Search Results (141)

Background and Clinical Significance: This paper presents a case of Vogt–Koyanagi–Harada (VKH)-like disease following nivolumab and ipilimumab therapy for squamous cell carcinoma of the lung, complicated by transient type 1 macular neovascularisation (MNV). Case Presentation: A 67-year-old man presented with reduced visual acuity, more pronounced in the left eye, accompanied by headache and neurosensory hearing loss for 10 days. He had been receiving combination therapy with nivolumab and ipilimumab for approximately nine weeks. Slit-lamp examination and multimodal imaging revealed multiple serous retinal detachments, choroidal folds, and bacillary layer detachment. A bilateral VKH-like syndrome was considered the most likely diagnosis, consistent with an immune-related adverse event (irAE). High-dose systemic corticosteroids were initiated, resulting in marked anatomical improvement and recovery of visual acuity. Following multidisciplinary discussion with the patient’s oncologist, ipilimumab was permanently discontinued and nivolumab was rechallenged in combination with chemotherapy after resolution of the ocular adverse events, given the progression of the underlying malignancy. Notably, optical coherence tomography angiography (OCTA) additionally demonstrated a type 1 non-exudative MNV, which resolved spontaneously during follow-up. Conclusions: Nivolumab and ipilimumab, targeting PD-1 and CTLA-4, respectively, are effective anticancer therapies but may induce immune-related adverse events involving the eye. VKH-like disease is a rare but potentially vision-threatening complication. Early recognition and prompt treatment are essential for favourable visual outcomes. In summary, this is a rare case of VKH-like disease associated with nivolumab and ipilimumab therapy, complicated by transient inflammatory type 1 MNV. Clear guidelines are needed regarding management of ocular immune-related adverse events and decisions on continuation or discontinuation of life-prolonging immunotherapy. Full article

Background: In recent decades, the incidence of colorectal cancer (CRC) has been rising worldwide. CRC ranks second in cancer-related mortality. The identification of reliable biomarkers for early diagnosis and prognosis prediction, along with a deeper understanding of the underlying molecular events, holds substantial promise for improving patient outcomes. The tissue inhibitor of the metalloproteinase 1 (TIMP1) gene is overexpressed in various gastrointestinal malignancies and contributes to tumor progression. However, its role in regulating the CRC tumor immune microenvironment (TIME) and its potential as a clinically actionable prognostic biomarker remain unclear. Methods: To probe how TIMP1 acts as a prognosis-related candidate biomarker in colorectal carcinoma, TCGA-derived datasets were adopted to conduct Kaplan–Meier survival assessment. We also investigated the connection between the expression abundance of TIMP1 and the infiltration of immune populations and intratumoral lymphocytes; furthermore, immune checkpoint-related genes were systematically assessed across multiple tumor types via the TISIDB and TIMER2.0 platforms, with particular emphasis on CRC. We adopted the ESTIMATE scoring system to figure out how TIMP1 gene expression correlates with the phenotypic properties of the colorectal-cancer TIME. We relied on the limma toolkit for the screening of differential transcripts from high-TIMP1 and low-TIMP1 cohorts. Enrichment assessments covering Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes entries were then carried out to predict the potential biological pathways associated with TIMP1. We constructed the protein–protein interaction map for TIMP1-interacting partners via the STRING repository. To further explore TIMP1-correlated genes, we performed Venn diagram intersection analysis combined with Spearman’s correlation test. Finally, quantitative reverse-transcription PCR was then implemented to detect TIMP1 messenger-RNA abundance inside the RKO colorectal carcinoma cell line as well as normal colonic epithelial CCD-18Co cells, which offered in vitro experimental verification for our bioinformatic outcomes. Results: According to outcome data, TIMP1 transcripts were markedly up-regulated in CRC specimens and cell lines relative to normal samples. Elevated TIMP1 expression served as a poor-prognosis indicator for overall survival (hazard ratio [HR] = 0.43, 95% confidence interval [CI] = 0.29–0.64, p < 0.001) and disease-specific survival (HR = 0.39, 95% CI = 0.22–0.68, p = 0.001) among colorectal-carcinoma patients. TIMP1-high and TIMP1-low groups exhibited notable differences in immune cell infiltration (CD8⁺ T, macrophage, mast, neutrophil, B, monocyte, dendritic, and CD4⁺ T cells). TIMP1 expression was also significantly correlated with tumor-infiltrating lymphocytes, key immune checkpoint genes (e.g., CD274 [PD-L1] and CTLA4), and immunomodulatory chemokines (e.g., CCL3 and CCL5). Twelve TIMP1-interacting DEGs were selected: COL5A1, FN1, PRG4, and a cluster of nine MMPs (MMP1/2/3/7/8/9/11/13/14), all of which showed significant positive correlations with TIMP1 (r = 0.31–0.63, all p < 0.001). Conclusions: TIMP1 expression correlates with features of the tumor immune microenvironment and extracellular matrix remodeling in CRC, suggesting that TIMP1 shows potential as a candidate biomarker. However, its potential as a therapeutic target warrants further experimental investigation. Full article

