Search Results (11,057)

Background/Objectives: Parkinson’s disease (PD) exhibits marked sexual dimorphism, with a higher incidence and earlier onset in men than in women. However, the impact of biological sex on systemic molecular alterations in PD remains poorly understood. This pilot study aimed to identify sex-specific circulating signatures associated with PD. Methods: Serum samples from a selected cohort of PD patients and healthy controls (HC) of both sexes were analyzed using an integrated biochemical and ¹H NMR-based metabolomic approach. Oxidative stress markers, antioxidant proteins, inflammatory mediators, matrix metalloproteinases, α-synuclein species, and circulating antibodies were evaluated. Results: This analysis indicated that, while global oxidative stress markers were unchanged, sex-related differences in antioxidant pathways were observed as suggested by the reduced Nrf2 expression observed in PD females and increased IL-6 levels, above all in male PD patients. MMP3 levels were significantly higher in female PD patients compared with males. Male patients showed higher levels of 52 kDa protease-resistant α-synuclein species, while females exhibited increased antibody titers against both monomeric and aggregated forms. Metabolomic profiling suggested a disease-associated metabolic remodeling in PD, with distinct sex-related metabolic signatures and a more pronounced and widespread metabolic dysregulation in males. Conclusions: These findings suggest that biological sex may contribute to systemic molecular heterogeneity in PD, with trends indicating more pronounced inflammatory and metabolic alterations in males and distinct immune-related responses in females. Given the exploratory nature of the study and the limited sample size, these observations should be interpreted cautiously and require validation in larger, independent cohorts. Nevertheless, the results support the importance of considering sex-related molecular differences in future biomarker studies and precision medicine approaches for PD. Full article

Background/Objectives: Celiac disease (CD) is a complex multifactorial disorder driven by genetic susceptibility and environmental triggers, with ultra-processed foods (UPFs) acting as potential disruptors of immune homeostasis. This study aimed to characterize the patterns and temporality of UPF consumption in a pediatric population with CD to provide evidence-based insights that can optimize the nutritional quality of a gluten-free diet (GFD) beyond mere gluten avoidance. Methods: A total of 128 children aged 5–14 years were enrolled, comprising a baseline cohort of 48 children newly diagnosed with CD (pre-GFD), 88 patients who had followed a GFD for at least 6 months (post-GFD), including 44 participants from the pre-GFD cohort prospectively re-evaluated after 12 months and 44 additional patients with established GFD adherence and a control group of 36 healthy children (CTRL). Dietary intake was assessed using three-day 24 h recalls. Food processing levels were determined using the NOVA classification system, and adherence to the Mediterranean Diet was evaluated via the KIDMED index. Results: At baseline, UPFs (NOVA 4) were the primary daily energy source for both celiac patients and controls, accounting for over 57% of total caloric intake, peaking during breakfast (~74%) and afternoon snacks (~81%). Longitudinal analysis showed that the nutritional profile and global UPF consumption remained remarkably stable after 12 months on a GFD, though a significant increase in vitamin B6 intake was observed (0.9 ± 0.4 vs. 1.1 ± 0.5 mg; p = 0.034). However, meal-pattern shifts occurred over the 12 months: celiac children significantly reduced their daily intake of culinary ingredients (NOVA 2; p = 0.029) and processed foods (NOVA 3; p = 0.025). Compared to healthy controls, post-GFD patients exhibited significantly lower Vitamin D intakes (4.6 ± 9.4 vs. 6.2 ± 12.3 µg/day; p = 0.008), meeting only 30.8% of the reference intake. Both groups presented inadequate intakes of iron, calcium, folate, magnesium, and zinc. Conclusions: Pediatric celiac patients exhibit a high, deeply ingrained consumption of UPFs that mirrors healthy controls and persists 12 months after starting a GFD. While the GFD alters meal processing dynamics, it fails to resolve baseline micronutrient insufficiencies and is associated with lower dietary vitamin D intake, highlighting the urgent need for targeted nutritional interventions that focus on whole food quality rather than just gluten elimination. Full article

