Radiation Necrosis, Pseudoprogression, Pseudoresponse, and Tumor Recurrence: Imaging Challenges for the Evaluation of Treated Gliomas

Zikou, Anastasia; Sioka, Chrissa; Alexiou, George Α.; Fotopoulos, Andreas; Voulgaris, Spyridon; Argyropoulou, Maria I.

doi:10.1155/2018/6828396

Cited by 175 publications

(157 citation statements)

References 61 publications

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“…A post-RT decrease in mode_ADC_FLAIR was significantly lower in those showing pseudoprogression compared with those who went on to show true early progression in our study. While pseudoprogression is well-documented in adult gliblastomas treated with RT + TMZ, typically seen within the first 3 months after radiation, 33 there are very few reports on DIPG. Chassot et al 34 reported 4/22 (18%) cases of pseudoprogression in children with DIPG treated with RT + TMZ and found no difference in overall survival between pseudoprogression and true progression cases.…”

Section: Discussionmentioning

confidence: 99%

Advanced ADC Histogram, Perfusion, and Permeability Metrics Show an Association with Survival and Pseudoprogression in Newly Diagnosed Diffuse Intrinsic Pontine Glioma: A Report from the Pediatric Brain Tumor Consortium

Vajapeyam

Brown

Billups³

et al. 2020

AJNR Am J Neuroradiol

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BACKGROUND AND PURPOSE: Diffuse intrinsic pontine glioma is a lethal childhood brain cancer with dismal prognosis and MR imaging is the primary methodology used for diagnosis and monitoring. Our aim was to determine whether advanced diffusion, perfusion, and permeability MR imaging metrics predict survival and pseudoprogression in children with newly diagnosed diffuse intrinsic pontine glioma. MATERIALS AND METHODS: A clinical trial using the poly (adenosine diphosphate ribose) polymerase (PARP) inhibitor veliparib concurrently with radiation therapy, followed by maintenance therapy with veliparib + temozolomide, in children with diffuse intrinsic pontine glioma was conducted by the Pediatric Brain Tumor Consortium. Standard MR imaging, DWI, dynamic contrast-enhanced perfusion, and DSC perfusion were performed at baseline and approximately every 2 months throughout treatment. ADC histogram metrics of T2-weighted FLAIR and enhancing tumor volume, dynamic contrast-enhanced permeability metrics for enhancing tumors, and tumor relative CBV from DSC perfusion MR imaging were calculated. Baseline values, post-radiation therapy changes, and longitudinal trends for all metrics were evaluated for associations with survival and pseudoprogression. RESULTS: Fifty children were evaluable for survival analyses. Higher baseline relative CBV was associated with shorter progression-free survival (P ¼ .02, Q ¼ 0.089) and overall survival (P ¼ .006, Q ¼ 0.055). Associations of higher baseline mean transfer constant from the blood plasma into the extravascular extracellular space with shorter progression-free survival (P ¼ .03, Q ¼ 0.105) and overall survival (P ¼ .03, Q ¼ 0.102) trended toward significance. An increase in relative CBV with time was associated with shorter progression-free survival (P , .001, Q , 0.001) and overall survival (P ¼ .004, Q ¼ 0.043). Associations of longitudinal mean extravascular extracellular volume fraction with progression-free survival (P ¼ .03, Q ¼ 0.104) and overall survival (P ¼ .03, Q ¼ 0.105) and maximum transfer constant from the blood plasma into the extravascular extracellular space with progression-free survival (P ¼ .03, Q ¼ 0.102) trended toward significance. Greater increases with time were associated with worse outcomes. True radiologic progression showed greater post-radiation therapy decreases in mode_ADC_FLAIR compared with pseudoprogression (means, À268.15 versus À26.11, P ¼ .01.) CONCLUSIONS: ADC histogram, perfusion, and permeability MR imaging metrics in diffuse intrinsic pontine glioma are useful in predicting survival and pseudoprogression. ABBREVIATIONS: DCE ¼ dynamic contrast-enhanced; DIPG ¼ diffuse intrinsic pontine glioma; K ep ¼ rate constant from extravascular extracellular space back into blood plasma; K trans ¼ transfer constant from blood plasma into extravascular extracellular space; OS ¼ overall survival; PBTC ¼ Pediatric Brain Tumor Consortium; PFS ¼ progression-free survival; rCBV ¼ relative CBV; RT ¼ radiation therapy; TMZ ¼ temozolomide; v e ¼ extravascular ext...

