Surrogate Marker Research Articles

Population-Based Evidence for the Use of Serum Neurofilaments as Individual Diagnostic and Prognostic Biomarkers in Amyotrophic Lateral Sclerosis.

Neurofilament light chains (NfL) and phosphorylated neurofilament heavy chains (pNfH), established as diagnostic and prognostic biomarkers in hospital-based amyotrophic lateral sclerosis (ALS) cohorts, are now surrogate markers in clinical trials. This study extends their evaluation to a population level, with the aim of advancing their full establishment and assessing the transferability of biomarker findings from controlled cohorts to real-world ALS populations. We measured serum NfL and pNfH levels in all ALS patients (n = 790) and general population controls (n = 570) with available baseline samples participating in the epidemiological ALS Registry Swabia, providing platform-specific (ELLA™) reference data and Z-scores for controls, as well as reference data, disease-specific Z-scores and longitudinal data in ALS. We evaluated the diagnostic and prognostic utility of neurofilaments and quantified the impact of ALS-related factors and non-ALS confounders. Neurofilaments showed high diagnostic and prognostic utility at the population level, with NfL superior to pNfH. The novel concept of a population-based ALS Z-score significantly improved the prognostic utility compared to absolute raw values. Both biomarkers increased more strongly with age in controls than in ALS, and age adjustment improved diagnostic accuracy. Our data show that disease progression rates, ALS phenotype, body mass index (BMI), and renal function need to be considered when interpreting neurofilament levels; longitudinal neurofilament levels were generally stable in individual patients, especially when adjusted for age and baseline levels. Population-based assessment enhances the utility of particularly serum NfL as a diagnostic and prognostic biomarker in ALS and improves the translation of findings from controlled cohorts to real-world populations. ANN NEUROL 2024;96:1040-1057.

Why effect sizes are systematically larger for progression-free survival than overall survival in cancer drug trials: prognostic scores as a way forward

Cancer drugs have accumulated the most approvals over the past years. Overall survival (OS) is considered the gold standard for cancer trial outcomes. However, its use has declined over the past years, in favor of surrogate endpoints, such as progression-free survival (PFS). PFS allows to assess outcomes earlier and, thus, accelerates approval of cancer drugs. Previous studies have demonstrated a poor correlation between PFS and OS. Using simulation models, we examined why PFS usually overestimates survival benefit. We created a publicly accessible web application that allows users to run the simulations with different parameter settings. Based on the findings, we propose that assessment of preliminary evidence should be based on a combination of OS result and prognostic scores that reflect the health status of surviving patients.

Phase angle as a marker of muscle quality: A systematic review and meta-analysis

Background & aimsPhase angle (PhA) is a biomarker derived from raw bioelectrical impedance analysis (BIA) values: resistance (R) and reactance (Xc). PhA reflects cellular membrane integrity and, as a result, has been considered a marker of fluid distribution, making it a potential prognostic indicator. A growing body of research demonstrates independent associations between PhA and muscle strength, mass, and composition. In this context, PhA has the extra potential to serve as a marker of muscle quality. However, the evidence supporting its use for this purpose is not well established. This study aimed to investigate the relationship between PhA and markers of muscle quality. MethodsThis systematic review and meta-analysis (Internal Prospective Register of Systematic Reviews – PROSPERO on a registration code: CRD42024507853) focused on observational studies assessing the relationship between PhA and markers of both concepts of muscle quality: the muscle quality index (MQI: strength by a unit of mass) and the muscle composition (i.e., skeletal muscle radiodensity [SMD], muscle echogenicity, muscle fat fraction, inter- and intramuscular adiposity). Risk of bias was assessed using the Newcastle-Ottawa Scale (NOS) and Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2), while the certainty of evidence was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. Meta-analyses with a random-effects model were conducted. ResultsSeventeen studies were included in this systematic review, encompassing 2,710 participants. Meta-analyses demonstrated that PhA had a moderate positive correlation coefficient with SMD (4 studies, 924 participants; r = 0.54, 95% confidence interval (CI) 0.38 to 0.69, heterogeneity (I2) = 92%) and good accuracy (85%) for classifying low SMD (2 studies, 390 participants; Area Under the Curve – AUC pooled 0.85, 95% CI 0.78 to 0.92, I2 = 0%). PhA was inversely-moderately correlated with muscle echogenicity (8 studies, 1,401 participants; r = - 0.42, 95% CI - 0.57 to - 0.24, I2 = 82%) and positively-weakly correlated with MQI (2 studies, 191 participants; r = 0.36, 95% CI 0.21 to 0.49, I2 = 17%). All studies had a higher risk of bias. The certainty of evidence ranged from low to very low. ConclusionDespite technical challenges, this study demonstrates the potential of PhA as a surrogate marker for muscle quality, particularly expressing muscle composition (SMD). Future studies should utilize BIA with standardized protocols to potentially establish specific cutoff values for PhA, thereby enhancing its diagnostic accuracy and clinical applicability. These studies could additionally explore the mechanisms underlying the associations between PhA and muscle quality aspects. In cases where technical factors are not easily controlled, the use of standardized PhA (SPhA), which converts PhA into Z-scores, could be beneficial. Although this warrants investigation, this approach (SPhA) has the potential to account for variables such as age, sex, device differences, and health status.

