20 results on '"Edelstein, DL"'
Search Results
2. Blood-based detection of RAS mutations to guide anti-EGFR therapy in colorectal cancer patients: concordance of results from circulating tumor DNA and tissue-based RAS testing
- Author
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Schmiegel, W, Scott, RJ, Dooley, S, Lewis, W, Meldrum, CJ, Pockney, P, Draganic, B, Smith, S, Hewitt, C, Philimore, H, Lucas, A, Shi, E, Namdarian, K, Chan, T, Acosta, D, Ping-Chang, S, Tannapfel, A, Reinacher-Schick, A, Uhl, W, Teschendorf, C, Wolters, H, Stern, J, Viebahn, R, Friess, H, Janssen, K-P, Nitsche, U, Slotta-Huspenina, J, Pohl, M, Vangala, D, Baraniskin, A, Dockhorn-Dworniczak, B, Hegewisch-Becker, S, Ronga, P, Edelstein, DL, Jones, FS, Hahn, S, Fox, SB, Schmiegel, W, Scott, RJ, Dooley, S, Lewis, W, Meldrum, CJ, Pockney, P, Draganic, B, Smith, S, Hewitt, C, Philimore, H, Lucas, A, Shi, E, Namdarian, K, Chan, T, Acosta, D, Ping-Chang, S, Tannapfel, A, Reinacher-Schick, A, Uhl, W, Teschendorf, C, Wolters, H, Stern, J, Viebahn, R, Friess, H, Janssen, K-P, Nitsche, U, Slotta-Huspenina, J, Pohl, M, Vangala, D, Baraniskin, A, Dockhorn-Dworniczak, B, Hegewisch-Becker, S, Ronga, P, Edelstein, DL, Jones, FS, Hahn, S, and Fox, SB
- Abstract
An accurate blood-based RAS mutation assay to determine eligibility of metastatic colorectal cancer (mCRC) patients for anti-EGFR therapy would benefit clinical practice by better informing decisions to administer treatment independent of tissue availability. The objective of this study was to determine the level of concordance between plasma and tissue RAS mutation status in patients with mCRC to gauge whether blood-based RAS mutation testing is a viable alternative to standard-of-care RAS tumor testing. RAS testing was performed on plasma samples from newly diagnosed metastatic patients, or from recurrent mCRC patients using the highly sensitive digital PCR technology, BEAMing (beads, emulsions, amplification, and magnetics), and compared with DNA sequencing data of respective FFPE (formalin-fixed paraffin-embedded) tumor samples. Discordant tissue RAS results were re-examined by BEAMing, if possible. The prevalence of RAS mutations detected in plasma (51%) vs. tumor (53%) was similar, in accord with the known prevalence of RAS mutations observed in mCRC patient populations. The positive agreement between plasma and tumor RAS results was 90.4% (47/52), the negative agreement was 93.5% (43/46), and the overall agreement (concordance) was 91.8% (90/98). The high concordance of plasma and tissue results demonstrates that blood-based RAS mutation testing is a viable alternative to tissue-based RAS testing.
- Published
- 2017
3. Budget Impact Analysis of Circulating Tumor DNA Testing for Colon Cancer in Commercial Health and Medicare Advantage Plans.
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Li Y, Heer AK, Sloane HS, Edelstein DL, Tie J, Gibbs P, and Barzi A
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- Humans, United States, Aged, Female, Male, Budgets, Middle Aged, Cost-Benefit Analysis, Colonic Neoplasms economics, Colonic Neoplasms diagnosis, Colonic Neoplasms blood, Colonic Neoplasms drug therapy, Colonic Neoplasms genetics, Medicare Part C economics, Circulating Tumor DNA blood, Circulating Tumor DNA genetics
- Abstract
Importance: In a randomized clinical trial, treatment guided by tumor-informed circulating tumor (ct)DNA testing reduced adjuvant chemotherapy use without compromising recurrence-free survival in patients with stage II colon cancer. The potential effects of adopting ctDNA testing into routine patient care is unknown., Objective: To compare the total cost of patient care scenarios with and without the adoption of ctDNA testing., Design, Setting, and Participants: This budget impact analysis was conducted from the perspectives of US commercial health and Medicare Advantage payers. A decision-analytical model was populated with age-specific incidence of colon cancer, use of adjuvant chemotherapy, and use of single-agent or multiagent regimens. Total cost was estimated with the costs of ctDNA testing, drug acquisition, administration, surveillance, and adverse events. The analysis was conducted from September 2023 to January 2024., Exposures: The adoption of ctDNA testing., Main Outcomes and Measures: The incremental cost in the first year following the adoption of ctDNA testing, where testing will affect patient treatment and costs., Results: In hypothetical plans with 1 million individuals covered, 35 commercial health plan members and 102 Medicare Advantage members aged 75 years and younger were eligible for ctDNA testing. In the base case with a 50% adoption rate, total cost savings were $221 684 (equivalent to $0.02 per member per month [PMPM]) for a commercial payer and $116 720 (equivalent to $0.01 PMPM) for a Medicare Advantage payer. Cost savings were robust to variations in assumptions of all parameters in the commercial population but sensitive to variations in assumptions of adjuvant chemotherapy use rates in the Medicare Advantage population. The number needed to test to avoid 1 patient receiving adjuvant chemotherapy was 4 in the commercial population and 10 in the Medicare Advantage population. The budget-neutral cost for ctDNA testing was $16 202 for a commercial payer and $5793 for a Medicare Advantage payer., Conclusions and Relevance: Use of tumor-informed ctDNA testing to guide adjuvant chemotherapy in postsurgery patients with stage II colon cancer was projected to result in cost savings for both commercial and Medicare Advantage payers. Adoption of ctDNA testing is therefore advantageous from a budgetary perspective.
- Published
- 2024
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4. Next-generation sequencing (NGS) profiling of matched tumor and circulating tumor DNA (ctDNA) in head and neck squamous cell carcinoma (HNSCC).
