INTRODUCTION: Pathogenesis of large B-cell lymphomas (LBCL) and follicular lymphomas (FL) is a multistep process associated with the development of diverse DNA alterations and consequent deregulation of critical cellular processes. Detection of tumor-associated mutations within non-tumor compartments (mainly plasma) is the basis of the 'liquid biopsy' concept. Apart from tumor mutational profiling, quantitative analysis of circulating tumor DNA (ctDNA) allows longitudinal assessment of tumor burden. ctDNA-based technologies provide a new tool for tumor diagnostics and treatment personalization. AREAS COVERED: Our review provides a comprehensive overview and summary of available ctDNA studies in LBCL and FL. The accuracy of ctDNA-based detection of lymphoma-associated DNA alterations is correlated to known LBCL and FL molecular landscape. Additionally, we summarized available evidence that supports and justifies the clinical use of ctDNA for lymphoma risk stratification, treatment response evaluation, and treatment response-adapted therapy. Lastly, we discuss other clinically important ctDNA applications: monitoring of lymphoma clonal evolution within resistance and/or relapse development and utilization of ctDNA for diagnostics in non-blood fluids and compartments (e.g. cerebrospinal fluid in primary CNS lymphomas). EXPERT OPINION: Despite certain challenges, including methodological standardization, ctDNA holds promise to soon become an integral part of lymphoma diagnostics and treatment management.
- MeSH
- Circulating Tumor DNA * blood genetics MeSH
- Lymphoma, Large B-Cell, Diffuse * diagnosis genetics therapy blood MeSH
- Lymphoma, Follicular * diagnosis genetics therapy blood MeSH
- Humans MeSH
- Mutation MeSH
- Biomarkers, Tumor * blood genetics MeSH
- Prognosis MeSH
- Liquid Biopsy methods MeSH
- Treatment Outcome MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
INTRODUCTION: Central nervous system (CNS) involvement in diffuse large B-cell lymphoma (DLBCL) is a rare but serious condition requiring accurate diagnostics. Cerebrospinal fluid (CSF) analysis plays a crucial role, particularly in cases where biopsy is not feasible, and imaging is inconclusive. AREAS COVERED: Chemical markers have limitations, particularly in low-cellularity samples. Novel molecular techniques, including circulating tumor DNA (ctDNA) analysis and microRNAs (miRNAs), are gaining prominence for their ability to detect gene mutations at diagnosis and monitor minimal residual disease during follow-up. The sensitivity and specificity of genetic mutations, particularly MYD88 L265P, in combination with interleukin-10 (IL-10) levels, are discussed. The literature search methodology involved reviewing relevant studies and clinical data.This review examines both traditional and emerging methods for CSF analysis in diagnosing CNS involvement in DLBCL. Conventional approaches such as cytomorphology, flow cytometry, and biochemical markers have limitations, particularly in low-cellularity samples. Novel molecular techniques, including ctDNA analysis and miRNAs, are gaining prominence for their ability to detect gene mutations at diagnosis and monitor minimal residual disease during follow-up. The sensitivity and specificity of genetic mutations, particularly MYD88 L265P, in combination with interleukin-10 (IL-10) levels, are discussed. The literature search methodology involved reviewing relevant studies and clinical data. EXPERT OPINION: Advancements in CSF biomarker analysis are improving the diagnosis of CNS lymphoma, aiding early detection and personalized treatment approaches. However, further research and broader clinical validation are necessary for their routine implementation.