Oral squamous cell carcinoma (OSCC) is a malignancy characterized by a complex immunosuppressive tumor microenvironment. Immunomodulatory cytokines and immune checkpoints such as PD-L1 (programmed death-ligand 1) and CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) play a crucial role in tumor development. Due to its high mortality rate, OSCC remains one of the major challenges in modern oncology. The aim of this retrospective study was to assess the expression of PD-L1, CTLA-4, IL-10, and IL-18 in paraffin-embedded tumor specimens and to analyze their associations with selected clinicopathological parameters in 79 patients treated surgically between 2011 and 2023. Most patients exhibited intermediate expression of PD-L1 (1–49%; 81.0%), CTLA-4 (1–49%; 87.3%), IL-18 (11–25%; 78.5%), and IL-10 (11–25%; 58.2%). PD-L1 and CTLA-4 expression showed a very strong association (p < 0.001, Cramer’s V = 0.823). IL-18 expression was negatively correlated with both PD-L1 (p = 0.017, Cramer’s V = 0.322) and CTLA-4 (p = 0.004, Cramer’s V = 0.322). A positive correlation between IL-18 and IL-10 expression was also observed (p < 0.001, Cramer’s V = 0.403). Among all analyzed biomarkers, only IL-10 expression showed a significant association with 5-year survival in univariate analysis (p = 0.009), with higher IL-10 expression associated with shorter survival. However, this finding did not retain statistical significance in multivariate analysis after adjustment for age and tumor stage. The results indicate a strong relationship between PD-L1 and CTLA-4, suggesting their complementary role in tumor-associated immunosuppression. The observed associations between IL-18 and PD-L1, and between IL-18 and CTLA-4, highlight the complexity of the mechanisms regulating the antitumor immune response. Although IL-10 did not retain independent prognostic significance, the findings from the univariate analysis may indicate a potential role for IL-10 in mechanisms related to tumor progression, warranting further investigation. Future studies should further clarify the interactions between cytokine-related immunoregulatory mechanisms and immune checkpoint pathways in OSCC, particularly in relation to IL-10, IL-18, PD-L1, and CTLA-4 expression. Full article

Background/Objectives: Rheumatoid arthritis (RA) is a chronic autoimmune disease marked by sustained synovial inflammation and systemic immune activation. Genetic polymorphisms in key immune-regulatory pathways are thought to influence both disease susceptibility and progression. This study aimed to characterize sequence variation within selected coding regions of TNFAIP3 and CTLA4 in Kurdish patients with RA and to evaluate circulating TNF-α and soluble CTLA-4 (sCTLA-4) levels in the same cohort. Methods: Eighty-seven participants (67 RA patients, 20 controls) were enrolled. Serum TNF-α and sCTLA-4 concentrations were quantified by ELISA. Genomic DNA was extracted and targeted Sanger sequencing of selected coding regions of TNFAIP3 and CTLA4 was performed in RA patients. Variant identification was conducted relative to GRCh38 and annotated using dbSNP and Genome Aggregation Database (gnomAD). GeneMANIA was used for network-based contextualization. Results: In the 218-bp targeted region of TNFAIP3, 103 sequence-level variant occurrences were identified in RA patients, including substitutions and insertion/deletion events. In the 136-bp targeted region of CTLA4, 33 sequence-level variant occurrences were identified, also including substitutions and insertion/deletion events. RA patients exhibited significantly elevated serum TNF-α levels compared with controls (p = 0.025), whereas sCTLA-4 levels did not differ significantly. Conclusions: This study provides the first targeted characterization of TNFAIP3 and CTLA4 genetic variation in Kurdish RA patients and integrates these findings with circulating inflammatory biomarkers. Although not designed to assess disease susceptibility, the study provides a valuable descriptive genetic resource for this population and complements existing evidence implicating NF-κB regulation and immune checkpoint signaling in RA. These findings establish a strong foundation for future case–control, genotype–phenotype, and functional investigations. Full article

