Serum sCD163 Levels Research Articles

The Beneficial Effect of Probiotics as an Adjuvant Treatment in Childhood Drug Resistant Epilepsy

Abstract Background Epilepsy is the most frequent chronic neurologic condition in children and every year >4.9 million people develop new-onset epilepsy. The foundation of treatment in epilepsy is drug therapy with anti- seizure medications (ASM). However, about one-third develop drug resistant epilepsy (DRE) due to inability to achieve seizure control despite the use of appropriate ASM. Recent studies indicate that gut dysfunction/dysbiosis is presumably involved in the pathogenesis of and susceptibility to epilepsy. The reconstruction of the intestinal microbiome through probiotic intervention has shown beneficial effects on DRE. Aim of the Work The aim of this study is to study safety and effectiveness of probiotics in controlling epileptic seizures in DRE patients by decreasing frequency and severity of seizures. Patients and Methods This study is a prospective study – Single arm Clinical Trial (Pilot study) conducted on 35 DRE patients at the neurology outpatient clinic, Pediatric Neurology Unit, Ain Shams University, from January to August, 2023, of which 14 (40%) dropped out due to socioeconomic reasons and non-compliance while 21 (60%) patients completed this clinical trial. All the results were calculated based on the 21 patient who completed the study. Patients were supplemented with probiotics for 4 months and assessed pre and post probiotics intake by the following tools: seizure assessment by Chalfont seizure severity scale, a blood sample taken to measure serum sCD14 as an inflammatory marker, an EEG was done and QOLIE-31 was used to asses quality of life. Probiotics (spores of antibiotic resistant Bacillus clausii; Enterogermina 2 Billion @ SANOFI) were used with the following doses daily for 4 months (as per SANOFI’s dose prescribtion): ages 1 year to 2 years: 1 vial per day, ages 2 years to 18 years: 2 vials per day. Results Our study included 21 participants; the median age at the time of the study was 11 years ranging from 2.5 to 15 years of age and the median age of onset of seizure was 7 ranging from 6 months to 12 years. The majority of participants were found to be female 15 (71.4%) and the rest were male 6 (28.4%). This clinical trial shows that probiotics could be a useful supplement in the treatment of DRE where 42.9% of our patients achieved the Therapeutic goal of reduction (≥50%) in the number of seizures & improvement in seizure severity (p-value < 0.001) and frequency (p-value < 0.005). Serum sCD14 levels were withdrawn as an inflammatory marker to understand the potential cause of the improvement in epileptic seizures and their levels were outstandingly improved between pre and post probiotics intake with p-value < 0.001. We also found that quality of life was significantly improved as measured by questionnaire QOLIE31 between pre and post probiotics intake in our patients in all its aspects with total score <0.001. We compared between our 2 main diagnoses (The GDD and Genetic epilepsy) and found that there was higher quality of life in the genetic group than the global developmental delay group with p-value < 0.001 mostly attributing this to the fact that most of the genetic patients had a higher starting point than their counterpart in their developmental history and other aspects. Our patients were also sub-divided into 2 groups based on the effectiveness of the probiotics in improving seizures frequency 50% or more and it was found that the effective group had a lower median age (7 years) than the non-effective group (12.5 years) delineating that younger age responds better to probiotics or management in general. Conclusion This study revealed that probiotics decrease the frequency and severity of seizures and improve the quality of life of drug resistant epilepsy patients. Since this is a pilot study and there are deficient data in this area, more studies are needed to evaluate the applicability, safety and the mechanism of action of probiotics.

Urinary soluble CD163 is a putative non-invasive biomarker for primary sclerosing cholangitis

Soluble CD163 (sCD163) is a selective marker of macrophages whose circulating levels have been found to be induced in patients with active inflammatory bowel disease (IBD). Urinary proteins are emerging as non-invasive diagnostic biomarkers, and here, sCD163 levels were measured in the urine of 18 controls and 63 patients with IBD by enzyme-linked immunosorbent assay. Urinary sCD163 levels did, however, not differentiate IBD patients from controls. Analysis of sCD163 in the serum of 51 of these patients did not show higher levels in IBD. Primary sclerosing cholangitis (PSC) is often associated with IBD, and sCD163 was higher in the urine of the 21 patients and in the serum of the 13 patients with PSC compared to patients with IBD. Of clinical relevance, urinary sCD163 levels were higher in PSC patients compared to those with other chronic liver diseases (n = 16), while serum sCD163 levels were comparable between the two groups. Serum sCD163 of IBD and PSC patients positively correlated with serum C-reactive protein. Serum creatinine and glomerular filtration rate, surrogate markers for renal function, did not significantly correlate with urinary or serum sCD163 levels in IBD or PSC patients. Moreover, urinary sCD163 was not related to fecal calprotectin levels whereas serum sCD163 of IBD patients showed a positive trend. PSC associated with IBD and PSC without underlying IBD had similar levels of urinary sCD163 while serum sCD163 tended to be higher in the latter group. In PSC patients, urinary sCD163 did not correlate with serum aminotransferase levels, gamma glutamyl transferase, alkaline phosphatase, bilirubin or the Model for End Stage Liver Disease score. Ursodeoxycholic acid was prescribed to our PSC patients and fecal levels of ursodeoxycholic acid and its conjugated forms were increased in PSC compared to IBD patients. Otherwise, fecal bile acid levels of IBD and PSC patients were almost identical, and were not correlated with urinary and serum sCD163 in PSC. In summary, our study identified urinary sCD163 as a potential biomarker for PSC.

