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1.
J Neurooncol. 2018 Nov 10. doi: 10.1007/s11060-018-03013-x. [Epub ahead of print]

Imaging tryptophan uptake with positron emission tomography in glioblastoma patients treated with indoximod.

Lukas RV1,2,3, Juhász C4,5, Wainwright DA6,7,8, James CD6,7,8, Kennedy E9, Stupp R10,6,7,8, Lesniak MS6,7,8.

Author information

1
Department of Neurology, Northwestern University, 710 N. Lake Shore Drive, Abbott Hall 1114, Chicago, IL, 60611, USA. rimas.lukas@nm.org.
2
Lurie Cancer Center, Northwestern University, Chicago, USA. rimas.lukas@nm.org.
3
Lou & Jean Malnati Brain Tumor Institute, Northwestern University, Chicago, USA. rimas.lukas@nm.org.
4
Neurology, and Neurosurgery, Department of Pediatrics, Wayne State University, Detroit, USA.
5
Karmanos Cancer Institute, Wayne State University, Detroit, USA.
6
Department of Neurosurgery, Northwestern University, Chicago, USA.
7
Lurie Cancer Center, Northwestern University, Chicago, USA.
8
Lou & Jean Malnati Brain Tumor Institute, Northwestern University, Chicago, USA.
9
NewLink Genetics, Ames, USA.
10
Department of Neurology, Northwestern University, 710 N. Lake Shore Drive, Abbott Hall 1114, Chicago, IL, 60611, USA.

Abstract

INTRODUCTION:

Glioblastoma (GBM) is the most frequent and aggressive primary tumor of the central nervous system, accounting for over 50% of all primary malignant gliomas arising in the adult brain. Even after surgical resection, adjuvant radiotherapy (RT) and temozolomide (TMZ) chemotherapy, as well as tumor-treating fields, the median survival is only 15-20 months. We have identified a pathogenic mechanism that contributes to the tumor-induced immunosuppression in the form of increased indoleamine 2,3 dioxygenase 1 (IDO1) expression; an enzyme that metabolizes the essential amino acid, tryptophan (Trp), into kynurenine (Kyn). However, real-time measurements of IDO1 activity has yet to become mainstream in clinical protocols for assessing IDO1 activity in GBM patients.

METHODS:

Pre-treatment and on-treatment α-[11C]-methyl-L-Trp (AMT) positron emission tomography (PET) with co-registered MRI was performed on patients with recurrent GBM treated with the IDO1 pathway inhibitor indoximod (D1-MT) and TMZ.

RESULTS:

Regional intratumoral variability of AMT within enhancing and non-enhancing tumor was noted at baseline. On treatment imaging revealed decreased regional uptake suggesting IDO1 pathway modulation with treatment.

CONCLUSIONS:

Here, we have validated the ability to use PET of the Trp probe, AMT, for use in visualizing and quantifying intratumoral Trp uptake in GBM patients treated with an IDO1 pathway inhibitor. These data serve as rationale to utilize AMT-PET imaging in the future evaluation of GBM patients treated with IDO1 enzyme inhibitors.

KEYWORDS:

1-MT; AMT; Biomarker; Glioblastoma; IDO; Indoximod; PET

2.
Neuro Oncol. 2018 Oct 22. doi: 10.1093/neuonc/noy169. [Epub ahead of print]

Multimodal Imaging-defined Subregions in Newly-diagnosed Glioblastoma: Impact on Overall Survival.

Author information

1
Department of Pediatrics, Wayne State University, Detroit, Michigan.
2
PET Center and Translational Imaging Laboratory, Children's Hospital of Michigan, Detroit Medical Center, Detroit, Michigan.
3
Department of Oncology, Wayne State University, Detroit, Michigan.
4
Department of Radiology, Wayne State University, Detroit, Michigan.
5
Karmanos Cancer Institute, Detroit, Michigan.
6
Department of Neurology, Wayne State University, Detroit, Michigan.
7
Department of Neurosurgery, Wayne State University, Detroit, Michigan.
8
Department of Biomedical Engineering, Wayne State University, Detroit, Michigan.

Abstract

BACKGROUND:

Although glioblastomas are heterogeneous brain-infiltrating tumors, their treatment is mostly focused on the contrast-enhancing tumor mass. In this study, we combined conventional MRI, diffusion-weighted imaging (DWI), and amino acid PET to explore imaging-defined glioblastoma subregions and evaluate their potential prognostic value.

METHODS:

Contrast-enhanced T1, T2/FLAIR MR images, apparent diffusion coefficient (ADC) maps from DWI, and alpha-[ 11C]-methyl-L-tryptophan (AMT)-PET images were analyzed in 30 patients with newly-diagnosed glioblastoma. Five tumor subregions were identified based on a combination of MRI contrast enhancement, T2/FLAIR signal abnormalities, and AMT uptake on PET. ADC and AMT uptake tumor/contralateral normal cortex (T/N) ratios in these tumor subregions were correlated, and their prognostic value was determined.

