Subgroup Of Patients Research Articles

Differential risk of cardiovascular complications in patients with type-2 diabetes mellitus in Ghana: A hospital-based cross-sectional study

Aim To characterize clinically relevant subgroups of patients with type-2 diabetes mellitus (T2DM) based on adiposity, insulin secretion, and resistance indices. Methods A cross-sectional study was conducted at Eastern Regional Hospital in Ghana from July to October 2021 to investigate long-term patients with T2DM. To select participants, a systematic random sampling method was employed. Demographic data was collected using a structured questionnaire and fasting blood samples were taken to measure glycemic and lipid levels. Blood pressure and adiposity indices were measured during recruitment. The risk of cardiovascular disease (CVD) was defined using Framingham scores and standard low-density lipoprotein thresholds. To analyze the data, k-means clustering algorithms and regression analysis were used. Results The study identified three groups in female patients according to body mass index, relative fat mass, glycated hemoglobin, and triglyceride-glucose index. These groups included the obesity-related phenotype, the severe insulin resistance phenotype, and the normal weight phenotype with improved insulin resistance. Among male patients with T2DM, two groups were identified, including the obesity-related phenotype with severe insulin resistance and the normal weight phenotype with improved insulin sensitivity. The severe insulin resistance phenotype in female patients was associated with an increased risk of high CVD (OR = 5.34, 95%CI:2.11–13.55) and metabolic syndrome (OR = 7.07; 95%CI:3.24–15.42). Among male patients, the obesity-related phenotype with severe insulin resistance was associated with an increased intermediate (OR = 21.78, 95%CI:4.17–113.78) and a high-risk CVD (OR = 6.84, 95%CI:1.45–32.12). Conclusions The findings highlight significant cardiometabolic heterogeneity among T2DM patients. The subgroups of T2DM patients characterized by obesity and/or severe insulin resistance with or without poor glycemic control, have increased risk of CVD. This underscores the importance of considering differences in adiposity, insulin secretion, and sensitivity indices when making clinical decisions for patients with T2DM.

Early Detection, Diagnosis, Prevention, and Treatment of Infection to Avoid Sepsis and Septic Shock in Severely Burned Patients: A Narrative Review

The early detection, diagnosis, anticipation, and therapy of infections to prevent sepsis and septic shock remain significant challenges in cases of grave burns. This narrative review explores various tools for early infection detection, including emerging biomarkers, the American Burn Association’s clinical criteria, and traditional blood parameters. A comparative study of the American Burn Association, Mann-Salinas, and Sepsis-3 criteria highlights the superior early detection capabilities of the Sepsis-3 criteria. However, the authors recommend that sepsis should be prospectively evaluated, identified, and classified by the intensive care group, rather than by relying solely on retrospective items, though the latter may still be necessary in certain cases. Advances in biomarker identification, including polymerase chain reaction (PCR) and gene expression (mRNA) profiling, offer diagnostic advantages over current methods, enabling early detection within 4 to 6 h of intensive care unit admission. Mass spectrometry also shows promise for the rapid determination of bacteria, yeast, and fungi based on bacteria protein profiles. Source control remains crucial, and the use of antibacterial topical agents has significantly improved the survival rates of severely burned patients. However, antibiotic selection must be made judiciously to avoid resistance. Despite these advancements, significant progress is still needed to improve the rapid identification, actual presence, prevention, and therapy of infections to reduce the incidence of sepsis and septic shock in this patient subgroup.

Association Between Genetically Proxied SLC12A2 Inhibition and Inflammatory Bowel Disease: A Mendelian Randomization Study.

The global rise in hypertension prompts the use of medications to manage blood pressure. However, selecting first-line drugs remains challenging as their efficacy often stems from blood pressure reduction rather than specific pharmacological actions. Evaluating interactions between antihypertensive drugs and common diseases can aid tailored treatment. Here, we assess the potential link between antihypertensives and inflammatory bowel disease (IBD). Summary-level coronary heart disease (CHD) data (184,305 individuals), systolic BP (SBP) data (757,601 individuals), ulcerative ileocolitis data (361,188 individuals), ulcerative colitis data (364,454 individuals), other ulcerative colitis data (361,619 individuals), and ulcerative proctitis data (361,700 individuals) were all from genome-wide association studies (GWASs), FinnGen or eQTL studies publicly accessible. The DrugBank10 and ChEMBL11 databases function to identify genes encoding protein products targeted by active constituents of BP-lowering drugs. Summary-data-based MR (SMR) estimated the associations between expressions of drug target genes and symptoms of IBD. A multivariable MR study was further conducted to examine if the observed association was direct association. Subsequently, we collected blood samples from IBD patients in the Gastroenterology Department of Gastroenterology, the First Affiliated Hospital of Anhui Medical University and blood from healthy individuals at the physical examination center. Real-time quantitative PCR was employed to detect the expression changes of drug target genes in the peripheral blood of patients with IBD. Furthermore, we used Caco2 cells to construct an in vitro model of IBD, examined the expression of the target molecules, and verified the potential of Bumetanide to improve IBD. SMR analysis revealed that enhanced SLC12A2 gene expression in blood (equivalent to a one standard deviation increase) was a risk factor for ulcerative ileocolitis (beta = 0.5861, se = 0.2972, p = 0.0486) and enhanced gene expression of ACE was a protective factor. Additionally, SCNN1D and SLC16A1 played protective roles of IBD, while NR3C1 was identified as a risk factor. However, among these genes, only SLC12A2 was considered to influence the progress of inflammatory bowel disease through systolic blood pressure based on Mendelian randomization analysis results. Other genes may be associated with IBD depending on the expression of their own proteins, independent of changes in blood pressure. In the peripheral blood of IBD patients and in vitro experiments, SCL12A2 has been shown to be highly expressed in IBD. In vitro experiments have confirmed that Bumetanide can inhibit SCL12A2 to improve tight junctions, reduce inflammation levels, and ameliorate IBD symptoms. Therapeutic inhibition of SCL12A2 may benefit patients with IBD. In the future, this study may contribute to the selection of more personalized antihypertensive medications for different subgroups of hypertensive patients.