Background/Objectives: Despite improved survival with immune checkpoint inhibitors, the optimal treatment after anti-PD-1 progression in metastatic melanoma remains unclear. This study compared survival outcomes and treatment responses between chemotherapy (CT)- and immunotherapy (IO)-based therapies administered after nivolumab progression in patients with BRAF-negative metastatic melanoma. Methods: This multicenter retrospective study included patients with BRAF-negative metastatic melanoma who developed disease progression during nivolumab treatment. Post-progression systemic therapies were categorized as CT- or IO-based treatments. Treatment responses were assessed according to RECIST version 1.1 criteria. Progression-free survival (PFS) and overall survival (OS) were analyzed using the Kaplan–Meier method, and prognostic factors were evaluated using Cox regression analyses. Results: A total of 141 patients were included. Following nivolumab progression, 107 (75.9%) received CT and 34 (24.1%) received IO. Based on best response to nivolumab, the objective response rate (ORR; CR + PR) was 55.1% in the CT group and 44.1% in the IO group. After post-nivolumab treatment, ORRs were 29.9% and 32.4% in the CT and IO groups, respectively, whereas complete response rates were higher with IO (21.2% vs. 3.0%). Median PFS was 4.17 months in the CT group and 3.9 months in the IO group (p = 0.403). Median OS was 7.83 and 8.17 months, respectively (p = 0.416). Elevated LDH level was identified as an independent adverse prognostic factor. Conclusions: In this multicenter real-world cohort, no statistically significant differences in survival were observed between patients receiving CT or IO after nivolumab progression. Given the retrospective, non-randomized study design, these findings should not be interpreted as evidence of comparative treatment efficacy. The higher CR rate observed with IO should be interpreted cautiously due to potential selection bias. Prospective studies are warranted to define the optimal treatment strategy after anti-PD-1 failure. Full article

Extracellular vesicles (EVs) are membrane-enclosed nanoparticles that mediate intercellular communication in the immune system by transferring proteins, nucleic acids, and lipids. Their biocompatibility, nanoscale size, and capacity for cell-type-selective delivery have stimulated growing interest in engineering EVs as therapeutic platforms. In this review, we discuss recent advances in EV engineering for immune regulation, focusing on surface display, cellular targeting, and cargo loading strategies. A central concept is that engineered EVs should not be viewed simply as delivery vehicles, but as programmable immune interfaces. EVs can integrate antigen specificity, target-cell recognition, therapeutic cargo delivery, and defined immunostimulatory or tolerogenic signals within a single nanoscale particle. By combining these modular elements, engineered EVs can be designed to direct immune responses in a context-dependent manner. We examine how this principle is being applied to cancer immunotherapy, immune suppression, and antigen-specific tolerance induction, including antigen-presenting EVs, cytotoxic and RNA-loaded EVs, checkpoint-modulatory EVs, MSC-derived EVs, and engineered platforms for autoimmune and inflammatory diseases. We also discuss the clinical translation of engineered EV therapeutics, with emphasis on manufacturing, characterization, potency assays, biodistribution, safety, and regulatory challenges. Together, current advances suggest that programmable EV immune interfaces may provide a versatile foundation for next-generation cancer immunotherapy and antigen-specific immune regulation. Full article

The gut microbiome of rainbow trout (Oncorhynchus mykiss) and Atlantic salmon (Salmo salar) is increasingly recognized as a functional interface linking dietary inputs, epithelial barrier integrity, mucosal immunity, environmental stress, disease susceptibility, and antimicrobial-resistance risk in intensive aquaculture. Based on available salmonid studies and relevant evidence from broader fish and aquaculture systems, this review synthesizes current knowledge on salmonid gut microbial composition, nutritional modulation, microbiome–mucosal immune interactions, aquaculture stressors, antibiotic exposure, antibiotic resistance genes (ARGs), mobile genetic elements (MGEs), metagenomics, multi-omics, and emerging microbiome-informed decision-support tools. Current evidence does not support a universally stable single-core microbiota in these species. Instead, community structure is shaped by developmental stage, freshwater–seawater transition, intestinal segment, digesta versus mucosa sampling, diet, temperature, stress, health status, and methodological workflow. Feed substitution and functional additives can remodel the gut microbiota, but these shifts should be interpreted alongside histology, barrier function, metabolic profiles, immune indicators, and disease-resistance phenotypes. Antibiotic exposure may reduce acute bacterial disease pressure while disturbing community structure and potentially enriching ARGs or ARG–MGE associations. Risk assessment should therefore move beyond ARG abundance toward host–ARG–MGE linkage using shotgun metagenomics, metagenome-assembled genomes, long-read sequencing, Hi-C, and externally validated multi-omics models. Machine learning and artificial intelligence approaches may support feature screening, risk stratification, and decision support, but their application in salmonid gut-health management remains at an early stage and requires external validation across sites, production stages, diets, and seasons. Full article

