Surrogate Marker Research Articles

Pathophysiology, Diagnosis, Prognosis, and Prevention of Poststroke Epilepsy: Clinical and Research Implications.

Poststroke epilepsy (PSE) is associated with higher mortality and poor functional and cognitive outcomes in patients with stroke. With the remarkable development of acute stroke treatment, there is a growing number of survivors with PSE. Although approximately 10% of patients with stroke develop PSE, given the significant burden of stroke worldwide, PSE is a significant problem in stroke survivors. Therefore, the attention of health policymakers and significant funding are required to promote PSE prevention research. The current PSE definition includes unprovoked seizures occurring more than 7 days after stroke onset, given the high recurrence risks of seizures. However, the pathologic cascade of stroke is not uniform, indicating the need for a tissue-based approach rather than a time-based one to distinguish early seizures from late seizures. EEG is a commonly used tool in the diagnostic work-up of PSE. EEG findings during the acute phase of stroke can potentially stratify the risk of subsequent seizures and predict the development of poststroke epileptogenesis. Recent reports suggest that cortical superficial siderosis, which may be involved in epileptogenesis, is a promising marker for PSE. By incorporating such markers, future risk-scoring models could guide treatment strategies, particularly for the primary prophylaxis of PSE. To date, drugs that prevent poststroke epileptogenesis are lacking. The primary challenge involves the substantial cost burden due to the difficulty of reliably enrolling patients who develop PSE. There is, therefore, a critical need to determine reliable biomarkers for PSE. The goal is to be able to use them for trial enrichment and as a surrogate outcome measure for epileptogenesis. Moreover, seizure prophylaxis is essential to prevent functional and cognitive decline in stroke survivors. Further elucidation of factors that contribute to poststroke epileptogenesis is eagerly awaited. Meanwhile, the regimen of antiseizure medications should be based on individual cardiovascular risk, psychosomatic comorbidities, and concomitant medications. This review summarizes the current understanding of poststroke epileptogenesis, its risks, prognostic models, prophylaxis, and strategies for secondary prevention of seizures and suggests strategies to advance research on PSE.

The effects of anaesthesia and analgesia on short- and long-term outcomes following colorectal cancer surgery

BACKGROUND Colorectal cancer (CRC) is the second most frequent cause of global cancer mortality. Most patients with CRC require surgical tumour resection, with certain stages of CRC (Stage II/III) also requiring postoperative chemotherapy. The timing of postoperative chemotherapy is largely determined by postoperative recovery. Delayed return to intended oncologic therapy (RIOT) by >8 weeks results in worse oncologic outcomes. RIOT is thus an important surrogate marker of outcome for patients with stage II/III CRC. We will test the hypothesis that anaesthetic technique during CRC resection surgery may affect RIOT. OBJECTIVE To test the association between anaesthetic and analgesic technique during CRC surgery and RIOT. To document Short-term Secondary outcomes including individual postoperative complications and a composite of all postoperative complications, the Comprehensive Complications Index (CCI) and to measure the time to recurrence (TTR) of cancer at 3 years. DESIGN This is a prospective, international, multicentre, observational cohort study. SETTING Global healthcare setting, with >140 centres in >30 nations. PATIENTS Inclusion criteria: All patients age >18 years, ASA I–III, with CRC stage I–III scheduled for elective CRC surgery (open or minimally invasive). Exclusion criteria: Uncontrolled renal or liver disease, restrictive (limiting mobility) heart failure or ischemic heart disease (ASA IV–V). Speech, language, or cognitive difficulties precluding signing informed consent to participate and Stage IV CRC. PRIMARY OUTCOME MEASURES Short -term: The duration from day of surgery to RIOT among patients expected to receive postoperative chemotherapy. Long-term: incidence of recurrence and time to recurrence (TTR) at 3 years after primary curative surgery SECONDARY OUTCOMES Postoperative complications within 30 days of surgery, length of hospital stay, Days at Home at 30 and 90 days (DAH-30, DAH-90) after surgery, and adverse events related to oncological treatment. We will also assess the burden of preoperative modifiable comorbid disease in patients. Exploratory endpoints will assess practice variation (including incidence of RIOT by demographic e.g. gender of patient, type of institution, country). RESULTS N/A. CONCLUSIONS N/A. TRIAL REGISTRATION The Effects of aNesthesia in COloREctal cancer outcome study: ENCORE, ClinicalTrials.gov Identifier: NCT04493905.

Liver histology is associated with long-term clinical outcomes in patients with metabolic dysfunction-associated steatohepatitis.