Assessing parotid gland function through diffusion weighted MRI during and post-radiotherapy in head and neck cancer patients

ObjectivesThe purpose of this study was to evaluate the usefulness of apparent diffusion coefficient (ADC) variation in irradiated parotid glands during and after 3D conformal radiotherapy (3DCRT). Materials and methodsThis study enrolled 15 head and neck cancer (HNC) patients who were treated with 3DCRT underwent diffusion weighted imaging (DWI) at rest and after gustatory stimulation in three time points as follows: before, during (one day after receiving the mean dose 26 Gy) and 6 months after the end of radiotherapy (RT). Salivary Ejection Fraction (SEF) data was also obtained from salivary gland scintigraphy (SGS) at the same three time points as MRI. Mean ADC at rest and after stimulation (ADCr, ADCs) and SEF were extracted from parotid region for three time points. Finally, SEF and changes of ADC over time at rest and after stimulation and in each time point were compared. ResultsDifference between mean ADCr before RT and during RT was not significant (p = 0.12). The ADCr values were significantly higher after RT than before RT (p = 0.003) and during RT (after dose 26 Gy) (p = 0.001). The difference between ADCr and ADCs in each time point showed that there is significant difference between ADCr and ADCs before RT (p = 0.005). Difference between these parameters after RT was also significant (p = 0.05). Non-significant difference (p = 0.21) between ADCr and ADCs during RT was observed. The result of SEF also was significantly lower after RT than during (p = 0.008) and before RT (p = 0.001). ConclusionMean ADC values could be used as a surrogate marker to characterize the parotid function in different stages of RT.

Multiple surrogates in the meta-analytic setting for normally distributed endpoints

The identification of good surrogate endpoints is a challenging endeavour. This may, at least partially, be attributable to the fact that most researchers have focused on the identification of a single surrogate endpoint. It is thus implicitly assumed that the treatment effect on the true endpoint (T) can be accurately predicted based on the treatment effect on one surrogate endpoint (S) only. Given the complex nature of many diseases and the different therapeutic pathways in which a treatment can impact T, this assumption may be too optimistic. For example, in oncology, the effect of a treatment often depends on both the treatment’s efficacy and its toxicity. In the present paper, the meta-analytic framework of Buyse et al. (2000) is extended to the setting where multiple S are considered. To cope with potential model convergence issues that often arise in a meta-analytic framework, several simplified model fitting strategies are proposed. Further, simulation studies are conducted to evaluate the properties of the estimated surrogacy metrics, and the new methodology is applied on a case study in schizophrenia. An online Appendix that details how the analyses can be conducted in practice (using the R package Surrogate) is also provided.

Neurofilament light chain: a biomarker at the crossroads of clarity and confusion for gene-directed therapies.

