Search Results (819)

Background: Colorectal cancer (CRC) is the third most diagnosed malignancy and the second leading cause of cancer-related mortality worldwide. Recent therapeutic advancements have significantly improved clinical management, underscoring the importance of routine molecular profiling to guide personalised treatment strategies. This study aims to evaluate the prognostic impact of main molecular alterations—including allele frequency (AF) of RAS mutations—on survival outcomes in a real-world hospital-based cohort of patients with metastatic CRC. Methods: A total of 208 consecutive patients with a histologically confirmed diagnosis of CRC and complete clinical, molecular, and survival data were retrospectively analysed. Somatic mutations in KRAS, NRAS, BRAF, and the occurrence of microsatellite instability (MSI) were assessed using pyrosequencing and real-time PCR assays, respectively, on formalin-fixed, paraffin-embedded tumour samples. Associations between mutational status, clinicopathological parameters, and overall survival (OS) were evaluated. Results: Overall, 138 patients (66.3%) harboured at least one somatic mutation: 115 (55.3%) in KRAS, 8 (3.8%) in NRAS, and 15 (7.2%) in BRAF. MSI was detected in 17/208 (8.2%) patients. A statistically significant improvement in OS was observed in patients lacking mutations in any of the three genes—referred to as wild-type (WT) patients—with BRAF mutated cases showing the worst survival (p = 0.041). Increasing age at the time of first-line therapy for advanced disease stage was associated with a statistically significant increase in the hazard of death (p = 0.031). Conclusions: In the advanced disease stage, RAS/BRAF wild-type colorectal cancers were significantly associated with a survival advantage. Full article

Background/Objectives: Liposarcoma represents a heterogeneous group of mesenchymal malignancies with distinct molecular profiles and clinical behaviors. While localized disease is managed with surgical resection, advanced or metastatic liposarcoma poses a significant therapeutic challenge due to limited response to traditional cytotoxic chemotherapy. This review summarizes current evidence-based systemic therapies and highlights recent advances in subtype-driven treatment strategies. Methods: We review key clinical trials supporting the use of anthracycline regimens, trabectedin, eribulin, and nuclear export inhibition with selinexor, as well as emerging targeted approaches directed at MDM2 and CDK4 amplification. In addition, we discuss the evolving role of immunotherapy, including checkpoint inhibitors and engineered T-cell receptor therapies targeting cancer–testis antigens. Results: Integrating molecular biology with therapeutic development, we emphasize the importance of histologic and genomic classification in guiding treatment selection and clinical trial design. Conclusion: Continued progress in biomarker-driven strategies and rational combination therapies is expected to further refine personalized treatment approaches and improve outcomes for patients with advanced liposarcoma. Full article

Lung cancer is one of the most common cancers worldwide, with non-small-cell lung cancer (NSCLC) being the most prevalent type. While surgical resection followed by adjuvant platinum-based chemotherapy has been the standard for curative-intent therapy for clinical stage II NSCLC since 2005, disappointing 5-year survival prompted the exploration of newer systemic therapies. In recent years, several landmark trials increasingly support the use of immunotherapy and molecular targeted treatments. The evidence for neoadjuvant chemoimmunotherapy is exciting, but the transition from a surgery-first approach to a new standard of care carries important challenges, including increased surgical attrition, intraoperative technical difficulty, and delays in care. This article provides a comprehensive review of the optimal treatments and emerging therapies for resectable stage II NSCLC. By systematically analyzing recent advances and challenges in NSCLC treatment strategies, we aim to highlight a paradigm shift toward a more molecularly guided, individualized treatment sequence in stage II NSCLC care, with the goal of maximizing each patient’s curative potential. Full article

Noonan syndrome (NS) is a paradigmatic rare, genetically heterogeneous, multisystem disorder belonging to the RASopathies family, caused by dysregulated RAS/MAPK signaling. It is characterized by distinctive craniofacial features, postnatal short stature, and a high prevalence of congenital cardiac defects, with pulmonary valve stenosis (PS) and hypertrophic cardiomyopathy (HCM) being the hallmark lesions. First described by Dr. Jacqueline Noonan in 1968, the molecular era began with the discovery of PTPN11 mutations in 2001, revolutionizing diagnosis, risk stratification, and understanding of pathogenesis. Strong genotype–phenotype correlations now guide prognosis and personalized management; for instance, RAF1 and RIT1 variants confer a high risk of severe, early-onset HCM, while PTPN11 is strongly linked to dysplastic PS. Cardiac involvement remains the central determinant of long-term outcomes, requiring continuous surveillance from the prenatal period through adulthood. Management is inherently multidisciplinary, addressing endocrine, hematologic, neurodevelopmental, and oncologic aspects. Recent consensus statements emphasize the critical need for structured transition from pediatric to adult care. Novelty arises from the potential of MEK inhibitors as targeted therapies for severe HCM and lymphatic complications. This review provides a comprehensive update on NS, integrating foundational clinical knowledge with contemporary molecular insights, advanced cardiologic management, and emerging frontiers in therapy and diagnostics, underscoring the necessity of a proactive, lifelong, and personalized care approach. Full article

