The association between bilirubin concentrations and inflammatory bowel disease: Insights from a systematic review and meta-analysis.

BACKGROUND: Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), poses a significant challenge to health care systems because of its chronic nature and increasing global prevalence. Effective management of IBD requires accurate diagnostic tools and biomarkers. This systematic review and meta-analysis aimed to evaluate the relationship between bilirubin concentrations and IBD activity and outcomes. METHODS: A comprehensive search of electronic databases identified 11 studies that included 2606 subjects with IBD and 3607 healthy controls. RESULTS: Bilirubin concentrations were significantly lower in subjects with IBD when compared to controls (SMD = -0.96, 95% CI -1.21 to -0.70; p < .001). Although substantial heterogeneity was observed, sensitivity analysis confirmed the robustness of the results. Publication bias was detected, but subgroup analyses did not significantly alter the results. Meta-regression showed that age was a significant factor influencing the association between bilirubin concentrations and IBD. Subgroup analyses showed a more pronounced reduction in bilirubin concentrations in subjects with CD than those with UC. CONCLUSION: This study supports the potential utility of bilirubin as a biomarker in IBD, emphasizing the need for further research to validate its clinical significance.

The potential role of serum amyloid A as biomarker of rheumatic diseases: a systematic review and meta-analysis.

The identification of novel, robust biomarkers for the diagnosis of rheumatic diseases (RDs) and the presence of active disease might facilitate early treatment and the achievement of favourable long-term outcomes. We conducted a systematic review and meta-analysis of studies investigating the acute phase reactant, serum amyloid A (SAA), in RD patients and healthy controls to appraise its potential as diagnostic biomarker. We searched PubMed, Scopus, and Web of Science from inception to 10 April 2024 for relevant studies. We evaluated the risk of bias and the certainty of evidence using the JBI Critical Appraisal Checklist and GRADE, respectively (PROSPERO registration number: CRD42024537418). In 32 studies selected for analysis, SAA concentrations were significantly higher in RD patients compared to controls (SMD = 1.61, 95% CI 1.24-1.98, p < 0.001) and in RD patients with active disease compared to those in remission (SMD = 2.17, 95% CI 1.21-3.13, p < 0.001). Summary receiving characteristics curve analysis showed a good diagnostic accuracy of SAA for the presence of RDs (area under the curve = 0.81, 95% CI 0.78-0.84). The effect size of the differences in SAA concentrations between RD patients and controls was significantly associated with sex, body mass index, type of RD, and study country. Pending the conduct of prospective studies in different types of RDs, the results of this systematic review and meta-analysis suggest that SAA is a promising biomarker for the diagnosis of RDs and active disease.

The role of bilirubin as a biomarker of rheumatic diseases: a systematic review and meta-analysis.

The identification of novel, yet easily measurable biomarkers of inflammation and oxidative stress might assist in the diagnosis and management of patients with rheumatic diseases (RDs). We conducted a systematic review and meta-analysis of studies investigating the circulating concentrations of bilirubin, the end product of heme metabolism and a potent endogenous antioxidant with anti-inflammatory properties, in patients with RDs and healthy controls. The electronic databases PubMed, Scopus, and Web of Science were searched from inception to 31 December 2023 for relevant articles. We evaluated the risk of bias and the certainty of evidence using the Joanna Briggs Checklist and the Grades of Recommendation, Assessment, Development, and Evaluation Working Group system, respectively. In 17 eligible studies, all with low risk of bias, compared to controls, patients with RDs had significantly lower concentrations of total bilirubin (standard mean difference, SMD=-0.68, 95% CI -0.91 to -0.44, p<0.001; I2 = 92.5%, p<0.001; low certainty of evidence), direct (conjugated) bilirubin (SMD=-0.67, 95% CI -0.92 to -0.41, p<0.001; I2 = 81.7%, p<0.001; very low certainty of evidence), and the active antioxidant and anti-inflammatory indirect (unconjugated) form of bilirubin (SMD=-0.71, 95% CI -1.18 to -0.24, p=0.003; I2 = 95.1%, p<0.001; very low certainty of evidence). The results of the meta-analysis were stable in sensitivity analysis. In meta-regression, there were no significant associations between the SMD of total bilirubin and several clinical and demographic characteristics, including age, male to female ratio, number of participants, liver enzymes and erythrocyte sedimentation rate. In subgroup analysis, the SMD of total bilirubin was significant across a range of RDs, including rheumatoid arthritis, systemic lupus erythematosus, primary Sjögren syndrome, and myositis. Therefore, the results of our systematic review and meta-analysis suggests that the reductions in bilirubin concentrations observed in patients with RDs reflect a state of impaired antioxidant and anti-inflammatory defence due to bilirubin consumption and highlight the promising role of this endogenous product as a biomarker of RDs. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42023500649.