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Section: Discussionmentioning

confidence: 99%

Advanced ADC Histogram, Perfusion, and Permeability Metrics Show an Association with Survival and Pseudoprogression in Newly Diagnosed Diffuse Intrinsic Pontine Glioma: A Report from the Pediatric Brain Tumor Consortium

Vajapeyam

Brown

Billups³

et al. 2020

AJNR Am J Neuroradiol

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“…Considering previous work showing that the ratio of [1-13 C]glycine to total HP signal (γ-glutamyl-[1-13 C]glycine plus [1-13 C]glycine) is positively correlated with GGT activity 31 , previous studies showing higher levels of GGT in U87 glioma cells compare to normal brain 19 , and our observation that higher HP [1-13 C]glycine production in tumor was associated with higher GGT expression in tumor tissue, our results collectively point to the potential of γ-glutamyl-[1-13 C]glycine as a HP probe to detect brain tumor in vivo in real time. Furthermore, tumor therapy, and in particular radiation, can lead to "pseudoprogression" -MRI changes that cannot easily distinguish between tumor recurrence and treatment effects [58][59][60] . Because HP γ-glutamyl-[1-13 C]glycine detects a molecular event specific to tumor, it could also help in evaluating treatment outcome.…”

Section: Discussionmentioning

confidence: 99%

In vivo detection of γ-glutamyl-transferase up-regulation in glioma using hyperpolarized γ-glutamyl-[1-13C]glycine

Batsios

Najac

Cao

et al. 2020

Sci Rep

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Glutathione (GSH) is often upregulated in cancer, where it serves to mitigate oxidative stress. γ-glutamyl-transferase (GGT) is a key enzyme in GSH homeostasis, and compared to normal brain its expression is elevated in tumors, including in primary glioblastoma. GGT is therefore an attractive imaging target for detection of glioblastoma. The goal of our study was to assess the value of hyperpolarized (HP) γ-glutamyl-[1-13 C]glycine for non-invasive imaging of glioblastoma. Nude rats bearing orthotopic U87 glioblastoma and healthy controls were investigated. Imaging was performed by injecting HP γ-glutamyl-[1-13 c]glycine and acquiring dynamic 13 C data on a preclinical 3T MR scanner. The signal-to-noise (SNR) ratios of γ-glutamyl-[1-13 C]glycine and its product [1-13 c]glycine were evaluated. Comparison of control and tumor-bearing rats showed no difference in γ-glutamyl-[1-13 C]glycine SNR, pointing to similar delivery to tumor and normal brain. In contrast, [1-13 c]glycine SnR was significantly higher in tumor-bearing rats compared to controls, and in tumor regions compared to normal-appearing brain. Importantly, higher [1-13 C]glycine was associated with higher GGT expression and higher GSH levels in tumor tissue compared to normal brain. Collectively, this study demonstrates, to our knowledge for the first time, the feasibility of using HP γ-glutamyl-[1-13 c]glycine to monitor GGt expression in the brain and thus to detect glioblastoma.Redox homeostasis is essential for managing oxidative stress and ensuring cell survival. Cancer cells, in particular, are often characterized by high levels of oxidative stress. This oxidative stress is the result of reactive oxygen species (ROS) that accumulate due to a variety of factors, including rapid cell proliferation, hypoxia, metabolic reprogramming and oncogenic signaling. The tripeptide glutathione (L-γ-glutamyl-L-cysteinyl-glycine, GSH) is the most abundant, non-enzymatic antioxidant molecule present in mammalian cells and plays a crucial role in regulating tumor oxidative stress due to its role in reducing ROS 1,2 . Several tumor types, including primary glioblastomas (GBMs), are characterized by elevated GSH levels, especially under hypoxic conditions 3 . Elevated GSH levels and reduced oxidative stress have also been linked to resistance to chemotherapy in GBMs 4 .GSH import is a critical step in the maintenance of both intracellular and extracellular redox status 5,6 . Although GSH can be transported out of cells and into the extracellular environment, most cells are incapable of importing intact GSH 7 . Instead, GSH is first degraded to its constituent amino acids 7,8 and the released amino acids are then transported into the cell and used as substrates for de novo GSH synthesis 6 . Specifically, GSH degradation is initiated by cleavage of the gamma-glutamyl bond 9 via the cell surface-bound glycoprotein gamma-glutamyl transpeptidase (GGT) whose catalytic site faces the extracellular environment 7,10-12 . After removal of the glutamyl group from GSH, cysteinylg...