Few studies have examined the risk of long-term clinical outcomes in patients with metabolic dysfunction-associated steatohepatitis in relation to liver histology. We aimed to study this using a real-world cohort. Adults (N = 702) recorded on Vanderbilt University Medical Center's Synthetic Derivative database (1984-2021) with evidence of metabolic dysfunction-associated steatohepatitis on liver biopsy were followed from the first biopsy until the first clinical event or last database entry (median: 4.7y). Risks of cirrhosis (N = 650), other noncirrhotic liver-related (N = 702) and cardiovascular-related outcomes (N = 660), and mortality due to liver, cardiovascular, or cancer events (N = 660) were determined as a function of baseline histology (fibrosis stage [F], lobular inflammation grade [LI], hepatocyte ballooning grade [HB], and steatosis score) adjusting for sex, age, diabetes, and weight-loss surgery. Cirrhosis risk was reduced for lower versus higher fibrosis stage (HR: F0-1 vs. F3: 0.22 [95% CI: 0.12-0.42]), LI1 versus LI2-3 (0.42 [0.19-0.97]), and HB1 versus HB2 (0.20 [0.08-0.50]). Lower fibrosis stage was associated with significantly lower risks of liver-related outcomes versus F4 cirrhosis (eg, F0-1: 0.12 [0.05-0.25]), whereas no differences were seen across baseline lobular inflammation, hepatocyte ballooning, and steatosis grades/scores. Lower versus higher lobular inflammation grade was associated with lower risks for liver-related outcomes in patients with weight-loss surgery. There was a trend for lower risks for cardiovascular-related and any long-term outcomes with lower versus higher fibrosis stage. Fibrosis stage and lobular inflammation and hepatocyte ballooning grades predict the risk of long-term outcomes, supporting the use of these histological features as potential surrogate markers of disease progression or clinical outcomes.

Spliced-Leader RNA as a Dynamic Marker for Monitoring Viable Leishmania Parasites During and After Treatment.

Accurate detection of viable Leishmania parasites is critical for evaluating visceral leishmaniasis (VL) treatment response at an early timepoint. We compared the decay of kinetoplast DNA (kDNA) and spliced-leader RNA (SL-RNA) in vitro, in vivo, and in a VL patient cohort. An optimized combination of blood preservation and nucleic acid extraction improved efficiency for both targets. SL-RNA degraded more rapidly during treatment than kDNA, and correlated better with microscopic examination. SL-RNA quantitative polymerase chain reaction emerges as a superior method for dynamic monitoring of viable Leishmania parasites. It enables individualized treatment monitoring for improved prognoses and has potential as an early surrogate endpoint in clinical trials.

Viral genomic variation and the severity of genital HSV-2 infection as quantified by shedding rate: a viral genome-wide association study.

The clinical severity of genital HSV-2 infection varies widely among infected persons with some experiencing frequent genital lesions while others are asymptomatic. The viral genital shedding rate is closely associated with and has been established as a surrogate marker of clinical severity. To assess the relationship between viral genetics and shedding, we assembled a set of 145 persons who had the severity of their genital herpes quantified through determination of their HSV genital shedding rate. An HSV-2 sample from each person was sequenced and biallelic variants among these genomes were identified. We found no association between metrics of genome-wide variation in HSV-2 and shedding rate. A viral genome-wide association study (vGWAS) identified the minor alleles of three individual unlinked variants as significantly associated with higher shedding rate (p<8.4x10-5): C44973T (A512T), a non-synonymous variant in UL22 (glycoprotein H); A74534G, a synonymous variant in UL36 (large tegument protein); and T119283C, an intergenic variant. We also found an association between the total number of minor alleles for the significant variants and shedding rate (p=6.6x10-7). These results add to a growing body of literature for HSV suggesting a connection between viral genetic variation and clinically important phenotypes of infection.

Myeloproliferative Neoplasm Symptom Assessment Total Symptom Score (MPN-SAF TSS) in Chronic Myeloproliferative Neoplasms, Related with Genetic Burden, and Thrombosis.

Myeloproliferative Neoplasm Symptom Assessment Total Symptom Score (MPN-SAF TSS) is a surrogate marker for symptom evaluation in Chronic Myeloproliferative Neoplasms. There is not enough data to show the relationship between MPN-SAF TSS, JAK2 mutation allele burden, and thrombosis. In this retrospective analysis, we aimed to determine the genetic burdens, clinical features, and relationship with MPN-SAF TSS in MPN patients. One hundred thirty JAK2V617F positive MPN were included in our study. We have calculated MPN-SAF TSS and compared it with clinical features. Patients with higher JAK2V617F mutation allele burden had higher MPN-SAF TSS (p-value 0,008). Patients with thrombosis had higher MPN-SAF TSS scores than patients without thrombosis (p-value 0.003). The mean MPN-SAF TSS was higher in primary myelofibrosis (PMF) patients compared to PV and ET patients. Thrombosis was associated with increased symptom severity in several domains, including fatigue, abdominal discomfort, inactivity, night sweats, pruritus, weight loss, and early satiety. Additionally, an increase in JAK2 allele burden was observed with higher symptom scores. The MPN-SAF TSS proved to be a reliable tool for assessing symptom burden in Turkish MPN patients. Furthermore, a significant association between thrombosis occurrence and symptom severity suggests that thrombotic events may contribute to symptom development. Notably, increasing JAK2 allele burden was correlated with more severe symptoms, highlighting its potential role in predicting disease burden. This study emphasizes the importance of symptom assessment in MPN patients and supports the incorporation of MPN-SAF TSS in routine clinical practice to enhance patient care and management.

Estimated Glomerular Filtration Rate Slope as an Endpoint in Cardiovascular Trials.

End stage kidney disease can be a slow process and it may be challenging to achieve required follow-up for sufficient events. Therefore, a surrogate kidney endpoint, such as estimated glomerular filtration rate (eGFR) slope maybe attractive to assess the kidney in cardiovascular trials, especially heart failure (HF). eGFR slope can generate informative results in a shorter follow-up period, has decreased risk of type-2 error, and is less sensitive to eGFR shifts compared with other surrogate kidney endpoints (eGFR decline≥40% or doubling creatinine). However, eGFR slope has its limitations with acute effects, heterogeneity in slope calculation/reporting, and deviations from linearity. eGFR slope is a kidney endpoint which may be well-suited for HF trials. Cross-collaborated guideline recommendations are needed to optimize the use of eGFR slope as a kidney endpoint in patients with HF.