Evaluating treatment effect modifiers using data from randomized two-sequence, two-period crossover clinical trials: application to a diabetes study

Abstract Type 2 diabetes is known as a heterogeneous disease with diverse pathophysiology. The identification of treatment effect modifiers for personalized medicine, however, has been difficult in basic research due to complex biological mechanisms related to various genetic and nongenetic factors, and in clinical research due to confounding bias and limited sample sizes. In this paper, we focus on a two-sequence, two-period crossover (CO) clinical trial of type 2 diabetes with baseline markers as a new strategy for analyzing treatment effect modification that allows confounding elimination and efficiency enhancement by within-patient treatment comparison. We provide a framework for statistical analysis of treatment effect modification and develop methods for testing for treatment effect modification and estimating individualized predictors of treatment differences in the CO trial with limited sample size. Numerical assessments showed that the efficiency of the proposed CO analysis was substantially higher than the standard analysis based on parallel-group comparison in these analyses. Application to the diabetes trial showed that markers based on gene expression in peripheral blood cells before pharmacological treatment significantly modified the effect of the treatment on the response and that marker-based predictors produced two subgroups of patients for whom different treatments should be recommended.

Study protocol of the METAPANC trial - intensified treatment in patients with local operable but oligometastatic pancreatic cancer - multimodal surgical treatment versus chemotherapy alone: a randomized controlled trial

Abstract Background Based on current guidelines, surgical treatment of hepatic oligometastases in patients with pancreatic ductal adenocarcinoma (PDAC) is not primarily recommended. Systematic chemotherapy is the therapy of choice for these patients. The relevance of subsequent surgical resection after chemotherapy remains unclear. This multicentre, randomized, controlled phase III trial is planned to evaluate whether resection of the primary tumor and liver metastases can improve overall survival in patients with PDAC with hepatic oligometastases in a multimodal treatment setting. Methods After an induction therapy with eight cyles of mFOLFIRINOX and a response assessment after four and eight cycles, patients will be randomized to either Arm 1 (perioperative mFOFIRINOX plus resection of the primary tumor with resection or ablation of all hepatic metastases) or Arm 2 (continuation of 4 cycles of the standard-of-care mFOLFIRINOX chemotherapy). This clinical trial will focus on a well-defined patient group with metastatic disease limited to the liver as the target organ, with a maximum of three metastases. Discussion METAPANC is the first international, randomized, controlled, open-label, multicentre, phase III clinical trial for curative intended surgical therapy of oligometastatic pancreatic cancer in Europe and America. The multimodal surgical treatment of patients with oligometastatic pancreatic cancer could significantly extend the overall survival of this patient group. A possible recommendation of this multimodal treatment regimen outside of clinical trials requires data from randomized controlled trials first. To identify patient subgroups that might benefit from multimodal surgical therapy, additional information on tumor genetics could supplement valid parameters. Trial registration EU Clinical Trials No. 2023-503558-10-00.

Autoantibodies in patients with fibromyalgia syndrome.

The objective of this study was to assess the frequency of IgG autoantibodies in patients with fibromyalgia syndrome (FMS), to characterize their binding to dorsal root ganglion (DRG) neurons and glial cells, and to assess whether specific DRG binding patterns correlate with clinical symptoms. Sera of a cohort of 184 patients with FMS and 55 control sera were used to test binding of patient IgG on rat DRG sections. ELISA, Western blot, and preadsorption tests were used to search for potential target antigens. We found binding to DRGs in 68 of 184 FMS sera and in none of the control sera. We could identify 9 binding clusters including binding to neurons and to cells labelled with the satellite glial cell marker fatty acid binding protein 7 (FABP7). Current pain intensity correlated positively with IgG binding to FABP7 immunoreactive structures, and burning pain was associated with binding to transient receptor potential vanilloid 1 immunoreactive neurons. Specific antibody detection revealed 13 of 68 sera positive for anti-citrullinated peptide antibodies, 9 of 68 positive for SOX1 antibodies, 7 of 68 positive for antibodies against the serotonin receptor 5HT1AR, and 3 of 68 positive for fibroblast growth factor 3 antibodies. Our findings support the notion of an immune activation in a subgroup of patients with FMS.

