• Contrast Media/chemistry
• Contrast Media/pharmacokinetics
• Magnetic Resonance Imaging/methods
• Humans
• Models, Biological
• Computational Biology
• Computer Simulation

• P30 CA033572 NCI NIH HHS
• R01 CA254271 NCI NIH HHS
• R01 NS115971 NINDS NIH HHS
• National Institutes of Health
• California Institute for Regenerative Medicine
• Ministero dell’Istruzione, dell’Università e della Ricerca
• Gruppo Nazionale per la Fisica Matematica

• DCE-MRI
• High-grade glioma
• Pdzk1
• Perfusion parameter
• Prognosis

• Adult
• Aged
• Female
• Humans
• Male
• Middle Aged
• Young Adult
• Brain Neoplasms/diagnostic imaging
• Brain Neoplasms/pathology
• Brain Neoplasms/blood supply
• Contrast Media
• Glioma/diagnostic imaging
• Glioma/pathology
• Glioma/blood supply
• Kaplan-Meier Estimate
• Magnetic Resonance Imaging/methods
• Neoplasm Grading
• Prognosis
• ROC Curve

• Arterial spin labeling
• Bevacizumab
• High-grade glioma
• Relative cerebral blood flow

• Male
• Female
• Humans
• Adult
• Middle Aged
• Aged
• Aged, 80 and over
• Bevacizumab/therapeutic use
• Brain Neoplasms/diagnostic imaging
• Brain Neoplasms/drug therapy
• Brain Neoplasms/blood supply
• Retrospective Studies
• Spin Labels
• Glioma/diagnostic imaging
• Glioma/drug therapy
• Glioma/pathology
• Prognosis
• Magnetic Resonance Imaging/methods
• Cerebrovascular Circulation/physiology

• JP20K08135 Japan Society for the Promotion of Science

Gastric cancer is the second most prevalent cancer and the second leading cause of cancer-related death in China. The prognosis of metastatic gastric cancer is poor with a median overall survival of 8–10 months. Apatinib, an oral small-molecule, selective vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor, is approved as third-line or subsequent therapy for gastric cancer in China. Several recent small-scale studies and case reports showed that it may be great help in improvement of prognosis as second-line treatment in patients with advanced or metastatic gastric cancer. Here, we present a case of advanced gastric adenocarcinoma with multiple hepatic metastases who was treated with apatinib plus paclitaxel as second-line therapy, realized a long progression-free survival of 37 months. Until 29 January 2022, the disease remains an efficacy of partial response. We believe that the good outcome of this case is not an accident, because of the typically hyper-vascular of his liver metastases, the treatment toxicities of hypertension and proteinuria, all may be potential predictive biomarkers for anti-angiogenic treatments.

• Diffusion
• Glioblastoma
• Imaging
• MRI
• PET
• Perfusion
• Spectroscopy

• Adult
• Amino Acids
• Brain Neoplasms/diagnostic imaging
• Brain Neoplasms/therapy
• Contrast Media
• Fluorodeoxyglucose F18
• Gadolinium
• Glioblastoma/diagnostic imaging
• Glioblastoma/therapy
• Humans
• Magnetic Resonance Imaging/methods
• Neurosurgeons
• Positron-Emission Tomography/methods
• Practice Guidelines as Topic

• JAS239
• animal model
• choline kinase
• clustering
• dynamic contrast-enhanced MRI
• glioblastoma
• intra-tumoral heterogeneity
• pharmacokinetic models

• dynamic contrast enhanced-magnetic resonance imaging
• monoclonal antibody
• physiologically based pharmacokinetic modeling
• tumor pharmacokinetics

• Animals
• Antibodies, Monoclonal/immunology
• Antibodies, Monoclonal/pharmacokinetics
• Antibodies, Monoclonal/therapeutic use
• Cell Line, Tumor
• Cetuximab/immunology
• Cetuximab/pharmacokinetics
• Contrast Media/chemistry
• Humans
• Magnetic Resonance Imaging
• Male
• Mice
• Models, Biological
• Neoplasms/blood
• Neoplasms/diagnostic imaging
• Neoplasms/drug therapy
• Neoplasms/immunology

