Elevated Serum C-reactive Protein Research Articles

Prognostic value of serum C-reactive protein level prior to second-line treatment in intermediate risk metastatic renal cell carcinoma patients.

e16065 Background: The later-line treatment of metastatic renal cell carcinoma (mRCC) has been drastically changing by the development of immune-oncology drugs and molecular targeted treatment in recent years. Although the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model is useful for second-line setting, this model has the problem that over 50% patients are classified as intermediate risk group. The aim of this study is to evaluate whether the serum C-reactive protein (CRP) levels prior to second-line treatment could divide intermediate risk group patients. Methods: We retrospectively reviewed 150 mRCC patients received second-line molecular targeted therapy. We assessed the prognostic impact of serum CRP levels prior to second-line treatment initiation to predict overall survival (OS) especially in intermediate risk group. Results: The median OS from second-line treatment of whole cohort and intermediate risk group were 24.6 (95%confidence interval, 95%CI:18.2-31.0) and 23.6 (95%CI:15.1-32.1) months. Thirty-three out of 82 (40%) intermediate risk patients demonstrated elevated baseline CRP levels. The median OS of elevated and non-elevated CRP group were 13.4 (95%CI:5.9-20.8) and 29.4 (95%CI:25.5-33.5) months, respectively (p = 0.001). The serum CRP elevation could predict prognosis in intermediate risk patients treated with second-line treatment (HR 2.5,95%CI:1.4-4.2, p = 0.001). Conclusions: The serum CRP levels at second-line treatment initiation could divide intermediate risk mRCC patients into two prognostic subgroups.

Elevated C-reactive Protein Levels Independently Predict the Development of Prediabetes Markers in Subjects with Normal Glucose Regulation.

Prediabetes is a precursor of diabetes and increases the risk of cardiovascular disease. Individuals with prediabetes reportedly have higher C-reactive protein levels, which is a risk factor for diabetes, relative to individuals with normal glucose regulation. Inflammation may play a role in the very early-phase deterioration of glucose metabolism, although there is insufficient knowledge regarding this relationship. Thus, we examined the association between serum C-reactive protein level and the development of three prediabetes markers. This study included 743 subjects with normal glucose regulation at baseline who completed oral glucose tolerance tests at baseline and after approximately 5 years. Subjects with a history of cardiovascular disease were excluded. During the 5-year follow-up, 55 subjects developed isolated impaired glucose tolerance (IGT; 2h-plasma glucose levels of 7.8-11.0 mmol/L), 24 subjects developed isolated impaired fasting glucose (IFG; fasting plasma glucose levels of 6.1-7.0 mmol/L), 3 subjects developed IFG plus IGT, and 53 subjects developed isolated elevated glycated hemoglobin levels (HbA1c; level of 41-47 mmol/mol). The multivariate analysis revealed that, relative to the lowest quartile, the highest serum C-reactive protein quartile was independently associated with an increased risk of developing isolated elevated HbA1c levels (odds ratio: 2.95, 95% confidence interval: 1.16-7.51, P=0.024) and marginally associated with an increased risk of developing impaired glucose tolerance plus diabetes. However, C-reactive protein levels were not associated with an increased risk of developing IFG. Elevated serum C-reactive protein levels independently predicted elevated HbA1c levels, but not IFG.

Clinicopathological features of clinical methotrexate-related lymphoproliferative disorders

Methotrexate (MTX) is one of the potent drugs for autoimmune diseases (ADs), especially for rheumatoid arthritis. Recent studies suggest that MTX should be immediately withdrawn when patients with AD develop lymphoproliferative disorder (LPD). However, biopsy cannot be performed for diagnosis because LPD regresses quickly after MTX withdrawal, thus making clinical MTX-LPD (c-MTX-LPD) challenging to diagnose. In this study, among the 28 patients with c-MTX-LPD, seven developed a proven LPD (p-LPD) after suspicious LPD (s-LPD) regression, six of which were Hodgkin lymphoma. Four of seven patients with p-LPD + died, whereas all patients with p-LPD– survived. The clinical manifestations indicative of p-LPD include fever, elevated serum C-reactive protein level, and soluble interleukin-2 receptor level. Anti-AD drugs did not appear to affect the pathogenesis of p-LPD development. P-LPD was not observed after 3 years from the time of s-LPD regression.

What Is the Diagnostic Accuracy of Alpha-Defensin and Leukocyte Esterase Test in Periprosthetic Shoulder Infection?