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“…The aim of PET/CT in this kind of patients and of molecular imaging more in general is to assess metabolically active lesions that are not necessarily evident on structural MRI [33]. In fact, on follow-up imaging it cannot clearly distinguish between recurrence and necrosis whereas PET, providing in vivo metabolic information, will show intense metabolic activity in case of recurrence and photopenia or reduced uptake of the tracer in the interested region in case of radiation necrosis [34].…”

Section: Diagnostic Imaging and Nuclear Medicine In Brain Tumorsmentioning

confidence: 99%

The Molecular Effects of Ionizing Radiations on Brain Cells: Radiation Necrosis vs. Tumor Recurrence

et al. 2019

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The central nervous system (CNS) is generally resistant to the effects of radiation, but higher doses, such as those related to radiation therapy, can cause both acute and long-term brain damage. The most important results is a decline in cognitive function that follows, in most cases, cerebral radionecrosis. The essence of radio-induced brain damage is multifactorial, being linked to total administered dose, dose per fraction, tumor volume, duration of irradiation and dependent on complex interactions between multiple brain cell types. Cognitive impairment has been described following brain radiotherapy, but the mechanisms leading to this adverse event remain mostly unknown. In the event of a brain tumor, on follow-up radiological imaging often cannot clearly distinguish between recurrence and necrosis, while, especially in patients that underwent radiation therapy (RT) post-surgery, positron emission tomography (PET) functional imaging, is able to differentiate tumors from reactive phenomena. More recently, efforts have been done to combine both morphological and functional data in a single exam and acquisition thanks to the co-registration of PET/MRI. The future of PET imaging to differentiate between radionecrosis and tumor recurrence could be represented by a third-generation PET tracer already used to reveal the spatial extent of brain inflammation. The aim of the following review is to analyze the effect of ionizing radiations on CNS with specific regard to effect of radiotherapy, focusing the attention on the mechanism underling the radionecrosis and the brain damage, and show the role of nuclear medicine techniques to distinguish necrosis from recurrence and to early detect of cognitive decline after treatment.

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Radiation Necrosis, Pseudoprogression, Pseudoresponse, and Tumor Recurrence: Imaging Challenges for the Evaluation of Treated Gliomas

Cited by 175 publications

References 61 publications

Advanced ADC Histogram, Perfusion, and Permeability Metrics Show an Association with Survival and Pseudoprogression in Newly Diagnosed Diffuse Intrinsic Pontine Glioma: A Report from the Pediatric Brain Tumor Consortium

Advanced ADC Histogram, Perfusion, and Permeability Metrics Show an Association with Survival and Pseudoprogression in Newly Diagnosed Diffuse Intrinsic Pontine Glioma: A Report from the Pediatric Brain Tumor Consortium

In vivo detection of γ-glutamyl-transferase up-regulation in glioma using hyperpolarized γ-glutamyl-[1-13C]glycine

The Molecular Effects of Ionizing Radiations on Brain Cells: Radiation Necrosis vs. Tumor Recurrence

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