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Economopoulou P, Spathis A, Kotsantis I, Maratou E, Anastasiou M, Moutafi MK, Kirkasiadou M, Pantazopoulos A, Giannakakou M, Edelstein DL, Sloane H, Fredebohm J, Jones FS, Kyriazoglou A, Gavrielatou N, Foukas P, Panayiotides I, and Psyrri A
- Subjects
- Humans, Squamous Cell Carcinoma of Head and Neck genetics, Pilot Projects, Mutation, High-Throughput Nucleotide Sequencing methods, Biomarkers, Tumor genetics, Circulating Tumor DNA genetics, Carcinoma, Non-Small-Cell Lung genetics, Lung Neoplasms genetics, Head and Neck Neoplasms genetics, Head and Neck Neoplasms therapy
- Abstract
Objectives: The aim of this pilot study was to evaluate the presence of somatic mutations in matched tumor and circulating DNA (ctDNA) samples from patients with primary head and neck squamous cell carcinoma (HNSCC) and assess the association of changes in ctDNA levels with survival., Materials and Methods: Our study included 62 patients with stage I-IVB HNSCC treated with surgery or radical chemoradiotherapy with curative intent. Plasma samples were obtained at baseline, at the end of treatment (EOT), and at disease progression. Tumor DNA was extracted from plasma (ctDNA) and tumor tissue (tDNA). The Safe Sequencing System was used assess the presence of pathogenic variants in four genes (TP53, CDKN2A, HRAS and PI3KCA) in both ctDNA and tDNA., Results: Forty-five patients had available tissue and plasma samples. Concordance of genotyping results between tDNA and ctDNA at baseline was 53.3%. TP53 mutations were most commonly identified at baseline in both ctDNA (32.6%) and tDNA (40%). The presence of mutations in this restricted set of 4 genes in tissue samples at baseline was associated with decreased overall survival (OS) [median 58.3 months for patients with mutations vs. 89 months for patients without mutations, p < 0.013]. Similarly, patients presenting with mutations in ctDNA had shorter OS [median 53.8 vs. 78.6 months, p < 0.037]. CtDNA clearance at EOT did not show any association with PFS or OS., Conclusions: Liquid biopsy enables real-time molecular characterization of HNSCC and might predict survival. Larger studies are needed to validate the utility of ctDNA as a biomarker in HNSCC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)
- Published
- 2023
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5. Prospective study evaluating dynamic changes of cell-free HPV DNA in locoregional viral-associated oropharyngeal cancer treated with induction chemotherapy and response-adaptive treatment.
- Author
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Rosenberg AJ, Izumchenko E, Pearson A, Gooi Z, Blair E, Karrison T, Juloori A, Ginat D, Cipriani N, Lingen M, Sloane H, Edelstein DL, Keyser K, Fredebohm J, Holtrup F, Jones FS, Haraf D, Agrawal N, and Vokes EE
- Subjects
- Adolescent, Adult, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Biomarkers, Tumor blood, Carboplatin administration & dosage, Chemoradiotherapy, Cisplatin administration & dosage, Feasibility Studies, Female, Humans, Induction Chemotherapy, Male, Middle Aged, Oropharyngeal Neoplasms blood, Oropharyngeal Neoplasms virology, Paclitaxel administration & dosage, Papillomavirus Infections virology, Prognosis, Prospective Studies, Treatment Outcome, Young Adult, Cell-Free Nucleic Acids blood, DNA, Viral blood, Drug Monitoring methods, Oropharyngeal Neoplasms drug therapy, Papillomaviridae genetics, Papillomavirus Infections blood
- Abstract
Background: Human papillomavirus (HPV)-associated oropharyngeal cancer (OPC) has a favorable prognosis which has led to efforts to de-intensify treatment. Response-adaptive de-escalated treatment is promising, however improved biomarkers are needed. Quantitative cell-free HPV-DNA (cfHPV-DNA) in plasma represents an attractive non-invasive biomarker for grading treatment response and post-treatment surveillance. This prospective study evaluates dynamic changes in cfHPV-DNA during induction therapy, definitive (chemo)radiotherapy, and post-treatment surveillance in the context of risk and response-adaptive treatment for HPV + OPC., Methods: Patients with locoregional HPV + OPC are stratified into two cohorts: High risk (HR) (T4, N3, [Formula: see text] 20 pack-year smoking history (PYH), or non-HPV16 subtype); Low risk (LR) (all other patients). All patients receive induction chemotherapy with three cycles of carboplatin and paclitaxel. LR with ≥ 50% response receive treatment on the single-modality arm (minimally-invasive surgery or radiation alone to 50 Gy). HR with ≥ 50% response or LR with ≥ 30% and < 50% response receive treatment on the intermediate de-escalation arm (chemoradiation to 50 Gy with cisplatin). All other patients receive treatment on the regular dose arm with chemoradiation to 70 Gy with concurrent cisplatin. Plasma cfHPV-DNA is assessed during induction, (chemo)radiation, and post-treatment surveillance. The primary endpoint is correlation of quantitative cfHPV-DNA with radiographic response., Discussion: A de-escalation treatment paradigm that reduces toxicity without compromising survival outcomes is urgently needed for HPV + OPC. Response to induction chemotherapy is predictive and prognostic and can select candidates for de-escalated definitive therapy. Assessment of quantitative cfHPV-DNA in the context of response-adaptive treatment of represents a promising reliable and convenient biomarker-driven strategy to guide personalized treatment in HPV + OPC., Trial Registration: This trial is registered with ClinicalTrials.gov on October 1
st , 2020 with Identifier: NCT04572100 ., (© 2021. The Author(s).)- Published
- 2022
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6. Secondary resistance to anti-EGFR therapy by transcriptional reprogramming in patient-derived colorectal cancer models.