Soluble Factors CD14, CD163, and Migration Inhibitory Factor Are Associated with Endometriosis-Related Infertility

Objectives: Myeloid cell-derived factors contribute to the immunopathology of endometriosis. Soluble CD14 (sCD14), CD163 (sCD163), and MIF serve as in vivo markers of myeloid function. However, these soluble molecules are largely unexplored in women with endometriosis-related infertility cases. We investigated three soluble markers, namely sCD14, sCD163, and MIF, in cases of infertility associated with endometriosis and correlated its level to the stage of endometriosis. Design: Eighty-seven women newly diagnosed with endometriosis or other benign gynecologic control cases linked to infertility were prospectively recruited and underwent diagnostic laparoscopy. Participants: Forty-four patients with endometriosis were included in this study, comprising 19 patients with early-endometriosis (stages I and II) and 25 late-endometriosis (stages III and IV) based on the revised American Society for Reproductive Medicine (rASRM) classification. The remaining 43 patients constituted a control group with infertility due to other causes. Methods: The levels of sCD14, sCD163, and MIF in serum and peritoneal fluid were assessed using ELISA. Results: Endometriosis women exhibited significantly higher serum levels of sCD163 and MIF levels compared to the control group. Both sCD163 and MIF levels displayed a positive correlation with the rASRM adhesion score. Moreover, the MIF level in serum had a positive correlation with the rASRM endometriosis score. In receiver operating characteristic analysis, serum sCD163 and MIF could significantly discriminate endometriosis and non-endometriosis in infertility cases. Limitations: Some limitations of the current study deserve to be underlined. First, the sensitive ELISA method was the sole-validated tool for detecting the markers in patient samples. Second, healthy or fertile women were not involved as the control group. Conclusions: The elevated systemic levels of sCD163 and MIF correlated with the severity of endometriosis. These soluble molecules have a potential diagnostic capacity as a non-invasive biomarker. Furthermore, our data warrants future studies on the underlying mechanism of sCD163 and MIF in endometriosis-related infertility.

Serum-Soluble CD163 Levels as a Prognostic Biomarker in Patients with Diffuse Large B-Cell Lymphoma Treated with Chemoimmunotherapy.

The majority of patients with Diffuse Large B-cell Lymphoma (DLBCL) will respond to first-line treatment and be cured. However, the disease is heterogeneous, and biomarkers able to discriminate patients with suboptimal prognosis are needed. M2 CD163-positive tumor-associated macrophages (TAMs) were shown to be implicated in DLBCL disease activity regulation. Serum-soluble CD163 (sCD163) functions as a scavenger receptor for haptoglobin-hemoglobin complexes and is mostly expressed by monocytes and macrophages. Its levels are used to determine macrophage activation. We aimed to determine serum sCD163 in a sample of DLBCL patients and study eventual correlations with parameters of disease activity or survival. Serum sCD163 levels were measured in 40 frozen sera from patients diagnosed with DLBCL and 30 healthy individuals (HIs) using an enzyme-linked immunosorbent assay (ELISA). Statistical analyses were performed using SPSS version 28. The results showed that patients who achieved complete response after standard-of-care immunochemotherapy and were alive and disease-free after 12 months of follow-up but had elevated sCD163 levels (above median) at diagnosis presented a significantly worse overall survival compared to those with initial serum sCD163 levels below the median (p = 0.03). Consequently, serum sCD163 levels in patients with DLBCL may constitute a marker of long-term response to chemoimmunotherapy.

Abstract A002: Serum levels of immune markers associated with pathological complete response (pCR) and immune-related adverse events (irAEs) in early-stage breast cancer patients receiving immune checkpoint inhibitor plus chemotherapy in the I-SPY 2 trial

