Search Results (2,495)

Circulating tumor DNA (ctDNA) profiling offers non-invasive insights for personalized prostate cancer management. This systematic review provides the first comprehensive appraisal of ctDNA assay methods, genomic targets, and their clinical correlations and proposes practical recommendations to guide future standardization and validation. We searched PubMed, ScienceDirect, Scopus, and the Cochrane Library starting December 2024 following PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines. From 229 records, 44 studies (10,631 patients) met the inclusion criteria. Plasma ctDNA analyzed by NGS predominantly profiled TP53 (72.7%), AR (70.4%), BRCA1/2 (61.3%), ATM (50%), RB1 (47.7%), and PTEN (41%). ctDNA positivity and specific key alterations correlated with poorer overall and progression-free survival. BRCA1/2-mutant patients benefited from Olaparib plus Abiraterone, while persistent alterations predicted early progression. Beyond synthesizing existing evidence, we identify key gaps, such as inconsistent reporting of variant allele fractions, limited diversity in study populations, and underexplored rare alterations. We recommend unified reporting standards (e.g., variant allele frequency thresholds and panel composition) and prioritized prospective trials to validate high-impact targets. These steps will accelerate the integration of ctDNA into routine precision oncology practice worldwide. Full article

The vascular anatomy of the stomach is both complex and highly variable, with direct implications for oncologic, bariatric, esophageal, and interventional procedures. This comprehensive review combines anatomical, radiological, and surgical evidence on arterial and venous variations in the stomach. The left gastric artery, traditionally the first branch of the coeliac trunk, often shows variants such as a direct aortic origin or association with an abnormal left hepatic artery. The right gastric artery most frequently arises from the proper hepatic artery, but its origin can vary significantly. The gastroepiploic arteries exhibit diversity in their origin, size, and connection patterns, with occasional duplication or absence. Additional vessels, including the posterior gastric artery and the short gastric arteries, also contribute to variations in arterial supply. Venous drainage largely follows the arterial pattern. The left and right gastric veins and the gastroepiploic venous arcade are major routes, while variants of the left gastric vein and the gastrocolic trunk (Henle’s trunk) contribute to complexity through different convergence patterns. These vascular variations have significant clinical implications, as they impact the safety of D2 lymphadenectomy, the risk of ischemic complications during laparoscopic sleeve gastrectomy, the success of gastric conduit formation in esophagectomy, and the effectiveness of transarterial embolization for upper gastrointestinal bleeding. Preoperative vascular mapping with multidetector computed tomography angiography and 3D reconstruction reliably defines individual anatomy, allowing for customized surgical planning and reducing operative risks. Recognizing both common and rare gastric vascular variants is essential for safe and effective surgical and endovascular management of gastric disease. Full article

Background: Germline genetic variants impacting splicing are a frequent cause of disease. The clinical interpretation of such variants is challenging for many reasons including the immense complexity of splicing mechanisms. While recent advances in splicing algorithms have improved the accuracy of splice prediction, predicting the nature and abundance of aberrant splicing remains challenging. As RNA testing becomes more mainstream in the clinical diagnostic setting, the complexities of interpretation are coming to light. Methods: Data from patients undergoing concurrent DNA and RNA testing were retrospectively reviewed for unusual splicing impacts to underscore some of these complexities and serve as exemplars in how to avoid pitfalls in the interpretation of sequence variants. Results: Seven rare variants with unusual splicing impacts are presented: a variant at a consensus donor nucleotide position lacking a splice impact (NF1 c.888+2T>C); a mid-exonic missense variant creating a novel donor site and a cryptic acceptor site resulting in pseudo-intronization (BRIP1 c.727A<G p.Ile243Val); one variant creating a spliceosome switch from U12 to U2 (LZTR1 c.2232G>A p.Ala744Ala); two variants that would be expected to result in nonsense-mediated-mRNA-decay triggering splicing impacts that obviated nonsense-mediated-decay (APC c.1042C>T p.Arg348Ter and BRCA2 c.6762del; c.6816_6841+1534del); and two variants causing splicing impacts through pyrimidine tract optimization (NF1 c.5750-184_5750-178dup and ATM c.3480G>T p.Val1160Val). Conclusions: Paired DNA and RNA testing revealed unexpected splice events altering variant interpretation, expanding our knowledge of clinically important splicing mechanisms and highlighting the benefit of RNA testing. Full article

