Molecular Diagnosis & Therapy最新文献

{"title":"Genetics of Cerebrotendinous Xanthomatosis.","authors":"Jennifer Hanson, Penelope E Bonnen","doi":"10.1007/s40291-026-00855-4","DOIUrl":"10.1007/s40291-026-00855-4","url":null,"abstract":"<p><p>Cerebrotendinous xanthomatosis (CTX) is rare, autosomal recessive inborn error of metabolism caused by biallelic pathogenic variants in CYP27A1, which encodes sterile 27 hydroxylase, a key enzyme in bile acid biosynthesis. Enzyme deficiency results in reduced cholic and chenodeoxycholic acid synthesis with accumulation of cholestanol, bile acid intermediates, and bile alcohols, producing a progressive multisystem disorder characterized by chronic diarrhea, juvenile-onset cataracts, tendons xanthomas, and neurological dysfunction. Although CTX typically begins in childhood, diagnosis is frequently delayed until adulthood, limiting the benefit of effective disease modifying therapy with chenodeoxycholic acid. Since the identification of CYP27A1, more than 200 pathogenic variants have been reported, including canonical loss of function alleles and missense variants with variable residual enzyme activity. In this review, we summarize the medical genetics, population genetics and genotype phenotype relationships of CTX. We highlight insights from large population databases that refine global incidence estimates, revealing population-specific enrichment of pathogenic variants and persistent underdiagnosis. We further review functional and clinical data demonstrating that stratification of CYP27A1 variants by functional effect, complete loss of function versus hypomorph alleles, correlates with clinical severity and biochemical phenotype. Finally, we discuss emerging advances in biochemical testing and newborn screening strategies that offer the potential for presymptomatic diagnosis, enabling timely initiation of therapy and prevention of irreversible disease manifestations. Integrating molecular, functional, and population genetic data provides a framework for improved variant interpretation, earlier diagnosis, and optimized therapeutic intervention in CTX.</p>","PeriodicalId":49797,"journal":{"name":"Molecular Diagnosis & Therapy","volume":" ","pages":"681-687"},"PeriodicalIF":5.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13319261/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148273455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heat Shock Proteins as Cancer Biomarkers: From Mechanism to Clinical Application.","authors":"Prajjwal Kushwaha, Ipsita Roy","doi":"10.1007/s40291-026-00851-8","DOIUrl":"10.1007/s40291-026-00851-8","url":null,"abstract":"<p><p>Molecular chaperones are an integral part of the proteostasis network of the cell that regulate client protein folding, substrate interactions, disaggregation, degradation, and intracellular trafficking, either independently or through coordinated action with co-chaperones. Among them, heat shock proteins have emerged as key players in cancer, largely owing to their ability to stabilize oncogenic proteins and support tumor initiation and malignant progression. Their expression is dysregulated in cancer cells and secreted into circulatory system as a consequence of oncogenic signaling pathways. Because of these properties, molecular chaperones, particularly heat shock proteins have gained traction as potential biomarkers for cancer detection, including in point-of-care diagnostic applications. However, as heat shock proteins are involved in basal cellular activities, their levels are perturbed in several other benign cellular conditions. This review highlights the multifaceted roles of molecular chaperones, with a focus on heat shock proteins, in cancer development and progression. It further discusses recent advances and perspectives on major heat shock proteins as biomarkers for cancer diagnosis, emphasizing their potential to improve diagnostic accuracy. Additionally, this review addresses current challenges and limitations associated with the diagnostic use of heat shock proteins, providing insights to guide future research and clinical translation.</p>","PeriodicalId":49797,"journal":{"name":"Molecular Diagnosis & Therapy","volume":" ","pages":"629-650"},"PeriodicalIF":5.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147976728","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Beyond Binary FISH Results: Targeted NGS Provides Deeper Characterization of MYC and Broader Genomic Alterations in DLBCL.","authors":"Mariana Bastos-Oreiro, Sara Fernández de Córdoba-Oñate, Ismael de la Iglesia-San Sebastián, Francisco Díaz-Crespo, María Chicano Lavilla, Juan Carlos Triviño, Raquel Fernández González, Miguel López-Esteban, Marina Gómez-Llobel, Paula Fernández Caldas, Pablo Silva, Javier Menárguez, Ramón García Sanz, Ismael Buño, Carolina Martínez-Laperche","doi":"10.1007/s40291-026-00857-2","DOIUrl":"10.1007/s40291-026-00857-2","url":null,"abstract":"","PeriodicalId":49797,"journal":{"name":"Molecular Diagnosis & Therapy","volume":" ","pages":"719"},"PeriodicalIF":5.