RESULTS:

A total of 115 MRI/PET-defined subregions were analyzed. Most tumors showed not only a high-AMT uptake (T/N ratio >1.65, N=27) but also a low-uptake subregion (N=21) within the contrast-enhancing tumor mass. High AMT uptake extending beyond contrast enhancement was also common (N=25) and was associated with low ADC (r=-0.40, p=0.05). Higher AMT uptake in the contrast-enhancing tumor subregions was strongly prognostic for overall survival (HR: 7.83, [95%]CI: 1.98-31.02, p=0.003), independent of clinical and molecular genetic prognostic variables. Non-resected high-AMT uptake subregions predicted the sites of tumor progression on post-treatment PET performed in 10 patients.

CONCLUSIONS:

Glioblastomas show heterogeneous amino acid uptake with high-uptake regions often extending into non-enhancing brain with high cellularity; non-resection of these predict the site of post-treatment progression. High tryptophan uptake values in MRI contrast-enhancing tumor subregions is a strong, independent imaging marker for longer overall survival.

3.
J Child Neurol. 2018 Nov;33(13):832-836. doi: 10.1177/0883073818796373. Epub 2018 Sep 5.

Evolution of Brain Glucose Metabolic Abnormalities in Children With Epilepsy and SCN1A Gene Variants.

Kumar A1, Juhász C1,2,3,4, Luat A2,3, Govil-Dalela T2,3, Behen ME1,2,3, Hicks MA5,6, Chugani HT1,2,3,7,8.

Author information

1
1 PET Center and Translational Imaging Laboratory, Children's Hospital of Michigan, Detroit, MI, USA.
2
2 Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA.
3
3 Department of Neurology, Wayne State University School of Medicine, Detroit, MI, USA.
4
4 Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, USA.
5
5 DMC University Laboratories, Detroit Medical Center, Detroit, MI, USA.
6
6 Center for Molecular Medicine & Genetics, Wayne State University School of Medicine, Detroit, MI, USA.
7
7 Division of Pediatric Neurology, Nemours A.I. DuPont Hospital for Children, Wilmington, DE, USA.
8
8 Thomas Jefferson University, Philadelphia, PA, USA.

Abstract

Three children with drug-refractory epilepsy, normal magnetic resonance image (MRI), and a heterozygous SCN1A variant underwent 2-deoxy-2-[18F]fluoro-d-glucose positron emission tomography (FDG-PET) scanning between age 6 months and 1 year and then at age 3 years 6 months to 5 years 5 months. Regional FDG uptake values were compared to those measured in age- and gender-matched pseudo-controls. At baseline, the brain glucose metabolic pattern in the SCN1A group was similar to that of the pseudo-controls. At follow-up, robust decreases of normalized FDG uptake was found in bilateral frontal, parietal and temporal cortex, with milder decreases in occipital cortex. Children with epilepsy and an SCN1A variant have a normal pattern of cerebral glucose metabolism at around 1 year of age but develop bilateral cortical glucose hypometabolism by age 4 years, with maximal decreases in frontal, parietal, and temporal cortex. This metabolic pattern may be characteristic of epilepsy associated with SCN1A variants and may serve as a biomarker to monitor disease progression and response to treatments.

KEYWORDS:

FDG-PET; SCN1A; epilepsy; genetics; longitudinal

4.
Hum Brain Mapp. 2018 Aug 23. doi: 10.1002/hbm.24354. [Epub ahead of print]

Objective PET study of glucose metabolism asymmetries in children with epilepsy: Implications for normal brain development.

Pilli VK1,2, Jeong JW1,3,2, Konka P1,2, Kumar A1,3,2, Chugani HT1,3,2, Juhász C1,3,2.

Author information

1
The Carman and Ann Adams Department of Pediatrics, Wayne State University, Detroit, Michigan.
2
PET Center and Translational Imaging Laboratory, Children's Hospital of Michigan, Detroit, Michigan.
3
Department of Neurology, Wayne State University, Detroit, Michigan.