Abstract Background: Surrogate biomarkers of efficacy and AEs are needed for therapy with immune checkpoint inhibitors (ICI). Although ICI treatments have demonstrated effectiveness in combating early-stage breast cancer (BC), predicting early response and the associated risk of irAEs are important considerations. In this study, we evaluated pre-treatment, early on-treatment, and early changes of serum immune markers in women with BC treated with neoadjuvant chemotherapy plus an ICI. Methods: Serum samples were obtained from 49 women with early stage HER2-negative BC enrolled in the I-SPY 2 trial who received paclitaxel plus an ICI (anti-PD-1) followed by anthracycline/cyclophosphamide. Serum was collected at baseline (T0) and 3 weeks after the first dose (T1). Serum samples were assayed by Ella multiplex immunoassays for 18 pre-selected immune markers, including soluble immune checkpoint molecules (sPD-L1, LAG-3), cytokines (IL-6, IL-8, IFNg, TNFa, IL-10, G-CSF, MCP-1), chemokines (CXCL9, CXCL10, CXCL11, CXCL13), molecules associated with angiogenesis/lymphangiogenesis (VEGF-C), and other markers reflecting immune inflammation/activation (C-Reactive Protein [CRP], CD163, sCD25, GranzymeB). Serum markers showing significant changes from T0 to T1 were identified with the Wilcoxon test. Associations between absolute levels or changes in serum markers and response to therapy (pCR) and/or irAEs were assessed with the Mann–Whitney test. Results: Serum IFNg, G-CSF, IL-10, LAG-3, CCL2, CXCL-10, sCD25, CXCL-9 and CXCL-11 significantly increased between T0 and T1 (P <0.0001, 0.014, <0.001, 0.043, <0.0001, 0.032, <0.0001, <0.0001, <0.0001, respectively). In hormone-receptor positive (HR+)/HER2- patients (N=29), low baseline IFNg serum levels were associated with response to therapy (P = 0.04). In addition, a decrease in sCD25 serum levels from T0 to T1 was strongly associated with response (P = 0.0047) in all HER2- patients. Immune-related AEs were reported for a small number of patients (N=9/49). Increases in serum levels of VEGF-C from T0 to T1 were significantly associated with irAEs (P = 0.0055). In addition, patients who developed irAEs had significantly higher T0 and T1 levels of CD163 (P = 0.022 and 0.024, respectively). Conclusions: Baseline serum level of IFNg and early changes in serum sCD25 levels could be used to monitor and predict clinical benefit from anti-PD-1 agents. This study also suggests that VEGF-C and CD163 may serve as possible candidate prognostic biomarkers for irAEs in patients receiving anti-PD-1 therapy in the early-stage BC setting. While our preliminary results are promising, additional validation in a larger sample size is crucial to confirm the observed trends. Therefore, candidate biomarkers from additional I-SPY 2 arms containing ICIs will be analyzed. Citation Format: Silver Alkhafaji, Denise M. Wolf, Amrita Basu, Lamorna Brown-Swigart, Rita Nanda, Minneta Liu, Gillian L. Hirst, Laura J. Esserman, Laura van 't Veer, Michael Campbell. Serum levels of immune markers associated with pathological complete response (pCR) and immune-related adverse events (irAEs) in early-stage breast cancer patients receiving immune checkpoint inhibitor plus chemotherapy in the I-SPY 2 trial [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A002.

Serum soluble toll-like receptor 4 and risk for clinical severity in COVID-19 patients

Toll-like receptor 4 (TLR4) signaling mediates sustained systemic inflammation in(COVID)-19 patients. We aimed to assess the serum levels of sTLR4 and sCD14 as negative regulators of Toll like receptor signaling and their association with laboratory markers and clinical severity in covid 19 patients. Ninety-eight patients with COVID-19 (70 severe and 28 non-severe) were enrolled in the study. Serum sCD14 andsTLR4were determined by ELISA. A significant increase in serum sTLR4 and sCD14 levels was detected in severe compared to non severe COVID19 patients.Receiver operating characteristic curve (ROC) analysis revealed significant diagnostic potential of serum sTLR4 and sCD14 in covid19 patients.We conclude that Serum sTLR4 and sCD14 may be promising clinical severity markers for COVID19 patients.

The beneficial effect of probiotics as an adjuvant treatment in childhood drug resistant epilepsy: A prospective pilot study.

One of the most common long-term neurological disorders affecting children is epilepsy. Even with effective antiseizure medications, one-third of epileptic patients develop drug-resistant epilepsy (DRE). Numerous treatments have been offered to these DRE patients, though with varying degrees of effectiveness. This study aimed to evaluate the effectiveness of probiotics in improving the quality of life (QoL) and lowering the severity and frequency of epileptic episodes in DRE patients. As well as to assess the anti-inflammatory effects of probiotics. DRE patients were daily supplemented with one probiotic for 4months. During these 4months, patients continued their routine anti-epileptics with no change in the doses. Before and following the 4-month trial, patients had their QoL evaluated using the validated Arabic version of QoL in epilepsy-31 inventory (QoLIE-31) questionnaire, an electroencephalogram (EEG) examination, and serum soluble CD14 (sCD14) evaluation by ELISA. Of the 21 DRE patients who completed the study, 42.9% achieved the therapeutic goal, which was a ≥50% reduction in seizures. After probiotic, there was a significant increase in time elapsed since the last seizure (p = 0.001) and a decrease in seizure duration (p = 0.038), frequency (p = 0.002), and severity by Chalfont Seizure Severity Score (p < 0.001), as compared to pre-probiotic data. Moreover, there was a significant decrease in serum levels of sCD14 (p < 0.001) and a significant improvement in QoL (p < 0.05). Probiotics may be used as a DRE adjuvant treatment. They can lessen the number and severity of seizures, alleviate the associated inflammation, and enhance the QoL for DRE patients.

Assessment of Serum Soluble CD30 Levels in Pediatric Kidney Transplant Recipients

BACKGROUND: CD30 is considered to be a marker for the activated immune system; however, its association with acute rejection and kidney graft function showed severe heterogeneity. AIM: The aim of this study is to examine the predictive value of soluble CD30 (sCD30) levels for kidney transplantation (KT) outcomes in children. MATERIALS AND METHODS: CD30 in serum was measured by ELISA technique in 50 pediatric kidney transplant recipients (KTRs) within 13.4 ± 4.5 days before and within 19.5 ± 9.2 days after KT. sCD30 values were correlated with clinical, laboratory, and immunosuppressive (IS) therapy data and graft function of included patients. Twenty age/gender-matched healthy controls participated as reference values for sCD30 levels. RESULTS: Our study revealed that serum levels of CD30 showed a significant relation between serum sCD30 levels: Pre/post-transplantation (p = 0.02) with increasing sCD30 levels after transplantation (71.60 pg/mL vs. 90.20 pg/mL). In the time, there were no relations between sCD30 with other parameters. CONCLUSIONS: Our results suggest that the measurement of serums CD30 levels may be used as a valuable biomarker in renal transplantation when it is measured pre/post-transplantation.

