Measures Of Systemic Inflammation Research Articles

Global Leadership Initiative on Malnutrition cachexia: an inflammation-first approach for the diagnosis of disease-related malnutrition.

The following article examines the rationale for an inflammation-first approach for diagnosing cachexia and how the current Global Leadership Initiative on Malnutrition (GLIM) framework may be adapted to facilitate this. Recently, the GLIM have published guidance on the measurement of inflammation in the context of cachexia, advocating that C-reactive protein (CRP) should be utilized for quantification. The inclusion of a systemic inflammatory biomarker for the diagnosis of cachexia questions whether it may be more aptly considered a systemic inflammatory syndrome. The current consensus of the GLIM is that cachexia is 'disease-related malnutrition with inflammation'. In line with this definition, the GLIM proposed a two-step diagnostic framework: screening for malnutrition using validated screening tools and then confirming the presence of disease-related malnutrition with phenotypic (nonvolitional weight loss, low BMI, and reduced muscle mass) and aetiologic criterion reduced food intake/assimilation, and inflammation or disease burden). The GLIM are to be commended for guidance on the measurement of systemic inflammation in their current proposal, given the relative importance to clinical outcomes in patients with cancer. However, the use of CRP is somewhat rudimentary and contrasts other cancer cachexia guidelines and contemporary clinical cancer research.

Study of C-reactive Protein Levels in Hypertensive Disorders of Pregnancy.

Introduction Globally, one of the main causes of maternal and perinatal deaths is hypertensive disorders of pregnancy (HDP). Preeclampsia is a pregnancy-specific syndrome characterized by high blood pressure and proteinuria after 20-week gestation. Women who develop preeclampsia are at increased risk for the development of many systemic complications. Materialsandmethods A cross-sectional study was conducted in the Department of Biochemistry, SHKM, Nuh, Haryana in collaboration with the Department of Obstetrics & Gynecology. 200 study subjects; Group 1: cases - 100 HDP, Group 2: controls - 100 age-matched normotensive pregnant women. The specimen of 3 mL venous blood was collected under aseptic precautions. The data was evaluated using statistical evaluation tools. Result Out of 200 subjects, mean C-reactive protein (CRP) levels were normal in three cases and 35 controls. Minor elevation of CRP was observed in 11 cases and 29 controls (very significant). Moderate elevation of CRP was observed in 61 cases and 36 controls (highly significant). Marked elevation of CRP was observed in 25 cases. Mean CRP levels increased from preeclampsia without severe features (3.9 mg/dL), preeclampsia with severe features (5.2 mg/dL), and eclampsia (12.7 mg/dL) when compared with the respective control group (1.1 mg/dL, 1.16 mg/dL, and 1.2 mg/dL). Conclusion There is a highly significant association between CRP levels and HDP. Additionally, one useful indicator of the severity of preeclampsia is CRP, a measure ofsystemic inflammation. Elevated CRP levels in mild PE can be used as an indicator of the progress of the disease and early prevention can be done.

Neutrophil lymphocyte ratio and heart type fatty acid binding protein as a prognostic marker in Myocardial infarction within 48h of admission.

The neutrophil to lymphocyte ratio (NLR) is a measure of systemic inflammation, whereas Heart type fatty acid protein (HFABP) is a cytosolic protein released early after acute coronary syndrome (ACS). The aim of this research study is to determine whether NLR and H-FAB are useful in predicting the prognosis in patients with ST segment elevation myocardial infarction (STEMI) 48h after admission. This is a prospective observational study conducted on 97 patients who had been admitted to emergency room with ST-elevation myocardial infarction in their ECG in a tertiary care centre of south India. The neutrophil-lymphocyte ratio was measured at the time of admission, 24th hour and 48th hour, and then compared with the outcome. To determine their significance in the MI episode, troponin-I and H-FABP were also measured. A significant correlation was found in the final outcomes of patients and the NLR at the time of admission and at 48h (p = 0.01). Additionally, a substantial correlation between NLR and various degrees of LV dysfunction was also observed (p = 0.01). H-FABP was found to be positive in all 97 of the patients examined, whereas Troponin-I was only found to be positive in 56.7%. The study's findings, indicated strong correlations between NLR and LVEF, indicated that NLR might serve as an early predictor of cardiac events which could be either poor prognosis or higher mortality. This research found that H-FABP may serve as an early MI diagnostic marker.