Validation of the Polish version of the Functional Oral Intake Scale against flexible endoscopic evaluation of swallowing and the International Dysphagia Diet Standardization Initiative Functional Diet Scale

IntroductionThe Functional Oral Intake Scale (FOIS) is a widely used instrument for assessing oral intake in dysphagic patients. Despite its frequent use, a validated version for the Polish population has been lacking.MethodsThis study aimed to validate the Polish adaptation of FOIS (FOIS-PL) by examining its concordance with Fiberoptic Endoscopic Evaluation of Swallowing (FEES) outcomes and the International Dysphagia Diet Standardization Initiative Functional Diet Scale (IDDSI-FDS) scores across patients with diverse clinical profiles. The primary outcome measures included the Penetration-Aspiration Scale (PAS) score from FEES, pharyngeal residue quantification, and IDDSI-FDS scores. A total of 302 participants with varying clinical conditions were recruited. The cohort included individuals with head and neck malignancies, cerebrovascular incidents, neuromuscular disorders, and other dysphagia aetiologies.ResultsPatients with gastroesophageal reflux disease and those post-thyroidectomy consistently exhibited oral food intake with a FOIS-PL score of ≥5. A strong inverse correlation was found between FOIS-PL scores and PAS scores (rho = −0.739; p < 0.001), indicating that reduced oral intake was associated with increased penetration or aspiration risk. Significant differences in FOIS-PL scores were evident across patient subgroups stratified by PAS severity (PAS ≤ 2, PAS 3–5, PAS > 5) and IDDSI levels. Lower FOIS-PL scores corresponded with more impaired swallowing safety (PAS > 5). The median FOISPL score was 5 for individuals with pharyngeal residue and 6 for those without (p < 0.001). Inter-rater reliability between evaluations conducted by a dietitian (FOIS I) and a speech-language pathologist (FOIS II) demonstrated high consistency (tau = 0.995; p < 0.001). Convergent validity was supported by strong correlations between FOIS-PL and IDDSI-FDS scores (FOIS I vs. IDDSI-FDS I: tau = 0.819; p < 0.001; FOIS II vs. IDDSI-FDS II: tau = 0.815; p < 0.001).ConclusionThe Polish version of the Functional Oral Intake Scale (FOIS-PL) is a valid and reliable tool for assessing oral intake in dysphagia. The findings demonstrate high accuracy, reliability, and validity, supporting its use across diverse clinical conditions.

Right ventricular dysfunction for prediction of long-term recovery in de novo HFrEF : a PROLONG-II substudy.

To analyse the predictive value of advanced markers of right ventricular (RV) function and RV-pulmonary arterial (PA) coupling in forecasting long-term left ventricular (LV) improvement in de novo heart failure with reduced ejection fraction (HFrEF). 260 patients (mean age 57years, 68% men) from the PROLONG-II study were included. PROLONG-II analysed patients with new-onset HFrEF receiving a wearable cardioverter-defibrillator. For this substudy, RV free wall longitudinal strain (RVFWS), tricuspid annular plane systolic excursion (TAPSE), fractional area change (FAC), and right ventricular-pulmonary artery (RV-PA) coupling ratios [RVFWS/systolic pulmonary artery pressure (PASP), TAPSE/PASP and FAC/PASP] at baseline and 3-month follow-up (early follow-up) were examined. LV improvement and non-improvement were defined as an LV ejection fraction (LVEF) of >35% or ≤35% at last available (long-term) follow-up. The median follow-up was 31.5months (IQR: 18.2-45.4), and 151 (58%) patients experienced LV improvement in the long term. No significant differences of RV function and markers of RV-PA coupling were observed at baseline; however, the subgroup of patients with long-term LVEF improvement showed better RV function at early follow-up (RVFWS -20.9±4.3 vs. -18.5±5.1%, TAPSE 19.7±5.1 vs. 17.4±4.9mm, FAC 39.7±8.5 vs. 35.2±9.4%, all P<0.01). In multivariable analysis, RVFWS at early follow-up was shown to be an independent predictor of later LV recovery [odds ratio 1.078 (95% confidence interval 1.010-1.150), P<0.05]. The non-improvers exhibited worse RV-PA coupling at early follow-up [RVFWS/PASP 0.82±0.35 vs. 0.65±0.35%/mmHg, TAPSE/PASP 0.71 (0.55-1.00) vs. 0.54 (0.35-0.75) mm/mmHg, FAC/PASP 1.54±0.61 vs. 1.24±0.75%/mmHg, all P<0.01]. RVFWS/PASP identified RV-PA uncoupling was associated with a higher risk of all-cause mortality (hazard ratio 4.64, 95% confidence interval 1.34-16.09, P=0.033). Persistent RV dysfunction, as indicated by both standard and advanced echocardiographic markers during the early follow-up period, implies a reduced potential for long-term LV recovery in patients with newly diagnosed HFrEF.

Adherence to delayed-release cysteamine in nephropathic cystinosis over time: data from the prospective CrYSTobs cohort study.

