) is a novel oral multi-targeted TKI that inhibits several receptors, including VEGFR, MET, and TAM kinases. In an expansion cohort of previously treated patients (pts) with clear cell renal cell carcinoma (ccRCC) from the phase 1b STELLAR-001 study (NCT03845166), single-agent zanza showed encouraging activity (ORR, 38%; disease control rate, 88%), with responses seen in VEGFR TKI–pretreated pts, and a manageable safety profile (Pal, IKCS NA 2023:Abs 1). Here, we investigate biomarkers associated with zanza from the STELLAR-001 ccRCC expansion cohort. Methods: Adult pts (N=32) with advanced ccRCC, ECOG ≤1, and 1–3 prior systemic anticancer therapies received zanza 100 mg once daily until unacceptable toxicity or no longer deriving clinical benefit. Circulating plasma biomarkers and immune cell populations in blood were assessed at baseline and on-study. IHC for AXL, c-Met, phosphorylated Met, and VEGFR2 was performed on archival tissue. Associations between response to zanza and biomarker levels (at baseline and treatment-related changes) were investigated by comparing zanza responders (CR/PR; n=10) and non-responders (SD/PD; n=19). The relation between baseline biomarker levels and prior exposure to VEGFR TKI was also evaluated. P values were determined using a Wilcoxon test ( P&lt;0.05 considered significant). Results: Zanza elicited significant changes in soluble biomarkers related to angiogenesis, tumor growth and metastasis, and immune modulation, including an increase in the circulating ligands VEGF ( P&lt;0.001) and GAS6 ( P&lt;0.001); decreases in ANG-1 ( P&lt;0.001) and ANG-2 ( P&lt;0.001), and the soluble angiogenic receptors, VEGFR2 ( P&lt;0.001) and TIE-2 ( P&lt;0.001). A decrease in levels of the chemokine, RANTES ( P&lt;0.001), and an increase in IFNγ ( P=0.039) and the pro-apoptotic protein, granzyme B ( P&lt;0.001) were also observed. An analysis of immune cell subsets showed that zanza raised activated cytotoxic T cell numbers ( P=0.002). Reductions in monocytes ( P=0.001), along with immunosuppressive subsets (total MDSCs [ P=0.013] and granulocytic MDSCs [ P=0.014]) were also observed. Response to zanza was associated with lower baseline levels of plasma biomarkers including CRP ( P=0.025) and HGF ( P=0.017), but not with any tissue biomarkers or zanza-mediated changes in immune cells or plasma biomarkers tested. Lower baseline levels of VEGFR2 were observed in pts with prior VEGFR TKI exposure ( P=0.042). Conclusions: Zanza in pts with advanced ccRCC leads to modulation of plasma biomarkers associated with angiogenesis and peripheral immune cell subsets consistent with its expected mechanism of action. The reduction in immunosuppressive immune cells and activation of effector immune cells by zanza support the rationale for combining zanza with immune checkpoint inhibitors. Given the small sample sizes, further investigation in larger studies is warranted. Clinical trial information: NCT03845166 .

Predictive biomarkers of response to the IRAK4/FLT3 inhibitor emavusertib in hematological malignancies.

6550 Background: Myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML) display a dynamic and diverse mutational landscape. Various mutations can induce the overexpression of a highly active long isoform of interleukin-1 receptor-associated kinase 4 (IRAK4), leading to downstream activation of transcription factors such as NFκB. This activation triggers inflammation, oncogenesis, and the survival of cancer cells. Emavusertib, a potent oral inhibitor of IRAK4 and FLT3, has demonstrated efficacy in pre-clinical leukemia models and in patients. In this abstract, we present data suggesting potential biomarkers of response to emavusertib based on clinical samples from the ongoing TakeAim Leukemia trial. Methods: In Phase I/IIa of the TakeAim Leukemia trial (NCT04278768), patients with relapsed/refractory (R/R) AML or high-risk MDS (hrMDS) received treatment with emavusertib monotherapy. Baseline and on treatment patient samples underwent RNA sequencing and proteomic analyses. RNA-seq was conducted on mononuclear cells from bone marrow or peripheral blood (n=42). Plasma proteins were quantified by the Luminex platform (n=51). Results: hrMDS patients responding to emavusertib monotherapy exhibited decreased gene expression levels of the NFκB target gene IL1β (P≤0.05) compared to non-responders. Protein analyses revealed that hrMDS responders had lower baseline levels of proliferation and migration-related factors, like Vascular Endothelial Growth Factor (VEGF-A) and CXCL12, in plasma compared to non-responders (P≤0.05). In AML samples, baseline VEGF-A levels were significantly higher in responders. The concentration of soluble PD1 (sPD1) increased in on-treatment samples in hrMDS patients (P≤0.05), but not in AML patient samples. Additionally, hrMDS samples presented lower IL2 and higher sCD47 levels compared to AML (P≤0.05). Conclusions: In this work, several baseline biomarkers indicative of a response to emavusertib were identified in patients with hematological malignancies. Responders in hrMDS showed lower baseline expression of the NFκB-associated pro-inflammatory gene, IL1β, and lower protein levels in plasma of the angiogenic factor VEGF-A and the chemokine CXCL12. In AML samples, responders have higher baseline levels of VEGF-A, indicating distinct predictive biomarkers for both pathologies. Other molecules of clinical interest, such as sPD1, showed increased concentrations in on-treatment plasma samples of hrMDS patients regardless of their response to emavusertib. Our findings highlight distinct baseline biomarkers for AML and hrMDS related to the pathophysiology of hematological malignancies. These results suggest that inflammatory and migration mediators, along with angiogenesis factors, hold potential as predictive biomarkers for assessing responses to emavusertib monotherapy treatment in hematological malignancies. Clinical trial information: NCT04278768 .

