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Article ; Online: Comparison of a PNA clamp PCR and an ARMS/Scorpion PCR assay for the detection of K-ras mutations.

Nordgård, Oddmund / Oltedal, Satu / Janssen, Emiel A M / Gilje, Bjørnar / Kørner, Hartwig / Tjensvoll, Kjersti / Smaaland, Rune

Diagnostic molecular pathology : the American journal of surgical pathology, part B

2012 Volume 21, Issue 1, Page(s) 9–13

Abstract: Point mutations in the K-ras gene have been shown to confer resistance against ... epidermal growth factor receptor-directed therapy of metastatic colorectal cancer. Accordingly, K-ras mutation testing has ... sensitive methods for detection of K-ras mutations: a peptide nucleic acid (PNA) clamp polymerase chain ...

Abstract	Point mutations in the K-ras gene have been shown to confer resistance against epidermal growth factor receptor-directed therapy of metastatic colorectal cancer. Accordingly, K-ras mutation testing has become mandatory in hospitals offering such treatment. We compared the performance and reagent costs of 2 sensitive methods for detection of K-ras mutations: a peptide nucleic acid (PNA) clamp polymerase chain reaction (PCR) assay and a commercially available amplification refractory mutation system/Scorpion (ARMS/S) PCR assay. Both methods were applied in parallel to 101 formalin-fixed, paraffin-embedded tumor and metastasis samples from patients with colon cancer. The PNA clamp PCR assay detected K-ras mutations in 35% (35 of 101) of the samples, whereas the ARMS/S PCR assay detected mutations in 27% (27 of 101) of them. There was 92% (93 of 101) concordance between the 2 methods and the κ coefficient for the comparison was 0.82. The 8 discordant cases were exclusively positive by PNA clamp PCR. Finally, the reagent costs of the PNA clamp PCR assay were estimated to be at least 20 times lower than the ARMS/S assay. We concluded that the high performance and low costs associated with the PNA clamp PCR assay encourage its use in the administration of personalized epidermal growth factor receptor-directed therapy.
MeSH term(s)	Adenocarcinoma/genetics ; Adenocarcinoma/secondary ; Colorectal Neoplasms/genetics ; Colorectal Neoplasms/pathology ; DNA Mutational Analysis/methods ; DNA, Neoplasm/analysis ; Gene Amplification ; Humans ; Peptide Nucleic Acids/genetics ; Peptide Nucleic Acids/metabolism ; Point Mutation ; Polymerase Chain Reaction/methods ; Proto-Oncogene Proteins p21(ras)/genetics
Chemical Substances	DNA, Neoplasm ; Peptide Nucleic Acids ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2)
Language	English
Publishing date	2012-03
Publishing country	United States
Document type	Comparative Study ; Journal Article
ZDB-ID	1098858-0
ISSN	1533-4066 ; 1052-9551
ISSN (online)	1533-4066
ISSN	1052-9551
DOI	10.1097/PDM.0b013e31821e59dc
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Article ; Online: Heterogeneous distribution of K-ras mutations in primary colon carcinomas: implications for EGFR-directed therapy.

Oltedal, Satu / Aasprong, Ole Gunnar / Møller, Jannicke H / Kørner, Hartwig / Gilje, Bjørnar / Tjensvoll, Kjersti / Birkemeyer, Elke M / Heikkilä, Reino / Smaaland, Rune / Nordgård, Oddmund

International journal of colorectal disease

2011 Volume 26, Issue 10, Page(s) 1271–1277

Abstract: Purpose: K-ras mutations predict resistance against epidermal growth factor receptor (EGFR ... the distribution of K-ras mutations in primary tumors and corresponding sentinel lymph nodes (SLNs ... were analyzed for K-ras mutations in codons 12 and 13 by a sensitive and quantitative ...