A systematic review and meta-analysis of the diagnostic accuracy of the neutrophil-to-lymphocyte ratio and the platelet-to-lymphocyte ratio in systemic lupus erythematosus.

The wide range of clinical and serological manifestations in systemic lupus erythematosus (SLE) and the lack of accepted diagnostic criteria warrant the identification of novel, more accurate biomarkers. Hematological indices derived from full blood cell counts, particularly the neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR), have shown promise in SLE; however, a critical appraisal of their diagnostic accuracy is lacking. We sought to address this issue by conducting a systematic review and meta-analysis of the diagnostic accuracy of the NLR and PLR in SLE. The electronic databases PubMed, Scopus, and Web of Science were systematically searched from inception to 15 March 2024 for studies reporting the sensitivity and specificity of the NLR and PLR, obtained by receiver operating characteristic (ROC) curve analysis, for the presence of SLE, disease severity, organ involvement (lupus nephritis, pericarditis, and pleural disease), and complications (infections). The risk of bias was assessed using the JBI Critical Appraisal Checklist (PROSPERO registration number: CRD42024531446). The NLR exhibited good accuracy for the diagnosis of SLE (eight studies; area under the curve, AUC = 0.81, 95% CI 0.78-0.85) and lupus nephritis (nine studies; AUC = 0.81, 95% CI 0.77-0.84), but not for severe disease (nine studies; AUC = 0.69, 95% CI 0.65-0.73) or infections (six studies; AUC = 0.73, 95% CI 0.69-0.77). The PLR exhibited good accuracy for the diagnosis of severe disease (six studies; AUC = 0.85, 95% CI 0.81-0.87). There were an insufficient number of studies to assess the accuracy of the PLR for the diagnosis of SLE, lupus nephritis, or infections. No study investigated the NLR and PLR in SLE patients with pericarditis or pleural disease. Therefore, the NLR and the PLR have a relatively high diagnostic accuracy for the presence of SLE and lupus nephritis (NLR) and severe disease (PLR). Further studies are warranted to determine whether the NLR and PLR, in combination with clinical evaluation and other serological biomarkers, can enhance the diagnosis and management of SLE.

A systematic review and meta-analysis of the association between the D-dimer and rheumatic diseases.

INTRODUCTION: There is good evidence that specific autoimmune rheumatic diseases (RDs), for example, rheumatoid arthritis and systemic lupus erythematosus (SLE), are associated with a state of hypercoagulability and an increased risk of venous thromboembolism (VTE). However, limited information regarding this association is available for other autoimmune or autoinflammatory RDs. We sought to address this issue by conducting a systematic review and meta-analysis of the association between the d-dimer, an established marker of hypercoagulability and VTE, and RDs and the possible clinical and demographic factors mediating this association. METHODS: We searched the electronic databases PubMed, Web of Science, and Scopus from inception to January 31, 2024. The risk of bias and the certainty of evidence were assessed using the Joanna Briggs Institute Critical Appraisal Checklist and GRADE, respectively. RESULTS: In 31 studies selected for analysis (2724 RD patients and 3437 healthy controls), RD patients had overall significantly higher d-dimer concentrations when compared to controls (standard mean difference = 0.93, 95% CI 0.76-1.10, p < .001; I2 = 86.1%, p < .001; moderate certainty of evidence). The results were stable in a sensitivity analysis. Significant associations were observed between the effect size of the between-group differences in d-dimer concentration and age, specific RD and RD category, RD duration, fibrinogen, plasminogen activator inhibitor, C-reactive protein, and erythrocyte sedimentation rate. CONCLUSIONS: Overall, patients with RDs have significantly higher d-dimer concentrations when compared with healthy controls, indicating a state of hypercoagulability. The alterations in d-dimer concentrations are mediated by age, specific RD and RD category, RD duration, and markers of anticoagulation and inflammation. Further research is warranted to investigate d-dimer concentrations across the spectrum of RDs and their utility in predicting and managing VTE in these patients (PROSPERO registration number: CRD42024517712).