Adherence to cysteamine in nephropathic cystinosis (NC) remains challenging. A better adherence with delayed-release (DR) compared to immediate-release (IR) cysteamine at 1year was previously shown. This study aimed to evaluate adherence to DR cysteamine at 2years. Treatment adherence was assessed using a medication event monitoring system; adherence ranged from 0 (poor) to 2 (good). Leukocyte cystine level was measured at each 3-month visit. Long-term follow-up data (7years after the end of the study) on self-reported adherence and quality of life was also obtained in a sub-group of patients. Seventeen patients with NC under DR cysteamine from three French centers were included at a median age of 13.9 (5.4-33.0) years. The median adherence score was 1.62 (0.03-1.98) over the 2-year follow-up, with 65% of patients having good adherence and 75% having partial or good adherence. No significant difference in leukocyte cystine level between baseline and 2years was found (0.8nmol vs. 0.4nmol, respectively; difference in median of - 1.0nmol; 95% CI - 0.7, 0.4; P = 0.64). Long-term follow-up data highlighted that no patient wished to switch back to IR cysteamine, as taking the medication twice rather than four times a day was easier. This study found a fairly good adherence to DR cysteamine over time. Decreasing the number of intakes per day may improve adherence and limit the side effects of the drug, representing an additional argument in favor of its use in patients with cystinosis.

2025 Clinical Trials Update on Hemophilia, VWD, and Rare Inherited Bleeding Disorders.

Clinical trial programs for inherited bleeding disorders feature an array of innovative prophylaxis options: engineered clotting factor concentrates, FVIIIa mimetics, gene therapies, and biologics to bolster thrombin generation (rebalancing agents). Increasingly, non-hemophilia bleeding disorders and a broader demographic (females, children, and infants) are being incorporated into study populations. Ongoing clinical trials broadly address three themes: (1) indication expansion for licensed therapeutics in previously uninvestigated patient subgroups or clinical scenarios, (2) evaluation of efficacy and safety among other bleeding disorders such as von Willebrand disease, platelet function defects, and rare clotting factor deficiencies, and (3) longitudinal assessment of approved treatments particularly with regard to longer-term efficacy outcomes such as musculoskeletal health and treatment-specific safety outcomes including thrombotic risk and liver health. With these new prophylaxis modalities, providers must have a nuanced understanding of each therapy's mechanism of action, advantages, side effect profile, therapeutic limitations, and impact on hemostasis and laboratory monitoring. Treatment is no longer "one size fits all." Rather, management is tailored to individual needs and preferences. Here, we review active investigational trials and highlight promising approaches in preclinical development, expanding the innovative, complex landscape of inherited bleeding disorders therapeutics.

Prediction of Palatoplasty Timing for Infants With Cleft Lip and Palate Using Machine Learning Algorithm.

This study aims to predict the timing of palatoplasty in infants with cleft lip and palate (CLP) using a machine learning (ML) algorithm. The study included 111 patients with nonsyndromic CLP. Patient subgroups were classified based on birth weight (criterion: -1 SD, low birth weight versus normal birth weight) and cheiloplasty timing (criterion: 5mo, early cheiloplasty versus late cheiloplasty). Growth trajectories at T2 were compared using T0-weight z-scores between the birth weight subgroups. Changes in the z-scores of weight and height from T1 to T2 were compared between the cheiloplasty timing subgroups. After training the tree-based ML models using cleft type, age, height, and weight at T0, T1, and T2, the palatoplasty timing was predicted with cleft type, weight at T0, and age, height, and weight at T1. The low-birth weight subgroup showed significant catch-up growth during T0-T1 and T0-T2 (all P<0.0001), resulting in no significant difference from the normal birth weight subgroup at T2. Compared with the late cheiloplasty subgroup, the early cheiloplasty subgroup underwent palatoplasty earlier (13.1 versus 14.3mo; P<0.0001) and showed higher growth rates of weight and height and a greater increase in weight z-scores from T1 to T2 (all P<0.001). The CatBoost algorithm, with a root mean square error of 1.6 months, accurately predicted the palatoplasty timing (mean: actual, 12.8±1.8mo versus prediction, 12.8±1.0mo). Use of ML-assisted prediction method may help clinicians decide the timing of personalized palatoplasty in infants with CLP.

Impact of tislelizumab + chemotherapy versus placebo + chemotherapy on patient-reported symptoms and disease progression by programmed death-ligand 1 expression in gastroesophageal adenocarcinoma: A post hoc analysis of the RATIONALE-305 trial.