Abstract	Purpose: K-ras mutations predict resistance against epidermal growth factor receptor (EGFR)-directed therapy of metastatic colorectal cancer (CRC). The purpose of this study was to analyze the distribution of K-ras mutations in primary tumors and corresponding sentinel lymph nodes (SLNs) from colon cancer patients. Methods: Tumor biopsies and SLNs from 158 patients with non-metastatic colon cancer were analyzed for K-ras mutations in codons 12 and 13 by a sensitive and quantitative peptide nucleic acid clamp PCR assay. Results: Analyses of single fresh-frozen tumor biopsies revealed K-ras mutations in 67 (42%) of the patients. Apparently low levels of K-ras mutations in 13 of the mutated primary tumors and the presence of K-ras mutations in SLNs from seven patients with a wild-type primary tumor biopsy suggested possible intratumoral heterogeneity for 20 of the patients. To confirm this hypothesis, we analyzed tissue sections from all available formalin-fixed, paraffin-embedded (FFPE) tumor blocks from these 20 patients. Ten of the patients had a mixture of tissue sections positive and tissue sections negative for K-ras mutations, two patients had K-ras mutations in all sections, and eight patients had no detectable K-ras mutations in tumor FFPE tissue blocks. Among these eight patients, five had K-ras mutations detected in SLNs. Thus, evidence supporting a heterogeneous distribution of K-ras mutations was obtained for 15 patients. Conclusions: Heterogeneous distribution of K-ras codon 12 and 13 mutations within primary tumor, or between primary tumor and lymph node metastases, was demonstrated for 15 (20%) of 74 colon cancer patients having K-ras mutations. This may have implications for tissue sampling routines with regard to EGFR-directed therapy of CRC, both in adjuvant and metastatic settings.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Colonic Neoplasms/genetics ; Colonic Neoplasms/pathology ; Colonic Neoplasms/therapy ; ErbB Receptors/antagonists & inhibitors ; ErbB Receptors/metabolism ; Formaldehyde ; Humans ; Middle Aged ; Molecular Targeted Therapy ; Mutation/genetics ; Paraffin Embedding ; Proto-Oncogene Proteins/genetics ; Proto-Oncogene Proteins p21(ras) ; Tissue Fixation ; ras Proteins/genetics
Chemical Substances	KRAS protein, human ; Proto-Oncogene Proteins ; Formaldehyde (1HG84L3525) ; ErbB Receptors (EC 2.7.10.1) ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2) ; ras Proteins (EC 3.6.5.2)
Language	English
Publishing date	2011-05-15
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	84975-3
ISSN	1432-1262 ; 0179-1958
ISSN (online)	1432-1262
ISSN	0179-1958
DOI	10.1007/s00384-011-1233-5
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Article ; Online: The pulmonary effects of STAT3 deficiency.

Gilje, Elizabeth A / Abbott, Jordan K

The Journal of allergy and clinical immunology

2023 Volume 152, Issue 2, Page(s) 368–370

MeSH term(s)	Humans ; Job Syndrome ; Immunoglobulin E ; STAT3 Transcription Factor/genetics ; STAT3 Transcription Factor/metabolism ; Mutation
Chemical Substances	Immunoglobulin E (37341-29-0) ; STAT3 Transcription Factor ; STAT3 protein, human
Language	English
Publishing date	2023-06-16
Publishing country	United States
Document type	Editorial ; Comment
ZDB-ID	121011-7
ISSN	1097-6825 ; 1085-8725 ; 0091-6749
ISSN (online)	1097-6825 ; 1085-8725
ISSN	0091-6749
DOI	10.1016/j.jaci.2023.06.003
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Article: High-fidelity DNA polymerase enhances the sensitivity of a peptide nucleic acid clamp PCR assay for K-ras mutations.

Gilje, Bjørnar / Heikkilä, Reino / Oltedal, Satu / Tjensvoll, Kjersti / Nordgård, Oddmund

The Journal of molecular diagnostics : JMD

2008 Volume 10, Issue 4, Page(s) 325–331

Abstract: ... for the detection of mutations in codons 12 and 13 of the K-ras gene based on a high-fidelity DNA polymerase ...

