Treatment Response Research Articles

Optimal Diagnostic and Treatment Response Threshold of the Eosinophilic Esophagitis Endoscopic Reference Score: A Single-Center Study of 102 Patients With Eosinophilic Esophagitis.

The proposed eosinophilic esophagitis (EoE) endoscopic reference score serves to diagnose and evaluate treatment responses in EoE. Nevertheless, the validated reference score thresholds for diagnosis and treatment response in Asian patients are yet to be established. This study aims to establish these thresholds for the first time among Asian patients with EoE. Patients presenting with ≥ 15 eosinophils/high power field and esophageal dysfunction symptoms between August 2007 and November 2021 were included. Age- and sex-matched non-EoE controls were also enrolled. Baseline characteristics, endoscopic reference score features, and scores were compared between patients and controls. Among patients, endoscopic reference score features and scores, along with peak eosinophil counts, were evaluated both before and after treatment. The optimal threshold was determined based on sensitivity, specificity, and the Youden index. Overall, 102 patients were enrolled (74.5% men; mean age, 46.9 years). The mean endoscopic reference score was 2.65 and 0.52 for patients and controls, respectively (P < 0.001). An endoscopic reference score ≥ 2 was identified as the optimal diagnostic threshold for EoE (sensitivity, 0.79; specificity, 0.86; Youden index, 0.66). Post-treatment data regarding endoscopic findings and histology were available for 30 patients. Regarding histologic response, an endoscopic reference score of ≤ 3 demonstrated the optimal threshold (sensitivity, 0.95; specificity, 0.88; Youden index, 0.83). The optimal diagnostic and treatment response thresholds were determined to be endoscopic reference scores of ≥ 2 and ≤ 3, respectively. Further studies involving a larger patient cohort are necessary to validate these findings.

Deprescribing Antidepressants in Children and Adolescents: A Systematic Review of Discontinuation Approaches, Cross-Titration, and Withdrawal Symptoms.

Background: Antidepressant medications, including selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), are commonly used to treat depressive, anxiety, and obsessive-compulsive disorders in youth. Yet, data on discontinuing these medications, withdrawal symptoms, and strategies to switch between them are limited. Methods: We searched PubMed and ClinicalTrials.gov through June 1, 2024, to identify randomized controlled trials assessing antidepressant discontinuation in youth. We summarized pediatric pharmacokinetic data to inform tapering and cross-titration strategies for antidepressants and synthesized these data with reports of antidepressant withdrawal. Results: Our search identified 528 published articles, of which 28 were included. In addition, 19 records were obtained through other methods, with 14 included. The corpus of records included 13 randomized, double-blind, placebo-controlled trials (3026 patients), including SSRIs (K = 10), SNRIs (K = 4), andTCAs (K = 1), ranging from 4 to 35 weeks. Deprescribing antidepressants requires considering clinical status, treatment response, and, in cross-titration cases, the pharmacokinetics and pharmacodynamics of both medications. Antidepressant withdrawal symptoms are related to the pharmacokinetics of the medication, which vary across antidepressants and may include irritability, palpitations, anxiety, nausea, sweating, headaches, insomnia, paresthesia, and dizziness. These symptoms putatively involve changes in serotonin transporter expression and receptor sensitivity, impacting the serotonin, dopamine, and norepinephrine pathways. Conclusions: Although approaches to deprescribing antidepressants in pediatric patients are frequently empirically guided, accumulating data related to the course of relapse and withdrawal symptoms, as well as the pharmacokinetic and pharmacodynamic properties of medications, should inform these approaches. Recommendations within this review support data-informed discussions of deprescribing-including when and how-that are critically important in the clinician-family-patient relationship.

Treatment patterns for advanced therapies in Canadians with moderate-to-severe inflammatory bowel disease: a retrospective cohort analysis

Abstract Many patients with inflammatory bowel disease (IBD) show an inadequate response or experience a loss of response to advanced therapies. Guidelines recommend dose optimization and switching among therapies until an optimal treatment response is attained. With several advanced treatments available, we aimed to evaluate the persistence of different therapeutic sequences in IBD. The RECORDED study was a retrospective cohort study of Canadians with moderate-to-severely active ulcerative colitis (UC) or Crohn’s disease (CD) who had been exposed to more than 1 advanced therapy between May 2015 and April 2021 for UC, and May 2016 and April 2021 for CD. The primary endpoint was time to permanent discontinuation of the first advanced treatment. Overall, 330 patients had CD and 344 had UC. The most common first-line treatments for CD and UC were adalimumab and infliximab, respectively. The median (95% CI) time to permanent discontinuation of first-line treatment was 12.3 (10.9, 13.6) months in patients with CD and 9.2 (8.2, 10.8) months for those with UC. The most common reason for treatment change across both diseases was lack of efficacy. First-line advanced treatments were optimized in 191 (58.1%) CD patients and 202 (59.1%) UC patients prior to permanent discontinuation. Second-line therapy was typically from a different class compared with the first-line treatment choice. The RECORDED study provides insights into the real-world sequencing and optimization patterns of advanced treatments in patients with moderate-to-severe IBD in Canada. Lack of efficacy was the most cited reason for switching to a different therapy.