Abstract

Clinical interpretation of cerebral positron emission tomography with 2-deoxy-2[F-18]fluoro-d-glucose (FDG-PET) images often relies on evaluation of regional asymmetries. This study was designed to establish age-related variations in regional cortical glucose metabolism asymmetries in the developing human brain. FDG-PET scans of 58 children (age: 1-18 years) were selected from a large single-center pediatric PET database. All children had a history of epilepsy, normal MRI, and normal pattern of glucose metabolism on visual evaluation. PET images were analyzed objectively by statistical parametric mapping with the use of age-specific FDG-PET templates. Regional FDG uptake was measured in 35 cortical regions in both hemispheres using an automated anatomical labeling atlas, and left/right ratios were correlated with age, gender, and epilepsy variables. Cortical glucose metabolism was mostly symmetric in young children and became increasingly asymmetric in older subjects. Specifically, several frontal cortical regions showed an age-related increase of left > right asymmetries (mean: up to 10%), while right > left asymmetries emerged in posterior cortex (including portions of the occipital, parietal, and temporal lobe) in older children (up to 9%). Similar trends were seen in a subgroup of 39 children with known right-handedness. Age-related correlations of regional metabolic asymmetries showed no robust gender differences and were not affected by epilepsy variables. These data demonstrate a region-specific emergence of cortical metabolic asymmetries between age 1-18 years, with left > right asymmetry in frontal and right > left asymmetry in posterior regions. The findings can facilitate correct interpretation of cortical regional asymmetries on pediatric FDG-PET images across a wide age range.

KEYWORDS:

asymmetry; brain development; children; cortex; glucose metabolism; positron emission tomography

PMID:
30136325
DOI:
10.1002/hbm.24354
Icon for Wiley

Publication type

Publication type

5.
Pediatr Neurol. 2018 Jul;84:11-20. doi: 10.1016/j.pediatrneurol.2018.04.005. Epub 2018 Apr 18.

A Multidisciplinary Consensus for Clinical Care and Research Needs for Sturge-Weber Syndrome.

Author information

1
Department of Neurology, Northwestern University, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.
2
Department of Pediatrics and Neurology, Wayne State University, Children's Hospital of Michigan, Detroit, Michigan.
3
Department of Radiology, Mayo Clinic, Rochester, Minnesota.
4
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.
5
Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida.
6
School of Communication Studies, Ohio University, Athens, Ohio.
7
Department of Pediatric Pathology, Medical College of Wisconsin, Milwaukee, Wisconsin.
8
Department of Dermatology, University of North Carolina, Chapel Hill, North Carolina.
9
Department of Neurology, Nemours DuPont Hospital for Children, Wilmington, Delaware.
10
The Sturge-Weber Foundation, Houston, Texas.
11
Department of Neurology, Harvard Medical School, Children's Hospital Boston, Boston, Massachusetts.
12
Department of Neurology and Rehabilitation, University of Illinois, Chicago, Illinois. Electronic address: jaloeb@uic.edu.

Abstract

BACKGROUND:

Sturge-Weber syndrome is a neurocutaneous disorder associated with port-wine birthmark, leptomeningeal capillary malformations, and glaucoma. It is associated with an unpredictable clinical course. Because of its rarity and complexity, many physicians are unaware of the disease and its complications. A major focus moving ahead will be to turn knowledge gaps and unmet needs into new research directions.

METHODS:

On October 1-3, 2017, the Sturge-Weber Foundation assembled clinicians from the Clinical Care Network with patients from the Patient Engagement Network of the Sturge-Weber Foundation to identify our current state of knowledge, knowledge gaps, and unmet needs.

RESULTS:

One clear unmet need is a need for consensus guidelines on care and surveillance. It was strongly recommended that patients be followed by multidisciplinary clinical teams with life-long follow-up for children and adults to monitor disease progression in the skin, eye, and brain. Standardized neuroimaging modalities at specified time points are needed together with a stronger clinicopathologic understanding. Uniform tissue banking and clinical data acquisition strategies are needed with cross-center, longitudinal studies that will set the stage for new clinical trials. A better understanding of the pathogenic roles of cerebral calcifications and stroke-like symptoms is a clear unmet need with potentially devastating consequences.

CONCLUSIONS:

Biomarkers capable of predicting disease progression will be needed to advance new therapeutic strategies. Importantly, how to deal with the emotional and psychological effects of Sturge-Weber syndrome and its impact on quality of life is a clear unmet need.

KEYWORDS:

Consensus statement; Imaging; Sturge-Weber syndrome; Treatment

Publication type

Publication type

6.
Epilepsia. 2018 Jul;59(7):1307-1315. doi: 10.1111/epi.14404. Epub 2018 May 22.

Evolution of lobar abnormalities of cerebral glucose metabolism in 41 children with drug-resistant epilepsy.

Govil-Dalela T1,2, Kumar A1,2,3,4, Behen ME1,4, Chugani HT1,2,4,5,6, Juhász C1,2,4,7.