Abstract	Sensitive detection of tumor-specific point mutations is of interest in both the early detection of cancer and the monitoring of treatment at a molecular level. Recently, peptide nucleic acid (PNA) clamp real-time PCR has provided a time-sparing and sensitive method for the detection of mutations in the presence of a large excess of wild-type DNA. We present the first report that the sensitivity of PNA clamp PCR is limited by the low fidelity of TaqDNA polymerase. Replication errors introduced by Taq polymerase in the PNA-binding site were amplified during PCR due to the resulting mismatches between PNA and DNA. To reduce the frequency of polymerase-induced errors, we developed a PNA clamp PCR assay for the detection of mutations in codons 12 and 13 of the K-ras gene based on a high-fidelity DNA polymerase. The sensitivity of our assay increased approximately 10-fold, significantly detecting mutant DNA diluted 20,000-fold in wild-type DNA (P = 0.025), compared with its detection at 2000-fold dilution (P = 0.039) when Taq polymerase was used. Our data suggest that the replication errors caused by Taq polymerase must be taken into consideration for PNA clamp PCR and for other methods based on selective PCR amplification, and that these assays can be enhanced by high-fidelity DNA polymerases.
MeSH term(s)	Base Sequence ; Cell Line, Tumor ; DNA Mutational Analysis/methods ; DNA-Directed DNA Polymerase/metabolism ; Genes, ras/genetics ; HT29 Cells ; Humans ; Models, Genetic ; Mutation ; Peptide Nucleic Acids/genetics ; Peptide Nucleic Acids/metabolism ; Polymerase Chain Reaction/methods ; Reproducibility of Results ; Taq Polymerase/metabolism
Chemical Substances	Peptide Nucleic Acids ; Taq Polymerase (EC 2.7.7.-) ; DNA-Directed DNA Polymerase (EC 2.7.7.7)
Language	English
Publishing date	2008-06-13
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2000060-1
ISSN	1943-7811 ; 1525-1578
ISSN (online)	1943-7811
ISSN	1525-1578
DOI	10.2353/jmoldx.2008.070183
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Zs.A 5146: Show issues

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Article ; Online: Detection of occult metastases in sentinel lymph nodes from colon cancer patients by K-ras mutation peptide nucleic acid clamp PCR.

Oltedal, Satu / Gilje, Bjørnar / Kørner, Hartwig / Aasprong, Ole Gunnar / Tjensvoll, Kjersti / Heikkilä, Reino / Smaaland, Rune / Nordgård, Oddmund

Annals of surgery

2010 Volume 251, Issue 6, Page(s) 1087–1091

Abstract: ... reaction) assay for K-ras mutations, using these mutations as a surrogate marker for tumor cells ... colon cancer. Of the 158 patients with successful SLN mapping, 67 (42%) had K-ras mutations detected ... in their primary tumors. We analyzed the SLNs from these patients by peptide nucleic acid clamp PCR for K-ras ...

Abstract	Objective: To identify colon cancer patients with occult lymph node metastases. Summary of background data: The prognostic value of regional lymph node (LN) metastases in colorectal cancer patients is well established. The disease recurrences nevertheless experienced by 20% to 30% of the LN negative patients suggest a potential for improvement in current LN diagnostics. We suspect that a subgroup of the patients that are LN negative by routine examination has occult LN metastases that are prognostically relevant. Methods: To identify these patients we applied ex vivo sentinel lymph node (SLN) mapping to colon cancer patients and analyzed the SLNs by a sensitive peptide nucleic acid clamp PCR (polymerase chain reaction) assay for K-ras mutations, using these mutations as a surrogate marker for tumor cells. Results: SLNs were identified in 158 (96%) of 164 prospectively recruited patients with localized colon cancer. Of the 158 patients with successful SLN mapping, 67 (42%) had K-ras mutations detected in their primary tumors. We analyzed the SLNs from these patients by peptide nucleic acid clamp PCR for K-ras mutations and found mutations in SLNs from 35 (52%) patients. At least one SLN from 14 (70%) of 20 patients with histologically proven regional LN metastases was positive for the K-ras mutation test. Interestingly, 21 (45%) of the 47 patients without known LN metastases had K-ras mutations detected in their SLNs. Conclusions: Sensitive detection of K-ras mutations in SLNs from colon cancer patients indicates the presence of occult metastases with potential prognostic implications.
MeSH term(s)	Adenocarcinoma/genetics ; Adenocarcinoma/mortality ; Adenocarcinoma/pathology ; Cell Line, Tumor ; Colonic Neoplasms/genetics ; Colonic Neoplasms/mortality ; Colonic Neoplasms/pathology ; Genes, ras/genetics ; Humans ; Lymphatic Metastasis/diagnosis ; Lymphatic Metastasis/genetics ; Mutation ; Peptide Nucleic Acids ; Polymerase Chain Reaction ; Prognosis ; Sentinel Lymph Node Biopsy ; Survival Rate ; Tumor Cells, Cultured
Chemical Substances	Peptide Nucleic Acids
Language	English
Publishing date	2010-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	340-2
ISSN	1528-1140 ; 0003-4932
ISSN (online)	1528-1140
ISSN	0003-4932
DOI	10.1097/SLA.0b013e3181dae1bc
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Article ; Online: Extracellular vesicles as a potential source of tumor-derived DNA in advanced pancreatic cancer.