- MeSH
- Circulating Tumor DNA cerebrospinal fluid genetics MeSH
- Molecular Diagnostic Techniques methods MeSH
- Lymphoma, Large B-Cell, Diffuse * diagnosis cerebrospinal fluid genetics pathology MeSH
- Interleukin-10 genetics cerebrospinal fluid MeSH
- Humans MeSH
- Meningeal Neoplasms * diagnosis cerebrospinal fluid genetics MeSH
- MicroRNAs genetics cerebrospinal fluid MeSH
- Mutation MeSH
- Myeloid Differentiation Factor 88 genetics MeSH
- Biomarkers, Tumor * cerebrospinal fluid genetics MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
BACKGROUND: Diagnosing primary or secondary CNS lymphoma (CNSL) is a clinical challenge due to the limitations of standard biopsy and imaging procedures despite established guidelines. Therefore, accurate biomarkers and analytical methods that are convenient for practical routine use are needed to diagnose and manage these aggressive lymphomas effectively. We evaluated the utility of minimally invasive circulating tumor DNA (ctDNA) detection in a prospective real-world scenario, moving this approach closer to clinical practice. METHODS: A total of 164 plasma, cerebrospinal fluid (CSF), and tumor samples from 56 CNSL patients were collected to analyze tumor DNA by the diagnostic next-generation sequencing (NGS) panel LYNX, enabling simultaneous analysis of gene variants, chromosomal aberrations, and antigen receptor rearrangements in targeted regions. RESULTS: The well-known genetic heterogeneity of CNSL was refined with integrative molecular data, showing the most frequent MYD88, PIM1, and KMT2D mutations and a broad spectrum of chromosomal aberrations, reflecting high genomic complexity. The multi-target approach achieved a substantially higher detection rate of CNS infiltration (90%) than tracking a single variant in gene MYD88 (46%). CSF clearly surpasses plasma if applying a routine (non-ultrasensitive) NGS approach and allows for more reliable evidence of CNS involvement than conventional flow cytometry (91% vs. 21%, p < 0.001). Parallel analysis of tumor DNA in both cell-free and cellular DNA from CSF makes the probability of primary or secondary CNS malignancy detection even higher. CONCLUSIONS: Our prospective, tissue-agnostic approach highlights the feasibility of ctDNA sequencing by a commonplace and affordable method, offering higher sensitivity to detect CNS infiltration with lymphoma than standard cell-analyzing techniques. We accentuate the benefit of a multi-target NGS approach and adequate CSF sampling to obtain satisfactory diagnostic yield. Less invasive liquid biopsy testing by comprehensive NGS complements standard procedures in the diagnostics and management of CNSL patients, especially when encountering limitations.
- Publication type
- Journal Article MeSH
Uroteliální karcinom patří v raných stadiích k nejčastějším nádorovým onemocněním, onkolog se však častěji setkává s pacienty s pokročilým onemocněním. Právě metastatický uroteliální karcinom zůstává velkou terapeutickou výzvou. Tradiční léčba byla a stále je postavena na chemoterapii obsahující platinový derivát, avšak za poslední roky i tato diagnóza prošla velkým vývojem a do léčby přibyly nové léky ze skupiny moderní imunoterapie. Zcela zásadní zlom pak přinesly kombinované režimy imunoterapie s konjugovanými protilátkami, kdy kombinace pembrolizumabu s enfortumab vedotinem přepsala doporučené postupy léčby uroteliálního karcinomu v první linii. Právě kombinovaná terapie se stane budoucností managementu uroteliálního karcinomu, tak jako je to patrné i u jiných nádorových onemocnění.
Muscle-invasive bladder cancer (MIBC) is an aggressive malignancy with a high risk of metastases and recurrence. The standard treatment involves neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy, yet approximately 50 % of patients relapse within three years. Neoadjuvant chemotherapy improves overall survival (OS) and pathological complete response (pCR). Emerging treatment strategies include neoadjuvant immunotherapy, with phase II trials demonstrating increased pCR rates with pembrolizumab and atezolizumab. The recently published NIAGARA trial established that perioperative durvalumab combined with chemotherapy reduces disease progression risk by 32 % (HR = 0.68) and mortality risk by 25 % (HR = 0.75). This supports perioperative immunotherapy as the new standard of care. Ongoing studies focus on combining ADCs and ICIs and leveraging ctDNA to refine patient selection. These advancements drive personalized oncology and optimize neoadjuvant therapy.