- Author
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Vangala D, Ladigan S, Liffers ST, Noseir S, Maghnouj A, Götze TM, Verdoodt B, Klein-Scory S, Godfrey L, Zowada MK, Huerta M, Edelstein DL, de Villarreal JM, Marqués M, Kumbrink J, Jung A, Schiergens T, Werner J, Heinemann V, Stintzing S, Lindoerfer D, Mansmann U, Pohl M, Teschendorf C, Bernhardt C, Wolters H, Stern J, Usta S, Viebahn R, Admard J, Casadei N, Fröhling S, Ball CR, Siveke JT, Glimm H, Tannapfel A, Schmiegel W, and Hahn SA
- Subjects
- Alleles, Animals, Cell Line, Clonal Evolution, Colorectal Neoplasms drug therapy, Colorectal Neoplasms metabolism, Colorectal Neoplasms pathology, Computational Biology, DNA Copy Number Variations, Disease Models, Animal, ErbB Receptors antagonists & inhibitors, ErbB Receptors metabolism, Gene Expression Profiling, High-Throughput Nucleotide Sequencing, Humans, Mice, Molecular Targeted Therapy, Mutation, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Exome Sequencing, Xenograft Model Antitumor Assays, Biomarkers, Tumor, Cellular Reprogramming genetics, Colorectal Neoplasms etiology, Drug Resistance, Neoplasm genetics, Transcription, Genetic
- Abstract
Background: The development of secondary resistance (SR) in metastatic colorectal cancer (mCRC) treated with anti-epidermal growth factor receptor (anti-EGFR) antibodies is not fully understood at the molecular level. Here we tested in vivo selection of anti-EGFR SR tumors in CRC patient-derived xenograft (PDX) models as a strategy for a molecular dissection of SR mechanisms., Methods: We analyzed 21 KRAS, NRAS, BRAF, and PI3K wildtype CRC patient-derived xenograft (PDX) models for their anti-EGFR sensitivity. Furthermore, 31 anti-EGFR SR tumors were generated via chronic in vivo treatment with cetuximab. A multi-omics approach was employed to address molecular primary and secondary resistance mechanisms. Gene set enrichment analyses were used to uncover SR pathways. Targeted therapy of SR PDX models was applied to validate selected SR pathways., Results: In vivo anti-EGFR SR could be established with high efficiency. Chronic anti-EGFR treatment of CRC PDX tumors induced parallel evolution of multiple resistant lesions with independent molecular SR mechanisms. Mutations in driver genes explained SR development in a subgroup of CRC PDX models, only. Transcriptional reprogramming inducing anti-EGFR SR was discovered as a common mechanism in CRC PDX models frequently leading to RAS signaling pathway activation. We identified cAMP and STAT3 signaling activation, as well as paracrine and autocrine signaling via growth factors as novel anti-EGFR secondary resistance mechanisms. Secondary resistant xenograft tumors could successfully be treated by addressing identified transcriptional changes by tailored targeted therapies., Conclusions: Our study demonstrates that SR PDX tumors provide a unique platform to study molecular SR mechanisms and allow testing of multiple treatments for efficient targeting of SR mechanisms, not possible in the patient. Importantly, it suggests that the development of anti-EGFR tolerant cells via transcriptional reprogramming as a cause of anti-EGFR SR in CRC is likely more prevalent than previously anticipated. It emphasizes the need for analyses of SR tumor tissues at a multi-omics level for a comprehensive molecular understanding of anti-EGFR SR in CRC., (© 2021. The Author(s).)
- Published
- 2021
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7. Routine Molecular Screening of Patients with Advanced Non-SmallCell Lung Cancer in Circulating Cell-Free DNA at Diagnosis and During Progression Using OncoBEAM TM EGFR V2 and NGS Technologies.
- Author
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Garcia J, Gauthier A, Lescuyer G, Barthelemy D, Geiguer F, Balandier J, Edelstein DL, Jones FS, Holtrup F, Duruisseau M, Grolleau E, Rodriguez-Lafrasse C, Merle P, Couraud S, and Payen L
- Subjects
- Biomarkers, Tumor, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung pathology, DNA Copy Number Variations genetics, Diagnostic Tests, Routine, Drug Resistance, Neoplasm genetics, ErbB Receptors genetics, Female, High-Throughput Nucleotide Sequencing, Humans, Male, Middle Aged, Mutation genetics, Neoplasm Staging, Protein Kinase Inhibitors administration & dosage, Carcinoma, Non-Small-Cell Lung blood, Cell-Free Nucleic Acids genetics, Circulating Tumor DNA blood, Early Detection of Cancer
- Abstract
Background and Objectives: The use of ultra-sensitive diagnostic tests to detect clinically actionable somatic alterations within the gene encoding the epidermal growth factor receptor (EGFR) within circulating cell-free DNA is an important first step in determining the eligibility of patients with non-small cell lung cancer to receive tyrosine kinase inhibitors., Methods: We present the clinical validation (accuracy, sensitivity, and specificity) of a highly sensitive OncoBEAM
TM EGFR V2 test, which we compare to a custom next-generation sequencing assay, for the treatment of patients with non-small cell lung cancer with EGFR tyrosine kinase inhibitor therapies. The OncoBEAMTM digital-polymerase chain reaction method detects 36 different EGFR alterations in circulating cell-free DNA, whereas the next-generation sequencing assay covers major solid tumor oncodrivers. Of the 540 samples analyzed with the OncoBEAMTM EGFR V2 test, 42.4% of patients had undergone molecular testing at diagnosis (N = 229/540) and 57.7% of patients during disease progression (N = 311/540)., Results: The sensitivity and specificity were measured for this BEAMing assay. The number of mutant beads and mutant allelic fraction were measured for each EGFR alteration and the level of detection was established at 0.1% for a median of 2861 genome equivalent (GE) in each reaction using HD780 horizon control DNA, as well as by an internal quality reference standard. Approximately 10%, 27%, and 63% of the 540 samples contained < 1500 GE, a range of 1500-3000 GE, and > 3000 GE, which corresponded to a maximal assay sensitivity of 2.0%, 0.5-0.1%, and 0.1-0.05% mutant allelic fraction, respectively. In a routine hospital setting, 11.4% of non-small cell lung cancer tumors were positive at diagnosis for EGFR alterations, while 43.7% samples harbored EGFR mutations at progression, among which 40.3% expressed EGFR resistance mutations after first-line tyrosine kinase inhibitor treatment with first- and second-generation drugs., Conclusions: The OncoBEAMTM EGFR V2 is a sensitive, robust, and accurate assay that delivers reproducible results. Next-generation sequencing and BEAMing technologies act complementarily in the routine molecular screening. We show that using a next-generation sequencing assay, despite its lower sensitivity, enables the identification of rare EGFR alterations or resistance mechanisms (mutation, deletion, insertion, and copy number variation) to orient first- and second-line treatments.- Published
- 2021
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8. Expanded Low Allele Frequency RAS and BRAF V600E Testing in Metastatic Colorectal Cancer as Predictive Biomarkers for Cetuximab in the Randomized CO.17 Trial.
