TY - JOUR

T1 - In vivo imaging of cell proliferation in meningioma using 3 '-deoxy-3 '-[F-18]fluorothymidine PET/MRI

AU - Bashir, Asma

AU - Binderup, Tina

AU - Vestergaard, Mark Bitsch

AU - Broholm, Helle

AU - Marner, Lisbeth

AU - Ziebell, Morten

AU - Fugleholm, Kåre

AU - Kjaer, Andreas

AU - Law, Ian

PY - 2020

Y1 - 2020

N2 - Purpose Positron emission tomography (PET) with 3 '-deoxy-3 '-[F-18]fluorothymidine ([F-18]FLT) provides a noninvasive assessment of tumour proliferation in vivo and could be a valuable imaging modality for assessing malignancy in meningiomas. We investigated a range of static and dynamic [F-18]FLT metrics by correlating the findings with cellular biomarkers of proliferation and angiogenesis. Methods Seventeen prospectively recruited adult patients with intracranial meningiomas underwent a 60-min dynamic [F-18]FLT PET following surgery. Maximum and mean standardized uptake values (SUVmax, SUVmean) with and without normalization to healthy brain tissue and blood radioactivity obtained from 40 to 60 min summed dynamic images (PET40-60) and 60-min blood samples were calculated. Kinetic modelling using a two-tissue reversible compartmental model with a fractioned blood volume (V-B) was performed to determine the total distribution volume (V-T). Expressions of proliferation and angiogenesis with key parameters including Ki-67 index, phosphohistone-H3 (phh3), MKI67, thymidine kinase 1 (TK1), proliferating cell nuclear antigen (PCNA), Kirsten RAt Sarcoma viral oncogene homolog (KRAS), TIMP metallopeptidase inhibitor 3 (TIMP3), and vascular endothelial growth factor A (VEGFA) were determined by immunohistochemistry and/or quantitative polymerase chain reaction. Results Immunohistochemistry revealed 13 World Health Organization (WHO) grade I and four WHO grade II meningiomas. SUVmax and SUVmean normalized to blood radioactivity from PET40-60 and blood sampling, and V-T were able to significantly differentiate between WHO grades with the best results for maximum and mean tumour-to-whole-blood ratios (sensitivity 100%, specificity 94-95%, accuracy 99%; P = 0.003). Static [F-18]FLT metrics were significantly correlated with proliferative biomarkers, especially Ki-67 index, phh3, and TK1, while no correlations were found with VEGFA or V-B. Using Ki-67 index with a threshold > 4%, the majority of [F-18]FLT metrics showed a high ability to identify aggressive meningiomas with SUVmean demonstrating the best performance (sensitivity 80%, specificity 81%, accuracy 80%; P = 0.024). Conclusion [F-18]FLT PET could be a useful imaging modality for assessing cellular proliferation in meningiomas.

AB - Purpose Positron emission tomography (PET) with 3 '-deoxy-3 '-[F-18]fluorothymidine ([F-18]FLT) provides a noninvasive assessment of tumour proliferation in vivo and could be a valuable imaging modality for assessing malignancy in meningiomas. We investigated a range of static and dynamic [F-18]FLT metrics by correlating the findings with cellular biomarkers of proliferation and angiogenesis. Methods Seventeen prospectively recruited adult patients with intracranial meningiomas underwent a 60-min dynamic [F-18]FLT PET following surgery. Maximum and mean standardized uptake values (SUVmax, SUVmean) with and without normalization to healthy brain tissue and blood radioactivity obtained from 40 to 60 min summed dynamic images (PET40-60) and 60-min blood samples were calculated. Kinetic modelling using a two-tissue reversible compartmental model with a fractioned blood volume (V-B) was performed to determine the total distribution volume (V-T). Expressions of proliferation and angiogenesis with key parameters including Ki-67 index, phosphohistone-H3 (phh3), MKI67, thymidine kinase 1 (TK1), proliferating cell nuclear antigen (PCNA), Kirsten RAt Sarcoma viral oncogene homolog (KRAS), TIMP metallopeptidase inhibitor 3 (TIMP3), and vascular endothelial growth factor A (VEGFA) were determined by immunohistochemistry and/or quantitative polymerase chain reaction. Results Immunohistochemistry revealed 13 World Health Organization (WHO) grade I and four WHO grade II meningiomas. SUVmax and SUVmean normalized to blood radioactivity from PET40-60 and blood sampling, and V-T were able to significantly differentiate between WHO grades with the best results for maximum and mean tumour-to-whole-blood ratios (sensitivity 100%, specificity 94-95%, accuracy 99%; P = 0.003). Static [F-18]FLT metrics were significantly correlated with proliferative biomarkers, especially Ki-67 index, phh3, and TK1, while no correlations were found with VEGFA or V-B. Using Ki-67 index with a threshold > 4%, the majority of [F-18]FLT metrics showed a high ability to identify aggressive meningiomas with SUVmean demonstrating the best performance (sensitivity 80%, specificity 81%, accuracy 80%; P = 0.024). Conclusion [F-18]FLT PET could be a useful imaging modality for assessing cellular proliferation in meningiomas.

KW - Meningioma

KW - [F-18]FLT

KW - Thymidine kinase 1

KW - Ki-67 index

KW - KI-67 IMMUNOHISTOCHEMISTRY

KW - MATRIX METALLOPROTEINASE-2

KW - RESPONSE ASSESSMENT

KW - BRAIN-TUMORS

KW - FLT-PET/CT

KW - RECURRENCE

KW - EXPRESSION

KW - KINETICS

KW - GRADE

KW - F-18

U2 - 10.1007/s00259-020-04704-2

DO - 10.1007/s00259-020-04704-2

M3 - Journal article

C2 - 32047966

VL - 47

SP - 1496

EP - 1509

JO - European Journal of Nuclear Medicine and Molecular Imaging

JF - European Journal of Nuclear Medicine and Molecular Imaging

SN - 1619-7070

ER -