365 Background: The relationship between patient-reported outcome (PRO)-based symptom scores, recurrent PRO-based symptomatic deterioration events (RDEs), and terminal events such as progression-free survival (PFS) are rarely examined in the oncology therapeutic domain. Thus, we applied a 3-component joint model (JM) framework aiming to illuminate more clinically interpretable associations between PRO-based treatment effects, RDEs, and PFS among subgroups of patients with programmed death-ligand 1 (PD-L1) expression of ≥1%, ≥5%, and ≥10%. Methods: The final analytic sample included 378 patients in the tislelizumab + chemotherapy arm (T+C) vs 401 in the placebo + chemotherapy arm (P+C) for the PD-L1 ≥1% subgroup, 238 in the T+C arm vs 237 in the P+C for the PD-L1 ≥5% subgroup, and 118 in the T+C arm vs 125 in the P+C arm for the PD-L1 ≥10% subgroup. Symptom domain scores from the EORTC QLQ-C30 and QLQ-STO22 symptom were modeled. Change from baseline (CFBL) in each domain was analyzed every cycle up to cycle 6, then every other cycle thereafter (up to cycle 25). The joint model was applied to all PD-L1 subgroups and comprised three components: 1) linear mixed model (LMM) predicting CFBL symptom scores, 2) Cox proportional hazard (CPH) model for disease progression (PFS as terminal event), and 3) frailty (random effects for RDEs) CPH model for time to PRO-based RDEs. Osoba’s 10-point threshold was used to define RDEs. Results: In the LMM, significant treatment efficacy for the T+C arm compared with the P+C arm was observed for the GHS/QoL ( P =0.0080) and dietary restriction scores ( P =0.0475) in the PD-L1 ≥5% subgroup. In the PD-L1 ≥1% subgroup, compared with the P+C arm, the T+C arm was associated with less worsening in pain/discomfort ( P =0.0376), upper gastrointestinal symptoms ( P =0.0088), and dietary restrictions ( P =0.0352). In the CPH model, the average hazard ratio indicated that compared with the P+C arm, the T+C arm was associated with a reduction in risk of disease progression across all PRO domains and PD-L1 subgroups. Lastly, the PRO-based RDE frailty predictions were strongly associated with PFS risk in the PD-L1 ≥1% and ≥5% subgroups for GHS/QoL, and in the PD-L1 ≥1% subgroup for physical functioning, fatigue, dysphagia-odynophagia, pain/discomfort, and dietary restrictions, as well as for pain/discomfort and dietary restrictions in the PD-L1 ≥5% subgroup. Conclusions: Through the 3-component JM, PRO-based effects were detected and demonstrated strong associations between PRO-based RDEs, and investigator-assessed PFS among varying PD-L1 expression levels. This framework may be a promising alternative for analyzing and interpreting PRO data in the context of PFS.

Non-invasive evaluation of Achilles tendon and its enthesis using ultrashort echo time adiabatic T1ρ (UTE-Adiab-T1ρ) magnetic resonance imaging (MRI) in psoriatic arthritis

PurposeThis cross-sectional study investigates the utility of the quantitative ultrashort echo time (UTE) adiabatic T1ρ (UTE-Adiab-T1ρ) magnetic resonance imaging (MRI) in detecting potential differences in Achilles tendons and entheses of patients with psoriatic arthritis disease (PsA) compared with asymptomatic volunteers. Material and MethodThe Achilles tendons of forty-four PsA patients (59 ± 15 years old, 38 % female) and thirty-seven asymptomatic volunteers (32 ± 10 years old, 51 % female) were scanned on a 3 T clinical scanner in the sagittal plane using a 3-inch surface coil. The 3D UTE-Adiab-T1ρ sequences with fat saturation (FS) were used to measure UTE-Adiab-T1ρ. Tenderness of the tendons, the SF-12 health survey, and visual analog scale (VAS) were recorded for the patients. The Kruskal Wallis test was used to examine the differences in UTE-Adiab-T1ρ values between asymptomatic volunteers and patients, as well as subgroups of patients with pain in the Achilles tendon region and those treated with Biologics. Spearman’s correlation coefficients were calculated between UTE-Adiab-T1ρ and patient evaluations. P values < 0.05 were considered significant. ResultsUTE-Adiab-T1ρ was significantly higher for the PsA group compared with the asymptomatic group in the enthesis (11.4 ± 2.6 ms vs. 10.4 ± 2.4 ms) and tensile tendon regions (9.8 ± 2.8 ms vs. 7.7 ± 1.7 ms). PsA patients with active Achilles pain showed significantly lower T1ρ in the entheses compared with other patients (10.7 ± 2.6 ms vs. 11.7 ± 2.5 ms). PsA patients treated with Biologics showed significantly lower T1ρ values in the tendon compared with other patients (9.5 ± 2.5 ms vs. 10.3 ± 3.3 ms). The VAS score of patients showed a significant negative but weak correlation (R = -0.2) with UTE-Adiab-T1ρ of the enthesis. Correlations with SF-12 scores were not significant. ConclusionThis study highlighted the UTE-Adiab-T1ρ sequence capability in evaluating tendons and entheses and their potential involvement in PsA disease or response to therapies.

A Belgian physician-initiated trial investigating the LifeStream peripheral stent graft system for the treatment of complex TASC C and D iliac lesions.

Due to the heterogeneity of literature findings, stent type selection for the endovascular treatment of complex aorto-iliac occlusive disease remains challenging. The BELSTREAM study, a physician-initiated, prospective, multicenter, single-arm study, aims to report the safety and efficacy of the balloon expandable LifeStream Peripheral Stent Graft System (BD, Tempe, Arizona, USA) for the treatment of complex TASC C and D aorto-iliac artery lesions. Seventy patients and 133 lesions were included at six Belgian institutions. The primary efficacy endpoint of the study is primary patency at 12 months' follow-up. The primary safety endpoint is freedom from periprocedural serious adverse events (SAEs). Primary patency rate at 12-month follow-up was 94.5%. Target Lesion Revascularization (TLR) was reported in three patients at 12-month follow-up, resulting in a freedom from TLR rate of 95.3%. In a subgroup of patients with aorto-iliac stenting in kissing configuration, primary patency at 12-month follow-up was 97.4% with freedom from TLR 97.9%. Freedom from a negative primary safety outcome (NPSO) was 100% at 30 days in the overall study patient population. The patency and freedom from TLR rates, low adverse event rates, and up to one year sustained improvement in clinical outcomes demonstrate that the LifeStream™ Balloon Expandable Vascular Covered Stent is a well-suited device for the treatment of complex TASC C and D lesions, the challenging kissing configuration included.