Soluble CD163; A Possible New Biomarker in Multiple Myeloma

INTRODUCTION Tumor associated macrophages (TAM) constitute a major part of the bone marrow microenvironment and play a pivotal role in growth of various hematologic malignancies, such as Multiple Myeloma (MM). Cytokines secreted by TAM, such as hemoglobin scavenger receptor CD163, can be detected in their soluble form (sCD163) and reflect the TAM burden. It was recently published that bone marrow TAMs protect neoplastic plasmacytes from chemotherapy-based apoptosis. In our study, we aimed to investigate the clinical utility of sCD163 in patients with Multiple Myeloma. PATIENTS AND METHODS One hundred and nineteen patients were included in the study of whom 80 had symptomatic MM, 30 appeared to have SMM and 8 had MGUS. Clinical and laboratory characteristics were reviewed, after patients' informed consent form. Their median age was 68 yrs (range, 30-89), 53% were men and 47%women; 39%, 27%, and 35% of MM patients were staged ISS1, ISS2 and ISS3 respectively. Serum sCD163 was tested in frozen sera collected at patients' diagnosis and in 30 healthy individuals (HI) . Measurements were performed by ELISA (Duo-Set R&amp;D Quantiquine) according to the manufacturer's instructions. Median value of variables was used as the cut off point. Median time to treatment (TTT) was 0 months (range,0-248) in MM patients and median overall survival (OS) was 67 months (range, 0-248). Statistical analysis was performed with the SPSS v.26 software. RESULTS Median sCD163 was 26618 pg/ml (11831- 35548) in HI, 24366 pg/ml (13166 - 27429) in MGUS, 27665 (18266-39088) pg/ml in SMM, and 27870 (20720-37478) pg/ml in MM patients.Significantly lower levels of CD163 were observed between MGUS and HI (p=0.001) and HI and MM patients (p=0.015). Shorter time to treatment was observed in all MM patients including SMM with sCD163 levels above median (p = 0.034). Patients who became symptomatic after 6 months of diagnosis were studied separately, with levels above the median indicating a shorter time to therapy (p=0.003). Also, a trend of shorter overall survival was observed in all patients (MM, SMM, MGUS) with levels of CD163 above median (p=0.07). CONCLUSION Our findings reveal that serum sCD163 levels differed in patients with MGUS, SMM, MM, and HI, and could predict TTT in MM, indicating that cells of the monocyte-macrophage lineage may play a role in disease pathophysiology and progression. sCD163 could eventually prove to be a significant prognostic factor in MM.

Effectiveness of rosuvastatin and pulmonary rehabilitation in patients with concurrent course of asthma, chronic obstructive pulmonary disease and diabetes mellitus type 2

The aim of this study was to assess the effectiveness of rosuvastatin and pulmonary rehabilitation in patients with asthma-COPD overlap (ACO) concurrent with type 2 diabetes (T2D).Material and methods. A total of 26 patients with ACO and T2D were examined, with an average age of 61 [55.6; 67.8]. In addition to standard therapy, patients in the main group were prescribed rosuvastatin and a pulmonary rehabilitation program. Treatment efficacy was assessed using questionnaires (CAT, ACQ, SGRQ), dyspnea severity scale (mMRC), BODE index, pulmonary function, bioimpedance analysis, 6-minute walk test, carbohydrate and lipid metabolism status, levels of 8-isoprostane, sCD14, CRP, stable nitric oxide (NO) metabolites - nitrite and nitrate ions, and endothelin-1 in the blood. Results. In the main group, a significant improvement was observed during the treatment course, including a 40% reduction in the BODE index (p&lt;0.05), a 33.4% decrease in dyspnea on the mMRC scale (p&lt;0.05), a 28.5% reduction in CAT, a 40.8% decrease in ACQ, and a 20.6% decrease in SGRQ. Other notable improvements included a 1.3% decrease in BMI, a 13% reduction in body fat percentage, a 23.5% decrease in visceral fat level, a 16% increase in patients' tolerance to physical activity, a 27.5% increase in FEV1 (p&lt;0.05), an 8.1% decrease in fasting blood glucose (p&lt;0.01), a 20% reduction in triglycerides (p&lt;0.05), a 24.9% decrease in LDL cholesterol, and a 27.2% decrease in total cholesterol (p&lt;0.05). Additionally, there was a 23.8% decrease in CRP levels (p&lt;0.05), a two-fold reduction in blood 8-isoprostane levels (p&lt;0.05), a 58% reduction in serum sCD14 levels, a 59.8% increase in stable nitric oxide metabolites (p&lt;0.05), and a 55% decrease in endothelin-1 levels (p&lt;0.05).Conclusions. The use of rosuvastatin and pulmonary rehabilitation significantly improves the quality of life for patients with the concurrent presentation of COPD, asthma, and T2D. It reduces the severity of dyspnea, enhances tolerance to physical activity, improves pulmonary function, lowers visceral fat levels and body fat percentage, enhances lipid profile, and improves endothelial function, all while concurrently reducing oxidative stress and systemic inflammation without worsening carbohydrate metabolism.