- MeSH
- Circulating Tumor DNA MeSH
- Immunotherapy methods MeSH
- Humans MeSH
- Urinary Bladder Neoplasms * drug therapy MeSH
- Neoadjuvant Therapy MeSH
- Intraoperative Care MeSH
- Antineoplastic Combined Chemotherapy Protocols MeSH
- Randomized Controlled Trials as Topic MeSH
- Check Tag
- Humans MeSH
- Publication type
- Review MeSH
Východiská: V managemente pacientov s kolorektálnym karcinómom (colorectal cancer – CRC) stále existuje priestor pre zlepšenie stratifikácie rizika a tým presnejšie „ušitie“ liečby na mieru. Veľmi sľubným sa v tomto ohľade javia biomarkery získavané prostredníctvom takzvanej tekutej biopsie, čo je neinvazívna metóda odberu telesných tekutín pacienta, najčastejšie periférnej krvi. Analyzujú sa rozličné biomarkery súvisiace s nádorom, ktoré môžu mať ako prognostickú, tak aj prediktívnu hodnotu. Jedným z najviac prebádaných nádorových biomarkerov je práve nádorová cirkulujúca DNA, ktorej spektrum využitia bolo spočiatku len u pokročilých a metastatických karcinómov a spočívalo v molekulárnom profilovaní alebo zisťovaní získanej rezistencie k liečbe. V súčasnosti sa využitie cirkulujúcej nádorovej DNA (ctDNA) posunulo už k skorým štádiám karcinómov, kde okrem iného slúži k identifikácii minimálnej reziduálnej choroby alebo k skorej diagnostike CRC. Doterajšie štúdie ukazujú veľmi sľubný potenciál týchto biomarkerov, ale k využitiu v klinickej praxi bude potrebné získať viac informácií a počkať na výsledky prebiehajúcich výskumov. Cieľ: V tomto prehľadovom článku sa budeme venovať ctDNA, jej aspektom, možnostiam diagnostiky a súčasnému využitiu v rámci CRC.
Background: Space still exists in the management of patients with colorectal cancer (CRC) for improving risk stratification and thus the precision of treatment tailoring. Quite promising in this regard are biomarkers acquired via liquid biopsy, which is a non-invasive method of body fluid draw, most commonly peripheral blood. A variety of biomarkers associated with the tumor are analyzed, which can have either prognostic or predictive value. Circulating tumor DNA (ctDNA) is one of the most explored tumor biomarkers. Initially, its utility spectrum was only in advanced or metastatic cancers and consisted of molecular profiling and detecting acquired resistance to treatment. Nowadays, the use of circulating tumor DNA has shifted to earlier cancer stages, where it can identify minimal residual disease or diagnose colorectal cancer early. Existing studies show promising potential of these biomarkers, but more information needs to be gathered and information from ongoing studies needs to be obtained in order to use them in everyday practice. Aim: In this review article, we will discuss ctDNA, its aspects, diag- nostic possibilities and current use in CRC.
BACKGROUND: To validate the clinical utility of a previously identified circulating tumor DNA methylation marker (meth-ctDNA) panel for disease detection and survival outcomes, meth-ctDNA markers were compared to PSA levels and PSMA PET/CT findings in men with different stages of prostate cancer (PCa). METHODS: 122 PCa patients who underwent [68Ga]Ga-PSMA-11 PET/CT and plasma sampling (03/2019-08/2021) were analyzed. cfDNA was extracted, and a panel of 8 individual meth-ctDNA markers was queried. PET scans were qualitatively and quantitatively assessed. PSA and meth-ctDNA markers were compared to PET findings, and their relative prognostic value was evaluated. RESULTS: PSA discriminated best between negative and tumor-indicative PET scans in all (AUC 0.77) and hormone-sensitive (hsPC) patients (0.737). In castration-resistant PCa (CRPC), the meth-ctDNA marker KLF8 performed best (AUC 0.824). CHST11 differentiated best between non- and metastatic scans (AUC 0.705) overall, KLF8 best in hsPC and CRPC (AUC 0.662, 0.85). Several meth-ctDNA markers correlated low to moderate with the tumor volume in all (5/8) and CRPC patients (6/8), while PSA levels correlated moderately to strongly with the tumor volume in all groups (all p < 0.001). CRPC overall survival was independently associated with LDAH and PSA (p = 0.0168, p < 0.001). CONCLUSION: The studied meth-ctDNA markers are promising for the minimally-invasive detection and prognostication of CRPC but do not allow for clinical characterization of hsPC. Prospective studies are warranted for their use in therapy response and outcome prediction in CRPC and potential incremental value for PCa monitoring in PSA-low settings.