The association of gene polymorphisms of adenosine and dopamine receptors with the response to caffeine citrate treatment in infants with apnea of prematurity: a prospective nested case-control study

BackgroundTo investigate the potential influence of adenosine and dopamine receptor genes polymorphisms in combination with clinical factors on the response of preterm infants to caffeine citrate treatment in apnea of prematurity (AOP).MethodsA prospective nested case-control study enrolled 221 preterm infants with gestational age < 34 weeks. These infants were divided into the response (n = 160) and the non-response groups (n = 61). 22 single-nucleotide polymorphisms in adenosine and dopamine receptor genes were genotyped. The basic characteristics and clinical outcomes of the two groups were compared. Univariate logistic regression analysis was performed to evaluate the differences in genotype distribution between the groups. Multivariable logistic regression analysis was performed to identify independent risk and protective factors and develop a nomogram to predict caffeine citrate response in preterm infants.ResultsPreterm infants in the non-response group had lower gestational age, lower birth weight, longer periods of oxygen supplementation and caffeine citrate use, and higher incidence of patent ductus arteriosus (PDA), bronchopulmonary dysplasia (BPD), neonatal respiratory distress syndrome (NRDS), retinopathy of prematurity (ROP), and brain injury (P < 0.05 for all). The ADORA1 rs10920573, ADORA2B rs2015353, ADORA3 rs10776728, DRD3 rs7625282, and DRD3 rs6280 gene polymorphisms were associated with caffeine citrate response in preterm infants (PFDR < 0.05 for all). The ADORA1 rs10920573 CC (aOR, 3.51; 95% CI, 1.34–9.25) and DRD3 rs6280 CT genotypes (aOR, 3.19; 95% CI, 1.53–6.65) were independent risk factors for non-response, whereas greater gestational age (aOR, 0.631; 95% CI, 0.53–0.75) was an independent protective factor for response. The concordance index of the nomogram was 0.764 (95% CI, 0.687–0.842), and the calibration and decision curve analysis indicated the nomogram had excellent predict performance.ConclusionsAdenosine receptor gene and dopamine receptor gene polymorphisms influence caffeine citrate treatment response in AOP. By combining genetic and clinical variables, it is possible to predict the response to caffeine citrate treatment in preterm infants.

Practice patterns for eosinophilic esophagitis vary widely among Canadian gastroenterologists: a nationwide survey

Abstract Introduction Eosinophilic esophagitis (EoE) is a chronic allergic, type 2, immune-mediated condition of the oesophagus, resulting in dysmotility and oesophageal stricturing. This study aims to identify practice variation among Canadian gastroenterologists treating adults with EoE. Methods A cross-sectional, web-based survey was distributed to Canadian gastroenterologists through the Canadian Association of Gastroenterology and administrations of Canadian universities. Results Seventy gastroenterologists completed the survey, with 59% working in academic practice or research. Overall, 90% of gastroenterologists require histological evidence of EoE to establish a diagnosis of EoE, while 50% require clinical symptoms of oesophageal dysfunction; 39% of gastroenterologists take less than 5 biopsies when assessing for EoE, with variability in biopsy location. Only 51% of respondents took biopsies in every case presenting with acute food bolus. Proton pump inhibitors were the initial therapy of 70% of gastroenterologists, with 11% using topical steroids. The preferred dietary approach was the 6-food elimination diet in 36%, followed by the 2-food elimination diet in 26%. Overall, 27% of participants did not use histologic improvement and 63% did not use endoscopic improvement to evaluate treatment response. Use of EoE Endoscopic Reference Score (EREFS) is low, with 56% being either unaware of what EREFS is or never using it. Most respondents feel Canadian guidelines would be helpful in their practice. Conclusions Eosinophilic esophagitis practice patterns among Canadian gastroenterologists are variable and differ from consensus guidelines. The development of Canadian guidelines and continuing medical education content can be considered to improve the management of EoE in Canada.

Myocardial DNA damage is responsible for the relationship between genotype and treatment response in patients with dilated cardiomyopathy

Abstract Background Dilated cardiomyopathy (DCM) is one of the leading causes of heart transplantation. Our group and others have previously reported that DNA damage accumulation in myocardial tissue and certain genetic variants such as those in LMNA are associated with treatment response and prognosis (ref 1-5). However, the potential association between myocardial DNA damage and genotype, and their contribution when combined to predicting treatment response, remains unclear. Methods We identified the deleterious variants in cardiomyopathy-related genes by analyzing the whole exome sequencing data from 89 patients with DCM who were recruited from two participating facilities. Immunostaining of γ-H2A.X, a DNA damage marker, was performed on endomyocardial biopsy specimens from the same patients, from which the percentage of nuclei positive for γ-H2A.X signals (%γ-H2A.X) was calculated. Left ventricular reverse remodeling (LVRR) was assessed by transthoracic echocardiography at 1 year after biopsy. We examined the associations among genotype, myocardial DNA damage, and the achievement of LVRR. Results Among the 89 patients with DCM, 11 (12.4%) carried pathogenic or likely pathogenic (P/LP) variants in sarcomere genes such as TTN, and 21 (23.6%) carried P/LP variants in non-sarcomere genes such as LMNA, while the rest had no P/LP variants in cardiomyopathy-related genes (Figure A). Patients with P/LP variants in sarcomere genes had a lower %γ-H2A.X [21.2 (10.7–29.0)% vs. 7.0 (4.3–12.4)%, P = 0.002] (Figure B), and a higher probability to achieve LVRR at 1-year (81.8% vs. 23.8%, P = 0.003) (Figure C) when compared to those with P/LP variants in non-sarcomere genes. The odds ratio for carriers of P/LP variants in sarcomere genes to achieve LVRR was 14.40 (95%CI 2.31–89.94) compared to that for carriers of P/LP variants in non-sarcomere genes. However, this effect was markedly attenuated after adjusting for the proportion of γ-H2A.X-positive nuclei [adjusted odds ratio 6.05 (95%CI 0.86–42.53)] (Table). Conclusions Among patients with DCM, carriers of P/LP variants in sarcomere genes showed less DNA damage and a favorable treatment response, when compared with carriers of P/LP variants in non-sarcomere genes. Our results suggest that myocardial DNA damage was partially responsible for the relationship between genotype and treatment response in patients with DCM.Figure, panels A-C

Exploring the Potential of Electronic Patient-Generated Health Data for Evaluating Treatment Response to Intramuscular Steroids in Rheumatoid Arthritis: Case Series.