Background: Hereditary hyperferritinemia-cataract syndrome (HHCS) is a rare autosomal dominant disorder characterized by persistently elevated serum ferritin and early-onset bilateral cataracts in the absence of systemic iron overload. It is caused by pathogenic variants in the iron-responsive element (IRE) of the FTL gene, leading to dysregulated L-ferritin synthesis. Methods: We evaluated a 12-year-old Czech girl with markedly elevated serum ferritin identified incidentally during workup for abdominal pain. Clinical assessment included biochemical, radiological, ophthalmological, and genetic testing of the proband and available family members. Results: Magnetic resonance imaging excluded systemic iron overload, while ophthalmological evaluation revealed bilateral cataracts. Family history indicated multiple affected relatives across three generations. Genetic testing confirmed a heterozygous FTL c.-168G>C variant. Additional screening for common HFE variants revealed heterozygous H63D in several family members, with no impact on ferritin or hepcidin levels. Beyond this case, we provide a comprehensive review of HHCS, including molecular mechanisms, an updated overview of reported FTL mutations, and ophthalmological features that distinguish HHCS cataracts from other congenital cataracts. Conclusions: This report underscores the translational relevance of combining molecular diagnostics, clinical evaluation, and family screening to improve recognition and management of HHCS, and to prevent misdiagnosis and unnecessary iron-depletion therapy. Full article

Background and Clinical Significance: Intracerebral hemorrhage (ICH) is a very rare complication following endovascular closure of direct carotid-cavernous fistulas (CCFs). When reported, ICH typically appears within the first 48 h after CCF closure. We performed an extensive literature review, starting from the case of a 48-year-old patient presenting with an intracerebral hemorrhage after CCF closure. Case Presentation: A 48-year-old woman with arterial hypertension developed an intracerebral hemorrhage in the right frontal lobe 12 days after successful closure of a traumatic CCF. The patient exhibited acute neurological deterioration in a previously hypoperfused territory. A narrative review identifies the classical molecular theory of hemodynamic dysregulation, known as Normal Perfusion Pressure Breakthrough (NPPB), as the principal pathophysiological mechanism. Other mechanisms such as oxidative stress, microglial activation, blood–brain barrier disruption, metalloproteinase expression, and possible genetic alterations such as ICA1L variants are also implicated. Conclusions: This case underscores the importance of considering molecular mechanisms in the pathophysiology of delayed post-endovascular treatment of ICH, as well as the need for hemodynamic monitoring and follow-up in patients with vascular comorbidities. Full article

Background and Objectives: Low-grade triple-negative breast carcinomas (LG-TNBCs) represent a rare subset of breast cancers that deviate from the aggressive clinical course typically associated with triple-negative tumors. This narrative review aims to consolidate current knowledge on LG-TNBCs, highlighting their diagnostic features, molecular characteristics, and clinical implications to guide appropriate patient management and prevent overtreatment. Materials and Methods: We conducted a comprehensive narrative review using PubMed/MEDLINE, Embase, and Scopus databases up to September 2025. Search terms included combinations of “triple-negative breast carcinoma”, “low-grade”, “adenoid cystic carcinoma”, “secretory carcinoma”, “acinic cell carcinoma”, “tall cell carcinoma with reversed polarity”, “low-grade adenosquamous carcinoma”, and “fibromatosis-like metaplastic carcinoma.” Studies reporting clinicopathologic, immunohistochemical, or molecular data were included. Results: LG-TNBCs include seven distinct entities: adenoid cystic carcinoma, secretory carcinoma, acinic cell carcinoma, tall cell carcinoma with reversed polarity, low-grade adenosquamous carcinoma, fibromatosis-like metaplastic carcinoma, and mucoepidermoid carcinoma. These neoplasms are characterized by distinct morphologic patterns, specific immunohistochemical profiles, and recurrent molecular alterations such as ETV6-NTRK3 fusions and MYB rearrangements. Despite their triple-negative immunoprofile, they demonstrate indolent clinical behavior with excellent prognosis and low metastatic potential, although local recurrence is reported in variants exhibiting infiltrative, locally aggressive behavior. Conclusions: Recognition of LG-TNBCs is essential to prevent overtreatment and guide personalized patient management. Molecular characterization provides diagnostic confirmation and therapeutic opportunities, particularly for NTRK-fusion-positive tumors treatable with targeted inhibitors, highlighting the importance of precision medicine in rare breast tumors. Full article