Neutrophil percentage-to-albumin ratio is a new diagnostic marker for spontaneous bacterial peritonitis: a prospective multicenter study

BackgroundThe neutrophil percentage-to-albumin ratio (NPAR) is a novel measure of systemic inflammation and infection. Low albumin levels increase the risk of infection, while high neutrophil counts indicate the presence of infection. Spontaneous bacterial peritonitis (SBP) is a serious infection in cirrhotic ascites, and the potential of NPAR in diagnosing SBP is not yet established.ObjectiveThe objective of this study is to determine the diagnostic value of NPAR in identifying SBP.PatientsThis prospective multicenter study included 465 patients diagnosed with cirrhotic ascites and SBP according to international guidelines. Demographic, clinical, and laboratory data were collected. The sensitivity and specificity of NPAR values for diagnosing SBP were assessed using the receiver operating characteristic curve.ResultsFor SBP diagnosis in the total cohort, NPAR of > 17 had a sensitivity of 85.71%, specificity of 66.67%, and 95% CI (42.1–99.6). In culture-positive SBP, the NPAR at a cut-off > 5.2 had a sensitivity of 85.71%, specificity of 83.33%, and 95% CI (0.709 to 0.979), while in culture-negative SBP, the NPAR at a cut-off > 2.1 had a sensitivity of 92.86%, specificity of 33.33% and CI (0.367 to 0.764). The multivariate analysis revealed that albumin (OR = 2.78, [1.11;3.98], INR (OR = 0.198, [0.066;0.596], creatinine (OR = 0.292, [0.1; 0.81], CRP (OR = 3.18, [1.239;4.52] total leukocytic count (TLC) (OR = 1.97, [1.878; 2.07], platelets (OR = 2.09, [0.99; 2.31] and neutrophil (OR = 3.43, [1.04;3.89] were significantly associated with higher prediction rates for culture positive SBP.ConclusionsNPAR could be a new, affordable, noninvasive test for diagnosing SBP.

Relationship Between Neutrophil-Lymphocyte Ratio and Treatment Retention in Individuals with Opioid Use Disorder

IntroductionInflammatory processes may play a role in the pathophysiology of substance use disorders. Chronic opiate use may lead to inflammation, and elevated inflammation markers have been observed in individuals with opioid use disorder (OUD). The Neutrophil-Lymphocyte Ratio (NLR) serves as an indicator of systemic inflammation. NLR can be employed in both diagnosis and treatment monitoring as an inflammatory marker to gauge the severity of OUD.ObjectivesOur aim was to assess the utility of NLR as a marker of chronic inflammation in diagnosing and monitoring treatment in individuals with OUD.MethodsA total of 200 patients with OUD and 78 healthy control subjects were enrolled in the study. Patients were initially admitted to a 28-day abstinence-based inpatient program and subsequently transitioned to outpatient buprenorphine/naloxone (B/N) maintenance treatment after hospitalization at the Alcohol and Substance Addiction Treatment Center in Trakya University School of Medicine (Edirne, Türkiye). NLR was employed as a measure of systemic inflammation. Blood samples were collected the morning following admission for detoxification. Patients were categorized into two groups: the treatment retention group and the dropout/relapse group based on their 3-month and 12-month follow-up results. Clinical data were obtained from patient records.ResultsAt the 3-month follow-up, the median NLR with interquartile range was 1.34 (1.05-1.99) in the treatment retention group (n=112) and 1.72 (1.11-2.46) in the dropout/relapse group (n=88). At the 12-month follow-up, the median NLR with interquartile range was 1.28 (0.88-1.85) in the treatment retention group (n=52) and 1.56 (1.07-2.33) in the dropout/relapse group (n=148). The median NLR in the control group (n=78) was 1.36 (1.12-1.74). According to the 3-month and 12-month follow-up data, the difference between the groups concerning NLR was statistically significant (χ2=9.072, p=0.011; χ2=11.165, p=0.004; respectively). Pairwise comparisons indicated that patients in the dropout/relapse group had significantly higher baseline NLR values than those in the treatment retention group and healthy controls according to the 3-month (p=0.038 and p=0.019, respectively) and 12-month follow-up data (p=0.012 and p=0.040, respectively). NLR did not differ significantly between the treatment retention and control groups in both follow-ups (p>0.05).ConclusionsOur findings suggest that elevated baseline NLR is associated with dropout/relapse in OUD, indicating its potential as a marker for treatment follow-up in these patients.Disclosure of InterestNone Declared

BIOPSYCHOSOCIAL DETERMINANTS OF COGNITIVE FUNCTION AMONG BLACK OLDER ADULTS

Abstract Black older adults in the United States have twice the risk of being diagnosed with Alzheimer’s disease and related dementias than their white counterparts. However, there remains a gap in knowledge of which factors may contribute to this disparity as well as mechanisms that either increase or decrease risk for poor cognitive outcomes, specifically in older Black adults. This presentation will highlight recent interdisciplinary population health research on the biopsychosocial determinants of cognitive function among Black adults 65 years and older in the Health and Retirement Study. Using within-group regression analyses, studies examine associations between multiple measures across neighborhood, psychosocial, and biomarker domains with cognitive function, measured by Telephone Interview for Cognitive Status scores (range: 0-35) which captures memory and overall mental status. We find that high neighborhood disorder and low social cohesion were associated with worse cognitive function, especially for more highly educated Black older adults and those living in urban communities. Greater frequency of experiences of everyday discrimination among Black older adults was also related to lower cognitive function. Volunteering and having a high sense of purpose in life were associated with better cognitive function for older Black men and women, while being physical active was associated with increased cognitive function for older Black women. C-reactive protein, a measure of systemic inflammation, was positively associated with cognitive function. Overall, this body of work demonstrates the need to further critically assess both risk and resilience processes underlying cognitive function among older Black adults towards reducing current cognitive health inequities.