Author information

1
Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA.
2
Department of Neurology, Wayne State University School of Medicine, Detroit, MI, USA.
3
Department of Radiology, Wayne State University School of Medicine, Detroit, MI, USA.
4
PET Center and Translational Imaging Laboratory, Children's Hospital of Michigan, Detroit, MI, USA.
5
Division of Pediatric Neurology, Nemours A. I. DuPont Hospital for Children, Wilmington, DE, USA.
6
Departments of Neurology and Pediatrics, Sidney Kimmel College of Medicine at Thomas Jefferson University, Philadelphia, PA, USA.
7
Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, USA.

Abstract

OBJECTIVE:

We analyzed long-term changes of lobar glucose metabolic abnormalities in relation to clinical seizure variables and development in a large group of children with medically refractory epilepsy.

METHODS:

Forty-one children (25 males) with drug-resistant epilepsy had a baseline positron emission tomography (PET) scan at a median age of 4.7 years; the scans were repeated after a median of 4.3 years. Children with progressive neurological disorders or space-occupying lesion-related epilepsy and those who had undergone epilepsy surgery were excluded. The number of affected lobes on 2-deoxy-2(18 F)-fluoro-D-glucose-PET at baseline and follow-up was correlated with epilepsy variables and developmental outcome.

RESULTS:

On the initial PET scan, 24 children had unilateral and 13 had bilateral glucose hypometabolism, whereas 4 children had normal scans. On the follow-up scan, 63% of the children showed an interval expansion of the hypometabolic region, and this progression was associated with persistent seizures. In contrast, 27% showed less extensive glucose hypometabolism at follow-up; most of these subjects manifested a major interval decrease in seizure frequency. Delayed development was observed in 21 children (51%) at baseline and 28 (68%) at follow-up. The extent of glucose hypometabolism at baseline correlated with developmental levels at the time of both baseline (r = .31, P = .05) and follow-up scans (r = .27, P = .09).

SIGNIFICANCE:

In this PET study of unoperated children with focal epilepsy, the lobar pattern of glucose hypometabolism changed over time in 90% of the cases. The results support the notion of an expansion of metabolic dysfunction in children with persistent frequent seizures and its association with developmental delay, and support that optimized medical treatment to control seizures may contribute to better neurocognitive outcome if no surgery can be offered.

KEYWORDS:

development; follow-up; pediatric epilepsy; positron emission tomography; seizure frequency

PMID:
29786852
PMCID:
PMC6031462
[Available on 2019-07-01]
DOI:
10.1111/epi.14404
Icon for Wiley
7.
Ann Clin Transl Neurol. 2018 Mar 12;5(4):502-506. doi: 10.1002/acn3.546. eCollection 2018 Apr.

Deep cerebral vein expansion with metabolic and neurocognitive recovery in Sturge-Weber syndrome.

Author information

1
Departments of Pediatrics and Neurology Wayne State University School of Medicine Children's Hospital of Michigan Detroit Medical Center Detroit Michigan.
2
Texas Child Neurology Plano Texas.

Abstract

We present longitudinal imaging data of a child with Sturge-Weber syndrome (SWS). At age 8 months, 3 weeks after initial seizures and prolonged motor deficit, MRI showed extensive right hemispheric SWS involvement with severe glucose hypometabolism on PET. She was treated with levetiracetam and aspirin. Follow-up imaging at age 29 months showed a robust interval expansion of enlarged deep medullary veins throughout the affected hemisphere along with a dramatic recovery of hemispheric metabolism and normalized neurocognitive functioning. These findings demonstrate a robust, multilobar hemispheric remodeling of deep venous collaterals that likely contributed to reversal of initial metabolic and neurocognitive deficits.

8.
J Neurooncol. 2018 Sep;139(2):239-249. doi: 10.1007/s11060-018-2869-6. Epub 2018 Apr 17.

Investigation of the aryl hydrocarbon receptor and the intrinsic tumoral component of the kynurenine pathway of tryptophan metabolism in primary brain tumors.

Author information

1
Department of Neurosurgery, Wayne State University, Detroit, MI, USA.
2
Department of Oncology, Wayne State University, Detroit, MI, USA.
3
Department of Pathology, Wayne State University, Detroit, MI, USA.
4
Department of Neurology, Wayne State University, Detroit, MI, USA.
5
Department of Pediatrics, Wayne State University, Detroit, MI, USA.
6
PET Center and Translational Imaging Laboratory, Children's Hospital of Michigan, Detroit, MI, USA.
7
Karmanos Cancer Institute, Detroit, MI, USA.
8
Department of Neurosurgery, Wayne State University, Detroit, MI, USA. smittal@med.wayne.edu.
9
Department of Oncology, Wayne State University, Detroit, MI, USA. smittal@med.wayne.edu.
10
Department of Biomedical Engineering, Wayne State University, Detroit, MI, USA. smittal@med.wayne.edu.
11
Karmanos Cancer Institute, Detroit, MI, USA. smittal@med.wayne.edu.

