Search Results (4,604)

Cholangiocarcinoma (CCA) is an aggressive malignancy with limited methods for early detection, necessitating the development of reliable biomarkers for diagnosis and management. However, conventional tumor markers, such as CA19-9 and CEA, exhibit insufficient diagnostic accuracy. Recent advancements in molecular genetics have identified several actionable mutations in CCA, enabling molecularly targeted therapies that improve survival in patients harboring these genetic alterations. Cancer panels, which facilitate multiplex genetic profiling, are critical for identifying these mutations. Studies indicate that several actionable mutations are detected in CCA cases, with patients receiving mutation-guided therapies achieving markedly better outcomes. Liquid biopsies, including cell-free DNA and circulating tumor DNA, offer real-time, non-invasive approaches to monitoring tumor dynamics, heterogeneity, and treatment responses. Furthermore, numerous studies have identified non-coding RNAs in serum and bile as promising biomarkers for the diagnosis and management of CCA. On the other hand, immunotherapy, particularly immune checkpoint inhibitors, has shown efficacy in subsets of CCA patients. However, the success of these therapies is often affected by the status of the tumor immune microenvironment (TME), underscoring the need for comprehensive TME analysis to predict responses to immune checkpoint inhibitors. Despite these advances, no single biomarker currently demonstrates sufficient sensitivity or specificity for clinical application. The integration of multi-omics approaches with cutting-edge technologies holds promise for enhancing diagnostic accuracy, optimizing treatment stratification, and advancing precision medicine in CCA. These developments highlight the transformative potential of biomarkers to improve early detection, prognostic assessment, and personalized therapeutic interventions for CCA. Full article

Background/Objectives: Down syndrome (DS), affecting 1 in 1000 births, has been linked to an increased risk of acute leukemia (AL). Patients with DS–acute lymphoblastic leukemia (DS-ALL) have historically had inferior outcomes when they have received risk-adapted therapy. Transient abnormal myelopoiesis (TAM) constitutes a transient leukemia with spontaneous remission in the neonatal period or represents a preleukemic state, preceding DS–acute myeloid leukemia (DS-AML). DS-AML has a better prognosis than that of AML without DS (NDS-AML) due to genetic and biological underlying features, a better response to chemotherapeutic agents, and a lower frequency of relapses. Methods: This retrospective cohort study presents the DS-AL outcomes from a nationwide survey in pediatric oncology centers. A total of 20 patients were studied, 10 with DS-ALL, 4 with DS-AML, 5 with TAM, and 1 with DS-AML after TAM, at median follow-ups of 9.25 (0.6–17.42) years and 7.25 (0.25–18.25) years for DS-ALL and DS-AML, respectively. Results: The median age at diagnosis was 4.7 (1.16–13.83) and 1.92 (1.25–3) years for ALL and AML, respectively. All DS-ALL patients had B-cell precursor ALL and achieved complete remission (CR). One patient relapsed and succumbed due to a severe infection. Three DS-AML patients had AMKL. All DS-AML patients achieved CR. One patient with TAM demanded treatment, all achieved CR, and one progressed to DS-AML. The overall survival (OS) was 70% and 80% for DS-ALL and DS-AML. Conclusions: The improved survival rates of our patients have been due to new protocols with less toxic therapies and better supportive care. Full article