Impact of tislelizumab + chemotherapy versus placebo + chemotherapy on patient-reported symptoms and overall survival (OS) by programmed death-ligand 1 (PD-L1) expression in advanced or metastatic esophageal squamous cell carcinoma (ESCC): A post hoc analysis of the RATIONALE-306 trial.

366 Background: While improved survival has been previously demonstrated, the impact of immunotherapy on HRQoL in ESCC has not been well examined. Traditional PRO-based analyses in oncology trials, such as time to deterioration (TTD) and mixed models for repeated measures (MMRMs), are limited by discounting recurrent PRO events. Thus, we applied a 3-component joint model (JM) framework to define more clinically interpretable associations between patient-reported symptoms, treatment effects, and OS among subgroups of patients with ESCC from RATIONALE-306, which met its primary endpoint, with PD-L1 expression of ≥1%, ≥5%, and ≥10%. Methods: The final analytic sample included 226 patients in the tislelizumab + chemotherapy arm (T+C), 242 in the placebo + chemotherapy arm (P+C) for PD-L1 ≥1%, 113 in the T+C arm and 103 in the P+C arm for PD-L1 ≥5%, and 168 in the T+C arm and 178 in the P+C arm for PD-L1 ≥10%.From EORTC QLQ-C30 and OES18, 7 keysymptom domains were modeled (GHS, physical functioning, fatigue, dysphagia, pain, reflux, dietary restrictions). PRO data were collected at baseline and at every treatment cycle (up to 6 cycles), then every other cycle, and at safety follow-up, and change from baseline (CFBL) was analyzed. The joint model comprised three components: 1) linear mixed model predicting CFBL symptom scores; 2) Cox proportional hazard model (CPH) for time to OS; and 3) frailty (random effects for recurrent deterioration events [RDEs]) CPH model for time to PRO-based RDEs. Osoba (1998) 10-point threshold was used to define RDEs. Results: Adjusted completion rates were &gt;90% in the ITT population for both arms. Significant T+C treatment effects wereobserved for physical functioning in PD-L1 ≥5% ( P =0.0476), and pain in PD-L1 ≥1% ( P =0.0028) and PD-L1 ≥5% ( P =0.0149) subgroups, but not in PD-L1 ≥10%. For other 5 symptoms (ie, GHS, fatigue, reflux, dysphagia, dietary restrictions), there were no statistically significant differences between treatment arms. However, T+C was associated with significant reductions in the risk of death across all 7 key symptoms and PD-L1 subgroups. As one example, with respect to interaction between pain and OS, T+C was associated with a 22% (HR, 0.78 [95% CI, 0.652-0.931]), 33% (HR, 0.67 [95% CI, 0.515-0.860]), and 47% (HR, 0.50 [95% CI, 0.344-0.720]) reduction in the risk of death in PD-L1 ≥1%, ≥5%, and ≥10%, respectively compared with P+C. Conclusions: In this analysis, the addition of tislelizumab to chemotherapy was associated with significantly less deterioration in multiple PRO symptoms including physical functioning and pain, alongside a lower risk of death, after adjusting for recurring deterioration events using a frailty model across multiple PD-L1 expression subgroups.

Overall survival (OS) of patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) treated with first-line (1L) FOLFIRINOX (FFX): Bridging the gap between the NAPOLI 3 trial and real-world practice.