Aspergillosis encompasses a heterogeneous spectrum of diseases caused by filamentous fungi of the genus Aspergillus, ranging from allergic airway disorders and chronic pulmonary infection to rapidly progressive invasive disease. Aspergillus fumigatus is the predominant pathogen worldwide, although other species, including Aspergillus flavus, Aspergillus terreus and cryptic species, contribute to morbidity and may exhibit intrinsic or acquired antifungal resistance. Early and accurate laboratory diagnosis is essential for timely treatment, appropriate antifungal selection, and stewardship. Traditional culture remains foundational, enabling confirmation of viable organisms, species-level identification, and antifungal susceptibility testing, but sensitivity is limited and turnaround times are prolonged. Non-culture approaches—including galactomannan, β-D-glucan, lateral flow assays, PCR, and next-generation sequencing—enhance diagnostic sensitivity, facilitate early detection, and allow identification of resistance-associated mutations. Optimal diagnostic performance is achieved through integrated, multimodal strategies combining laboratory tests with clinical and radiological findings. In invasive disease, concurrent use of biomarkers and molecular assays improves specificity and positive predictive value, while in allergic bronchopulmonary aspergillosis, immunological markers remain central. Future directions include standardised molecular protocols, novel antigenic and host-based biomarkers, and cost-effective, risk-adapted diagnostic algorithms to refine detection, guide therapy, and improve patient outcomes. Full article

Metastatic pancreatic ductal adenocarcinoma (PDAC) is typically treated with fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) or gemcitabine plus nab-paclitaxel (GnP), but the choice between regimens remains largely empirical. This narrative review summarizes biomarkers with potential to inform first-line selection in metastatic PDAC, emphasizing genomic and transcriptomic correlates of differential benefit. Recent head-to-head trials, particularly Pancreatic Adenocarcinoma Signature Stratification for Treatment (PASS-01) and GENERATE (Japan Clinical Oncology Group [JCOG] 1611), indicate that modified FOLFIRINOX (mFOLFIRINOX) is not uniformly superior to GnP, strengthening the rationale for biomarker-guided selection. The strongest evidence favoring platinum-based/FOLFIRINOX strategies involves homologous recombination repair deficiency (HRD), especially alterations in germline breast cancer gene 1/2 (BRCA1/2) or partner and localizer of BRCA2 (PALB2), as well as broader genomic scar signatures. Transcriptomic subtype and GATA-binding protein 6 (GATA6) expression are promising but remain unsettled because retrospective data favor classical/GATA6-high disease for FOLFIRINOX, whereas PASS-01 suggested better outcomes with GnP in classical tumors. Candidate biomarkers favoring GnP include high human equilibrative nucleoside transporter 1 (hENT1), low class III β-tubulin (TUBB3) expression, and exploratory phosphatidylinositol 3-kinase (PI3K)/KIT/NOTCH pathway mutation signals. Comprehensive molecular profiling also identifies actionable alterations that may redirect patients to targeted therapy or clinical trials rather than standard chemotherapy alone. Importantly, no biomarker has yet been prospectively validated in a biomarker-stratified randomized trial with regimen selection as the primary endpoint; all biomarker-regimen associations described in this review should therefore be considered hypothesis-generating rather than practice-defining. Nevertheless, the convergence of genomic, transcriptomic, and organoid-based approaches makes biologically informed first-line selection increasingly feasible in metastatic PDAC. Full article