Abstract

INTRODUCTION:

There is mounting evidence supporting the role of tryptophan metabolism via the kynurenine pathway (KP) in the pathogenesis of primary brain tumors. Under normal physiological conditions, the KP is the major catabolic pathway for the essential amino acid tryptophan. However, in cancer cells, the KP becomes dysregulated, depletes local tryptophan, and contributes to an immunosuppressive tumor microenvironment.

METHODS:

We examined the protein expression levels (in 73 gliomas and 48 meningiomas) of the KP rate-limiting enzymes indoleamine 2,3-dioxygenase (IDO) 1, IDO2, and tryptophan 2,3-dioxygenase (TDO2), as well as, the aryl hydrocarbon receptor (AhR), a carcinogenic transcription factor activated by KP metabolites. In addition, we utilized commercially available small-molecules to pharmacologically modulate IDO1, IDO2, TDO2, and AhR in patient-derived glioma and meningioma cell lines (n = 9 each).

RESULTS:

We observed a positive trend between the grade of the tumor and the average immunohistochemical staining score for IDO1, IDO2, and TDO2, with TDO2 displaying the strongest immunostaining. AhR immunostaining was present in all grades of gliomas and meningiomas, with the greatest staining intensity noted in glioblastomas. Immunocytochemical staining showed a positive trend between nuclear localization of AhR and histologic grade in both gliomas and meningiomas, suggesting increased AhR activation with higher tumor grade. Unlike enzyme inhibition, AhR antagonism markedly diminished patient-derived tumor cell viability, regardless of tumor type or grade, following in vitro drug treatments.

CONCLUSIONS:

Collectively, these results suggest that AhR may offer a novel and robust therapeutic target for a patient population with highly limited treatment options.

KEYWORDS:

Aryl hydrocarbon receptor; Gliomas; Immunosuppressive kynurenine pathway; Meningiomas; Primary patient-derived tumor cells; Tryptophan metabolism

PMID:
29667084
PMCID:
PMC6092214
[Available on 2019-09-01]
DOI:
10.1007/s11060-018-2869-6
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9.
Epilepsy Behav. 2018 Mar;80:202-207. doi: 10.1016/j.yebeh.2018.01.012. Epub 2018 Feb 3.

Cognitive and motor outcomes in children with unilateral Sturge-Weber syndrome: Effect of age at seizure onset and side of brain involvement.

Author information

1
Departments of Pediatrics and Neurology, Wayne State University School of Medicine, Children's Hospital of Michigan, Detroit Medical Center, 3901 Beaubien St., Detroit, MI 48201, USA. Electronic address: aluat@dmc.org.
2
Departments of Pediatrics and Neurology, Wayne State University School of Medicine, Children's Hospital of Michigan, Detroit Medical Center, 3901 Beaubien St., Detroit, MI 48201, USA.
3
Departments of Pediatrics and Neurology, Wayne State University School of Medicine, Children's Hospital of Michigan, Detroit Medical Center, 3901 Beaubien St., Detroit, MI 48201, USA; Department of Neurology, School of Medicine, Thomas Jefferson University, Philadelphia, PA, USA; Division of Pediatric Neurology, Nemours A.I. DuPont Hospital for Children, 1600 Rockland Rd., Wilmington, Delaware, 19803, USA.

Abstract

PURPOSE:

Most children with Sturge-Weber syndrome (SWS) develop seizures that may contribute to neurocognitive status. In this study, we tested the hypothesis that very early seizure onset has a particularly detrimental effect on the cognitive and/or motor outcomes of children with unilateral SWS. We also tested whether side of SWS brain involvement modulates the effect of seizure variables on the pattern of cognitive abnormalities.

METHODS:

Thirty-four children (22 girls; mean age 6.1years) with unilateral SWS and history of epilepsy in a longitudinal cohort underwent neurological and cognitive evaluations. Global intelligent quotient (GIQ), verbal intelligent quotient (VIQ), nonverbal intelligent quotient (IQ), and motor function were correlated with epilepsy variables, side and extent of brain involvement on magnetic resonance imaging (MRI).

RESULTS:

Mean age at seizure onset was 1.3years (0.1-6years) and mean IQ at follow-up was 86 (45-118). Age at seizure onset showed a logarithmic association with IQ, with maximum impact of seizures starting before age 1year, both in uni- and multivariate regression analyses. In the left SWS group (N=20), age at seizure onset was a strong predictor of nonverbal IQ (p=0.001); while early seizure onset in the right-hemispheric group had a more global effect on cognitive functions (p=0.02). High seizure frequency and long epilepsy duration also contributed to poor outcome IQ independently in multivariate correlations. Children with motor involvement started to have seizures at/before 7months of age, while frontal lobe involvement was the strongest predictor of motor deficit in a multivariate analysis (p=0.017).