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Loree JM, Dowers A, Tu D, Jonker DJ, Edelstein DL, Quinn H, Holtrup F, Price T, Zalcberg JR, Moore MJ, Karapetis CS, O'Callaghan CJ, Waring P, Kennecke HF, Hamilton SR, and Kopetz S
- Subjects
- Adult, Aged, Aged, 80 and over, Cetuximab pharmacology, Colorectal Neoplasms genetics, Colorectal Neoplasms mortality, DNA Mutational Analysis, Drug Resistance, Neoplasm genetics, Female, GTP Phosphohydrolases genetics, Gene Frequency, Humans, Male, Membrane Proteins genetics, Middle Aged, Mutation, Progression-Free Survival, Proto-Oncogene Proteins B-raf genetics, Proto-Oncogene Proteins p21(ras) genetics, Biomarkers, Tumor genetics, Cetuximab therapeutic use, Colorectal Neoplasms drug therapy
- Abstract
Purpose: Expanded RAS/BRAF mutations have not been assessed as predictive for single-agent cetuximab in metastatic colorectal cancer (mCRC), and low mutant allele frequency (MAF) mutations are of unclear significance. We aimed to establish cetuximab efficacy in optimally selected patients using highly sensitive beads, emulsion, amplification, and magnetics (BEAMing) analysis, capable of detecting alterations below standard clinical assays., Patients and Methods: CO.17 trial compared cetuximab versus best supportive care (BSC) in RAS/BRAF -unselected mCRC. We performed RAS/BRAF analysis on microdissected tissue of 242 patients in CO.17 trial using BEAMing for KRAS/NRAS (codons 12/13/59/61/117/146) and BRAF V600E. Patients without BEAMing but with previous Sanger sequencing-detected mutations were included., Results: KRAS, NRAS , and BRAF mutations were present in 53%, 4%, and 3% of tumors, respectively. Cetuximab improved overall survival [OS; HR, 0.51; 95% confidence interval (CI), 0.32-0.81; P = 0.004] and progression-free survival (PFS; HR, 0.25; 95% CI, 0.15-0.41; P < 0.0001) compared with BSC in RAS/BRAF wild-type patients. Cetuximab did not improve OS/PFS for KRAS-, NRAS- , or BRAF- mutated tumors, and tests of interaction confirmed expanded KRAS ( P = 0.0002) and NRAS ( P = 0.006) as predictive, while BRAF mutations were not ( P = 0.089). BEAMing identified 14% more tumors as RAS mutant than Sanger sequencing, and cetuximab lacked activity in these patients. Mutations at MAF < 5% were noted in 6 of 242 patients (2%). One patient with a KRAS A59T mutation (MAF = 2%) responded to cetuximab. More NRAS than KRAS mutations were low MAF (OR, 20.50; 95% CI, 3.88-96.85; P = 0.0038)., Conclusions: We establish single-agent cetuximab efficacy in optimally selected patients and show that subclonal RAS/BRAF alterations are uncommon and remain of indeterminate significance., (©2020 American Association for Cancer Research.)
- Published
- 2021
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9. Blood-based RAS mutation testing: concordance with tissue-based RAS testing and mutational changes on progression.
- Author
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Germetaki T, Nicholls C, Adams RA, Braun M, Rogan J, Moghadam S, Lenfert E, Lukas A, Edelstein DL, Jones FS, and Saunders MP
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- Adult, Aged, Aged, 80 and over, Alleles, Circulating Tumor DNA, DNA Mutational Analysis methods, DNA Mutational Analysis standards, Disease Progression, Female, Humans, Liquid Biopsy methods, Liquid Biopsy standards, Male, Middle Aged, Neoplasm Metastasis, Neoplasm Staging, Neoplasms blood, Neoplasms therapy, Time-to-Treatment, Biomarkers, Tumor, Genes, ras, Mutation, Neoplasms diagnosis, Neoplasms genetics
- Abstract
Aim: To determine the concordance between plasma and tissue RAS mutation status in metastatic colorectal cancer patients to gauge whether blood-based testing is a viable alternative. We also evaluated the change in mutation status on progression. Materials/methods: RAS testing was performed on plasma from patients commencing first-line therapy (OncoBEAM™ RAS CEIVD kit). Results were then compared with formalin-fixed paraffin embedded tumor samples. Results: The overall percentage agreement (concordance) was 86.0% (86/100), which demonstrates that blood-based testing is an alternative to tissue-based testing. Reproducibility was 100% between three laboratories and 20% showed changes in their RAS mutational status on progression. Conclusion: These results show good concordance between tissue and plasma samples and suggest the need for longitudinal plasma testing during treatment to guide management decisions.
- Published
- 2020
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10. Profiling of circulating tumor DNA in plasma of non-small cell lung cancer patients, monitoring of epidermal growth factor receptor p.T790M mutated allelic fraction using beads, emulsion, amplification, and magnetics companion assay and evaluation in future application in mimicking circulating tumor cells.