Background/Objectives: Periodontitis is a chronic inflammatory disease that leads to systemic low-grade inflammation. Systemic low-grade inflammation has been found in patients with age-related macular degeneration (AMD). In this systematic review and meta-analysis, we evaluated the association between periodontitis and AMD. Methods: We searched 11 scientific literature databases on 16th December 2024 for studies of a diagnosis of periodontitis and prevalent or incident AMD. Eligible studies underwent a qualitative review and meta-analysis of the association. Study selection, data extraction, and risk of bias within studies were made in duplicate by two authors and conferred with a senior author. Results: Seven studies eligible for review included in total 149,217 individuals. Across the seven studies, different study designs, diagnoses and definitions of periodontitis, and diagnosis and definitions of AMD were employed. Our meta-analysis showed an association between periodontitis and AMD with an odds ratio of 1.42 (95% CI: 1.12 to 1.78; p = 0.003). Conclusions: Periodontitis is significantly associated with AMD. Unlike genetic predisposition and high age, which are important risk factors of AMD that cannot be modified, periodontitis is a risk factor that can be treated and potentially eliminated, thus allowing for a personalized approach for risk elimination in AMD. Attention should be given to the dental health of patients at risk of AMD. Full article

Background: Celiac disease (CD) is a chronic immune-mediated systemic disorder induced by gluten in genetically predisposed individuals, requiring lifelong management through a strict gluten-free diet (GFD). Although its global prevalence is around 1%, awareness and diagnosis remain suboptimal, contributing to challenges in disease management. Objectives: To assess the awareness, knowledge, and experiences of Bulgarian CD patients and caregivers regarding CD, diagnosis, and dietary adherence. Methods: A structured survey was conducted to evaluate patient and caregiver knowledge, awareness, and experiences with CD, focusing on the diagnostic process and dietary practices. Data were collected from a sample of Bulgarian CD patients and their caregivers. Results: The majority of the 191 respondents (94%) recognized CD as a lifelong condition, but only 26.7% correctly identified its autoimmune, systemic nature. The average diagnostic delay was 8.1 months, with over 50% of patients relying on serological tests alone, consistent with recent non-biopsy guidelines. Dietary adherence was significantly hindered by misconceptions about gluten-containing grains and societal barriers. Notably, 83.6% of participants reported bringing their own food when eating outside. Conclusions: The findings underscore the need for targeted public health initiatives, enhanced healthcare provider training, and improved dietary education to address knowledge gaps, expedite diagnosis, and improve dietary adherence. Such interventions could help reduce the psychosocial burden of CD and enhance the quality of life for affected individuals. Full article

Although the pathogenesis of the neurodegenerative phenomena of Huntington’s disease (HD) is not well known, in the last 30 years, numerous data have been published that suggest a possible role of oxidative stress. The majority of studies regarding this issue were performed in different experimental models of this disease (neurotoxic models such as intraperitoneal injection of 3-nitropropionic acid or intrastriatal injection of quinolinic acid, transgenic animal models for HD, and cell cultures) and, less frequently, in samples of brain tissue, plasma/serum, blood cells, and other tissues from patients with a genetic–molecular diagnosis of presymptomatic and symptomatic HD compared to healthy controls. In this narrative review, we have summarized the data from the main studies in which oxidative stress parameters have been measured both in patients with HD and in experimental models of the same disease, as well as the few studies on gene variants involved in oxidative stress in patients with HD. Most studies addressing this issue in experimental models of HD have shown an increase in markers or oxidative stress, a decrease in antioxidant substances, or both. However, the results of studies on patients with HD have not been conclusive as few studies have been published on the matter. However, a meta-analysis of blood studies on HD patients (including a pool of serum and blood cell studies) has shown an increase in lipid peroxidation markers, OH8dG concentrations, and GPx activity and a decrease in GSH levels. Future prospective and multicenter studies with a long-term follow-up period involving a large number of HD patients and healthy controls are needed to address this topic. Full article