Silver nanoparticles (AgNPs) have attracted substantial scientific interest in biomedical research owing to their unique physicochemical characteristics, broad-spectrum antimicrobial activity, plasmonic properties, and therapeutic versatility. Although conventional physicochemical synthesis methods enable controlled NPs fabrication, their dependence on hazardous reagents, elevated energy input, and environmentally detrimental processing conditions has stimulated the development of sustainable biogenic alternatives. Biological synthesis utilizing plants, microorganisms, fungi, algae, and purified biomolecules has emerged as an eco-friendly and bio-compatible strategy for AgNP fabrication, enabling simultaneous reduction, stabilization, and intrinsic biofunctionalization of NPs. However, traditional biogenic synthesis remains constrained by limited mechanistic understanding, poor batch reproducibility, inadequate control over physicochemical properties, and challenges in large-scale manufacturing. Recent advances in bioengineering have transformed this field through the integration of metabolic engineering, synthetic biology, microfluidic-assisted synthesis, artificial intelligence-guided process optimization, and continuous-flow biomanufacturing, collectively enabling precision fabrication of biogenic AgNPs with enhanced uniformity, scalability, and functional tunability. Furthermore, strategic surface engineering and functionalization have expanded the applicability of biogenic AgNPs across targeted anticancer therapy, antimicrobial intervention, wound healing, regenerative medicine, drug delivery, and theranostic imaging. Despite these advancements, critical challenges remain regarding nano–bio interactions, toxicological safety, regulatory compliance, and translational scalability. Unlike conventional reviews focused primarily on green synthesis approaches, this review critically highlights emerging bioengineering paradigms that enable programmable, scalable, and precision-controlled biogenic AgNP fabrication. This review comprehensively examines next-generation paradigms and strategies for AgNPs biosynthesis, elucidates the molecular mechanisms governing their formation, highlights emerging functionalization and biomedical application paradigms, and discusses current translational barriers. Forming biogenic composites of AgNPs and heteroatom doped carbon nanodots needs intense research in near future. Full article

Focused ultrasound (FUS)-mediated therapies have evolved with the advent of modern ultrasound-guided technology and MRI imaging, moving from their initial use as thermal ablation to a multifunctional platform for thermal and non-thermal ablation, immunomodulation, and targeted drug delivery. This narrative review explores the potential, limitations, and challenges of ablative high-intensity focused ultrasound (HIFU) therapies: HIFU thermal ablation and non-thermal ablation, histotripsy, as well as non-ablative low-intensity focused ultrasound (LIFU) applications in the management of hepatobiliary cancers. HIFU and histotripsy are reviewed as alternative or complementary treatment options in liver tumors, as well as their potential as bridging therapy. Histotripsy is addressed as a theranostic tool, not only by combining ablation with real-time ultrasound imaging guidance, but also by integrating it with sonobiopsy. It facilitates a liquid sonobiopsy of the ablated tumor by releasing intact tumor antigens and damage-associated molecular patterns, leading to potential molecular profiling. LIFU-induced targeted drug delivery (sono-chemotherapy), sonodynamic therapy, radiosensitization, immunomodulation of the immunosuppressive tumor microenvironment (sono-immunotherapy), and the potential to enhance the effect of immune checkpoint inhibitors in these malignancies are discussed. Since FUS-assisted procedures exhibit dual actions through therapeutic functionality associated with intra- and post-procedural ultrasound imaging guidance, they could have value as a theranostic tool in hepatobiliary interventional oncology. Although promising, the available clinical evidence for FUS-mediated therapies in hepatobiliary malignancies consists predominantly of early-stage feasibility studies, retrospective observational cohorts, and non-randomized comparative analyses. Further studies focused on standardized protocols, validation through large-scale, multicenter, prospective randomized clinical trials comparing FUS-based therapies with established treatments, and long-term follow-up of oncological efficacy could define their future role in multimodal oncological strategies. Full article

Upper tract urothelial carcinoma (UTUC) presents distinct diagnostic and therapeutic challenges because of its rarity, anatomic constraints, frequent understaging at biopsy, and risk of systemic recurrence after radical nephroureterectomy. Current perioperative management is driven primarily by clinicopathologic risk factors, which may be insufficient to identify occult molecular residual disease (MRD) or to determine which patients are most likely to benefit from systemic therapy. This narrative review summarizes available evidence on circulating tumor DNA (ctDNA) in UTUC and related urothelial carcinoma settings, classifies the level of evidence supporting each application, and proposes a research framework for prospective evaluation. The strongest UTUC-specific evidence supports ctDNA as a prognostic biomarker associated with recurrence risk, whereas predictive validity for selecting chemotherapy, immune checkpoint inhibitors, antibody-drug conjugates, targeted therapy, or surveillance intensity remains unproven. Evidence from muscle-invasive bladder cancer, including ctDNA-correlative and ctDNA-guided perioperative trials, provides biologic rationale but should not be directly translated into routine UTUC care without disease-specific validation. We outline key implementation questions, including target population, assay selection, timing, false-positive and false-negative results, lead-time bias, and integration of plasma ctDNA with utDNA. Prospective UTUC-specific trials are needed to determine whether ctDNA-guided perioperative strategies improve survival, reduce unnecessary toxicity, and are cost-effective. Full article