Comparison of Triglyceride–Glucose (TyG) Index and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) Index in Prediction of Male Hypogonadism

Several studies have shown the association between decreased insulin sensitivity and the risk of male hypogonadism. Homeostatic model assessment of insulin resistance (HOMA-IR) is a well-established marker of decreased insulin sensitivity. The triglyceride–glucose index (TyG), calculated as ln fasting triglyceride mg/dL× fasting glucose mg/dL/2, was recently suggested to be a cheaper and a reliable surrogate marker to detect insulin resistance (IR). Our aim was to compare the performance of those two indexes in the prediction of male hypogonadism. The data on 192 men from infertile couples (18–50 years; sperm concentration &lt;20 x 106/mL) and 199 population-based matched controls collected during the years 2009–2012 (baseline) were evaluated retrospectively. Half of these subjects (72 subfertile men and 122 controls) were reinvestigated 5–10 years later (median year (range): 7 (5–10)). The patients receiving any hormonal therapy were excluded. Hypogonadism was defined as fasting, morning serum testosterone below 12 nmol/L. In receiver operating characteristic curve analysis, the optimal diagnostic cutoff values for baseline HOMA-IR and TyG to predict MetS at re-examination were 2.68 (Area Under Curve (AUC) = 0.886, p &lt; 0.001) and 8.60 (AUC = 0.816, p &lt;0.001), respectively. Moreover, in binary logistic regression analysis performed on the whole cohort using these thresholds for high values of HOMA-IR and high TyG, the odds-ratios (ORs) for hypogonadism were 6.48 (95% Confidence Interval (CI): 3.77–11.2; p &lt;0.001) and 3.58 (95% CI: 2.17–5.94; p &lt;0.001), respectively. Even though high HOMA-IR levels provided better risk estimates, high TyG was also highly related to the risk of hypogonadism. These markers can be utilized to identify men being at high risk of hypogonadism.

Association between surrogate marker of insulin resistance and bone mineral density in US adults without diabetes.

Patients with osteoporosis are often diagnosed with type 2 diabetes or prediabetes. Insulin resistance is a prediabetic state, and triglyceride glucose-body mass index (TyG-BMI) has been recognized as a potential predictor of it, valuable in assessing prediabetes, atherosclerosis, and other diseases. However, the validity of TyG-BMI in osteoporosis studies remains inadequate. The purpose of this study was to evaluate the relationship between TyG-BMI and BMD as well as the effect of TyG-BMI on the odds of developing osteoporosis in US adults without diabetes. National Health and Nutrition Examination Survey data were obtained. The relationship between TyG-BMI and BMD was evaluated via multivariate linear regression models. Smoothed curve fitting and threshold effect analysis explored potential non-linear relationships, and age, gender, and race subgroup analyses were performed. In addition, multivariate logistic regression models were employed to analyze its potential role in the development of osteoporosis. In a study of 6501 participants, we observed a significant positive correlation between the TyG-BMI index and BMD, even after adjusting for covariates and categorizing TyG-BMI. The study identified specific TyG-BMI folding points-112.476 for the total femur BMD, 100.66 for the femoral neck BMD, 107.291 for the intertrochanter BMD, and 116.58 for the trochanter BMD-indicating shifts in the relationship's strength at these thresholds. While the association's strength slightly decreased after the folding points, it remained significant. Subgroup analyses further confirmed the positive TyG-BMI and BMD correlation. Multivariate linear regression analyses indicated a lower osteoporosis risk in participants with higher TyG-BMI levels, particularly in menopausal women over 40 and men over 60. This study suggests a positive correlation between BMD and TyG-BMI in US adults without diabetes. Individuals with higher levels of TyG-BMI may have a lower risk of osteoporosis.

Left bundle branch area pacing in the setting of cardiac amyloidosis: a case series