• UL1 TR001412 NCATS NIH HHS
• CA246785 NCI NIH HHS
• (no number) Center for Protein Therapeutics
• R01 CA204192 NCI NIH HHS
• R01 CA246785 NCI NIH HHS
• CA204192 NCI NIH HHS

Temporal and spatial resolution of dynamic contrast-enhanced MR imaging (DCE-MRI) is critical to reproducibility, and the reproducibility of high-resolution (HR) DCE-MRI was evaluated. Thirty consecutive patients suspected to have brain tumors were prospectively enrolled with written informed consent. All patients underwent both HR-DCE (voxel size, 1.1 × 1.1 × 1.1 mm³; scan interval, 1.6 s) and conventional DCE (C-DCE; voxel size, 1.25 × 1.25 × 3.0 mm³; scan interval, 4.0 s) MRI. Regions of interests (ROIs) for enhancing lesions were segmented twice in each patient with glioblastoma (n = 7) to calculate DCE parameters (K^trans, V_p, and V_e). Intraclass correlation coefficients (ICCs) of DCE parameters were obtained. In patients with gliomas (n = 25), arterial input functions (AIFs) and DCE parameters derived from T2 hyperintense lesions were obtained, and DCE parameters were compared according to WHO grades. ICCs of HR-DCE parameters were good to excellent (0.84–0.95), and ICCs of C-DCE parameters were moderate to excellent (0.66–0.96). Maximal signal intensity and wash-in slope of AIFs from HR-DCE MRI were significantly greater than those from C-DCE MRI (31.85 vs. 7.09 and 2.14 vs. 0.63; p < 0.001). Both 95^th percentile K^trans and V_e from HR-DCE and C-DCE MRI could differentiate grade 4 from grade 2 and 3 gliomas (p < 0.05). In conclusion, HR-DCE parameters generally showed better reproducibility than C-DCE parameters, and HR-DCE MRI provided better quality of AIFs.

Advances in sub-Nyquist–sampled dynamic contrast-enhanced (DCE) MRI enable monitoring of brain tumors with millimeter resolution and whole-brain coverage. Such undersampled quantitative methods need careful characterization regarding achievable test-retest reproducibility.

To demonstrate a fully automated high-resolution whole-brain DCE MRI pipeline with 30-fold sparse undersampling and estimate its reproducibility on the basis of reference regions of stable tissue types during multiple posttreatment time points by using longitudinal clinical images of high-grade glioma.

Two methods for sub-Nyquist–sampled DCE MRI were extended with automatic estimation of vascular input functions. Continuously acquired three-dimensional k-space data with ramped-up flip angles were partitioned to yield high-resolution, whole-brain tracer kinetic parameter maps with matched precontrast-agent T1 and M₀ maps. Reproducibility was estimated in a retrospective study in participants with high-grade glioma, who underwent three consecutive standard-of-care examinations between December 2016 and April 2019. Coefficients of variation and reproducibility coefficients were reported for histogram statistics of the tracer kinetic parameters plasma volume fraction and volume transfer constant (K^trans) on five healthy tissue types.

The images from 13 participants (mean age ± standard deviation, 61 years ± 10; nine women) with high-grade glioma were evaluated. In healthy tissues, the protocol achieved a coefficient of variation less than 57% for median K^trans, if K^trans was estimated consecutively. The maximum reproducibility coefficient for median K^trans was estimated to be at 0.06 min^–1 for large or low-enhancing tissues and to be as high as 0.48 min^–1 in smaller or strongly enhancing tissues.

A fully automated, sparsely sampled DCE MRI reconstruction with patient-specific vascular input function offered high spatial and temporal resolution and whole-brain coverage; in healthy tissues, the protocol estimated median volume transfer constant with maximum reproducibility coefficient of 0.06 min^–1 in large, low-enhancing tissue regions and maximum reproducibility coefficient of less than 0.48 min^–1 in smaller or more strongly enhancing tissue regions.