Dendritic cell (DC)-based cancer immunotherapy remains limited by heterogeneous immune responses and variable clinical efficacy. CD86, a key co-stimulatory molecule, is traditionally regarded as a marker of dendritic cell maturation; however, accumulating evidence suggests that CD86 expression is regulated by immune checkpoint interactions, inflammatory signaling, and tumor microenvironment-associated immune modulation. In this review, we summarize current evidence regarding the molecular mechanisms governing CD86 regulation, including MARCH1-mediated ubiquitination and CTLA-4-mediated trans-endocytosis, and discuss how suppressive cytokines, hypoxia, and metabolic stress influence dendritic cell function within the tumor microenvironment (TME). We further review the heterogeneity of CD86 regulation across dendritic cell subsets and immune contexts, as well as its potential relevance in secondary lymphoid organs and tumor-associated immune responses. In addition, we discuss current evidence regarding soluble CD86 (sCD86) and its reported associations with immune activation and dysregulated immune states in cancer. Current evidence supports that CD86 regulation is shaped by integrated co-stimulatory signaling, immune checkpoint interactions, and tumor microenvironment-associated suppression. Importantly, CD86 may function not only as a dendritic cell maturation marker but also as a dynamic immunoregulatory molecule with context-dependent implications in cancer immunity. However, substantial uncertainties remain regarding its mechanistic role, prognostic value, and therapeutic relevance across different tumor settings. Future mechanistic and translational studies are needed to clarify these unresolved issues. Full article

Background: The immunological factors associated with long-term hepatitis C virus (HCV)-specific humoral immunity after cure remain uncharacterized, particularly in people with HIV (PWH). This study investigated T-cell immunophenotypes and plasma biomarkers associated with anti-E2 binding (HCV-E2Abs) and neutralizing antibody (HCV-nAbs) titers 5 years after achieving sustained virologic response (SVR). Methods: This cross-sectional study analyzed 64 PWH with cured HCV and prior advanced fibrosis. We quantified plasma antibody titers against 5 HCV genotypes, T-cell phenotypes (n = 58), and plasma biomarkers (n = 50). Associations were assessed using Generalized Linear Models (gamma distribution, log-link function) adjusted for clinical confounders, reporting adjusted Arithmetic Mean Ratios (aAMRs) and false discovery rate (FDR)-corrected q-values. Results: Higher frequencies of CD4⁺ T-cell activation (CD38⁺; aAMR = 1.58; q = 0.028) and soluble CD27 levels (aAMR = 1.46; q = 0.038) were associated with higher HCV-E2Abs titers. In contrast, memory T-cell activation across CD4⁺ and CD8⁺ compartments (HLA-DR⁺ and CD38+; all q < 0.10) and elevated soluble immune checkpoints (sCD28, sPD-L2, sLAG-3, sCTLA-4; all q < 0.10) were associated with preserved HCV-nAbs titers. Conversely, a higher frequency of naïve CD8⁺ T-cells was associated with lower neutralization capacity (aAMR = 0.41; q = 0.042). Regarding inflammatory markers, soluble TNF-RI was positively associated with neutralizing titers (aAMR = 1.44; q = 0.019), whereas IL-18 was inversely associated (aAMR = 0.53; q = 0.019). Conclusions: Specific activated T-cell subsets, checkpoint shedding, and selective inflammatory signals were associated with higher long-term HCV-nAbs titers in PWH. In contrast, higher frequencies of naïve CD8⁺ T-cells and elevated IL-18 levels were associated with reduced neutralizing capacity. Full article