Abstract Background Cardiac amyloidosis (CA) is a highly prevalent cause of congestive heart failure. It often requires cardiac pacing due atrioventricular conduction (AV) system disorders, often with cardiac resynchronization (CRT) to prevent development/deterioration of left ventricular (LV) dysfunction. Left bundle branch area pacing (LBBAP) is an emerging alternative to CRT, offering a strict physiological LV activation and very limited use of iodinated contrast. The feasibility of LBBAP in CA is considered limited due to the presence of septal pseudohypertrophy which theoretically limits left-sided conduction system engagement. Purpose To evaluate the feasibility and effectiveness of LBBAP in cardiac amyloidosis. Methods Consecutive patients with CA (both light-chain -AL- or wild-type transtiretin -wtATTr) with a pacing indication for AV conduction disorders were enrolled. Patients underwent baseline echocardiographic examination. LBBAP was achieved by means of stylet-driven leads advanced transeptally (right ventricle (RV) to LV) via dedicated delivery systems, with continuous monitoring of 12-lead electrocardiographic morphology and impedance until a typical QRS morphology in V1 was obtained (usually rSr’ or Sr’). Standard measures for left bundle (LB) capture were used (stimulus to peak R in V6 – S-RV6, V6-V1 interpeak interval, presence of transition in these measures during threshold testing, presence of fascicular signal during spontaneous QRS). Results Between January 2022 and June 2023, among 63 patients undergoing LBBAP, 7 patients (11%) had CA, 2 AL (28%) and 5 (72%) wtATTR. Patients were prevalently old (78±7 y) males (6, 85%); LV mean septal thickness was 17±2 mm (min 16, max 20 mm) and mean LV ejection fraction (LVEF) was 45±6%. Indications were PR prolongation in 3, bradycardic atrial fibrillation and LB branch block (LBBB) in 2, primary LBBB in 1 and chronic RV pacing in 1. Baseline QRS duration was 145±47 ms (QRS&amp;lt;120 ms: 97±15 ms, QRS&amp;gt;120 ms: 182±13 ms). LBBAP success was 100%. Fascicular electrograms were observed in ¾ of patients without LBBB; S-RV6 interval was 74 ±11 ms (³70 ms in 3), RV6-RV1 interpeak interval was 47±9 ms (³ 30 ms in 6 patients). DQRS in baseline broad QRS was -52 ms and +32 ms in narrow. No complications were observed. Over a short follow up of 6 months, an increase in average LVEF was observed (LVEF at 6 months: 51±3%, p&amp;lt;0.05). Conclusions In patients with CA, LBBAP is easily achievable with stylet-driven systems with frequent selective engagement of conduction system. QRS narrowing in baseline broad QRS is significant while QRS broadening in baseline narrow QRS is limited. Early results regarding follow-up of surrogate endpoint such as LVEF are promising.

Correlation between Lesions Size Index (LSI) and impedance dynamics during radiofrequency ablation for atrial fibrillation: impact of lesion duration and contact force

Abstract Introduction Impedance drop has been employed as a surrogate marker for lesion formation with its magnitude correlated to lesion size in in-vitro studies. The Lesion Size Index (LSI), and algorithm from Abbott Medical, serves as a predictor for lesion formation during radiofrequency (RF) ablation. While this formula integrates contact force (CF), lesion duration and power, it currently leaks impedance information. The new module of Ensite Cardiac Mapping system (Abbot) is capable of measuring the "filtered" impedance during each RF lesion, effectively eliminating artifacts from cardiac and respiratory oscillations. The objective of this study is to examine the correlation between the LSI and the average impedance drop during RF lesion formation. Methods We included a total of 18 consecutive patients who underwent catheter ablation for atrial fibrillation (AF) with Ensite Mapping System (Abbot). In all cases, 40 watts (W) were applied and the target LSI was set as 5 for the posterior wall and 6 for the anterior wall. For each lesion, the software automatically annotated the initial impedance, final impedance, average impedance drop (filtered), lesion duration and average contact forced (CF). The correlation between LSI, impedance drop and CF was assessed. Results A total of 1300 RF lesions delivered during AF ablation were analyzed. Mean LSI was 5.3 ± 0.8, mean average impedance drop was 10.9± 5 ohms and mean CF 12.3±6 grams (g). The LSI showed a weak but statistically significant correlation with the impedance drop (Person correlation=0.3; p&amp;lt;0.001). When ablation lesions were grouped by duration (&amp;lt;20 seconds, 21-40, 41-60, &amp;gt;60 seconds), the correlation between LSI and impedance drop remained weak but statistically significant for lesions shorter than 20 seconds (p&amp;lt;0.001) and lesions between 21 and 40 seconds (p&amp;lt;0.001). However, there was no longer correlation for lesions between 40-60 seconds and those longer than 60 seconds (Figure1). Mean CF for each group (from &amp;lt;20 to &amp;gt;60 seconds) was 15 ±7 g vs 11 ±5 g vs 9 ± 3 g vs 7± 3g respectively (p&amp;lt;0.001) (Figure 2), suggesting that the CF is key to improve the predictive value of LSI. Conclusions The LSI shows a weak correlation with the average impedance drop during AF ablation. This correlation is influenced by lesion duration, which is ultimately dependent on CF. These findings emphasize the ongoing need to optimize predictive models for RF lesion formation in the ever-evolving landscape of AF treatment.Figure 1Table 1

Preoperative abnormal bone mineral density as a prognostic indicator in patients undergoing gastrectomy for gastric cancer: A cohort study.

Predicting postgastrectomy relapse and mortality in patients with gastric cancer (GC) remains challenging, with limitations to traditional staging systems such as the tumor-node-metastasis (TNM) system. This study aimed to investigate the impact of preoperative Hounsfield unit (HU) values, which serve as a surrogate marker for bone mineral density (BMD), in predicting survival outcomes in patients with GC. A retrospective analysis was conducted on data from patients with GC who underwent curative-intent gastrectomy. Opportunistic abdominopelvic computed tomography images were used to assess HU values at the 3rd lumbar vertebra (L3). These values were then categorized using a cutoff value of 110 HU, which has been established in previous studies as a determinant for abnormal versus normal BMD. Cox regression analysis established predictor models for overall survival (OS). Among 501 initial patients, 478 met the inclusion criteria. Multivariate analyses revealed HU values (hazard ratio, 1.51), along with other factors (the 5-factor modified frailty index, type of gastrectomy, TNM stage, anemia, and serum albumin level), as significant predictors of OS. The full model (FM) incorporating these variables demonstrated superior discrimination ability compared to the baseline model (BM), which is based solely on the TNM stage (concordance index: 0.807 vs 0.709; P < .001). Furthermore, the FM outperformed the BM in predicting OS risks at 36- and 60-months post-surgery. In conclusion, among patients undergoing gastrectomy for GC, those with HU values ≤ 110 (indicating abnormal BMD) at the L3 level, as determined through opportunistic CT scans, exhibited a poorer prognosis than those with HU values > 110 (indicating normal BMD). Integrating HU with other clinicopathological parameters enhances predictive accuracy, facilitating individualized risk stratification and treatment decision-making, which could potentially lead to improved survival outcomes.