Post-Hypofractionated Radiotherapy Neutrophil-to-Lymphocyte Ratio in Soft Tissue Sarcomas is a Prognostic Biomarker of Recurrence and Distant Metastases

The neutrophil-to-lymphocyte ratio (NLR) is a measure of systemic inflammation, and known to be prognostic of outcomes and treatment response across different cancer types, including soft tissue sarcomas (STS). Our study aims to determine if in patients with STS treated with pre-operative hypofractionated radiotherapy (HFRT), post-RT NLR is prognostic of recurrence, metastasis, and overall survival. We performed a single-center retrospective analysis of patients treated pre-operatively with 30 Gy in 5 fractions between 2016 and 2023. Clinical, demographic, radiation therapy (RT), and complete blood count (CBC) data were collected from medical records. The NLR calculation was performed by dividing the absolute neutrophils count by the absolute lymphocytes count. We dichotomized the variable into NLR ≤4 and >4. The CBC utilized to calculate NLR was only used if done <6 months post-RT. For post-RT NLR outcomes associations, we used univariable and multivariable logistic regression analyses adjusting for age, gender, tumor size, and histology. For continuous variables we used mean ± standard deviation. Analyses were done with SPSS. A p-value <0.05 was considered significant. We identified 40 patients that received HFRT and had a CBC within 6 months after RT. The mean age was 66 ± 17.5 years. There were 17 (42.5%) females and 23 (57.5%) males. The histologies were myxofibrosarcoma (17.5%), leiomyosarcoma (7.5%), pleomorphic spindle cell sarcoma (10%), myxoid liposarcoma (5%). Other histologies with n<2 accounted for 65%. The mean tumor size was 7.1cm (± 6.4) and the mean NLR 5.3 ± 0.6. The median follow-up was 15.4 ±2.2 months. The patients with recurrence and metastases were the same {n = 13 (32.5%)}, and 3 patients died of disease. Univariable analyses for NLR > 4 showed increased recurrence and metastases (Odds ratio (OR): 8, CI 95% = {1.48 - 43.4}, p = 0.016). The multivariable analyses also showed that post-RT NLR > 4, was associated with increased recurrence and metastases (OR: 7.73, CI 95% = {1.17- 50.9}, p- value = 0.034). Age, gender, histology, and tumor size were not significant variables (Table 1). In both univariable and multivariable analyses NLR > 4 was not associated with decreased overall survival (p = 0.998). To our knowledge, this is the first study assessing the immune response using neutrophil-to-lymphocyte ratio as a prognostic biomarker in STS treated with pre-operative hypofractionated radiotherapy. In this population, an NLR > 4 was prognostic for recurrence and distant metastasis, but not for overall survival. This study highlights the need for a better understanding of the immuno-biological effects of RT, which should be further addressed in the context of clinical trials due to its simplicity and potential prognostic value.

Prognostic importance of neutrophil-lymphocyte ratio in non-dialysis chronic kidney disease patients—a hospital-based prospective cohort

Aim: In patients with cancer, ischemic heart disease, and peripheral vascular disease, the neutrophil-lymphocyte ratio (NLR), a measure of systemic inflammation, has been demonstrated to predict mortality. This study aimed to evaluate the inflammatory status, and also examine the impact of NLR on renal outcomes (mortality and composite endpoints) in non-dialysis chronic kidney disease (CKD) patients. Methods: This prospective cohort was conducted at a tertiary care public teaching hospital. The NLR greater than 3.53 was taken as an indication of systemic inflammation. The outcome measures include composite endpoints (end-stage renal disease, dialysis commencement, doubling serum creatinine from the baseline), and mortality. Kaplan-Meier plots and a multivariate Cox proportional hazard model were employed to analyze the outcomes. Results: A cohort of 360 patients aged 53.7 years ± 13.9 years had a median follow-up of 14 months ± 4.24 months and was evaluated for inflammatory status and renal outcomes. The proportion of inflammation was found to be 101 (28.7%). Higher NLR levels had shown an increased incidence of mortality (5.3%) and composite endpoints (12.3%). In reference to the NLR quartile (Q1), the highest quartile (Q4) had shown 3 times increased hazards for mortality and 95.0% increased risk of hazards for composite endpoints Q4 hazard ratio (HR) 3.09; 95% confidence interval (CI) 1.38–6.91 (P = 0.006), and Q4 HR 1.93; 95% CI 1.22–3.08 (P = 0.005), respectively. Higher NLR was positively associated with urea, creatinine, alkaline phosphatase, Pt-Global web tool©/Patient-Generated Subjective Global Assessment score and negatively correlated with estimated glomerular filtration rate, albumin, hemoglobin. Conclusions: NLR is a potential predictor of mortality and composite endpoints in CKD patients even before they undergo dialysis. Additionally, inflammation should be regarded as a common comorbid condition in CKD patients due to its high prevalence.