690 Background: NALIRIFOX (liposomal irinotecan + 5-fluorouracil/leucovorin + oxaliplatin) demonstrated significantly improved OS compared to 1L gemcitabine + nab-paclitaxel in the phase 3 NAPOLI 3 trial (NCT04083235). The median OS (95% CI) in the NALIRIFOX intention-to-treat population (N= 383) was 11.1 (10.0, 12.1) months. However, the relative efficacy of NALIRIFOX versus FFX (irinotecan + 5-fluorouracil/leucovorin + oxaliplatin), another standard of care for 1L treatment of mPDAC, has not been studied. To further contextualize findings from NAPOLI 3 trial, the current study described OS among patients treated with 1L FFX in the real-world setting. Methods: Three cohorts of patients with mPDAC treated with 1L FFX were identified from the Flatiron Health database. The all-comer cohort included all adult patients with mPDAC treated with 1L FFX since January 2014. Among them, the trial-aligned cohort included patients with mPDAC treated with 1L FFX between January 1, 2020 and July 31, 2022 (to align with the time period of NAPOLI 3 trial) who met the eligibility criteria of NAPOLI 3. Finally, a subgroup of patients in the trial-aligned cohort who received modified FFX (mFFX) regimen composed the trial-aligned mFFX cohort. OS was assessed using Kaplan-Meier analysis. Results: The all-comer cohort consisted of 3,271 patients. The trial-aligned cohort included 219 patients, of whom 154 (70%) were treated with mFFX. The distribution of baseline characteristics was similar across three cohorts (Table). The median age of the trial-aligned cohort was 65 years old, with 46% of patients being female, 67% being White, and 47% having ECOG score of 1. The median OS (95% CI) in the all-comer cohort and trial-aligned cohort was 9.0 (8.5, 9.3) months and 9.1 (7.8, 10.9) months, respectively; the median OS (95% CI) was 8.6 (7.3, 10.5) months in the trial-aligned mFFX cohort. Conclusions: NALIRIFOX regimen in the NAPOLI 3 trial showed numerically improved OS compared to FFX, including mFFX, in the real-world setting. Analysis adjusting for baseline characteristics are warranted and will provide further insights for the comparative efficacy of the two regimens. Characteristics of real-world FOLFIRINOX cohorts. All-comer cohort(N=3,271) Trial-aligned cohort(N=219) Trial-aligned mFFX cohort (N=154) Baseline characteristics Age, years, mean (SD) 63.5 (9.0) 64.6 (8.2) 65.1 (8.5) Female, n (%) 1,377 (42.1) 100 (45.7) 68 (44.2) White, n (%) 2,118 (64.8) 146 (66.7) 100 (64.9) ECOG score = 1, n (%) 1,327 (48.9)* 103 (47.0) 77 (50.0) Endpoint Median OS, months (95% CI) 9.0 (8.5, 9.3) 9.1 (7.8, 10.9) 8.6 (7.3, 10.5) Abbreviations: CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; OS, overall survival; SD, standard deviation. *Proportion calculated based on 2,711 patients with ECOG available at baseline.

Dienogest treatment of symptomatic adenomyosis: An in-depth meta-analysis.

Adenomyosis is a common gynecological disease and a major contributor to dysmenorrhea that substantially reduces the quality of life of the affected. Dienogest has emerged as a promising drug for treating adenomyosis. A few systematic reviews and meta-analyses on this topic have been published recently. However, these meta-analyses were typically based on 2-7 studies, even though numerical data could have been extracted and more studies have been published. Moreover, it is unclear whether there is any characteristic of the patients that is associated with more pronounced improvement after treatment, or which patient subgroup, if any, would benefit most from the dienogest treatment. To evaluate the efficacy of dienogest in alleviating dysmenorrhea associated with adenomyosis and identifying study/patient characteristics that contribute to a better therapeutic response. An in-depth meta-analysis incorporating more recent published studies. An in-depth meta-analysis of 14 studies published up to March 2024, involving 637 patients was conducted, using the visual analog scale (VAS) scores on dysmenorrhea severity as the primary outcome measure. Subgroup analyses and multivariable regression were performed to explore potential factors influencing the treatment effect. Dienogest significantly improved dysmenorrhea, with a mean reduction in VAS scores of 6 on a 10-point scale. Subgroup analyses indicated that dienogest was effective across varying severities of dysmenorrhea and different treatment durations. Notably, patients with higher baseline VAS scores and longer treatment durations experienced greater reductions in VAS scores. Dienogest substantially alleviates dysmenorrhea in women with adenomyosis, particularly among those with severe baseline dysmenorrhea and extended treatment periods. However, variability in patient responses and the potential for adverse effects underscores the importance of individualized treatment strategies. Further large-scale, long-term comparative studies and randomized clinical trials are warranted to optimize treatment outcomes and better understand patient-specific factors.

Optokinetic After-Nystagmus: A Marker for Migraine? A Prospective Observational Study.

Vestibular migraine (VM), particularly its chronic variant, poses a diagnostic challenge. Patients suffering from VM may not have the characteristic headaches associated with the dizziness. In these cases, a marker for migraine pathology in general could help appropriately diagnose certain types of dizziness as migrainous despite these patients not meeting current diagnostic criteria for VM. Migraine patients in general (headache and vestibular) are known to share a tendency toward intolerance of certain stimuli, including busy visual stimuli. True optokinetic stimulation, measured by the production of optokinetic after-nystagmus (OKAN) simulates these busy visual stimuli. Prospective observational study comparing response to optokinetic stimulation between migraine patients and controls. Questionnaires regarding general sensitivities to busy visual stimuli were completed prior to beginning the study. Both subjective and objective markers of stress were measured before and after exposure to the stimulus. Initial slow-phase velocity, slow cumulative eye position, and adjusted time constant of OKAN were compared between the 2 groups. The groups differed only with regard to sensitivity to blinking lights and history of motion sickness on initial questionnaire. Regarding subjective symptoms of discomfort, migraine patients tended to report higher scores than controls both before and after testing, but there was no significant difference from before to after stimulus in each group's scores. There were no statistically-significant differences between initial slow-phase velocity, slow cumulative eye position, and adjusted time constant of OKAN between groups. In this study, OKAN measurements were not useful in differentiating migraine patients at large from control subjects. We hypothesize that there may be a distinct subgroup of migraine patients that are more sensitive to visually-disturbing situations that may differ from other migraine sufferers. Future studies will aim to identify such patients and compare them to controls.

