2023

Jump to: 2022

15 pages, 3713 KiB

Open AccessArticle

Plasma Immune Proteins and Circulating Tumor DNA Predict the Clinical Outcome for Non-Small-Cell Lung Cancer Treated with an Immune Checkpoint Inhibitor

by Simone Stensgaard, Astrid Thomsen, Sofie Helstrup, Peter Meldgaard and Boe S. Sorensen

Cancers 2023, 15(23), 5628; https://doi.org/10.3390/cancers15235628 - 29 Nov 2023

Viewed by 1011

Abstract

Immunotherapy has altered the therapeutic landscape for patients with non-small-cell lung cancer (NSCLC). The immune checkpoint inhibitor pembrolizumab targets the PD-1/PD-L1 signaling axis and produces durable clinical responses, but reliable biomarkers are lacking. Using 115 plasma samples from 42 pembrolizumab-treated patients with NSCLC, [...] Read more.

Immunotherapy has altered the therapeutic landscape for patients with non-small-cell lung cancer (NSCLC). The immune checkpoint inhibitor pembrolizumab targets the PD-1/PD-L1 signaling axis and produces durable clinical responses, but reliable biomarkers are lacking. Using 115 plasma samples from 42 pembrolizumab-treated patients with NSCLC, we were able to identify predictive biomarkers. In the plasma samples, we quantified the level of 92 proteins using the Olink proximity extension assay and circulating tumor DNA (ctDNA) using targeted next-generation sequencing. Patients with an above-median progression-free survival (PFS) had significantly higher expressions of Fas ligand (FASLG) and inducible T-cell co-stimulator ligand (ICOSLG) at baseline than patients with a PFS below the median. A Kaplan–Meier analysis demonstrated that high levels of FASLG and ICOSLG were predictive of longer PFS and overall survival (OS) (PFS: 10.83 vs. 4.49 months, OS: 27.13 vs. 18.0 months). Furthermore, we identified a subgroup with high expressions of FASLG and ICOSLG who also had no detectable ctDNA mutations after treatment initiation. This subgroup had significantly longer PFS and OS rates compared to the rest of the patients (PFS: 25.71 vs. 4.52 months, OS: 34.62 vs. 18.0 months). These findings suggest that the expressions of FASLG and ICOSLG at baseline and the absence of ctDNA mutations after the start of treatment have the potential to predict clinical outcomes. Full article

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13 pages, 3144 KiB

Open AccessArticle

Absolute Quantification of Pan-Cancer Plasma Proteomes Reveals Unique Signature in Multiple Myeloma

by David Kotol, Jakob Woessmann, Andreas Hober, María Bueno Álvez, Khue Hua Tran Minh, Fredrik Pontén, Linn Fagerberg, Mathias Uhlén and Fredrik Edfors

Cancers 2023, 15(19), 4764; https://doi.org/10.3390/cancers15194764 - 28 Sep 2023

Viewed by 1189

Abstract

Mass spectrometry based on data-independent acquisition (DIA) has developed into a powerful quantitative tool with a variety of implications, including precision medicine. Combined with stable isotope recombinant protein standards, this strategy provides confident protein identification and precise quantification on an absolute scale. Here, [...] Read more.

Mass spectrometry based on data-independent acquisition (DIA) has developed into a powerful quantitative tool with a variety of implications, including precision medicine. Combined with stable isotope recombinant protein standards, this strategy provides confident protein identification and precise quantification on an absolute scale. Here, we describe a comprehensive targeted proteomics approach to profile a pan-cancer cohort consisting of 1800 blood plasma samples representing 15 different cancer types. We successfully performed an absolute quantification of 253 proteins in multiplex. The assay had low intra-assay variability with a coefficient of variation below 20% (CV = 17.2%) for a total of 1013 peptides quantified across almost two thousand injections. This study identified a potential biomarker panel of seven protein targets for the diagnosis of multiple myeloma patients using differential expression analysis and machine learning. The combination of markers, including the complement C1 complex, JCHAIN, and CD5L, resulted in a prediction model with an AUC of 0.96 for the identification of multiple myeloma patients across various cancer patients. All these proteins are known to interact with immunoglobulins. Full article

