Peritumoral edema shown by MRI predicts poor clinical outcome in glioblastoma

Wu, Chenxing; Lin, Ge; Zhang, Lin; Zhang, Jiandong; Liu, Shui‐Yuan; Zhou, Chaowei

doi:10.1186/s12957-015-0496-7

Cited by 81 publications

(72 citation statements)

References 36 publications

(43 reference statements)

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“…Glioblastoma multiforme (GBM) is characterized by aggressive malignant infiltrative growth and is associated with a dismal prognosis [ 28 ]. Current standard of care for non-invasive glioblastoma diagnosis is MRI [ 29 , 30 ], which often offers acceptable information regarding the size and shape of the tumor. However, this tool is often unable to characterize the underlying histopathology of the disease.…”

Section: Resultsmentioning

confidence: 99%

Radioiodinated PARP1 tracers for glioblastoma imaging

et al. 2015

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BackgroundAlthough the understanding of the genetic and molecular basis of cancer has advanced significantly over the past several decades, imaging and treatment options for glioblastoma patients have been more limited (N Engl J Med 359:492-507, 2008). This is in part due to difficulties in diagnosing this disease early, combined with its diffuse, infiltrative growth. This study was aimed at the development of a novel diagnostic tool for glioblastoma through the synthesis of a small molecule based on radioiodinated poly(ADP-ribose)polymerase 1 (PARP1) targeted tracers. This PARP1 is a biomarker that is overexpressed in glioblastoma tissue, but has only low expression levels in the healthy brain (Neoplasia 16:432-40, 2014).MethodsA library of PARP1 inhibitors (iodo-PARPis) was synthesized. Based on their pharmacokinetic properties and nuclear PARP1 binding, the most successful inhibitor was radiolabeled with 131I and 124I. Biodistribution as well as imaging experiments were performed in orthotopic and subcutaneous mouse models of glioblastoma.ResultsOne member of our iodo-poly(ADP-ribose)polymerase 1 (PARP1) inhibitor library, I2-PARPi, shows promising biophysical properties for in vivo application. All synthesized tracers have IC50 values in the nanomolar range (9 ± 2–107 ± 4 nM) and were able to inhibit the uptake of a fluorescent PARP1 inhibitor analog (PARPi-FL). I2-PARPi was able to reduce the uptake of PARPi-FL by 78 ± 4 % in vivo. In mouse models of glioblastoma, we show that the radioiodinated inhibitor analog has high uptake in tumor tissue (U251 MG xenograft, tumor, 0.43 ± 0.06 %ID/g; brain, 0.01 ± 0.00 %ID/g; muscle, 0.03 ± 0.01 %ID/g; liver, 2.35 ± 0.57 %ID/g; thyroid, 0.24 ± 0.06 %ID/g). PET and SPECT imaging performed in orthotopic glioblastoma models with [124I]- and [131I]-I2-PARPi showed selective accumulation in the tumor tissue. These results were also verified using autoradiography of tumor sections, which displayed focal selective uptake of the tracer in the tumor regions as confirmed by histology. The uptake could be blocked through pre-injection of excess unlabeled PARP1 inhibitor (Olaparib).ConclusionsWe have successfully synthesized and radioiodinated the PARP1 selective tracer I2-PARPi. The novel tracer shows selective binding to tumor tissue, both in vitro and in models of glioblastoma, and has the potential to serve as a selective PET imaging agent for brain tumors.Electronic supplementary materialThe online version of this article (doi:10.1186/s13550-015-0123-1) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Radioiodinated PARP1 tracers for glioblastoma imaging

et al. 2015

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“…On the other hand, the IDH1mt tumors have a diffuse appearance on MRI without a well-defined enhancing rim and with higher uptake in the edema region, on account of infiltrating cells. Previous studies have linked poor survival with the peritumoral edema volume (52) and tumor volume (27). Moreover, IDH1mt tumors are known to have less edema (49).…”

Section: Discussionmentioning

confidence: 99%

Tumor cell phenotype and heterogeneity differences in IDH1 mutant vs wild-type gliomas