Utility of SARS-CoV-2 Subgenomic RNA in Kidney Transplant Recipients Receiving Remdesivir.

There is no reliable microbiological marker to guide responses to antiviral treatment in kidney transplant recipients (KTR) with COVID-19. We aimed to evaluate the dynamics of subgenomic RNA (sgRNA) RT-PCR before and after receiving treatment with remdesivir compared with genomic RNA (gRNA) RT-PCR and its use as a surrogate marker of viral replication. We analyzed gRNA and sgRNA at baseline and after remdesivir treatment in KTR who received remdesivir for SARS-CoV-2 infection from November 2021 to February 2022. Thirty-four KTR received remdesivir for SARS-CoV-2 infection. The median time since transplantation was 80months (IQR 3-321) and 75% of patients had previously received 3 doses of a mRNA SARS-CoV-2 vaccine. Three patients (8%) were classified with mild, 25 (73%) with moderate, and 6 (17%) with severe SARS-CoV-2 infection. Thirty-two (94%) patients received 5 doses of remdesivir and two patients received 2 doses. The median time between symptom onset to remdesivir treatment was 5days (IQR 3-8.5). The median days of hospitalization were 6 (IQR 2-112). gRNA was positive in all patients at baseline and after remdesivir. Five (15%) patients had negative sgRNA at baseline and 20 (59%) after receiving remdesivir. Patients presenting with negative sgRNA at baseline were discharged from hospital in≤6days without complications. Moreover, those with negative sgRNA after remdesivir therapy did not require ICU admission and had favorable outcomes. Nevertheless, patients with positive sgRNA after antiviral treatment presented worse outcomes, with 47% requiring ICU admission and the three (9%) recorded deaths in the study were in this group. Based on these data, we hypothesize that sgRNA may have clinical utility to help monitor virologic response more accurately than gRNA in KTR who receive remdesivir. Moreover, patients with negative sgRNA at baseline may not require antiviral treatment and others presenting positive sgRNA at day 5 could benefit from prolonged or combined therapies.

Spatiotemporal stability of digital twin-guided atrial fibrillation dominant frequency sites and the clinical outcome of catheter ablation

Abstract Background Although the dominant frequency (DF) may localize the reentrant drivers of atrial fibrillation (AF), its meandering nature makes it difficult to localize as an extra-pulmonary vein (extra-PV) target. Purpose We explored and quantified the spatiotemporal stability of DF by sophisticated digital-twin maps and the association with the rhythm outcome of clinical AF catheter ablation (AFCA). Methods We retrospectively examined the DF sites in the digital twin integrated by high-density electroanatomical maps (EAM) of 170 patients previously included in the CUVIA-AF2 trial (male 70.6%, 59.2±11.3 years old, 100% persistent AF). We monitored 34 seconds of virtual AF and analyzed DF sites in 10 different left atrial (LA) regions at 3 consecutive periods (6 seconds each after 16sec induction and blanking periods). The spatiotemporal stability index (STSI) was calculated to quantify mean DF's spatial and temporal variability. During protocol-based rhythm follow-up, we assessed the atrial arrhythmia recurrence rate by dividing patients into two groups based on STSI 0.75. Results During the simulation, 108 out of 170 (63.5%) patients obtained mean DF values in all three consecutive periods. There were 26 (24.1%) patients in the stable DF group (STSI ≥0.75, Stable group) and 82 (75.9%) patients in the unstable DF group (STSI &amp;lt;0.75, Unstable group). Although the proportion of patients with hypertension (73.1 vs. 47.6%, p=0.041) was higher and left ventricular end-diastole diameter (51.3±3.9 vs. 49.0±4.4 mm, p=0.020) was larger in the stable DF group than in the unstable DF group, other parameters, including LA size, LA voltage, or AF ablation targets, did not differ between two groups. During the median 19 [15-22] months follow-up, the atrial arrhythmia recurrence rate of the Stable group is higher than that of the Unstable group (log-rank p=0.031, HR = 2.06, CI [1.06-4.01]) Conclusions We found that the temporally stable DF in EAM-integrated virtual AF, the potential extra-PV AF drivers, is a surrogate marker of the adverse rhythm outcome of AFCA. A prospective clinical trial targeting the spatiotemporally stable DF will be warranted.