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17 pages, 1303 KiB

Open AccessReview

The Current Landscape of Glioblastoma Biomarkers in Body Fluids

by Saba Zanganeh, Elham Abbasgholinejad, Mohammad Doroudian, Nazanin Esmaelizad, Fatemeh Farjadian and Soumya Rahima Benhabbour

Cancers 2023, 15(15), 3804; https://doi.org/10.3390/cancers15153804 - 26 Jul 2023

Cited by 2 | Viewed by 1838

Abstract

Glioblastoma (GBM) is a highly aggressive and lethal primary brain cancer that necessitates early detection and accurate diagnosis for effective treatment and improved patient outcomes. Traditional diagnostic methods, such as imaging techniques and tissue biopsies, have limitations in providing real-time information and distinguishing [...] Read more.

Glioblastoma (GBM) is a highly aggressive and lethal primary brain cancer that necessitates early detection and accurate diagnosis for effective treatment and improved patient outcomes. Traditional diagnostic methods, such as imaging techniques and tissue biopsies, have limitations in providing real-time information and distinguishing treatment-related changes from tumor progression. Liquid biopsies, used to analyze biomarkers in body fluids, offer a non-invasive and dynamic approach to detecting and monitoring GBM. This article provides an overview of GBM biomarkers in body fluids, including circulating tumor cells (CTCs), cell-free DNA (cfDNA), cell-free RNA (cfRNA), microRNA (miRNA), and extracellular vesicles. It explores the clinical utility of these biomarkers for GBM detection, monitoring, and prognosis. Challenges and limitations in implementing liquid biopsy strategies in clinical practice are also discussed. The article highlights the potential of liquid biopsies as valuable tools for personalized GBM management but underscores the need for standardized protocols and further research to optimize their clinical utility. Full article

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21 pages, 396 KiB

Open AccessReview

The Importance of Detecting, Quantifying, and Characterizing Exosomes as a New Diagnostic/Prognostic Approach for Tumor Patients

by Mariantonia Logozzi, Nicola Salvatore Orefice, Rossella Di Raimo, Davide Mizzoni and Stefano Fais

Cancers 2023, 15(11), 2878; https://doi.org/10.3390/cancers15112878 - 23 May 2023

Cited by 6 | Viewed by 1931

Abstract

Exosomes are extracellular vesicles (EVs) of nanometric size studied for their role in tumor pathogenesis and progression and as a new source of tumor biomarkers. The clinical studies have provided encouraging but probably unexpected results, including the exosome plasmatic levels’ clinical relevance and [...] Read more.

Exosomes are extracellular vesicles (EVs) of nanometric size studied for their role in tumor pathogenesis and progression and as a new source of tumor biomarkers. The clinical studies have provided encouraging but probably unexpected results, including the exosome plasmatic levels’ clinical relevance and well-known biomarkers’ overexpression on the circulating EVs. The technical approach to obtaining EVs includes methods to physically purify EVs and characterize EVs, such as Nanosight Tracking Analysis (NTA), immunocapture-based ELISA, and nano-scale flow cytometry. Based on the above approaches, some clinical investigations have been performed on patients with different tumors, providing exciting and promising results. Here we emphasize data showing that exosome plasmatic levels are consistently higher in tumor patients than in controls and that plasmatic exosomes express well-known tumor markers (e.g., PSA and CEA), proteins with enzymatic activity, and nucleic acids. However, we also know that tumor microenvironment acidity is a key factor in influencing both the amount and the characteristics of the exosome released by tumor cells. In fact, acidity significantly increases exosome release by tumor cells, which correlates with the number of exosomes that circulate through the body of a tumor patient. Full article

16 pages, 1339 KiB

Open AccessArticle

Cell-Free RNA from Plasma in Patients with Neuroblastoma: Exploring the Technical and Clinical Potential

by Nathalie S. M. Lak, Anne Seijger, Lieke M. J. van Zogchel, Nina U. Gelineau, Ahmad Javadi, Lily Zappeij-Kannegieter, Laura Bongiovanni, Anneloes Andriessen, Janine Stutterheim, C. Ellen van der Schoot, Alain de Bruin and Godelieve A. M. Tytgat

