Histomolecular Validation of [18F]-FACBC in Gliomas Using Image-Localized Biopsies.

BACKGROUND: Gliomas have a heterogeneous nature, and identifying the most aggressive parts of the tumor and defining tumor borders are important for histomolecular diagnosis, surgical resection, and radiation therapy planning. This study evaluated [18F]-FACBC PET for glioma tissue classification. METHODS: Pre-surgical [18F]-FACBC PET/MR images were used during surgery and image-localized biopsy sampling in patients with high- and low-grade glioma. TBR was compared to histomolecular results to determine optimal threshold values, sensitivity, specificity, and AUC values for the classification of tumor tissue. Additionally, PET volumes were determined in patients with glioblastoma based on the optimal threshold. [18F]-FACBC PET volumes and diagnostic accuracy were compared to ce-T1 MRI. In total, 48 biopsies from 17 patients were analyzed. RESULTS: [18F]-FACBC had low uptake in non-glioblastoma tumors, but overall higher sensitivity and specificity for the classification of tumor tissue (0.63 and 0.57) than ce-T1 MRI (0.24 and 0.43). Additionally, [18F]-FACBC TBR was an excellent classifier for IDH1-wildtype tumor tissue (AUC: 0.83, 95% CI: 0.71-0.96). In glioblastoma patients, PET tumor volumes were on average eight times larger than ce-T1 MRI volumes and included 87.5% of tumor-positive biopsies compared to 31.5% for ce-T1 MRI. CONCLUSION: The addition of [18F]-FACBC PET to conventional MRI could improve tumor classification and volume delineation.

18F-FACBC and 18F-FDG PET/MRI in the evaluation of 3 patients with primary central nervous system lymphoma: a pilot study.

BACKGROUND: This PET/MRI study compared contrast-enhanced MRI, 18F-FACBC-, and 18F-FDG-PET in the detection of primary central nervous system lymphomas (PCNSL) in patients before and after high-dose methotrexate chemotherapy. Three immunocompetent PCNSL patients with diffuse large B-cell lymphoma received dynamic 18F-FACBC- and 18F-FDG-PET/MRI at baseline and response assessment. Lesion detection was defined by clinical evaluation of contrast enhanced T1 MRI (ce-MRI) and visual PET tracer uptake. SUVs and tumor-to-background ratios (TBRs) (for 18F-FACBC and 18F-FDG) and time-activity curves (for 18F-FACBC) were assessed. RESULTS: At baseline, seven ce-MRI detected lesions were also detected with 18F-FACBC with high SUVs and TBRs (SUVmax:mean, 4.73, TBRmax: mean, 9.32, SUVpeak: mean, 3.21, TBRpeak:mean: 6.30). High TBR values of 18F-FACBC detected lesions were attributed to low SUVbackground. Baseline 18F-FDG detected six lesions with high SUVs (SUVmax: mean, 13.88). In response scans, two lesions were detected with ce-MRI, while only one was detected with 18F-FACBC. The lesion not detected with 18F-FACBC was a small atypical MRI detected lesion, which may indicate no residual disease, as this patient was still in complete remission 12 months after initial diagnosis. No lesions were detected with 18F-FDG in the response scans. CONCLUSIONS: 18F-FACBC provided high tumor contrast, outperforming 18F-FDG in lesion detection at both baseline and in response assessment. 18F-FACBC may be a useful supplement to ce-MRI in PCNSL detection and response assessment, but further studies are required to validate these findings. Trial registration ClinicalTrials.gov. Registered 15th of June 2017 (Identifier: NCT03188354, https://clinicaltrials.gov/study/NCT03188354 ).

Diagnostic accuracy of anti-3-[18F]-FACBC PET/MRI in gliomas.