Mobile health devices are increasingly available, presenting exciting opportunities to remotely collect high-frequency, electronic patient-generated health data (ePGHD). This novel data type may provide detailed insights into disease activity outside usual clinical settings. Assessing treatment responses, which can be hampered by the infrequency of appointments and recall bias, is a promising, novel application of ePGHD. Drugs with short treatment effects, such as intramuscular steroid injections, illustrate the challenge, as patients are unlikely to accurately recall treatment responses at follow-ups, which often occur several months later. Retrospective assessment means that responses may be over- or underestimated. High-frequency ePGHD, such as daily, app-collected, patient-reported symptoms between clinic appointments, may bridge this gap. However, the potential of ePGHD remains untapped due to the absence of established definitions for treatment response using ePGHD or established methodological approaches for analyzing this type of data. This study aims to explore the feasibility of evaluating treatment responses to intramuscular steroid therapy in a case series of patients with rheumatoid arthritis tracking daily symptoms using a smartphone app. We report a case series of patients who collected ePGHD through the REmote Monitoring Of Rheumatoid Arthritis (REMORA) smartphone app for daily remote symptom tracking. Symptoms were tracked on a 0-10 scale. We described the patients' longitudinal pain scores before and after intramuscular steroid injections. The baseline pain score was calculated as the mean pain score in the 10 days prior to the injection. This was compared to the pain scores in the days following the injection. "Response" was defined as any improvement from the baseline score on the first day following the injection. The response end time was defined as the first date when the pain score exceeded the pre-steroid baseline. We included 6 patients who, between them, received 9 steroid injections. Average pre-injection pain scores ranged from 3.3 to 9.3. Using our definitions, 7 injections demonstrated a response. Among the responders, the duration of response ranged from 1 to 54 days (median 9, IQR 7-41), average pain score improvement ranged from 0.1 to 5.3 (median 3.3, IQR 2.2-4.0), and maximum pain score improvement ranged from 0.1 to 7.0 (median 4.3, IQR 1.7 to 6.0). This case series demonstrates the feasibility of using ePGHD to evaluate treatment response and is an important exploratory step toward developing more robust methodological approaches for analysis of this novel data type. Issues highlighted by our analysis include the importance of accounting for one-off data points, varying response start times, and confounders such as other medications. Future analysis of ePGHD across a larger population is required to address issues highlighted by our analysis and to develop meaningful consensus definitions for treatment response in time-series data.

Eosinophilic cationic protein and D-Dimer are potential biomarkers to predict response to antihistamines but not to omalizumab in chronic spontaneous urticaria

ABSTRACT Introduction: Biomarkers that could reliably anticipate the effectiveness of antihistamines and omalizumab in treating chronic spontaneous urticaria (CSU) have not been conclusively identified. Our objective was to examine how eosinophilic cationic protein (ECP), tryptase, D-dimer, and total Immunoglobulin E (IgE) impact the response to antihistamine and omalizumab treatments in individuals with CSU. Methods: In this cross-sectional retrospective study, CSU patients that had undergone treatment with either antihistamines or omalizumab for a minimum of 12 weeks between 2015 and 2021 at an Allergy and Immunology Department were analyzed. Several demographic and laboratory parameters including eosinophil counts, mean platelet volüme (MPV), sedimentation, C-reactive protein (CRP), antinuclear antibodies (ANA) and Anti-thyroperoxidase (Anti-TPO) and total IgE, tryptase, ECP and D-dimer were retrived from patient files. The association of these biomarkers with Urticaria Control Test (UCT) and the effect of these biomarkers on treatment response were evaluated. Treatment response was assessed using the UCT, with a score of UCT ≥ 12 indicating a responder and UCT < 12 indicating a non responder. Results: The patients in the omalizumab group were older, had a longer disease duration and had worse urticaria control (lower baseline UCT scores). 421 patients were treated with antihistamines and 88 patients were treated with omalizumab. ECP was found to be inversely correlated with baseline UCT (p < 0.001 r=−0.268). ECP and D-dimer levels of non-responder patients in the antihistamine group were significantly higher than in responder patients (ECP: 49 ng/mL vs 28.1 ng/mL, p < 0.001) (D-dimer: 0.60 mg/L vs 0.30 mg/L, p < 0.001), while there were no significant difference in terms of tryptase and total IgE. These four biomarkers were similar, in omalizumab responders and non responders. Conclusion: In this study with CSU, we looked at predictors of responses to treatments. ECP can serve as a marker of poor urticaria control and may predict antihistamine refractoriness along with D-dimer.

Microfibrillar-associated protein 4 as a predictive biomarker of treatment response in patients with chronic inflammatory diseases initiating biologics: secondary analyses based on the prospective BELIEVE cohort study.