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Garcia J, Wozny AS, Geiguer F, Delherme A, Barthelemy D, Merle P, Tissot C, Jones FS, Johnson C, Xing X, Xu Z, Edelstein DL, Brevet M, Souquet PJ, Rodriguez-Lafrasse C, Payen L, and Couraud S
- Subjects
- Alleles, Carcinoma, Non-Small-Cell Lung blood, DNA Mutational Analysis, Disease Progression, ErbB Receptors genetics, Gene Expression Profiling methods, Genetic Association Studies, High-Throughput Nucleotide Sequencing, Humans, Liquid Biopsy methods, Lung Neoplasms blood, Mutation, Neoplastic Cells, Circulating metabolism, Neoplastic Cells, Circulating pathology, Biomarkers, Tumor, Carcinoma, Non-Small-Cell Lung diagnosis, Carcinoma, Non-Small-Cell Lung genetics, Circulating Tumor DNA, DNA, Neoplasm, Lung Neoplasms diagnosis, Lung Neoplasms genetics
- Abstract
Cell-free plasma DNA (cfDNA) and mimicking circulating tumor cells (mCTCs) have demonstrated tremendous potential for molecular diagnosis of cancer and have been rapidly implemented in specific settings. However, widespread clinical adoption still faces some obstacles. The purpose was to compare the performance of a BEAMing (beads, emulsion, amplification, and magnetics) assay (OncoBEAM™-epidermal growth factor receptor [EGFR] [Sysmex Inostics]) and a next-generation sequencing assay (NGS; 56G Oncology panel kit, Swift Bioscience) to detect the p.T790M EGFR mutation in cfDNA of non-small cell lung cancer (NSCLC) patients. CfDNA samples (n = 183) were collected within our hospital from patients having a known EGFR sensitizing mutation, and presenting disease progression while under first-line therapy. EGFR mutations were detected using NGS in 42.1% of samples during progression in cfDNA. Testing using the OncoBEAM™-EGFR assay enabled detection of the p.T790M EGFR mutation in 40/183 NSCLC patients (21.8%) versus 20/183 (10.9%), using the NGS assay. Samples that were only positive with the OncoBEAM™-EGFR assay had lower mutant allelic fractions (Mean = 0.1304%; SD ± 0.1463%). In addition, we investigated the detection of p.T790M in mCTCs using H1975 cells. These cells spiked into whole blood were enriched using the ClearCellFX1 microfluidic device. Using the OncoBEAM™-EGFR assay, p.T790M was detected in as few as 1.33 tumoral cells/mL. Overall, these findings highlight the value of using the OncoBEAM™-EGFR to optimize detection of the p.T790M mutation, as well as the complementary clinical value that each of the mutation detection assay offers: NGS enabled the detection of mutations in other oncogenes that may be relevant to secondary resistance mechanisms, whereas the OncoBEAM™-EGFR assay achieved higher sensitivity for detection of clinically actionable mutations., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)
- Published
- 2019
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11. From validity to clinical utility: the influence of circulating tumor DNA on melanoma patient management in a real-world setting.
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Rowe SP, Luber B, Makell M, Brothers P, Santmyer J, Schollenberger MD, Quinn H, Edelstein DL, Jones FS, Bleich KB, Sharfman WH, and Lipson EJ
- Subjects
- Adult, Aged, Aged, 80 and over, Alleles, Cohort Studies, Disease Progression, Female, Humans, Male, Middle Aged, Mutation genetics, Neoplasm Metastasis, Reproducibility of Results, Young Adult, Circulating Tumor DNA blood, Melanoma blood
- Abstract
Melanoma currently lacks a reliable blood-based biomarker of disease activity, although circulating tumor DNA (ctDNA) may fill this role. We investigated the clinical utility (i.e., impact on clinical outcomes and interpretation of radiographic data) of measuring ctDNA in patients with metastatic or high-risk resected melanoma. Patients were prospectively accrued into ≥ 1 of three cohorts, as follows. Cohort A: patients with radiographically measurable metastatic melanoma who underwent comparison of ctDNA measured by a BEAMing digital PCR assay to tissue mutational status and total tumor burden; when appropriate, determinations about initiation of targeted therapy were based on ctDNA data. Cohorts B and C: patients with BRAF- or NRAS-mutant melanoma who had either undergone surgical resection of high-risk disease (cohort B) or were receiving or had received medical therapy for advanced disease (cohort C). Patients were followed longitudinally with serial ctDNA measurements with contemporaneous radiographic imaging to ascertain times to detection of disease activity and progressive disease, respectively. The sensitivity and specificity of the ctDNA assay were 86.8% and 100%, respectively. Higher tumor burden and visceral metastases were found to be associated with detectable ctDNA. In two patients in cohort A, ctDNA test results revealed a targetable mutation where tumor testing had not; both patients experienced a partial response to targeted therapy. In four of 30 patients with advanced melanoma, ctDNA assessments indicated evidence of melanoma activity that predicted radiographic evidence of disease progression by 8, 14, 25, and 38 weeks, respectively. CtDNA was detectable in three of these four patients coincident with radiographic evaluations that alone were interpreted as showing no evidence of neoplastic disease. Our findings provide evidence for the clinical utility of integrating ctDNA data in managing patients with melanoma in a real-world setting., (© 2018 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)
- Published
- 2018
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12. Cross-platform comparison for the detection of RAS mutations in cfDNA (ddPCR Biorad detection assay, BEAMing assay, and NGS strategy).