Resistin and omentin in breast cancer: A systematic review and meta-analysis.

Breast cancer (BC) is the most frequently diagnosed cancer and a leading cause of cancer-related mortality among women globally. Resistin, omentin and ghrelin, adipokines involved in inflammation and metabolic regulation, have been implicated in cancer development, yet their associations with BC remain unclear. This systematic review and meta-analysis aimed to elucidate the relationships between resistin, omentin, and ghrelin concentrations and BC, while exploring potential moderators such as body mass index (BMI) and menopausal status. A comprehensive search of electronic databases up to 13 May 2024 identified studies comparing resistin and omentin, but not ghrelin, concentrations in BC patients and healthy controls. Standardized mean differences (SMDs) were calculated using random-effects models, and meta-regression and subgroup analyses were performed to investigate sources of heterogeneity. Analysis of 11 studies showed that BC patients exhibited significantly higher resistin concentrations compared to controls, with a pooled SMD of 2.05 (95 % CI 1.24 to 2.86, p < 0.001). Meta-regression indicated that BMI significantly moderated the resistin-BC association (p = 0.003). In contrast, omentin concentrations presented a complex picture, with a pooled SMD of -0.27 (95 % CI -1.39 to 0.84, I^2 = 96.2 %, p < 0.001), indicating substantial heterogeneity and inconclusive results, whereas only one study investigated ghrelin. Our findings support a significant association between elevated resistin concentrations and BC, suggesting a potential role of resistin in BC pathophysiology. The data on omentin and ghrelin remain inconclusive, warranting further investigation. Future research should focus on large, longitudinal studies with standardized methodologies to validate these findings and clarify the role of adipokines in BC.

Investigating bilirubin concentrations in schizophrenia: A systematic review and meta-analysis.

Schizophrenia, a severe mental disorder characterized by chronic disability and poor quality of life, has been shown to be associated with alterations in redox balance. Recent research has suggested a potential link between the antioxidant bilirubin and schizophrenia, although findings have been inconsistent. To address this gap, we conducted a systematic review and meta-analysis to evaluate possible alterations in bilirubin concentrations in schizophrenia. A comprehensive search of major databases was conducted to identify articles reporting total and unconjugated bilirubin in schizophrenic patients and healthy controls in case-control studies. Our meta-analysis included 18 studies investigating 16,245 participants. The pooled results did not reveal any significant association between schizophrenia and total bilirubin concentrations. Additionally, such effect was strongly influenced by the results of a single study in sensitivity analysis. Subgroup and meta-regression analyses based on various factors such as study design, sample size, and geographical region showed no significant associations with the effect size, nor they identified sources of heterogeneity. Furthermore, publication bias assessments were conducted to ensure the robustness of the findings. Overall, our findings summarize the available evidence regarding the possible role of bilirubin as a biomarker of schizophrenia and highlight the importance of conducting further research in this area.

Ischemia-modified albumin in rheumatic diseases: A systematic review and meta-analysis.