The diagnosis of periprosthetic joint infection (PJI) after total shoulder arthroplasty (TSA) is challenging, especially in patients with Cutibacterium (formerly Propionibacterium) acnes infection. Despite the increasing number of patients with PJI of the shoulder, there are still no robust data regarding diagnostic tests in detecting shoulder PJI. (1) What are the sensitivity, specificity, and negative- and positive-predictive values for the alpha-defensin enzyme-linked immunosorbent assay test in detecting PJI after TSA? (2) What are the diagnostic accuracies in detecting shoulder PJI for synovial alpha-defensin, leukocyte esterase Test, and serum C-reactive protein (CRP)? All patients with painful TSA, who underwent joint aspiration to validate or exclude a PJI, between July 2015 and February 2018 were enrolled in this single-center study. Further indications for aspiration were as follows: planned revision arthroplasty, early loosening and clinical signs of infections, especially serum CRP elevation. A total of 121 patients were aspirated to exclude or verify a PJI, and 16 patients were excluded. In all, 105 patients with a mean age of 68 years (± 12 years) were included for analysis. Patients who underwent TSA were considered aseptic or septic according to the Musculoskeletal Infection Society criteria. Twenty-four patients had a PJI, and the remaining 81 patients were in the aseptic group. The microbiologic evaluation including polymicrobial infection showed C. (formerly P.) acnes in 15 patients (63%). Synovial fluid was then analyzed using microbiology cultures, alpha-defensin immunoassay, and leukocyte esterase. The specificity, sensitivity, and positive-predictive and negative-predictive values were calculated for each test. The overall accuracy for alpha-defensin was 91% (95% confidence interval [CI], 84.4-96); sensitivity was 75% (95% CI, 53-90), specificity was 96% (95% CI, 90-99), negative predictive value was 93% (95% CI, 85-97), and positive predictive value was 86% (95% CI, 64-97). In contrast, the overall accuracy for leukocyte esterase was 76% (95% CI, 61-88), sensitivity was 50% (95% CI, 21-79), specificity was 87% (95% CI, 69-96), positive predictive value 60% (95% CI, 26-88) and negative predictive value was 81% (95% CI, 64-93). Summarizing the study results, the alpha-defensin ELISA and leukocyte esterase tests had less sensitivity in detecting shoulder PJI than previously reported TKA or THA results. The quality and low amount of joint fluid is the difficult part of the diagnostic. C. (formerly P.) acnes was the most common cause of PJI. Focusing on low-grade infections, alpha-defensin has shown its advantages in diagnosing PJI regardless pathogen virulence. Since the diagnostic of a PJI is always a synopsis of findings, the alpha-defensin and leukocyte esterase test can be used as adjunct diagnostic tool in patients with painful TSA. We propose further prospective studies to improve the diagnostic and confirm the results. Level III, diagnostic study.

Impact of C‐reactive protein on Band 3 protein function in human erythrocytes

C‐reactive protein (CRP) has a functional role in the inflammatory process and its concentration increases in circulation during inflammatory events. Transcriptional induction of the CRP gene mainly occurs in hepatocytes in the liver in response to increased levels of inflammatory cytokines, especially interleukin‐6 (IL‐6), therefore CRP is used as a clinical marker of inflammation. Elevated serum CRP levels are related to different inflammatory diseases such as cholecystitis, cardiovascular disease, cancer, type 2 diabetes, appendicitis and pancreatitis. The present study addressed the impact of CRP on Band 3 protein (B3p) function in human erythrocytes. The activity of B3p, mediating Cl−/HCO3− exchange through erythrocytes membrane, can be monitored by measuring the rate constant for SO4= uptake. Blood was withdrawn from both patients with acute inflammation (13 ♀, 9 ♂, age range 28–75 years) and healthy volunteers (10 ♀, 10 ♂, age 28–70 years). CRP levels higher than 8 mg/L were considered as a strong predictor of inflammatory disease and the rate constant for SO4= uptake was measured by a turbidimetric method. Elevated serum CRP levels induced a significant increase in both anion exchange capability through B3p and in SO4= trapped by the cells with respect to control (healthy volunteers). Once serum CRP levels in patients with acute inflammation were brought back to control values, anion exchange capability through B3p was restored. The present findings show that: i) measurement of the rate constant for SO4= uptake is a suitable tool to monitor the effect of elevated serum CRP levels on human erythrocytes due to acute inflammation; ii) high CRP levels seem to accelerate anion exchange capability through B3p; iii) inflammation remission seems to correspond to B3p function restoration. Future studies will evaluate whether this acceleration may depend on an altered Bp3 conformation possibly affecting B3p crosslink with Hb, or on altered oxidative and phosphorylative signaling on B3p function, in an attempt of better understanding the impact of inflammation processes on erythrocytes homeostasis.Support or Funding InformationNoneThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

C-reactive protein (CRP) rs3093059C predicts poor mizolastine response in chronic spontaneous urticaria patients with elevated serum CRP level.