Optimizing pressure-guided cryoablation of pulmonary veins

Abstract Background Pressure-guided cryoablation (PGC) is a contrast-free technique used to isolate Pulmonary Veins (PV) in order to treat atrial fibrillation (AF). In this technique the main goal is to achieve a wedge curve to assure adequate vein occlusion(1). As the wedge curve is not always clear, we hypothesize that the wedge pressures (systolic, diastolic and mean) could be useful as reliable surrogate markers. Purpose The aim of this study is to evaluate wedge pressures in individual vein occlusions in a cohort of patients referred for PV isolation using PGC. Methods Between February 2022 and October 2023, 23 patients (7 female, 13 paroxysmal AF) underwent PV isolation using PGC protocol. No REDOs were included. The procedure was intended to obtain PV isolation with one shot of 240 seconds. All patients underwent computed tomography angiography or MRI of LA and PV. A 28-mm Cryoballoon and a Intracardiac echo were used in all the procedures. Invasive radial arterial and LA pressures were registered. We analysed all the shots per vein and compared data between successful and unsuccessful isolation. Multivariate statistical analysis was performed, being the PV isolation the main outcome. Results There were realized 125 applications in 92 veins, being isolated 100% of them. One vein (left superior) was isolated after application in inferior ipsilateral vein, so it was considered successful as there was no need of additional applications. Eleven applications were performed as a bonus, so they were not considered for the isolated-non isolated analysis. Wedge curve was obtained in 112/119 applications (the 7 applications with not adequate wedge curve were 3 in right superior and 4 in right inferior pulmonary veins). In 5 applications the graphic curve was not reliable, but the pressure values were registered. There were significative differences in nadir temperature, systolic, diastolic and mean vein pressures, and the presence of a wedge curve. In the multivariate analysis, the nadir temperature (OR 0.79 CI95% 0.70–0.90) and the diastolic vein pressure at occlusion (OR 1.16 CI95% 1.01–1.36) were the only independent predictor factors of PV isolation. Conclusion With these results, we conclude that the monitoring of diastolic PV pressure during applications and the nadir temperature are the best markers to predict a successful isolation in the PGC.Figure 1.Pressure waveformTable 1.Application characteristics

Biomarker endpoints in cancer cachexia clinical trials: Systematic Review 5 of the cachexia endpoint series.

Regulatory agencies require evidence that endpoints correlate with clinical benefit before they can be used to approve drugs. Biomarkers are often considered surrogate endpoints. In cancer cachexia trials, the measurement of biomarkersfeatures frequently. The aim of this systematic review was to assess the frequency and diversity of biomarker endpoints in cancer cachexia trials. A comprehensive electronic literature search of MEDLINE, Embase and Cochrane (1990-2023) was completed. Eligible trials met the following criteria: adults (≥18years), prospective design, more than 40 participants, use of a cachexia intervention for more than 14days and use of a biomarker(s) as an endpoint. Biomarkers were defined as any objective measure that was assayed from a body fluid, including scoring systems based on these assays. Routine haematology and biochemistry to monitor intervention toxicity were not considered. Data extraction was performed using Covidence, and reporting followed PRISMA guidance (PROSPERO: CRD42022276710). A total of 5975 studies were assessed, of which 52 trials (total participants=6522) included biomarkers as endpoints. Most studies (n=29, 55.7%) included a variety of cancer types. Pharmacological interventions (n=27, 51.9%) were most evaluated, followed by nutritional interventions (n=20, 38.4%). Ninety-nine different biomarkers were used across the trials, and of these, 96 were assayed from blood. Albumin (n=29, 55.8%) was assessed most often, followed by C-reactive protein (n=22, 42.3%), interleukin-6 (n=16, 30.8%) and tumour necrosis factor-α (n=14, 26.9%), the latter being the only biomarker that was used to guide sample size calculations. Biomarkers were explicitly listed as a primary outcome in six trials. In total, 12 biomarkers (12.1% of 99) were used in six trials or more. Insulin-like growth factor binding protein 3 (IGFBP-3) and insulin-like growth factor 1 (IGF-1) levels both increased significantly in all three trials in which they were both used. This corresponded with a primary outcome, lean body mass, and was related to the pharmacological mechanism. Biomarkers were predominately used as exploratory rather than primary endpoints. The most commonly used biomarker, albumin, was limited by its lack of responsiveness to nutritional intervention. For a biomarker to be responsive to change, it must be related to the mechanism of action of the intervention and/or the underlying cachexia process that is modified by the intervention, as seen with IGFBP-3, IGF-1 and anamorelin. To reach regulatory approval as an endpoint, the relationship between the biomarker and clinical benefit must be clarified.