Eosinophils are highly granulated white blood and tissue cells that play complex roles in the immune system including host protection against helminthic parasites, viruses, fungi, and bacteria. These bone marrow-derived cells cause tissue damage in a range of diseases and disorders, particularly in allergy, asthma, and chronic rhinosinusitis with nasal polyps. Eosinophils are recruited to tissues in response to chemotactic signals, and during inflammation, they release a plethora of mediators, including immunoregulatory cytokines, through multiple pathways involving degranulation, respiratory burst, lipid mediator release, exosome release, and extracellular trap formation. Degranulation from eosinophils has been implicated as a major effector mechanism in airway diseases, particularly late phase asthma responses and in nasal polyps from patients with chronic rhinosinusitis. In degranulation responses, eosinophils release numerous granule proteins by classical exocytosis, compound exocytosis, piecemeal degranulation, and cytolysis, which refers to cell lysis through membrane rupture and cell destruction. Cytolysis can lead to suicidal extracellular trap formation, which is a regulated form of cell death involving the release of extracellular DNA traps and granule proteins. Granule release from eosinophils is dependent on activation of specific and tightly regulated intracellular signaling pathways, including Rac and Rab guanosine triphosphatases, soluble NSF attachment protein (SNAP) receptors (SNAREs), Cdk5 kinase, and actin dynamics. These observations have shown selective and nonredundant roles for signaling in degranulation responses. In this review, we explore findings from the literature on the mechanisms controlling granule-derived mediator release from eosinophils. Full article

Asthma is a heterogeneous chronic airway disease in which oxidative stress (OS) plays a central mechanistic role beyond classical immune-mediated inflammation. Reactive oxygen and nitrogen species (ROS/RNS), generated by recruited inflammatory cells and activated airway structural cells, drive epithelial injury, mucus hypersecretion, airway remodeling, and modulate key transcription factors including nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. This review synthesizes current evidence on the multilevel redox-based determinants of asthma severity, spanning from genetic polymorphisms to circulating biomarkers. We examine serum antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), peroxiredoxins (PRDXs), and the thioredoxin (Trx) system as dynamic indicators of systemic redox status and disease severity, alongside oxidative enzymes including NADPH oxidases and dual oxidases (NOX/DUOX), xanthine oxidase (XO), and myeloperoxidase (MPO) that serve as upstream sources of airway oxidant burden. Functional genetic polymorphisms in antioxidant genes (SOD2, CAT, glutathione S-transferase mu 1/glutathione S-transferase theta 1 (GSTM1/GSTT1), heme oxygenase-1 (HO-1), NAD(P)H quinone dehydrogenase 1 (NQO1), nuclear factor erythroid 2-related factor 2/Kelch-like ECH-associated protein 1 (Nrf2/KEAP1)) and oxidative enzyme genes including nitric oxide synthase 1/2/3 (NOS1/2/3), MPO, cytochrome b-245 alpha chain (CYBA), and xanthine dehydrogenase (XDH) are reviewed as modulators of individual redox capacity and asthma susceptibility, with particular attention to gene–environment interactions. We further discuss oxidative damage biomarkers, including malondialdehyde (MDA), 8-isoprostanes, 4-hydroxynonenal, 8-oxo-7, 8-dihydro-2′-deoxyguanosine, protein carbonyls, 3-nitrotyrosine, and advanced oxidation protein products as indicators of lipid, DNA, and protein oxidation that correlate with disease activity and control. The roles of micronutrient cofactors in modulating antioxidant enzyme function and their potential as contextual biomarkers are also addressed. Additionally, emerging evidence on microRNAs (miRNAs) linked to OS biology in asthma is presented. Finally, we critically evaluate the challenges limiting clinical translation, including biomarker non-specificity, analytical variability, gene–environment complexity, and the absence of standardized reference ranges. This integrated framework supports the development of multilevel redox prognostic panels combining genetic, enzymatic, and oxidative damage readouts for improved asthma phenotyping, severity stratification, and personalized therapeutic approaches. Full article

