Unconventional non-amino acidic PET radiotracers for molecular imaging in gliomas.

PURPOSE: The objective of this review was to explore the potential clinical application of unconventional non-amino acid PET radiopharmaceuticals in patients with gliomas. METHODS: A comprehensive search strategy was used based on SCOPUS and PubMed databases using the following string: ("perfusion" OR "angiogenesis" OR "hypoxia" OR "neuroinflammation" OR proliferation OR invasiveness) AND ("brain tumor" OR "glioma") AND ("Positron Emission Tomography" OR PET). From all studies published in English, the most relevant articles were selected for this review, evaluating the mostly used PET radiopharmaceuticals in research centers, beyond amino acid radiotracers and 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG), for the assessment of different biological features, such as perfusion, angiogenesis, hypoxia, neuroinflammation, cell proliferation, tumor invasiveness, and other biological characteristics in patients with glioma. RESULTS: At present, the use of non-amino acid PET radiopharmaceuticals specifically designed to assess perfusion, angiogenesis, hypoxia, neuroinflammation, cell proliferation, tumor invasiveness, and other biological features in glioma is still limited. CONCLUSION: The use of investigational PET radiopharmaceuticals should be further explored considering their promising potential and studies specifically designed to validate these preliminary findings are needed. In the clinical scenario, advancements in the development of new PET radiopharmaceuticals and new imaging technologies (e.g., PET/MR and the application of the artificial intelligence to medical images) might contribute to improve the clinical translation of these novel radiotracers in the assessment of gliomas.

Apparent diffusion coefficient for molecular subtyping of non-gadolinium-enhancing WHO grade II/III glioma: volumetric segmentation versus two-dimensional region of interest analysis.

OBJECTIVES: To investigate if quantitative apparent diffusion coefficient (ADC) measurements can predict genetic subtypes of non-gadolinium-enhancing gliomas, comparing whole tumour against single slice analysis. METHODS: Volumetric T2-derived masks of 44 gliomas were co-registered to ADC maps with ADC mean (ADCmean) calculated. For the slice analysis, two observers placed regions of interest in the largest tumour cross-section. The ratio (ADCratio) between ADCmean in the tumour and normal appearing white matter was calculated for both methods. RESULTS: Isocitrate dehydrogenase (IDH) wild-type gliomas showed the lowest ADC values throughout (p < 0.001). ADCmean in the IDH-mutant 1p19q intact group was significantly higher than in the IDH-mutant 1p19q co-deleted group (p < 0.01). A volumetric ADCmean threshold of 1201 × 10-6 mm2/s identified IDH wild-type with a sensitivity of 83% and a specificity of 86%; a volumetric ADCratio cut-off value of 1.65 provided a sensitivity of 80% and a specificity of 92% (area under the curve (AUC) 0.9-0.94). A slice ADCratio threshold for observer 1 (observer 2) of 1.76 (1.83) provided a sensitivity of 80% (86%), specificity of 91% (100%) and AUC of 0.95 (0.96). The intraclass correlation coefficient was excellent (0.98). CONCLUSIONS: ADC measurements can support the distinction of glioma subtypes. Volumetric and two-dimensional measurements yielded similar results in this study. KEY POINTS: • Diffusion-weighted MRI aids the identification of non-gadolinium-enhancing malignant gliomas • ADC measurements may permit non-gadolinium-enhancing glioma molecular subtyping • IDH wild-type gliomas have lower ADC values than IDH-mutant tumours • Single cross-section and volumetric ADC measurements yielded comparable results in this study.

In vivo assessment of tumor heterogeneity in WHO 2016 glioma grades using diffusion kurtosis imaging: Diagnostic performance and improvement of feasibility in routine clinical practice.