Acute and chronic Food Protein-Induced Enterocolitis Syndrome (FPIES) has been well characterized in children; otherwise, neonatal FPIES (N-FPIES) remains poorly understood. In terms of pathophysiology, neonatal FPIES appears to have a more prevalent TH2 response and is characterized by specific clinical features that make the diagnosis challenging. Genetic and environmental risk factors may predispose to the development of FPIES. Recent evidence indicates that a characteristic microbiota signature may lead to barrier dysfunction, reduced regulatory T cells, and abnormal intestinal production of serotonin, responsible for the symptoms of FPIES. Regarding clinical presentation, newborns with FPIES may not fully meet the current guideline’s diagnostic criteria at disease onset, being more similar to clinical entity specific of neonatal age than to acute FPIES in infants and children. Hence, differentiation from other neonatal medical and surgical conditions—particularly necrotizing enterocolitis (NEC)—remains a critical challenge for clinicians. This present review highlights our current understanding of N-FPIES, in term of pathophysiology, clinical presentation diagnosis, and treatment strategies. Refining diagnostic criteria for N-FPIES represents a clinical priority to help physicians in diagnosing and managing this challenging condition. Last, but not least, larger clinical trials are needed to optimize treatment practices in term and preterm newborns with FPIES. Full article

Osteogenesis imperfecta (OI) is a rare hereditary connective tissue disorder. Diagnosis is typically clinical; genetic testing can contribute. Objectives: We are presenting a case series of type I OI in Romanian patients, showcasing the difficulties in diagnostic and case management in pediatric and adult cases. Methods: Nine patients were referred to the Regional Centre for Medical Genetics (CRGM), Dolj, Craiova, between 2021 and 2024. Genetic testing was conducted using the commercially available kit Illumina^® TruSight™ One. Results: Most of the patients showed blue sclerae, significant fracture history, and reduced stature. In our case series, the genetic variants for seven of the cases identified are primarily in the COL1A1 and COL1A2 genes. Our study reveals significant clinical variability among patients, even among those with identical genetic variants. This emphasizes the importance of tailored surgical and rehabilitation programs to improve the quality of life for these patients. Conclusions: Our study contributes to the genetic landscape of OI. Future research should aim to include larger, more diverse cohorts and incorporate advanced genetic analysis techniques to identify additional genetic variants and mechanisms involved in OI. Full article

Long QT syndrome (LQTS) presents a group of inheritable channelopathies with prolonged ventricular repolarization, leading to syncope, ventricular tachycardia, and sudden death. Differentiating LQTS genotypes is crucial for targeted management and treatment, yet conventional genetic testing remains costly and time-consuming. This study aims to improve the distinction between LQTS genotypes, particularly LQT3, through a novel electrocardiogram (ECG)-based approach. Patients with LQT3 are at elevated risk due to arrhythmia triggers associated with rest and sleep. Employing a database of genotyped long QT syndrome E-HOL-03-0480-013 ECG signals, we introduced two innovative parameterization techniques—area under the ECG curve and wave transformation into the unit circle—to classify LQT3 against LQT1 and LQT2 genotypes. Our methodology utilized single-lead ECG data with a 200 Hz sampling frequency. The support vector machine (SVM) model demonstrated the ability to discriminate LQT3 with a recall of 90% and a precision of 81%, achieving an F1-score of 0.85. This parameterization offers a potential substitute for genetic testing and is practical for low frequencies. These single-lead ECG data could enhance smartwatches’ functionality and similar cardiovascular monitoring applications. The results underscore the viability of ECG morphology-based genotype classification, promising a significant step towards streamlined diagnosis and improved patient care in LQTS. Full article