Neurofilament light chain (NfL) is a promising biomarker for neurodegenerative diseases, measurable in both CSF and blood upon neuroaxonal damage. While CSF analysis was traditionally used, blood-based assays now offer a less invasive alternative. NfL levels correlate with disease severity and progression in conditions like Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis and Huntington's disease. Clinical trials demonstrate its utility as a pharmacodynamic biomarker in MS and ALS. The FDA's approval of Tofersen for SOD1-ALS based on NfL reduction underscores its growing acceptance as surrogate marker. However, challenges remain in standardizing assays, interpreting clinical correlations, low specificity and understanding the dynamics between CSF and blood NfL levels. Addressing these issues is crucial for maximizing NfL's potential in neurodegenerative disease management.

A case series on endometrial cancer in multipara and their prognostication based on IHC markers

Endometrial carcinoma is one of the leading gynecological malignancies across the globe. With advent of molecular analysis, establishing an accurate treatment plan and improving patient outcome has become eminent. In resource limited settings like India, surrogate IHC markers like hormonal receptor expression are congruous substitutes that aid to accurately predict patient prognosis. In this case series, expression of hormonal receptors in multiparous women and it’s association with patient outcome seen as disease free survival at a span of 2 years was compared. This study opines inclusion of hormonal receptors in evaluation of endometrial carcinoma patients to accurately comment on patient outcome.

Detailed Lipid Profiles and Lipid-related Residual Risk after 12-week 10 mg Rosuvastatin Treatment for Acute Myocardial Infarction.

Objective We aimed to reveal detailed on-treatment lipid profiles, lipid-related surrogate markers, and factors predicting failure to achieve the guideline-recommended lipid management goal following guideline-recommended statin treatment in Japanese patients with acute myocardial infarction (AMI). Methods and Results Sixty AMI patients who underwent coronary intervention and had received rosuvastatin 10 mg/day since the start of their hospitalization were assessed for on-treatment lipid-related profiles, including high-sensitivity C-reactive protein, small dense low-density lipoprotein cholesterol (sd LDL-C), and lipoprotein (a), at the 12-week follow-up. Patients who failed to achieve the guideline-recommended lipid management at 12 weeks were defined as the "unachieved group." Univariate and multivariate logistic regression analyses were performed to evaluate the predictors of inclusion in the unachieved group after high-dose statin treatment. Despite the use of high-dose rosuvastatin, 61.7% of the enrolled AMI patients were included in the unachieved group. In addition, the unachieved group had higher sd LDL-C and lipoprotein (a) levels than the achieved group. Logistic regression analyses demonstrated that low baseline high-density lipoprotein cholesterol (HDL-C) levels and the absence of diabetes were predictors of inclusion in the unachieved group. Conclusion More than half of the Japanese AMI patients treated with rosuvastatin 10 mg/day did not achieve the guideline-recommended goal of lipid management and still had lipid-related residual risk at 12 weeks. Particular attention should be paid to patients with low baseline HDL-C levels and those without diabetes with regard to their on-treatment lipid profiles.

Cerebral Infarct Growth: Pathophysiology, Pragmatic Assessment, and Clinical Implications.

Cerebral ischemic injury occurs when blood flow drops below a critical level, resulting in an energy failure. The progressive transformation of hypoperfused viable tissue, the ischemic penumbra, into infarction is a mechanism shared by patients with ischemic stroke if timely reperfusion is not achieved. Yet, the pace at which this transformation occurs, known as the infarct growth rate (IGR), exhibits remarkable heterogeneity among patients, brain regions, and over time, reflecting differences in compensatory collateral flow and ischemic tolerance. We review (1) the pathophysiology of infarct growth, (2) the advantages and pitfalls of different approaches of IGR measurement, (3) research gaps for future studies, and (4) the clinical implications of stroke progressor phenotypes. The estimated average IGR in patients with acute large vessel occlusion stroke is 5.4 mL/h although there is wide variability based on ischemic stroke subtype, occlusion location, presence of collaterals, and patient baseline status. The IGR can be calculated using various pragmatic strategies, mostly either quantifying the extension of the infarct at a particular time and dividing this measure by the time that elapsed from symptom onset to imaging assessment or by using collateral blood flow status as a radiological surrogate marker. The IGR defines a spectrum of clinical stroke phenotypes, often dichotomized into fast and slow progressors. An IGR ≥10 mL/h and the perfusion metric hypoperfusion intensity ratio ≥0.5 are commonly used definitions of fast progressors. A nuanced understanding of the IGR and stroke progressor phenotypes could have clinical implications, including informing prognostication, acute decision-making in peripheral-to-comprehensive transfer patients eligible for thrombectomy, and selection for adjuvant neuroprotective agents.