Major Depressive Disorder (MDD) has a multifactorial etiology and pathogenesis that significantly impacts an individual’s quality of life. One of the possible correlations for its onset is the activation of inflammatory responses resulting in neurodegeneration and, consequently, the emergence of depressive symptoms. Interleukin-1β is a regulatory cytokine of the immune and nervous systems that acts on several processes, including mood regulation. This systematic review analyzed the IL1B (C-511T) (rs16944) variant’s CC and CT genotype frequencies and their associations with MDD in different populations while also verifying the TT genotype’s influence on response to antidepressant therapy. This review involved searching five databases, and articles were selected according to the PECOS inclusion criteria, resulting in eight articles. The findings highlight distinct clinical outcomes: the CC genotype was more frequently associated with greater MDD symptom severity, whereas the TT genotype was predominantly associated with antidepressant treatment response; thus, these associations should not be considered equivalent in terms of susceptibility to disease onset. However, despite these findings, other studies have found no significant association between this genetic variant and MDD. Therefore, further studies across different populations are needed to better understand the role of this polymorphism in the etiology of this disorder. Full article

Background: Vitamin D is involved not only in calcium–phosphate homeostasis but also in immune and endothelial regulation. Vitamin D deficiency has been suggested to worsen disease activity in systemic lupus erythematosus (SLE). Environmental and lifestyle factors, including seasonal sun exposure, smoking, diet, and supplementation, may influence vitamin D status and disease manifestations. This study aimed to evaluate the association between serum 25-hydroxyvitamin D [25(OH)D] levels, disease activity, and anti-double-stranded DNA (anti-dsDNA) antibody titers in patients with SLE, taking selected lifestyle and environmental factors into account. Methods: Serum 25(OH)D concentrations, SLE disease activity assessed by the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score, and anti-dsDNA antibody titers were measured in patients with SLE and healthy controls. Blood samples were collected during sunny (April–September) and non-sunny (October–March) months. Information on vitamin D supplementation, smoking status, and dietary habits was obtained using a structured questionnaire. Associations between vitamin D status, disease activity, anti-dsDNA seropositivity, season of blood collection, supplementation, smoking, and diet were analyzed statistically. Results: Patients with SLE had significantly higher mean serum 25(OH)D levels than controls, mainly due to frequent vitamin D supplementation. No significant associations were observed between serum 25(OH)D levels and SLEDAI-2K scores or anti-dsDNA antibody positivity. Seasonality, smoking status, and adherence to special diets were not significantly related to disease activity or anti-dsDNA seropositivity. Vitamin D supplementation was strongly associated with sufficient 25(OH)D levels but did not translate into reduced disease activity or lower anti-dsDNA prevalence. Conclusions: Serum 25(OH)D concentration was not associated with clinical or immunological activity of SLE in this cross-sectional study, despite effective correction of deficiency through supplementation. These findings likely reflect the heterogeneity of SLE and the limitations of single time-point assessments, although regular monitoring and individualized vitamin D supplementation may still be considered in SLE care, particularly in the context of recommended photoprotection. Full article

Background/Objectives: Sarcoidosis is a multisystem inflammatory disease characterized by heterogeneous clinical manifestations and variable disease severity. Hematological inflammatory markers, including the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), mean platelet volume (MPV), red cell distribution width (RDW), and systemic immune-inflammation index (SII), have recently attracted attention as accessible indicators of systemic inflammation in sarcoidosis. This study aimed to evaluate radiological stage, symptom burden, pulmonary function parameters, and hematological markers in patients with sarcoidosis. Methods: This retrospective multicenter cohort study included histopathologically confirmed sarcoidosis patients from 10 centers. Demographic characteristics, clinical manifestations, pulmonary function test parameters, serum angiotensin-converting enzyme (ACE) levels, and hematological inflammatory markers (MPV, RDW, NLR, PLR, SII) were evaluated. Patients were categorized according to radiological stage (stage 0–I vs. stage II–IV), symptomatic status, and symptom burden (<3 vs. ≥3 symptoms). Results: Among 458 patients included in the study, stage I (47.8%) and stage II (46.9%) disease were the predominant radiological presentations. Patients with stage II–IV disease were older and demonstrated significantly lower forced expiratory volume in one second (FEV1), forced vital capacity (FVC), FEV1/FVC ratio, and diffusing capacity for carbon monoxide (DLCO) values together with higher serum ACE levels compared with stage 0–I disease. Dyspnea, weight loss, and extrapulmonary involvement were more frequent in stage 2–4 disease. No significant associations were observed between radiological stage and NLR, PLR, or SII values. MPV and RDW values differed significantly between symptomatic and asymptomatic patients. Patients with ≥3 symptoms demonstrated significantly lower pulmonary function parameters together with statistically significant higher NLR, PLR, and SII values. In multivariate analyses, only the SII demonstrated an independent association with a high symptom burden. Conclusions: Serum ACE levels were associated with advanced radiological stage, whereas hemogram-derived inflammatory indices, particularly the NLR, PLR, and SII, were associated with symptom burden rather than radiological stage in sarcoidosis and may reflect symptomatic inflammatory activity. Full article