Currently, there are no reliable biomarkers for predicting treatment response in chronic inflammatory diseases (CIDs). To determine whether serum microfibrillar-associated protein 4 (MFAP4) levels can predict the treatment response to biological therapy in patients with CIDs. The BELIEVE study was originally designed as a prospective, multi-center cohort study of 233 patients with either rheumatoid arthritis, psoriatic arthritis, psoriasis, axial spondyloarthritis, Crohn's disease, or ulcerative colitis, initiating treatment with a biologic agent (or switching to another). Clinical assessment and blood sample collection were performed at baseline and 14-16 weeks after treatment initiation. The primary analyses included participants with available blood samples at baseline; missing data were handled as non-responders. The patients were stratified into the upper tertile of serum MFAP4 (High MFAP4) versus a combined category of middle and lower tertiles (Other MFAP4). The primary outcome was the proportion of patients with clinical response to biologic therapy after 14-16 weeks. 211 patients were included in the primary analysis population. The mean age was 43.7 (SD: 14.8) years, and 120 (59%) were female. Positive treatment response was observed in 41 (59%) and 69 (49%) for High MFAP4 and Other MFAP4, respectively. When adjusting for pre-specified variables (CID, age, sex, smoking status, and BMI), the adjusted OR was 2.28 (95% CI: 1.07 to 4.85) for a positive treatment outcome in the High MFAP4 group. A high MFAP4 status before initiating biological treatment is associated with a positive clinical response, when adjusting for confounding factors.

Clinical phenotyping and treatment response in patients with chronic heart failure: a latent class analysis from a Japanese multicentre registry

Abstract Background There are diversities of pathophysiology and co-morbidities in patients with chronic heart failure (HF), irrespective of left ventricular ejection fraction (LVEF). Therefore, the identification of subgroups with different outcomes and treatment response patterns may help to tailor strategies to each individual HF patient. Purpose We sought to identify phenogroups of patients with different prognosis and response to medical therapies in patients with chronic HF. Methods A total of 1565 patients with a broad spectrum of LVEF in a prospective multicentre registry of patients with chronic HF were enrolled between January 2020 and December 2023. Latent class analysis was performed in each subgroup using 80 features including patients’ demographics, laboratory, and echocardiographic data. The optimal number of phenogroups was determined using the first minimum of the Bayesian information criterion. The primary outcome was a composite of all-cause death and hospitalisation due to worsening HF. Results The analysis subclassified patients into six phenogroups. Patients in phenogroup A (young non-ischaemic cardiomyopathy, n = 242, 15.5%) were the youngest and had lower LVEF and lowest prevalence of coronary artery disease (CAD) and other comorbidities. Phenogroup B (atrial fibrillation [AF] and small left atrium, n = 282, 18.0%) had higher proportion of AF but smaller left atrium volume. Phenogroup C (ischaemic cardiomyopathy, n = 204, 13.0%) had the highest proportion of CAD and lower LVEF. Phenogroup D (classical HF with preserved ejection fraction [HFpEF], n =308, 19.7%) had the highest age, proportion of female, LVEF and thickness of LV wall. Phenogroup E (elderly and AF , n = 235, 15.0%) had higher age, the highest proportion of AF and largest left atrium volume. Phenogroup F (biventricular failure and multiple comorbidities, n = 294, 18.8%) had the highest proportion of co-morbidities and the lowest LVEF, right ventricular systolic function and renal function. During a median follow-up period of 538 (interquartile range 286-701) days, the incidence of the primary outcome significantly differed among the phenogroups (P &amp;lt; 0.001, Figure 1). Regarding treatment response for renin-angiotensin system blockers and beta blockers, there were no significant associations between the use of renin-angiotensin system blockers and the risk of the primary outcome among the phenogroups whereas the use of beta-blockers was significantly associated with increased risk of the primary outcome in patients classified to phenogroup D (classical HFpEF) (hazard ratio 1.83 95% confidence interval 1.05-3.19) among the phenogroups (Figure 2). Conclusion We identified six phenogroups with distinct clinical outcomes in patients with chronic HF, and the use of beta-blockers might have unfavorable effect in the classical HFpEF phenogroup. This phenotyping provides novel risk stratification and may aid in clinical decision making.Clinical outcomes among the phenogroupsTreatment effect among the phenogroups

Non-invasive assessment of left ventricular hemodynamic forces in hypertrophic cardiomyopathy