Cancers 2023, 15(7), 2108; https://doi.org/10.3390/cancers15072108 - 31 Mar 2023

Cited by 2 | Viewed by 2080

Abstract

Neuroblastoma affects mostly young children, bearing a high morbidity and mortality. Liquid biopsies, e.g., molecular analysis of circulating tumor-derived nucleic acids in blood, offer a minimally invasive diagnostic modality. Cell-free RNA (cfRNA) is released by all cells, especially cancer. It circulates in blood [...] Read more.

Neuroblastoma affects mostly young children, bearing a high morbidity and mortality. Liquid biopsies, e.g., molecular analysis of circulating tumor-derived nucleic acids in blood, offer a minimally invasive diagnostic modality. Cell-free RNA (cfRNA) is released by all cells, especially cancer. It circulates in blood packed in extracellular vesicles (EV) or attached to proteins. We studied the feasibility of analyzing cfRNA and EV, isolated by size exclusion chromatography (SEC), from platelet-poor plasma from healthy controls (n = 40) and neuroblastoma patients with localized (n = 10) and metastatic disease (n = 30). The mRNA content was determined using several multiplex droplet digital PCR (ddPCR) assays for a neuroblastoma-specific gene panel (PHOX2B, TH, CHRNA3) and a cell cycle regulation panel (E2F1, CDC6, ATAD2, H2AFZ, MCM2, DHFR). We applied corrections for the presence of platelets. We demonstrated that neuroblastoma-specific markers were present in plasma from 14/30 patients with metastatic disease and not in healthy controls and patients with localized disease. Most cell cycle markers had a higher expression in patients. The mRNA markers were mostly present in the EV-enriched SEC fractions. In conclusion, cfRNA can be isolated from plasma and EV and analyzed using multiplex ddPCR. cfRNA is an interesting novel liquid biopsy-based target to explore further. Full article

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19 pages, 3196 KiB

Open AccessArticle

Integrative Analyses Reveal the Anticancer Mechanisms and Sensitivity Markers of the Next-Generation Hypomethylating Agent NTX-301

by Byungho Lim, Dabin Yoo, Younghwa Chun, Areum Go, Ji Yeon Kim, Ha Young Lee, Rebecca J. Boohaker, Kyung-Jin Cho, Sunjoo Ahn, Jin Soo Lee, DooYoung Jung and Gildon Choi

Cancers 2023, 15(6), 1737; https://doi.org/10.3390/cancers15061737 - 13 Mar 2023

Cited by 2 | Viewed by 1510

Abstract

Epigenetic dysregulation characterized by aberrant DNA hypermethylation is a hallmark of cancer, and it can be targeted by hypomethylating agents (HMAs). Recently, we described the superior therapeutic efficacy of a novel HMA, namely, NTX-301, when used as a monotherapy and in combination with [...] Read more.

Epigenetic dysregulation characterized by aberrant DNA hypermethylation is a hallmark of cancer, and it can be targeted by hypomethylating agents (HMAs). Recently, we described the superior therapeutic efficacy of a novel HMA, namely, NTX-301, when used as a monotherapy and in combination with venetoclax in the treatment of acute myeloid leukemia. Following a previous study, we further explored the therapeutic properties of NTX-301 based on experimental investigations and integrative data analyses. Comprehensive sensitivity profiling revealed that NTX-301 primarily exerted anticancer effects against blood cancers and exhibited improved potency against a wide range of solid cancers. Subsequent assays showed that the superior efficacy of NTX-301 depended on its strong effects on cell cycle arrest, apoptosis, and differentiation. Due to its superior efficacy, low doses of NTX-301 achieved sufficiently substantial tumor regression in vivo. Multiomics analyses revealed the mechanisms of action (MoAs) of NTX-301 and linked these MoAs to markers of sensitivity to NTX-301 and to the demethylation activity of NTX-301 with high concordance. In conclusion, our findings provide a rationale for currently ongoing clinical trials of NTX-301 and will help guide the development of novel therapeutic options for cancer patients. Full article