Circulating levels of FoxP3, M2 (sCD163) and IGF-1 as potential biomarkers associated with Laryngeal Squamous Cell Carcinoma in Tunisian patients

ABSTRACT We aim to assess the clinical impact of circulating levels of sCD163, FoxP3, IGF-1 in LSCC patients (Laryngeal Squamous Cell Carcinoma). The concentrations of sCD163, FoxP3, and IGF-1 were measured using ELISA test in the serum samples collected from 70 pretreatment LSCC patients and 70 age and sex-matched healthy controls. Statistical analysis was performed using ANOVA to compare the two groups, and the correlation between markers and clinical parameters. Receiver-Operator Characteristic (ROC) curve analysis was conducted to determine the optimal cutoff values and evaluate the diagnostic impact of these markers. Significant differences in the levels of sCD163, FoxP3, and IGF-1 were observed between LSCC patients and the control group, with respective p-values of 0.01, 0.022, <0.0001. The determined cutoff values for sCD163, FoxP3, IGF-1 concentrations were 314.55 ng/mL, 1.69 ng/mL, and 1.69 ng/mL, respectively. The corresponding area under the curve (AUC) values were 0.67 (95% CI: 0.57–0.76), 0.70 (95% CI: 0.61–0.80), 0.84 (95% CI: 0.76–0.92), respectively. Furthermore, it was found that IGF-1 concentrations exceeding 125.20 ng/mL were positively correlated with lymph node metastasis. Elevated serum levels of sCD163, FoxP3 and IGF-1 are associated with the diagnosis of LSCC. IGF-1 appears to be the most promising indicator for the LSCC progression.

Gut microbiota and metabolomics profiles in patients with chronic stable angina and acute coronary syndrome.

Cardiovascular disease (CVD) is the leading cause of death worldwide. The gut microbiota and its associated metabolites may be involved in the development and progression of CVD, although the mechanisms and impact on clinical outcomes are not fully understood. This study investigated the gut microbiome profile and associated metabolites in patients with chronic stable angina (CSA) and acute coronary syndrome (ACS) compared with healthy controls. Bacterial alpha diversity in stool from patients with ACS or CSA was comparable to healthy controls at both baseline and follow-up visits. Differential abundance analysis identified operational taxonomic units (OTUs) assigned to commensal taxa differentiating patients with ACS from healthy controls at both baseline and follow-up. Patients with CSA and ACS had significantly higher levels of trimethylamine N-oxide compared with healthy controls (CSA: 0.032 ± 0.023 mmol/L, P < 0.01 vs. healthy, and ACS: 0.032 ± 0.023 mmol/L, P = 0.02 vs. healthy, respectively). Patients with ACS had reduced levels of propionate and butyrate (119 ± 4 vs. 139 ± 5.1 µM, P = 0.001, and 14 ± 4.3 vs. 23.5 ± 8.1 µM, P < 0.001, respectively), as well as elevated serum sCD14 (2245 ± 75.1 vs. 1834 ± 45.8 ng/mL, P < 0.0001) and sCD163 levels (457.3 ± 31.8 vs. 326.8 ± 20.7 ng/mL, P = 0.001), compared with healthy controls at baseline. Furthermore, a modified small molecule metabolomic and lipidomic signature was observed in patients with CSA and ACS compared with healthy controls. These findings provide evidence of a link between gut microbiome composition and gut bacterial metabolites with CVD. Future time course studies in patients to observe temporal changes and subsequent associations with gut microbiome composition are required to provide insight into how these are affected by transient changes following an acute coronary event.NEW & NOTEWORTHY The study found discriminative microorganisms differentiating patients with acute coronary syndrome (ACS) from healthy controls. In addition, reduced levels of certain bacterial metabolites and elevated sCD14 and sCD163 were observed in patients with ACS compared with healthy controls. Furthermore, modified small molecule metabolomic and lipidomic signatures were found in both patient groups. Although it is not known whether these differences in profiles are associated with disease development and/or progression, the findings provide exciting options for potential new disease-related mechanism(s) and associated therapeutic target(s).

A comparison of serum inflammatory parameters in progressive forms of multiple sclerosis

IntroductionMultiple sclerosis (MS) is a chronic, inflammatory demyelinating disease of the central nervous system. Primary progressive MS (PPMS) is diagnosed in approximately 10–15 % of MS patients. Disease-modifying therapies (DMT) are less effective in modifying the course of progressive types of MS. It seems that inflammatory processes differ in the MS subtypes. ObjectivesThe objective of this study was to assess differences in the inflammatory parameters between PPMS and other courses of MS. Materials and methodsA total of 84 subjects were included in the study. The study group was divided according to the course of MS into the following categories: PPMS (n = 24); SPMS—secondary progressive multiple sclerosis (n = 14); RRMS—relapsing–remitting multiple sclerosis (n = 46). PPMS patients were further divided into treated with ocrelizumab and treatment-naive groups. The concentrations of serum inflammatory parameters were evaluated. ResultsPPMS and SPMS significantly differed in the serum levels of sCD30, gp130, sIL-6R alpha, osteopontin, pentraxin-3 and sTNF-R1. The serum concentrations of IFN-alpha2, IL-10, IL-20, IL-29 and osteopontin significantly differed between PPMS and RRMS. The serum levels of BAFF, IL-19, IL-20, pentraxin-3, s-TNF-R1 and s-TNF-R2 significantly differed between PPMS treated with ocrelizumab and treatment-naive. ConclusionAlthough inflammatory processes take part in the pathogenesis of all types of MS, they differ between MS courses. Serum inflammatory parameters seem to be promising biomarkers in helping to differentiate courses of MS, and in assessing reactions to DMT treatment. Further investigations on their usage are required.