Remotely Supervised Weight Loss and Exercise Training to Improve Rheumatoid Arthritis Cardiovascular Risk: Rationale and Design of the Supervised Weight Loss Plus Exercise Training-Rheumatoid Arthritis Trial.

Patients with rheumatoid arthritis (RA) remain at an increased risk for cardiovascular disease (CVD) and mortality. RA CVD results from a combination of traditional risk factors and RA-related systemic inflammation. One hypothetical means of improving overall RA CVD risk is through reduction of excess body weight and increased physical activity. Together, weight loss and physical activity can improve traditional cardiometabolic health through fat mass loss, while also improving skeletal muscle health. Additionally, disease-related CVD risk may improve as both fat mass loss and exercise reduce systemic inflammation. To explore this hypothesis, 26 older persons with RA and overweight/obesity will be randomized to 16 weeks of a usual care control arm or to a remotely Supervised Weight Loss Plus Exercise Training (SWET) program. A caloric restriction diet (targeting 7% weight loss) will occur via a dietitian-led intervention, with weekly weigh-ins and group support sessions. Exercise training will consist of both aerobic training (150 minutes/week moderate-to-vigorous exercise) and resistance training (twice weekly). The SWET remote program will be delivered via a combination of video conference, the study YouTube channel, and study mobile applications. The primary cardiometabolic outcome is the metabolic syndrome Z score, calculated from blood pressure, waist circumference, high-density lipoprotein cholesterol, triglycerides, and glucose. RA-specific CVD risk will be assessed with measures of systemic inflammation, disease activity, patient-reported outcomes, and immune cell function. The SWET-RA trial will be the first to assess whether a remotely supervised, combined lifestyle intervention improves cardiometabolic health in an at-risk population of older individuals with RA and overweight/obesity.

Effect of early antibiotic exposure on survival of patients receiving atezolizumab plus bevacizumab but not sorafenib for unresectable HCC: A sub-analysis of the phase III IMbrave150 study.

597 Background: The combination of atezolizumab plus bevacizumab (A+B) is the standard of care for patients (pts) with unresectable/advanced hepatocellular carcinoma (HCC). Emerging evidence suggest a detrimental role of early antibiotics (ATB) exposure in immunotherapy recipients. However, it is unclear whether ATB affect outcomes of pts receiving A+B. Methods: We conducted a patient-level analysis of subjects receiving either A+B or Sorafenib (Sor) within the IMbrave150 trial to assess the impact of early ATB exposure (ATB+, i.e. +/-30 from treatment initiation) on overall (OS) and progression-free survival (PFS). Differences in median (m) OS and mPFS were estimated by the Kaplan-Meier method. Cox proportional regression models were used to assess the prognostic impact of ATB+ adjusting for race, age, baseline AFP, baseline ALBI grade, continent of origin and neutrophil-to-lymphocyte ratio, a measure of systemic inflammation. Results: Data of 420 IMbrave150 participants were made available by Vivli. Among them, 278 received A+B and 142 Sor. Most pts were of ECOG performance status 0 (65%); 47% had extrahepatic spread, 40% had macrovascular invasion and 35% had AFP&gt;400 ng/mL. Viral aetiology (39% HBV and 24% HCV) was the most common risk factor for HCC. Overall, 60 pts in the A+B arm (21.5%) and 31 (21.8%) in the Sor group were ATB+. Baseline characteristics were well balanced across ATB groups, except for region of origin, with a higher proportion of Asian pts in ATB+ (60% vs 45%; p=0.01). After a median follow-up of 10.38 months (95%CI:8.6-12.5), OS and PFS rates at 12 months were 72.3% and 9.7% in A+B; 64.8%, and 1.4% in Sor, respectively. ATB+ exposure was associated with increased risk of death both in univariate (HR 1.67; 95%CI 1.04-2.69) and multivariate models (HR 1.62; 95%CI 1.40-1.89) in the A+B (p for interaction &lt;0.001), but not in the Sor arm (univariate HR 0.63; 95%CI 0.32-1.25; multivariate HR 0.70; 95%CI 0.31-1.60). Similarly, the risk of progression was increased for ATB+ pts in the A+B arm (univariate HR 1.68; 95%CI 1.03-2.71; multivariate HR 1.59; 95%CI 1.40-1.81), but not in the Sor arm (univariate HR 0.51;95%CI 0.26-1.01; multivariate HR 0.53; 95%CI 0.21-1.30) with positive p for interaction (p=0.002). Objective response rate (ORR) according to RECIST v.1.1 did not differ between ATB+ (28.0%) and ATB- (30.0%) in A+B (p=0.68). Conclusions: In a post-hoc sub-analysis of IMbrave150 we demonstrate for the first time the negative impact of early antibiotics exposure on outcomes of patients receiving A+B but not in those treated with Sor. Prospective translational studies should evaluate the role of ATB-mediated gut dysbiosis as a proposed mechanism underlying the adverse outcome in immunotherapy-recipients.