Background/Objectives: Immune checkpoint inhibitors (ICIs) have transformed cancer therapy, providing substantial survival benefits across a wide range of malignancies. However, ICI-associated renal toxicity encompasses a broad spectrum of clinical entities, ranging from nonspecific acute kidney injury to well-defined immune-mediated nephropathies with distinct pathophysiological mechanisms. Methods: We performed a large-scale pharmacovigilance study using the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database to evaluate immune-mediated nephropathy associated with ICIs from January 2014 to March 2025. To improve specificity and minimize misclassification, the analysis was restricted to well-defined immune-mediated renal adverse events identified using MedDRA Preferred Terms, excluding nonspecific acute kidney injury. Disproportionality analysis was conducted using reporting odds ratios (RORs) with 95% confidence intervals (CIs) to assess associations between individual ICIs, treatment regimens, and nephropathy reporting. Results: Among 203,652 ICI-related adverse event reports (irAEs), 2361 (1.12%) involved immune-mediated nephropathy. Compared with other irAEs (non-nephropathy), immune-mediated nephropathy was more frequently reported in patients aged ≥ 65 years and in those with lung and genitourinary malignancies. Tubulointerstitial nephritis was the predominant subtype. Higher reporting signals were observed with cemiplimab and pembrolizumab, whereas durvalumab and atezolizumab demonstrated lower reporting signals. Combination regimens involving PD-1 and CTLA-4 inhibitors were associated with higher reporting frequencies compared with monotherapy. Conclusions: This real-world pharmacovigilance analysis identifies clinically relevant differences in immune-mediated nephropathy reporting across ICI classes and treatment strategies. PD-1 inhibitors and PD-1/CTLA-4 combination regimens were associated with higher reporting signals, suggesting potential variation in renal safety profiles. These findings should be interpreted cautiously, given the inherent limitations of spontaneous reporting systems, but they provide hypothesis-generating evidence to support future prospective studies with detailed clinical and histopathological correlation. Full article

Since the first approval of CTLA-4 blockade for melanoma, immune checkpoint inhibitors (ICIs) have expanded into a major class of cancer therapy, with more than 100 FDA-approved oncological indications across metastatic and earlier-stage disease settings, including use as monotherapy and in combination regimens. Preclinical research has largely focused on myocarditis and atherosclerosis, but a wider set of phenotypes, such as non-inflammatory left ventricular dysfunction (NILVD), arrhythmias, and vasculitis, can be observed, and they are rarely connected within a single mechanistic model. We aim to build a systems-oriented, mechanistic framework of the most widely studied biological processes; it will link the main checkpoint pathways to relevant cardiac and vascular cell types, molecular pathways, immune synapses, and candidate biomarkers. We searched PubMed, Scopus, and Web of Science using combinations of terms for immune checkpoint inhibition and cardiovascular-immune-related adverse events that provide mechanistic insight into cardiac-immune-related adverse reactions (irAEs). An AI-assisted semantic clustering approach was used only to organize the included literature. The integrated framework identifies PD-1/PD-L1 as the dominant mechanistic hub linking T-cell activation, endothelial recruitment, myocardial injury, and vascular inflammation. Across phenotypes, a shared immune core involving checkpoint pathways, cytokine signaling, and leukocyte trafficking coexists with phenotype-restricted mediators that may bias injury toward myocarditis, vascular inflammation, conduction-system disease, or NILVD. KEGG analyses support the enrichment of T-cell receptor signaling, Th17 differentiation, JAK-STAT signaling, cytokine–cytokine receptor interaction, and lipid and atherosclerosis pathways. Candidate biomarkers emerging from the reviewed literature include troponin, IL-6, CXCL9/CXCL10/CXCL13, S100A family proteins, ROCK2, HLA-linked susceptibility signals, and T-cell receptor clonality markers. The AI-assisted clustering broadly recapitulated the expert-defined thematic structure while identifying finer semantic neighborhoods within the literature. This framework provides a support map for further hypotheses about toxicity patterns with current and next-generation checkpoint strategies on the cardiac system, while AI-assisted clustering provides a complementary method for organizing the literature rather than an independent source of biological inference. Full article