Lapin, Morten / Tjensvoll, Kjersti / Nedrebø, Karoline / Taksdal, Eline / Janssen, Hans / Gilje, Bjørnar / Nordgård, Oddmund

PloS one

2023 Volume 18, Issue 9, Page(s) e0291623

Abstract: Tumor-derived extracellular vesicles (EVs) are reported to contain nucleic acids, including DNA. Several studies have highlighted the potential of EV-derived DNA (evDNA) as a circulating biomarker, even demonstrating that evDNA can outperform cell-free ... ...

Abstract	Tumor-derived extracellular vesicles (EVs) are reported to contain nucleic acids, including DNA. Several studies have highlighted the potential of EV-derived DNA (evDNA) as a circulating biomarker, even demonstrating that evDNA can outperform cell-free DNA (cfDNA) in terms of sensitivity. Here, we evaluated EVs as a potential source of tumor-derived DNA in patients with advanced pancreatic cancer. evDNA from both DNase-treated and untreated EV samples was analyzed to determine whether the DNA was primarily located internally or outside (surface-bound) the EVs. To assess whether methodology affected the results, we isolated EVs using four different methods for small EV isolation and differential centrifugation for isolating large EVs. Our results indicated that the DNA content of EVs was significantly less than the cfDNA content isolated from the same plasma volume (p < 0.001). Most of the detected evDNA was also located on the outside of the vesicles. Furthermore, the fraction of tumor-derived DNA in EVs was similar to that found in cfDNA. In conclusion, our results suggest that quantification of evDNA, as a source of tumor-derived DNA, does not add information to that obtained with cfDNA, at least not in patients with advanced pancreatic cancer.
MeSH term(s)	Humans ; DNA ; Nucleic Acids ; Cell-Free Nucleic Acids ; Extracellular Vesicles ; Pancreatic Neoplasms/genetics ; Pancreatic Neoplasms
Chemical Substances	DNA (9007-49-2) ; Nucleic Acids ; Cell-Free Nucleic Acids
Language	English
Publishing date	2023-09-14
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0291623
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Article ; Online: Impact of extent of resection on outcome from glioblastoma using the RANO resect group classification system: a retrospective, population-based cohort study.

Bjorland, Line Sagerup / Mahesparan, Rupavathana / Fluge, Øystein / Gilje, Bjørnar / Dæhli Kurz, Kathinka / Farbu, Elisabeth

Neuro-oncology advances

2023 Volume 5, Issue 1, Page(s) vdad126

Abstract: Background: Extent of resection (EOR) is associated with survival in glioblastoma. A standardized classification for EOR was lacking until a system was recently proposed by the response assessment in neuro-oncology (RANO) resect group. We aimed to ... ...