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19 pages, 2203 KiB

Open AccessArticle

Canine-Inspired Chemometric Analysis of Volatile Organic Compounds in Urine Headspace to Distinguish Prostate Cancer in Mice and Men

by Mark Woollam, Amanda P. Siegel, Adam Munshi, Shengzhi Liu, Sunil Tholpady, Thomas Gardner, Bai-Yan Li, Hiroki Yokota and Mangilal Agarwal

Cancers 2023, 15(4), 1352; https://doi.org/10.3390/cancers15041352 - 20 Feb 2023

Cited by 6 | Viewed by 1931

Abstract

Canines can identify prostate cancer with high accuracy by smelling volatile organic compounds (VOCs) in urine. Previous studies have identified VOC biomarkers for prostate cancer utilizing solid phase microextraction (SPME) gas chromatography–mass spectrometry (GC-MS) but have not assessed the ability of VOCs to [...] Read more.

Canines can identify prostate cancer with high accuracy by smelling volatile organic compounds (VOCs) in urine. Previous studies have identified VOC biomarkers for prostate cancer utilizing solid phase microextraction (SPME) gas chromatography–mass spectrometry (GC-MS) but have not assessed the ability of VOCs to distinguish aggressive cancers. Additionally, previous investigations have utilized murine models to identify biomarkers but have not determined if the results are translatable to humans. To address these challenges, urine was collected from mice with prostate cancer and men undergoing prostate cancer biopsy and VOCs were analyzed by SPME GC-MS. Prior to analysis, SPME fibers/arrows were compared, and the fibers had enhanced sensitivity toward VOCs with a low molecular weight. The analysis of mouse urine demonstrated that VOCs could distinguish tumor-bearing mice with 100% accuracy. Linear discriminant analysis of six VOCs in human urine distinguished prostate cancer with sensitivity = 75% and specificity = 69%. Another panel of seven VOCs could classify aggressive cancer with sensitivity = 78% and specificity = 85%. These results show that VOCs have moderate accuracy in detecting prostate cancer and a superior ability to stratify aggressive tumors. Furthermore, the overlap in the structure of VOCs identified in humans and mice shows the merit of murine models for identifying biomarker candidates. Full article

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18 pages, 1249 KiB

Open AccessArticle

Protein Signatures and Individual Circulating Proteins, including IL-6 and IL-15, Associated with Prognosis in Patients with Biliary Tract Cancer

by Troels D. Christensen, Kasper Madsen, Emil Maag, Ole Larsen, Lars Henrik Jensen, Carsten P. Hansen, Alice Markussen, Dan T. S. Høgdall, Inna M. Chen, Dorte Nielsen and Julia S. Johansen

Cancers 2023, 15(4), 1062; https://doi.org/10.3390/cancers15041062 - 07 Feb 2023

Cited by 2 | Viewed by 2008

Abstract

Biliary tract cancer (BTC) is a rare gastrointestinal cancer with a dismal prognosis. Biomarkers with clinical utility are needed. In this study, we investigated the association between survival and 89 immuno-oncology-related proteins, with the aim of identifying prognostic biomarkers for BTC. The study [...] Read more.

Biliary tract cancer (BTC) is a rare gastrointestinal cancer with a dismal prognosis. Biomarkers with clinical utility are needed. In this study, we investigated the association between survival and 89 immuno-oncology-related proteins, with the aim of identifying prognostic biomarkers for BTC. The study included patients with BTC (n = 394) treated at three Danish hospitals. Patients were divided into four cohorts: the first-line discovery cohort (n = 202), first-line validation cohort (n = 118), second-line cohort (n = 56), and surgery cohort (n = 41). Plasma protein levels were measured using a proximity extension assay (Olink Proteomics). Twenty-seven proteins were associated with overall survival (OS) in a multivariate analysis in the discovery cohort. In the first-line validation cohort, high levels of interleukin (IL)-6, IL-15, mucin 16, hepatocyte growth factor, programmed cell death ligand 1, and placental growth factor were significantly associated with poor OS in univariate Cox regression analyses. When adjusting for performance status, location, and stage, the association was significant only for IL-6 (hazard ratio (HR) = 1.25, 95% confidence interval (CI) 1.08–1.46) and IL-15 (HR = 2.23, 95% CI 1.48–3.35). Receiver operating characteristic analyses confirmed IL-6 and IL-15 as the strongest predictors of survival. Combining several proteins into signatures further improved the ability to distinguish between patients with short (<6 months) and long survival (>18 months). The study identified several circulating proteins as prognostic biomarkers in patients, with BTC, IL-6, and IL-15 being the most promising markers. Combining proteins in a prognostic signature improved prognostic performance, but future studies are needed to determine the optimal combination and thresholds. Full article