Adverse events (AEs) –derived biomarker in predicting clinical outcomes in patients with colorectal cancer (CRC) treated with immunotherapy (IC).

132 Background: There are insufficient studies evaluating the role of AEs in CRC patients treated with IC. This study aims to transform AEs from traditional toxicity evaluation tools to informative biomarkers for assessing treatment efficacy by utilizing modern analytical strategies. Methods: We analyzed a single arm study of 51 mismatch repair proficient, refractory CRC patients (NCT03712943) treated with regorafenib and nivolumab. Data for analysis included CTCAE version 5 AE data, RECIST treatment response, progression-free survival (PFS), and overall survival (OS). Analytic approach leveraged multiple AE parameters to develop a set of innovative AE biomarkers. One AE biomarker of interest was treatment related low-grade early AEs (TR-LG-AE) which was defined as frequency of all TR-LG-AEs occurring between the 1st day and day 30 after the 1st treatment. Results: TR-LG-AE was associated with treatment response (p&lt;0.001 by ANOVA trend test). Patients with higher AE events tended to be a responder, compared to PD patients with a lower frequency of AE events. The TR-LG-AE also correlated with improved PFS and OS with hazard ratio of 0.83 (p=0.01) and 0.89 (p=0.03), respectively. Accordingly, patients were grouped into high versus low TR-LG-AE based on optimal cutoff of 6 events for further analysis. The dichotomized TR-LG-AE (high vs low) showed significant association with survival outcomes (median PFS: 15.3 vs 3.7 months; p&lt;0.001; median OS: 21.9 vs 9 months; p=0.02). Further interaction analysis showed patients with high TR-LG-AE had improved PFS regardless of occurrence of high-grade AE (HG-AE) (p=0.01), suggesting its independence of HG-AE. Individual AE analysis identified patients experienced with early low-grade rash maculo-papular, lipase increased, or hypertension had improved PFS (p&lt;0.001). In biomarker analysis, one key mutation biomarker, RAS, did not show significant association with survival outcomes (PFS: p=0.66; OS: p=0.81). In contrast, integration with TR-LG-AE led to remarkable improvement. Specifically, the TR-LG-AE was able to help improve RAS classification by identifying patients with better treatment benefit. Specifically, patients with RAS mutation and high TR-LG-AE experiences had a median PFS of 15.3 months compared to others (median PFS of 3.7 months; p=0.007), and a median OS of 21.9 months compared to others (median OS of 9.4 months; p=0.04). Conclusions: The study demonstrated utility of AE in predicting clinical outcomes in CRC, similar to our previous findings in lung cancer. Moreover, it discovered that integration of AE-derived biomarkers with molecular biomarkers could produce a more robust classifier than when considered individually. This analysis is the first of its kind to identify subgroups of CRC patients that benefit from IC treatment.

Is treatment delivery of perioperative FLOT therapy in locally advanced OGA associated with recurrence-free survival?

391 Background: Although perioperative FLOT therapy is a standard for locally advanced oesophagogastric adenocarcinoma (LA-OGA), completing all cycles, especially in the adjuvant chemotherapy (ACT) phase, is often challenging. This study examined the survival impact of treatment delivery in LA-OGA patients receiving FLOT therapy. Methods: 423 patients who underwent radical resection at The Royal Marsden Hospital from 2017 to 2023 were screened. Major inclusion criteria included patients with LA-OGA (cT2≤ and Nany or Tany and N+), treated with FLOT (at least one cycle of neoadjuvant chemotherapy) and radical resection, with an ECOG performance status of 0–2. Patients were divided into therapy incomplete (Tx Incomp, less than eight cycles of FLOT) and therapy (Tx comp) groups. We performed univariate and multivariate analyses, as well as propensity score matching (PSM) analysis, to evaluate whether treatment delivery was associated with recurrence-free survival (RFS) and overall survival (OS). Kaplan-Meier curves and restricted mean survival times (RMST) up to 36 months were used to evaluate the survival time. The primary endpoint was the 3-year RFS and OS rate. Results: Of the screened patients, 210 met the inclusion criteria, with 79 (38%) in the Tx Incomp and 131 (62%) in the Tx comp group, and 50 (24%) patients did not receive ACT. The median follow-up time was 26.5 months. The 3-year RFS and OS rates in the Tx Incomp and Tx comp groups after PSM were 54% vs 59% (p=0.14) (RMST difference: 4.04 months, p=0.09) and 58% vs 78% (p=0.04) (RMST difference: 6.15 months, p&lt;0.001), respectively. Multivariable analysis showed a significant impact of Tx comp on OS (HR 0.53, 95% CI: 0.32-0.88). In the subgroup of ypN-positive patients, a significant difference of RMST in OS rate was observed between those who started ACT and those who did not start ACT (RMST difference: 7.89 months, p=0.01), whereas no significant difference was found in the ypN-negative group (RMST difference: 0.65 months, p=0.75). Conclusions: This study suggests that completing FLOT therapy is associated with better OS. The impact of ACT might differ according to ypN stage.