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Garcia J, Forestier J, Dusserre E, Wozny AS, Geiguer F, Merle P, Tissot C, Ferraro-Peyret C, Jones FS, Edelstein DL, Cheynet V, Bardel C, Vilchez G, Xu Z, Bringuier PP, Barritault M, Brengle-Pesce K, Guillet M, Chauvenet M, Manship B, Brevet M, Rodriguez-Lafrasse C, Hervieu V, Couraud S, Walter T, and Payen L
- Abstract
CfDNA samples from colon (mCRC) and non-small cell lung cancers (NSCLC) (CIRCAN cohort) were compared using three platforms: droplet digital PCR (ddPCR, Biorad); BEAMing/OncoBEAM™-RAS-CRC (Sysmex Inostics); next-generation sequencing (NGS, Illumina), utilizing the 56G oncology panel (Swift Biosciences). Tissue biopsy and time matched cfDNA samples were collected at diagnosis in the mCRC cohort and during 1st progression in the NSCLC cohort. Excellent matches between cfDNA/FFPE mutation profiles were observed. Detection thresholds were between 0.5-1% for cfDNA samples examined using ddPCR and NGS, and 0.03% with BEAMing. This high level of sensitivity enabled the detection of KRAS mutations in 5/19 CRC patients with negative FFPE profiles. In the mCRC cohort, comparison of mutation results obtained by testing FFPE to those obtained by testing cfDNA by ddPCR resulted in 47% sensitivity, 77% specificity, 70% positive predictive value (PPV) and 55% negative predictive value (NPV). For BEAMing, we observed 93% sensitivity, 69% specificity, 78% PPV and 90% NPV. Finally, sensitivity of NGS was 73%, specificity was 77%, PPV 79% and NPV 71%. Our study highlights the complementarity of different diagnostic approaches and variability of results between OncoBEAM™-RAS-CRC and NGS assays. While the NGS assay provided a larger breadth of coverage of the major targetable alterations of 56 genes in one run, its performance for specific alterations was frequently confirmed by ddPCR results., Competing Interests: CONFLICTS OF INTEREST Dr. Cheynet and Dr. Brengel-Pesce are employees of BioMérieux SA. Daniel Edelstein and Frederick Jones are employees of Sysmex Inostics, Inc. Dr. Xu reports to be employed by Sophia Genetics. Dr. Forestier reports personal fees from AMGEN, personal fees from SANOFI, personal fees from MERCK, personal fees from CELGENE, personal fees from ROCHE, personal fees from IPSEN, outside the submitted work. Dr. Bringuier reports personal fees from Astra Zeneca, outside the submitted work. Dr. Brevet reports grants from Astra Zeneca, personal fees from MSD, personal fees from BMS, grants from Pfizer, outside the submitted work. Dr. Garcia and Dr Payen report grants from Sysmex-innostics during the conduct of the study. Dr. Couraud reports grants and non-financial support from Sysmex Innostics, grants and personal fees from Astra Zeneca, grants from Merck, grants and personal fees from BMS, during the conduct of the study; grants and personal fees from Astra Zeneca, grants, personal fees and other from Pfizer, grants, personal fees and other from Roche, grants, personal fees and other from Chugai, grants, personal fees and other from MSD, grants, personal fees and other from Boehringher Ingelheim, grants and personal fees from Lilly, grants and personal fees from Novartis, grants and personal fees from Laidet Medical, grants from Amgen, other from Eformed, outside the submitted work. Other authors have nothing to disclose.
- Published
- 2018
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13. Blood-based detection of RAS mutations to guide anti-EGFR therapy in colorectal cancer patients: concordance of results from circulating tumor DNA and tissue-based RAS testing.
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Schmiegel W, Scott RJ, Dooley S, Lewis W, Meldrum CJ, Pockney P, Draganic B, Smith S, Hewitt C, Philimore H, Lucas A, Shi E, Namdarian K, Chan T, Acosta D, Ping-Chang S, Tannapfel A, Reinacher-Schick A, Uhl W, Teschendorf C, Wolters H, Stern J, Viebahn R, Friess H, Janssen KP, Nitsche U, Slotta-Huspenina J, Pohl M, Vangala D, Baraniskin A, Dockhorn-Dworniczak B, Hegewisch-Becker S, Ronga P, Edelstein DL, Jones FS, Hahn S, and Fox SB
- Subjects
- Aged, Colorectal Neoplasms drug therapy, ErbB Receptors antagonists & inhibitors, Female, Humans, Male, Colorectal Neoplasms blood, Colorectal Neoplasms genetics, DNA, Neoplasm blood, DNA, Neoplasm genetics, Genes, ras, Mutation
- Abstract
An accurate blood-based RAS mutation assay to determine eligibility of metastatic colorectal cancer (mCRC) patients for anti-EGFR therapy would benefit clinical practice by better informing decisions to administer treatment independent of tissue availability. The objective of this study was to determine the level of concordance between plasma and tissue RAS mutation status in patients with mCRC to gauge whether blood-based RAS mutation testing is a viable alternative to standard-of-care RAS tumor testing. RAS testing was performed on plasma samples from newly diagnosed metastatic patients, or from recurrent mCRC patients using the highly sensitive digital PCR technology, BEAMing (beads, emulsions, amplification, and magnetics), and compared with DNA sequencing data of respective FFPE (formalin-fixed paraffin-embedded) tumor samples. Discordant tissue RAS results were re-examined by BEAMing, if possible. The prevalence of RAS mutations detected in plasma (51%) vs. tumor (53%) was similar, in accord with the known prevalence of RAS mutations observed in mCRC patient populations. The positive agreement between plasma and tumor RAS results was 90.4% (47/52), the negative agreement was 93.5% (43/46), and the overall agreement (concordance) was 91.8% (90/98). The high concordance of plasma and tissue results demonstrates that blood-based RAS mutation testing is a viable alternative to tissue-based RAS testing., (© 2016 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)
- Published
- 2017
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14. Risk of Colorectal and Other Cancers in Patients With Serrated Polyposis.
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Edelstein DL, Cruz-Correa M, Soto-Salgado M, Axilbund JE, Hylind LM, Romans K, Blair C, Wiley E, Tersmette AC, Offerhaus JA, and Giardiello FM
- Subjects
- Adult, Aged, Cohort Studies, Female, Humans, Male, Middle Aged, Risk Assessment, Young Adult, Adenoma epidemiology, Colonic Polyps complications, Colorectal Neoplasms epidemiology
- Abstract
Patients with serrated polyposis develop multiple colorectal hyperplastic and/or serrated sessile adenomas/polyps. We investigated the risk of colorectal and other cancers by analyzing data from 64 patients with serrated polyposis (mean age at diagnosis, 54 y; 41% men; 92% white) listed in the Johns Hopkins Polyposis Registry. Medical, endoscopic, and histopathology reports were evaluated. Six patients (9.4%) had a history of colorectal cancer, diagnosed at a mean age of 56 years; 6 additional patients (9.4%) had at least 1 advanced colorectal adenoma. Extracolonic cancers were found in 16% of the study population. The standard incidence ratio for colorectal cancer in patients with serrated polyposis was 18.72 (95% confidence interval, 6.87-40.74) and for extracolonic cancer was 31.20 (95% confidence interval, 14.96-57.37), compared with the Surveillance, Epidemiology, and End Results population. Patients with serrated polyposis therefore have a high risk for colorectal cancer and require vigilant colorectal surveillance, starting at the time of diagnosis of serrated polyposis. The risk of extracolonic cancer also appears to be increased, but this requires further evaluation., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
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15. Serrated polyposis: rapid and relentless development of colorectal neoplasia.