Circulating levels of Low Density Granulocytes and cell-free DNA as predictors of cardiovascular disease and bone deterioration in SLE patients.

The present work evaluates the predictive value of low-density-granulocytes (LDG) for the development of cardiovascular disease (CVD) and/or bone deterioration (BD) in a six-year prospective study in Systemic Lupus Erythematosus (SLE). Considering the high SLE-LDG capacity to form Neutrophil Extracellular Traps (NETs), circulating levels of total cell-free DNA (cirDNA) and relative amounts of mitochondrial and nuclear DNA (mtDNA and nDNA, respectively) were tested as LDG-associated biomarkers to identify SLE patients at risk of CVD and BD. To this end, the frequency of total blood LDGs, as well as the CD16negCD14neg (nLDG) and CD16posCD14low (pLDG) subsets, was quantified by flow cytometry in 33 controls and 144 SLE patients. Total cirDNA and relative amounts of mitochondrial (mtDNA) and nuclear (nDNA) cell-free DNA were measured by fluorometry or qPCR in plasma from a subgroup of 117 patients and 23 controls at enrolment. Our findings showed increased blood levels of SLE-nLDGs at enrolment associated with prospective CVD development (pCVD) and the presence of BD, thus revealing LDG expansion as a predictor of both comorbidities in SLE progression. The amounts of the different types of circulating DNA analysed were increased in patients, especially those presenting traditional CV-risk factors or subclinical atheromatosis. Similar to nLDGs, the nDNA concentration could predict the development of pCVD in SLE, supporting the quantification of cirDNA levels as a surrogate marker of LDGs in clinical practice.

Association Between Zinc Status and Insulin Resistance/Sensitivity Check Indexes in Gestational Diabetes Mellitus

Gestational diabetes mellitus (GDM) is considered the most common metabolic disorder of the pregnancy period. It is characterized by pancreatic beta-cell dysfunction in the setting of chronic insulin resistance. Zinc is a nutrient involved in numerous metabolic processes and shows a relationship with glycometabolic disorders and GDM. The latest data have demonstrated the association of zinc with insulin sensitivity and resistance. The exact role of zinc in the connection with indexes of insulin resistance and insulin sensitivity is still not fully clarified. The aim of the study is to analyze the newly calculated indexes Glu/Zn, Ins/Zn, and HOMA-IR/Zn as surrogate markers to explore the correlation between serum zinc status and some indexes of insulin sensitivity and insulin resistance. The possible role of these indexes as markers of insulin resistance in pregnant women was analyzed too. An ROC analysis demonstrated that HOMA-IR/Zn with AUC 0.989, p < 0.001 (95% CI 0.967–1.000) and Ins/Zn with AUC 0.947, p < 0.001 (95% CI 0.889–1.000) in the GDM group, and only HOMA-IR/Zn index with AUC 0.953, p < 0.001 (95% CI 0.877–1.000) in healthy pregnant women, have good power as markers of insulin resistance in both groups. We speculate that these new ratios could be suitable for the assessment of pregnant women at high risk of insulin resistance development and, probably, for the evaluation of the specific pathophysiologic characteristics of women with GDM.

Suggested guide to using lactate gap as a surrogate marker in the diagnosis of ethylene glycol overdose.