MetfOrmin BenefIts Lower Extremities with Intermittent Claudication (MOBILE IC): randomized clinical trial protocol

BackgroundPeripheral artery disease (PAD) affects over 230 million people worldwide and is due to systemic atherosclerosis with etiology linked to chronic inflammation, hypertension, and smoking status. PAD is associated with walking impairment and mobility loss as well as a high prevalence of coronary and cerebrovascular disease. Intermittent claudication (IC) is the classic presenting symptom for PAD, although many patients are asymptomatic or have atypical presentations. Few effective medical therapies are available, while surgical and exercise therapies lack durability. Metformin, the most frequently prescribed oral medication for Type 2 diabetes, has salient anti-inflammatory and promitochondrial properties. We hypothesize that metformin will improve function, retard the progression of PAD, and improve systemic inflammation and mitochondrial function in non-diabetic patients with IC.Methods200 non-diabetic Veterans with IC will be randomized 1:1 to 180-day treatment with metformin extended release (1000 mg/day) or placebo to evaluate the effect of metformin on functional status, PAD progression, cardiovascular disease events, and systemic inflammation. The primary outcome is 180-day maximum walking distance on the 6-min walk test (6MWT). Secondary outcomes include additional assessments of functional status (cardiopulmonary exercise testing, grip strength, Walking Impairment Questionnaires), health related quality of life (SF-36, VascuQoL), macro- and micro-vascular assessment of lower extremity blood flow (ankle brachial indices, pulse volume recording, EndoPAT), cardiovascular events (amputations, interventions, major adverse cardiac events, all-cause mortality), and measures of systemic inflammation. All outcomes will be assessed at baseline, 90 and 180 days of study drug exposure, and 180 days following cessation of study drug. We will evaluate the primary outcome with linear mixed-effects model analysis with covariate adjustment for baseline 6MWT, age, baseline ankle brachial indices, and smoking status following an intention to treat protocol.DiscussionMOBILE IC is uniquely suited to evaluate the use of metformin to improve both systematic inflammatory responses, cellular energetics, and functional outcomes in patients with PAD and IC.Trial Registration: The prospective MOBILE IC trial was publicly registered (NCT05132439) November 24, 2021.

C-REACTIVE PROTEIN AND BRAIN MORPHOLOGY

Abstract The process by which aging leads to increased risk for Alzheimer’s disease and dementia is not entirely understood, but one hypothesized contributor is the occurrence of low-grade inflammation in older age. In this study, we examined how peripheral levels of C-reactive protein (CRP), a measure of systemic inflammation, relate to brain structure and diffusion in a group of older adult men. After excluding twenty-seven participants for confounding medical conditions, we analyzed a final sample of 426 community-dwelling men from the Vietnam Era Twin Study of Aging, who were assessed at average age 68 for plasma levels of CRP and underwent structural and diffusion brain imaging. Linear mixed models adjusting for family relatedness, age, medical morbidity, and BMI examined associations of CRP with whole brain volume, whole gray and white matter volumes, global fractional anisotropy (FA), and global mean diffusivity (MD). Higher CRP was related to lower whole brain volume (β = -.13, p = .006), including lower whole white matter volume (β = -.22, p &amp;lt;.001) but not whole gray matter volume (p = .08). Higher CRP was related to lower global FA (β = -.51, p = .012) but not global MD (p = .203). Regionally, a relationship of higher CRP to lower FA was found in the anterior thalamic radiation (β = -.51, p = .010), which is implicated in a variety of higher order cognitive processes. These results suggest a link between peripheral inflammation and lower white matter integrity in older adult men, the implications of which for cognitive aging and dementia should be further explored.