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147989767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Considering Tumour Sidedness is Critical for Accurate Interpretation of Liquid Biopsy Results in Metastatic Colorectal Cancer.","authors":"Marta Toledano-Fonseca, Icíar de la Fuente, María José Ortiz-Morales, Pablo Cano-Ramírez, Gema Pulido-Cortijo, María Teresa Cano-Osuna, María Victoria García-Ortiz, María Auxiliadora Gómez-España, Antonio Rodríguez-Ariza, Enrique Aranda","doi":"10.1007/s40291-026-00856-3","DOIUrl":"10.1007/s40291-026-00856-3","url":null,"abstract":"<p><strong>Background: </strong>Colorectal cancer is one of the most common and deadly malignancies worldwide. Traditionally, all colon tumours have been treated as a single entity, but growing evidence shows that tumour behaviour differs markedly according to tumour sidedness. Right-sided and left-sided tumours exhibit distinct molecular profiles, prognoses and therapeutic responses. A liquid biopsy is a minimally invasive approach to monitor tumour dynamics in real time, offering valuable prognostic and predictive insights into metastatic colorectal cancer. However, despite increasing research on liquid biopsy-based biomarkers, the potential impact of tumour sidedness on their interpretation has not been systematically explored.</p><p><strong>Methods: </strong>We evaluated circulating RAS mutational status, RAS mutant allele fraction and cell-free DNA concentration and fragmentation in plasma from 232 patients with metastatic colorectal cancer.</p><p><strong>Results: </strong>Our findings reveal that tumour sidedness substantially modulates the prognostic value of these circulating biomarkers. In left-sided tumours, worse outcomes were associated with the presence of circulating RAS mutations, higher cell-free DNA concentrations and elevated carcinoembryonic antigen levels. In contrast, among right-sided tumours, only mutant allele fraction levels revealed significant prognostic relevance.</p><p><strong>Conclusions: </strong>Our results demonstrate that tumour sidedness critically influences liquid biopsy interpretation in metastatic colorectal cancer, underscoring the need to incorporate the primary tumour location into the clinical assessment of circulating biomarkers.</p>","PeriodicalId":49797,"journal":{"name":"Molecular Diagnosis & Therapy","volume":" ","pages":"707-717"},"PeriodicalIF":5.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13319506/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148297140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Liquid Biopsy in Primary CNS Tumors: Bridging Biology, Technology, and Clinical Care.","authors":"Catalina Trejo-Becerril, Ariela Souroujon-Torun, Lucia Taja-Chayeb, Alexandra Díaz-Alba, Enrique Caballé-Pérez, David Aguilar-Cardoso, Sylvia Harari-Arakindji, Alejandro Rodríguez-Camacho, Sergio Moreno-Jimenez, Rogelio Trejo, Alipio González-Vázquez, José Omar Navarro-Fernández, Bernardo Cacho-Díaz, Talia Wegman-Ostrosky","doi":"10.1007/s40291-026-00849-2","DOIUrl":"10.1007/s40291-026-00849-2","url":null,"abstract":"<p><p>Liquid biopsy has emerged as a minimally invasive approach for the molecular characterization and longitudinal monitoring of primary central nervous system (CNS) tumors. Although extensively validated in systemic malignancies, its clinical application in CNS tumors is challenged by the blood-brain barrier, low analyte abundance, and heterogeneous assay performance. Recent advances have expanded the spectrum of detectable tumor-derived components, including circulating tumor DNA (ctDNA), cell-free DNA, extracellular vesicles, RNA species, nucleosomes, metabolites, and lipids, across multiple biofluids such as cerebrospinal fluid (CSF), plasma, serum, urine, saliva, and tears. The aim of this study was to review the biological foundations, analytes, biofluids, clinical applications, and technical limitations of liquid biopsy in primary CNS tumors, with emphasis on diagnostic, prognostic, and surveillance value. We synthesized current evidence on tumor-derived analytes detectable through liquid biopsy, their molecular correlates, and their performance across biofluids. CSF is consistently the most informative biofluid for CNS tumors, with higher analyte concentration and superior concordance with tumor tissue compared