INTRODUCTION: The identification of novel, easily measurable disease biomarkers might enhance the diagnosis and management of patients with rheumatic diseases (RDs). We conducted a systematic review and meta-analysis of ischemia-modified albumin (IMA), a marker of oxidative stress, acidosis, and ischemia, in RD patients and healthy controls. METHODS: We searched PubMed, Web of Science, and Scopus from inception to January 15, 2024. The risk of bias and the certainty of evidence were assessed using the Joanna Briggs Institute Critical Appraisal Checklist and GRADE, respectively. RESULTS: In 20 studies investigating a total of 1188 RD patients (mean age 45 years, 64% females) and 981 healthy controls (mean age 44 years, 66% females), RD patients had significantly higher IMA concentrations when compared to controls (standard mean difference, SMD = 0.50, 95% CI: 0.18-0.83, p = .003; I2 = 92.4%, p < .001; low certainty of evidence). In subgroup analysis, the pooled SMD was significantly different in studies investigating ankylosing spondylitis (p < .001), Behçet's disease (p < .001), and rheumatoid arthritis (p = .033), but not familial Mediterranean fever (p = .48). Further associations were observed between the pooled SMD and the broad classification of autoimmune and/or autoinflammatory diseases, the study country, and the method used to measure IMA. CONCLUSION: Our study suggests that IMA is a promising biomarker of oxidative stress, acidosis, and ischemia, as it can effectively discriminate between patients with different types of RDs and healthy controls. Our results warrant confirmation in longitudinal studies of patients with different types of RDs and different ethnicities (PROSPERO registration number: CRD42024509126).

The relationship between haemoglobin concentrations and obstructive sleep apnea syndrome: A systematic review and meta-analysis.

BACKGROUND: This systematic review and meta-analysis investigates the relationship between haemoglobin (Hb) concentrations and obstructive sleep apnea syndrome (OSAS). METHODS: Following PRISMA guidelines, we searched PubMed, EMBASE, and Cochrane Library from inception to March 8, 2024. Eligible studies included cross-sectional, cohort, and case-control designs comparing Hb concentrations in OSAS patients and healthy controls. Two reviewers independently screened records and extracted data. The risk of bias was assessed using the Joanna Briggs Institute checklist. RESULTS: A total of 27 studies involving 6499 OSAS subjects and 5199 controls were included. Hb concentrations were significantly higher in OSAS patients compared to controls (SMD: 0.28; 95 % CI: 0.18 to 0.39; I2 = 84.4 %). Subgroup analysis by OSAS severity showed that severe OSAS patients had higher Hb concentrations than those with mild/moderate OSAS. Sensitivity analyses confirmed the robustness of the findings. However, 7 studies reported opposite results, indicating possible regional or methodological differences. CONCLUSION: Hb concentrations are elevated in OSAS patients, with higher levels observed in severe cases. The significant heterogeneity and the predominance of studies from Turkey highlight the need for further research in diverse populations. Limitations include potential publication bias and variability in study designs.

Ocular Tics and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS).

Little is known about ocular tics in Pediatric Autoimmune Neuropsychiatric Disorders associated with Streptococcal infections (PANDAS). In this retrospective study, we examined the clinical records of children with motor tics referred to the Ophthalmology Unit, Azienda Ospedaliero-Universitaria di Sassari, Italy, in 2010-2019. The presence of ocular tics was investigated. Data about antistreptolysin O (ASO) and anti-DNase B antibody titers, erythrocyte sedimentation rate (ESR), plasma C-reactive protein (CRP), and antibiotic use were recorded. Forty children (thirty-four boys and six girls; mean age: 7.65 ± 2.5 years) with motor tics were identified; thirty-three (82.5%) showed ocular tics. Children with ocular tics had significantly higher titers of anti-DNase B antibodies (p = 0.04) and CRP (p = 0.016) than those with extraocular tics. A diagnosis of PANDAS was made in 24 (60%) children. PANDAS children with oculomotor tics had significantly higher titers of anti-DNase B antibodies (p = 0.05) than those with extraocular tics. Oral antibiotics were given to 25/33 (76%) children with ocular tics and 21/24 (87.5%) with PANDAS. All treated patients showed marked improvement/complete resolution of symptoms. Results suggest that higher titers of anti-DNase B antibodies may be implicated in the pathogenesis of ocular tics in PANDAS. Oral antibiotics may be beneficial in improving ocular tics. Further research is necessary to confirm our findings.

Association between blood Pentraxin-3 concentrations and rheumatic diseases: A systematic review and meta-analysis.