INCREASED SOLUBLE SERUM CD163 (SCD163) LEVELS PREDICT A SHORT DISEASE FREE SURVIVAL IN DIFFUSE LARGE B‐CELL LYMPHOMA (DLBCL)

Introduction: Monocyte counts were found of prognostic significance in DLBCL, implying the possible contribution of monocyte-macrophage lineage cells in disease pathogenesis. These cells secrete among others sCD163, the role of which has not been investigated yet. Aims: To study eventual correlation of serum sCD163 levels with prognosis in DLBCL. Patients and Methods: Twenty-six DLBCL patients were studied with a median follow-up time of 21 months (2–138). Ten were diagnosed in early stages (1 and 2) while the resting majority was in advanced stages (3 and 4). Six patients (23%) relapsed early during disease course. Seven patients succumbed to their disease and other 3 from other causes. SerumCD163 measurements were performed by ELISA (Duo-Set R&D Quantiquine) according to the manufacturer’s instructions in frozen sera kept at diagnosis. The SPSS v.26 software was used for statistical analysis and survival curves were drawn by Kaplan-Mayer method and compared by the log-rank test. Results: Serum sCD163 levels ranged from 34072 to 164912 pg/mL (median 134672 pg/mL) in patients and from 104420 to >140000 pg/mL (median 117952 pg/mL) in 15 healthy individuals. Patients with serum sCD163 levels above median had a higher probability of relapse and a shorter disease free survival (p = 0.004), compared to the others (figure). Overall survival was not affected by sCD163 levels. Keywords: aggressive B-cell non-Hodgkin lymphoma, diagnostic and prognostic biomarkers, targeting the tumor microenvironment No conflicts of interests pertinent to the abstract.

Soluble CD163 is a predictor of fibrosis and hepatocellular carcinoma development in nonalcoholic steatohepatitis

BackgroundNonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. The serum level of soluble CD163 (sCD163), a macrophage activation marker, is associated with liver tissue changes; however, its prognostic value is unknown. Here, we determined the utility of sCD163 as a marker for hepatocellular carcinoma (HCC) and prognostic marker for NAFLD.MethodsThis retrospective study obtained data regarding serum sCD163 levels, liver histology, and background factors associated with NAFLD in 287 patients (men/women, 140/147; average age, 53 ± 14 years) with NAFLD who underwent liver biopsy. Repeated liver biopsies of 287 patients with NAFLD (5.0 ± 2.7 years) were compared regarding serum sCD163 levels and liver tissue changes (stage, grade, steatosis, and NAFLD activity score).ResultsSerum sCD163 levels increased with the progression of liver fibrosis and inflammation (both P < 0.05) and were particularly helpful in distinguishing cases of Grade 4 fibrosis (P < 0.001). Levels of sCD163 significantly decreased in patients with NAFLD exhibiting alleviated fibrosis and inflammation (P < 0.05). We could also predict the development of HCC and associated mortality based on serum sCD163 levels at the time of NAFLD diagnosis. Serum sCD163 levels were higher in patients with HCC than in patients without HCC (1074 ± 379 ng/ml vs. 669 ± 261 ng/ml; P < 0.0001), and the same trend was observed for mortality.ConclusionsThe serum sCD163 level reflects the progression of fibrosis and inflammation in liver tissues, showing much promise as a noninvasive biomarker for nonalcoholic steatohepatitis and NAFLD as well as a possible predictor of HCC development and patient prognosis.

Longitudinal Changes in Immune Activation Serum Biomarkers Prior to Diagnosis and Risk of B-cell NHL Subtypes.

To examine the contribution of B-cell activation molecules to B-cell follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL), a prospective study was conducted using pre-diagnosis serial serum samples from the US Department of Defense Serum Repository. Each case (n = 142 FL, n = 211 DLBCL) was matched to two controls on age, gender, race, military branch, and blood collection dates. Immune activation molecules (IL1β, IL2, IL4, IL5, IL6, IL10, IL12, CXCL13, IL8, TNFα, IFNγ, GM-CSF, VEGF, sCD30, IgE) were quantified using ELISA or multiplex immunometric (Luminex) assay. Longitudinal data were analyzed using linear mixed modeling. As serial specimens were collected over several years before diagnosis, we evaluated the temporal dynamics of these markers. Increased serum levels of sCD30, CXCL13, and to a lesser extent IL10, were associated with both FL and DLBCL in cases compared with controls, with a median follow-up of 5.5 years from the earliest specimen collection to diagnosis date. Significant increasing sCD30 and CXCL13 trajectories for FL and DLBCL subtypes were noted starting at the earliest time points and with IL10 levels increasing significantly at time points closer to diagnosis. These results suggest that sCD30, CXCL13, and IL10 may contribute to the etiology of FL and DLBCL and are potential biomarkers for these non-Hodgkin lymphoma subtypes. The increasing trajectories of the B-cell activation molecules, sCD30, CXCL13, and to a lesser extent IL10, may indicate early disease-induced effects or reflect the chronic stimulation of B-cells that promotes the development of FL and DLBCL subtypes.