with plasma. CtDNA in CSF reliably identifies hallmark alterations, including IDH1/2, H3K27M, TERT, BRAF, ATRX, TP53, 1p/19q codeletion, and MYCN amplification, thereby enabling better diagnosis, molecular classification, and therapeutic stratification. Plasma-based assays are less sensitive but remain valuable for longitudinal monitoring, especially when combined with ultrasensitive sequencing or fragmentomic approaches. Emerging biomarkers, including nucleosome footprints, exosomes, proteins, microRNA (miRNA)/long noncoding RNA (lncRNA)/circular RNA (circRNA) signatures, lipidomic panels, and metabolites such as D-2-hydroxyglutarate, show potential for integration into multimodal diagnostics. Liquid biopsy provides a powerful and rapidly evolving tool for the minimally invasive molecular assessment of CNS tumors. While CSF remains the optimal matrix for diagnosis and characterization, advances in ultrasensitive detection methods increasingly support the feasibility of plasma and urine for longitudinal follow-up. Integrating liquid biopsy with advanced imaging and tissue-based data will likely transform diagnostic accuracy, therapeutic decision-making, and real-time monitoring of CNS tumors.</p>","PeriodicalId":49797,"journal":{"name":"Molecular Diagnosis & Therapy","volume":" ","pages":"587-613"},"PeriodicalIF":5.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147845287","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting Cytotoxic T-Cell Effector Function with Granzyme B PET: Translational Advances Toward Predicting Immunotherapy Outcomes.","authors":"Luca Filippi, Priscilla Guglielmo, Esra Arslan, Elife Akgün, Laura Evangelista","doi":"10.1007/s40291-026-00858-1","DOIUrl":"10.1007/s40291-026-00858-1","url":null,"abstract":"<p><p>The clinical success of cancer immunotherapy has highlighted the urgent need for biomarkers capable of capturing dynamic and functional anti-tumor immune activity. Granzyme B (GzmB), a serine protease released by activated cytotoxic CD8⁺ T lymphocytes and natural killer cells during target-cell killing, represents a proximal and mechanistically linked marker of immune effector function. Positron emission tomography (PET) tracers targeting GzmB enable non-invasive, whole-body assessment of cytotoxic activity in vivo, potentially overcoming the spatial and temporal limitations of tissue biopsy and conventional imaging. Preclinical investigations using ⁶⁸Ga- and ¹⁸F-labeled peptide-based tracers, including [⁶⁸Ga]Ga-NOTA-GZP and [¹⁸F]AlF-mNOTA-GZP, consistently demonstrate early discrimination between responders and non-responders to immune checkpoint blockade and combination therapies, often preceding measurable tumor shrinkage or metabolic changes on [¹⁸F]FDG PET. Emerging first-in-human studies further support the feasibility, safety, and predictive potential of GzmB PET across multiple tumor types. Despite promising results, several challenges remain, including optimal imaging timing, signal heterogeneity related to non-canonical GzmB sources, and the need for standardized quantitative thresholds and multicenter validation. Overall, GzmB PET represents a biologically grounded and translationally advanced approach for early response assessment, patient stratification, and potential theranostic applications in precision immuno-oncology.</p>","PeriodicalId":49797,"journal":{"name":"Molecular Diagnosis & Therapy","volume":" ","pages":"561-573"},"PeriodicalIF":5.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148139646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Real-Time Detection of Colorectal Cancer Using Topical Application of a pH-Activatable Fluorophore.","authors":"Daan G J Linders, Jinhui Ser, Md Shamim, Aida Baibussunova, Jasmijn C J Loggers, Gilbert Noordam, Davey van den Burg, Gijs J D van Acker, Onno R Guicherit, Marinke Westerterp, Peter J K Kuppen, Andreas W K S Marinelli, Denise E Hilling, Elke E M Peters, Satoshi Kashiwagi, Maged Henary, Hak Soo Choi, Alexander L Vahrmeijer","doi":"10.1007/s40291-026-00853-6","DOIUrl":"10.1007/s40291-026-00853-6","url":null,"abstract":"<p><strong>Introduction: </strong>Standard treatment for locally advanced rectal cancer involves neoadjuvant chemoradiation therapy (nCRT) followed by total mesorectal excision, but this approach carries significant morbidity and often results in incomplete resections owing to poor intraoperative tumor visualization. For patients with complete response to nCRT, a watch-and-wait (W&W) strategy can spare surgery, but current imaging techniques inadequately identify complete responders, leading to regrowth in ~ 30% of cases. To improve nCRT response assessment and guide resections, we developed PH10, a topically applied, pH-activatable near-infrared (NIR) fluorescent probe for rapid, tumor-specific imaging.