Heart failure with preserved ejection fraction (HFpEF) is a prevalent and heterogeneous syndrome with limited therapeutic options, making accurate risk stratification essential yet challenging. Traditional tools such as the H2FPEF and HFA-PEFF scores incorporate few variables and demonstrate modest prognostic performance. Machine learning (ML) offers enhanced risk prediction by integrating multidimensional clinical, imaging, biomarker, and molecular data. This review summarizes current ML applications in HFpEF, including random forests, gradient boosting, support vector machines, and deep learning, highlighting their superior discrimination and ability to reveal phenotypic subgroups with distinct outcomes. We also address practical considerations such as interpretability, real-world validation, and integration into clinical workflows, as well as challenges related to data bias, generalizability, and regulatory requirements. Future opportunities include real-time clinical decision support, digital health integration, and interventional ML to guide personalized therapy. ML holds significant potential to advance precision care and improve outcomes in HFpEF. Full article

The genomic landscape of myelodysplastic syndromes/neoplasms (MDS), a heterogeneous group of myeloid malignancies defined by bone marrow cell dysplasia with ineffective hematopoiesis, includes somatic and, less frequently, germline mutations in hematopoietic stem and progenitor cells, along with chromosomal abnormalities. The latest World Health Organization 2022 classification of myeloid neoplasms, as well as stratification in lower-risk (LR) and higher-risk (HR) MDS using either the Revised International Prognostic Scoring System (IPSS-R) or the Molecular International Prognostic Scoring System (IPSS-M), guide prognostic assessment and risk-adjusted therapy. We report the case of an 81-year-old patient diagnosed with LR-MDS according to IPSS-R that exhibited direct progression to acute myeloid leukemia. The retrospective analysis of paired DNA samples from MDS and leukemic phases, obtained four months apart, using both targeted next-generation sequencing and single nucleotide polymorphism array, indicated swift alterations in the genomic profile, being suggested that the leukemic clone emerged from the clone harboring homozygous TET2 and heterozygous SRSF2 variants that acquired RUNX1, BCOR, BCORL1 likely pathogenic mutations and trisomy 13. By employing IPSS-M for prognostic evaluation at the MDS phase, the patient would have been assigned to the HR-MDS category with a possible benefit from hypomethylating agent therapy. Risk stratification is of pivotal importance in a patient-centered approach to MDS treatment being significantly improved by incorporating the molecular genetic findings. Full article

Neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS; Lou Gehrig’s disease), represent a growing global health burden characterized by progressive neuronal loss and functional decline. Despite decades of intensive research, effective disease-modifying therapies remain limited, underscoring the urgent need for innovative therapeutic strategies. This review highlights recent advances in the understanding of disease etiology and emerging treatment approaches, with a particular focus on modalities with translational potential. We discussed novel disease-modifying interventions, including gene and cell therapies, RNA-targeting strategies, and immunotherapies aimed at clearing misfolded proteins such as amyloid-β, tau, and α-synuclein. In parallel, we examined the evolving recognition of neuroinflammation and mitochondrial dysfunction as actionable therapeutic targets, alongside progress in precision medicine and biomarker-guided approaches that enable early diagnosis and individualized treatment. Additionally, we summarized developments in repurposed pharmacological agents, neuroprotective compounds, and lifestyle interventions, emphasizing the importance of integrative, multimodal strategies. Across AD, PD, and ALS, convergent molecular mechanisms, including protein misfolding, oxidative stress, and disrupted proteostasis, present opportunities for cross-disease therapeutic targeting. Finally, we addressed key challenges and future directions, including translating preclinical efficacy into clinical success, optimizing CNS-targeted delivery systems, and navigating ethical considerations surrounding gene editing and stem cell therapies. Full article