BACKGROUND: Among the Pentraxins, the long Pentraxin-3 (PTX-3) is associated with several processes, particularly in the earliest phases of the innate humoral response. Increased blood PTX-3 concentrations have been observed in a wide range of conditions, from infectious to cardiovascular disorders. Since its increase is more rapid than C-reactive protein (CRP), PTX-3 can be useful to detect and monitor early inflammation. To dissect its pathophysiological role in rheumatic diseases (RD), we conducted a systematic review and meta-analysis comparing blood PTX-3 concentrations in RD patients and healthy individuals and investigating possible associations with clinical, demographic, and study characteristics. METHODS: We performed a search of published evidence until April 2024 in PubMed, Web of Science and Scopus, which led to the selection of 60 relevant manuscripts from a total of 1072 records. RESULTS: Our synthesis revealed a statistically significant difference in PTX-3 concentrations between RD patients and controls (standard mean difference, SMD = 1.02, 95% CI 0.77-1.26, p < .001), that correlated with CRP concentrations. The effect size was associated with geographical region of study conduction, RD type, with a reduction of the observed heterogeneity in patients with low LDL-cholesterol and triglycerides concentrations. CONCLUSIONS: Our study has shown a significant increase in blood PTX-3 concentrations in RD patients, which was associated with specific patient characteristics. Nevertheless, additional studies are needed to better define the utility of measuring PTX-3 in the early phase of RD. Our study was conducted in compliance with the PRISMA 2020 statement (study protocol available at PROSPERO CRD42024516600).

The association between the neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and monocyte-to-lymphocyte ratio and systemic sclerosis and its complications: a systematic review and meta-analysis.

Introduction: The identification of new, easily measurable biomarkers might assist clinicians in diagnosing and managing systemic sclerosis (SSc). Although the full blood count is routinely assessed in the evaluation of SSc, the diagnostic utility of specific cell-derived inflammatory indices, i.e., neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR), has not been critically appraised in this patient group. Methods: We conducted a systematic review and meta-analysis of studies investigating the NLR, PLR, and MLR, in SSc patients and healthy controls and in SSc patients with and without relevant complications. PubMed, Scopus, and Web of Science were searched from inception to 23 February 2024. Risk of bias and certainty of evidence were assessed using validated tools. Results: In 10 eligible studies, compared to controls, patients with SSc had significantly higher NLR (standard mean difference, SMD=0.68, 95% CI 0.46 to 0.91, p<0.001; I2 = 74.5%, p<0.001), and PLR values (SMD=0.52, 95% CI 0.21 to 0.83, p=0.001; I2 = 77.0%, p=0.005), and a trend towards higher MLR values (SMD=0.60, 95% CI -0.04 to 1.23, p=0.066; I2 = 94.1%, p<0.001). When compared to SSc patients without complications, the NLR was significantly higher in SSc with interstitial lung disease (ILD, SMD=0.31, 95% CI 0.15 to 0.46, p<0.001; I2 = 43.9%, p=0.11), pulmonary arterial hypertension (PAH, SMD=1.59, 95% CI 0.04 to 3.1, p=0.045; I2 = 87.6%, p<0.001), and digital ulcers (DU, SMD=0.43, 95% CI 0.13 to 0.74, p=0.006; I2 = 0.0%, p=0.49). The PLR was significantly higher in SSc patients with ILD (SMD=0.42, 95% CI 0.25 to 0.59, p<0.001; I2 = 24.8%, p=0.26). The MLR was significantly higher in SSc patients with PAH (SMD=0.63, 95% CI 0.17 to 1.08, p=0.007; I2 = 66.0%, p=0.086), and there was a trend towards a higher MLR in SSc patients with ILD (SMD=0.60, 95% CI -0.04 to 1.23, p=0.066; I2 = 94.1%, p<0.001). Discussion: Pending the results of appropriately designed prospective studies, the results of this systematic review and meta-analysis suggest that blood cell-derived indices of inflammation, particularly the NLR and PLR, may be useful in the diagnosis of SSc and specific complications. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024520040.

Platelet Dynamics in Neurodegenerative Disorders: Investigating the Role of Platelets in Neurological Pathology.