PURPOSE: The primary aim was to evaluate whether anti-3-[18F]FACBC PET combined with conventional MRI correlated better with histomolecular diagnosis (reference standard) than MRI alone in glioma diagnostics. The ability of anti-3-[18F]FACBC to differentiate between molecular and histopathological entities in gliomas was also evaluated. METHODS: In this prospective study, patients with suspected primary or recurrent gliomas were recruited from two sites in Norway and examined with PET/MRI prior to surgery. Anti-3-[18F]FACBC uptake (TBRpeak) was compared to histomolecular features in 36 patients. PET results were then added to clinical MRI readings (performed by two neuroradiologists, blinded for histomolecular results and PET data) to assess the predicted tumor characteristics with and without PET. RESULTS: Histomolecular analyses revealed two CNS WHO grade 1, nine grade 2, eight grade 3, and 17 grade 4 gliomas. All tumors were visible on MRI FLAIR. The sensitivity of contrast-enhanced MRI and anti-3-[18F]FACBC PET was 61% (95%CI [45, 77]) and 72% (95%CI [58, 87]), respectively, in the detection of gliomas. Median TBRpeak was 7.1 (range: 1.4-19.2) for PET positive tumors. All CNS WHO grade 1 pilocytic astrocytomas/gangliogliomas, grade 3 oligodendrogliomas, and grade 4 glioblastomas/astrocytomas were PET positive, while 25% of grade 2-3 astrocytomas and 56% of grade 2-3 oligodendrogliomas were PET positive. Generally, TBRpeak increased with malignancy grade for diffuse gliomas. A significant difference in PET uptake between CNS WHO grade 2 and 4 gliomas (p < 0.001) and between grade 3 and 4 gliomas (p = 0.002) was observed. Diffuse IDH wildtype gliomas had significantly higher TBRpeak compared to IDH1/2 mutated gliomas (p < 0.001). Adding anti-3-[18F]FACBC PET to MRI improved the accuracy of predicted glioma grades, types, and IDH status, and yielded 13.9 and 16.7 percentage point improvement in the overall diagnoses for both readers, respectively. CONCLUSION: Anti-3-[18F]FACBC PET demonstrated high uptake in the majority of gliomas, especially in IDH wildtype gliomas, and improved the accuracy of preoperatively predicted glioma diagnoses. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT04111588, URL: https://clinicaltrials.gov/study/NCT04111588.

Pelvic PET/MR attenuation correction in the image space using deep learning.

Introduction: The five-class Dixon-based PET/MR attenuation correction (AC) model, which adds bone information to the four-class model by registering major bones from a bone atlas, has been shown to be error-prone. In this study, we introduce a novel method of accounting for bone in pelvic PET/MR AC by directly predicting the errors in the PET image space caused by the lack of bone in four-class Dixon-based attenuation correction. Methods: A convolutional neural network was trained to predict the four-class AC error map relative to CT-based attenuation correction. Dixon MR images and the four-class attenuation correction µ-map were used as input to the models. CT and PET/MR examinations for 22 patients ([18F]FDG) were used for training and validation, and 17 patients were used for testing (6 [18F]PSMA-1007 and 11 [68Ga]Ga-PSMA-11). A quantitative analysis of PSMA uptake using voxel- and lesion-based error metrics was used to assess performance. Results: In the voxel-based analysis, the proposed model reduced the median root mean squared percentage error from 12.1% and 8.6% for the four- and five-class Dixon-based AC methods, respectively, to 6.2%. The median absolute percentage error in the maximum standardized uptake value (SUVmax) in bone lesions improved from 20.0% and 7.0% for four- and five-class Dixon-based AC methods to 3.8%. Conclusion: The proposed method reduces the voxel-based error and SUVmax errors in bone lesions when compared to the four- and five-class Dixon-based AC models.

European Association of Nuclear Medicine (EANM) Focus 4 consensus recommendations: molecular imaging and therapy in haematological tumours.