Published under a CC BY 4.0 license.

Online supplemental material is available for this article.

See also the editorial by Lenkinski in this issue.

• Bevacizumab
• Diffusion tensor imaging
• Glioma
• Magnetic resonance imaging

• Bevacizumab/therapeutic use
• Brain Neoplasms/diagnostic imaging
• Brain Neoplasms/drug therapy
• Contrast Media
• Diffusion Tensor Imaging
• Glioma/diagnostic imaging
• Glioma/drug therapy
• Humans
• Magnetic Resonance Imaging
• Neoplasm Recurrence, Local/diagnostic imaging
• Neoplasm Recurrence, Local/drug therapy
• Prognosis

Patient-derived orthotopic glioma xenograft models are important platforms used for pre-clinical research of glioma. In the present study, the diagnostic ability of magnetic resonance imaging (MRI) was examined with regard to the identification of biomarkers obtained from patient-derived glioma xenografts and human tumors. Conventional MRI, diffusion weighted imaging and dynamic contrast-enhanced (DCE)-MRI were used to analyze seven pairs of high grade gliomas with their corresponding xenografts obtained from non-obese diabetic-severe-combined immunodeficiency nude mice. Tumor samples were collected for transcriptome sequencing and histopathological staining, and differentially expressed genes were screened between the original tumors and the corresponding xenografts. Gene Ontology (GO) analysis was performed to predict the functions of these genes. In 6 cases of xenografts with diffuse growth, the degree of enhancement was significantly lower compared with the original tumors. Histopathological staining indicated that the microvascular area and microvascular diameter of the xenografts were significantly lower compared with the original tumors (P=0.009 and P=0.007, respectively). In one case, there was evidence of nodular tumor growth in the mouse. Both MRI and histopathological staining showed a clear demarcation between the transplanted tumors and the normal brain tissues. The relative apparent diffusion coefficient values of the 7 cases examined were significantly higher compared with the corresponding original tumors (P=0.001) and transfer coefficient values derived from DCE-MRI of the tumor area was significantly lower compared with the original tumors (P=0.016). GO analysis indicated that the expression levels of extracellular matrix-associated genes, angiogenesis-associated genes and immune function-associated genes in the original tumors were higher compared with the corresponding xenografts. In conclusion, the data demonstrated that the MRI features of patient-derived xenograft glioma models in mice were different compared with those of the original patient tumors. Differential gene expression may underlie the differences noted in the MRI features between original tumors and corresponding xenografts. The results of the present study highlight the precautions that should be taken when extrapolating data from patient-derived xenograft studies, and their applicability to humans.

• Dynamic contrast-enhanced
• Glioma
• Ki-67
• Magnetic resonance imaging

• Dynamic contrast-enhanced T1-weighted perfusion MR imaging (DCE-pMRI)
• Epidermal growth factor receptor (EGFR)
• Glioblastoma (GB)
• Isocitrate dehydrogenase 1 (IDH1)
• Oligodendrocyte transcription factor 2 (OLIG2)

• Adult
• Aged
• Aged, 80 and over
• Brain Neoplasms/diagnostic imaging
• Brain Neoplasms/genetics
• Brain Neoplasms/metabolism
• Brain Neoplasms/surgery
• Contrast Media
• ErbB Receptors/metabolism
• Female
• Glioblastoma/diagnostic imaging
• Glioblastoma/genetics
• Glioblastoma/metabolism
• Glioblastoma/surgery
• Humans
• Image Processing, Computer-Assisted
• Immunohistochemistry
• Isocitrate Dehydrogenase/genetics
• Isocitrate Dehydrogenase/metabolism
• Ki-67 Antigen/metabolism
• Magnetic Resonance Angiography
• Male
• Middle Aged
• Oligodendrocyte Transcription Factor 2/metabolism
• Pilot Projects
• Retrospective Studies
• Tumor Suppressor Protein p53/genetics