PURPOSE: To assess the diagnostic performance of normalized and non-normalized diffusion kurtosis imaging (DKI) metrics extracted from different tumor volume data for grading glioma according to the integrated approach of the revised 2016 WHO classification. MATERIALS AND METHODS: Sixty patients with histopathologically confirmed glioma, who provided written informed consent, were retrospectively assessed between 01/2013 and 08/2016 from a prospective trial approved by the local institutional review board. Mean kurtosis (MK) and mean diffusivity (MD) metrics from DKI were assessed by two blinded physicians from four different volumes of interest (VOI): whole solid tumor including (VOItu-ed) and excluding perifocal edema (VOItu), infiltrative zone (VOIed), and single slice of solid tumor core (VOIslice). Intra-class correlation coefficient (ICC) was calculated to assess inter-rater agreement. One-way ANOVA was used to compare MK between 2016 CNS WHO tumor grades. Friedman's test compared MK and MD of each VOI. Spearman's correlation coefficient was used to correlate MK with 2016 CNS WHO tumor grades. ROC analysis was performed on MK for significant results. RESULTS: The MK assessment showed excellent inter-rater agreement for each VOI (ICC, 0.906-0.955). MK was significantly lower in IDHmutant astrocytoma (0.40±0.07), than in 1p/19q-confirmed oligodendroglioma (0.54±0.10, P=0.001) or IDHwild-type glioblastoma (0.68±0.13, P<0.001). MK and 2016 WHO tumor grades were strongly and positively correlated (VOItu-ed, r=0.684; VOItu, r=0.734; VOIed, r=0.625; VOIslice, r=0.698; P<0.001). CONCLUSIONS: Non-normalized MK values obtained from VOItu and VOIslice showed the best reproducibility and highest diagnostic performance for stratifying glioma according to the integrated approach of the recent 2016 WHO classification.

Assessment of Progression-Free-Survival in Glioblastomas by Intratreatment Dynamic Contrast-Enhanced MRI.

PURPOSE: The efficacy of concomitant chemoradiation in patients with glioblastomas (GBMs) cannot be reliably assessed until several weeks after therapy completion. Our aim was to evaluate dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) as an early predictive assay for the progression-free-survival. METHODS AND MATERIALS: A total of 22 patients with primary GBMs underwent DCE-MRI before, during and after completion of adjuvant chemoradiation. K (trans) (transfer constant between the intravascular and extravascular, extracellular space), v(e) (extracellular, extravascular volume) and IAUGC (initial area under the gadolinium concentration time curve) and their changes into treatment were assessed as prognostic markers (12 months of progression-free-survival (PFS)). RESULTS: Both responders (7 subjects) and non-responders (15 subjects) experienced a reduction in the baseline IAUGC and v(e) values during the early phase of the treatment. This reduction was more prominent in the responders and was statistically significant for the v(e) (P = 0.04). Baseline K (trans) values among responders demonstrated statistically significant reduction during the early phase of treatment (P = 0.001). Multivariate Cox regression analysis demonstrated significant relationship between response and the early changes in K (trans) values during the treatment (P = 0.04). Trend to significant prognostic value demonstrated the baseline K (trans), v(e) and IAUGC as well as the changes of IAUGC and K (trans) upon therapy completion. CONCLUSIONS: Early perfusion changes during concomitant chemoradiation in GBMs can be detected by means of DCE-MRI and have significant prognostic value for the 12-month PFS.

Intraoperative MR Imaging in Neurosurgery.

Intraoperative magnetic resonance imaging (iMRI) has dramatically expanded and nowadays presents state-of-the-art technique for image-guided neurosurgery, facilitating critical precision and effective surgical treatment of various brain pathologies. Imaging hardware providing basic imaging sequences as well as advanced MRI can be seamlessly integrated into routine surgical environments, which continuously leads to emerging indications for iMRI-assisted surgery. Besides the obvious intraoperative diagnostic yield, the initial clinical benefits have to be confirmed by future-controlled long-term studies.

Hybrid MR-PET in Neuroimaging.

Hybrid magnetic resonance (MR)-positron emission tomography (MR-PET) is a novel technology with advantages over sequential MR and PET imaging, allowing maintain full individual diagnostic performance with negligible mutual interference between the two hardware settings. Obvious synergies between MR and PET in acquisition of anatomical, functional, and molecular information for neurological diseases into one single image pave the way for establishing clear clinical indications for hybrid MR-PET as well as addressing unmet neuroimaging needs in future clinics and research. Further developments in attenuation correction, quantification, workflow, and effective MR-PET data management might unfold the full potential of integrated multimodality imaging.