Abstract	Background: Extent of resection (EOR) is associated with survival in glioblastoma. A standardized classification for EOR was lacking until a system was recently proposed by the response assessment in neuro-oncology (RANO) resect group. We aimed to assess EOR in an unselected glioblastoma cohort and use this classification system to evaluate the impact on survival in a real-world setting. Methods: We retrospectively identified all patients with histologically confirmed glioblastoma in Western Norway between 1.1.2007 and 31.12.2014. Volumetric analyses were performed using a semi-automated method. EOR was categorized according to the recent classification system. Kaplan-Meier method and Cox proportional hazard ratios were applied for survival analyses. Results: Among 235 included patients, biopsy (EOR class 4) was performed in 50 patients (21.3%), submaximal contrast enhancement (CE) resection (EOR class 3) in 66 patients (28.1%), and maximal CE resection (EOR class 2) in 119 patients (50.6%). Median survival was 6.2 months, 9.2 months, and 14.9 months, respectively. Within EOR class 2, 80 patients underwent complete CE resection (EOR class 2A) and had a median survival of 20.0 months, while 39 patients had a near-total CE resection, with ≤1 cm Conclusions: RANO resect group classification for the extent of resection reflected outcome from glioblastoma in a real-world setting. There was significantly superior survival after complete CE resection compared to near-total resection.
Language	English
Publishing date	2023-09-26
Publishing country	England
Document type	Journal Article
ZDB-ID	3009682-0
ISSN	2632-2498 ; 2632-2498
ISSN (online)	2632-2498
ISSN	2632-2498
DOI	10.1093/noajnl/vdad126
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Book ; Online: Sensitivity and Discovery Potential of the PROSPECT Experiment

Gilje, Karin

2015

Abstract: Measurements of the reactor antineutrino flux and spectrum compared to model predictions have revealed an apparent deficit in the interaction rates of reactor antineutrinos and an unexpected spectral deviation. PROSPECT, the Precision Reactor Oscillation ...

Abstract	Measurements of the reactor antineutrino flux and spectrum compared to model predictions have revealed an apparent deficit in the interaction rates of reactor antineutrinos and an unexpected spectral deviation. PROSPECT, the Precision Reactor Oscillation Spectrum measurement, is designed to make a precision measurement of the antineutrino spectrum from a research reactor and search for signs of an eV-scale sterile neutrino. PROSPECT will be located at the High Flux Isotope Reactor (HFIR) at Oak Ridge National Laboratory and make use of a Highly Enriched Uranium reactor for a measurement of the pure U-235 antineutrino spectrum. An absolute measurement of this spectrum will constrain reactor models and improve our understanding of the reactor antineutrino spectrum. Additionally, the planned 3-ton lithium-doped liquid scintillator detector is ideally suited to perform a search for sterile neutrinos. This talk will focus on the sensitivity and discovery potential of PROSPECT and the detector design to achieve these goals. Comment: Presentation at the DPF 2015 Meeting of the American Physical Society Division of Particles and Fields, Ann Arbor, Michigan, August 4-8, 2015
Keywords	Physics - Instrumentation and Detectors ; High Energy Physics - Experiment
Subject code	660
Publishing date	2015-10-31
Publishing country	us
Document type	Book ; Online
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Article ; Online: Monitoring of circulating tumour DNA in advanced pancreatic ductal adenocarcinoma predicts clinical outcome and reveals disease progression earlier than radiological imaging.

Edland, Karin Hestnes / Tjensvoll, Kjersti / Oltedal, Satu / Dalen, Ingvild / Lapin, Morten / Garresori, Herish / Glenjen, Nils / Gilje, Bjørnar / Nordgård, Oddmund

Molecular oncology

2023 Volume 17, Issue 9, Page(s) 1857–1870

Abstract: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with a need for better tools to guide treatment selection and follow-up. The aim of this prospective study was to investigate the prognostic value and treatment monitoring potential of ... ...