#646 SGLT2 inhibitor alleviates hypomagnesemia in patients with chronic kidney disease: a retrospective observational study

Abstract Background and Aims Magnesium (Mg2+) is a critical component in numerous biological processes. Hypomagnesemia is associated with an increased risk of cardiovascular events and vascular calcification in individuals with and without chronic kidney disease (CKD). Sodium-glucose cotransporter-2 (SGLT2) inhibitors have been proposed for treating CKD, based on their reported benefits to the kidney and cardiovascular system and in increasing serum Mg2+ levels in patients with type 2 diabetes mellitus. However, the underlying mechanisms remain unclear. In this retrospective observational study, we aimed to investigate the changes in serum Mg2+ levels after administering SGLT2 inhibitors and to identify factors contributing to these changes. Method We retrospectively examined 57 patients with CKD who received treatment at Wakayama Medical University between January 1, 2017, and December 31, 2022. We assessed changes in serum Mg2+ levels at baseline and 1, 3, and 6 months post-treatment. Patients were stratified into tertiles based on baseline Mg2+ levels. Multivariate regression analyses were conducted to identify factors associated with changes in Mg2+ levels. Results SGLT2 inhibitor treatment was associated with a significant increase in serum Mg2+ levels in the low and intermediate tertiles but not in the high tertile. Multivariate analysis revealed that gender, baseline serum Mg2+, and sodium-chloride difference were independent predictors of the increase in serum Mg2+ levels. Conclusion SGLT2 inhibitor treatment in CKD patients is associated with an increase in serum Mg2+ levels, particularly in those with lower baseline levels. The serum Mg2+-improving effect of SGLT2 inhibitors is influenced by baseline serum Mg2+ levels, sodium-chloride difference, and gender. These findings suggest the potential utility of SGLT2 inhibitors for treating hypomagnesemia in CKD.

Association Between Baseline Serum Lipids and Severity of Dry Eye Symptoms in Acne Patients Treated with Isotretinoin.

Isotretinoin is a commonly prescribed medication for moderate-to-severe acne. Elevated triglycerides and total cholesterol, as well as eye dryness, are frequent side effects of isotretinoin. Objective:This study aims to examine the association between serum baseline levels of triglycerides and total cholesterol with regards to the severity of dry eye symptoms in acne patients treated with isotretinoin. The study was a retrospective review of acne patients treated with isotretinoin for at least four months at the dermatology clinics of Qassim University Medical City, Saudi Arabia. Thirty patients were included in the study as they met the inclusion criteria. Baseline levels of triglycerides and total cholesterol were reviewed for these patients. The Ocular Surface Disease Index (OSDI) questionnaire was sent and filled out by the study participants to assess the severity of eye dryness. 30 patients were included in the study, with 16 (53.3%) females and 14 (46.7%) males. The average age of participants was 22.1 years. The duration of treatment was between 120 and 140 days in 13 (43.3%) participants and 140 and 180 days in 17 (56.7%) participants. The mean ± 1 standard deviation (SD) was reported for each of the three variables, with an Ocular Surface Disease Index (OSDI) score of 27.6 ± 19.2, a baseline total cholesterol of 4.4 ± 0.9 mmol/L, and a baseline triglyceride level of 0.83 ± 0.4 mmol/L. Using a multiple linear regression model, baseline triglycerides and total cholesterol were used as predictors of the OSDI score. There was a significant dependent interaction between baseline total cholesterol and triglycerides and their effect on the OSDI score, with a higher OSDI score at higher levels of both triglycerides and cholesterol and a lower OSDI score at lower levels of both triglycerides and cholesterol. The study result showed that, in acne patients treated with isotretinoin for at least four months, a higher baseline level of both triglycerides and total cholesterol is associated with worse dry eye symptoms compared to those with lower baseline levels. The study concluded that baseline levels of triglycerides and total cholesterol arebothsignificant predictors of the severity of dry eye symptoms in acne patients treated with isotretinoin. Despite study limitations due to the small sample size, we hope that, based on our findings, this will open the door to future studies with a larger sample sizeto further confirmour findingsgeneralizethe result, andapply it to clinical practice so that clinicians may identify those at higher risk of severe eye dryness before starting isotretinoin and subsequently be able to recommend specific measures to minimize symptoms of eye dryness.