It is of vital importance to find radiologic biomarkers that can accurately predict treatment response. Usually, the initiation of antiangiogenic therapy causes a rapid decrease in the contrast enhancing tumor. However, the treatment response is observed only in a fraction of patients due to the partial radiological response secondary to stabilization of abnormal vessels which does not essentially indicate a true antitumor effect. Perfusion-weighted magnetic resonance imaging (PW-MRI) techniques have shown implicitness as a strong imaging biomarker for gliomas since they give hemodynamic information of blood vessels. Hence, there is a rapid expansion of PW-MRI related studies and clinical applications.

To determine the diagnostic performance of PW-MRI techniques including: (A) dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI); and (B) dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) for evaluating response to antiangiogenic therapy in patients with recurrent gliomas.

Databases such as PubMed (MEDLINE included), EMBASE, and Google Scholar were searched for relevant original articles. The included studies were assessed for methodological quality with the Quality Assessment of Diagnostic Accuracy Studies 2 tool. Medical imaging follow-up or histopathological analysis was used as the reference standard. The data were extracted by two reviewers independently, and then the sensitivity, specificity, summary receiver operating characteristic curve, area under the curve (AUC), and heterogeneity were calculated using Meta-Disc 1.4 software.

This study analyzed a total of six articles. The overall sensitivity for DCE-MRI and DSC-MRI was 0.69 [95% confidence interval (CI): 0.53-0.82], and the specificity was 0.99 (95%CI: 0.93-1) by a random effects model (DerSimonianee-Laird model). The likelihood ratio (LR) +, LR-, and diagnostic odds ratio (DOR) were 12.84 (4.54-36.28), 0.35 (0.22-0.53), and 24.44 (7.19-83.06), respectively. The AUC (± SE) was 0.9921 (± 0.0120), and the Q* index (± SE) was 0.9640 (± 0.0323). For DSC-MRI, the sensitivity was 0.73, the specificity was 0.98, the LR+ was 7.82, the LR- was 0.32, the DOR was 31.65, the AUC (± SE) was 0.9925 (± 0.0132), and the Q* index was 0.9649 (± 0.0363). For DCE-MRI, the sensitivity was 0.41, the specificity was 0.97, the LR+ was 5.34, the LR- was 0.71, the DOR was 8.76, the AUC (± SE) was 0.9922 (± 0.2218), and the Q* index was 0.8935 (± 0.3037).

This meta-analysis demonstrated a beneficial value of PW-MRI (DSC-MRI and DCE-MRI) in monitoring the response of recurrent gliomas to antiangiogenic therapy, with reasonable sensitivity, specificity, +LR, and -LR.

• Glioma
• Perfusion-weighted magnetic resonance imaging
• Dynamic contrast-enhanced magnetic resonance imaging
• Dynamic susceptibility contrast magnetic resonance imaging
• Anti-vascular endothelial growth factor
• Antiangiogenic
• Meta-analysis

• Angiogenesis
• VEGF
• bevacizumab
• glioblastoma
• hypoxia
• perfusion

Antiangiogenic therapy is a universal approach to the treatment of malignant gliomas but fails to prolong the overall survival of newly diagnosed or recurrent glioblastoma patients. Imaging biomarkers are quantitative imaging parameters capable of objectively describing biological processes, pathological changes and treatment responses in some situations and have been utilized for outcome predictions of malignant gliomas in anti-angiogenic therapy. Advanced magnetic resonance imaging techniques (including perfusion-weighted imaging and diffusion-weighted imaging), positron emission computed tomography and magnetic resonance spectroscopy are imaging techniques that can be used to acquire imaging biomarkers, including the relative cerebral blood volume (rCBV), K^trans, and the apparent diffusion coefficient (ADC). Imaging indicators for a better prognosis when treating malignant gliomas with antiangiogenic therapy include the following: a lower pre- or post-treatment rCBV, less change in rCBV during treatment, a lower pre-treatment K^trans, a higher vascular normalization index during treatment, less change in arterio-venous overlap during treatment, lower pre-treatment ADC values for the lower peak, smaller ADC volume changes during treatment, and metabolic changes in glucose and phenylalanine. The investigation and utilization of these imaging markers may confront challenges, but may also promote further development of anti-angiogenic therapy. Despite considerable evidence, future prospective studies are critically needed to consolidate the current data and identify novel biomarkers.