</p><p><strong>Methods: </strong>PH10, a small-molecule cyanine analog, was tested in murine models and on human tumor specimens (n = 11). Fluorescence activation, tumor specificity, and tumor-to-background ratio (TBR) were evaluated in vivo and ex vivo within clinically relevant timeframes.</p><p><strong>Results: </strong>PH10 enabled rapid and specific tumor visualization, achieving a median TBR of 3.2 within 1 min in vivo in murine models and 2.2 within 10 min ex vivo on human samples. The probe demonstrated high specificity for tumor tissue within the acidic tumor microenvironment without requiring systemic administration or prolonged incubation.</p><p><strong>Conclusions: </strong>PH10 is a promising, fast-acting topical NIR agent for real-time tumor detection during colorectal cancer endoscopy and surgery. Its simplicity and rapid kinetics support potential clinical translation. Moreover, its pH-activatable mechanism may extend its utility to other solid cancers with acidic microenvironments.</p>","PeriodicalId":49797,"journal":{"name":"Molecular Diagnosis & Therapy","volume":" ","pages":"689-706"},"PeriodicalIF":5.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13319260/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148007229","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic Strategies Targeting the Molecular Pathogenesis of Myotonic Dystrophy Type 1: Current Status and Future Directions.","authors":"Mohamed Chahine, Vamsi Krishna Murthy Ginjupalli, Dominic Jauvin, Mohamed Boutjdir","doi":"10.1007/s40291-026-00848-3","DOIUrl":"10.1007/s40291-026-00848-3","url":null,"abstract":"<p><p>Myotonic dystrophy type 1 is the most prevalent adult-onset muscular dystrophy and is characterized by progressive muscle weakness, myotonia, cardiac conduction defects, endocrine dysfunction, and central nervous system involvement. Myotonic dystrophy type 1 is caused by an unstable CTG repeat expansion in the 3' untranslated region of the DMPK gene, which produces toxic CUG-expanded transcripts that sequester RNA-binding proteins such as Muscleblind-like, induce widespread alternative splicing defects, and drive an RNA gain-of-function mechanism rather than simple DMPK haploinsufficiency. Despite major advances in understanding the molecular pathogenesis of myotonic dystrophy type 1, there is still no approved cure or disease-modifying therapy. This review summarizes the molecular basis of myotonic dystrophy type 1 and provides an in-depth overview of emerging therapeutic strategies that directly target the underlying pathogenic cascade at the DNA and RNA levels. Gene therapy-based approaches, including CRISPR-mediated genome editing, aim to reduce or eliminate the expanded CTG repeats or expanded DMPK allele and its toxic transcripts. In parallel, a broad spectrum of RNA-directed interventions is being developed, encompassing antisense oligonucleotides, antibody-penetrating and cell-penetrating peptide-conjugated antisense oligonucleotides to enhance skeletal and cardiac muscle delivery, small interfering RNAs, and microRNA-based tools such as antagomiRs. Additional strategies exploit engineered RNA-binding proteins and peptide decoys to disrupt toxic ribonuclear aggregates, polyadenylation signal-driven premature transcriptional termination to selectively silence mutant DMPK, and small molecules that modulate RNA metabolism, dissolve CUG RNA foci, or correct downstream mis-splicing. By integrating data from preclinical models and ongoing clinical trials, including recent advances with muscle‑targeted antisense oligonucleotide conjugates and gene therapy, this review outlines the current status, strengths, and limitations of these mechanism-based therapies for myotonic dystrophy type 1. The discussion highlights key translational challenges such as efficient delivery to skeletal muscle, the heart, and brain, long-term safety, and robust pharmacodynamic biomarkers as well as opportunities for combination and next-generation approaches aimed at converting molecular correction into durable clinical benefit for patients with myotonic dystrophy type 1.</p>","PeriodicalId":49797,"journal":{"name":"Molecular Diagnosis & Therapy","volume":" ","pages":"545-560"},"PeriodicalIF":5.