IRON DEFICIENCY ANEMIA AFTER CARDIAC SURGERY: IS THERE AN ADDED VALUE OF THERAPY WITH SUCROSOMIAL IRON ON TOP ON FERRIC CARBOXYMALTOSE? PRELIMINARY DATA

Abstract Background IDA after CS increases mortality, serious adverse events and length of stay; it also has a negative impact on the cardiac rehabilitation (CR) program. The FCM is the gold standard for IDA patients (P). However short–term treatment of IDA after CS using FMC or SI showed a significant similar improvement of key hematological parameters (HP) and in functional capacity . The aim of the study was to evaluate whether the use of both therapies had an additional positive effect. Methods 26 consecutive IDA P, (normal ventricular function, mean age 71,5 ± 8y), after the admission in in in–patient Cardiac Rehabilitation were all treated with FCM (group A) and a part (group B, n 13) also with SI. The study design included a single dose of 1000 mg of FCM at T1 (at 8–10 days from CS) and after a dose of 60 mg of SI per day from T1 to T2 (the day of discharge 10 days after) until T3, 15 days after. Measures of efficacy included changes from baseline in HP and natriuretic peptides (NP). Results The data are shown in the Table. The statistical analysis was conducted with the Mann Whitney test (non–parametric). At baseline there were no differences in Vit B12, folate and reticulocytes. No P had a deficiency of Vit.B12 or of reticulocytes; 57% had a folate deficiency (higher prevalence in the group B, 4.0 ±2.1 vs. 9.5±11.7 ns). Hb and other HP increased significantly, with no differences between the two groups. The increase in Transferrin Saturation (Tsat) was greater (but ns) in group B with lower baseline level. The ferritin (F) level was much higher in group A; the delta is also significant. Iin group B the F remains stable, while in grupo A it doubles (+94%). No significant differences were observed in others parameters. The NP level was lower at T3 in group B; the data does not appear to be clinically relevant, for the different baseline values (the delta was not significant). Conclusions It is mandatory to look for folate deficiency, for optimal management of IDA after CS. The SI can mitigate the high levels of F, consequence of the inflammatory state following CS. Furthermore, it is known that FCM can induce a further increase in F may be due to a low–grade pro–inflammatory effect correlated to the high level of iron deposition in macrophages . Also relevant is the positive impact on TSAT with the possibility of reaching the guidelines–level more quickly. The increase in the number of cases will allow us to achieve more certain results.

A nation-wide medical record database study: Value of hepatitisB surface antigen loss in chronic hepatitisB patients in Japan.

HepatitisB surface antigen (HBsAg) seroclearance is considered to be one of the best surrogate endpoints of functional cure for hepatitisB virus (HBV) infection. However, evidence regarding the relationship between achieving HBsAg seroclearance or a low baseline HBsAg level, and long-term clinical outcomes in Japanese patients with chronic HBV infection remains to be confirmed in a real-world setting. A retrospective observational cohort study was performed with an electronic medical record database, including data from 230 hospitals across Japan. Chronic HBV infection was defined as two consecutive, positive HBsAg laboratory measurements for HBV infection. The date of the second positive was used as a baseline to identify subsequent HBsAg seroclearance and liver disease progression. In the database, 2523 patients with chronic HBV infection were identified as the chronic hepatitisB (CHB) cohort. Among the CHB cohort with an average observational period of 5.19±3.87years, 202 patients (8%) achieved HBsAg seroclearance after baseline. They had a lower risk of developing hepatocellular carcinoma (HCC) (adjusted hazard ratio [aHR] 0.206, p<0.01) and cirrhosis (aHR 0.361, p<0.01). When the CHB cohort was stratified into two groups based on baseline HBsAg levels (<100IU/mL and ≥100IU/mL), patients with a lower baseline level of HBsAg (<100IU/mL) had a lower risk of developing liver disease (HCC aHR 0.600, p<0.01; cirrhosis aHR 0.618, p<0.05). These results confirm the clinical significance of HBsAg seroclearance and low HBsAg level at baseline with respect to long-term outcomes of patients with CHB in the Japanese population.