Anemia of chronic disease (ACD) is a condition linked to chronic immune activation secondary to a wide range of infectious, inflammatory, and autoimmune diseases. It is characterized by a state of iron-restricted erythropoiesis, in which prolonged activation of cytokines leads to retention of iron within the reticulo-endothelial system, driven primarily by hepcidin. Reduced iron availability contributes to a blunted response by erythropoietin and impaired erythropoiesis, in addition to a shortened red cell lifespan. In patients found to have anemia and evidence of chronic inflammation, parameters such as mean cell volume, iron studies, percentage of hypochromic red cells, reticulocyte hemoglobin content, and levels of ferritin, serum transferrin receptor, hepcidin, erythropoietin, and GDF15 are all used to build a picture of anemia of chronic disease. Following this, management normally utilizes erythropoietin-stimulating agents alongside parenteral iron supplementation when treatment of the underlying cause is not available. Newer therapies, such as hypoxia-inducible factor prolyl hydroxylase inhibitors and hepcidin inhibitors, also play a role, while cytokine targets, carbon dots, androgens, and other therapies are emerging as possible treatment routes. Despite its high prevalence, there remain few standardized methods of diagnosis or management in anemia of chronic disease. This narrative review explores long-standing and emerging practices in the diagnosis and management of this condition to ensure an up-to-date understanding. Full article

Background/Objectives: Systemic sclerosis (SSc) is a heterogeneous systemic autoimmune rheumatic disease characterized by immune dysregulation, vasculopathy, and fibrosis involving the skin and internal organs. Interstitial lung disease (ILD), pulmonary arterial hypertension (PAH), and cardiac involvement remain major causes of morbidity and mortality, yet prediction of disease progression and therapeutic responsiveness remains difficult. Methods: This narrative review summarizes studies of circulating blood biomarkers in SSc, with emphasis on literature published since 2020 and on Japanese multicenter longitudinal cohort studies. Disease-specific autoantibodies were intentionally excluded from the main scope, and the review focuses on soluble biomarkers measurable in peripheral blood that reflect inflammation, endothelial injury, and fibrotic remodeling. Results: Multiple cytokines, chemokines, adhesion molecules, endothelial markers, extracellular vesicle-associated molecules, and extracellular matrix (ECM)-related molecules have been associated with disease activity, organ involvement, prognosis, and therapeutic response in SSc. Clinically established biomarkers such as KL-6 and surfactant protein-D (SP-D) for SSc-associated interstitial lung disease (ILD), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) for pulmonary arterial hypertension (PAH), are already used as adjunctive tools in routine clinical assessment, whereas many other candidate biomarkers, including interleukin (IL)-6, CCL2, CXCL8, CXCL4, intercellular adhesion molecule-1 (ICAM-1), CCL18, periostin, endostatin, endothelin-1, extracellular vesicle signatures, and ECM turnover markers remain at varying stages of clinical validation. In particular, Japanese multicenter longitudinal studies have demonstrated the prognostic significance of circulating chemokines and adhesion molecules in early SSc and, more recently, identified biomarker-based clusters associated with distinct pulmonary trajectories. Recent multidimensional proteomic and transcriptomic approaches further support biologically based patient stratification in SSc. Conclusions: Blood biomarkers may contribute to risk stratification, prediction of organ progression, and future precision medicine in SSc. Integrated biomarker signatures may better capture the biological heterogeneity of SSc than single biomarkers alone. However, most candidate biomarkers still require external validation, assay standardization, and demonstration of incremental value over conventional clinical variables before routine clinical implementation. Full article

Vertigo, dizziness, and oculomotor disturbances may occur as manifestations of immune-mediated disorders affecting the inner ear, central vestibular pathways, or multisystem autoimmune disease. Although uncommon, these conditions are clinically important because delayed recognition may lead to irreversible hearing loss, vestibular dysfunction, or neurological disability. This review summarizes the clinical presentation, diagnostic approach, and treatment of immune-mediated vestibular and oculomotor disorders. We suggest a practical classification into isolated immune-mediated inner ear disease, systemic autoimmune disorders with audio-vestibular involvement, and autoimmune disorders of the central or peripheral nervous system affecting balance and eye movements. Red flags for such conditions include bilateral or progressive symptoms, fluctuating audio-vestibular deficits, associated neurological signs, and accompanied autoimmune disease. Corticosteroids remain the main first-line treatment in many of these disorders, mainly due to missing data from controlled trials. Steroid-sparing immunosuppressants, biologics, and tumor-directed therapies are effective in many cases; however, because of the missing data, they are only used in selected entities without any other choice. A structured neuro-otological and immunological workup is essential to improve diagnostic accuracy and enable timely therapy. Full article