Ethylene glycol (EG) poisoning, if not diagnosed rapidly, can lead to poor patient outcomes. Gas Chromatography (GC) is primarily used for EG quantitation which is rarely available, and the turn-around time may be prolonged. Most lactate results from point-of care (POCT) methods are falsely elevated in EG poisoning compared with automated chemistry analyser results. In combination the lactate gap (POCT-Automated chemistry) can be used as surrogate marker in just about all laboratories to indicate likely EG toxicity and guide treatment. A male presented by ambulance to hospital with severe agitation requiring mechanical ventilation to facilitate ongoing management. Venous blood gas analysis confirmed a high anion gap metabolic acidosis (HAGMA) with an elevated lactate. The lactate and osmolarity measured in the laboratory showed a normal lactate and high osmolarity, giving a large osmolar gap. The patient was immediately commenced on renal replacement therapy for presumed EG poisoning to minimize kidney injury, and the treatment continued for 19 hours. A very high EG concentration was confirmed by GC the next day. An elevated lactate gap along with a HAGMA and osmolar gap can provide rapid surrogate laboratory data indicating EG poisoning enabling timely treatment and better patient outcomes.

Development of clinical questions and outcomes on Clinical Practice Guideline of Fire Needling Therapy for Herpes Zosters

To develop the clinical questions and outcomes of Clinical Practice Guideline of Fire Needling Therapy for Herpes Zosters based on Norms of Formulation and Evaluation for the Clinical Guideline on Acupuncture and Moxibustion released by World Federation of Acupuncture and Moxibustion Societies. Combined the investigation with expert consultation and consensus method, and taken clinicians (members) of Chinese Association of Acupuncture and Moxibustion as the subjects, the clinical questions concerned were collected and the two-round consultation was conducted among expert group by letter. In the first round questionnaire, using the voting method, the relevant clinical questions in intervention measures were collected; and in the second round, with the Delphi method adopted, the importance of clinical questions and outcomes in the investigation was scored. A total of 200 structured clinical questions proposed by 153 clinicians and the clinical experience with 13 kinds of combined therapies involved and fire needling as the key measure were collected. The authority coefficient (Cr) of the Delphi questionnaire was >0.70, and the coefficient of variation for the importance scores of alternative clinical questions and outcomes was 0.06-0.26 and 0.12-0.47, respectively. The top 10 clinical questions and 12 outcomes (6 outcomes referred to the patients either in the acute stage or the post-neuralgia stage) were included, with the importance score of clinical questions>4, the importance score of outcomes>6, and the coefficient of variation ≤0.25. The clinical questions and outcomes of Clinical Practice Guideline of Fire Needling Therapy for Herpes Zosters are formulated, which provides the research basis for the recommendation development of the guideline.

Do sociodemographic and health predictors affect the non-insulin-based insulin resistance index? A cross-sectional study.

Insulin resistance (IR) is considered a risk factor for cardiovascular diseases (CVD). Therefore, early diagnosis of IR is clinically significant for primary and secondary CVD prevention initiatives. In addition, non-insulin metabolic indices may be useful for diagnosing IR. The first objective was to estimate the triglyceride and glucose (TyG) index and the metabolic score for insulin resistance (METS-IR) index values in a local community with high social deprivation and increased cardiovascular risk according to the Systematic Coronary Risk Evaluation scale. The second objective was to identify significant sociodemographic and health predictors for the TyG index and METS-IR index. This cross-sectional study was conducted in the local community of Janów district in eastern Poland and consisted of 2 stages. The 1st stage involved basic research (n = 4,040), while the 2nd stage involved enhanced diagnostics (n = 2,657). Data from the 2nd stage was used for the analyses. Anthropometric and physiological measurements were taken, blood was drawn for laboratory tests, selected sociodemographic and health variables were evaluated, and the TyG index and METS-IR index were calculated. The mean TyG index score in the study group was 8.65 (±0.58), and the mean METS-IR index score was 41.45 (±9.02). Both indices were significantly associated with age, male sex, smoking, and systolic blood pressure (SBP) in a multivariable model. In addition, alcohol consumption and body mass index (BMI) were significantly correlated with the TyG index, whereas education was significantly associated with the METS-IR index. Our results show the association between IR and sociodemographic and health variables in a group with a high social deprivation rate and increased cardiovascular risk. Early detection of cardiometabolic risk is important for both primary and secondary CVD prevention. In primary healthcare, this can be accomplished through surrogate markers of IR.