Background: Vitamin D-dependent rickets type 1A (VDDR1A) is a rare autosomal recessive disorder caused by mutations in the CYP27B1 gene, leading to a deficiency in active vitamin D (1,25-dihydroxyvitamin D). This study examines the genotypic and phenotypic characteristics of VDDR1A in Vietnamese children. Patients and Methods: A retrospective analysis was conducted on 19 Vietnamese children diagnosed with VDDR1A. Clinical, radiological, biochemical, and molecular data were collected. Rickets Severity Scores (RSSs), biochemical parameters, and height standard deviation scores (HtSDSs) were used to assess the severity of the condition. Results: The study included 19 children from 17 families (ten males and nine females). The median age of rickets diagnosis was 19.2 months, while with VDDR1A, the median time of diagnosis was 7.5 months. Common symptoms among the children included thickened wrists and ankles (19/19), genu varum or genu valgum (18/19), failure to thrive (18/19), rachitic rosary (12/19), and delayed walking (11/19). The radiographic features showed that all children had cupping, splaying, and fraying, twelve children had rachitic rosary, and six exhibited pseudofractures. The biochemical findings showed severe hypocalcemia, normal or mildly low serum phosphate, elevated alkaline phosphatase and parathyroid hormone levels, and normal serum 25-hydroxyvitamin D levels. Genetic analysis identified biallelic CYP27B1 variants, including one known pathogenic frameshift mutation, c.1319_1325dup p.(Phe443Profs*24), one novel likely pathogenic missense variant, c.616C>T p.(Arg206Cys), and one novel pathogenic frameshift mutation, c.96_97del p.(Ala33Thrfs*299). The c.1319_1325dup p.(Phe443Profs*24) variant was the most common, present in 18 out of 19 children. Conclusions: The children with VDDR1A in this study presented with growth failure and skeletal deformities. Key findings included severe hypocalcemia, elevated alkaline phosphatase and parathyroid hormone levels, normal or elevated 25(OH)D, and high RSSs. Predominant frameshift mutations in CYP27B1, especially c.1319_1325dup, highlighted the importance of early genetic diagnosis for optimal management. Additionally, two novel CYP27B1 variants were identified, expanding the known mutation spectrum of VDDR1A. Full article

Intracranial aneurysm (IA) is a common cerebrovascular disease in which sacral aneurysms occurring in the Wills ring region can lead to devastating subarachnoid hemorrhage. Despite advances in research, the underlying mechanisms of IA formation and rupture remain incompletely understood, hindering early diagnosis and effective treatment. This review comprehensively summarizes the current landscape of IA biomarkers, encompassing genetic markers, DNA, RNA, inflammatory molecules, oxidative stress proteins, and extracellular matrix (ECM) components. Accumulating evidence suggests that various biomarkers are associated with different stages of IA pathogenesis, including initiation, progression, and rupture. Aberrant ECM composition and remodeling have been observed in IA patients, and extracellular matrix-degrading enzymes are implicated in IA growth and rupture. Biomarker research in IA holds great potential for improving clinical outcomes. Future studies should focus on validating the existing biomarkers, identifying novel ones, and investigating their underlying mechanisms to facilitate the development of personalized preventive and therapeutic strategies for IA. Full article

Neoplastic disorders, particularly malignant carcinomas, are complex systemic diseases characterized by unregulated cellular proliferation, the invasion of adjacent tissues, and potential metastasis to distant bodily sites. Among the diverse spectrum of cancer subtypes, malignant melanoma is a highly aggressive form of cutaneous cancer originating in melanocytes, the pigment-producing cells resident in the skin. This malignancy is distinguished by its rapid and uncontrolled growth, as well as its propensity for metastasis to vital organs, thereby posing significant challenges to therapeutic intervention and prognostication. Early detection of melanoma is crucial for optimizing patient outcomes, as diagnosis at an advanced stage often yields a poor prognosis and limited treatment options. Diagnostic modalities for melanoma encompass comprehensive clinical evaluations by dermatologists; radiological imaging techniques such as ultrasonography, magnetic resonance imaging (MRI), computed tomography (CT) scans; and excisional biopsies for accurate histopathological assessment. Malignant melanoma is typically treated with surgery to remove the tumor, followed by immunotherapy to enhance the immune response, targeted therapy for tumors with specific genetic mutations, chemotherapy for advanced stages, radiation therapy to manage metastasis, and other adjunct therapies. This review presents the properties and possible adjunct therapeutic effects against malignant melanoma of quercetin found in the literature and explores, based on the observed physicochemical properties and biological activity, its potential development as a topical formulation for cutaneous application. Quercetin is a naturally occurring flavonoid compound abundant in various plant-based food sources, including apples, onions, berries, and citrus fruits, and has exhibited promising antiproliferative, antioxidant, and anticancer properties. Its distinctive biochemical structure enables quercetin to effectively neutralize reactive oxygen species and modulate key carcinogenic pathways, thereby rendering it a potential candidate for therapeutic intervention in managing malignant tumors, including melanoma. Full article