Combined PET/MR: The Real Work Has Just Started. Summary Report of the Third International Workshop on PET/MR Imaging; February 17-21, 2014, Tübingen, Germany.

This paper summarises the proceedings and discussions at the third annual workshop held in Tübingen, Germany, dedicated to the advancement of the technical, scientific and clinical applications of combined PET/MRI systems in humans. Two days of basic scientific and technical instructions with "hands-on" tutorials were followed by 3 days of invited presentations from active researchers in this and associated fields augmented by round-table discussions and dialogue boards with specific themes. These included the use of PET/MRI in paediatric oncology and in adult neurology, oncology and cardiology, the development of multi-parametric analyses, and efforts to standardise PET/MRI examinations to allow pooling of data for evaluating the technology. A poll taken on the final day demonstrated that over 50 % of those present felt that while PET/MRI technology underwent an inevitable slump after its much-anticipated initial launch, it was now entering a period of slow, progressive development, with new key applications emerging. In particular, researchers are focusing on exploiting the complementary nature of the physiological (PET) and biochemical (MRI/MRS) data within the morphological framework (MRI) that these devices can provide. Much of the discussion was summed up on the final day when one speaker commented on the state of PET/MRI: "the real work has just started".

Maximizing the extent of resection and survival benefit of patients in glioblastoma surgery: high-field iMRI versus conventional and 5-ALA-assisted surgery.

AIMS: A safe total resection followed by adjuvant chemoradiotherapy should be the primary goal in the treatment of glioblastomas (GBMs) to enable patients the longest survival possible. 5-aminolevulinic acid (5-ALA)- and intraoperative MRI (iMRI)-assisted surgery, have been shown in prospective randomized trials to significantly improve the extent of resection (EOR) and subsequently survival of patients with GBMs. No direct comparison of surgical results between both techniques has been published to date. We analyzed the additional value of iMRI in glioblastoma surgery compared to conventional surgery with and without 5-ALA. METHODS: Residual tumor volumes, clinical parameters and 6-month progression-free survival (6M-PFS) rates after GBM resection were analyzed retrospectively for 117 patients after conventional, 5-ALA and iMRI-assisted surgery. RESULTS: Mean residual tumor volume (range) after iMRI-assisted surgery [0.5 (0.0-4.7) cm(3)] was significantly smaller compared to the residual tumor volume after 5-ALA-guided surgery [1.9 (0.0-13.2) cm(3); p = .022], which again was significantly smaller than in conventional white-light surgery [4.7 (0.0-30.6) cm(3); p = .007]. Total resections were significantly more common in iMRI- (74%) than in 5-ALA-assisted (46%, p = .05) or white-light surgery (13%, p = .03). Improvement of the EOR by using iMRI was safely achievable as peri- and postoperative morbidities were comparable between cohorts. Total resections increased 6M-PFS from 32% to 45%. CONCLUSIONS: Analysis of residual tumor volumes, total resections and neurological outcomes demonstrate that iMRI may be significantly superior to 5-ALA and white-light surgery for glioblastomas at comparable peri- and postoperative morbidities. Longer 6M-PFS was observed in patients with total resections.

Correlation between cerebral blood volume measurements by perfusion-weighted magnetic resonance imaging and two-year progression-free survival in gliomas.

Our goal was to determine whether relative cerebral blood volume (rCBV) can serve as an adjunct to histopathologic grading in the assessment of gliomas, with the hypothesis that rCBV can predict two-year survival. We evaluated 29 newly diagnosed gliomas (13 WHO grade II, seven grade III, nine grade IV; 17 astrocytomas, 12 oligodendroglial tumors). Dynamic susceptibility-weighted contrast-enhanced perfusion MR images and CBV maps were obtained. rCBVmax measurements (maximum tumor CBV/contralateral normal tissue CBV) and progression-free survival (PFS) were recorded. Receiver operating characteristic curves and Kaplan-Meier survival curves were calculated for rCBVmax and histologic grade. rCBVmax measurements differed between gliomas without (2.38 +/- 1.22) and with progression (5.57 +/- 2.84) over two years. The optimal rCBVmax cut-off value to predict progression was 2.95. rCBVmax < 2.95 was a significant predictor of two-year PFS, almost as accurate as WHO grade II. In the pure astrocytoma subgroup, the optimal rCBVmax cut-off value to predict progression was 2.85. In this group rCBVmax < 2.85 was a significant predictor of two-year PFS, an even better predictor of two-year PFS than WHO grade II. rCBVmax can be used to predict two-year PFS in patients with gliomas, independent of pathologic findings, especially in tumors without oligodendroglial components.