Abstract Background Hemodynamic force (HDF) analysis allows non-invasive measurement of intraventricular pressure gradients, portraying cyclic spatial-temporal interaction between blood and tissues. Impaired HDFs have been implicated in early detecting of adverse cardiac remodelling and treatment response in various cardiovascular disorders, providing insights into cardiac physiology not offered by traditional cardiovascular imaging (1). Mainly explored in heart failure, HDF analysis has not been previously applied to hypertrophic cardiomyopathy (HCM). Purpose To investigate differences in systo-diastolic function in HCM patients compared to healthy controls using HDF analysis. Methods Forty patients with HCM diagnosis (20 obstructive and 20 non-obstructive) were retrospectively evaluated in comparison with 22 healthy controls. Left ventricular (LV) HDFs were derived from routine transthoracic apical 4-, 2- and 3-chamber views using a dedicated software. Apical-basal HDF curves were generated, where positive deflections represent forces directed from the LV apex to the base, whilst negative ones are directed toward the apex. Amplitude and timing parameters were derived, the latter indexed to total cardiac cycle duration. Results Table 1 shows the demographic, clinical and echocardiographic characteristics of HCM compared to controls. Patients with HCM were older, had a slower heart rate due to treatment with beta-blockers, and showed hypercontractility, as expressed by higher LV ejection fraction. Compared to controls, HCM patients showed reduced LV longitudinal force, i.e. the force during the whole cardiac cycle (4.17% [2.36-5.52] vs. 6.01% [4.73-7.78], p=0.002), shorter time interval to systolic peak (0.15 [0.12-0.16] vs. 0.19 [0.17-0.20], p &amp;lt;0.001), and shorter duration of LV impulse (0.29 [0.27-0.32] vs. 0.34 [0.32-0.37], p &amp;lt;0.001) (Figure 1). However, no differences in terms of systolic force peak (p=0.283) or LV impulse intensity (p=0.689) were detected. During the transition between systole and diastole, LV suction (i.e. the interval including late systolic deceleration and early diastolic suction) was significantly longer (0.26 [0.22-0.29] vs. 0.23 [0.21-0.25], p=0.023) but less pronounced (6.30% [4.56-8.44] vs. 8.72% [6.71-12.59], p=0.005), likely reflecting a relaxation impairment from the very beginning of diastole. Such impairment was maintained during early diastolic filling, where the amplitude of the positive deceleration flow force was severely reduced in HCM compared to controls (2.98% [1.98-4.58] vs. 7.11% [4.55-8.72], p &amp;lt;0.001). Conclusions HDF analysis in HCM patients revealed unique systolic and diastolic changes reflecting faster LV contraction during systole and slower and weaker LV forces during diastole. This analysis deepens our understanding of HCM mechanic abnormalities and may help assess response to innovative treatment options.

Effects of platelet-rich plasma combined with exercise therapy for one year on knee osteoarthritis: retrospective cohort study

BackgroundPlatelet-rich plasma (PRP) is a promising treatment for knee osteoarthritis (OA). However, exercise therapy and activities of daily living (ADL) guidance are recommended as core treatments in the Osteoarthritis Research Society International (OARSI) guidelines. However, the effects of PRP combined with exercise therapy are not fully understood. This study aimed to clarify the effectiveness of this treatment.MethodsWe assigned patients diagnosed with knee OA and treated between January 2021 and December 2022 to groups who underwent PRP + exercise (PE), PRP (P), or exercise (E) therapy. Outcomes were evaluated using Knee Injury and Osteoarthritis Outcome Scores (KOOS) before, and 1, 3, and 12 months after treatment. Within-group comparisons according to the time of each score were statistically assessed using a one-way analysis of variance, then differences were analyzed using Bonferroni multiple comparisons p < 0.05). Treatment responses were determined using Outcome Measures in Rheumatology (OMERACT)-OARSI Responder criteria.ResultsPre-treatment KOOS did not significantly differ among the groups. Pain in the PE group improved within 1 month, symptoms, ADL, and quality of life (QOL) improved after 3, months and continued for 12 months. Pain and symptoms improved in the P group within 1 month, but ADLs and the QOL did not significantly change. Pain improved after 3 months in the E group and ADL, and QOL improved by 12 months. The response among the groups was the highest for the PE, with 50.0% at 1 and 3 months, and 65.0% at 12 months.ConclusionsTherapy with PRP immediately relieved pain, whereas exercise conferred late, but enduring effects. Combining PRP with exercise conferred synergistic advantages that persisted for up to 12 months.

Treatment of Post-COVID-19 POTS by inhibiting FcRn: a phase 2 randomized, placebo controlled, double-blind, proof of concept study with efgartigimod

Abstract Background While the underlying pathophysiology is unknown, post–COVID-19 postural orthostatic tachycardia syndrome (POTS) may be related to immune dysfunction and autoimmunity precipitated by SARS-CoV-2 infection. Various autoantibodies, including those targeting G-protein coupled receptors (GPCRs), have been observed in patients with POTS. Binding of these autoantibodies to adrenergic receptors, which are prototypical GPCRs, has been hypothesized to modulate receptor activity, increase sympathetic tone, and cause tachycardia. Moreover, IgG anti-GPCR autoantibodies, acting as partial agonists, are thought to decrease the effect of peripheral vasomotor control, leading to an increased sympathetic response to upright posture that can result in postural tachycardia in the absence of hypotension. Purpose We hypothesize that a reduction in autoantibody levels by efgartigimod, a FcRn-antagonist, will ameliorate the underlying immune-mediated pathogenesis and lead to clinical improvements in patients who developed POTS following COVID-19 infection. We propose a phase II multicenter, randomized, placebo-controlled, double-blind, proof-of-mechanism study initiated to evaluate the safety and efficacy of efgartigimod in adults with post–COVID-19 POTS. Methods Adult patients diagnosed with new-onset of POTS following SARS-CoV-2 infection are eligible for participation in the study. Prior COVID-19 must be confirmed by documentation of historical PCR test, and POTS diagnosis must meet consensus criteria. Study subjects must have moderate to severe autonomic symptoms (COMPASS-31 score ≥ 35 points at screening). Approximately 42 patients will be randomly allocated (2:1) to receive weekly intravenous efgartigimod or placebo for 24 weeks. At the end of the treatment period, participants who complete the study may roll over into an open-label extension (OLE). The co-primary endpoints are change from baseline to week 24 in the COMPASS-31 and Malmo POTS Symptom Score as well as safety and tolerability outcomes. Key secondary endpoints include assessments of disease activity, fatigue, cognitive function, walking capacity and quantitative autonomic testing. Additional exploratory endpoints include intraepidermal small fiber densities (optional), sudomotor innervation (optional) and peripheral blood biomarkers to define histopathological and immune determinants associated with treatment response. Conclusions This phase II study of efgartigimod will evaluate the effect of FcRn inhibition on disease pathology and the potential for therapeutic benefit in patients with post–COVID-19 POTS.