Addition of Brentuximab Vedotin to Gemcitabine in Relapsed or Refractory T-Cell Lymphoma: Final Analysis of a Lysa Multicenter, Phase II Study. "the TOTAL Trial"

Background : Outcome of relapse/refractory (R/R) peripheral T-cell lymphoma (PTCL) patients (pts) is usually poor. [Mak, 2013]. Brentuximab vedotin (Bv) monotherapy is approved for R/R anaplastic large cell-lymphoma (ALCL) with long term responders [Pro, 2017] and for 1st line in association with polychemotherapy [Horwitz, 2019] in all CD30+ PTCL (with no restriction related to expression cut-off). We designed a phase 2 study for R/R CD30+ PTCL combining gemcitabine (G) and Bv with the aim to increase the overall response rate (ORR) by 15%, compared to gemcitabine monotherapy (35%) [O'Connor, 2019] and among secondary endpoints to evaluate BV maintenance and the impact of both CD30 expression and soluble CD30 (sCD30) on response and survival. Patients and Methods: : Patients with confirmed CD30+ (≥5%) PTCL with measurable disease who failed or were refractory to 1-3 systemic therapy (excluding G and Bv) and ECOG performance status < 3 were eligible. Pts received 4 (28-days) cycles of G and Bv induction phase (GBvIP) (G : 1000mg/m² at D1 and D15 plus Bv: 1.8 mg/kg at D8) followed, in pts with complete (CR) or partial remission (PR) and non-eligible for SCT, by up to 12 (21-days) cycles of Bv (1.8 mg/kg) maintenance phase (BvMP). The primary endpoint was ORR (CR + PR) according to Lugano criteria (CT-scan-based). CD30 expression was semi-quantitatively assessed by immunohistochemistry (IHC) and serum sCD30 levels were determined by ELISA. (NCT03496779). Results: From April 2018 to October 2019, 71 pts with PTCL (47 males, 24 females) were enrolled. Central pathology review according to 2017 WHO criteria found nodal TFH-PTCL (34 ; 47.9%) [including AITL (27 ; 38%) and other nodal PTCL-TFH (7 ; 9.9%)] ; ALK- ALCL (14 ; 27%) ; PTCL-NOS (9 ; 13%) ; ALK+ ALCL (5 ; 7%), EATL (2 ; 2.8%) and other entities (7 ; 9.9%). Median age was 66 years (20-79), 65 pts (91.6%) were stage III-IV. ECOG status was ≥ 2 in 45 pts (63%). The number of prior lines were 1 (57), 2 (11) or 3 (3) and 28 pts (39.4%) had a refractory disease. In intention to treat analysis, the ORR after GBvIP was 46.5% including CR (14;19.7%), PR (19;26.8%). Among the 33 responders, 27 initiated BvMP as well as 1 non responding pt (with SD but a complete metabolic response). The median number of BvMP cycles was 9 (range 1-12). At least one G≥3 AE were recorded in 58/71 pts during GBvIP and 11/28 pts during BvMP. AE led to treatment discontinuation in 9/71 pts (GBvIP) and 14/28 pts (BvMP). Overall a polyneuropathy of G≥1 was recorded in 9/71 pts (GBvIP) and 14/28 pts (BvMP). After a median follow-up of 26.5 (0.5-42.1) months (mo), the median progression free survival (PFS) and overall survival (OS) were respectively 4.5 mo (95%CI [3.5 - 10]) (Figure 1A) and 12.9 mo (95%CI [8.6 - 25.5]). Among the 33 pts in PR/CR after GBvIP, the duration of response since inclusion (DOR) was 15.8 mo (95%CI [10.4 - (-)]) By univariate analysis, ORR was negatively influenced by high LDH (p=0.008) with borderline impact of ECOG (p=0.058), and both PFS and OS were reduced by refractory disease status at screening (p=0.031 and p=0.007) and non-ALCL histology (p=0.049 and p=0.041). CD30 expression was investigated on tumor samples collected either at screening (55.5%) or (if not available) at diagnosis (39,7%) or at previous relapse (4.8%). In pts with ALCL, CD30 expression was constant and high (>75% of tumor cells) along with a significant higher level of sCD30 compared to non ALCL pts. In non ALCL pts, the median % of CD30-positive tumor cells was 12.5% [0 - 12.5]. Focusing on non-ALCL pts we found a high impact of sCD30 level >120 ng/mL on both ORR, DOR, PFS and OS while CD30 expression on tumor cells did not appear to influence the results. (Figure 1B ; Table 1) Conclusion : According to our initial hypothesis, the addition of Bv to G is active in R/R CD30+ PTCLs both in terms of ORR, CR. In responding pts, the DOR exceeding 15 mo with very long responders suggests the value of Bv maintenance. Not surprisingly ALCL were associated with better results, but this treatment is also effective in non ALCL pts including a significant proportion of TFH lymphoma pts. Besides ALCL pts, biomarkers are needed to predict which pts could benefit the most of Bv based therapy. In line with a previous report [Horwitz, 2014], we did not find a clear impact of CD30 expression on tumor cells, however we demonstrate that baseline serum sCD30 at treatment initiation was strongly correlated with both response and outcome. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Increased PRR14 and VCAM-1 level in serum of patients with Parkinson's disease.