CORRELATES OF ELEVATED C-REACTIVE PROTEIN AMONG BLACK OLDER ADULTS: EVIDENCE FROM THE HEALTH AND RETIREMENT STUDY

Abstract Substantial evidence documents gender and racial disparities in C-reactive protein (CRP), a measure of systemic inflammation, among older adults. Yet, the comparative approaches of these studies may obscure distinct risk and protective factors associated with elevated CRP among older Black Americans. To pinpoint opportunities for intervention, this study utilizes a “within-group approach” to identify the sociodemographic, psychosocial, behavioral, and health-related determinants of elevated CRP among older Black women and men. The sample consisted of 2,420 Black respondents aged 51+ in the Health and Retirement Study (2006-2016). Gender-stratified, random effects logistic regression models were used to examine determinants of elevated CRP (&amp;gt;3.0 mg/L). More than 50% of Black women had elevated CRP, and we found that younger age, Medicaid, lower mastery, religiosity, overweight/obesity, physical inactivity, and ADLs contributed to elevated CRP among this group. In contrast, elevated CRP was reported among only 37.25% of Black men, for whom financial distress was associated with lower odds of elevated CRP; religiosity, less neighborhood cohesion, current smoking, overweight/obesity, ADLs, and more chronic conditions were associated with greater odds of elevated CRP among this group. Sociodemographic factors had a limited association with elevated CRP among older Black Americans. Rather, a range of psychosocial, behavioral, and health-related factors were more influential determinants of elevated CRP among older Black Americans. Most notably, findings demonstrate distinct determinants of CRP among Black women and men, underscoring the critical need to further evaluate the risk and protective mechanisms undergirding disparities among this aging population.

The mechanistic role of neutrophil lymphocyte ratio perturbations in the leading non communicable lifestyle diseases.

Inflammation plays a critical role in the development and progression of chronic diseases like type 2 diabetes mellitus, coronary artery disease, and chronic obstructive pulmonary disease. Inflammatory responses are indispensable for pathogen control and tissue repair, but they also cause collateral damage. A chronically activated immune system and the resultant immune dysregulation mediated inflammatory surge may cause multiple negative effects, requiring tight regulation and dampening of the immune response to minimize host injury. While chronic diseases are characterized by systemic inflammation, the mechanistic relationship of neutrophils and lymphocytes to inflammation and its correlation with the clinical outcomes is yet to be elucidated. The neutrophil to lymphocyte ratio (NLR) is an easy-to-measure laboratory marker used to assess systemic inflammation. Understanding the mechanisms of NLR perturbations in chronic diseases is crucial for risk stratification, early intervention, and finding novel therapeutic targets.We investigated the correlation between NLR and prevalent chronic conditions as a measure of systemic inflammation. In addition to predicting the risk of impending chronic conditions, NLR may also provide insight into their progression. This review summarizes the mechanisms of NLR perturbations at cellular and molecular levels, and the key inflammatory signaling pathways involved in the progression of chronic diseases. We have also explored preclinical studies investigating these pathways and the effect of quelling inflammation in chronic disease as reported by a few in vitro, in vivo studies, and clinical trials.

Correlates of Elevated C-Reactive Protein Among Black Older Adults: Evidence From the Health and Retirement Study.

Substantial evidence documents gender and racial disparities in C-reactive protein (CRP), a measure of systemic inflammation, among older adults. Yet, the comparative approaches of these studies may obscure distinct risk and protective factors associated with elevated CRP among older Black Americans. To pinpoint opportunities for intervention, this study utilizes a "within-group approach" to identify the sociodemographic, psychosocial, behavioral, and health-related correlates of elevated CRP among older Black women and men. The sample consisted of 2,420 Black respondents aged 51 and older in the Health and Retirement Study (2006-2016). Gender-stratified, random effects logistic regression models were used to examine correlates of elevated CRP (>3.0 mg/L). More than 50% of Black women had elevated CRP, and younger age, Medicaid, lower mastery, religiosity, overweight/obesity, physical inactivity, and activities of daily living (ADLs) contributed to elevated CRP among this group. In contrast, elevated CRP was reported among only 37.25% of Black men, for whom financial distress was associated with lower odds of elevated CRP; religiosity, less neighborhood cohesion, current smoking, overweight/obesity, ADLs, and more chronic conditions were associated with greater odds of elevated CRP among this group. Sociodemographic factors had a limited association with elevated CRP among older Black Americans. Rather, a range of psychosocial, behavioral, and health-related factors were more influential determinants of elevated CRP among older Black Americans. Most notably, findings demonstrate distinct correlates of CRP among Black women and men, underscoring the critical need to further evaluate the risk and protective mechanisms undergirding disparities among this aging population.

Ulcerated melanoma: Systems biology evidence of inflammatory imbalance towards pro-tumourigenicity.

Microscopic ulceration is an independent predictor of melanoma death. Here, we used systems biology to query the role of host and tumour-specific processes in defining the phenotype. Albumin level as a measure of systemic inflammation was predictive of fewer tumour-infiltrating lymphocytes and poorer survival in the Leeds Melanoma Cohort. Ulcerated melanomas were thicker and more mitotically active (with corresponding transcriptomic upregulated cell cycle pathways). Sequencing identified tumoural p53 and APC mutations, and TUBB2B amplification as associated with the phenotype. Ulcerated tumours had perturbed expression of cytokine genes, consistent with protumourigenic inflammation and histological and transcriptomic evidence for reduced adaptive immune cell infiltration. Pathway/network analysis of multiomic data using neural networks highlighted a role for the β-catenin pathway in the ulceration, linking genomic changes in the tumour to immunosuppression and cell proliferation. In summary, the data suggest that ulceration is in part associated with genomic changes but that host factors also predict melanoma death with evidence of reduced immune responses to the tumour.