Chronic spontaneous urticaria (CSU) is a frequent disorder with recurrent itchy wheals and/or angioedema, and nearly 35% patients respond poorly to non-sedating H1 antihistamine treatment. CRP gene encodes the C-reactive protein, which is involved in the pathogenesis of CSU. To investigate the impacts of CRP polymorphisms on the susceptibility and therapeutic efficacy in the South Han CSU patients, we enrolled 145 CSU patients in our study. After 4-week non-sedating H1 antihistamine monotherapy treatment, more than 50% reduction of the severity score is considered as effective, or else non-effective. The CRP rs3093059T/C and rs2794521G/A genotypes of patients were determined by Sequenom MassARRAY. Functional studies including relative luciferase assay and β-hexosaminidase assay were conducted in HEK293T cells or RBL-2H3 cells to explore the function of variants. Forty (62.50%) CSU patients were effective when treated with mizolastine, and 55 (72.4%) patients were effective in the desloratadine group. We found that the patients carried with rs3093059TT genotype were significantly associated with good response (OR=4.20, P=0.015), had lower serum CRP, IL-6 and TNF-α levels than the CT/CC genotypes. In vitro, the rs3093059C allele exhibited significantly higher luciferase activity than wild allele (P<0.001). From the β-hexosaminidase assay, we observed the inhibiting degranulation effects by mizolastine and this effect is weakened when with a higher dose CRP in RBL-2H3 cells. Our findings suggested that CSU patients carrying the rs3093059C allele may respond poorly to mizolastine with elevated serum CRP level.

Abstract WP204: Low-grade Inflammation is Associated With Apathy Indirectly Through Deep White Matter Lesions in Community-dwelling Older Adults

Background: Low-grade inflammation is implicated in the pathogenesis of small vessel disease of the brain. Furthermore, systemic inflammation has been associated with apathy. Because our previous study showed the association between deep white matter lesions (DWMLs) and apathy, we investigated the association between inflammation, DWMLs, and apathy. Methods: We analyzed the brain magnetic resonance imaging (MRI) findings in 259 community-dwelling adults (122 men and 137 women) with a mean age of 64.8 years. Serum concentrations of high-sensitivity C-reactive protein (CRP) were measured by a quantitative enzyme-linked immunosorbent assay with a sensitivity of 22 ng/L. Each item of the Starkstein apathy scale was quantified on a visual analogue scale. The association between silent brain lesions and CRP was tested using the forward stepwise method of logistic regression analysis. We used structural equation modeling (SEM) to test the contribution of inflammation and silent brain lesions to the apathetic behavior. Results: Although CRP level distribution was highly skewed (median: 0.589 mg/L, interquartile range: 0.292-1.326 mg/L), log-transformed CRP values (log10 CRP) were normally distributed. Medium to high tertiles of CRP were associated with metabolic syndrome. Logistic regression analysis revealed that log10 CRP (odds ratio [OR]: 2.90; 95% confidence interval [95%CI]: 1.25-6.71) was independently associated with confluent but not total DWMLs. Metabolic syndrome and age were also associated with confluent DWMLs. Path analysis based on SEM indicated that the direct path from log10 CRP to DWMLs was significant (β = 0.12, P = 0.039). The direct paths from metabolic syndrome to log10 CRP and to DWMLs were also significant. The direct path from DWMLs to apathy was significant (β = –0.17, P = 0.007) as was the direct path from education to apathy (β = 0.18, P = 0.003). However, the direct path from log10 CRP to apathy was not significant. The measures of model fitness showed that the presented model reasonably fit the data. Conclusions: Independent of common vascular risk factors, elevated serum CRP levels were associated with confluent DWMLs. Although DWMLs were associated with apathy, direct association between inflammation and apathy was not shown.

Buffered or impaired: Maternal anemia, inflammation and breast milk macronutrients in northern Kenya.