•

Anti-angiogenic therapy only benefits specific populations of glioma patients.

• 18F-FDOPA, 3,4-dihydroxy-6-[18F]-fluoro-l-phenylalanine
• 18F-FLT, [18F]-fluoro-3-deoxy-3-L-fluorothymidine
• ADC, apparent diffusion coefficient
• AVOL, arterio-venous overlap
• Anti-angiogenic
• BBB, blood brain barrier
• Biomarkers
• CBF, cerebral blood flow
• CBV, cerebral blood volume
• CNS, central nervous system
• CT, computed tomography
• D-2HG, D-2-hydroxypentanedioic acid
• DCE-MRI, dynamic contrast-enhanced magnetic resonance imaging
• DSC-MRI, dynamic susceptibility contrast magnetic resonance imaging
• DWI, diffusion-weighted imaging
• FDG, fluorodeoxyglucose
• FLAIR, fluid-attenuated inversion recovery
• FSE pcASL, fast spin echo pseudocontinuous artery spin labeling
• GBM, glioblastoma
• Glioma
• Imaging
• Ktrans, volume transfer constant between blood plasma and extravascular extracellular space
• MRI, magnetic resonance imaging
• MRS, magnetic resonance spectroscopy
• OS, overall survival
• PET, positron emission computed tomography
• PFS, progression-free survival
• PWI, perfusion-weighted imaging
• RANO, Response Assessment in Neuro-Oncology
• ROI, region of interest
• RSI, restriction spectrum imaging
• SUV, standardized uptake value
• TMZ, temozolomide
• Therapy
• VAI, vessel architectural imaging
• VEGF-A, vascular endothelial growth factor A
• VNI, vascular normalization index.
• fDMs, functional diffusion maps
• nGBM, newly diagnosed glioblastoma
• rCBF, relative cerebral blood flow
• rCBV, relative cerebral blood volume
• rGBM, recurrent glioblastoma

Imaging plays several key roles in managing brain tumors, including diagnosis, prognosis, and treatment response assessment. Ongoing challenges remain as new therapies emerge and there are urgent needs to find accurate and clinically feasible methods to noninvasively evaluate brain tumors before and after treatment. This review aims to provide an overview of several advanced imaging modalities including magnetic resonance imaging and positron emission tomography (PET), including advances in new PET agents, and summarize several key areas of their applications, including improving the accuracy of diagnosis and addressing the challenging clinical problems such as evaluation of pseudoprogression and anti-angiogenic therapy, and rising challenges of imaging with immunotherapy.

• 18F-DOPA
• 18F-FET
• 18F-FLT
• PET-CT
• brain tumor
• glioblastoma
• iRANO
• immunotherapy
• neuro-oncology
• radiomics

• Dynamic contrast-enhanced magnetic resonance imaging
• Histologic response prediction
• Soft tissue sarcoma
• Volume transfer constant
• Voxel-wise analysis

• dynamic contrast enhanced
• glioma
• magnetic resonance imaging
• pharmacokinetic models
• texture analysis

• Bevacizumab
• Glioblastoma
• Glioma stem cell
• Hypoxia
• Immunotherapy

• Diffusion
• Glioblastoma
• Glioma
• MRI
• Perfusion
• Pseudoprogression
• Spectroscopy

• Contrast Media
• Glioma/blood supply
• Glioma/diagnostic imaging
• Humans
• Magnetic Resonance Imaging/methods
• Magnetic Resonance Imaging/trends
• Perfusion