CONCLUSION:

These findings suggest that seizure onset prior to age 1year has a profound effect on severity of cognitive and motor dysfunction in children with SWS; however, the effect of seizures on the type of cognitive deficit is influenced by laterality of brain involvement.

KEYWORDS:

Cognitive function; Epilepsy; Outcome; Seizure onset; Sturge–Weber syndrome

PMID:
29414553
PMCID:
PMC5845773
[Available on 2019-03-01]
DOI:
10.1016/j.yebeh.2018.01.012
Icon for Elsevier Science
10.
Hum Brain Mapp. 2018 Apr;39(4):1596-1606. doi: 10.1002/hbm.23937. Epub 2017 Dec 23.

Metabolic correlates of cognitive function in children with unilateral Sturge-Weber syndrome: Evidence for regional functional reorganization and crowding.

Kim JA1,2, Jeong JW1,2,3, Behen ME1,2, Pilli VK1,2, Luat A2,3, Chugani HT1,2,3,4,5, Juhász C1,2,3.

Author information

1
PET Center and Translational Imaging Laboratory, Children's Hospital of Michigan, Detroit, Michigan, USA.
2
The Carman and Ann Adams Department of Pediatrics, Wayne State University School of Medicine, Detroit, Michigan, USA.
3
Department of Neurology, Wayne State University School of Medicine, Detroit, Michigan, USA.
4
Department of Neurology, Nemours DuPont Hospital for Children, Wilmington, Delaware, USA.
5
Department of Neurology, School of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.

Abstract

To evaluate metabolic changes in the ipsi- and contralateral hemisphere in children showing a cognitive profile consistent with early reorganization of cognitive function, we evaluated the regional glucose uptake, interhemispheric metabolic connectivity, and cognitive function in children with unilateral SWS. Interictal 2-deoxy-2[18 F]fluoro-D-glucose (FDG)-PET scans of 27 children with unilateral SWS and mild epilepsy and 27 age-matched control (non-SWS children with epilepsy and normal FDG-PET) were compared using statistical parametric mapping (SPM). Regional FDG-PET abnormalities calculated as SPM(t) scores in the SWS group were correlated with cognitive function (IQ) in left- and right-hemispheric subgroups. Interhemispheric metabolic connectivity between homotopic cortical regions was also calculated. Verbal IQ was substantially (≥10 points difference) higher than non-verbal IQ in 61% of the right- and 71% of the left-hemispheric SWS group. FDG SPM(t) scores in the affected hemisphere showed strong positive correlations with IQ in the left-hemispheric, but not in right-hemispheric SWS group in several frontal, parietal, and temporal cortical regions. Significant positive interhemispheric metabolic connectivity, present in controls, was diminished in the SWS group. In addition, the left-hemispheric SWS group showed inverse metabolic interhemispheric correlations in specific parietal, temporal, and occipital regions. FDG SPM(t) scores in the same regions of the right (unaffected) hemisphere showed inverse correlations with IQ. These findings suggest that left-hemispheric lesions in SWS often result in early reorganization of verbal functions while interfering with ("crowding") their non-verbal cognitive abilities. These cognitive changes are associated with specific metabolic abnormalities in the contralateral hemisphere not directly affected by SWS.

KEYWORDS:

PET; cognitive function; crowding; metabolic connectivity; reorganization; sturge-weber syndrome

PMID:
29274110
PMCID:
PMC5847469
[Available on 2019-04-01]
DOI:
10.1002/hbm.23937
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11.
Neuropediatrics. 2017 Oct;48(5):385-389. doi: 10.1055/s-0037-1603515. Epub 2017 Jun 1.

GNAQ Mutation in the Venous Vascular Malformation and Underlying Brain Tissue in Sturge-Weber Syndrome.

Author information

1
Department of Pediatrics, Wayne State University, Detroit, Michigan, United States.
2
Children's Hospital of Michigan, Detroit, Michigan, United States.
3
Department of Neurology, Wayne State University, Detroit, Michigan, United States.
4
Department of Neurosurgery, Wayne State University, Detroit, Michigan, United States.
5
Department of Pathology, Wayne State University, Detroit, Michigan, United States.
6
Division of Pediatric Neurology, Nemours Alfred I. DuPont Hospital for Children, Wilmington, Delaware, United States.
7
Thomas Jefferson University School of Medicine, Philadelphia, Pennsylvania, United States.
8
Department of Oncology, Wayne State University, Detroit, Michigan, United States.
PMID:
28571101
PMCID:
PMC5587372
DOI:
10.1055/s-0037-1603515
[Indexed for MEDLINE]
Free PMC Article
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12.
Dev Med Child Neurol. 2017 Sep;59(9):952-958. doi: 10.1111/dmcn.13433. Epub 2017 Apr 11.