Given the paucity of high-certainty evidence, and differences in opinion on the use of nuclear medicine for hematological malignancies, we embarked on a consensus process involving key experts in this area. We aimed to assess consensus within a panel of experts on issues related to patient eligibility, imaging techniques, staging and response assessment, follow-up, and treatment decision-making, and to provide interim guidance by our expert consensus. We used a three-stage consensus process. First, we systematically reviewed and appraised the quality of existing evidence. Second, we generated a list of 153 statements based on the literature review to be agreed or disagreed with, with an additional statement added after the first round. Third, the 154 statements were scored by a panel of 26 experts purposively sampled from authors of published research on haematological tumours on a 1 (strongly disagree) to 9 (strongly agree) Likert scale in a two-round electronic Delphi review. The RAND and University of California Los Angeles appropriateness method was used for analysis. Between one and 14 systematic reviews were identified on each topic. All were rated as low to moderate quality. After two rounds of voting, there was consensus on 139 (90%) of 154 of the statements. There was consensus on most statements concerning the use of PET in non-Hodgkin and Hodgkin lymphoma. In multiple myeloma, more studies are required to define the optimal sequence for treatment assessment. Furthermore, nuclear medicine physicians and haematologists are awaiting consistent literature to introduce volumetric parameters, artificial intelligence, machine learning, and radiomics into routine practice.

Predicting Regions of Local Recurrence in Glioblastomas Using Voxel-Based Radiomic Features of Multiparametric Postoperative MRI.

The globally accepted surgical strategy in glioblastomas is removing the enhancing tumor. However, the peritumoral region harbors infiltration areas responsible for future tumor recurrence. This study aimed to evaluate a predictive model that identifies areas of future recurrence using a voxel-based radiomics analysis of magnetic resonance imaging (MRI) data. This multi-institutional study included a retrospective analysis of patients diagnosed with glioblastoma who underwent surgery with complete resection of the enhancing tumor. Fifty-five patients met the selection criteria. The study sample was split into training (N = 40) and testing (N = 15) datasets. Follow-up MRI was used for ground truth definition, and postoperative structural multiparametric MRI was used to extract voxel-based radiomic features. Deformable coregistration was used to register the MRI sequences for each patient, followed by segmentation of the peritumoral region in the postoperative scan and the enhancing tumor in the follow-up scan. Peritumoral voxels overlapping with enhancing tumor voxels were labeled as recurrence, while non-overlapping voxels were labeled as nonrecurrence. Voxel-based radiomic features were extracted from the peritumoral region. Four machine learning-based classifiers were trained for recurrence prediction. A region-based evaluation approach was used for model evaluation. The Categorical Boosting (CatBoost) classifier obtained the best performance on the testing dataset with an average area under the curve (AUC) of 0.81 ± 0.09 and an accuracy of 0.84 ± 0.06, using region-based evaluation. There was a clear visual correspondence between predicted and actual recurrence regions. We have developed a method that accurately predicts the region of future tumor recurrence in MRI scans of glioblastoma patients. This could enable the adaptation of surgical and radiotherapy treatment to these areas to potentially prolong the survival of these patients.

Prognostic value of combined MTV and ADC derived from baseline FDG PET/MRI in aggressive non-Hodgkins lymphoma.