Prognostic Significance and Treatment Response Associations of Genetic Mutations in Chronic Myelomonocytic Leukemia: A Retrospective Cohort Study

Background: This retrospective cohort study investigates the prognostic significance of genetic mutations in Chronic Myelomonocytic Leukemia (CMML) and their association with treatment responses among patients treated at a single institution, juxtaposed with a statewide dataset from Kentucky. Methods: The study includes 51 patients diagnosed with CMML under the World Health Organization criteria from January 2005 to December 2023. It examines their genomic profiles and subsequent survival outcomes. The analysis also categorizes patients into CMML-1 and CMML-2 subtypes and assesses survival differences between transformed and non-transformed cases. Results: Mutations in TET2, ASXL1, and SRSF2 were found to significantly influence survival, establishing their roles as critical prognostic markers. Additionally, the cohort from the University of Kentucky exhibited distinct survival patterns compared to the broader Kentucky state population, suggesting that demographic and treatment-related factors could underlie these variances. Conclusions: This research underscores the pivotal role of targeted genetic profiling in deciphering the progression of CMML and refining therapeutic strategies. The findings emphasize the necessity for advanced genetic screening in managing CMML to better understand individual prognoses and optimize treatment efficacy, thereby offering insights that could lead to personalized treatment approaches.

Detection and risk stratification of cardiac amyloidosis patients by integration of imaging and non-imaging data using a machine learning approach

Abstract Background With the advent of amyloid-targeting therapies, early and reliable diagnosis as well as precise risk estimation of cardiac amyloidosis (CA) have become of substantial importance. While the current diagnostic approach relies on difficult-to-standardize, visual interpretation of 99mTc-scintigraphy, risk assessment is largely based on a combination of blood and imaging parameters. Purpose Aim of this study is to assess the possibility of machine learning-based integration of scintigraphy, echocardiography, and non-imaging parameters such as blood parameters and comorbidities for the detection and risk stratification of patients with CA. Methods This study included all patients who underwent 99mTc-scintigraphy at a university affiliated tertiary care centre between 2010 and 2023. Two machine learning models were developed, and the relative predictive importance of their parameters were assessed (Figure 1): First, a model to detect patients with CA-suggestive uptake (Perugini grade 2/3) on 99mTc-scintigraphy scans; Second, a model to assess the risk of patients with CA-suggestive uptake for future heart failure hospitalization (HFH). A total of 58 features were extracted from electronic health records including blood, echocardiographic, demographic parameters and comorbidities. Scintigraphy imaging features were extracted from the raw imaging data using a deep learning approach. For the time to HFH prediction, a random survival forest machine learning model was employed. Results Overall, 12 380 consecutively enrolled patients were included, 279 (2.3%) of which were affected by CA-suggestive uptake. The machine learning model showed higher accuracy for the detection of CA (AUC 0.96 [95% CI 0.95-0.97], sensitivity 0.78 [95% CI 0.77-0.80] and specificity 0.99 [95% CI 0.99-0.99]. In the outcome analysis, the machine model showed good accuracy in predicting future HFH (C-index 0.71 [95% CI 0.68-0.75]). Parameter importance for the time to event analysis revealed right ventricular diameter, previous diagnosis of chronic heart failure and creatine kinase as the three most important predictors (Figure 2). Conclusions Detection of patients with cardiac amyloidosis and their risk estimation for heart failure can be aided using machine learning-based integration of imaging and non-imaging data. Our findings may guide novel approaches for assessing disease progression and treatment response.

Prognostic Evaluation of Conversion Therapy Following Hepatic Arterial Infusion Chemotherapy or Immunotherapy in Patients with Advanced or Transarterial Chemoembolization Unsuitable Intermediate-Stage Hepatocellular Carcinoma-A retrospective cohort study.

Patients with advanced-stage or intermediate-stage hepatocellular carcinoma (HCC) unsuitable for transarterial chemoembolization (TACE) had poor prognoses. Recent advancements in hepatic arterial infusion chemotherapy (HAIC) and immune checkpoint inhibitors (ICIs) have demonstrated higher tumor response rates, which improved overall survival (OS). HAIC achieves an OS rate of approximately 14.5-15.3 months with a 39.1-42.5% tumor response rate. In comparison, ICIs have a 12-14 month OS rate with a 26-33% tumor response rate. Given these promising responses, this study evaluates the efficacy of conversion therapy with curative intent following HAIC or ICIs, focusing on survival outcomes. We retrospectively analyzed 80 patients with advanced or TACE-unsuitable intermediate HCC. Patients completed two HAIC or four ICI cycles, followed by Response Evaluation Criteria in Solid Tumors (RECIST) criteria imaging. Based on demographics, cirrhosis status, Barcelona Clinic Liver Cancer classification (BCLC) stage, treatment responses, and treatment modality, survival impacts were analyzed. OS was compared between HAIC and immunotherapy groups. The effect of conversion therapy with curative intent on survival outcomes was analyzed using a Cox regression model. Among the 80 patients, 26 achieved positive response (CR/PR) with HAIC or ICIs, and 9 of them subsequently underwent conversion therapy with curative intent. Key prognostic factors included Child-Pugh stage B vs. A (HR=2.21, p=0.041), BCLC stage C vs. B (HR=4.38, p=0.011), and elevated AFP levels (HR=5.02, p&lt;0.001). Positive responders saw substantial survival benefits (HR=0.26, p=0.001). Patients undergoing conversion therapy exhibited significantly enhanced survival. Median OS was 13.58 months with standard therapy, while the curative intent surgery group did not reach the median OS (p=0.002). For CR/PR patients, 48-month survival was 75.0% for the curative surgery group versus 38.0% for standard treatment. Conversion therapy with curative intent following HAIC or ICIs might enhances survival in patients with advanced or TACE-unsuitable intermediate-stage HCC.