Clinical and metabolic correlates of cerebral calcifications in Sturge-Weber syndrome.

Author information

1
Division of Pediatric Neurology, The Carman and Ann Adams Department of Pediatrics, Children's Hospital of Michigan, Wayne State University, Detroit, MI, USA.
2
Department of Radiology, Wayne State University, Detroit, MI, USA.
3
Department of Family Medicine and Public Health Sciences, Wayne State University, Detroit, MI, USA.
4
Division of Neurology, Nemours/Alfred I DuPont Hospital for Children, Wilmington, DE, USA.

Abstract

AIM:

To evaluate clinical and metabolic correlates of cerebral calcifications in children with Sturge-Weber syndrome (SWS).

METHOD:

Fifteen children (11 females, four males; age range 7mo-9y, mean 4y 1mo) with unilateral SWS underwent baseline and follow-up magnetic resonance imaging (MRI) with susceptibility weighted imaging (SWI), glucose metabolism positron emission tomography (PET), and neurocognitive assessment (mean follow-up 1y 8mo). Calcified brain volumes measured on SWI were correlated with areas of abnormal glucose metabolism, seizure variables, and cognitive function (IQ).

RESULTS:

Ten children had brain calcification at baseline and 11 at follow-up. Mean calcified brain volume increased from 1.69 to 2.47cm3 (p=0.003) in these children; the rate of interval calcified volume increase was associated with early onset of epilepsy (Spearman's rho [rs ]=-0.63, p=0.036). Calcified brain regions showed a variable degree of glucose hypometabolism with the metabolic abnormalities often extending to non-calcified cerebral lobes. Larger calcified brain volumes at baseline were associated with longer duration of epilepsy (rs =0.69, p=0.004) and lower outcome IQ (rs =-0.53, p=0.042).

INTERPRETATION:

Brain calcifications are common and progress faster in children with SWS with early epilepsy onset, and are associated with a variable degree of hypometabolism, which is typically more extensive than the calcified area. Higher calcified brain volumes may indicate a risk for poorer neurocognitive outcome.

PMID:
28397986
PMCID:
PMC5568960
DOI:
10.1111/dmcn.13433
[Indexed for MEDLINE]
Free PMC Article
Icon for Wiley Icon for PubMed Central
13.
Hum Brain Mapp. 2017 Jun;38(6):3098-3112. doi: 10.1002/hbm.23577. Epub 2017 Mar 21.

Objective 3D surface evaluation of intracranial electrophysiologic correlates of cerebral glucose metabolic abnormalities in children with focal epilepsy.

Author information

1
Departments of Pediatrics and Neurology, School of Medicine, Wayne State University, Detroit, Michigan.
2
Translational Imaging Laboratory, PET Center, Children's Hospital of Michigan, Detroit, Michigan.
3
Department of Neurology, Nemours DuPont Hospital for Children, Wilmington, Delaware.
4
Thomas Jefferson University School of Medicine, Philadelphia, Pennysylvania.

Abstract

To determine the spatial relationship between 2-deoxy-2[18 F]fluoro-D-glucose (FDG) metabolic and intracranial electrophysiological abnormalities in children undergoing two-stage epilepsy surgery, statistical parametric mapping (SPM) was used to correlate hypo- and hypermetabolic cortical regions with ictal and interictal electrocorticography (ECoG) changes mapped onto the brain surface. Preoperative FDG-PET scans of 37 children with intractable epilepsy (31 with non-localizing MRI) were compared with age-matched pseudo-normal pediatric control PET data. Hypo-/hypermetabolic maps were transformed to 3D-MRI brain surface to compare the locations of metabolic changes with electrode coordinates of the ECoG-defined seizure onset zone (SOZ) and interictal spiking. While hypometabolic clusters showed a good agreement with the SOZ on the lobar level (sensitivity/specificity = 0.74/0.64), detailed surface-distance analysis demonstrated that large portions of ECoG-defined SOZ and interictal spiking area were located at least 3 cm beyond hypometabolic regions with the same statistical threshold (sensitivity/specificity = 0.18-0.25/0.94-0.90 for overlap 3-cm distance); for a lower threshold, sensitivity for SOZ at 3 cm increased to 0.39 with a modest compromise of specificity. Performance of FDG-PET SPM was slightly better in children with smaller as compared with widespread SOZ. The results demonstrate that SPM utilizing age-matched pseudocontrols can reliably detect the lobe of seizure onset. However, the spatial mismatch between metabolic and EEG epileptiform abnormalities indicates that a more complete SOZ detection could be achieved by extending intracranial electrode coverage at least 3 cm beyond the metabolic abnormality. Considering that the extent of feasible electrode coverage is limited, localization information from other modalities is particularly important to optimize grid coverage in cases of large hypometabolic cortex. Hum Brain Mapp 38:3098-3112, 2017.