PURPOSE: The aim of this prospective study was to investigate the prognostic value of metabolic tumor volume (MTV) and apparent diffusion coefficient (ADC) from baseline FDG PET/MRI compared to established clinical risk factors in terms of progression free survival (PFS) at 2 years in a cohort of diffuse large B-cell Lymphoma (DLBCL) and high-grade-B-cell lymphoma (HGBCL). METHODS: Thirty-three patients and their baseline PET/MRI examinations were included. Images were read by two pairs of nuclear medicine physicians and radiologists for defining lymphoma lesions. MTV was computed on PET, and up to six lymphoma target lesions with restricted diffusion was defined for each PET/MRI examination. Minimum ADC (ADCmin) and the corresponding mean ADC (ADCmean) from the target lesion with the lowest ADCmin were included in the analyses. For the combined PET/MRI parameters, the ratio between MTV and the target lesion with the lowest ADCmin (MTV/ADCmin) and the corresponding ADCmean (MTV/ADCmean) was calculated for each patient. Clinical, histological, and PET/MRI parameters were compared between the treatment failure and treatment response group, while survival analyses for each variable was performed by using univariate Cox regression. In case of significant variables in the Cox regression analyses, Kaplan-Meier survival analyses with log-rank test was used to study the effect of the variables on PFS. RESULTS: ECOC PS scale ≥2 (p = 0.05) and ADCmean (p = 0.05) were significantly different between the treatment failure group (n = 6) and those with treatment response (n = 27). Survival analyses showed that ADCmean was associated with PFS (p = 0.02, [HR 2.3 for 1 SD increase]), while combining MTV and ADC did not predict outcome. In addition, ECOG PS ≥2 (p = 0.01, [HR 13.3]) and histology of HGBCL (p = 0.02 [HR 7.6]) was significantly associated with PFS. CONCLUSIONS: ADCmean derived from baseline MRI could be a prognostic imaging biomarker for DLBCL and HGBCL. Baseline staging with PET/MRI could therefore give supplementary prognostic information compared to today's standard PET/CT.

Diagnostic Value of 18 F-FACBC PET/MRI in Brain Metastases.

PURPOSE: The study aims to evaluate whether combined 18 F-FACBC PET/MRI could provide additional diagnostic information compared with MRI alone in brain metastases. PATIENTS AND METHODS: Eighteen patients with newly diagnosed or suspected recurrence of brain metastases received dynamic 18 F-FACBC PET/MRI. Lesion detection was evaluated on PET and MRI scans in 2 groups depending on prior stereotactic radiosurgery (SRS group) or not (no-SRS group). SUVs, time-activity curves, and volumetric analyses of the lesions were performed. RESULTS: In the no-SRS group, 29/29 brain lesions were defined as "MRI positive." With PET, 19/29 lesions were detected and had high tumor-to-background ratios (TBRs) (D max MR , ≥7 mm; SUV max , 1.2-8.4; TBR, 3.9-25.9), whereas 10/29 lesions were undetected (D max MR , ≤8 mm; SUV max , 0.3-1.2; TBR, 1.0-2.7). In the SRS group, 4/6 lesions were defined as "MRI positive," whereas 2/6 lesions were defined as "MRI negative" indicative of radiation necrosis. All 6 lesions were detected with PET (D max MR , ≥15 mm; SUV max , 1.4-4.2; TBR, 3.6-12.6). PET volumes correlated and were comparable in size with contrast-enhanced MRI volumes but were only partially congruent (mean DSC, 0.66). All time-activity curves had an early peak, followed by a plateau or a decreasing slope. CONCLUSIONS: 18 F-FACBC PET demonstrated uptake in brain metastases from cancer of different origins (lung, gastrointestinal tract, breast, thyroid, and malignant melanoma). However, 18 F-FACBC PET/MRI did not improve detection of brain metastases compared with MRI but might detect tumor tissue beyond contrast enhancement on MRI. 18 F-FACBC PET should be further evaluated in recurrent brain metastases.

A comparison of FDG PET/MR and PET/CT for staging, response assessment, and prognostic imaging biomarkers in lymphoma.