Background. Hypophosphatasia (HPP) is a rare genetic disorder caused by impaired tissue non-specific alkaline phosphatase (ALPL/TNSALP) activity that impacts the musculoskeletal and neurological systems. It is extremely variable, with up to six forms of increasing severity. The large phenotypic variability and the still remaining high number of variants of uncertain significance (VUS) in the ALPL gene represent a conundrum for clinicians dealing with people suspected to be suffering from HPP. Methods. We applied a multi-faceted bench-based and high-throughput bioinformatics analysis to investigate the effect of 21 ALPL variants (18 deleterious—pathogenic or likely pathogenic—and 3 VUS) on the structure and function of the mutated encoded protein. The results were compared with available clinical and biochemical data. Results. Most variants were downregulated or not expressed by Western blot analysis. Impairment of the enzymatic activity was confirmed in vitro for all variants by a specific colorimetric enzymatic assay. In silico prediction was in line with functional data and allowed for preliminary categorization of variants based on their impact on both the overall stability of the protein complex and local structural alterations. Coherence among bioinformatics, experimental and clinical data was documented for more than 70% of the variants. Conclusions. Functional and in silico characterizations of ALPL variants in people with a suspicion of HPP offer integrative strategies to genotyping in assisting clinicians for diagnosis confirmation in doubtful cases. Full article

Background: Severe hypertriglyceridemia (SHTG) is associated with acute pancreatitis, metabolic dysfunction, and increased cardiovascular risk. Its genetic architecture ranges from rare biallelic variants causing familial chylomicronemia syndrome (FCS) to more prevalent polygenic or multifactorial chylomicronemia syndromes (MCS). Methods: We systematically reviewed scientific literature up to 2025 for studies reporting genetic data, clinical features, or therapeutic outcomes in adults with triglycerides (TG) ≥ 500 mg/dL. Extracted data were synthesized for genotype, polygenic risk score (PRS), TG levels, metabolic comorbidities, hepatic steatosis, pancreatitis, and treatment response. Results: Ten studies (n = 2521) were included. FCS due to biallelic LPL, APOC2, GPIHBP1, or LMF1 variants accounted for <5% of cases and showed extreme TG elevations (>2800 mg/dL) with pancreatitis prevalence (>70%). APOA5, APOC3, and APOB variants were associated with intermediate TG levels and high rates of metabolic dysfunction-associated steatotic liver disease (MASLD). Polygenic hypertriglyceridemia represented ~70–80% of cases, with TG ≈ 2200 mg/dL and pancreatitis prevalence 15–20%, largely modulated by metabolic triggers. MASLD was present in >70% of polygenic cases, supporting a “two-hit” model where hepatic overproduction of TG-rich lipoproteins amplifies TG excess. Interventional trials demonstrated TG reductions with APOC3 antisense therapy (70–80%) and ANGPTL3 inhibition (50–55%), while GLP-1RA significantly reduced hepatic fat (30–35%) and resolved NASH in up to 59% of patients. Conclusions: SHTG displays a genotype–phenotype gradient: FCS is linked to recurrent pancreatitis, whereas polygenic/MCS forms are closely associated with MASLD and metabolic dysfunction. These findings support a precision-medicine approach integrating genetic testing and PRS-guided strategies—prioritizing APOC3/ANGPTL3 inhibitors for FCS and combined TG-lowering plus metabolic therapies for MCS—to reduce pancreatitis recurrence and liver disease. Full article

The analysis of published data on geophagy in humans, including manifestations of its variant known as “pica”, as well as information on geochemical endemics associated with geophagy and rare earth elements, together with our own research experience, allows us to conclude that geophagy in humans, as well as in animals, is primarily a natural, evolutionarily determined form of maintaining the necessary balance of rare earth elements in the neuroimmunoendocrine system. Disturbances in the composition and concentration of necessary rare earth elements (REE) in the structures of the most important protective and controlling system in the mammalian organism lead to disorders of mineral and general metabolism in the body and, as a result, to geochemical endemics. Geochemical endemics occur in landscapes with anomalous levels of biologically available REE forms, i.e., levels that differ significantly both towards deficiency and towards exceeding background levels. The imbalance in the metabolism of other chemical elements in the body seems to have a subordinate importance in the mechanism of occurrence of geochemical endemics in relation to REE. Full article