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147718737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From Gene to Hope: Rett Syndrome and the Rise of Molecular Therapies.","authors":"Yoann Leblay, Marie-Solenne Felix, Jean-Christophe Roux, Nicolas Panayotis","doi":"10.1007/s40291-026-00847-4","DOIUrl":"10.1007/s40291-026-00847-4","url":null,"abstract":"<p><p>Rett syndrome is a rare X-linked neurodevelopmental disorder caused by mutations in MECP2, a gene critical for neuronal function, chromatin organization, and synaptic plasticity. After a period of apparently normal early development, individuals with Rett syndrome experience rapid regression followed by lifelong neurological impairment. Notably, preclinical studies have shown that restoration of MeCP2 expression can reverse established symptoms in adult mice, positioning Rett syndrome as a promising target for molecular therapies. However, MECP2 is extremely dosage sensitive and both insufficient and excessive expression are harmful, creating a narrow therapeutic window and a major challenge for treatment design. This review examines the evolving landscape of gene- and RNA-based therapies for Rett syndrome, with a focus on strategies that enable precise MeCP2 replacement, dosage control, and widespread central nervous system delivery. We discuss clinical-stage adeno-associated virus gene replacement programs, including TSHA-102 and NGN-401, highlighting their vector designs, regulatory elements, delivery approaches, and emerging clinical data. Advances in adeno-associated virus capsid engineering and vector optimization aimed at improving neuronal targeting while minimizing peripheral exposure and immune toxicity are also reviewed. Beyond gene supplementation, we explore approaches that restore endogenous MECP2 regulation, such as reactivation of the inactive X chromosome, as well as DNA and RNA editing strategies. Collectively, these advances reflect a shift toward precision-regulated therapies for Rett syndrome that may provide a model for treating other dosage-sensitive neurodevelopmental disorders.</p>","PeriodicalId":49797,"journal":{"name":"Molecular Diagnosis & Therapy","volume":" ","pages":"575-585"},"PeriodicalIF":5.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147677968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of a Nomogram to Predict Therapeutic Resistance in Metastatic Melanoma Using Longitudinal ctDNA Kinetics.","authors":"Hunter A Miller, Annalara G Fischer, Michael E Egger, Kavitha Yaddanapudi, Maiying Kong, Melissa B Hall, Mark W Linder","doi":"10.1007/s40291-026-00840-x","DOIUrl":"10.1007/s40291-026-00840-x","url":null,"abstract":"<p><strong>Background and objective: </strong>Early detection of treatment resistance and progression in metastatic melanoma may improve outcomes, but current surveillance relies on intermittent radiographic imaging that may lag behind dynamic tumor biology. Circulating tumor DNA (ctDNA), a minimally invasive and increasingly validated biomarker, enables real-time disease monitoring. Longitudinal (kinetic) changes in ctDNA over time have been proposed to provide greater insight into disease activity than isolated measurements; however, few studies have evaluated the prognostic significance of longitudinal ctDNA kinetics across extended timepoints. We aimed to assess the relationship between ctDNA concentration, ctDNA longitudinal kinetics, and future radiographic progression in patients receiving systemic therapy.</p><p><strong>Methods: </strong>We quantified BRAF V600E/V600K, or NRAS Q61 ctDNA using droplet digital polymerase chain reaction from longitudinal plasma samples from patients with metastatic cutaneous melanoma. A multivariate Cox proportional hazards model using a time-to-event framework was fit, treating each patient as contributing multiple 100-day landmark intervals. Predictors of future progression included percent variant allele frequency at each follow-up assessment and Δ% variant allele frequency/month (velocity).</p><p><strong>Results: </strong>The model incorporating both single timepoint measures and kinetic ctDNA features achieved strong internal discrimination between progression versus non-progression events within 100 days (100-day time-dependent area under the curve = 0.88) and was used to build a nomogram. Compared with nomogram derived high-risk visits, low-risk visits showed significantly improved progression-free survival (p = 0.00021).</p><p><strong>Conclusions: </strong>Using a longitudinal time-to-event modeling framework, this proof-of-concept study demonstrates the feasibility of kinetic ctDNA-based risk estimation throughout systemic treatment. Both single-point ctDNA measures and their kinetics may serve as indicators of future disease progression.</p>","PeriodicalId":49797,"journal":{"name":"Molecular Diagnosis & Therapy","volume":" ","pages":"515-527"},"PeriodicalIF":5.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147437327","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}