Current status and guidelines for the assessment of tumour vascular support with dynamic contrast-enhanced computed tomography.

Dynamic contrast-enhanced computed tomography (DCE-CT) assesses the vascular support of tumours through analysis of temporal changes in attenuation in blood vessels and tissues during a rapid series of images acquired with intravenous administration of iodinated contrast material. Commercial software for DCE-CT analysis allows pixel-by-pixel calculation of a range of validated physiological parameters and depiction as parametric maps. Clinical studies support the use of DCE-CT parameters as surrogates for physiological and molecular processes underlying tumour angiogenesis. DCE-CT has been used to provide biomarkers of drug action in early phase trials for the treatment of a range of cancers. DCE-CT can be appended to current imaging assessments of tumour response with the benefits of wide availability and low cost. This paper sets out guidelines for the use of DCE-CT in assessing tumour vascular support that were developed using a Delphi process. Recommendations encompass CT system requirements and quality assurance, radiation dosimetry, patient preparation, administration of contrast material, CT acquisition parameters, terminology and units, data processing and reporting. DCE-CT has reached technical maturity for use in therapeutic trials in oncology. The development of these consensus guidelines may promote broader application of DCE-CT for the evaluation of tumour vascularity. Key Points • DCE-CT can robustly assess tumour vascular support • DCE-CT has reached technical maturity for use in therapeutic trials in oncology • This paper presents consensus guidelines for using DCE-CT in assessing tumour vascularity.

Simultaneous PET/MR imaging in a human brain PET/MR system in 50 patients--current state of image quality.

OBJECTIVES: The present work illustrates the current state of image quality and diagnostic accuracy in a new hybrid BrainPET/MR. MATERIALS AND METHODS: 50 patients with intracranial masses, head and upper neck tumors or neurodegenerative diseases were examined with a hybrid BrainPET/MR consisting of a conventional 3T MR system and an MR-compatible PET insert. Directly before PET/MR, all patients underwent a PET/CT examination with either [18F]-FDG, [11C]-methionine or [68Ga]-DOTATOC. In addition to anatomical MR scans, functional sequences were performed including diffusion tensor imaging (DTI), arterial spin labeling (ASL) and proton-spectroscopy. Image quality score of MR imaging was evaluated using a 4-point-scale. PET data quality was assessed by evaluating FDG-uptake and tumor delineation with [11C]-methionine and [68Ga]-DOTATOC. FDG uptake quantification accuracy was evaluated by means of ROI analysis (right and left frontal and temporo-occipital lobes). The asymmetry indices and ratios between frontal and occipital ROIs were compared. RESULTS: In 45/50 patients, PET/MR examination was successful. Visual analysis revealed a diagnostic image quality of anatomical MR imaging (mean quality score T2 FSE: 1.27±0.54; FLAIR: 1.38±0.61). ASL and proton-spectroscopy was possible in all cases. In DTI, dental artifacts lead to one non-diagnostic dataset (mean quality score DTI: 1.32±0.69; ASL: 1.10±0.31). PET datasets of PET/MR and PET/CT offered comparable tumor delineation with [11C]-methionine; additional lesions were found in 2/8 [(68)Ga]-DOTATOC-PET in the PET/MR. Mean asymmetry index revealed a high accordance between PET/MR and PET/CT (1.5±2.2% vs. 0.9±3.6%; mean ratio (frontal/parieto-occipital) 0.93±0.08 vs. 0.96±0.05), respectively. CONCLUSIONS: The hybrid BrainPET/MR allows for molecular, anatomical and functional imaging with uncompromised MR image quality and a high accordance of PET results between PET/MR and PET/CT. These results justify the application of this technique in further clinical studies and may contribute to the transfer into whole-body PET/MR systems.