Background: Neurological disorders, particularly those associated with aging, pose significant challenges in early diagnosis and treatment. The identification of specific biomarkers, such as platelets (PLTs), has emerged as a promising strategy for early detection and intervention in neurological health. This systematic review aims to explore the intricate relationship between PLT dynamics and neurological health, focusing on their potential role in cognitive functions and the pathogenesis of cognitive disorders. Methods: Adhering to PRISMA guidelines, a comprehensive search strategy was employed in the PubMed and Scholar databases to identify studies on the role of PLTs in neurological disorders published from 2013 to 2023. The search criteria included studies focusing on PLTs as biomarkers in neurological disorders, their dynamics, and their potential in monitoring disease progression and therapy effectiveness. Results: The systematic review included 104 studies, revealing PLTs as crucial biomarkers in neurocognitive disorders, acting as inflammatory mediators. The findings suggest that PLTs share common features with altered neurons, which could be utilised for monitoring disease progression and evaluating the effectiveness of treatments. PLTs are identified as significant biomarkers for detecting neurological disorders in their early stages and understanding the pathological events leading to neuronal death. Conclusions: The systematic review underscores the critical role of PLTs in neurological disorders, highlighting their potential as biomarkers for the early detection and monitoring of disease progression. However, it also emphasises the need for further research to solidify the use of PLTs in neurological disorders, aiming to enhance early diagnosis and intervention strategies.

Ischemia-Modified Albumin (IMA) Is Associated with Poor Survival in Patients with Newly Diagnosed Idiopathic Pulmonary Fibrosis (IPF): A Pilot Study.

There are increasing efforts to better predict adverse outcomes for idiopathic pulmonary fibrosis (IPF). Our aim was to assess the prognostic potential of ischemia-modified albumin (IMA), an established circulating marker of ischemia and, more recently, oxidative stress, in a cohort of 56 IPF patients recruited between 2015 and 2023 at the University of Sassari, Italy. Demographic and functional parameters and serum IMA concentrations were measured at baseline. Non-survivors had significantly higher IMA concentrations vs. survivors (508 ± 64 vs. 474 ± 42 mABSU, respectively; p = 0.035). The Kaplan-Meier analysis showed a significant association between higher IMA values and poor survival (HR: 3.32, 95% CI from 1.06 to 10.4, p = 0.039). In the Cox regression analysis, this association remained significant after adjusting for the force expiratory volume at 1 s, the total lung capacity, lymphocyte count, and pharmacological treatment (HR: 1.0154, 95% CI from 1.0035 to 1.0275, p = 0.01). IMA, an oxidative stress biomarker measurable using relatively simple and available methods, is independently associated with mortality in IPF. Therefore, its determination may enhance risk stratification and treatment decisions. Prospective studies involving larger cohorts are needed to confirm this association and to endorse the use of IMA in routine practice.

Arginine metabolomics in mood disorders.

Alterations of nitric oxide (NO) homeostasis have been described in mood disorders. However, the analytical challenges associated with the direct measurement of NO have prompted the search for alternative biomarkers of NO synthesis. We investigated the published evidence of the association between these alternative biomarkers and mood disorders (depressive disorder or bipolar disorder). Electronic databases were searched from inception to the June 30, 2023. In 20 studies, there was a trend towards significantly higher asymmetric dimethylarginine (ADMA) in mood disorders vs. controls (p = 0.072), and non-significant differences in arginine (p = 0.29), citrulline (p = 0.35), symmetric dimethylarginine (SDMA; p = 0.23), and ornithine (p = 0.42). In subgroup analyses, the SMD for ADMA was significant in bipolar disorder (p < 0.001) and European studies (p = 0.02), the SMDs for SDMA (p = 0.001) and citrulline (p = 0.038) in European studies, and the SMD for ornithine in bipolar disorder (p = 0.007), Asian (p = 0.001) and American studies (p = 0.005), and patients treated with antidepressants (p = 0.029). The abnormal concentrations of ADMA, SDMA, citrulline, and ornithine in subgroups of mood disorders, particularly bipolar disorder, warrant further research to unravel their pathophysiological role and identify novel treatments in this group (The protocol was registered in PROSPERO: CRD42023445962).

Red Cell Distribution Width as a Predictor of Survival in Patients with Hepatocellular Carcinoma.