The aim of the current study was to investigate the diagnostic performance of FDG PET/MR compared to PET/CT in a patient cohort including Hodgkins lymphoma, diffuse large B-cell lymphoma, and high-grade B-cell lymphoma at baseline and response assessment. Sixty-one patients were examined with FDG PET/CT directly followed by PET/MR. Images were read by two pairs of nuclear medicine physicians and radiologists. Concordance for lymphoma involvement between PET/MR and the reference standard PET/CT was assessed at baseline and response assessment. Correlation of prognostic biomarkers Deauville score, criteria of response, SUVmax, SUVpeak, and MTV was performed between PET/MR and PET/CT. Baseline FDG PET/MR showed a sensitivity of 92.5% and a specificity 97.9% compared to the reference standard PET/CT (κ 0.91) for nodal sites. For extranodal sites, a sensitivity of 80.4% and a specificity of 99.5% were found (κ 0.84). Concordance in Ann Arbor was found in 57 of 61 patients (κ 0.92). Discrepancies were due to misclassification of region and not lesion detection. In response assessment, a sensitivity of 100% and a specificity 99.9% for all sites combined were found (κ 0.92). There was a perfect agreement on Deauville scores 4 and 5 and criteria of response between the two modalities. Intraclass correlation coefficient (ICC) for SUVmax, SUVpeak, and MTV values showed excellent reliability (ICC > 0.9). FDG PET/MR is a reliable alternative to PET/CT in this patient population, both in terms of lesion detection at baseline staging and response assessment, and for quantitative prognostic imaging biomarkers.

18F-FACBC PET/MRI in the evaluation of human brain metastases: a case report.

BACKGROUND: Patients with metastatic cancer to the brain have a poor prognosis. In clinical practice, MRI is used to delineate, diagnose and plan treatment of brain metastases. However, MRI alone is limited in detecting micro-metastases, delineating lesions and discriminating progression from pseudo-progression. Combined PET/MRI utilises superior soft tissue images from MRI and metabolic data from PET to evaluate tumour structure and function. The amino acid PET tracer 18F-FACBC has shown promising results in discriminating high- and low-grade gliomas, but there are currently no reports on its use on brain metastases. This is the first study to evaluate the use of 18F-FACBC on brain metastases. CASE PRESENTATION: A middle-aged female patient with brain metastases was evaluated using hybrid PET/MRI with 18F-FACBC before and after stereotactic radiotherapy, and at suspicion of recurrence. Static/dynamic PET and contrast-enhanced T1 MRI data were acquired and analysed. This case report includes the analysis of four 18F-FACBC PET/MRI examinations, investigating their utility in evaluating functional and structural metastasis properties. CONCLUSION: Analysis showed high tumour-to-background ratios in brain metastases compared to other amino acid PET tracers, including high uptake in a very small cerebellar metastasis, suggesting that 18F-FACBC PET can provide early detection of otherwise overlooked metastases. Further studies to determine a threshold for 18F-FACBC brain tumour boundaries and explore its utility in clinical practice should be performed.

18F-FACBC PET/MRI in Diagnostic Assessment and Neurosurgery of Gliomas.

PURPOSE: This pilot study aimed to evaluate the amino acid tracer F-FACBC with simultaneous PET/MRI in diagnostic assessment and neurosurgery of gliomas. MATERIALS AND METHODS: Eleven patients with suspected primary or recurrent low- or high-grade glioma received an F-FACBC PET/MRI examination before surgery. PET and MRI were used for diagnostic assessment, and for guiding tumor resection and histopathological tissue sampling. PET uptake, tumor-to-background ratios (TBRs), time-activity curves, as well as PET and MRI tumor volumes were evaluated. The sensitivities of lesion detection and to detect glioma tissue were calculated for PET, MRI, and combined PET/MRI with histopathology (biopsies for final diagnosis and additional image-localized biopsies) as reference. RESULTS: Overall sensitivity for lesion detection was 54.5% (95% confidence interval [CI], 23.4-83.3) for PET, 45.5% (95% CI, 16.7-76.6) for contrast-enhanced MRI (MRICE), and 100% (95% CI, 71.5-100.0) for combined PET/MRI, with a significant difference between MRICE and combined PET/MRI (P = 0.031). TBRs increased with tumor grade (P = 0.004) and were stable from 10 minutes post injection. PET tumor volumes enclosed most of the MRICE volumes (>98%) and were generally larger (1.5-2.8 times) than the MRICE volumes. Based on image-localized biopsies, combined PET/MRI demonstrated higher concurrence with malignant findings at histopathology (89.5%) than MRICE (26.3%). CONCLUSIONS: Low- versus high-grade glioma differentiation may be possible with F-FACBC using TBR. F-FACBC PET/MRI outperformed MRICE in lesion detection and in detection of glioma tissue. More research is required to evaluate F-FACBC properties, especially in grade II and III tumors, and for different subtypes of gliomas.