The etiology of acute myeloid leukemia (AML) is complex, including genetic and environmental abnormalities. The immune system anomalies play an essential role in the process of leukemogenesis. However, the immunopathological factors, including abnormal T helper (Th) subsets, contributing to the initiation and progression of this neoplasm, require further investigation. Considering the previously mentioned data, we decided to study the expression pattern of transcription factors T-bet, Foxp3, and RORγt that regulate Th1, Treg, and Th17, respectively, in acute myeloid leukemia with correlation to clinical and other investigation data and treatment outcomes. This study was conducted on 80 newly diagnosed patients with AML recruited from the National Cancer Institute, Cairo University, and 25 healthy control subjects. The AML patient cohort consisted of 30 females (37.5%) and 50 males (62.5%), ranging from 18 to 74 years old. The control group was 8 females (32%) and 17 males (68%), with ages ranging from 23 to 40 years old. Samples were provided from the bone marrow of donor cases for allogeneic bone marrow transplantation. The diagnosis of acute myeloid leukemia was based on morphologic and cytochemical evaluation, immunophenotyping, and complementary cytogenetics according to WHO criteria. Upshift from the normal T-bet intensity of power (MFI), RORγt⁺ CD4⁺ T lymphocyte frequency (%) with downshift from the normal FOXP3 intensity of power (MFI), may suggest a state of inflammation. In contrast, an upshift from the normal FOXP3⁺ CD4⁺ T lymphocyte frequency (%) may reflect a state of immunosuppression in the bone marrow microenvironment of AML. Combined, they constitute a sophisticated scenario of immunological disorder in AML. Co-expression of T-bet and RORγt transcription factors in CD4⁺ T lymphocytes in both normal and AML groups may suggest CD4⁺ T lymphocyte plasticity. Full article

Background/Objectives: Primary cutaneous B-cell lymphomas (PCBCL) are a rare and heterogeneous group of non-Hodgkin lymphomas that are confined to the skin at diagnosis and exhibit a tendency for cutaneous recurrence. The 5th edition of the World Health Organization and the 2022 International Consensus Classification recognize three main subtypes: primary cutaneous follicle center lymphoma (PCFCL), primary cutaneous marginal zone lymphoma/lymphoproliferative disorder (PCMZL/LPD), and primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL,LT). These subtypes differ in clinical behavior, histopathologic features, immunophenotype, and molecular alterations. Diagnosis and management remain challenging for clinicians. This review aims to provide a comprehensive overview of the defining features and current treatment strategies for PCBCL. Methods: This narrative review synthesizes current literature on the clinical, morphologic, immunohistochemical, and molecular characteristics of PCBCL. It also evaluates the diagnostic utility of immunohistochemistry, gene expression profiling, and molecular assays, particularly in distinguishing primary cutaneous disease from secondary cutaneous involvement by systemic lymphomas. Results: PCFCL arises from germinal center B-cells and must be differentiated from nodal follicular lymphoma. PCMZL/LPD is derived from post-germinal center B-cells and is often linked to chronic antigenic stimulation. Both PCFCL and PCMZL/LPD are indolent and associated with favorable outcomes. By contrast, PCDLBCL,LT is an aggressive lymphoma characterized by genetic alterations activating the NF-κB pathway, commonly including mutations to MYD88 and CD79B. Treatment strategies vary by subtype, ranging from localized therapies for indolent lymphomas to systemic chemoimmunotherapy for aggressive PCBCL. Emerging therapies, such as Bruton tyrosine kinase inhibitors and immunoregulatory agents, are being investigated for relapsed/refractory disease. Conclusions: PCBCL encompass distinct clinicopathologic entities with subtype-specific diagnostic and therapeutic considerations. While current management is guided by clinical behavior, significant knowledge gaps remain regarding the molecular mechanisms underlying skin tropism, immune evasion, and disease progression. Future research could focus on improving molecular characterization and developing personalized and immune-based therapies to enhance outcomes. This review consolidates current knowledge and highlights innovations aimed at advancing the diagnosis and treatment of PCBCL in clinical practice. Full article

