Concordance Among Pathologists in the Second Cardiac Allograft Rejection Gene Expression Observational Study (CARGO II)

Crespo-Leiro, María G.; Zuckermann, Andreas; Bara, Christoph; Mohaçsi, Paul; Schulz, Uwe; Boyle, Andrew; Ross, Heather J.; Parameshwar, Jayan; Zakliczyński, Michał; Fiocchi, R; Stypmann, Joerg; Hoefer, Daniel; Lehmkuhl, H.; Deng, Mario C.; Leprince, Pascal; Berry, Gerald J.; Marboe, Charles C.; Stewart, Susan; Tazelaar, Henry D.; Baron, Helen; Coleman, Ian Charles; Vanhaecke, Johan

doi:10.1097/tp.0b013e31826e19e2

Cited by 151 publications

(133 citation statements)

References 12 publications

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“…Substantial interobserver variability exists in the grading of heart biopsies (2, 14), and acute rejection may be missed when taking small biopsies of myocardial tissue, owing to the inhomogeneous nature of inflammatory infiltrates and graft damage. The concordance of biopsy interpretation among cardiac pathologists was examined in the context of the CARGO II study (14): the overall, all-grade agreement was found to be 71%, and the positive agreement for biopsies assigned a grade ≥2R was less than 30%. It is possible to infer a sensitivity and a selectivity for the biopsy from these observed rates of concordance.…”

Section: Discussionmentioning

confidence: 99%

“…It is possible to infer a sensitivity and a selectivity for the biopsy from these observed rates of concordance. Considering all biopsies graded 0 and 1R as negative and biopsies graded ≥2R as positive, the estimated sensitivity of biopsy is 0.58 and the selectivity is 0.96 [data in Table 1 and (14)]. In comparing our cfdDNA data with biopsy, using a threshold of 0.25%, we find a sensitivity of 0.58 and a selectivity of 0.87 (also considering 0 and 1R biopsies together as negative and ≥2R as positive).…”

Section: Discussionmentioning

confidence: 99%

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Circulating Cell-Free DNA Enables Noninvasive Diagnosis of Heart Transplant Rejection

et al. 2014

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Monitoring allograft health is an important component of posttransplant therapy. Endomyocardial biopsy is the current gold standard for cardiac allograft monitoring but is an expensive and invasive procedure. Proof of principle of a universal, noninvasive diagnostic method based on high-throughput screening of circulating cell-free donor-derived DNA (cfdDNA) was recently demonstrated in a small retrospective cohort. We present the results of a prospective cohort study (65 patients, 565 samples) that tested the utility of cfdDNA in measuring acute rejection after heart transplantation. Circulating cell-free DNA was purified from plasma and sequenced (mean depth, 1.2 giga–base pairs) to quantify the fraction of cfdDNA. Through a comparison with endomyocardial biopsy results, we demonstrate that cfdDNA enables diagnosis of acute rejection after heart transplantation, with an area under the receiver operating characteristic curve of 0.83 and sensitivity and specificity that are comparable to the intrinsic performance of the biopsy itself. This noninvasive genome transplant dynamics approach is a powerful and informative method for routine monitoring of allograft health without incurring the risk, discomfort, and expense of an invasive biopsy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Circulating Cell-Free DNA Enables Noninvasive Diagnosis of Heart Transplant Rejection

et al. 2014

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“…32,33 Endomyocardial biopsies scored according to the working formulation of 1990 were reclassified based on the revised working formulation of 2004. To avoid bias introduced by different pathologists, 34 all included samples were scored by the same team of pathologists. According to the ISHLT definition of rejection, only patients with an EMB scored as a rejection grade ≥ 2R were considered to experience a clinically relevant AR, which was treated with antirejection therapy consisting of 1 g methylprednisolone on three consecutive days.…”

Section: Study Populationmentioning

confidence: 99%

Thymus-Derived Regulatory T Cells Infiltrate the Cardiac Allograft Before Rejection

et al. 2015

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“…For instance, the AlloMap (CareDx, Brisbane, CA) can be used to reduce the frequency of biopsy without altering clinical outcomes (29). In addition, sampling error can be an issue with endomyocardial biopsy and pathological interpretation of biopsies is subject to bias and significant intra-observer variability (30, 31). We believe that [ 18 F]PET is less subject to sampling bias and provides a quantitative means to assess rejection throughout the entire graft.…”

Section: Discussionmentioning

confidence: 99%

Use of [18F]FDG Positron Emission Tomography to Monitor the Development of Cardiac Allograft Rejection

et al. 2015

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Background Positron Emission Tomography (PET) has the potential to be a specific, sensitive and quantitative diagnostic test for transplant rejection. To test this hypothesis, we evaluated 18F-labeled fluorodeoxyglucose ([18F]FDG) and 13N-labeled ammonia ([13N]NH3) small animal PET imaging in a well-established murine cardiac rejection model. Methods Heterotopic transplants were performed using minor MHC mismatched B6.C-H2bm12 donor hearts in C57BL/6(H-2b) recipients. C57BL/6 donor hearts into C57BL/6 recipients served as isograft controls. [18F]FDG PET imaging was performed weekly between post-transplant days 7 and 42 and the percent injected dose was computed for each graft. [13N]NH3 imaging was performed to evaluate myocardial perfusion. Results There was a significant increase in [18F]FDG uptake in allografts from day 14 to day 21 (1.6% to 5.2%; P<0.001) and uptake in allografts was significantly increased on post-transplant days 21 (5.2% vs. 0.9%; P=0.005) and 28 (4.8% vs. 0.9%; P=0.006) compared to isograft controls. Furthermore, [18F]FDG uptake correlated with an increase in rejection within allografts between days 14 and 28 post-transplant. Finally, the uptake of [13N]NH3 was significantly lower relative to the native heart in allografts with chronic vasculopathy compared to isograft controls on day 28 (P=0.01). Conclusions PET imaging with [18F]FDG can be used following transplantation to monitor the evolution of rejection. In addition, decreased uptake of [13N]NH3 in rejecting allografts may be reflective of decreased myocardial blood flow. These data suggest that combined [18F]FDG and [13N]NH3 PET imaging could be used as a non-invasive, quantitative technique for serial monitoring of allograft rejection and has potential application in human transplant recipients.

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Concordance Among Pathologists in the Second Cardiac Allograft Rejection Gene Expression Observational Study (CARGO II)

Cited by 151 publications

References 12 publications

Circulating Cell-Free DNA Enables Noninvasive Diagnosis of Heart Transplant Rejection

Circulating Cell-Free DNA Enables Noninvasive Diagnosis of Heart Transplant Rejection

Thymus-Derived Regulatory T Cells Infiltrate the Cardiac Allograft Before Rejection

Use of [18F]FDG Positron Emission Tomography to Monitor the Development of Cardiac Allograft Rejection

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