Correction to: Nonlinear deformation of tractography in ultrasound-guided low-grade gliomas resection.

The author would like to include grant number of NSERC Discovery grant in the acknowledgement section of the original article.

Nonlinear deformation of tractography in ultrasound-guided low-grade gliomas resection.

PURPOSE: In brain tumor surgeries, maximum removal of cancerous tissue without compromising normal brain functions can improve the patient's survival rate and therapeutic benefits. To achieve this, diffusion MRI and intra-operative ultrasound (iUS) can be highly instrumental. While diffusion MRI allows the visualization of white matter tracts and helps define the resection plan to best preserve the eloquent areas, iUS can effectively track the brain shift after craniotomy that often renders the pre-surgical plan invalid, ensuring the accuracy and safety of the intervention. Unfortunately, brain shift correction using iUS and automatic registration has never been shown for brain tractography so far despite its rising significance in brain tumor resection. METHODS: We employed a correlation-ratio-based nonlinear registration algorithm to account for brain shift through MRI-iUS registration and used the recovered deformations to warp both the brain anatomy and tractography seen in pre-surgical plans. The overall technique was demonstrated retrospectively on four patients who underwent iUS-guided low-grade brain gliomas resection. RESULTS: Through qualitative and quantitative evaluations, the preoperative MRI and iUS scans were well realigned after nonlinear registration, and the deformed brain tumor volumes and white matter tracts showed large displacements away from the pre-surgical plans. CONCLUSIONS: We are the first to demonstrate the technique to track nonlinear deformation of brain tractography using real clinical MRI and iUS data, and the results confirm the need for updating white matter tracts due to tissue shift during surgery.

Multimodal 18F-Fluciclovine PET/MRI and Ultrasound-Guided Neurosurgery of an Anaplastic Oligodendroglioma.

BACKGROUND: Structural magnetic resonance imaging (MRI) and histopathologic tissue sampling are routinely performed as part of the diagnostic workup for patients with glioma. Because of the heterogeneous nature of gliomas, there is a risk of undergrading caused by histopathologic sampling errors. MRI has limitations in identifying tumor grade and type, detecting diffuse invasive growth, and separating recurrences from treatment induced changes. Positron emission tomography (PET) can provide quantitative information of cellular activity and metabolism, and may therefore complement MRI. In this report, we present the first patient with brain glioma examined with simultaneous PET/MRI using the amino acid tracer 18F-fluciclovine (18F-FACBC) for intraoperative image-guided surgery. CASE DESCRIPTION: A previously healthy 60-year old woman was admitted to the emergency care with speech difficulties and a mild left-sided hemiparesis. MRI revealed a tumor that was suggestive of glioma. Before surgery, the patient underwent a simultaneous PET/MRI examination. Fused PET/MRI, T1, FLAIR, and intraoperative three-dimensional ultrasound images were used to guide histopathologic tissue sampling and surgical resection. Navigated, image-guided histopathologic samples were compared with PET/MRI image data to assess the additional value of the PET acquisition. Histopathologic analysis showed anaplastic oligodendroglioma in the most malignant parts of the tumor, while several regions were World Health Organization (WHO) grade II. CONCLUSIONS: 18F-Fluciclovine uptake was found in parts of the tumor where regional WHO grade, cell proliferation, and cell densities were highest. This finding suggests that PET/MRI with this tracer could be used to improve accuracy in histopathologic tissue sampling and grading, and possibly for guiding treatments targeting the most malignant part of extensive and eloquent gliomas.