#2122 Dynamics of peritoneal transport and peritoneal dialysis outcomes

Abstract Background and Aims Volume overload is one of the most important factors associated with cardiovascular disease in peritoneal dialysis (PD) patients. On the other hand, the dynamics of peritoneal transport predicts important changes in the peritoneal membrane associated with local and systemic inflammation, which may be important for the progression of cardiovascular disease. The changes in free water transport (FWT) over time can characterize the development of peritoneal fibrosis. In a prospective study with retrospective historical control, the influence of the initial status and dynamics of peritoneal FWT on the outcomes of peritoneal dialysis, hard and surrogate cardiovascular outcomes was evaluated. Method According ISPD Recommendations (2021) the function of peritoneal membrane solute transfer was evaluated in classical PET in the exchange of 2 liters of 2.5% glucose solution with the calculation of the creatinine D/P4 ratio, which was used in the analysis as a continuous value (peritoneal solute transfer rate - PSTR), as well as categorized into high, medium-high, medium-low and low (H, HA, LA, L, respectively) levels of peritoneal transport. The mass transfer coefficient (MTAC) was also calculated. The ultrafiltration function of the membrane and its dynamics were evaluated by measuring the transport of water through small pores and free water through ultrapores, in double mini-PET (in two one-hour exchanges with solutions of 4.25% and 1.5% glucose). FWT is the calculated value; the primary measured value is the degree of reduction of sodium in the dialysis solution one hour after the start of the exchange (dipNa) formed as a result of electrolyte-free water transport through ultrapores (aquaporins), which dilutes dialysate. Results Table 1 shows the average values of peritoneal transport indicators at the beginning of follow-up and the annual changes calculated over the entire period of prospective follow-up for each patient. Major adverse cardiovascular events (Table 2) were recorded with a relatively low frequency, but significantly differed by incidence between the subgroups with high (H) and high-average (HA) peritoneal transport, on the one hand, and low-average (LA) and low(L), on the other: 0.626 ± 0.049 vs. 0.320 ± 0.042 events per year; p&amp;lt;0.001, (49% fewer events). Similarly, there was a significant difference in the MACE incidence between patients with slow and rapid decrease in free water transport (divided by the median of the rate of in free water transport decrease): 0.414 ± 0.044 vs. 0.510 ± 0.051 events per year; p &amp;lt; 0.001, (19% fewer events). The same calculations for nonfatal cardiovascular events showed a fewer incidence of 47.2% and 17.1%, respectively. Thus, patients with a high transport status (according to the PET test) and patients with a rapid decrease in water transport through aquaporins (indicating an increase in fibrotic changes in the peritoneal mesothelium), accompanied also by an increase in peritoneal permeability to solutes, including glucose, are at greater risk of progression of cardiovascular disease. Conclusion In addition to confirming the link between the initial status of peritoneal transport and the subsequent incidence of cardiovascular events, it would be interesting to confirm the influence of cardiovascular disease (as a proinflammatory condition and as a factor of volume overload, forcing the wider use of concentrated solutions which damage the peritoneum) on the progression of peritoneal fibrosis, but according to available materials it was not possible due to the limited number of patients in the study (especially – patients with repeated assessments of peritoneal transport after the cardiovascular events) and low frequency of peritoneal transport monitoring, on the one hand, and uncertainty in identifying the exact time of development of heart failure and the need for revascularization. Continued prospective observation would clarify these links.

#2459 Matching-adjusted indirect comparison of eGFR in patients with immunoglobulin A nephropathy treated with Nefecon (TRF budesonide) or sparsentan

Abstract Background and Aims Primary immunoglobulin A nephropathy (IgAN) is an immune-mediated disease that can lead to kidney failure, need for dialysis and kidney transplantation, and early death. IgAN is the most common type of primary glomerulonephritis globally, with an estimated worldwide incidence of 2.5 per 100 000 individuals per year. Estimated glomerular filtration rate (eGFR) is a measure of renal function and is accepted as a surrogate endpoint for clinical trials evaluating kidney function deterioration. In December 2023, the US Food and Drug Administration (FDA) granted full approval to Nefecon (marketed as Tarpeyo® by Calliditas Therapeutics), a targeted-release formulation of budesonide, to reduce the loss of kidney function in adults with IgAN at risk of disease progression, based on the Phase 3 NefIgArd clinical trial. In February 2023, sparsentan (marketed as Filspari™ by Travere Therapeutics) was granted accelerated approval by the FDA to reduce proteinuria in adults with primary IgAN at risk of rapid disease progression, generally a urine protein–creatinine ratio (UPCR) ≥1.5 g/g, based on the Phase 3 PROTECT study. Matching-adjusted indirect comparison (MAIC) is a widely accepted and relevant methodology for comparing treatments across trials in the absence of head-to-head comparisons. In this analysis, we aimed to compare the effects of Nefecon and sparsentan on kidney function deterioration in patients with IgAN, as assessed by eGFR. Method An anchored MAIC was performed to estimate the relative effect of Nefecon and sparsentan on the absolute eGFR change from baseline at 9, 12 and 24 months, with common comparators of optimized renin–angiotensin system inhibition for NefIgArd and irbesartan for PROTECT. Patient-level data from NefIgArd were used to select a population matched to PROTECT, and the following baseline characteristics were used to determine the weights: mean age (years), sex (% male), race (% white), mean eGFR (mL/min/1.73 m2), mean UPCR (g/g), urine albumin–creatinine ratio (UACR) (% with UACR &amp;gt;1.1 g/g), and urinary protein excretion (% with urinary protein excretion &amp;gt;1.8 g/day). Absolute change in eGFR was analyzed using a mixed model for repeated measures (MMRM) method, including baseline, 3-, 6-, 9-, 12-, 18- and 24-month data, baseline eGFR, baseline eGFR-by-time interaction, treatment, and treatment-by-time interaction. The MAIC weights were incorporated into the MMRM. A Bayesian fixed-effects network meta-analysis was performed on the relative effect from PROTECT and the weighted relative effect from NefIgArd, measured by the estimated absolute change from baseline in eGFR. Results The matching-adjustment of the NefIgArd patient population to the PROTECT population is shown in Table 1. The weighted NefIgArd population exhibits very similar baseline characteristics to the PROTECT population. The effective sample size of the weighted NefIgArd population is 208. Results from the anchored MAIC showed statistically and clinically significant favorable effects of Nefecon versus sparsentan on eGFR for all time points analyzed (Fig. 1). Mean differences in the absolute change in eGFR of 5.68 mL/min/1.73 m2 (95% credible interval [Crl] 3.14, 8.20; p &amp;lt; 0.001), 3.48 mL/min/1.73 m2 (95% Crl 0.97, 5.97; p = 0.006) and 3.28 mL/min/1.73 m2 (95% Crl 0.02, 6.51; p = 0.048) were observed when comparing Nefecon with sparsentan at 9 months vs 36 weeks, 12 months vs 48 weeks, and 24 months vs 106 weeks, respectively. Conclusion After accounting for differences in the patient populations from the NefIgArd and PROTECT trials, the anchored MAIC showed that treatment with Nefecon 16 mg/day for 9 months was associated with greater eGFR benefit compared with continuous treatment with sparsentan 400 mg/day over 2 years, with significant differences observed as early as 9 months after treatment initiation and sustained up to 2-years of follow-up.