Effects of hearing acuity on psychophysiological responses to effortful speech perception

In recent studies, psychophysiological measures have been used as markers of listening effort, but there is limited research on the effect of hearing loss on such measures. The aim of the current study was to investigate the effect of hearing acuity on physiological responses and subjective measures acquired during different levels of listening demand, and to investigate the relationship between these measures. A total of 125 participants (37 males and 88 females, age range 37–72 years, pure-tone average hearing thresholds at the best ear between -5.0 to 68.8 dB HL and asymmetry between ears between 0.0 and 87.5 dB) completed a listening task. A speech reception threshold (SRT) test was used with target sentences spoken by a female voice masked by male speech. Listening demand was manipulated using three levels of intelligibility: 20 % correct speech recognition, 50 %, and 80 % (IL20 %/IL50 %/IL80 %, respectively). During the task, peak pupil dilation (PPD), heart rate (HR), pre-ejection period (PEP), respiratory sinus arrhythmia (RSA), and skin conductance level (SCL) were measured. For each condition, subjective ratings of effort, performance, difficulty, and tendency to give up were also collected. Linear mixed effects models tested the effect of intelligibility level, hearing acuity, hearing asymmetry, and tinnitus complaints on the physiological reactivity (compared to baseline) and subjective measures. PPD and PEP reactivity showed a non-monotonic relationship with intelligibility level, but no such effects were found for HR, RSA, or SCL reactivity. Participants with worse hearing acuity had lower PPD at all intelligibility levels and showed lower PEP baseline levels. Additionally, PPD and SCL reactivity were lower for participants who reported suffering from tinnitus complaints. For IL80 %, but not IL50 % or IL20 %, participants with worse hearing acuity rated their listening effort to be relatively high compared to participants with better hearing. The reactivity of the different physiological measures were not or only weakly correlated with each other. Together, the results suggest that hearing acuity may be associated with altered sympathetic nervous system (re)activity. Research using psychophysiological measures as markers of listening effort to study the effect of hearing acuity on such measures are best served by the use of the PPD and PEP.

Copeptin Stimulation by Combined Intravenous Arginine and Oral LevoDopa/Carbidopa in Healthy Short Children and Children with the Polyuria-Polydipsia Syndrome

Introduction: Stimulated copeptin may provide an alternative to water deprivation testing (WDT) in the evaluation of polyuria-polydipsia syndrome (PPS). Though best studied, arginine stimulation alone produces a modest copeptin response in children. We investigated the effectiveness of the arginine + LevoDopa/Carbidopa stimulation test (ALD-ST) for copeptin. Methods: 47 healthy short children (controls), 10 children with primary polydipsia, and 10 children with AVP deficiency received arginine hydrochloride (500 mg/kg intravenously over 30 min) and Levodopa/carbidopa (10:1 ratio; 175 mg of l-Dopa/m2 BSA) orally. Serum copeptin was measured at 0, 60, 90, and 120 min. Results: In controls, ALD-ST increased copeptin from a median of 7.0 pmol/L (IQR 5.0–10.0) to a peak of 44.0 pmol/L (IQR 21.4–181.0) between 60 and 120 min (p < 0.001). Copeptin peak was higher in subjects who experienced nausea or vomiting (57%) than in those who did not (131.0 pmol/L [IQR 42.5–193.8] vs. 22.7 pmol/L [IQR 16.0–33.7], p < 0.001). While subjects with primary polydipsia had similar baseline (8.5 pmol/L [IQR 8.0–11.0]) and stimulated (125.2 pmol/L [IQR 87.6–174.0]) copeptin levels as controls, subjects with AVP deficiency had lower baseline (2.5 pmol/L [IQR 2.0–3.1]) and peak levels (4.6 pmol/L [IQR 2.4–6.0]). A peak copeptin of ≥9.3 pmol/L best predicted absence of complete or partial AVP deficiency with a sensitivity of 100% and specificity of 80%. Conclusions: ALD-ST induced a robust peak copeptin in healthy short children and children with primary polydipsia. Nausea/vomiting, a side effect of ALD-ST, amplified the copeptin response. The ALD-ST may be a suitable initial screening test in children with PPS.