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2022

Jump to: 2023

16 pages, 1153 KiB

Open AccessArticle

Evolution of RAS Mutations in Cell-Free DNA of Patients with Tissue RAS Wild-Type Metastatic Colorectal Cancer Receiving First-Line Treatment: The PERSEIDA Study

by Manuel Valladares-Ayerbes, Pilar Garcia-Alfonso, Jorge Muñoz Luengo, Paola Patricia Pimentel Caceres, Oscar Alfredo Castillo Trujillo, Rosario Vidal-Tocino, Marta Llanos, Beatriz Llorente Ayala, Maria Luisa Limon Miron, Antonieta Salud, Luis Cirera Nogueras, Rocio Garcia-Carbonero, Maria Jose Safont, Esther Falco Ferrer, Jorge Aparicio, Maria Angeles Vicente Conesa, Carmen Guillén-Ponce, Paula Garcia-Teijido, Maria Begoña Medina Magan, Isabel Busquier, Mercedes Salgado and Ariadna Lloansí Vila Show full author list Hide full author list

Cancers 2022, 14(24), 6075; https://doi.org/10.3390/cancers14246075 - 09 Dec 2022

Cited by 3 | Viewed by 1761

Abstract

The serial analysis of cell-free DNA (cfDNA) enables minimally invasive monitoring of tumor evolution, providing continuous genetic information. PERSEIDA was an observational, prospective study assessing the cfDNA RAS (KRAS/NRAS) mutational status evolution in first-line, metastatic CRC, RAS wild-type (according [...] Read more.

The serial analysis of cell-free DNA (cfDNA) enables minimally invasive monitoring of tumor evolution, providing continuous genetic information. PERSEIDA was an observational, prospective study assessing the cfDNA RAS (KRAS/NRAS) mutational status evolution in first-line, metastatic CRC, RAS wild-type (according to baseline tumor tissue biopsy) patients. Plasma samples were collected before first-line treatment, after 20 ± 2 weeks, and at disease progression. One hundred and nineteen patients were included (102 received panitumumab and chemotherapy as first-line treatment—panitumumab subpopulation). Fifteen (12.6%) patients presented baseline cfDNA RAS mutations (n = 14 [13.7%], panitumumab subpopulation) (mutant allele fraction ≥0.02 for all results). No patients presented emergent mutations (cfDNA RAS mutations not present at baseline) at 20 weeks. At disease progression, 11 patients (n = 9; panitumumab subpopulation) presented emergent mutations (RAS conversion rate: 19.0% [11/58]; 17.7% [9/51], panitumumab subpopulation). In contrast, three (5.2%) patients presenting baseline cfDNA RAS mutations were RAS wild-type at disease progression. No significant associations were observed between overall response rate or progression-free survival and cfDNA RAS mutational status in the total panitumumab subpopulation. Although, in patients with left-sided tumors, a significantly longer progression-free survival was observed in cfDNA RAS wild-type patients compared to those presenting cfDNA RAS mutations at any time. Continuous evaluation of RAS mutations may provide valuable insights on tumor molecular dynamics that can help clinical practice. Full article

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36 pages, 3054 KiB

Open AccessReview

The microRNA Lifecycle in Health and Cancer

by Laura Adriana de Rooij, Dirk Jan Mastebroek, Nicky ten Voorde, Elsken van der Wall, Paul Joannes van Diest and Cathy Beatrice Moelans

Cancers 2022, 14(23), 5748; https://doi.org/10.3390/cancers14235748 - 23 Nov 2022

Cited by 12 | Viewed by 3129

Abstract

MicroRNAs (miRNAs) are small non-coding RNAs of ~22 nucleotides that regulate gene expression at the post-transcriptional level. They can bind to around 60% of all protein-coding genes with an average of 200 targets per miRNA, indicating their important function within physiological and pathological [...] Read more.