Background/Objectives: Kimura disease is a rare, chronic immune-mediated disorder that classically produces painless head-and-neck masses, regional lymphadenopathy, blood eosinophilia, and a raised serum immunoglobulin E (IgE). Almost all reported patients are young East Asian men, and the condition is seldom encountered in the Middle East, where it is easily mistaken for lymphoma or another eosinophilic disorder. We describe a histologically confirmed case in a Saudi adolescent and review the literature to compare treatment strategies and outcomes across populations. Methods: We documented the clinical course, laboratory profile, histopathological findings, and 15-month outcome of the patient, and searched PubMed for reported cases of Kimura disease, with emphasis on pediatric and non-Asian series. Results: A 16-year-old boy presented with a one-year history of painless right cervical swelling, constitutional symptoms and striking eosinophilia (36%; absolute eosinophil count 6.5 × 10⁹/L). Hematological malignancy was excluded through bone-marrow examination, flow cytometry and molecular studies. Excisional lymph node biopsy revealed the diagnostic triad—reactive follicular hyperplasia, a dense eosinophilic infiltrate with microabscesses, and vascular proliferation—together with IgE-positive immunostaining. Complete remission followed surgical excision alone and was maintained at 15 months without systemic corticosteroids. Conclusions: Kimura disease occurs well beyond its traditional geographic boundaries and belongs in the differential diagnosis of eosinophilia accompanied by lymphadenopathy. Although corticosteroids remain the mainstay for extensive disease, relapse on tapering is common, whereas complete excision can secure lasting remission in localized pediatric disease while sparing patients from steroid-related toxicity. Full article

Background/Objectives: Although outcomes in Hodgkin lymphoma (HL) have improved substantially, patients with advanced-stage disease, comorbidities, or relapsed/refractory presentations can still fare poorly. Blood-based indices of systemic inflammation and nutrition are derived from routine tests, but their value beyond established prognostic models is uncertain. We examined the association of the baseline Gustave Roussy Immune Score (GRIm) and Glasgow Prognostic Score (GPS) with treatment response, progression-free survival (PFS), and overall survival (OS) in HL, focusing on their performance relative to the seven-factor International Prognostic Score (IPS-7). Methods: We retrospectively analysed 110 adults with histologically confirmed HL treated at a tertiary haematology centre between January 2015 and December 2025. GPS, GRIm, and IPS-7 were calculated from data recorded at diagnosis. Treatment response was classified as complete versus non-complete. Outcomes were assessed with Kaplan–Meier analysis, log-rank tests, Cox regression, Harrell’s C-index, and likelihood-ratio testing. Results: Most patients had advanced-stage disease (69.1%) and received ABVD-based treatment (94.5%); complete response was achieved in 90 (81.8%). GPS and GRIm were not significantly associated with non-complete response, whereas IPS-7 was. Over a median follow-up of 39.5 months, 28 patients (25.5%) progressed or died and 17 (15.5%) died. In univariable Cox analysis, high GRIm risk (HR = 2.68, 95% CI 1.17–6.14), higher GPS (HR = 2.18 per point, 95% CI 1.23–3.89), and higher IPS-7 (HR = 2.10 per point, 95% CI 1.59–2.77) predicted shorter PFS. For OS, GPS and IPS-7 were significant, whereas GRIm was not. After adjustment for IPS-7, neither GPS nor GRIm remained independently associated with PFS or OS, and adding either score to IPS-7 produced only small, non-significant gains in discrimination. Conclusions: Baseline GPS and GRIm were associated with survival on univariable analysis, particularly for PFS, but their incremental value beyond IPS-7 was limited. These scores may help describe baseline inflammatory and nutritional risk and should not be regarded as alternatives to established HL prognostic models. In particular, GPS and GRIm were not significantly associated with treatment response and should be viewed as supportive markers requiring external validation, rather than as tools that can independently guide treatment decisions. Full article