Pancreatic ductal adenocarcinoma (PDAC) and biliary tract cancers (BTCs) remain highly lethal gastrointestinal malignancies because of late presentation, marked molecular heterogeneity, and limited durable benefit from conventional systemic therapy. This narrative review summarizes recent advances in both diseases, focusing on practice-informing clinical trials, biomarker-driven treatment strategies, and translational insights into tumor biology and resistance. In PDAC, progress includes refinement of perioperative management, broader germline and somatic testing, recognition of DNA damage repair-deficient subsets, and development of KRAS-directed therapies and rational combination strategies. In BTCs, especially intrahepatic cholangiocarcinoma, comprehensive molecular profiling has expanded precision oncology through actionable alterations such as FGFR2 rearrangements, IDH1 mutations, HER2 amplification/overexpression, BRAF V600E, NTRK fusions, and MSI-high/dMMR status. Immunotherapy has a clearer role in selected BTC populations, whereas in PDAC benefit remains largely restricted to rare biomarker-defined subsets. Across both diseases, circulating tumor DNA is emerging as a promising tool for prognostication, minimal residual disease assessment, response monitoring, and early resistance detection. Contemporary care increasingly depends on early molecular profiling, individualized treatment sequencing, and integration of targeted therapies, biomarker-guided immunotherapy, and clinical trials. Full article

Antiretroviral drugs (ARVDs) remain the cornerstone of HIV/AIDS management, but their therapeutic efficacy and safety are highly influenced by bioconversion processes such as hepatic metabolism and enzymatic transformation. Variability in metabolic pathways, mediated by cytochrome P450 enzymes and other liver-based systems, contributes to interindividual differences in drug response, toxicity, and resistance. Recent advances in artificial intelligence, particularly artificial neural networks (ANNs), offer promising tools for modeling and optimizing these complex bioconversion processes. ANNs are capable of learning nonlinear relationships from high-dimensional datasets, making them ideal for predicting the pharmacokinetic parameters, enzyme–substrate interactions, and metabolic stability of ARVDs. This review explores the emerging role of ANNs in understanding and optimizing the metabolic transformation of antiretroviral agents. Key applications are discussed, including prediction of drug–enzyme interactions, in silico modeling of hepatic clearance, and simulation of enzyme kinetics. The integration of molecular descriptors, omics data, and clinical parameters into ANN models allows for improved prediction accuracy and personalized therapy. Furthermore, ANN-based tools can aid in early-stage drug development by identifying metabolic liabilities and guiding structural modifications to enhance metabolic stability. Despite their potential, challenges such as data scarcity, model interpretability, and standardization remain. Future research should focus on hybrid models combining ANN with mechanistic pharmacokinetics, the incorporation of real-world patient data, and validation against experimental outcomes. Overall, ANNs represent a powerful approach to optimizing ARVDs bioconversion, with the potential to improve efficacy, reduce toxicity, and support the development of next-generation antiretroviral therapies Full article

Endometrial cancer (EC) is increasingly recognized as a heterogeneous disease, yet current treatment strategies often fail to explain why tumors with similar molecular profiles respond differently or develop resistance. This gap points to regulatory mechanisms beyond static genomic alterations. Epigenetic dysregulation through DNA methylation, histone modification, and non-coding RNA (ncRNAs) networks acts as a dynamic and reversible system that governs how tumors adapt under therapeutic pressure. In EC, alterations affecting key regulators such as MLH1, PTEN, and hormone receptors directly influence sensitivity to immunotherapy, targeted therapy, and endocrine treatment, defining treatment-responsive and treatment-resistant states. These observations shift the role of epigenetics from a descriptive feature of tumor biology to a determinant of therapeutic behaviour. Epigenetic states influence immune recognition, pathway activation, and cell cycle control, thereby shaping response to chemotherapy and immune checkpoint blockade. Biomarkers derived from these alterations, including methylation signatures and circulating RNAs, offer opportunities for patient stratification and longitudinal monitoring of treatment response. Therapeutically, targeting epigenetic regulators provides a strategy to reverse resistance and restore treatment sensitivity. DNA methyltransferase and histone deacetylase inhibitors, particularly in combination with established therapies, have shown potential to enhance treatment efficacy. Emerging approaches, including locus-specific epigenetic editing and liquid biopsy–guided monitoring, further support adaptive treatment strategies. Integrating epigenetic reprogramming into clinical decision-making offers a practical path toward improving treatment response and overcoming resistance in EC. Here, we propose an Epigenetic State–Response Framework (ESRF) in which dynamic epigenetic states define treatment-sensitive and resistant phenotypes, map to specific therapeutic vulnerabilities, and can be actively reprogrammed to restore treatment response. Full article