Serum Albumin and Neutrophil-to-Lymphocyte Ratio, Two Independent Factor Predicting Survival in Patients with Follicular Lymphoma: A Multi-Institutional Retrospective Cohort of 741 FL, from the Latin American Lymphoproliferative Study Group (GELL)

Introduction: The neutrophil-lymphocyte ratio (NLR) is a measure of systemic inflammation that appears prognostic in different cancers. Although the exact mechanism remains to be elucidated, reduced lymphocyte intra tumor infiltration coupled with the formation of neutrophil extracellular traps (or NETosis) have been postulated as endogenous mechanisms for tissue damage and inflammation. Along this line, serum albumin has also been studied as a biomarker of inflammation and has been associated to prognosis in certain cancers. We have previously reported on the prognostic value of the NLR and serum albumin in diffuse large B-cell lymphoma (Villela, ASH meeting, 2019; Castro, ASH meeting, 2019) and peripheral T-cell lymphoma, not otherwise specified (Idrobo, ASH meeting, 2019), but nothing on follicular lymphoma (FL) yet. Therefore, we aim to investigate the role of different biomarkers on the prognosis of patients with FL diagnosed and managed in Latin America.Methods: We analyzed patients with FL diagnosed between 2010 and 2020 from 30 centers in 10 Latin American countries. The study outcomes were overall survival (OS) and progression-free survival (PFS) in relation to different biomarkers. Kaplan-Meier and log-rank test were used for survival analysis. Univariate and multivariate Cox regression analysis were used to estimate hazard ratios (HR) with a 95% confidence interval (CI) and adjusted to the Follicular Lymphoma International Prognostic Index (FLIPI) score. Outcomes with a p-value <0.05 were considered statistically significant.Results: We identified 939 FL patients; 741 were included for the final analysis (median age 58 y, female 52%). There was no significant correlation between the NLR and other clinical factors such as: age, clinical stage, histological FL grading, and chemotherapy regimen used. A cutoff of 2.15 for NLR was defined as the maximum point for sensitivity and specificity based on ROC analysis. Table 1 and 2 summarizes the results from the univariate and multivariate analysis for 2 years OS and PFS, respectively. Both, serum albumin <3.5 g/dL and a NLR >2.15 were independently associated with worse OS (adjusted, aHR 2.48 [1.26-4.91], p=0.009; and 2.55 [1.21-5.37], p=0.014) and PFS (aHR 1.62 [1.03-2.55], p=0.038; 2.22 [1.45-3.40], p<0.001), respectively. The lymphocyte:monocyte ratio (LMR) was not found to be prognostic for OS or PFS, although with a trend for worse PFS with a LMR ≤2.5. With a median follow of 43 months, (95% CI: 40-47), the survival rates in patients with FL and albumin <3.5 were OS of 83% (vs. 95%) and PFS of 70% (vs. 83%); whereas in patients with NLR >2.15 the survival rates were OS of 91% (vs. 96%) and PFS of 75% (vs. 88%) (Figures 1 and 2; table 3).Conclusions: In this study, serum albumin and NLR emerge as reliable predictors for survival for FL patients in Latin America. Although these markers have been associated to an increased inflammatory state in cancer patients; other factors such as poor nutritional status, and advanced disease stage due to delayed access to specialized cancer care in our region may have contributed to the observed outcome. Further studies are needed to better understand the role of these biomarkers on lymphoma care and to validate our findings. Lastly, we are currently working on evaluating these biomarkers on existing prognostic models and to improve prognostication for FL patients in Latin America. [Display omitted] DisclosuresOtero: ASTRA ZENECA: Current Employment. Ramirez-Ibarguen: Asofarma: Consultancy; MSD: Consultancy; Abbvie: Speakers Bureau; Astra Zeneca: Speakers Bureau; Janssen: Speakers Bureau; Roche: Speakers Bureau; Takeda: Consultancy, Speakers Bureau. Perini: Roche: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Speakers Bureau; MSD: Consultancy, Speakers Bureau; Janssen: Consultancy, Other: Travel/Accommodations/Expenses, Speakers Bureau; Takeda: Speakers Bureau; Abbvie: Consultancy, Other: Travel/Accommodations/Expenses, Speakers Bureau. Castillo: Abbvie: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy; Roche: Consultancy; TG Therapeutics: Research Funding.