MicroRNAs (miRNAs) are small non-coding RNAs of ~22 nucleotides that regulate gene expression at the post-transcriptional level. They can bind to around 60% of all protein-coding genes with an average of 200 targets per miRNA, indicating their important function within physiological and pathological cellular processes. miRNAs can be quickly produced in high amounts through canonical and non-canonical pathways that involve a multitude of steps and proteins. In cancer, miRNA biogenesis, availability and regulation of target expression can be altered to promote tumour progression. This can be due to genetic causes, such as single nucleotide polymorphisms, epigenetic changes, differences in host gene expression, or chromosomal remodelling. Alternatively, post-transcriptional changes in miRNA stability, and defective or absent components and mediators of the miRNA-induced silencing complex can lead to altered miRNA function. This review provides an overview of the current knowledge on the lifecycle of miRNAs in health and cancer. Understanding miRNA function and regulation is fundamental prior to potential future application of miRNAs as cancer biomarkers. Full article

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11 pages, 288 KiB

Open AccessReview

UroVysion^TM Fluorescence In Situ Hybridization in Urological Cancers: A Narrative Review and Future Perspectives

by Chunjin Ke, Zhiquan Hu and Chunguang Yang

Cancers 2022, 14(21), 5423; https://doi.org/10.3390/cancers14215423 - 03 Nov 2022

Cited by 4 | Viewed by 1588

Abstract

UroVysion^TM is a fluorescence in situ hybridization assay that was developed for the detection of bladder cancer (UC accounted for 90%) in urine specimens. It consists of fluorescently labeled DNA probes to the pericentromeric regions of chromosomes 3, 7, 17 and to [...] Read more.

UroVysion^TM is a fluorescence in situ hybridization assay that was developed for the detection of bladder cancer (UC accounted for 90%) in urine specimens. It consists of fluorescently labeled DNA probes to the pericentromeric regions of chromosomes 3, 7, 17 and to the 9p21 band location of the P16 tumor suppressor gene, which was approved by the Food and Drug Administration (FDA) in 2001 and 2005, respectively, for urine detection in patients with suspected bladder cancer and postoperative recurrence monitoring. Furthermore, recent studies also demonstrated that U-FISH was useful for assessing superficial bladder cancer patients’ response to Bacillus Calmette–Guérin therapy and in detecting upper tract urothelial carcinoma. Therefore, positive U-FISH was well known to urologists as a molecular cytogenetic technique for the detection of UC. However, with the continuous enrichment of clinical studies at home and abroad, U-FISH has shown a broader application space in the detection of various urinary primary tumors and even metastatic tumors. This review focuses on summarizing the research status of U-FISH in UC, non-urothelial carcinoma and metastatic tumor, so as to strengthen urologists’ more comprehensive understanding of the application value of U-FISH and better complete the accurate diagnosis and treatment of urological cancers. Full article

22 pages, 1051 KiB

Open AccessReview

Diagnosis Biomarkers of Cholangiocarcinoma in Human Bile: An Evidence-Based Study

by Fang Bao, Jiayue Liu, Haiyang Chen, Lu Miao, Zhaochao Xu and Guixin Zhang

Cancers 2022, 14(16), 3921; https://doi.org/10.3390/cancers14163921 - 13 Aug 2022

Cited by 4 | Viewed by 2683

Abstract

Cholangiocarcinoma (CCA) is a multifactorial malignant tumor of the biliary tract, and the incidence of CCA is increasing in recent years. At present, the diagnosis of CCA mainly depends on imaging and invasive examination, with limited specificity and sensitivity and late detection. The [...] Read more.