Background and Objectives. Hepatocellular carcinoma (HCC) and the intrahepatic biliary tract cancers are estimated to rank sixth for incidence among solid cancers worldwide, and third for mortality rates. A critical issue remains the need for accurate biomarkers for risk stratification and overall prognosis. The aim of this study was to investigate the ability of a biomarker of heterogeneity of the size of red blood cells, the red cell distribution width (RDW), to predict survival in patients with HCC. Materials and Methods. A consecutive series of patients with a histologic diagnosis of HCC were included into this study irrespective of their age, stage of the disease, and treatment administered, and followed-up for a period of three years. Demographic, anthropometric [age, sex, body mass index (BMI)], and clinical data (Charlson Comorbidity Index, Child-Pugh score, etc.), along with laboratory tests were retrieved from clinical records. Results. One-hundred and four patients were included in this study. Among them, 54 (69%) were deceased at the end of the follow-up. Higher RDW values, but not other hematological and biochemical parameters, were significantly associated with mortality in both univariate and multivariate analysis. The optimal RDW cut-off value identified with the Youden test for survival was 14.7%, with 65% sensitivity and 74% specificity (AUC = 0.718, 95% CI 0.622-0.802, p < 0.001). Kaplan-Meier survival curves showed significantly lower survival with higher RDW values (HR = 3.5204; 95% CI 1.9680-6.2975, p < 0.0001) with a mean survival of 30.9 ± 9.67 months for patients with RDW ≤ 14.7% and 22.3 ± 11.4 months for patients with RDW > 14.7%. Conclusions. The results of our study showed that RDW can perform better than other blood-based biomarkers in independently predicting prognosis in patients with HCC.

Heavy metals in biological samples of cancer patients: a systematic literature review.

The majority of the so-called heavy metals are suspected to be involved in a number of pathologies and play a role in human carcinogenesis. Some of them (i.e. arsenic (As), cadmium (Cd), chromium (Cr), lead (Pb), mercury (Hg) and nickel (Ni)) have been defined as carcinogens, increasing the susceptibility of tumor development and progression in humans. Moreover, Ni, Cr, Cd, Hg, and Pb together with zinc (Zn) and iron (Fe), may be capable of stimulating the progression of breast cancer and reducing a patient's sensitivity to treatment through alterations to DNA methylation. In patients with gastric cancers, levels of various heavy metals are augmented and hypothesized to amplify the expression of the human epidermal growth factor receptor type 2 gene. Cd may increase the risk of lung cancer development and have a negative impact on the overall survival of lung cancer patients. To investigate the relation between heavy metals in biological samples and risk, occurrence and survival cancer individuals, a comprehensive review work was performed, with a focus on breast, lung, prostate and gastric cancers. An extensive search strategy was devised to ensure relevant literature could be identified, with the PECO framework being adopted to facilitate this and identify key search terms. As evidenced in this review, there is substantial data to support the hypothesis that heavy metals influence tumor development and progression. Unluckily the number of papers dealing with the determination of metals directly in samples from cancer tissues is still rather limited, so we decided to expand the scope of this review also to analyses carried out on other biological samples, as urine, plasma, hair, nail, etc. The studies reviewed showed that several limitations and current knowledge gaps are present in the literature that require further investigation to improve our comprehension of the impact of different heavy metals on tumorigenesis.

A Systematic Review and Meta-Analysis of Mean Platelet Volume and Platelet Distribution Width in Patients with Obstructive Sleep Apnoea Syndrome.

Obstructive sleep apnoea syndrome (OSAS) is a highly prevalent yet underestimated disorder caused by the complete or partial obstruction of the upper airways. Although polysomnography is the gold standard for OSAS diagnosis, there is an active search for easily accessible biomarkers of disease presence and severity, particularly those reflecting morphological changes in specific blood cells. We investigated the associations between the presence and severity of OSAS, continuous positive airway pressure (CPAP) treatment, mean platelet volume (MPV), and platelet distribution width (PDW), routinely assessed as part of the complete blood count. From 262 retrieved records from PubMed, the Web of Science, Scopus, and Google Scholar, 31 manuscripts were selected for a final analysis, 30 investigating MPV and 15 investigating PDW. MPV was not statistically different between OSAS patients and healthy controls; however, it progressively increased with disease severity. By contrast, OSAS patients had significantly higher PDW values than controls (SMD = 0.40, 95% CI: 0.25 to 0.56; p ˂ 0.001), and the difference increased with disease severity. In a univariate meta-regression, there were significant associations between the MPV and publication year, the apnoea-hypopnea index, and diabetes mellitus, while no associations were observed with the PDW. No significant between-group differences were observed in the subgroup analyses. These data suggest that PDW, and to a lesser extent, MPV, are potential biomarkers of OSAS and require further research to ascertain their pathophysiological significance (PROSPERO, CRD42023459413).