Maternal anemia has adverse consequences for the mother-infant dyad. To evaluate whether and how milk nutrient content may change in ways that could "buffer" infants against the conditions underlying maternal anemia, this study assessed associations between milk macronutrients and maternal iron-deficiency anemia (IDA), non-iron-deficiency anemia (NIDA), and inflammation. A secondary analysis of cross-sectional data and milk from northern Kenya was conducted (n = 204). The combination of hemoglobin and transferrin receptor defined IDA/NIDA. Elevated serum C-reactive protein defined acute inflammation. The effects of IDA, NIDA, and inflammation on milk macronutrients were evaluated in regression models. IDA (β = 0.077, p = .022) and NIDA (β = 0.083, p = .100) predicted higher total protein (ln). IDA (β = -0.293, p = .002), NIDA (β = -0.313, p = .047), and inflammation (β = -0.269, p = .007) each predicted lower fat (ln); however, anemia accompanying inflammation predicted higher fat (β = 0.655, p = .007 for IDA and β = 0.468, p = .092 for NIDA). NIDA predicted higher lactose (β = 1.020, p = .003). Milk macronutrient content both increases and decreases in the presence of maternal anemia and inflammation, suggesting a more complicated and dynamic change than simple impairment of nutrient delivery during maternal stress. Maternal fat delivery to milk may be impaired under anemia. Mothers may buffer infant nutrition against adverse conditions or poor maternal health by elevating milk protein (mothers with IDA/NIDA), lactose (mothers with NIDA), or fat (mothers with anemia and inflammation). This study demonstrates the foundational importance of maternal micronutrient health and inflammation or infection for advancing the ecological understanding of human milk nutrient variation.

Factors associated with post-relapse survival in patients with recurrent cervical cancer: the value of the inflammation-based Glasgow Prognostic Score

PurposeThe aim of the present study was to assess the value of the Glasgow Prognostic Score (GPS) as a prognostic tool for predicting post-relapse survival (PRS) in patients with recurrent cervical cancer.MethodsWe retrospectively evaluated the data of 116 patients with recurrent cervical cancer in whom serologic biomarkers had been assessed at the time of relapse. The GPS was calculated as follows: patients with elevated serum C-reactive protein levels and hypoalbuminemia were allocated a score of 2, and those with 1 or no abnormal value were allocated a score of 1 and 0, respectively. To assess the association between factors including the GPS and PRS, we performed uni- and multivariate survival analyzes.ResultsAfter a median follow-up of 20.9 months from recurrence, a 5-year PRS rate of 25% (SE 4.7%) was observed. Only in 29.8% of the patients, recurrence was limited to the pelvis. In uni- and multivariate survival analyzes, the GPS [HR 1.6 (95% CI 0.9–2.4), p = 0.01], a history of radiation therapy as part of initial treatment [HR 2.7 (95% CI 1.1–6.9), p = 0.03], and the presence of peritoneal carcinomatosis or multiple sites of relapse [HR 4.2 (95% CI 1.9–9.3), p < 0.001] were associated with shorter PRS. The GPS correlated with higher squamous cell carcinoma antigen levels (p = 0.001), shorter median PRS (p = 0.009), and less intensive treatment for relapse (p = 0.02).ConclusionsA higher GPS at the time of relapse, a history of radiation therapy, and the presence of peritoneal carcinomatosis or multiple sites of relapse are independently associated with shorter PRS in patients with recurrent cervical cancer.

Evaluating Hematologist's Knowledge of CAR T-Cell Therapy in Hematologic Malignancies

Background: The objective of this study was to assess current clinical practices of hematologist/oncologist (hem/onc) specialists related to chimeric antigen receptor (CAR) T-cell therapy in hematologic malignancies, in order to identify knowledge, competency, and practice gaps and barriers to optimal care.Methods: A continuing medical education (CME)-certified clinical practice assessment consisting of 25 multiple choice questions was developed to measure knowledge, skills, attitudes, and competence of hem/onc specialists regarding CAR T-cell therapy. The survey instrument was made available online to physicians without monetary compensation or charge. Respondent confidentiality was maintained, and responses were de-identified and aggregated prior to analyses. The activity launched on December 22, 2017 with global distribution, and participant responses are still being collected at the time of abstract submission.Results: At the time of this report there are 192 hem/onc activity participants, collection is on-going. Demographics are listed in Table 1 and levels of confidence and barriers to incorporating CAR T-cell therapy are listed in Table 2.•Foundational Knowledge•Sub-optimal knowledge was demonstrated in the area of CAR components, dosing, and FDA-approved indications.•Over half (61%) could not correctly identify the components of a CAR construct (antigen-specific domain and the signaling domain).•Almost half (45%) of the participants did not recognize that currently approved CAR T-cell therapies are dosed as a single infusion.•25% demonstrated inaccurate knowledge by recommending patients wait 4 weeks after CAR T-cell infusion before driving.•Over half (62%) of participants could not identify the FDA-approved indication for axicabtagene ciloleucel.Knowledge of Clinical Trial Data•Very low awareness of efficacy data seen with various CAR T-cell products used to treat R/R B-cell ALL (ELIANA trial), R/R DLBCL (ZUMA-1, JULIET, TRANSCEND trials).•Only 32% identified the correct CR/CRi rate seen with tisagenlecleucel in the ELIANA trial.•Only 25% correctly identified the CR rate seen with axicabtagene ciloleucel in the ZUMA-1 trial.•Only 32% demonstrated knowledge of the 6-month DFS rate for patients in the JULIET trial that had a CR at 3 months.•Only 25% identified the association between the dose of JCAR017 and response rates from the TRANSCEND trial.Knowledge and Competence Managing Adverse Events•Lack of competence recognizing and treating CAR T-cell associated adverse events such as cytokine release syndrome (CRS) and neurotoxicity.•Almost half (44%) could not identify signs of CRS associated with CAR T-cell therapy and 43% lack knowledge that elevated serum C-reactive protein (CRP) is associated with the highest level of CRS (in patients with lymphoma receiving axicabtagene ciloleucel).•41% could not identify that the mechanism of tocilizumab is to block IL-6 signaling.•Over a third (35%) were unable to identify signs/symptoms/causes of neurotoxicity associated with CAR T-cell therapy.•More than half of the learners (54%) could not identify the appropriate role of corticosteroid therapy after CAR T-cell administration in managing CRS and neurotoxicity.Conclusions: This activity found knowledge and competence deficits for hem/onc practitioners related to using CAR T-cell therapy for the treatment of patients with hematologic malignancies. Additionally, the activity demonstrated large gaps in confidence discussing CAR T-cell therapy with patients/families and managing adverse events. There is sub-optimal awareness of CAR T-cell foundational knowledge, clinical trial data, and recognition of common therapy related adverse events and management strategies. Additional education is needed to improve the knowledge, competence, and confidence of academic and community hem/onc specialists who care for patients with hematologic malignancies receiving CAR T-cell therapy as well as strategies for integrating novel agents into clinical practice. [Display omitted] DisclosuresNeelapu:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Poseida: Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Research Funding; Karus: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Unum Therapeutics: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