- MeSH
- Circulating Tumor DNA genetics blood MeSH
- Edetic Acid analogs & derivatives MeSH
- Gallium Isotopes * MeSH
- Middle Aged MeSH
- Humans MeSH
- DNA Methylation * genetics MeSH
- Biomarkers, Tumor * genetics blood MeSH
- Prostatic Neoplasms, Castration-Resistant genetics blood diagnostic imaging MeSH
- Prostatic Neoplasms * genetics blood diagnostic imaging MeSH
- Positron Emission Tomography Computed Tomography * methods MeSH
- Prognosis MeSH
- Prostate-Specific Antigen * blood genetics MeSH
- Cross-Sectional Studies MeSH
- Gallium Radioisotopes * MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Publication type
- Journal Article MeSH
- Comparative Study MeSH
Prostate cancer remains a leading cause of cancer-related mortality in men, with advanced stages posing significant treatment challenges due to high morbidity and mortality. Among genetic alterations, TP53 mutations are among the most prevalent in cancers and are strongly associated with poor clinical outcomes and therapeutic resistance. This review investigates the role of TP53 mutations in prostate cancer progression, prognosis, and therapeutic development. A comprehensive analysis of preclinical and clinical studies was conducted to elucidate the molecular mechanisms, clinical implications, and potential therapeutic approaches associated with TP53 alterations in prostate cancer. TP53 mutations are highly prevalent in advanced stages, contributing to genomic instability, aggressive tumor phenotypes, and resistance to standard treatments. Emerging evidence supports the utility of liquid biopsy techniques, such as circulating tumor DNA analysis, for detecting TP53 mutations, providing prognostic value and facilitating early intervention strategies. Novel therapeutic approaches targeting TP53 have shown promise in preclinical settings, but their clinical efficacy requires further validation. Overall, TP53 mutations represent a critical biomarker for disease progression and therapeutic response in prostate cancer. Advances in detection methods and targeted therapies hold significant potential to improve outcomes for patients with TP53-mutated prostate cancer. Further research is essential to integrate TP53-based strategies into routine clinical practice.
- Publication type
- Journal Article MeSH
- Review MeSH
OBJECTIVES: To evaluate the role of circulating tumor DNA (ctDNA) as a prognostic and predictive biomarker in the perioperative management of muscle-invasive bladder cancer (MIBC). METHODS: We conducted a systematic literature review using PubMed, MEDLINE, and Embase, following PRISMA guidelines. Studies from January 2013 to March 2024 were included if they examined ctDNA in MIBC patients undergoing radical cystectomy (RC) and perioperative chemotherapy or immunotherapy. RESULTS: Eight studies were included. ctDNA detected before RC was associated with poor recurrence-free survival and higher risk of nodal and locally advanced disease. Postoperative ctDNA levels correlated with shorter disease-free survival and higher recurrence rates. ctDNA clearance during neoadjuvant chemotherapy was predictive of treatment response. ctDNA status post-neoadjuvant immunotherapy correlated with pathological outcomes and recurrence rates. CONCLUSIONS: ctDNA is a promising biomarker for predicting oncological outcomes in MIBC, with potential to guide perioperative treatment decisions. Further randomized controlled trials are needed to validate these findings.