Abstract	Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with a need for better tools to guide treatment selection and follow-up. The aim of this prospective study was to investigate the prognostic value and treatment monitoring potential of longitudinal circulating tumour DNA (ctDNA) measurements in patients with advanced PDAC undergoing palliative chemotherapy. Using KRAS peptide nucleic acid clamp-PCR, we measured ctDNA levels in plasma samples obtained at baseline and every 4 weeks during chemotherapy from 81 patients with locally advanced and metastatic PDAC. Cox proportional hazard regression showed that ctDNA detection at baseline was an independent predictor of progression-free and overall survival. Joint modelling demonstrated that the dynamic ctDNA level was a strong predictor of time to first disease progression. Longitudinal ctDNA measurements during chemotherapy successfully revealed disease progression in 20 (67%) of 30 patients with ctDNA detected at baseline, with a median lead time of 23 days (P = 0.01) over radiological imaging. Here, we confirmed the clinical relevance of ctDNA in advanced PDAC with regard to both the prediction of clinical outcome and disease monitoring during treatment.
MeSH term(s)	Humans ; Circulating Tumor DNA/genetics ; Prospective Studies ; Mutation ; Pancreatic Neoplasms/diagnostic imaging ; Pancreatic Neoplasms/drug therapy ; Pancreatic Neoplasms/genetics ; Carcinoma, Pancreatic Ductal/diagnostic imaging ; Carcinoma, Pancreatic Ductal/drug therapy ; Carcinoma, Pancreatic Ductal/genetics ; Disease Progression ; Biomarkers, Tumor/genetics ; Pancreatic Neoplasms
Chemical Substances	Circulating Tumor DNA ; Biomarkers, Tumor
Language	English
Publishing date	2023-06-28
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2415106-3
ISSN	1878-0261 ; 1574-7891
ISSN (online)	1878-0261
ISSN	1574-7891
DOI	10.1002/1878-0261.13472
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Article ; Online: Comprehensive ctDNA Measurements Improve Prediction of Clinical Outcomes and Enable Dynamic Tracking of Disease Progression in Advanced Pancreatic Cancer.

Lapin, Morten / Edland, Karin H / Tjensvoll, Kjersti / Oltedal, Satu / Austdal, Marie / Garresori, Herish / Rozenholc, Yves / Gilje, Bjørnar / Nordgård, Oddmund

Clinical cancer research : an official journal of the American Association for Cancer Research

2023 Volume 29, Issue 7, Page(s) 1267–1278

Abstract: Purpose: Circulating tumor DNA (ctDNA) has emerged as a promising tumor-specific biomarker in pancreatic cancer, but current evidence of the clinical potential of ctDNA is limited. In this study, we used comprehensive detection methodology to explore ... ...

Abstract	Purpose: Circulating tumor DNA (ctDNA) has emerged as a promising tumor-specific biomarker in pancreatic cancer, but current evidence of the clinical potential of ctDNA is limited. In this study, we used comprehensive detection methodology to explore the utility of longitudinal ctDNA measurements in patients with advanced pancreatic cancer. Experimental design: A targeted eight-gene next-generation sequencing panel was used to detect point mutations and copy-number aberrations (CNA) in ctDNA from 324 pre-treatment and longitudinal plasma samples obtained from 56 patients with advanced pancreatic cancer. The benefit of ctDNA measurements to predict clinical outcome and track disease progression was assessed. Results: We detected ctDNA in 35/56 (63%) patients at baseline and found that it was an independent predictor of shorter progression-free survival (PFS) and overall survival (OS). After initiation of treatment, ctDNA levels decreased significantly before significantly increasing by the time of progression. In some patients, ctDNA persistence was observed after the first chemotherapy cycles, and it was associated with rapid disease progression and shorter OS. Longitudinal monitoring of ctDNA levels in 27 patients for whom multiple samples were available detected progression in 19 (70%) patients. The median lead time of ctDNA measurements on radiologically determined progression/time of death was 19 days (P = 0.002), compared with 6 days (P = 0.007) using carbohydrate antigen 19-9. Conclusions: ctDNA is an independent prognostic marker that can be used to detect treatment failure and disease progression in patients with advanced pancreatic cancer.
MeSH term(s)	Humans ; Prognosis ; Circulating Tumor DNA/genetics ; Mutation ; Pancreatic Neoplasms/drug therapy ; Pancreatic Neoplasms/genetics ; Pancreatic Neoplasms/pathology ; Disease Progression ; Biomarkers, Tumor ; Pancreatic Neoplasms
Chemical Substances	Circulating Tumor DNA ; Biomarkers, Tumor
Language	English
Publishing date	2023-01-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-22-3526
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