Association between ischemia-modified albumin (IMA) and peripheral endothelial dysfunction in rheumatoid arthritis patients.

The identification of circulating biomarkers of endothelial dysfunction (ED), a precursor to atherosclerosis, in rheumatoid arthritis (RA) would facilitate early risk stratification and prevention strategies. Ischemia-modified albumin (IMA) has emerged as a potential biomarker of oxidative stress, ischemia, and ED. However, studies examining the relationship between IMA and ED in RA patients are lacking. We measured serum IMA concentrations by using an albumin cobalt binding test and peripheral vasodilatory capacity by EndoPAT in 113 RA patients without previous cardiovascular events enrolled in the EDRA study (ClinicalTrials.gov: NCT02341066). The mean peripheral vasodilatory capacity, expressed by the log of reactive hyperemia index (logRHI), was 0.82, corresponding to 27% RA patients having ED. The mean plasma concentrations of IMA were 0.478 absorbance units. We observed a significant and inverse association between peripheral vasodilatory capacity and serum IMA concentrations (rho = - 0.22, p = 0.02). In univariate logistic regression, ED was significantly associated with serum IMA concentrations [OR 1173 (95% CI 1.3568 to 101,364), p = 0.040) and higher disease activity. In multivariate logistic regression, the independent association between ED and IMA remained significant after correction for disease activity and other RA-confounders [OR 2252 (95% CI 1.0596 to 4,787,505), p = 0.048 in Model 1; OR 7221 (95% CI 4.1539 to 12,552,859), p = 0.02 in Model 2]. Conclusions: This study suggests that IMA is a promising biomarker of ED in RA. Further research is needed to confirm our findings and determine the clinical utility of IMA in detecting and managing early atherosclerosis in RA patients.

Combination of mutations in genes controlling DNA repair and high mutational load plays a prognostic role in pancreatic ductal adenocarcinoma (PDAC): a retrospective real-life study in Sardinian population.

BACKGROUND: Patients with pancreatic ductal adenocarcinoma (PDCA) carrying impaired mismatch repair mechanisms seem to have an outcome advantage under treatment with conventional chemotherapy, whereas the role for the tumor mutation burden on prognosis is controversial. In this study, we evaluated the prognostic role of the mutated genes involved in genome damage repair in a real-life series of PDAC patients in a hospital-based manner from the main Institution deputed to surgically treat such a disease in North Sardinia. METHODS: A cohort of fifty-five consecutive PDAC patients with potentially resectable/border line resectable PDAC (stage IIB-III) or oligometastatic disease (stage IV) and tumor tissue availability underwent next-generation sequencing (NGS)-based analysis using a panel containing driver oncogenes and tumor suppressor genes as well as genes controlling DNA repair mechanisms. RESULTS: Genes involved in the both genome damage repair (DR) and DNA mismatch repair (MMR) were found mutated in 17 (31%) and 15 (27%) cases, respectively. One fourth of PDAC cases (14/55; 25.5%) carried tumors presenting a combination of mutations in repair genes (DR and MMR) and the highest mutation load rates (MLR-H). After correction for confounders (surgery, adjuvant therapy, stage T, and metastasis), multivariate Cox regression analysis indicated that mutations in DR genes (HR = 3.0126, 95% CI 1.0707 to 8.4764, p = 0.0367) and the MLR (HR = 1.0018, 95%CI 1.0005 to 1.0032, p = 0.009) were significantly related to worse survival. CONCLUSIONS: The combination of mutated repair genes and MLR-H, which is associated with a worse survival in our series of PDAC patients treated with conventional chemotherapy protocols, might become a predictive biomarker of response to immunotherapy in addition to its prognostic role in predicting survival.