The growing demand for rare-earth-free electric machines, driven by supply shortages and price volatility of rare earth elements, has accelerated research into applying alternative hard magnetic materials. This study investigates the challenging complete replacement of high-performance rare earth permanent magnets with low-cost ferrites, which exhibit significantly lower magnetic properties, in permanent magnet synchronous motors (PMSMs) for light electric vehicles (LEVs). While maintaining the original stator structure, output power, and speed requirements of a reference spoke-type PMSM, the research employs ANSYS Motor-CAD for comprehensive electromagnetic analysis and mass minimization of different design variants. The obtained results demonstrate the feasibility of ferrite-based designs while quantifying critical trade-offs in power density versus substantial cost and material availability advantages. This work provides valuable insights into the practical limitations and optimization approaches for rare-earth-free PMSM designs in sustainable mobility applications. Full article

Leigh syndrome is a rare, progressive mitochondrial disorder of childhood. Early diagnosis is often challenging due to nonspecific clinical manifestations. We report a 1-month-old male infant initially referred for suspected congenital muscular torticollis who ultimately received a diagnosis of Leigh syndrome. Despite unremarkable perinatal history, he subsequently developed persistent feeding difficulties, recurrent vomiting, failure to thrive, and global developmental delay. Early neurological assessment revealed poor repertoire patterns on General Movement Assessment. The Neonatal Oral-Motor Assessment Scale (NOMAS) demonstrated dysfunctional oral-motor control, whereas the video fluoroscopic swallowing study (VFSS) revealed aspiration during swallowing. Brain MRI revealed symmetric basal ganglia lesions. Expanded whole-exome sequencing identified a pathogenic MT-ATP6 m.8993T>G variant with high heteroplasmy level (>90% in blood), confirming the diagnosis of Leigh syndrome. The variant was maternally inherited, although neither the mother nor the older sibling exhibited clinical features of mitochondrial disease. Leigh syndrome can initially manifest with subtle systemic features rather than overt neurological features. Persistent feeding difficulties and growth delay in infancy warrant thorough evaluation, including neuroimaging and comprehensive genomic testing, to enable timely diagnosis and optimize clinical management. Full article

Introduction: In hemoglobinopathies, the amount of globin synthesis in hemoglobin (Hb) or its structure is altered. Clinical features are related to the rate and kind of structural aberrations. The heterozygous form of the Lepore syndrome resembles minor thalassemia both clinically and hematologically. On electrophoresis, abnormal Hb Lepore fractions are found at a rate of 5–15%, with a mildly higher percentage of HbF and lower HbA. In general, Hb Lepore heterozygotes are asymptomatic. Case presentation: A 32-year-old male was admitted to our hospital with complaints of pain and swelling in multiple large joints and high-grade fever for 11 days. His past history was unremarkable; one of his sisters had the β-thalassemia trait. On physical examination, he was moderately anemic, with mild hepatomegaly and normal spleen; both knees and ankles were tender and swollen. Laboratory showed mild microcytic hypochromic anemia with variables similar to the thalassemia trait and signs of inflammation with very high CRP, serum ferritin, and leukocytosis. Blood sugars were increased. Hb electrophoresis showed an abnormal pattern with mild elevation in HbS, normal Hb F, mild reduction in HbA, and high HbA2, compatible with heterozygosity for the Hb Lepore beta chain variant. He was initially diagnosed with diabetes (treated with insulin) and sepsis from unknown origin, but fever and joint pains did not respond to NSAIDs or antibiotics. He had very good response on high-dose methylprednisolone. Undifferentiated arthritis was diagnosed in the patient with Hb Lepore, and he was treated with oral prednisolone and sulfasalazine (SSZ). At follow up, the patient was doing well. He refused further investigations and did not allow testing on his family members. In summary: Hb Lepore is a rare hemoglobinopathy linked to thalassemia, which may manifest with musculoskeletal problems. Our patient with the Hb Lepore trait presented with undifferentiated polyarthritis and fever, but in our case, a causal relationship remains unclear. This is one of the first adult cases of Hb Lepore in Bangladesh and the first with arthritis of unknown origin. The prevalence of Hb Lepore in Bangladesh is unknown. Full article