Radiation and chemo-sensitizing effects of DNA-PK inhibitors are proportional in tumors and normal tissues.

Inhibitors of DNA-PK sensitize cancers to radiotherapy and DNA-damaging chemotherapies, with candidates in clinical trials. However, the degree to which DNA-PK inhibitors also sensitize normal tissues remains poorly characterized. In this study we compare tumor growth control and normal tissue sensitization following DNA-PK inhibitors in combination with radiation and etoposide. FaDu tumor xenografts implanted in mice were treated with 10 - 15Gy irradiation ± 3 - 100 mg/kg AZD7648. A dose-dependent increase in time to tumor volume doubling following AZD7648 was proportional to an increase in toxicity scores of the overlying skin. Similar effects were seen in the intestinal jejunum, tongue and FaDu tumor xenografts of mice assessed for proliferation rates at 3.5 days after treatment with etoposide or 5Gy whole body irradiation ± DNA-PK inhibitors AZD7648 or peposertib (M3814). Additional organs were examined for sensitivity to DNA-PK inhibitor activity in ATM-deficient mice, where DNA-PK activity is indicated by surrogate marker γH2AX. Inhibition was observed in heart, brain, pancreas, thymus, tongue and salivary glands of ATM-deficient mice treated with the DNA-PK inhibitors relative to radiation alone. Similar reductions are also seen in ATM-deficient FaDu tumor xenografts where both pDNA-PK and γH2AX staining could be performed. Conclusions: DNA-PK inhibitor-mediated sensitization to radiation and DNA-damaging chemotherapy is not limited to tumor tissues, but also extends to normal tissues sustaining DNA damage. These data are useful for interpretation of the sensitizing effects of DNA damage repair inhibitors, where a therapeutic index showing greater cell-killing effects on cancer cells is crucial for optimal clinical translation.

#2079 The impact of body composition measures on survival and cardiovascular events in patients with chronic kidney disease

Abstract Background and Aims Multimorbidity, frailty and sarcopenia are increasingly prevalent in people with chronic kidney disease (CKD). Creatinine Muscle Index (CMI) has been proposed as a novel surrogate marker of muscle mass, and lower CMI was associated with frailty and increased mortality in the Atherosclerosis Risk in Community Study [1]. Waist to hip ratio (WHR) has also been proposed as a surrogate marker of visceral adiposity. In order to investigate the impact of body composition on outcomes, we analysed data collected from a large CKD cohort using CMI and WHR as markers of muscle mass and adiposity respectively to examine their effects on 5-year survival and cardiovascular events. Method 1741 people with CKD stage 3 were recruited from 32 primary care practices. Cystatin C was measured using the Abbott c16000 Analyser (Abbott Diagnostics). eGFR cystatin (eGFRcys) was calculated using the CKD-EPI Cystatin C Equation (2012). CMI was calculated as the product of serum creatinine and eGFRcys (CMI [mg/day per 1.73 m2]= eGFRcys [ml/min per 1.73 m2] × serum creatinine [mg/dl] × 1 dl/100 ml × 1440 min/day). Cox proportional hazard model was used to examine if CMI and WHR predicted death or cardiovascular events. Results Mean age of the participants was 72.9 ± 9 years. Mean eGFRCr was 53.5 ± 11.8 ml/min/1.73 m2. Mean eGFRcys was 45.1 ± 16.0 ml/min/1.73 m2. Mean CMI was 766.45 ± 239.2 mg/day/1.73 m2. 300 (17.2%) participants died during 5 years of observation. In a Cox proportional hazards model which included CMI, WHR and age, lower CMI per standard deviation change (B = −0.202, HR 0.817, p = 0.007), higher WHR per standard deviation change (B = 0.313, HR 1.37, p &amp;lt; 0.001) and age at baseline (B = 0.088, HR 1.09, p &amp;lt; 0.001) were independent predictors of mortality at year 5 of follow-up. CMI per standard deviation change also predicted cardiovascular events at 5 years using a univariable cox proportional hazards model, (B = −0.095, HR 0.91, p = 0.03). Conclusion Lower CMI (a surrogate measure of muscle mass) and higher WHR (a surrogate for visceral adiposity) independently predicted 5 year mortality and cardiovascular events in this predominantly elderly population with CKD stage 3. We conclude that body composition has an important impact on mortality and cardiovascular events in patients with CKD and the mechanisms of this merits further investigation. This could inform future interventions that reduce visceral adiposity and improve muscle mass in people with CKD.