Abstract 4138332: Lipoprotein (a), Triglyceride-Glucose Index and Incident Atherosclerotic Cardiovascular Disease (ASCVD): Analysis of the UK Biobank

Background: The triglyceride-glucose index (TyG), an inexpensive novel surrogate marker for insulin resistance, and lipoprotein (a) [Lp(a)] are both risk factors for atherosclerotic cardiovascular disease (ASCVD). However, it is uncertain whether TyG modifies the relationship of Lp(a) with incident ASCVD. Objective: To investigate the relationship of Lp(a) and TyG with the risk of incident ASCVD. Methods: We included UK Biobank participants without ASCVD at enrollment. Baseline TyG was calculated as ln[fasting triglycerides (mg/dL) × fasting plasma glucose (mg/dL)/2]. We classified TyG values as high (≥75th percentile) or low (<75th percentile), and Lp(a) levels, in nmol/L, as <125 or ≥125. Participants were then stratified into four groups: Group-1: Low TyG with Lp(a), <125, Group-2: Low TyG with Lp(a) ≥125, Group-3: High TyG with Lp(a) <125, and Group-4: High TyG with Lp(a) ≥125. We used multivariable Cox regression to estimate the risk of ASCVD (a composite of peripheral arterial disease, coronary artery disease, myocardial infarction, ischemic stroke, and cardiovascular mortality) of TyG and Lp(a) adjusted for the other, and in the four combination groups. Results: Eligible participants (N=254,377) had a mean (SD) age of 56.0 (8.1) years, and 53.2% were female. The median follow-up was 14.6 years. In separate models additionally adjusted for cardiovascular risk factors (see Figure legend), the hazard ratio (HR [95% CI]) for ASCVD was 1.18(1.13–1.23) for Lp(a) ≥125 nmol/L (vs. <125 nmol/L), adjusted for TyG, and 1.09(1.05–1.13) for high TyG (vs. low), adjusted for Lp(a). A statistically significant interaction between TyG and Lp(a) was observed in the fully adjusted model (p <0.001). Compared to Group-1 (low TyG with Lp(a) <125nmol/L), the adjusted HR (95% CI) of incident ASCVD in Group-2, -3 and -4 were: 1.07(1.04–1.13), 1.15 (1.09–1.21) and 1.34(1.25–1.44), respectively (Figure). Conclusions: These findings demonstrate that TyG and Lp(a) are associated with incident ASCVD risk independently of each other. Moreover, TyG modified the effect of Lp(a) on ASCVD, suggesting that insulin resistance may amplify the atherogenic, inflammatory, and/or thrombotic effects of Lp(a), thereby further increasing ASCVD risk.

Abstract 4141457: Forms of Childhood Maltreatment and Subclinical Cardiovascular Disease Risk in Black men and women

Background: Exposure to specific forms of childhood maltreatment have been associated with cardiovascular disease (CVD) risk factors and CVD events in adulthood. Heterogenous experiences of childhood maltreatment across race and sex exist, yet there is little evidence regarding these relationships and CVD risk in Black populations. Aims: To investigate the association between various forms of childhood maltreatment (emotional, general, physical, and sexual abuse) and surrogate markers of vascular dysfunction and test whether sex modify these associations. Methods: Forms of childhood maltreatment and indices of vascular function were assessed in a cohort of healthy Black adults without known CVD (n=404) from a large metropolitan southeastern city. Childhood maltreatment was assessed using the Early Trauma Inventory short form (ETISR-SF) consisting of physical, sexual, emotional, and general domains. A trauma severity index score was calculated by summing the indexes for each of the four domains. Higher scores are indicative of higher traumatic life events before age 18 years. Outcomes of central augmentation index (cAIx) corrected for a heart rate of 75 bpm and carotid femoral pulse wave velocity (CfPWV) were measured as indices of wave reflections and arterial stiffness using applanation tonometry (Sphygmocor Inc.), and central pulse pressure (CPP) was calculated as the difference between the aortic systolic and diastolic blood pressures. Associations between each domain and outcomes were assessed using multivariate-adjusted and sex-stratified linear regression models. Results: Mean age of the cohort was 53 + 10.3 years, 61% women. Exposure to emotional [ b = -1.5%, 95%CI: -2.7,-0.3] and physical abuse [ b = -1.3%, 95%CI: -2.5,-0.2] was associated with cAIx overall but not CPP or CfPWV after adjusting for sociodemographic, clinical factors, health behaviors, and depressive symptoms. Significant emotional abuseXsex ( P= 0.014) and physical abuseXsex ( P=< 0.001) interactions were identified for cAIx. Among women, physical abuse was associated with higher cAIx [ b =1.5%, 95%CI: 0.6, 2.4] and among men emotional [ b =-1.6%, 95%CI: -3.2, -0.0] and physical [ b =-1.7%, 95%CI: -3.1, -0.3] abuse was associated with lower cAIx. Conclusions: Exposure to emotional and physical abuse as children was associated with vascular dysfunction; moreover, exposure to physical abuse among women and not men have adverse clinical implications for CVD risk and prospects for enhanced preventive care.

