Browsing by Subject "Liquid biopsy"
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Item A Novel Blood-Based Panel of Methylated DNA and Protein Markers for Detection of Early-Stage Hepatocellular Carcinoma(Elsevier, 2021) Chalasani, Naga P.; Ramasubramanian, Tiruvidaimarudur S.; Bhattacharya, Abhik; Olson, Marilyn C.; Edwards, David K., V; Roberts, Lewis R.; Kisiel, John B.; Reddy, K. Rajender; Lidgard, Graham P.; Johnson, Scott C.; Bruinsma, Janelle J.; Medicine, School of MedicineBackground & aims: Hepatocellular carcinoma (HCC) can be treated effectively if detected at an early stage. Recommended surveillance strategies for at-risk patients include ultrasound with or without α-fetoprotein (AFP), but their sensitivity is suboptimal. We sought to develop a novel, blood-based biomarker panel with improved sensitivity for early-stage HCC detection. Methods: In a multicenter, case-control study, we collected blood specimens from patients with HCC and age-matched controls with underlying liver disease but without HCC. Ten previously reported methylated DNA markers (MDMs) associated with HCC, methylated B3GALT6 (reference DNA marker), and 3 candidate proteins, including AFP, were assayed and analyzed by a logistic regression algorithm to predict HCC cases. The accuracy of the multi-target HCC panel was compared with that of other blood-based biomarkers for HCC detection. Results: The study included 135 HCC cases and 302 controls. We identified a multi-target HCC panel of 3 MDMs (HOXA1, EMX1, and TSPYL5), B3GALT6 and 2 protein markers (AFP and AFP-L3) with a higher sensitivity (71%, 95% CI: 60-81%) at 90% specificity for early-stage HCC than the GALAD score (41%, 95% CI: 30-53%) or AFP ≥7.32 ng/mL (45%, 95% CI: 33-57%). The AUC for the multi-target HCC panel for detecting any stage HCC was 0.92 compared with 0.87 for the GALAD score and 0.81 for AFP alone. The panel performed equally well in important subgroups based on liver disease etiology, presence of cirrhosis, or sex. Conclusions: We developed a novel, blood-based biomarker panel that demonstrates high sensitivity for early-stage HCC. These data support the potential for liquid biopsy detection of early-stage HCC to clinically benefit at-risk patients.Item Editorial: Emerging Biomarkers in Genitourinary Tumors(Frontiers, 2019-04-26) Montironi, Rodolfo; Santoni, Matteo; Cimadamore, Alessia; Lopez-Beltran, Antonio; Cheng, Liang; Pathology and Laboratory Medicine, School of MedicineItem Emerging Prognostic Biomarkers in Testicular Germ Cell Tumors: Looking Beyond Established Practice(Frontiers, 2018-11-28) Chovanec, Michal; Albany, Constantine; Mego, Michal; Montironi, Rodolfo; Cimadamore, Alessia; Cheng, Liang; Pathology and Laboratory Medicine, School of MedicineTesticular germ cell tumors are unique among solid cancers. Historically, this disease was deadly if progressed beyond the stage I. The implementation of cisplatin-based chemotherapy regimens has drastically changed the clinical outcome of metastatic testicular cancer. Several biomarkers were established to refine the prognosis by International Germ Cell Collaborative Group in 1997. Among these, the most significant were primary tumor site; metastatic sites, such as non-pulmonary visceral metastases; and the amplitude of serum tumor markers α-fetoprotein, β-chorionic gonadotropin, and lactate dehydrogenase. Since then, oncology has experienced discoveries of various molecular biomarkers to further refine the prognosis and treatment of malignancies. However, the ability to predict the prognosis and treatment response in germ cell tumors did not improve for many years. Clinical trials with novel targeting agents that were conducted in refractory germ cell tumor patients have proven to have negative outcomes. With the recent advances and developments, novel biomarkers emerge in the field of germ cell tumor oncology. This review article aims to summarize the current knowledge in the research of novel prognostic biomarkers in testicular germ cell tumors.Item Liquid Biopsy as Surrogate