Factors predicting treatment response to biological and targeted synthetic disease-modifying antirheumatic drugs in psoriatic arthritis - a systematic review and meta-analysis.

The therapeutic response of patients with psoriatic arthritis (PsA) varies greatly and is often unsatisfactory. Accordingly, it is essential to individualise treatment selection to minimise long-term complications. This study aimed to identify factors that might predict treatment response to biological and targeted synthetic disease-modifying antirheumatic drugs (bDMARDs and tsDMARDs) in patients with PsA and to outline their potential application using artificial intelligence (AI). Five electronic databases were screened to identify relevant studies. A random-effects meta-analysis was performed for factors that were investigated in at least four studies. Finally, 37 studies with a total of 17,042 patients were included. The most frequently investigated predictors in these studies were sex, age, C-reactive protein (CRP), the Health Assessment Questionnaire (HAQ), BMI, and disease duration. The meta-analysis revealed that male sex (odds ratio (OR) = 2.188, 95% confidence interval (CI) = 1.912-2.503) and higher baseline CRP (1.537, 1.111-2.125) were associated with greater treatment response. Older age (0.982, 0.975-0.99), higher baseline HAQ score (0.483, 0.336-0.696), higher baseline DAPSA score (0.789, 0.663-0.938), and higher baseline tender joint count (TJC) (0.97, 0.945-0.996) were negatively correlated with the response to therapy. The other factors were not statistically significant but might be of clinical importance in the context of a complex AI test battery. Further studies are needed to validate these findings and identify novel factors that could guide personalised treatment decisions for PsA patients, in particular in developing AI applications. In accordance with the latest medical developments, decision-support tools based on supervised learning algorithms have been proposed as a clinical application of these predictors. Key messages • Given the often unsatisfactory and unpredictable therapeutic response in patients with Psoriatic Arthritis (PsA), treatment selection must be highly individualized. • A systematic literature review was conducted to identify the most reliable predictors of treatment response to biologic and targeted synthetic disease-modifying antirheumatic drugs in PsA patients. • The potential integration of these predictors into AI tools for routine clinical practice is discussed.

Effects of Sacubitril/Valsartan on all-cause hospitalizations in heart failure: participant-level pooled analysis of PARADIGM-HF and PARAGON-HF

Abstract Background Sacubitril/valsartan is indicated to reduce the risk of cardiovascular (CV) death and heart failure (HF) hospitalizations in patients with chronic HF. However, many of these patients are older and have multiple comorbidities that increase the risk of hospitalizations other than HF, yet the effects of sacubitril/valsartan on hospitalizations of any cause have not been well described. Methods PARADIGM-HF and PARAGON-HF were phase-3, global multicenter randomized clinical trials that evaluated sacubitril/valsartan versus enalapril (in PARADIGM-HF) or valsartan (in PARAGON-HF) across the spectrum of left ventricular ejection fraction (LVEF; ≤40% in PARADIGM-HF and ≥45% in PARAGON-HF). We pooled individual participant-level data from these 2 trials to examine the effects of sacubitril/valsartan on time-to-first investigator-reported all-cause and cause-specific hospitalization using Cox proportional hazards models, stratified by geographic region and trial. We additionally examined heterogeneity in treatment response by LVEF. Results Over 2.8 years median follow-up, among 13,194 participants in the pooled PARADIGM-HF/PARAGON-HF, sacubitril/valsartan significantly reduced the risk of all-cause hospitalizations compared with renin-angiotensin system inhibitor (HR 0.92; 95% CI 0.88-0.97; P=0.002); Figure 1 Panel A. The absolute risk reduction (ARR) was 2.1 per 100 patient-years corresponding to a number-needed-to-treat (NNT) of 48 patient-years of treatment exposure to prevent 1 all-cause hospitalization. Reductions in overall hospitalizations among patients with identifiable causes (N=5,783) seemed to be primarily driven by lower rates of cardiac and pulmonary hospitalizations associated with sacubitril/valsartan. Patients treated with sacubitril/valsartan did not have a higher rate of composite non-cardiac hospitalizations (Figure 1 Panel B). Similarly, sacubitril/valsartan reduced the risk of the composite of all-cause hospitalization or all-cause mortality (HR 0.92; 95% CI 0.87-0.96; P&amp;lt;0.001), with an ARR of 2.5 per 100 patients-years and an NNT of 40 patient-years. For all-cause hospitalization, we observed significant heterogeneity by LVEF as a continuous measure (Pinteraction=0.027); treatment effects were most apparent in those with an LVEF below 60% (HR 0.91 95% CI 0.86-0.96; Figure 2). Conclusions In a pooled analysis of &amp;gt;13,000 patients with chronic HF, sacubitril/valsartan reduced hospitalization for any reason with benefits most apparent among those with an LVEF below normal.