Objectives: Hemophagocytic lymphohistiocytosis (HLH) is a rare but life-threatening hyperinflammatory syndrome increasingly reported with immune checkpoint inhibitors (ICIs). However, comparative real-world data across different ICI classes and treatment strategies are limited. This study aimed to characterize HLH reporting patterns associated with ICIs and to compare disproportionality signals among PD-1 inhibitors, PD-L1 inhibitors, and combination regimens using the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). Methods: A retrospective pharmacovigilance analysis was performed using FAERS reports submitted between 2013 and 2025. HLH-related cases were identified using core Medical Dictionary for Regulatory Activities (MedDRA) Preferred Terms. Reporting odds ratios (RORs) with 95% confidence intervals (Cis) were calculated to assess disproportionality across ICI treatment strategies, with ICI monotherapy as the reference. Restricted analyses compared PD-1 inhibitors, PD-L1 inhibitors, and ICI plus CTLA-4 inhibitor therapy. Results: A total of 733 HLH-related reports associated with ICIs were identified. The median age was 65 years (range 1–92), and 54.9% of patients were male. Lung cancer (34.4%) and melanoma (16.0%) were the most frequently reported malignancies. ICI monotherapy accounted for 34.7% of cases, while combination regimens included ICI plus chemotherapy (31.6%), ICI plus targeted therapy (17.8%), and ICI plus CTLA-4 inhibitors (15.9%). All cases were classified as serious adverse events; hospitalization occurred in 69.2% and death in 25.1%. Compared with monotherapy, combination regimens showed higher reporting odds of HLH, with the strongest signal for ICI plus targeted therapy (ROR 2.17, 95% CI 1.72–2.73). PD-1 inhibitors demonstrated higher reporting odds than PD-L1 inhibitors (ROR 1.86, 95% CI 1.41–2.46). Conclusions: This large real-world pharmacovigilance analysis demonstrates differential HLH reporting patterns across ICI classes and treatment strategies. Higher reporting odds with combination regimens and PD-1 inhibitors highlight the need for heightened clinical vigilance, particularly in combination treatment settings. Full article

Plaque psoriasis (PP) is a chronic immune-mediated skin disorder characterized by T-cell dysregulation and an imbalance between regulatory T cells (Treg) and T helper 17 (Th17) cells. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), a key inhibitory checkpoint molecule expressed on Treg cells, and its soluble isoform (sCTLA-4) are critical regulators of peripheral immune tolerance and may contribute to PP pathogenesis. This case–control study evaluated the association between the +49 A>G variant of the CTLA4 gene (rs231775) and susceptibility to PP in a mestizo population from western Mexico and assessed serum sCTLA-4 levels. A total of 204 patients with PP and 214 control subjects (CS) were genotyped using PCR-RFLP, and sCTLA-4 concentrations were measured by ELISA. The AG genotype was the most frequent in both groups (49% in PP and 53% in CS), with no significant differences in genotype or allele distributions. Serum sCTLA-4 levels were significantly higher in CS compared to patients (p < 0.05), and no genotype-dependent differences were observed. The rs231775 variant was not associated with PP susceptibility in this population. However, reduced circulating sCTLA-4 levels in patients suggest impaired CTLA-4-mediated immune regulation independent of this variant. Full article

Cancer immunotherapy has recently become an essential approach for treating cancer, showing considerable promise as a substitute for surgery, radiation therapy, and conventional chemotherapy. It primarily aims to boost the host’s natural defense system to combat cancer malignancies by utilizing components of immune checkpoint blockades (ICBs), mainly programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), along with elements of adoptive cellular therapies (ACTs) like Chimeric Antigen Receptor (CAR) therapy, T Cell Receptor (TCR) therapy and Tumor-Infiltrating Lymphocyte (TIL) therapy. However, cancer cells tend to undermine the effectiveness of cancer immunotherapeutic strategies by employing one or more immune evasion mechanisms. This review briefly highlights how key mechanisms of cancer immune evasion confer resistance to immunotherapy and how the Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 (CRISPR)/Cas9 systems, as gene-editing tools, are poised to enhance cancer immunotherapy for treating challenging cancers. We emphasize that (CRISPR/Cas9) systems can be used to explore and positively alter the genes of the immune system, boosting the effectiveness of cancer immunotherapy by editing immune checkpoints, TILs, and CAR-T cells, and disrupting genes, facilitating tumors’ evasion of the immune system. Furthermore, we highlight the growing interest in emerging base editor technology to engineer natural killer (NK) cells to overcome NK-cell-based immunotherapy challenges, particularly human leukocyte antigens (HLA)-mediated limitations, and to engineer CAR-T cells for improved immunotherapy outcomes. Full article