Squamous cell cancer of hypopharynx and larynx - evaluation of metastatic nodal disease based on computed tomography perfusion studies.

BACKGROUND AND PURPOSE: In patients with squamous cell cancer metastatic disease in lymph nodes still remains the single most important negative predicting factor and when detected, it reduces overall 5-year survival by 50%. The aim of the study was to evaluate contrast-enhanced computed tomography (CECT) with computed tomography perfusion (CTP) examination in order to differentiate malignant from non-malignant cervical lymph nodes in patients with squamous cell cancer of hypopharynx and larynx. MATERIAL/METHODS: This was a prospective three-center study. From November 2007 until March 2010 33 consecutive patients with squamous cell cancer of the hypopharynx and 27 patients with laryngeal cancer underwent computed tomography (CT) examination followed by CTP. During first part of examination 80 ml of contrast was administered, with flow rate 1 ml/s and 100 s delay; standard head and neck examination was performed. Next, perfusion images were acquired with the coverage of 8 cm and different groups of lymph nodes were evaluated - groups II, III, IV and V. Perfusion maps for basic parameters (blood flow [BF], blood volume [BV], mean transit time [MTT] and permeability surface [PS]) were reconstructed for all patients using dedicated software. The long and short axis diameters, the density of the node before and after contrast medium administration and average values of each perfusion parameter were calculated for every node separately. Results were compared with histologic analysis of resected nodes. RESULTS: Out of the total number of 293 nodes evaluated on CECT and CTP it was possible to correlate 208 resected nodes with histologic findings. 125 of them were proven to be malignant and 83 were benign. Malignant nodes showed remarkably higher density and hyperperfusion, comparing to benign ones. The average density values in Hounsfield units (HU) for cervical nodes were: 91.9HU for metastatic comparing to 72.3 HU for non-metastatic, but this difference did not show statistical significance. The average value of BF in malignant nodes was 136.4 ml/100g/min, BV was 7.7 ml/100g, MTT was 4.4s and PS was 19.4 ml/100g/min. The average values for benign nodes were: BF was 80.7 ml/100g/min, BV was 4.7 ml/100g, MTT was 5.6s and PS was 12.8 ml/100g/min. Comparing to non-malignant nodes, malignant ones showed significantly higher BF, BV and PS values (p<0.05). CONCLUSIONS: Although CECT findings may draw our attention, pointing at abnormal morphology of the node, CTP seems to provide additional functional information regarding its possible malignancy. CTP may be useful in differentiation between malignant and benign lymph nodes, based on evaluation of the value of BF, BV and PS.

Effects of the ABO-mismatch between donor and recipient of cryopreserved arterial homografts.

AIM: Cryopreserved arterial homograft (CAH) is a well-established substitute material for in situ reconstruction of vascular infections. However, their degeneration remains serious complication. Although several studies propose ABO-mismatching between CAH-donor and -recipient as the main reason, the results are controversial. We compared the outcome between ABO-compatible and ABO-incompatible CAH recipients to evaluate the contribution of ABO-mismatching. METHODS: Between January 2004 and December 2007, a retrospective review in 32 patients who underwent CAH-implantation was performed. The patients were divided in ABO-incompatible (group A: 17/32 patients; 53%) and ABO-compatible (group B: 15/32 patients; 47%) to CAH donor. Leucocytes, platelets and C-reactive protein (CRP) levels were recorded during the in-hospital stay. These were correlated with the surface of implanted homograft (SIH). Mid-term survival- and freedom-from-reoperation (FFR) rates were also calculated. RESULTS: In both groups, peak of leucocytes and CRP was recorded on third postoperative day (POD3) and regarding platelets lowest values on POD1. Interestingly, a second CRP-peak was reported on POD8 in group A (A: 172±104mg/L vs. B: 75±55mg/L, P=0.01). No relationship between second CRP-peak and SIH was found. After 27 months median follow-up (range, 5-49 months), survival- (65% vs. 84%, P=0.28) and FFR-rates (94% vs. 93%, P=0.98) remained comparable. CONCLUSION: We consider that the second CRP-peak expresses an early cytoimmunologic response of ABO-incompatible recipients against CAH. However, we did not find any relationship between ABO-incompatibility and poor mid-term outcome in terms of reoperation or mortality. Longer surveillance of our patients is mandatory.