Cholangiocarcinoma (CCA) is a multifactorial malignant tumor of the biliary tract, and the incidence of CCA is increasing in recent years. At present, the diagnosis of CCA mainly depends on imaging and invasive examination, with limited specificity and sensitivity and late detection. The early diagnosis of CCA always faces the dilemma of lacking specific diagnostic biomarkers. Non-invasive methods to assess the degree of CAA have been developed throughout the last decades. Among the many specimens looking for CCA biomarkers, bile has gotten a lot of attention lately. This paper mainly summarizes the recent developments in the current research on the diagnostic biomarkers for CCA in human bile at the levels of the gene, protein, metabolite, extracellular vesicles and volatile organic compounds. Full article

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14 pages, 1362 KiB

Open AccessArticle

Monitoring of Measurable Residual Disease Using Circulating DNA after Allogeneic Hematopoietic Cell Transplantation

by Miguel Waterhouse, Sandra Pennisi, Dietmar Pfeifer, Florian Scherer, Robert Zeiser, Justus Duyster, Hartmut Bertz, Jürgen Finke and Jesús Duque-Afonso

Cancers 2022, 14(14), 3307; https://doi.org/10.3390/cancers14143307 - 07 Jul 2022

Cited by 1 | Viewed by 1671

Abstract

Relapse of the underlying disease is a frequent complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In this study, we describe the clinical utility of measurable residual disease (MRD) and mixed chimerism (MC) assessment in circulating cell-free DNA (cfDNA) analysis to detect earlier [...] Read more.

Relapse of the underlying disease is a frequent complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In this study, we describe the clinical utility of measurable residual disease (MRD) and mixed chimerism (MC) assessment in circulating cell-free DNA (cfDNA) analysis to detect earlier relapse in patients with hematological malignancies after allo-HSCT. A total of 326 plasma and peripheral blood mononuclear cell (PBMCs) samples obtained from 62 patients with myeloid malignancies were analyzed by droplet-digital PCR (median follow-up: 827 days). Comparison of MC in patients at relapse and in complete remission identified an optimal discriminating threshold of 18% of recipient-derived cfDNA. After performing a targeted next-generation sequencing (NGS) panel, 136 mutations in 58 patients were detected. In a total of 119 paired samples, the putative mutations were detected in both cfDNA and PBMCs in 73 samples (61.3%). In 45 samples (37.8%) they were detected only in cfDNA, and in only one patient (0.9%) were they detected solely in DNA from PBMCs. Hence, in 6 out of 23 patients (26%) with relapse after allo-HSCT, MRD positivity was detected earlier in cfDNA (mean 397 days) than in DNA derived from PBMCs (mean 451 days). In summary, monitoring of MRD and MC in cfDNA might be useful for earlier relapse detection in patients with myeloid malignancies after allo-HSCT. Full article

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12 pages, 984 KiB

Open AccessArticle

Dynamics of RAS/BRAF Mutations in cfDNA from Metastatic Colorectal Carcinoma Patients Treated with Polychemotherapy and Anti-EGFR Monoclonal Antibodies

by Anna Maria Rachiglio, Laura Forgione, Raffaella Pasquale, Carlo Antonio Barone, Evaristo Maiello, Lorenzo Antonuzzo, Antonino Cassata, Giuseppe Tonini, Roberto Bordonaro, Gerardo Rosati, Alberto Zaniboni, Sara Lonardi, Daris Ferrari, Giovanni Luca Frassineti, Stefano Tamberi, Salvatore Pisconti, Francesca Di Fabio, Cristin Roma, Armando Orlandi, Tiziana Latiano, Angela Damato, Giampaolo Tortora, Carmine Pinto and Nicola Normanno Show full author list Hide full author list

Cancers 2022, 14(4), 1052; https://doi.org/10.3390/cancers14041052 - 18 Feb 2022

Cited by 2 | Viewed by 2181

Abstract

Analysis of plasma-derived cell-free DNA (cfDNA) might allow for the early identification of resistance in metastatic colorectal carcinoma (mCRC) patients receiving anti-EGFR monoclonal antibodies. We tested plasma samples from the Erbitux Metastatic Colorectal Cancer Strategy (ERMES) phase III trial of FOLFIRI+Cetuximab in first-line [...] Read more.

