Quantitative accuracy of positron emission tomography/magnetic resonance and positron emission tomography/computed tomography for cervical cancer.

With the spread of positron emission tomography/magnetic resonance (PET/MR), the question of comparability of studies becomes important. We aim to determine whether PET/MR and PET/computed tomography (PET/CT) are comparable for the case of cervical cancer. Fifteen cervical cancer patients identified by either a radiation oncologist or an oncologic surgeon had both PET/MR and PET/CT performed for initial staging within 3 weeks. We then compared the results both quantitatively (measuring standardized uptake values [SUVs] on visible lesions) as well as qualitatively (having radiologists and nuclear medicine physicians interprets the results). While interpretations between PET/MR and PET/CT varied in many cases, SUVs of primary lesions were similar to within 25% in all but one case, and correlation coefficient was 0.92. Maximum SUV ranged between 4.9 and 25.2 for PET-MR and between 5.8 and 30.4 for PET-CT for primary tumors and between 1.5 and 18.8 for PET-MR and between 1.8 and 20.8 for PET-CT for nodes. However, clinical reads often varied significantly between PET/MR and PET/CT. This suggests that SUV is similar on PET/MR and PET/CT although the differing anatomic modalities available for correlation may make the difference in terms of qualitative interpretation.

Evaluation of PET/MRI for Tumor Volume Delineation for Head and Neck Cancer.

INTRODUCTION: Computed tomography (CT), combined positron emitted tomography and CT (PET/CT), and magnetic resonance imaging (MRI) are commonly used in head and neck radiation planning. Hybrid PET/MRI has garnered attention for potential added value in cancer staging and treatment planning. Herein, we compare PET/MRI vs. planning CT for head and neck cancer gross tumor volume (GTV) delineation. MATERIAL AND METHODS: We prospectively enrolled patients with head and neck cancer treated with definitive chemoradiation to 60-70 Gy using IMRT. We performed pretreatment contrast-enhanced planning CT and gadolinium-enhanced PET/MRI. Primary and nodal volumes were delineated on planning CT (GTV-CT) prospectively before treatment and PET/MRI (GTV-PET/MRI) retrospectively after treatment. GTV-PET/MRI was compared to GTV-CT using separate rigid registrations for each tumor volume. The Dice similarity coefficient (DSC) metric evaluating spatial overlap and modified Hausdorff distance (mHD) evaluating mean orthogonal distance difference were calculated. Minimum dose to 95% of GTVs (D95) was compared. RESULTS: Eleven patients were evaluable (10 oropharynx, 1 larynx). Nine patients had evaluable primary tumor GTVs and seven patients had evaluable nodal GTVs. Mean primary GTV-CT and GTV-PET/MRI size were 13.2 and 14.3 cc, with mean intersection 8.7 cc, DSC 0.63, and mHD 1.6 mm. D95 was 65.3 Gy for primary GTV-CT vs. 65.2 Gy for primary GTV-PET/MRI. Mean nodal GTV-CT and GTV-PET/MRI size were 19.0 and 23.0 cc, with mean intersection 14.4 cc, DSC 0.69, and mHD 2.3 mm. D95 was 62.3 Gy for both nodal GTV-CT and GTV-PET/MRI. CONCLUSION: In this series of patients with head and neck (primarily oropharynx) cancer, PET/MRI and CT-GTVs had similar volumes (though there were individual cases with larger differences) with overall small discrepancies in spatial overlap, small mean orthogonal distance differences, and similar radiation doses.

Alternate Metabolic Programs Define Regional Variation of Relevant Biological Features in Renal Cell Carcinoma Progression.

PURPOSE: Clear cell renal cell carcinoma (ccRCC) has recently been redefined as a highly heterogeneous disease. In addition to genetic heterogeneity, the tumor displays risk variability for developing metastatic disease, therefore underscoring the urgent need for tissue-based prognostic strategies applicable to the clinical setting. We have recently employed the novel PET/magnetic resonance (MR) image modality to enrich our understanding of how tumor heterogeneity can relate to gene expression and tumor biology to assist in defining individualized treatment plans. EXPERIMENTAL DESIGN: ccRCC patients underwent PET/MR imaging, and these images subsequently used to identify areas of varied intensity for sampling. Samples from 8 patients were subjected to histologic, immunohistochemical, and microarray analysis. RESULTS: Tumor subsamples displayed a range of heterogeneity for common features of hypoxia-inducible factor expression and microvessel density, as well as for features closely linked to metabolic processes, such as GLUT1 and FBP1. In addition, gene signatures linked with disease risk (ccA and ccB) also demonstrated variable heterogeneity, with most tumors displaying a dominant panel of features across the sampled regions. Intriguingly, the ccA- and ccB-classified samples corresponded with metabolic features and functional imaging levels. These correlations further linked a variety of metabolic pathways (i.e., the pentose phosphate and mTOR pathways) with the more aggressive, and glucose avid ccB subtype. CONCLUSIONS: Higher tumor dependency on exogenous glucose accompanies the development of features associated with the poor risk ccB subgroup. Linking these panels of features may provide the opportunity to create functional maps to enable enhanced visualization of the heterogeneous biologic processes of an individual's disease. Clin Cancer Res; 22(12); 2950-9. ©2016 AACR.

Hemogenic endothelial cell specification requires c-Kit, Notch signaling, and p27-mediated cell-cycle control.

Delineating the mechanism or mechanisms that regulate the specification of hemogenic endothelial cells from primordial endothelium is critical for optimizing their derivation from human stem cells for clinical therapies. We previously determined that retinoic acid (RA) is required for hemogenic specification, as well as cell-cycle control, of endothelium during embryogenesis. Herein, we define the molecular signals downstream of RA that regulate hemogenic endothelial cell development and demonstrate that cell-cycle control is required for this process. We found that re-expression of c-Kit in RA-deficient (Raldh2(-/-)) primordial endothelium induced Notch signaling and p27 expression, which restored cell-cycle control and rescued hemogenic endothelial cell specification and function. Re-expression of p27 in RA-deficient and Notch-inactivated primordial endothelial cells was sufficient to correct their defects in cell-cycle regulation and hemogenic endothelial cell development. Thus, RA regulation of hemogenic endothelial cell specification requires c-Kit, notch signaling, and p27-mediated cell-cycle control.

Mdm2 is required for survival of hematopoietic stem cells/progenitors via dampening of ROS-induced p53 activity.

Mdm2 is an E3 ubiquitin ligase that targets p53 for degradation. p53(515C) (encoding p53R172P) is a hypomorphic allele of p53 that rescues the embryonic lethality of Mdm2(-/-) mice. Mdm2(-/-) p53(515C/515C) mice, however, die by postnatal day 13 resulting from hematopoietic failure. Hematopoietic stem cells and progenitors of Mdm2(-/-) p53(515C/515C) mice were normal in fetal livers but were depleted in postnatal bone marrows. After birth, these mice had elevated reactive oxygen species (ROS) thus activating p53R172P. In the absence of Mdm2, stable p53R172P induced ROS and cell cycle arrest, senescence, and cell death in the hematopoietic compartment. This phenotype was partially rescued with antioxidant treatment and upon culturing of hematopoietic cells in methycellulose at 3% oxygen. p16 was also stabilized because of ROS, and its loss increased cell cycling and partially rescued hematopoiesis and survival. Thus, Mdm2 is required to control ROS-induced p53 levels for sustainable hematopoiesis.