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Edelstein DL, Axilbund JE, Hylind LM, Romans K, Griffin CA, Cruz-Correa M, and Giardiello FM
- Subjects
- Adenoma genetics, Adenoma surgery, Adult, Aged, Cohort Studies, Colonic Polyps surgery, Colonoscopy, Colorectal Neoplasms genetics, Colorectal Neoplasms surgery, Endoscopy, Gastrointestinal, Female, Follow-Up Studies, Humans, Male, Middle Aged, Pedigree, Recurrence, Registries, Retrospective Studies, Young Adult, Adenoma diagnosis, Cell Transformation, Neoplastic, Colonic Polyps pathology, Colorectal Neoplasms diagnosis, Precancerous Conditions
- Abstract
Objective: Serrated (hyperplastic) polyposis (SP) is a rare disorder with multiple colorectal hyperplastic polyps and often sessile serrated adenomas/polyps (SSA/P) or adenomas. Although associated with colorectal cancer, the course of SP is not well described., Design: 44 patients with SP were studied. The results of 146 colonoscopies with median follow-up of 2.0 years (range 0-30) and a median of 1.0 years (range 0.5-6) between surveillance colonoscopies were evaluated. Findings from oesophogastroduodenoscopy examinations were analysed., Results: The mean age at diagnosis of SP was 52.5 ± 11.9 years (range 22-78). In two pedigrees (5%) another family member had SP. None of 22 patients had gastroduodenal polyps. All patients had additional colorectal polyps at surveillance colonoscopy. SSA/P or adenomas were found in 25 patients (61%) at first colonoscopy and 83% at last colonoscopy. Recurrent SSA/P or adenomas occurred in 68% of patients at surveillance colonoscopy. Three patients had colorectal cancer. Eleven patients (25%) underwent surgery (mean time from diagnosis of SP 2.0 ± 0.9 years). After surgery all seven surveyed patients developed recurrent polyps in the retained colorectum (4/7 had SSA/P or adenomas). No association was found between colorectal neoplasia and sex, age at diagnosis of SP or initial number of colorectal polyps., Conclusions: In SP, rapid and unrelenting colorectal neoplasia development continues in the intact colorectum and retained segment after surgery. These findings support the possibility of annual colonoscopic surveillance, consideration for colectomy when SSA/P or adenomas are encountered and frequent postoperative endoscopic surveillance of the retained colorectum.
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- 2013
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16. Detection of familial adenomatous polyposis with orthogonal polarized spectroscopy of the oral mucosa vasculature.
- Author
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Basiri A, Edelstein DL, Graham J, Nabili A, Giardiello FM, and Ramella-Roman JC
- Subjects
- Adenomatous Polyposis Coli genetics, Case-Control Studies, Colorectal Neoplasms diagnosis, Colorectal Neoplasms etiology, Colorectal Neoplasms pathology, Female, Genetic Predisposition to Disease, Genetic Testing, Humans, Lasers, Light, Male, Mouth Mucosa blood supply, Pedigree, Refractometry instrumentation, Refractometry methods, Risk Factors, Spectrum Analysis instrumentation, Adenomatous Polyposis Coli diagnosis, Mouth Mucosa pathology, Spectrum Analysis methods
- Abstract
Familial Adenomatous Polyposis (FAP) is an autosomal dominant disease characterized by the development of multiple colonic polyps at younger age with a near 100% lifetime risk of colorectal cancer. The determination of FAP is made after extensive clinical evaluation and genetic testing of at risk individuals. We investigated a novel spectro-polarimetric imaging system capable of capturing high-resolution images of the oral mucosa at different wavelengths in an attempt to distinguish patients with FAP from controls. Results of a clinical trial show that the system is capable of separating FAP positive individuals from controls by measuring the individuals' oral vascular density and complexity., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
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- 2011
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17. A new phenotypic manifestation of familial adenomatous polyposis.
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Edelstein DL, Giardiello FM, Basiri A, Hylind LM, Romans K, Axilbund JE, Cruz-Correa M, and Ramella-Roman JC
- Subjects
- Adult, Female, Humans, Male, Middle Aged, Mouth Mucosa pathology, Phenotype, Vascular Endothelial Growth Factor A analysis, Adenomatous Polyposis Coli complications, Mouth Mucosa blood supply
- Abstract
Familial adenomatous polyposis (FAP) is an autosomal dominant disease with hundreds of colorectal adenomas in teenagers and progression to colorectal cancer if colectomy is not performed. We investigated the association of two phenotypic manifestations-oral mucosal vascular density (OMVD) and oral mucosal reflectance (OMR)--with FAP and patients with multiple colorectal adenomas. Thirty-three patients with FAP from 29 unrelated pedigrees with APC gene mutation, 5 with multiple adenomas and no known gene mutations, and 50 population controls were evaluated for the two different manifestations utilizing a photographic/spectrophotometric system capturing images and reflectance at various wavelengths. Statistical analysis was performed with student t test and test performance characteristics were calculated. There were no significant differences in demographic variables between the FAP and control group. A significant difference in OMVD between FAP patients and controls was noted, P < 0.001. The sensitivity and specificity of oral mucosal vascular density for FAP was 91 and 90%, respectively. No association between this phenotypic manifestation and age or gender was found. All 5 patient with multiple polyps were positive for OMVD and the value was significantly higher than controls, P = 0.002. No significant difference was noted in OMR between the two patient groups and controls. OMVD is a new phenotypic manifestation in patients with FAP and also may identify those with multiple adenomas without known gene mutation.
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- 2011
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18. Detection of tumor DNA at the margins of colorectal cancer liver metastasis.