Background: Endometriosis is a complex condition that impairs women’s quality of life and reproductive potential. Its diagnosis remains significant challenge for clinicians. The aim of the study was to investigate cancer-like immune evasion mechanisms in endometriosis and to develop a novel diagnostic model using machine learning. Methods: In this study, we measured the levels of soluble forms of the following immune markers in blood serum and peritoneal fluid (PF): sMICA, sMICB, sEng, sCD25, s4-1BB, sB7.2, sCTLA-4, sPD-L1, sPD-1, sTIM-3, sLAG-3, and sGal-9. Results: sMICB levels in PF differed across endometriosis stages and were higher in patients with endometriosis-associated adhesions. sMICA levels in PF were elevated in women with endometriosis-associated infertility. The disease severity was inversely correlated with serum sB7.2 levels and positively correlated with serum sTIM-3 levels. A logistic regression model achieved an accuracy = 0.79, AUC = 0.94, and F1-score = 0.88, whereas XGBoost performed better with accuracy = 0.94, AUC = 0.95, and F1-score = 0.96. The key predictive features in both models were sMICB serum level and patients’ pain score. Conclusions: Our results demonstrate the potential role of sMICA and sMICB shedding in endometriosis and present a novel, minimally invasive diagnostic approach. Full article

Lung cancer remains the leading cause of cancer-related mortality worldwide and is frequently diagnosed at advanced stages, when metastatic dissemination is already present. Tumour hybrid cells (THCs) are rare circulating cells formed through fusion between cancer stem cells with leukocytes, predominantly monocytes. These cells combine traits from both lineages, conferring enhanced migratory, invasive and immune-evasive capacities that could promote metastasis. In parallel, soluble immune checkpoints (sICs) have emerged as minimally invasive biomarkers and indicators of systemic immune dysregulation and tumour-driven immune escape. In this study, 31 patients with lung cancer were prospectively enrolled at La Paz University Hospital (Madrid, Spain). Circulating THCs were quantified by spectral flow cytometry, and plasma sICs concentrations were determined using multiplex immunoassays. Patients were stratified by metastatic status and survival. Variables showing the strongest discriminative capacity were integrated into multivariable logistic regression models. Number of THCs, and levels of sCTLA-4, s-41BB, sLAG-3, and sTIM-3 exhibited the strongest discrimination for metastasis, while THCs, sLAG-3, and sTIM-3 distinguished deceased from surviving patients. Integrating predictive models demonstrated high accuracy, and survival analyses supported their prognostic significance. These findings indicate circulating THCs and selected sICs represent promising liquid biomarkers for monitoring lung cancer progression and patient outcomes. Full article

Background/Objectives. Globally, hepatocellular carcinoma (HCC) is the sixth most prevalent cancer and represents the third leading cause of cancer-related mortality. Despite advances in diagnosis and treatment, the overall prognosis of HCC remains poor, largely due to late-stage presentation and high rates of vascular invasion. Portal vein thrombosis constitutes a significant complication of HCC, with an occurrence rate of 35–50%. Portal vein tumour thrombosis (PVTT) represents an aggressive form that is closely linked to decreased patient survival. The incidence of PVTT increases over time, from approximately 21% in the first year after diagnosis to nearly 46% by the third year, highlighting its high prevalence and progressive nature. The introduction of immunotherapy has marked a paradigm shift in the management of HCC. Immune checkpoint inhibitors, particularly those targeting the PD-1/PD-L1 and CTLA-4 pathways, have demonstrated durable responses and significant survival benefits in certain patients with advanced HCC. Furthermore, emerging evidence suggests that combining immunotherapy with local or systemic therapies, such as trans arterial chemoembolization, hepatic arterial infusion chemotherapy, radiotherapy or tyrosine kinase inhibitors, may further enhance antitumor efficacy by modulating the tumour microenvironment and promoting synergistic immune activation. Method: This narrative review provides a comprehensive evaluation of immunotherapy in patients with HCC and PVTT, with a focus on its efficacy as both monotherapy and in combination with other treatment modalities in terms of tumour response, progression-free survival, and overall survival. It also addresses safety, patient selection, and emerging strategies to optimize outcomes in this high-risk population. Conclusions: The combination of multiple therapies could improve the patient’s prognosis by achieving objective response rate of almost 82%, disease control rate of 97% and progression free survival of 12.9 months with quadruple therapy (HAIC-TACE combined with targeted and immunotherapy). Full article