A simple and rapid-acting approach for the reduction of C-reactive protein

C-reactive protein (CRP) is an acute-phase protein which can bind to and aggregate oxidized low-density lipoprotein (ox-LDL) particles, thereby enhancing the uptake of oxLDL by macrophages. This finally leads to the formation of foam cells that are a typical characteristic of atherosclerotic plaques. Serum CRP has been shown to bind to phospholipids such as phophatidylcholine (PC), phosphatidylglycerol (PG) and phosphatidylserine (PS). Owing to the rapid and efficient clearance of nanoliposomes from the circulation by the liver, we hypothesized that nanoliposomes composed of the mentioned phospholipids can serve as a potential tool to lower elevated serum CRP levels following acute inflammation. To evaluate this hypothesis, nanoliposomal formulations containing hydrogenated soy phosphatidylcholine (HSPC), a combination of HSPC and 1,2-distearoyl-sn-glycero-3-phosphoglycerol (DSPG), and a combination of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) and 1,2-dioleoyl-sn-glycero-3-phospho-l-serine (DOPS) were prepared using lipid film hydration method followed by extrusion at the final concentration of 20 mM. To elevate circulating CRP levels in mice, 0.1 ml of Freund’s complete adjuvant (CFA) containing 5 mg/ml heat-killed Mycobacterium tuberculosis was subcutaneously injected into the hind paw of the mice. CFA-challenged mice were intravenously treated with nanoliposomal formulations at the dose of 250 μmol/kg 16 h after CFA challenge that is coincided with peak serum CRP level. After 2 h, the blood was collected and serum level of CRP was measured using a quantitative sandwich enzyme-linked immunosorbent assay. All nanoliposomal formulations showed a size range from 100 to 150 nm in diameter and a polydispersity index of < 0.1. Results showed that all nanoliposomal formulations including DOPC/DOPS, HSPC and HSPC/DSPG could significantly decrease serum levels of CRP by 82.76% (74.44–86.92%, p = 0.0001), 44.41% (35.79–50.21%, p = 0.0001) and 38.47% (17.21–43.52%, p=0.0002) [Median (interquartile range)], respectively, when compared with the control group. Dexamethasone as a standard could decrease serum CRP level by 27.47% (16.32–31.63%, p = 0.0025) which was a smaller effect compared with the nanoliposomal preparations. In conclusion, negatively charged nanoliposomes could efficiently reduce the elevated serum levels of CRP in CFA-challenged mice.