Glioblastoma (GBM) is the most common primary malignant brain tumor that nearly always results in a bad prognosis. Temozolomide plus radiotherapy (TEM+RAD) is the most common treatment for newly diagnosed GBM. With the development of molecularly targeted drugs, several clinical trials were reported; however, the efficacy of the treatment remains controversial. So we attempted to measure the dose of the molecularly targeted drug that could improve the prognosis of those patients. The appropriate electronic databases (PubMed, MEDLINE, EMBASE, and the Cochrane Library) were searched for relevant studies. A meta-analysis was performed after determining which studies met the inclusion criteria. Six randomized, controlled trials (RCTs) were identified for this meta-analysis, comprising 2,637 GBM patients. The benefit of overall survival (OS) was hazard ratio (HZ), 0.936 [95% confidence interval (CI), 0.852–1.028]. The benefit with respect to progression-free survival (PFS) rate was HZ of 0.796 (95% CI, 0.701–0.903). OS benefit of cilengitide was HZ of 0.792 (95% CI, 0.642–0.977). The adverse effects higher than grade 3 were 57.7% in the experimental group and 44.1% in the placebo group (odds ratio, 1.679; 95% CI, 1.434–1.967). The addition of molecularly targeted drugs to TEM + RAD did not improve the OS of patients with GBM; however, it did improve PFS in patients treated by cilengitide who could not get improvement in OS. The rate of adverse effects was higher in the experimental group than in the placebo group.

• arterial spin labeling
• bevacizumab
• cerebral blood flow
• overall survival
• progression-free survival
• recurrent high-grade gliomas

The prognostic value of the dynamic contrast-enhanced (DCE) MRI perfusion and its histogram analysis-derived metrics is not well established for high-grade glioma (HGG) patients. The aim of this prospective study was to investigate DCE perfusion transfer coefficient (K^trans), vascular plasma volume fraction (v_p), extracellular volume fraction (v_e), reverse transfer constant (k_ep), and initial area under gadolinium concentration time curve (IAUGC) as predictors of progression-free (PFS) and overall survival (OS) in HGG patients.

Sixty-nine patients with suspected anaplastic astrocytoma or glioblastoma underwent preoperative DCE-MRI scans. DCE perfusion whole tumor region histogram parameters, clinical details, and PFS and OS data were obtained. Univariate, multivariate, and Kaplan–Meier survival analyses were conducted. Receiver operating characteristic (ROC) curve analysis was employed to identify perfusion parameters with the best differentiation performance.

On univariate analysis, v_e and skewness of v_p had significant negative impacts, while k_ep had significant positive impact on OS (P < 0.05). v_e was also a negative predictor of PFS (P < 0.05). Patients with lower v_e and IAUGC had longer median PFS and OS on Kaplan–Meier analysis (P < 0.05). K^trans and v_e could also differentiate grade III from IV gliomas (area under the curve 0.819 and 0.791, respectively).

High v_e is a consistent predictor of worse PFS and OS in HGG glioma patients. v_p skewness and k_ep are also predictive for OS. K^trans and v_e demonstrated the best diagnostic performance for differentiating grade III from IV gliomas.

• Dynamic contrast-enhanced MRI
• Gliomas
• Perfusion transfer coefficient
• Vascular plasma volume fraction

• Angiogenesis
• DCE-MRI
• Glioblastoma
• VEGF

• Biomarker
• Glioma
• Magnetic resonance imaging
• Perfusion
• Pharymacodynamic
• Predictive
• Prognostic

• Bevacizumab
• Brain
• Glioblastoma
• Leakage
• Perfusion

• Bevacizumab
• Glioblastoma
• Immunotherapy
• MGMT
• Nitrosourea
• Temozolomide

• Bevacizumab
• DCE MRI
• High-grade glioma
• Perfusion MRI
• Quantitative image analysis

• diffusion
• high-grade glioma
• imaging biomarker
• perfusion
• physiologic imaging