Background: Diabetes mellitus is characterized by elevated blood sugar due to absolute or relative insulin deficiency. Diabetes is classified as type 1 (T1D) or type 2 diabetes (T2D), gestational diabetes, and other types, such as monogenic diabetes, exocrine pancreatic disorders, and medication-induced diabetes. Objectives: This review article provides an overview of diabetes genetics, covering polygenic, monogenic, and syndromic forms of the disorder with emphasis on aspects to help clinicians in diagnosis, management, and counseling, but also to foster valuable knowledge for diabetic researchers in identifying phenotypes that will help inform gene discovery. Key Findings: Most cases of T1D and T2D are polygenic with environmental triggers. T1D results from autoimmune destruction of pancreatic beta cells leading to absolute insulin deficiency. Genetic studies of T1D have focused on the identification of loci associated with increased susceptibility to T1D. Early studies showed a linkage between T1D and several human leukocyte antigen (HLA) susceptibility loci on chromosome 6. Genome-wide association studies (GWAS) have identified more than 100 HLA- and non-HLA loci that increase susceptibility to T1D. It has been well established that a substantial portion of the genetic risk for T1D is encoded in the HLA locus. The non-HLA loci INS, CTLA4, IL2RA, IFIH1, and PTPN22 make moderate contributions to T1D risk. Many other non-HLA loci have small effects to the phenotype and are relevant to autoimmunity, but they are yet to be identified. T2D, on the other hand, is associated with obesity and insulin resistance with relative insulin deficiency. Thousands of gene variants that are common and contribute small effects have also been identified through GWAS to contribute to T2D risk, but the rarer variants may confer significant risk to an individual’s risk. Common variants in the TCF7L2 locus consistently carry one of the largest risks associated with T2D with a reported 1.7-fold disease odds for homozygous carriers. The usefulness of individual variants for genetic counseling in the common forms of diabetes has been limited in clinical settings in the past. The development of polygenic risk scores (PRS) and partitioned polygenic risk scores (PPRS), statistics derived from GWAS, are being used to predict and classify diabetes. The performance of PRS and PPRS varies by ancestry and type of diabetes. The PRS performs better with T1D, with an area under the curve and receiver operating characteristics (AUC-ROC) ranging from 0.87 to 0.93, compared to 0.72–0.75 for T2D. The genetic architecture of T2D is markedly more polygenic than T1D, and the PPRS has been useful in assessing risk in that setting. Monogenic diabetes comprises several dysglycemic disorders that include neonatal diabetes, maturity-onset diabetes of the young (MODY), and other genetic syndromes that have diabetes either as an associated finding and/or as a complication. Some of the monogenic diabetes gene variants have incomplete penetrance and variable expressivity leading to different ages of onset and variable presentation even within the same family. Hence some patients with these conditions have been previously diagnosed as having T1D or T2D. Many monogenic disorders follow Mendelian inheritance patterns, so genetic counseling is relatively straightforward if pathogenic variants are found to be inherited from a parent. Counseling for forms of diabetes due to maternally inherited mitochondrial cytopathies, such as MELAS and Kearns–Sayres syndrome, is not straightforward due to the occurrence of two or more populations of genetically distinct mitochondrial DNAs in the cells (heteroplasmy); the higher the percent of pathogenic variants in a cell or tissue, the greater the chance for affectation of disorder. Implications: Early stages of diabetes may be asymptomatic, and improvement in methodologies to identify individuals at high risk is important so prevention strategies can be targeted to susceptible individuals to slow or obviate the onset of disease and to minimize complications. Conclusions: Diabetes is a heterogeneous disorder, and accurate definition of phenotypes in the setting of non-syndromic and syndromic forms, development of powerful statistical methodologies, use of next-generation sequencing applications to interrogate the genome, incorporation of epigenetic mechanisms in statistical modeling and accurate curation of gene variants, will help us to realize application of genomic medicine and to inform diabetes care. Full article