Association Between Serum C-Reactive Protein Concentration and Nutritional Status of Malignant Tumor Patients

Background: The level of the systemic inflammatory marker C-reactive protein (CRP) is elevated in many patients with malignant disease and may be related to nutritional status.Objective: To analyze the association between serum CRP levels in patients with malignant tumors and their nutritional status.Method: A total of 3,692 cases were analyzed and the serum CRP levels were determined using an immunometric assay. Nutritional status was assessed by using patient-generated subjective global assessment (PG-SGA). The biochemical evaluation of prealbumin (PA), albumin (ALB), cholesterol (CHOL), and triglycerides (TG) were assayed within 48 h admission to the hospital. The association between serum CRP concentration and the nutritional status, the stage of the tumor and other factors was analyzed by univariate and multivariate logistic regression analysis.Result: Elevated serum CRP was observed in 47.6% (1,548/3,269) of patients compared with the reference value, and the median CRP concentration was 18.29 mg/l. Patient serum CRP concentrations in the malnourished group (PG-SGA B + C) were higher than in the well-nourished (PG-SGA A) patients (P < 0.05). The serum CRP level was related to the patients' age, gender, tumor stage, and was affected by hepatitis, liver cirrhosis, diabetes, but it has no effect on hypertension. The CRP high patients had lower PA and ALB levels, lower Karnofsky performance status scores, and higher PG-SGA scores (P < 0.05), and there was no relationship with CHOL and TG levels. Weight loss in the previous 1 mo was seen with CRP positive patients (P < 0.05).Conclusion: Almost 50% of malignant tumor patients had elevated serum CRP levels indicating a systemic inflammatory state. The nutritional status was worse in cancer patients with higher concentrations of serum CRP. The level of CRP was associated with the tumor stage, and, as stage is a prognostic factor, so can CRP be used as a prognostic maker in malignant tumors patients.

P2.01-88 C-Reactive Protein (CRP) as a Predictive Marker for Survival in Patients with Advanced NSCLC Treated with First Line Pembrolizumab Monotherapy

Pembrolizumab have shown longer activity in patients with advanced non-small cell lung cancer (NSCLC) especially when PD-L1 expression was high. But even with high PD-L1 expression, more than half of them failed to response. We focused on C-reactive protein (CRP), inflammatory protein measured routinely in clinical practice, to find out its role as predictive biomarker for pembrolizumab. We analyzed advanced NSCLC patients with PD-L1 high expression (EGFR mutation (-), EML-4-ALK fusion (-)) who were treated with pembrolizumab as first-line therapy in our clinical practice. Patients received pembrolizumab (200mg/body, q3W) until progressive disease or unacceptable toxicity. During treatment period we measured serum biochemistry and blood cell count regularly. We evaluated the association the factors such as serum marker including inflammatory protein, age, performance status, histology, smoking status, prior radiation therapy and presence or absence of immune-related adverse events after treatment with the effect such as antitumor response, progression-free survival (PFS) and overall survival (OS). A total of 31 patients treated with pembrolizumab from March 2017 to February 2018 were analyzed for this research. Their characteristics were: median age 72 (range 37-84),male/female 24/7, adenocarcinoma/squamous cell carcinoma/pleomorphic carcinoma/neuroendocrine carcinoma/NOS 17/5/3/1/5, clinical stage IIIB/IV/recurrence 3/21/7, median CRP level at pretreatment 1.15mg/dL (0.07-15.27). Among the candidate biomarker, there were no association except for CRP. Serum CRP level at pretreatment was not predictive, but change of serum CRP level at 6 weeks after anti-PD-1 therapy initiation was most predictive in the analysis. Depressed CRP group showed longer PFS and OS than elevated group (PFS: p=0.08, HR 0.29, OS: p=0.08, HR 0.28, log-rank test). Our analysis suggests that serum CRP elevation at 6 weeks of treatment predict for longer survival when pembrolizumab was given as first-line treatment. This finding might be related to inflammation status of patients and efficacy of anti-PD-1 inhibitor.

The impact of fetal umbilical artery Doppler pulsatility index on childhood respiratory function and atopy: a prospective case-control study

Objective: To determine if an elevated fetal umbilical artery Doppler pulsatility index is associated with abnormal respiratory function and atopy in children aged 12 years.Methods: This prospective case-control study compared children that had an elevated fetal umbilical artery Doppler pulsatility index (>90th centile) to those with a normal pulsatility index (<90th centile). All subjects were delivered at full-term and with appropriate growth for gestational age. Outcome measures included; (i) presence of asthma and/or atopy; (ii) spirometry measurements and (iii) serum C-reactive protein and leptin. Multiple regression was used to account for parental smoking, childhood age, gender and socioeconomic status.Results: 174 children with an average age of 12.1 (±0.6 SD), 48% of who were male were included in the analysis. Of the 174, 99 (57%) were in the normal umbilical artery Doppler pulsatility index group and 75 (43%) elevated umbilical artery Doppler pulsatility index groups. The overall proportion of subjects with asthma was 28% (48/174) and atopy 56% (98/174). No association was found between elevated fetal umbilical artery Doppler pulsatility index and asthma (p = .47) or atopy (p = .75) at age 12 years. Similarly there was no association between FEV1(%) (p = .96), forced vital capacity (FVC)(%) (p = .98), elevated serum C-reactive protein (p = .69) or leptin (p = .20) and an elevated fetal umbilical artery Doppler pulsatility index.Conclusions: An elevated umbilical artery Doppler at 28-weeks gestation in the absence of prematurity or fetal growth restriction is not associated with altered respiratory function or the presence of atopy in children aged 12 years. These findings support the theory that such disease has a multifactorial pathophysiology.