Radiotherapy for Breast Cancer, Systemic Inflammation, and Cancer Recurrence

Post-radiotherapy lymphopenia is common. Higher neutrophil:lymphocyte ratio (NLR), a measure of systemic inflammation, has been associated with breast cancer recurrence after radiotherapy (RT) induced lymphopenia in patients with triple negative disease, a highly immunogenic subtype. However, tumor infiltrating lymphocytes are predictive of treatment response in all subtypes. The goal of this study was to determine if local breast RT is associated with an increased NLR, and if systemic inflammation is associated with breast cancer recurrence.We prospectively followed 177 women with Stage I-III breast cancer who were assessed with complete blood cell counts with differential before RT, the last week of RT, 3-6 weeks and 1-year post-RT. NLR was calculated at each time point. 35% of patients received 39.9 Gy in 15 fractions (fxs) with an 8.1 Gy simultaneous integrated boost while 65% received 50 Gy in 25 fxs with a 10-16 Gy boost. 44% of patients received supraclavicular RT. Wilcoxon rank sum tests were performed to determine changes in NLR over time and to compare NLRs among patients who did and did not recur. Univariate and multivariable analyses were performed to identify predictors of increased NLR at each time point, and generalized estimating equation models were performed to account for the correlated measures for recurrence free survival (RFS).53% of subjects were non-Hispanic White (NHW) and 44% were African American. 35% had Stage IIB-IIIC disease. 53%, 25%, and 22% of tumors were ER+/Her2-, Her2+, and triple negative, respectively. Median NLR significantly increased the last week of RT (3.45 range 0.78-42.50) relative to baseline (1.95 range 0.34-11.29; P < 0.001). On multivariable analysis, patients who were NHW (P = 0.02), had triple negative tumors (P = 0.03), or received higher total radiation doses (P = 0.007) had a significant acute systemic inflammatory response to RT, reflected in higher NLR the last week of RT. After RT was complete, median NLR for the entire cohort continued to be significantly higher than baseline measures up to 1 year-post RT (P < 0.005 for all comparisons). Median follow up was 56 months (range 8-167). 5-year RFS was 91.3%. There were no significant differences in NLR at each timepoint between patients who did and did not recur. In the multivariable model, treatment with supraclavicular RT was the only predictor of recurrence (P = 0.04).Our findings indicate a sustained impact of local breast RT on the systemic inflammatory response, particularly in NHW patients with triple negative tumors who receive conventional rather than hypofractionated RT. In this study with a low number of recurrences, NLR did not predict for RFS in our diverse population. However, the persistent inflammatory response detected in the blood during and long after local breast RT may contribute to long-term side effects which occur months to years after treatment.

Metformin therapy is not associated with the lower prevalence of ascending aortic aneurysm in diabetic patients.

Metformin therapy has previously been associated with reduced abdominal aortic aneurysm growth rate in diabetic patients and shown to suppress the formation and progression of abdominal aortic aneurysm in normoglycemic mice. Here, we investigated the association between Metformin treatment and prevalence of aneurysm in the ascending aorta (AscAA). A total of 734 patients undergoing open-heart surgery for AscAA and/or aortic valve disease were studied. Diabetes status and medication use were self-reported by the patients in a systematic questionnaire. Aortic dilatation was defined as an aortic root or ascending aortic diameter ≥4.0 cm. High-sensitivity C-reactive protein levels were assessed as a measure of systemic inflammation. We could confirm the inverse association between diabetes and AscAA prevalence (16% vs 43.9%, for diabetic and non-diabetic patients, respectively; Odds ratio 0.243; 95% CI, 0.129-0.460, P < 0.001). Furthermore, in diabetic patients, Metformin treatment was associated with lower high-sensitivity C-reactive protein levels. There was, however, no difference in the prevalence of AscAA among diabetic patients with and without Metformin treatment (16% vs 16% for treated and non-treated patients, respectively; OR 1.039; 95% CI 0.26-4.19, P = 0.957). Our data do not support a protective effect of Metformin therapy in AscAA formation. 161, 173.

Racial differences in the systemic inflammatory response to prostate cancer.

Systemic inflammation may increase risk for prostate cancer progression, but the role it plays in prostate cancer susceptibility is unknown. From a cohort of over 10,000 men who had either a prostate biopsy or transurethral resection that yielded a benign finding, we analyzed 517 incident prostate cancer cases identified during follow-up and 373 controls with one or more white blood cell tests during a follow-up period between one and 18 years. Multilevel, multivariable longitudinal models were fit to two measures of systemic inflammation, neutrophil-to-lymphocyte ratio (NLR) and monocyte-to-lymphocyte ratio (MLR), to determine NLR and MLR trajectories associated with increased risk for prostate cancer. For both measures, we found no significant differences in the trajectories by case/control status, however in modeling NLR trajectories there was a significant interaction between race (white or Black and case-control status. In race specific models, NLR and MLR values were consistently higher over time among white controls than white cases while case-control differences in NLR and MLR trajectories were not apparent among Black men. When cases were classified as aggressive as compared to non-aggressive, the case-control differences in NLR and MLR values over time among white men were most apparent for non-aggressive cases. For NLR among white men, significant case-control differences were observed for the entire duration of observation for men who had inflammation in their initial prostate specimen. It is possible that, among white men, monitoring of NLR and MLR trajectories after an initial negative biopsy may be useful in monitoring prostate cancer risk.