Background/Objectives: Cerebral folate transporter deficiency is characterized by pauses and regression in general development stages, with ataxia, choreoathetoid movements, and myoclonic epilepsy generally resistant to treatment. The aim of this study was to comprehensively evaluate cases followed up in two centres in Türkiye for a diagnosis of folate receptor-α deficiency. Methods: The study included nine cases from six different families. Results: The patients comprised 22.2% males and there was parental consanguinity in 88.9% of cases. The mean age at which complaints were first noticed was 3.7 years, and the age of definitive diagnosis was 10.4 years. The most frequently seen first complaints were febrile convulsions and attention deficit-hyperactivity-learning difficulties. The diagnosis most commonly made before the definitive diagnosis was epilepsy, and the first seizure occurred at a mean of 5.2 years. On cranial imaging, white matter involvement, cerebellar atrophy and cerebral atrophy were determined most often. Definitive diagnosis was established solely through clinical findings and genetic analysis. Three different variants in the FOLR1 gene were determined. Treatment with folinic acid at a dose of 5.2 mg/kg/day of PO was started at the age of 9.8 years on average, and intravenous folinate was started at different doses. Conclusions: This study stands out as one of the largest case series in the literature and identifies a previously unreported novel variant. Our study suggests that FOLR1-related CFD should be considered in cases with febrile convulsions, developmental delay, ataxia, autism spectrum disorder, acquired microcephaly, and MRI findings of white matter involvement and cerebellar atrophy. Due to an asymptomatic early period, CFD diagnosis may be delayed, and treatment after symptom onset may be less effective. Incorporating FOLR1 gene analysis into newborn screening programmes could facilitate early diagnosis and treatment. It is thought that the application of vagus nerve stimulation, in addition to folinic acid and anticonvulsant drug treatment, could be effective in seizure control. Full article

India’s population complexity presents varied challenges in genetic research, and while facilities have gained traction in tier-1 and -2 cities, reliance on international collaborations often delays such investigations. COVID-19 further exacerbated the issues with such sample sharing. Congenital Hyperinsulinism (CHI) is a rare genetic disorder of pancreatic β-cells causing hypoglycaemia in children due to abnormal insulin secretion. Given India’s high birth rate and consanguineous populations, annual CHI cases are estimated to be around up to 10,000, with up to 50% having unexplained genetic causes. Diffuse or atypical lesions in such patients often necessitate near-total-pancreatectomy, risking pancreatic exocrine insufficiency and diabetes, requiring lifelong therapy. Also, novel genetic variations complicate accurate diagnosis, risk assessment, and counselling, emphasising the need for rapid genetic assessment to prevent neurological injuries and inform treatment decisions. Despite significant efforts at many institutes, there are no dedicated organisations for CHI in India. With the implementation of the National Policy for Rare Diseases 2021, we plan to form a non-profit organisation, “Congenital Hyperinsulinism India Association (CHIA)”, comprising paediatric endocrinologists, paediatricians, geneticists, and independent researchers. The aims of this association are to generate a national database registry of patients, formulate a parent support group and CHIA consortium, design patient information leaflets, as well as foster genomic collaborations and promote clinical trials. Such steps will help sensitise the health authorities and policy makers, urging them to improve the allocation of health budgets for rare diseases, as well as empower patients and their families, contributing towards a better quality of life. Full article