- Author
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Holdhoff M, Schmidt K, Diehl F, Aggrawal N, Angenendt P, Romans K, Edelstein DL, Torbenson M, Kinzler KW, Vogelstein B, Choti MA, and Diaz LA Jr
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- Adult, Aged, Biopsy, Needle, Class I Phosphatidylinositol 3-Kinases, Colorectal Neoplasms pathology, Colorectal Neoplasms surgery, DNA, Neoplasm analysis, Female, Genes, p53, Hepatectomy, Humans, Liver Neoplasms secondary, Liver Neoplasms surgery, Male, Middle Aged, Mutation, Phosphatidylinositol 3-Kinases genetics, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins p21(ras), ras Proteins genetics, Colorectal Neoplasms genetics, DNA, Neoplasm genetics, Genes, APC, Liver Neoplasms genetics
- Abstract
Purpose: Defining an adequate resection margin of colorectal cancer liver metastases is essential for optimizing surgical technique. We have attempted to evaluate the resection margin through a combination of histopathologic and genetic analyses., Experimental Design: We evaluated 88 samples of tumor margins from 12 patients with metastatic colon cancer who each underwent partial hepatectomy of one to six liver metastases. Punch biopsies of surrounding liver tissue were obtained at 4, 8, 12, and 16 mm from the tumor border. DNA from these biopsies was analyzed by a sensitive PCR-based technique, called BEAMing, for mutations of KRAS, PIK3CA, APC, or TP53 identified in the corresponding tumor., Results: Mutations were identified in each patient's resected tumor and used to analyze the 88 samples circumscribing the tumor-normal border. Tumor-specific mutant DNA was detectable in surrounding liver tissue in 5 of these 88 samples, all within 4 mm of the tumor border. Biopsies that were 8, 12, and 16 mm from the macroscopic visible margin were devoid of detectable mutant tumor DNA and of microscopically visible cancer cells. Tumors with a significant radiologic response to chemotherapy were not associated with any increase in mutant tumor DNA in beyond 4 mm of the main tumor., Conclusions: Mutant tumor-specific DNA can be detected beyond the visible tumor margin, but never beyond 4 mm, even in patients whose tumors were larger prior to chemotherapy. These data provide a rational basis for determining the extent of surgical excision required in patients undergoing resection of liver metastases., (©2011 AACR.)
- Published
- 2011
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19. Rapid development of colorectal neoplasia in patients with Lynch syndrome.
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Edelstein DL, Axilbund J, Baxter M, Hylind LM, Romans K, Griffin CA, Cruz-Correa M, and Giardiello FM
- Subjects
- Adaptor Proteins, Signal Transducing genetics, Adolescent, Adult, Age Factors, Aged, Aged, 80 and over, Colonoscopy, Female, Humans, Male, Middle Aged, MutL Protein Homolog 1, MutS Homolog 2 Protein genetics, Mutation, Nuclear Proteins genetics, Young Adult, Colon pathology, Colorectal Neoplasms, Hereditary Nonpolyposis pathology
- Abstract
Background & Aims: Patients with Lynch syndrome have a high risk for colorectal adenomas and carcinomas. We evaluated the development of colorectal neoplasia in these patients., Methods: We assessed serial colonoscopy findings from 54 persons from 29 pedigrees with pathogenic mutations in MSH2 or MLH1; we evaluated the development of colorectal neoplasia by age, sex, tumor location, and number (mean follow-up time, 9.3 years; colonoscopy interval, 1.7 ± 1.2 years; 112 adenomas and 31 cancers). Differences in colorectal phenotype were analyzed by genotype, and dwell time was calculated for advanced neoplasias., Results: Among mutation carriers, the cumulative risk of colorectal neoplasia was 43% by age 40 years and 72% by 80 years. There were no statistically significant associations between time to development of colorectal neoplasia and sex or mutation type. Most female patients had left-sided neoplasms, whereas most male patients developed right-sided lesions. The mean cumulative numbers of neoplastic lesions in patients were 1.3 ± 0.5 by age 30 years and 7.6 ± 6.8 by age 80 years. Polyp dwell time was 33.0 ± 16.2 months and 35.2 ± 22.3 months for advanced adenoma and colorectal cancer, respectively. The 5-year survival rate for patients with colorectal cancer was 96%., Conclusions: High percentages of individuals with pathogenic mutations in MSH2 or MLH1 develop colorectal neoplasia by age 40. Left-sided colorectal neoplasias are more frequent in female patients. The development of 3 or more colorectal neoplasms by age 30 years indicates a possible polyposis syndrome rather than Lynch syndrome. Polyp dwell time is short for advanced neoplasias, arguing for annual colonoscopic screening and surveillance., (Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.)
- Published
- 2011
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20. Occurrence of colorectal adenomas in younger adults: an epidemiologic necropsy study.
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Pendergrass CJ, Edelstein DL, Hylind LM, Phillips BT, Iacobuzio-Donahue C, Romans K, Griffin CA, Cruz-Correa M, Tersmette AC, Offerhaus GJ, and Giardiello FM
- Subjects
- Adult, Aged, Aged, 80 and over, Colon, Descending, Female, Humans, Male, Maryland epidemiology, Middle Aged, Prevalence, Racial Groups, Risk Factors, Sex Factors, Adenoma epidemiology, Colorectal Neoplasms epidemiology
- Abstract
Background & Aims: The colorectal adenoma is the precursor lesion in virtually all colorectal cancers. Occurrence of colorectal adenomas has been studied in older adults but analysis in younger adults is lacking., Methods: The prevalence by age, sex, race, and location, and the number of colorectal adenomas detected was investigated using epidemiologic necropsy in 3558 persons ages 20 to 89 autopsied from 1985 to 2004 at the Johns Hopkins Hospital. Results were standardized to the general population. Younger adults 20 to 49 years old were compared with older adults 50 to 89 years old., Results: The prevalence of colorectal adenomas in younger adults increased from 1.72% to 3.59% from the third to the fifth decade of life and then sharply increased after age 50. In younger adults, adenomas were more prevalent in men than in women (risk ratio, 1.09; 95% confidence interval, 1.07-1.11) and in whites than in blacks (risk ratio, 1.28; 95% confidence interval, 1.26-1.31). Overall, both younger and older adults had predominately left-sided adenomas, but blacks in both age groups had more right-sided adenomas. Occurrence of 2 or more adenomas in younger adults and 5 or more in older adults was greater than 2 SDs from the mean., Conclusions: Colorectal adenomas infrequently occur in younger adults and are more prevalent in the left colon. Irrespective of age, blacks have more right-sided adenomas, suggesting the need for screening the entire colorectum. Two or more adenomas in younger adults and 5 or more in older adults represents polyp burden outside the normal expectation.
- Published
- 2008
- Full Text
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