Background/Objectives: Family history is a known risk factor for multiple myeloma (MM) and its precursor condition, monoclonal gammopathy of undetermined significance (MGUS). Previous genome-wide association studies (GWASs) have identified 35 common loci associated with MM risk and 21 associated with MGUS. The objective of this study was to identify less common and rare genetic loci predisposing to MM/MGUS through whole-exome sequencing (WES)-based linkage analysis. Methods:Multipoint linkage analysis was conducted using the Multipoint Engine for Rapid Likelihood Inference (MERLIN) with the Lander–Green algorithm on germline WES data from 79 pedigrees with 2 or more affected relatives (120 MM, 86 MGUS, and 21 unaffected). Genome-wide linkage was evaluated using 12,946 independent single-nucleotide variants (linkage disequilibrium r² < 0.05). Results: Significant linkage was observed at chromosome 6q22.33–q24.2 by the non-parametric model (logarithm-of-odds (LOD) = 3.3) and suggestive linkage by the dominant parametric model (heterogeneity LOD (HLOD) = 2.5). Fourteen rare variants within this region were prioritized using family-specific partial LOD scores and in silico functional prediction tools. Nine of these variants, REPS1, THEMIS, TAAR6, AHI1, VNN1, VNN3, MTFR2/FAM54A, LAMA2, and PHACTR2, overlapped immune-regulatory regions in blood cell lines and were not previously identified in GWASs. Conclusions: This study demonstrates the utility of applying a linkage analysis framework to familial WES data for identifying genomic regions and candidate genes that may contribute to MM/MGUS predisposition. These findings provide new insight into the inherited risk and etiology of familial MM and MGUS. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver condition globally, driven by strong genetic and environmental components. This review summarizes recent advances in understanding the genetic architecture of MASLD. Genome-wide association studies (GWAS) have identified several key risk variants, primarily in genes such as PNPLA3, TM6SF2, GCKR, and MBOAT7, which influence hepatic lipid metabolism and disease progression. By utilizing surrogate markers of MASLD, researchers have also identified numerous putative MASLD-associated genes, warranting further investigation through functional genomics approaches. Next-generation sequencing techniques have uncovered rare variants in genes like APOB and ABCB4, as well as protective variants in HSD17B13 and CIDEB. This review discusses the potential of polygenic risk scores for disease stratification and the development of genetically informed therapeutic strategies. Additionally, it explores the future of functional genomics approaches in discovering novel treatment strategies. While the evolving genetic landscape of MASLD provides promising insights for precision medicine approaches in diagnosis, prognosis, and treatment, significant translational gaps remain. Addressing these challenges will be critical for realizing the full potential of personalised approaches in clinical management. This review synthesizes these findings and discusses their implications for future research and clinical practice in MASLD. Full article

RASopathies are a heterogeneous group of genetic syndromes caused by germline mutations in genes encoding proteins of the RAS/MAPK pathway, which are essential in the regulation of cell proliferation, differentiation and survival. Although characterized by common phenotypic manifestations such as craniofacial dysmorphism, congenital heart defects, and growth retardation, an aspect of great clinical relevance is the increased risk of sudden cardiac death, especially in relation to hypertrophic cardiomyopathy (HCM) and ventricular arrhythmias. Pathogenic variants in genes such as RAF1, RIT1, PTPN11, BRAF and SHOC2 have been associated with phenotypes with increased incidence of HCM, sometimes with early onset and a rapidly evolving course. The literature highlights the importance of early identification of patients at risk; however, specific surveillance protocols and follow-up strategies are defined in expert guidelines. This literature review aims to provide an updated overview of the main RASopathies with cardiac involvement, highlighting the genotype-phenotype correlations, the pathogenic mechanisms underlying sudden cardiac death, and current diagnosis, monitoring, and prevention strategies. The aim is to promote greater clinical awareness and encourage a multidisciplinary approach aimed at reducing mortality in these rare genetic conditions. Full article