for Tissue for Molecular Profiling in Pancreatic Cancer: A Meta-Analysis Towards Precision Medicine(MDPI, 2019-08-10) Luchini, Claudio; Veronese, Nicola; Nottegar, Alessia; Cappelletti, Vera; Daidone, Maria G.; Smith, Lee; Parris, Christopher; Brosens, Lodewijk A. A.; Caruso, Maria G.; Cheng, Liang; Wolfgang, Christopher L.; Wood, Laura D.; Milella, Michele; Salvia, Roberto; Scarpa, Aldo; Pathology and Laboratory Medicine, School of MedicineLiquid biopsy (LB) is a non-invasive approach representing a promising tool for new precision medicine strategies for cancer treatment. However, a comprehensive analysis of its reliability for pancreatic cancer (PC) is lacking. To this aim, we performed the first meta-analysis on this topic. We calculated the pooled sensitivity, specificity, positive (LR+) and negative (LR-) likelihood ratio, and diagnostic odds ratio (DOR). A summary receiver operating characteristic curve (SROC) and area under curve (AUC) were used to evaluate the overall accuracy. We finally assessed the concordance rate of all mutations detected by multi-genes panels. Fourteen eligible studies involving 369 patients were included. The overall pooled sensitivity and specificity were 0.70 and 0.86, respectively. The LR+ was 3.85, the LR- was 0.34 and DOR was 15.84. The SROC curve with an AUC of 0.88 indicated a relatively high accuracy of LB for molecular characterization of PC. The concordance rate of all mutations detected by multi-genes panels was 31.9%. LB can serve as surrogate for tissue in the molecular profiling of PC, because of its relatively high sensitivity, specificity and accuracy. It represents a unique opportunity to be further explored towards its introduction in clinical practice and for developing new precision medicine approaches against PC.Item Making the Rounds: Exploring the Role of Circulating Tumor DNA (ctDNA) in Non-Small Cell Lung Cancer(MDPI, 2022-08-12) Shields, Misty Dawn; Chen, Kevin; Dutcher, Giselle; Patel, Ishika; Pellini, Bruna; Medicine, School of MedicineAdvancements in the clinical practice of non-small cell lung cancer (NSCLC) are shifting treatment paradigms towards increasingly personalized approaches. Liquid biopsies using various circulating analytes provide minimally invasive methods of sampling the molecular content within tumor cells. Plasma-derived circulating tumor DNA (ctDNA), the tumor-derived component of cell-free DNA (cfDNA), is the most extensively studied analyte and has a growing list of applications in the clinical management of NSCLC. As an alternative to tumor genotyping, the assessment of oncogenic driver alterations by ctDNA has become an accepted companion diagnostic via both single-gene polymerase chain reactions (PCR) and next-generation sequencing (NGS) for advanced NSCLC. ctDNA technologies have also shown the ability to detect the emerging mechanisms of acquired resistance that evolve after targeted therapy. Furthermore, the detection of minimal residual disease (MRD) by ctDNA for patients with NSCLC after curative-intent treatment may serve as a prognostic and potentially predictive biomarker for recurrence and response to therapy, respectively. Finally, ctDNA analysis via mutational, methylation, and/or fragmentation multi-omic profiling offers the potential for improving early lung cancer detection. In this review, we discuss the role of ctDNA in each of these capacities, namely, for molecular profiling, treatment response monitoring, MRD detection, and early cancer detection of NSCLC.Item Measure Twice: Promise of Liquid Biopsy in Pediatric High-Grade Gliomas(Elsevier, 2020-01-28) Dietz, Matthew S.; Beach, Catherine Z.; Barajas, Ramon; Parappilly, Michael S.; Sengupta, Sidharth K.; Baird, Lissa C.; Ciporen, Jeremy N.; Han, Seunggu J.; Loret de Mola, Rebecca; Cho, Yoon Jae; Nazemi, Kellie J.; McClelland, Shearwood, III; Wong, Melissa H.; Jaboin, Jerry J.; Radiation Oncology, School of MedicinePurpose To review and critique the current state of liquid biopsy in pHGG. Materials and Methods Published literature was reviewed for