Biomarkers for monitoring patients with cardiac amyloidosis during transthyretin-stabilizer therapy

Abstract Introduction Cardiac amyloidosis is characterized by deposition of amyloid fibrils in the heart, leading to structural abnormalities and functional impairments resulting in heart failure. Amyloid transthyretin amyloidosis cardiomyopathy (ATTR-CM) is the most common form with increasing incidence due to growing awareness and improved diagnosis. The ATTR stabilizer tafamidis serves as the first specific therapy approved for ATTR-CM, and many promising substances are in late-stage clinical trials. With growing numbers of patients receiving stabilizer therapy, valid tools for monitoring treatment response and detecting disease progression are currently lacking. Here, we aim to assess systemic and cardiac biomarkers in patients receiving stabilizer therapy. Method All individuals diagnosed with ATTR-CM at our university hospital, were systematically assessed for eligibility in this study. We enrolled patients who were undergoing therapy with tafamidis. Biomarkers including Hemoglobin (Hb), Creatinine, estimated glomerular filtration rate (eGFR), International Normalized Ratio (INR), C-reactive protein (CRP), Troponin and NT-proBNP were examined at baseline and during 6 and 12 months follow-up. Wilcoxon signed rank test was used for statistical analysis. The study was approved by the local ethics committee (23-11500-BO). Results 194 patients were included in the analysis with median age of 80 (76-83) years (86,6% male). Results showed an impaired renal function at baseline (all mean ± SD) with creatinine 1.24 ± 0.46 mg/dl and eGFR 58.64 ± 18.24 ml/min/kg with statistically significant increase after 6 months in creatinine (1.31 ± 0.51 mg/dl, p&amp;lt;0.001) and eGFR (55.06 ± 17.65 ml/min/kg, p&amp;lt;0.001) and after 12 months (creatinine 1.35 ± 0.54 mg/dl, p&amp;lt;0.001, eGFR 53.27 ± 17.68 ml/min/kg, p&amp;lt;0.001). Hb showed a significant increase after 6 (13.61 ± 1.78 g/dl, p&amp;lt;0.001) and 12 months (13.6 ± 1.79 g/dl, p&amp;lt;0.001), compared to baseline (13.41 ± 1.71 g/dl, p&amp;lt;0.001). Comparison of baseline values for CRP (0.08 ± 1.18 mg/dl), Troponin (86.33 ± 190.6 ng/l), NT-pro BNP (4703 ± 4385 pg/ml) and INR (1.25 ± 0.46) after 6 (CRP p=0.28, Troponin p=0.7, NT-pro BNP p=0.97, INR p=0.91) and 12 months (CRP p=0.12, Troponin p=0.59, NT-pro BNP p=0.78, INR p=0.28) showed no significant changes. Conclusion Although troponin and BNP are routinely used and recommended as biomarker for monitoring patients with ATTR-CM, the diagnostic value may be insufficient to assess therapy response. Results emphasize the need to identify new biomarkers to adequately reflect the specific aspects of ATTR-CM disease progression. This study reveals significant alterations in creatinine and eGFR due to a worsening of kidney function, but an increase of Hb, suggesting a potential indicator for treatment response. Future research should explore innovative approaches like proteomic analysis as promising approach for both diagnostic and prognostic biomarkers.

Neoadjuvant chemotherapy followed by definitive local treatment in locally advanced sinonasal squamous cell carcinoma

BackgroundSinonasal squamous cell carcinoma (SCC) is a rare disease entity, comprising less than 5% of malignancies of the head and neck. While surgery is the primary treatment approach, neoadjuvant and adjuvant therapies play crucial roles in enhancing the prognosis of patients undergoing treatment with the goal of cure. In this study, we aimed to explore the treatment outcomes of neoadjuvant chemotherapy (NAC) in patients with locally advanced sinonasal SCC.MethodsMedical records of patients diagnosed of locally advanced (cT3-4b, N0-3) sinonasal SCC treated with a definitive aim between January 2005 and March 2023 were retrospectively reviewed. Patients were categorized into the following groups based on the initial treatment: NAC followed by surgery, NAC followed by concurrent chemoradiotherapy (CCRT), definitive CCRT, or upfront surgery. Initial treatment plan was decided by a multidisciplinary team. Primary endpoint was overall survival (OS) and objective response rate, and secondary endpoints were progression free survival (PFS), cumulative incidence of local and distant failures, and treatment-related toxicity. The treatment response was assessed according to the RECIST criteria.ResultsTotal 126 patients were included, and the median follow-up period was 25.6 months. The objective response rate to NAC was 48.2%. The subsequent resection rate was 70%, 42.9%, and 16.7% for patients with stage T3, T4a, and T4b disease, respectively. Two-year progression-free survival did not differ significantly between the NAC followed by surgery and upfront surgery groups (53.6% vs. 60.6%, P = 0.615) or between the NAC followed by CCRT and definitive CCRT groups (26.7% vs. 37.4%, P = 0.506).ConclusionNAC may be a valuable treatment option for patients with locally advanced sinonasal SCC, as it provides an opportunity for curative surgery and exhibits non-inferior oncological outcomes compared with upfront definitive local treatments.