BackgroundRegarding the complexity of Parkinson's disease (PD), the identification of reliable biomarkers is of great significance for improving the accuracy of diagnosis and monitoring disease progression. Recently, some studies suggested that serum proline-rich protein 14 (PRR14), vascular cell adhesion molecule-1 (VCAM-1), and soluble CD163 (sCD163) factors may be associated with PD, even as potential biomarkers. However, the role of these serum factors is still unclear.ObjectivesThis study aimed to explore the alterations of serum PRR14, VCAM-1, and sCD163 levels during PD progression, and their association with disease-related variables of PD.MethodsWe performed the assessment of scale tests and the detection of serum samples in patients with PD (n = 100) and healthy controls (HCs, n = 100). Furthermore, we investigated the association between serum factors and sex, cognitive impairments, H&Y (Hohn and Yahr), age at onset (AAO), and other variables in patients with PD.ResultsPatients with PD exhibited increased PRR14 and VCAM-1 serum levels compared with HCs. No significant differences were found in serum levels of sCD163. Subgroup analysis uncovered increased VCAM-1 in the female and male subgroups (PD and HCs). Among patients with PD, decreased PRR14 and increased VCAM-1 were associated with severer cognitive impairments and severer PD (H&Y), respectively. Bivariate correlation analysis revealed that there was a positive correlation between VCAM-1 and AAO.ConclusionsIncreased serum levels of PRR14 and VCAM-1 suggest that inflammation and defective autophagy may play vital roles in the pathogenesis of PD. However, the potential mechanisms remain to be elucidated.

Macrophage Activation Markers Predict Liver-Related Complications in Primary Biliary Cholangitis.

Primary biliary cholangitis (PBC) has a wide variation in clinical presentation and course. There is no significant correlation between these symptoms and the disease stage, although patients with more advanced stages generally have more symptoms. It is important to develop biomarkers in order to identify patients with an increased risk of complications and end-stage liver disease. This study investigated surrogate markers for risk estimation of PBC-related complications, including a study population of 77 patients with PBC who underwent liver biopsy and were measured for serum levels of macrophage activation markers, soluble CD163 (sCD163), soluble mannose receptor (sMR), and zonulin. Patients with PBC were divided into symptomatic (Group S, n = 20) and asymptomatic (Group A, n = 57) groups. The correlations of histological stages based on both Scheuer and Nakanuma classifications with the three serum markers were investigated. The Nakanuma classification involves grading for liver fibrosis and bile duct loss. The three biomarkers were assessed for their diagnostic ability to identify patients with PBC having high risk of developing complications. The predictive factors of these complications were examined as well. Group S had significantly higher serum sMR (p = 0.011) and sCD163 (p = 0.048) levels versus Group A. A composite index of sMR and sCD163 measurements had significantly better prediction performance than sCD163 alone (p = 0.012), although not when compared to sMR alone (p = 0.129). Serum sMR was an independent factor for developing complications on both univariate (Odds ratio (OR) = 30.20, 95% confidence interval (95% CI): 3.410–267.0, p = 0.00220), and multivariate (OR = 33.70, 95% CI: 3.6600–311.0, p = 0.0019) analyses. Patients with PBC having sMR of ≥56.6 had a higher incidence of clinical complications versus those with a sMR of <56.6. Serum sMR predicts the development of complications in patients with PBC. sMR plus sCD163 showed better predictive power than either marker alone, although the addition of sCD163 did not improve the predictive power of sMR. Future prospective studies are required in order to validate the findings of the present study.

Soluble CD163: a novel independent prognostic biomarker in patients with metastatic renal cell carcinoma.

The hemoglobin-haptoglobin scavenger receptor CD163 is present in both a membrane-bound form on monocytes and macrophages (mCD163) and a shed soluble circulating form (sCD163). CD163 is a well-described marker of M2-like tumor-associated macrophages, but in patients with metastatic renal cell carcinoma (mRCC), monocyte mCD163 and serum sCD163 levels have not previously been investigated and associated with patient overall survival (OS). Here, we report mCD163 expression on peripheral blood monocytes, as well as sCD163 serum levels, in samples from 89 patients newly diagnosed with mRCC and 20 healthy controls. We found that in mRCC patients, compared to healthy controls, monocyte mCD163 levels were reduced (P < 0.001) whereas serum sCD163 levels were increased (P = 0.004). Moreover, an inverse correlation between mCD163 and sCD163 levels (P = 0.04) was shown. In survival analyses, intermediary levels of monocyte mCD163 were associated with longest OS, compared to both lower and higher mCD163 levels, which were both associated with worse outcomes (P < 0.01). Further, higher levels of sCD163 at diagnosis were associated with poor OS in both univariate (P < 0.001) and multivariate analysis (HR = 1.28; 95%CI 1.09-1.50, P = 0.002). Importantly, stratification by low vs. high sCD163 was able to separate patients with International Metastatic RCC Database Consortium (IMDC) intermediate risk (IMDCINT) into two subgroups with different OS (P = 0.03): IMDCINT-sCD163LOW showed survival similar to IMDCFAV patients, and IMDCINT-sCD163HIGH showed survival similar to IMDCPOOR patients. Thus, baseline sCD163 is a novel independent biomarker of OS in mRCC, and using sCD163 as an add-on biomarker may improve prognostic value for patients in the heterogenous IMDC intermediate group.