Incidental Intracranial Findings and Their Clinical Impact; The HUNT MRI Study in a General Population of 1006 Participants between 50-66 Years.

OBJECTIVES: Evaluate types and prevalence of all, incidental, and clinically relevant incidental intracranial findings, i.e. those referred to primary physician or clinical specialist, in a cohort between 50 and 66 years from the Nord-Trøndelag Health (HUNT) study. Types of follow-up, outcome of repeated neuroimaging and neurosurgical treatment were assessed. MATERIAL AND METHODS: 1006 participants (530 women) underwent MRI of the head at 1.5T consisting of T1 weighted sagittal IR-FSPGR volume, axial T2 weighted, gradient echo T2* weighted and FLAIR sequences plus time of flight cerebral angiography covering the circle of Willis. The nature of a finding and if it was incidental were determined from previous radiological examinations, patient records, phone interview, and/or additional neuroimaging. Handling and outcome of the clinically relevant incidental findings were prospectively recorded. True and false positives were estimated from the repeated neuroimaging. RESULTS: Prevalence of any intracranial finding was 32.7%. Incidental intracranial findings were present in 27.1% and clinically relevant findings in 15.1% of the participants in the HUNT MRI cohort. 185 individuals (18.4%) were contacted by phone about their findings. 40 participants (6.2%) underwent ≥ 1 additional neuroimaging session to establish etiology. Most false positives were linked to an initial diagnosis of suspected glioma, and overall positive predictive value of initial MRI was 0.90 across different diagnoses. 90.8% of the clinically relevant incidental findings were developmental and acquired cerebrovascular pathologies, the remaining 9.2% were intracranial tumors, of which extra-axial tumors predominated. In total, 3.9% of the participants were referred to a clinical specialist, and 11.7% to their primary physician. 1.4% underwent neurosurgery/radiotherapy, and 1 (0.1%) experienced a procedure related postoperative deficit. CONCLUSIONS: In a general population between 50 and 66 years most intracranial findings on MRI were incidental, and >15% of the cohort was referred to clinical-follow up. Hence good routines for handling of findings need to be in place to ensure timely and appropriate handling.

PET/MR brain imaging: evaluation of clinical UTE-based attenuation correction.

UNLABELLED: One of the greatest challenges in PET/MR imaging is that of accurate MR-based attenuation correction (AC) of the acquired PET data, which must be solved if the PET/MR modality is to reach its full potential. The aim of this study was to investigate the performance of Siemens' most recent version (VB20P) of MR-based AC of head PET data, by comparing it to CT-based AC. METHODS: (18)F-FDG PET data from seven lymphoma and twelve lung cancer patients examined with a Biograph mMR PET/MR system were reconstructed with both CT-based and MR-based AC, avoiding sources of error arising when comparing PET data from different systems. The resulting images were compared quantitatively by measuring changes in mean SUV in ten different brain regions in both hemispheres, as well as the brainstem. In addition, the attenuation maps (µ maps) were compared regarding volume and localization of cranial bone. RESULTS: The UTE µ maps clearly overestimate the amount of bone in the neck, while slightly underestimating the amount of bone in the cranium, and the localization of bone in the cranial region also differ from the CT µ maps. In air/tissue interfaces in the sinuses and ears, the MRAC method struggles to correctly classify the different tissues. The misclassification of tissue is most likely caused by a combination of artefacts and the insufficiency of the UTE method to accurately separate bone. Quantitatively, this results in a combination of overestimation (0.5-3.6 %) and underestimation (2.7-5.2 %) of PET activity throughout the brain, depending on the proximity to the inaccurate regions. CONCLUSIONS: Our results indicate that the performance of the UTE method as implemented in VB20P is close to the theoretical maximum of such an MRAC method in the brain, while it does not perform satisfactorily in the neck or face/nasal area. Further improvement of the UTE MRAC or other available methods for more accurate segmentation of bone should be incorporated.