Association of phenylalanine and tyrosine metabolism with mortality and response to nutritional support among patients at nutritional risk: a secondary analysis of the randomized clinical trial EFFORT

BackgroundElevated phenylalanine serum level is a surrogate marker of whole-body proteolysis and has been associated with increased mortality in critically ill patients. Tyrosine is a metabolite of phenylalanine and serves as a precursor of thyroid hormones and catecholamines with important functions in the oxidative stress response among others. Herein, we examined the prognostic significance of phenylalanine, tyrosine, as well as its metabolites nitrotyrosine, L-3,4-dihydroxyphenylalanine (DOPA), and dopamine regarding clinical outcomes and response to nutritional therapy in patients at nutritional risk.MethodsThis is a secondary analysis of the Effect of Early Nutritional Support on Frailty, Functional Outcomes, and Recovery of Malnourished Medical Inpatients Trial (EFFORT), a randomized controlled trial investigating individualized nutritional support compared to standard care in patients at risk of malnutrition. The primary outcome was 30-day all-cause mortality.ResultsWe analyzed data of 238 patients and found a significant association between low plasma levels of phenylalanine [adjusted HR 2.27 (95% CI 1.29 to 3.00)] and tyrosine [adjusted HR 1.91 (95% CI 1.11 to 3.28)] with increased 30-day mortality. This association persisted over a longer period, extending to 5 years. Additionally, trends indicated elevated mortality rates among patients with low nitrotyrosine and high DOPA and dopamine levels. Patients with high tyrosine levels showed a more pronounced response to nutritional support compared to patients with low tyrosine levels (HR 0.45 versus 1.46, p for interaction = 0.02).ConclusionIn medical inpatients at nutritional risk, low phenylalanine and tyrosine levels were associated with increased short-and long-term mortality and patients with high tyrosine levels showed a more pronounced response to nutritional support. Further research is warranted to gain a deeper understanding of phenylalanine and tyrosine pathways, their association with clinical outcomes in patients at nutritional risk, as well as their response to nutritional therapy.Clinical trial registrationwww.clinicaltrials.gov, identifier NCT02517476.

Logistic organ dysfunction system as an early risk stratification tool after aneurysmal subarachnoid hemorrhage

AbstractAneurysmal subarachnoid hemorrhage (aSAH) not only causes neurological deficits but also influences extracerebral organ functions. The Logistic Organ Dysfunction System (LODS) reliably captures organ dysfunctions and predicts mortality of critically ill patients. This study investigated LODS in the setting of aSAH as a surrogate marker for early brain injury (EBI). Patients with aSAH treated between 2012 and 2020 were retrospectively analyzed. LODS was calculated within 24 h upon admission applying functional parameters for each organ system. The EBI was evaluated based on 1-persistent loss of consciousness, 2-global cerebral edema, and 3-intracranial blood burden. The outcome was assessed with the modified Rankin scale (mRS) at 3-months after ictus (mRS > 2 = unfavorable outcome). A total of 324 patients with a mean age of 55.9 years were included. Severe EBI (EBI grade ≥ 3) was found in 38% (124/324) of patients. Higher LODS score correlated with severe EBI (p < 0.0001) and poor outcome (p < 0.0001). LODS with a cutoff of 7 allowed a reliable discrimination (AUC 78%, p < 0.0001) of patients with severe from those with mild EBI. The LODS-calculation as an early risk stratification and prognostic tool reliably reflected the severity of EBI after aSAH and correlated with outcome.