Berens

Sood²,

Barnholtz‐Sloan

et al. 2019

Preprint

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34Glioma is recognized to be a highly heterogeneous CNS malignancy, whose diverse cellular composition 35 and cellular interactions have not been well characterized. To gain new clinical-and biological-insights 36 into the genetically-bifurcated IDH1 mutant (mt) vs wildtype (wt) forms of glioma, we integrated 37 multiplexed immunofluorescence single cell data for 43 protein markers across cancer hallmarks, in 38 addition to cell spatial metrics, genomic sequencing and magnetic resonance imaging (MRI) quantitative 39 features. Molecular and spatial heterogeneity scores for angiogenesis and cell invasion differ between 40 IDHmt and wt gliomas irrespective of prior treatment and tumor grade; these differences also persisted 41 in the MR imaging features of peritumoral edema and contrast enhancement volumes. Longer overall 42 survival for IDH1mt glioma patients may reflect generalized altered cellular, molecular, spatial 43 heterogeneity which manifest in discernable radiological manifestations. 44 45 48 While gliomas are relatively rare in the general population with an average annual age-adjusted 49 incidence of 6.2 per 100,000, these primary brain tumors contribute significant morbidity and mortality, 50 with glioblastoma carrying a 5-year survival rate of less than 6%(1). 51 52 The landscape of our knowledge about molecular features required for accurate diagnosis and prognosis 53 for glioma patients has advanced greatly in the last decade (2-5). Molecular subclassification highlights 54 different genetic underpinnings of glioblastoma (6), which offer some prognostic insight (7), likely 55 attributable, in part, to gene expression patterns influencing vulnerability to radiation (8). The World 56 Health Organization (WHO) classifies gliomas into defined categories based upon histologic and 57 molecular features and are assigned into four grades of increasing aggressiveness. Additionally, the 58 methylation status of O6-methylguanine-DNA methyltransferase (MGMT) has been implicated as a 59 useful biomarker for conferring tumor resistance to alkylating chemotherapies; methylation of the 60 MGMT promoter leads to transcriptional silencing of MGMT, which is associated with loss of MGMT 61 expression and increased response to alkylating chemotherapies such as temozolomide (TMZ) (9). 62 Analysis of DNA methylation from gliomas identified a DNA methylation-based phenotype, G-CIMP, 63 which is characterized by global hypermethylation of CpG islands and is predictive of increased survival; 64 this G-CIMP phenotype is associated with isocitrate dehydrogenase (IDH) mutation status (3, 4, 10). 4 65 66 IDH wild type (wt) in histologically defined low-grade gliomas is associated with poor clinical prognosis 67 that more resembles glioblastoma multiforme (GBM), which generally lack IDH mutation (IDHmt) (3, 11). 68 Conversely, IDH mutations are observed in the majority of lower-grade gliomas and are associated with 69 better clinical outcomes. In low-grade gliomas with IDH mutations, 1p/19q codeletion is further 70 associated wit...

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“…The purpose of our study was not to quantify the exact volume of edema, but rather to determine the edema-generating strength of metastasis by different histological subtypes. Similar categorizations were used in other studies measuring edema thickness adjacent to meningiomas and gliomas [9,10]. …”

Section: Discussionmentioning

confidence: 99%

Significance of Primary Tumor Location and Histology for Brain Metastasis Development and Peritumoral Brain Edema in Lung Cancer

et al. 2016

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Background: Brain metastasis of lung cancer adversely affects overall survival (OS) and quality of life, while peritumoral brain edema is responsible for life-threatening complications. Methods: We retrospectively analyzed the clinicopathological and cerebral radiological data of 575 consecutive lung cancer patients with brain metastases. Results: In adenocarcinoma and squamous cell carcinoma, peritumoral brain edema was more pronounced than in small-cell lung cancer (p < 0.001 and p < 0.001, respectively). There was a positive correlation between the size of metastasis and the thickness of peritumoral brain edema (p < 0.001). It was thicker in supratentorial tumors (p = 0.019), in younger patients (≤50 years) (p = 0.042), and in females (p = 0.016). The time to development of brain metastasis was shorter in central than in peripheral lung cancer (5.3 vs. 9.0 months, p = 0.035). Early brain metastasis was characteristic for adenocarcinomas. A total of 135 patients had brain only metastases (N0 disease) characterized by peripheral lung cancer predominance (p < 0.001) and a longer time to development of brain metastasis (9.2 vs. 4.4 months, p < 0.001). OS was longer in the brain only subgroup than in patients with N1-3 diseases (p < 0.001). Conclusions: The clinicopathological characteristics of lung cancer are related to the development and radiographic features of brain metastases. Our results might be helpful in selecting patients who might benefit from prophylactic cranial irradiation.

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Peritumoral edema shown by MRI predicts poor clinical outcome in glioblastoma

Cited by 81 publications

References 36 publications

Radioiodinated PARP1 tracers for glioblastoma imaging

Radioiodinated PARP1 tracers for glioblastoma imaging

Tumor cell phenotype and heterogeneity differences in IDH1 mutant vs wild-type gliomas

Significance of Primary Tumor Location and Histology for Brain Metastasis Development and Peritumoral Brain Edema in Lung Cancer

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