articles related to liquid biopsy in pediatric glioma and adult glioma with a focus on high-grade gliomas. Results This review discusses the current state of liquid biomarkers of pHGG and their potential applications for liquid biopsy development. Conclusions While nascent, the progress toward identifying circulating analytes of pHGG primes the field of neuro-oncoogy for liquid biopsy development.Item Multicancer Early Detection Tests: A State-of-the-Art Review for Otolaryngologists(Wiley, 2024-10-26) Kennedy, Elena; Durm, Greg; Farlow, Janice L.; Otolaryngology -- Head and Neck Surgery, School of MedicineObjective: To provide a review of the science and applicability of current multi-cancer early detection (MCED) tests for otolaryngologists. Data sources: PubMed, clinicaltrials.gov, company websites. Review methods: Using PRISMA methodology, primary literature regarding MCED tests was queried from April 26 to May 12, 2024 using MCED search terms. Ongoing clinical trials incorporating MCED screens were identified via the National Institutes of Health clinicaltrials.gov website. Company websites for available or upcoming MCED tests were reviewed. Conclusion: Long-term robust data regarding the performance characteristics, effects on clinical outcomes, and cost-utility of MCED tests for head and neck cancer are currently lacking. Otolaryngologists should be aware of the implications of MCED tests as these assays become more widely used. Implications for practice: Although not FDA-approved or covered by insurances at the time of writing of this manuscript, MCED testing is rapidly gaining interest, and patients with positive tests are presenting to otolaryngologists for evaluation. While MCED technologies hold great promise for early detection of disease and potential reduction of morbidity and mortality, more study is needed about their utility for head and neck cancer and optimal diagnostic workflows.Item Recent Advances in Liquid Biopsy in Patients With Castration Resistant Prostate Cancer(Frontiers, 2018-09-24) Di Nunno, Vincenzo; Gatto, Lidia; Santoni, Matteo; Cimadamore, Alessia; Lopez-Beltran, Antonio; Cheng, Liang; Scarpelli, Marina; Montironi, Rodolfo; Massari, Francesco; Pathology and Laboratory Medicine, School of MedicineManagement of localized and advanced prostate cancer benefits from several therapeutic options with a surprising improvement in terms of clinical outcome. The selection of patients more likely to benefit from a specific approach still remains a key issue as well as the early identification of patients with aggressive disease which could benefit from a more aggressive treatment strategy. The lack of reliable bio-marker in castration resistant setting able to monitor response to treatment and early inform about tumor progression is an emerging issue. Accordingly, circulating DNA and circulating tumor cells appears a promising and attractive approach despite to date practical applications of these techniques are few and not validated. The aim of this review of the literature is to explore current knowledge on liquid biopsy in prostate cancer focusing on possible future applications.Item Structural variation and fusion detection using targeted sequencing data from circulating cell free DNA(Oxford University Press, 2019-04-23) Gawroński, Alexander R.; Lin, Yen-Yi; McConeghy, Brian; LeBihan, Stephane; Asghari, Hossein; Koçkan, Can; Orabi, Baraa; Adra, Nabil; Pili, Roberto; Collins, Colin C.; Sahinalp, S. Cenk; Hach, Faraz; Medicine, School of MedicineMOTIVATION: Cancer is a complex disease that involves rapidly evolving cells, often forming multiple distinct clones. In order to effectively understand progression of a patient-specific tumor, one needs to comprehensively sample tumor DNA at multiple time points, ideally obtained through inexpensive and minimally invasive techniques. Current sequencing technologies make the 'liquid biopsy' possible, which involves sampling a patient's blood or urine and sequencing the circulating cell free DNA (cfDNA). A certain percentage of