High-grade B-cell lymphomas (HGBCLs) are aggressive blood cancers with a severe disease course, especially when the central nervous system (CNS) is involved. Standard histological examination depends on tissue availability and is currently supplemented with molecular tests, as the status of MYC, BCL2, or BCL6 gene rearrangements is required for proper lymphoma classification. This case report demonstrates the relevance of cerebrospinal fluid (CSF) cell-free DNA testing by integrative next-generation sequencing (NGS) panel. The benefit of this approach resided in tumor genotyping alongside the proof of CNS progression despite MRI negativity, revealing a clonal relationship with the primary tumor lesion. In addition, our strategy allowed us to classify the tumor as DLBCL/HGBL-MYC/BCL2 entity. In clinical practice, such a minimally invasive approach provides a more sensitive tool than standard imaging and cell analyzing techniques, enabling more accurate disease monitoring and relapse prediction in particular cases.
- MeSH
- Lymphoma, B-Cell genetics pathology diagnosis diagnostic imaging MeSH
- Circulating Tumor DNA genetics MeSH
- Lymphoma, Large B-Cell, Diffuse genetics pathology MeSH
- Middle Aged MeSH
- Humans MeSH
- Neoplasm Recurrence, Local pathology genetics MeSH
- Magnetic Resonance Imaging * MeSH
- Biomarkers, Tumor genetics MeSH
- Central Nervous System Neoplasms genetics pathology diagnostic imaging MeSH
- High-Throughput Nucleotide Sequencing * MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Case Reports MeSH
Gliomas are the most common brain tumor type in children and adolescents. To date, diagnosis and therapy monitoring for these tumors rely on magnetic resonance imaging (MRI) and histopathological as well as molecular analyses of tumor tissue. Recently, liquid biopsies (LB) have emerged as promising tool for diagnosis and longitudinal tumor assessment potentially allowing for a more precise therapeutic management. However, the optimal strategy for monitoring gliomas by LB remains to be determined. In this study, we analyzed circulating tumor DNA (ctDNA) from 78 liquid biopsies (plasma n = 44, cerebrospinal fluid n = 34 (CSF)) of 35 glioma patients, determining H3F3A K28M (K27M) and BRAF V600E mutation allele frequency using droplet digital PCR (ddPCR). All results were correlated to clinically relevant parameters including diagnostic imaging and CSF aspiration site (ventricular vs lumbar) with respect to tumor localization. Regarding diagnostic accuracy, the calculated sensitivity score in the H3F3A K27M cohort was 84.61% for CSF and 73.68% for plasma. In the BRAF V600E cohort, we determined a sensitivity of 83.3% in plasma and 80% in CSF. The overall specificity was 100%. With respect to the CSF aspiration, the intra-operatively obtained CSF demonstrated 100% detection rate, followed by ventricular CSF obtained via Ommaya Reservoir/shunt puncture (93%) and CSF obtained via lumbar puncture (66%). Notably, this further correlated with the proximity of the CSF site to tumor localization. Longitudinal CSF monitoring demonstrated a good correlation to clinical and radiological disease evolution. Importantly, we show for the first time that monitoring BRAF V600E by ddPCR could serve as treatment response assessment in gliomas. In summary, our observation may inform recommendations with regard to location of CSF aspiration when incorporating LB into future treatment protocols.
- MeSH
- Circulating Tumor DNA cerebrospinal fluid genetics MeSH
- Child MeSH
- Adult MeSH
- Glioma * genetics pathology diagnosis MeSH
- Histones * genetics MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Mutation MeSH
- Biomarkers, Tumor * genetics cerebrospinal fluid MeSH
- Brain Neoplasms * genetics diagnosis pathology MeSH
- Child, Preschool MeSH
- Proto-Oncogene Proteins B-raf * genetics MeSH
- Liquid Biopsy methods MeSH
- Check Tag
- Child MeSH
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Male MeSH
- Child, Preschool MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