Euploid miscarriage is associated with elevated serum C-reactive protein levels in infertile women

Euploid miscarriage is associated with elevated serum C-reactive protein levels in infertile women

Biomarkers of Systemic Inflammation and Growth in Early Infancy are Associated with Stunting in Young Tanzanian Children

Stunting can afflict up to one-third of children in resource-constrained countries. We hypothesized that low-grade systemic inflammation (defined as elevations in serum C-reactive protein or alpha-1-acid glycoprotein) in infancy suppresses the growth hormone–insulin-like growth factor (IGF) axis and is associated with subsequent stunting. Blood samples of 590 children from periurban Dar es Salaam, Tanzania, were obtained at 6 weeks and 6 months of age as part of a randomized controlled trial. Primary outcomes were stunting, underweight, and wasting (defined as length-for-age, weight-for-age and weight-for-length z-scores < −2) between randomization and endline (18 months after randomization). Cox proportional hazards models were constructed to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) of time to first stunting, underweight, and wasting as outcomes, with measures of systemic inflammation, insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) as exposures, adjusting for numerous demographic and clinical variables. The incidences of subsequent stunting, underweight, and wasting were 26%, 20%, and 18%, respectively. In multivariate analyses, systemic inflammation at 6 weeks of age was significantly associated with stunting (HR: 2.14, 95% CI: 1.23, 3.72; p = 0.002). Children with higher levels of IGF-1 at 6 weeks were less likely to become stunted (HR: 0.58, 95% CI: 0.37, 0.93; p for trend = 0.019); a similar trend was noted in children with higher levels of IGF-1 at 6 months of age (HR: 0.50, 95% CI: 0.22, 1.12; p for trend = 0.07). Systemic inflammation occurs as early as 6 weeks of age and is associated with the risk of future stunting among Tanzanian children.

Matrix sieving-enforced retrograde transcytosis regulates tissue accumulation of C-reactive protein.

Circulating proteins larger than 3 nm can be transported across continuous endothelial barrier of blood vessels via transcytosis. However, excessive accumulation of serum proteins within the vessel walls is uncommon even for those abundant in the circulation. The aim of this study was to investigate how transcytosis regulates tissue accumulation of the prototypical acute-phase reactant C-reactive protein (CRP) and other serum proteins. Transcytosis of CRP as well as of transferrin and low-density lipoprotein across aortic endothelial cells is bidirectional with directional preference from the apical (blood) to basolateral (tissue) direction both in vitro and in vivo. This directional preference is, however, reversed by the basement membrane (BM) matrix underlying the basolateral surface of endothelial cells. This is due to the sieving effect of the BM that physically hinders the diffusion of transcytosed proteins from the apical compartment towards underlying tissues, resulting in immediate retrograde transcytosis that limits basolateral protein accumulation. Conversely, CRP produced within vessel wall lesions can also be transported into the circulation. Our findings identify matrix sieving-enforced retrograde transcytosis as a general mechanism that prevents excessive tissue accumulation of blood-borne proteins and suggest that lesion-derived CRP might also contribute to elevated serum CRP levels associated with increased risk for cardiovascular diseases.

Dietary Magnesium and Chronic Disease.

Although official magnesium (Mg) dietary reference intakes are open to question, a significant number of adults likely have intakes that are in the range of 50%-99% of the requirement. This moderate or marginal (subclinical) deficient Mg intake generally is asymptomatic. Animal studies, however, indicate that moderate or subclinical Mg deficiency primes phagocytic cells for the release of proinflammatory cytokines leading to chronic inflammatory and oxidative stress. Human studies have found that dietary Mg is inversely related to serum or plasma C-reactive protein (CRP). Individuals with apparently deficient Mg intakes have an increased likelihood of serum or plasma CRP ≥3.0mg/L, considered an indicator of chronic inflammatory stress that increases the risk for chronic disease. In addition, elevated serum or plasma CRP in individuals with chronic disease is decreased by Mg supplementation, which suggests that Mg decreases the risk for chronic disease. The importance of dietary Mg intake on the risk for chronic disease through affecting inflammatory and oxidative stress is supported by numerous meta-analyses and systematic reviews that have found dietary Mg is inversely associated with chronic diseases such hypertension, ischemic heart disease, stroke, metabolic syndrome, diabetes, and colorectal cancer.