this DNA originates from the tumor, known as circulating tumor DNA (ctDNA). The ratio of ctDNA may be extremely low in the sample, and the ctDNA may originate from multiple tumors or clones. These factors present unique challenges for applying existing tools and workflows to the analysis of ctDNA, especially in the detection of structural variations which rely on sufficient read coverage to be detectable. RESULTS: Here we introduce SViCT , a structural variation (SV) detection tool designed to handle the challenges associated with cfDNA analysis. SViCT can detect breakpoints and sequences of various structural variations including deletions, insertions, inversions, duplications and translocations. SViCT extracts discordant read pairs, one-end anchors and soft-clipped/split reads, assembles them into contigs, and re-maps contig intervals to a reference genome using an efficient k-mer indexing approach. The intervals are then joined using a combination of graph and greedy algorithms to identify specific structural variant signatures. We assessed the performance of SViCT and compared it to state-of-the-art tools using simulated cfDNA datasets with properties matching those of real cfDNA samples. The positive predictive value and sensitivity of our tool was superior to all the tested tools and reasonable performance was maintained down to the lowest dilution of 0.01% tumor DNA in simulated datasets. Additionally, SViCT was able to detect all known SVs in two real cfDNA reference datasets (at 0.6-5% ctDNA) and predict a novel structural variant in a prostate cancer cohort.Item Validation of a Novel Multitarget Blood Test Shows High Sensitivity to Detect Early Stage Hepatocellular Carcinoma(Elsevier, 2022) Chalasani, Naga P.; Porter, Kyle; Bhattacharya, Abhik; Book, Adam J.; Neis, Brenda M.; Xiong, Kong M.; Ramasubramanian, Tiruvidaimarudur S.; Edwards, David K., V; Chen, Irene; Johnson, Scott; Roberts, Lewis R.; Kisiel, John B.; Reddy, K. Rajender; Singal, Amit G.; Olson, Marilyn C.; Bruinsma, Janelle J.; Medicine, School of MedicineBackground & aims: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Although biannual ultrasound surveillance with or without α-fetoprotein (AFP) testing is recommended for at-risk patients, sensitivity for early stage HCC, for which potentially curative treatments exist, is suboptimal. We conducted studies to establish the multitarget HCC blood test (mt-HBT) algorithm and cut-off values and to validate test performance in patients with chronic liver disease. Methods: Algorithm development and clinical validation studies were conducted with participants in an international, multicenter, case-control study. Study subjects had underlying cirrhosis or chronic hepatitis B virus; HCC cases were diagnosed per the American Association for the Study of Liver Diseases criteria and controls were matched for age and liver disease etiology. Whole blood and serum were shipped to a central laboratory and processed while blinded to case/control status. An algorithm was developed for the mt-HBT, which incorporates methylation biomarkers (HOXA1, TSPYL5, and B3GALT6), AFP, and sex. Results: In algorithm development, with 136 HCC cases (60% early stage) and 404 controls, the mt-HBT showed 72% sensitivity for early stage HCC at 88% specificity. Test performance was validated in an independent cohort of 156 HCC cases (50% early stage) and 245 controls, showing 88% overall sensitivity, 82% early stage sensitivity, and 87% specificity. Early stage sensitivity in clinical validation was significantly higher than AFP at 20 ng/mL or greater (40%; P < .0001) and GALAD (gender, age, Lens culinaris agglutinin-reactive AFP, AFP, and des-γ-carboxy-prothrombin score) of -0.63 or greater (71%; P = .03), although AFP and GALAD at these cut-off values had higher specificities (100% and 93%, respectively). Conclusions: The mt-HBT may significantly improve early stage HCC detection for patients undergoing HCC surveillance, a critical step to increasing curative treatment opportunities and reducing mortality.