Perfusion CT in squamous cell carcinoma of the upper aerodigestive tract: long-term predictive value of baseline perfusion CT measurements.

BACKGROUND AND PURPOSE: PCT studies hold short-term predictive value in patients treated with chemoradiotherapy. Our aim was to examine the long-term predictive value of baseline PCT studies for local tumor control and overall survival in SCCA of the upper aerodigestive tract treated with chemoradiotherapy. MATERIALS AND METHODS: Eighty-four patients with advanced SCCA underwent PCT followed by concomitant chemoradiation. The acquired perfusion maps represented BF, BV, MTT, and PS. Visual analysis of the parametric maps for identification of tumor perfusion patterns was conducted. ROC curves, t tests, and Kaplan-Meier survival curves were plotted for local disease control and overall survival. RESULTS: The median time of local tumor control was 24 months. The BF and PS values were significantly higher in patients who had no recurrence than in those with local failure (P < or = .02). The BF and PS were predictive (P < or = .0006) but BV and MTT held no significant predictive values for local tumor control. The patients with high BF and PS had a longer local tumor control than the patients with hypoperfused tumors (P = .0007). A visually detected BF-BV mismatch had a sensitivity/specificity of 63%/66% (P = .03) and 59%/69% (P = .03) for local tumor control and OS, respectively. Patients without mismatch lived significantly longer than patients with mismatch (P = .01). CONCLUSIONS: BF, PS, and mismatch of BF-BV are significant predictors of local tumor control after chemoradiation in SCCA of the upper aerodigestive tract.

Changes in perfusion CT of advanced squamous cell carcinoma of the head and neck treated during the course of concomitant chemoradiotherapy.

BACKGROUND AND PURPOSE: Concomitant chemoradiation is a promising therapy for the treatment of locoregionally advanced head and neck carcinoma. The purpose of this study was to prospectively evaluate early changes in primary tumor perfusion parameters during concomitant cisplatin-based chemoradiotherapy of locoregionally advanced SCCHN and to evaluate their predictive value for response of the primary tumor to therapy. MATERIALS AND METHODS: Twenty patients with locoregionally advanced SCCHN underwent perfusion CT scans before therapy and after completion of 40 Gy and 70 Gy of chemoradiotherapy. BF, BV, MTT, and PS of primary tumors were quantified. Differences in perfusion and tumor volume values during the therapy as well as between responders and nonresponders were analyzed, and ROC curves were used to assess predictive value of the baseline and follow-up functional parameters. RESULTS: The tumor volumes at 40 Gy and at 70 Gy were significantly lower compared with baseline values (P = .014 and P = .007). In the 6 nonresponders, measurements after 40 Gy showed a nonsignificant trend of increased BF, BV, and PS values compared with the baseline values (P = .06). In 14 responders, a significant reduction of BF values was recorded after 40 Gy (P = .04) and after 70 Gy (P = .01). In responders, BV values showed a reduction after 40 Gy followed by a plateau after 70 Gy (P = .04), whereas in nonresponders there was a nonsignificant elevation of the BV. Baseline BV predicted short-term tumor response with a sensitivity of 60% and specificity of 100% (P = .01). After completion of 40 Gy of concomitant chemoradiation BV was a more significant predictor than were BF and MTT. CONCLUSIONS: The results suggest that in advanced SCCHN the perfusion CT monitoring might be of predictive value for identifying tumors that may respond to cisplatin-based chemoradiotherapy.

Switching on the lights for real-time multimodality tumor neuroimaging: The integrated positron-emission tomography/MR imaging system.

A recent report of the feasibility of simultaneous PET/MR imaging of the healthy human brain has sparked excitement in the field of neuroimaging because of its potential influence and utility in clinical neuroscience research. The aim of this communication is to discuss the benefits and current drawbacks of the hybrid imaging system and to highlight some perspectives of the new technique for brain neoplasms.