Analysis of plasma-derived cell-free DNA (cfDNA) might allow for the early identification of resistance in metastatic colorectal carcinoma (mCRC) patients receiving anti-EGFR monoclonal antibodies. We tested plasma samples from the Erbitux Metastatic Colorectal Cancer Strategy (ERMES) phase III trial of FOLFIRI+Cetuximab in first-line treatment of RAS/BRAF wild-type mCRC. Samples were collected at baseline (n = 37), at 8 weeks of treatment (n = 32), progressive disease (PD; n = 36) and 3 months after PD (n = 21). cfDNA testing was performed using the Idylla™ ctKRAS and ctNRAS-BRAF tests and the Oncomine Pan-Cancer Cell-Free Assay. Analysis of basal samples revealed RAS/BRAF mutations in 6/37 cases. A transient RAS positivity not associated with PD was observed at 8 weeks in five cases that showed no mutations at baseline and PD. The frequency of mutant cases increased at PD (33.3%) and decreased again at 3 months after PD (9.5%). The median progression-free survival (mPFS) of patients RAS/BRAF mutant at PD was 7.13 months versus 7.71 months in wild-type patients (p = 0.3892). These data confirm that the occurrence of RAS/BRAF mutations in mCRC patients receiving anti-EGFR agents is relatively frequent. However, the cfDNA dynamics of RAS mutations in patients treated with anti-EGFR agents plus polychemotherapy are complex and might not be directly associated with resistance to treatment. Full article

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15 pages, 1776 KiB

Open AccessArticle

The Role of New Technologies in the Diagnosis and Surveillance of Non-Muscle Invasive Bladder Carcinoma: A Prospective, Double-Blinded, Monocentric Study of the XPERT© Bladder Cancer Monitor and Narrow Band Imaging© Cystoscopy

by Gad Singer, Venkat M. Ramakrishnan, Uwe Rogel, Andreas Schötzau, Daniel Disteldorf, Philipp Maletzki, Jean-Pascal Adank, Marc Hofmann, Tilo Niemann, Sylvia Stadlmann, Antonio Nocito, Kurt Lehmann and Lukas J. Hefermehl

Cancers 2022, 14(3), 618; https://doi.org/10.3390/cancers14030618 - 26 Jan 2022

Cited by 7 | Viewed by 2926

Abstract

Follow-up is essential for the early detection of recurrent non-muscle invasive bladder cancers (NMIBC). This study investigates the clinical relevance of new diagnostic tools such as an mRNA-based urine test (XPERT© Bladder Cancer Monitor, XBCM) and Narrow Band Imaging© (NBI) and compares them [...] Read more.

Follow-up is essential for the early detection of recurrent non-muscle invasive bladder cancers (NMIBC). This study investigates the clinical relevance of new diagnostic tools such as an mRNA-based urine test (XPERT© Bladder Cancer Monitor, XBCM) and Narrow Band Imaging© (NBI) and compares them with the established follow-up diagnostics (white-light cystoscopy (WLC) and urine cytology). This was a prospective, double-blind, single-center study that involved patients undergoing NMIBC screening at a tertiary care center. Enrollment occurred between January 2018 and March 2020. In addition to standard care (WLC, cytology, and ultrasound), patients underwent XBCM urine testing and NBI cystoscopy. In total, 301 WLCs were performed; through this, 49 patients demonstrated NMIBC recurrence. NBI cystoscopy was congruent with WLC in all patients. Cytology showed a sensitivity (SE) and specificity (SP) of 27% and 97% (PPV: 65%; NPV 87%), respectively, whereas XBCM showed SE and SP of 58% and 89%, respectively (PPV: 51%; NPV: 92%; AUC: 0.79 (0.716–0.871)). Subgroup analysis showed improved SE and similar SP (PPV, NPV) for high grade (HG) recurrence, with a SE of 74% and SP of 89% (39%, 97%). NBI cystoscopy does not necessarily provide additional benefit over standard WLC. However, the XBCM may provide better SE and a diagnostic advantage in instances of HG disease recurrence. Full article

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