Being born small for gestational age reduces white matter integrity in adulthood: a prospective cohort study.

BACKGROUND: Being born small for gestational age (SGA) (birth weight <10th percentile) is connected to decreased white matter (WM) integrity in newborns and increased prevalence of psychiatric symptoms in adulthood. The aims of this study were to investigate whether being born SGA at term affects WM integrity in young adulthood and to explore possible relationships between fractional anisotropy (FA) and pre- and perinatal factors and cognitive and psychiatric outcomes in adulthood in SGA and controls. METHODS: Diffusion tensor imaging and tract-based spatial statistics were conducted to test for voxelwise differences in FA in SGAs (n = 46) and controls (n = 57) at 18-22 y. RESULTS: As compared with controls SGAs had reduced FA in ventral association tracts and internal/external capsules. In the SGAs, no relationship was found between FA and intrauterine head growth in the third trimester, although total intelligence quotient was negatively correlated to FA. In controls, a positive correlation was found between FA and brain growth in the third trimester and maternal smoking. No relationship was found between FA and psychiatric measures in SGAs or controls. CONCLUSION: These results demonstrate that being born SGA leads to reduced WM integrity in adulthood, and suggest that different factors modulate the development of WM in SGA and control groups.

Effect of collagenase and hyaluronidase on free and anomalous diffusion in multicellular spheroids and xenografts.

BACKGROUND: A critical step in the delivery of nanomedicines to tumour cells is transporting these particles through the extracellular matrix. Tumour-specific anticancer agents, such as encapsulated drugs, proteins, and genes, show low uptake in tumour tissue. It is not clear whether the collagen network or the glycosaminoglycan gel plays the most important role in limiting the interstitial transport of macromolecules. Therefore, we measured the effect of the collagen- and hyaluronan-degrading enzymes, collagenase and hyaluronidase, on interstitial diffusion. MATERIALS AND METHODS: Human osteosarcomas were grown as multicellular spheroids and xenografts in dorsal skinfold window chambers. Diffusion of fluorescein isothiocyanate (FITC)-dextran molecules was measured by fluorescence recovery after photobleaching based on two-photon scanning laser excitation. RESULTS: Collagenase, hyaluronidase, and relaxin increased the diffusion coefficient of the 2-MDa FITC-dextrans in the spheroids, but 150-kDa FITC-dextran diffusion was not affected by the enzymatic treatment. In tumour tissue in vivo, collagenase and hyaluronidase increased the diffusion of the 150-kDa FITC-dextrans. In xenografts, anomalous diffusion occurred, whereas only free diffusion was seen in spheroids. CONCLUSION: The results indicate that the collagen network has a greater impact on the interstitial diffusion of macromolecules in tumour tissue than the hyaluronan gel.

Diffusion measured by fluorescence recovery after photobleaching based on multiphoton excitation laser scanning microscopy.

Fluorescence recovery after photobleaching (FRAP) is a widely used method to measure diffusion. The technique is normally based on one-photon excitation, which limits diffusion to two dimensions due to extended photobleaching in the axial direction. Multiphoton excitation, on the other hand, creates a well-defined focal volume. In the present work, FRAP based on a scanning laser beam and two-photon excitation is used to measure diffusion of macromolecules in solution and gels, as well as in the extracellular matrix in multicellular spheroids and tumor tissue in dorsal chambers. The bleaching profile is determined experimentally in immobilized gels, and for small scanning areas (approximately twice the lateral radius of the laser beam) a Gaussian bleaching distribution is found. In addition, the bleaching profile is determined theoretically based on the convolution of the Gaussian point spread function and a circular scanning area. The diffusion coefficient is determined by fitting a mathematical model based on a Gaussian laser beam profile to the experimental recovery curve. The diffusion coefficient decreases with increasing complexity of the sample matrix and increasing the amount of collagen in the gels. The potential of using two-photon laser scanning microscopes for noninvasive diffusion measurements in tissue is demonstrated.