Hard-to-treat autoimmune hepatitis and primary biliary cholangitis: The dawn of a new era of pharmacological treatment.

Patients with hard-to-treat autoimmune hepatitis (AIH) or primary biliary cholangitis (PBC) are defined a posteriori as those who do not show a sufficient response or are intolerant to pharmacological treatments, thus not achieving biochemical surrogate endpoints that are associated with long-term liver-related-event-free survival. The absence of a recently harmonized definition of 'complete biochemical response within 6 months (CBR≤6M)', which is defined as the normalization of serum transaminase and IgG levels below the upper limit of normal (ULN) at ≤6 months after treatment initiation is regarded as hard-to-treat AIH. The implementation of CBR≤6M, in turn, has been facilitating clinical trials, e.g., between azathioprine and mycophenolate mofetil, to reconsider appropriate first-line steroid sparing agents, leading to a reduction in the number of hard-to-treat AIH cases. Regarding PBC, one of the disseminated definitions of hard-to-treat patients is the absence of POISE criteria, which are evaluated at 12 months with serum alkaline phosphatase and bilirubin levels, after the introduction of ursodeoxycholic acid. Hard-to-treat PBC not meeting the POISE criteria has very recently been the target population for the U.S. FDA-approved second-line drugs, elafibranor and seladelpar. In future pharmacological treatment of AIH and PBC, the primary objective for AIH is likely to focus on lowering the number of hard-to-treat patients with personalized steroid sparing treatment regimens. A challenging goal in PBC treatment is the further optimization of treatment surrogate endpoints, even to the stricter ALP normalization, with which an indication of second- or later-line drugs might be expanded, but could ultimately lengthen patients' long-term survival.

BIOM-11. PROGNOSTIC VALUE OF H3K27ME3 AND EZH2 IN ASTROCYTOMA, IDH-MUTANT

Abstract BACKGROUND H3K27 trimethylation (H3K27me3), catalyzed by EZH2, regulates gene expression through epigenetic mechanisms. H3K27me3 is used as a surrogate marker in pathology for diffuse midline glioma, ependymoma. However, the clinical value of H3K27me3 and EZH2 in astrocytoma, IDH-mutant has not been reported. The aim of this study was to evaluate the clinical significance of H3K27me3 and EZH2 in astrocytoma, IDH-mutant. METHODS A total of 30 patients with astrocytoma, IDH-mutant treated at our institute were included. The patients were divided into 2 groups according to the expression of immunohistochemistry (IHC) for H3K27me3. The following factors were analyzed; age, WHO grade, IHC for EZH2, CDKN2A status, ki67-index and extent of resection. The CDKN2A status was diagnosed by IHC for MTAP and was confirmed by NGS-based CGP test in some cases. Kaplan–Meier analysis and Cox regression analysis were performed to analyze overall survival (OS) and progression-free survival (PFS). RESULTS According to WHO classification 2021, astrocytomas were classified as follows: WHO grade2: 20 cases, grade 3: 2 cases, grade 4: 8 cases. Seventeen patients were identified as H3K27me3 positive, while fourteen patients were classified as H3K27me3 negative. The proportion of WHO grade 3 or 4 and ki-67 index were significantly higher in the H3K27me3 positive group (p=0.0011, 0.0036, respectively). OS and PFS were significantly longer in H3K27me3 positive group (p=0.0379, 0.0025). Furthermore, in the analysis of WHO grade 2/3, double-positive expression of H3K27me3 and EZH2 showed significantly shorter PFS and OS than the other group (p=0.0114 and 0.0068, respectively). In Cox regression analysis, H3K27me3 showed the highest likelihood ratio for OS (p=0.01061). CONCLUSIONS In Astrocytoma, IDH-mutant, the H3K27me3 positive group showed poor prognosis than H3K27me3 negative group. In addition, patients with double-positive expression of H3K27me3 and EZH2 demonstrated more unfavorable prognosis. H3K27me3 and EZH2 could be prognostic markers for astrocytoma, IDH-mutant.