Association Between Elevated C-Reactive Protein Levels and Prediabetes in Adults, Particularly Impaired Glucose Tolerance.

Prediabetes is a precursor of diabetes and increases the risk for cardiovascular disease. A high C-reactive protein (CRP) level is a risk factor for diabetes, and individuals with prediabetes have higher CRP levels than those with normal glucose tolerance. In addition, systemic inflammation may play a role in the early-phase deterioration of glucose metabolism. We examined the association between serum CRP levels and prediabetes. Overall, 4,101 subjects without diabetes underwent oral glucose tolerance tests. Levels of serum CRP were divided into quartiles; the lowest quartile was used as the reference when calculating odds ratios (ORs) and confidence intervals. Isolated fasting glucose, isolated glucose tolerance and elevated glycated hemoglobin levels (i.e. between 42 and 47 mmol/mol [6.0% to 6.4%]) were indicative of prediabetes. In the multiple logistic regression analysis, the ORs (95% confidence intervals) for impaired glucose tolerance, impaired fasting glucose and elevated glycated hemoglobin levels corresponding to the highest quartile of CRP levels were 1.67 (1.31 to 2.14); 1.62 (1.15 to 2.28); and 1.47 (1.14 to 1.90), respectively. In the stratified analysis, the ORs for impaired glucose tolerance were consistently higher in the uppermost quartile than in the reference quartile in both the presence and absence of hypertension or dyslipidemia. In contrast, the ORs for impaired fasting glucose in the uppermost quartile were higher only in the presence of hypertension and dyslipidemia, and the OR for elevated glycated hemoglobin levels in the uppermost quartile was higher only in the presence of hypertension. Elevated serum CRP levels are associated with prediabetes, particularly impaired glucose tolerance.

The 2018 Definition of Periprosthetic Hip and Knee Infection: An Evidence-Based and Validated Criteria

BackgroundThe introduction of the Musculoskeletal Infection Society (MSIS) criteria for periprosthetic joint infection (PJI) in 2011 resulted in improvements in diagnostic confidence and research collaboration. The emergence of new diagnostic tests and the lessons we have learned from the past 7 years using the MSIS definition, prompted us to develop an evidence-based and validated updated version of the criteria. MethodsThis multi-institutional study of patients undergoing revision total joint arthroplasty was conducted at 3 academic centers. For the development of the new diagnostic criteria, PJI and aseptic patient cohorts were stringently defined: PJI cases were defined using only major criteria from the MSIS definition (n = 684) and aseptic cases underwent one-stage revision for a noninfective indication and did not fail within 2 years (n = 820). Serum C-reactive protein (CRP), D-dimer, erythrocyte sedimentation rate were investigated, as well as synovial white blood cell count, polymorphonuclear percentage, leukocyte esterase, alpha-defensin, and synovial CRP. Intraoperative findings included frozen section, presence of purulence, and isolation of a pathogen by culture. A stepwise approach using random forest analysis and multivariate regression was used to generate relative weights for each diagnostic marker. Preoperative and intraoperative definitions were created based on beta coefficients. The new definition was then validated on an external cohort of 222 patients with PJI who subsequently failed with reinfection and 200 aseptic patients. The performance of the new criteria was compared to the established MSIS and the prior International Consensus Meeting definitions. ResultsTwo positive cultures or the presence of a sinus tract were considered as major criteria and diagnostic of PJI. The calculated weights of an elevated serum CRP (>1 mg/dL), D-dimer (>860 ng/mL), and erythrocyte sedimentation rate (>30 mm/h) were 2, 2, and 1 points, respectively. Furthermore, elevated synovial fluid white blood cell count (>3000 cells/μL), alpha-defensin (signal-to-cutoff ratio >1), leukocyte esterase (++), polymorphonuclear percentage (>80%), and synovial CRP (>6.9 mg/L) received 3, 3, 3, 2, and 1 points, respectively. Patients with an aggregate score of greater than or equal to 6 were considered infected, while a score between 2 and 5 required the inclusion of intraoperative findings for confirming or refuting the diagnosis. Intraoperative findings of positive histology, purulence, and single positive culture were assigned 3, 3, and 2 points, respectively. Combined with the preoperative score, a total of greater than or equal to 6 was considered infected, a score between 4 and 5 was inconclusive, and a score of 3 or less was not infected. The new criteria demonstrated a higher sensitivity of 97.7% compared to the MSIS (79.3%) and International Consensus Meeting definition (86.9%), with a similar specificity of 99.5%. ConclusionThis study offers an evidence-based definition for diagnosing hip and knee PJI, which has shown excellent performance on formal external validation.