KEYWORDS:

FDG PET; SPM; electrocorticography; epilepsy surgery; pediatric epilepsy; seizure onset

PMID:
28322026
PMCID:
PMC5475408
DOI:
10.1002/hbm.23577
[Indexed for MEDLINE]
Free PMC Article
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14.
J Neurosurg. 2018 Feb;128(2):414-421. doi: 10.3171/2016.9.JNS16452. Epub 2017 Feb 24.

Alternating electric tumor treating fields for treatment of glioblastoma: rationale, preclinical, and clinical studies.

Author information

1
Departments of 1 Neurosurgery.
2
Oncology.
3
Karmanos Cancer Institute, Wayne State University, Detroit, Michigan.
4
Neurology, and.
5
Department of Neurological Surgery, NewYork-Presbyterian Hospital/Weill Cornell Medical Center, New York; and.
6
Department of Biomedical Engineering, Cornell University, Ithaca, New York.
7
Pediatrics.

Abstract

OBJECTIVE Treatment for glioblastoma (GBM) remains largely unsuccessful, even with aggressive combined treatment via surgery, radiotherapy, and chemotherapy. Tumor treating fields (TTFs) are low-intensity, intermediate-frequency, alternating electric fields that have antiproliferative properties in vitro and in vivo. The authors provide an up-to-date review of the mechanism of action as well as preclinical and clinical data on TTFs. METHODS A systematic review of the literature was performed using the terms "tumor treating fields," "alternating electric fields," "glioblastoma," "Optune," "NovoTTF-100A," and "Novocure." RESULTS Preclinical and clinical data have demonstrated the potential efficacy of TTFs for treatment of GBM, leading to several pilot studies, clinical trials, and, in 2011, FDA approval for its use as salvage therapy for recurrent GBM and, in 2015, approval for newly diagnosed GBM. CONCLUSIONS Current evidence supports the use of TTFs as an efficacious, antimitotic treatment with minimal toxicity in patients with newly diagnosed and recurrent GBM. Additional studies are needed to further optimize patient selection, determine cost-effectiveness, and assess the full impact on quality of life.

KEYWORDS:

GBM = glioblastoma; LYG = life years gained; MDR = multidrug resistant; NSCLC = non–small cell lung cancer; NovoTTF-100A; OS = overall survival; Optune; PFS = progression-free survival; QALY = quality-adjusted life year; QOL = quality of life; TMZ = temozolomide; TTF = tumor treating field; TTP = time to disease progression; alternating electric fields; newly diagnosed glioblastoma; oncology; recurrent glioblastoma; tumor treating fields

15.
Clin Nucl Med. 2017 May;42(5):341-347. doi: 10.1097/RLU.0000000000001577.

Prognostic Molecular and Imaging Biomarkers in Primary Glioblastoma.

Author information

1
From the Department of *Pediatrics, Wayne State University, Detroit; †PET Center and Translational Imaging Laboratory, Children's Hospital of Michigan, Detroit; Departments of ‡Neurosurgery, and §Neurology, Wayne State University, Detroit; ∥Karmanos Cancer Institute, Detroit; and ¶Deparment of Oncology, Wayne State University, Detroit, Michigan.

Abstract

PURPOSE:

Several molecular glioma markers (including isocitrate dehydrogenase 1 [IDH1] mutation, amplification of the epidermal growth factor receptor [EGFR], and methylation of the O6-methylguanine-DNA methyltransferase [MGMT] promoter) have been associated with glioblastoma survival. In this study, we examined the association between tumoral amino acid uptake, molecular markers, and overall survival in patients with IDH1 wild-type (primary) glioblastoma.

PATIENTS AND METHODS:

Twenty-one patients with newly diagnosed IDH1 wild-type glioblastomas underwent presurgical MRI and PET scanning with alpha[C-11]-L-methyl-tryptophan (AMT). MRI characteristics (T2- and T1-contrast volume), tumoral tryptophan uptake, PET-based metabolic tumor volume, and kinetic variables were correlated with prognostic molecular markers (EGFR and MGMT) and overall survival.

RESULTS:

EGFR amplification was associated with lower T1-contrast volume (P = 0.04) as well as lower T1-contrast/T2 volume (P = 0.04) and T1-contrast/PET volume ratios (P = 0.02). Tumors with MGMT promoter methylation showed lower metabolic volume (P = 0.045) and lower tumor/cortex AMT unidirectional uptake ratios than those with unmethylated MGMT promoter (P = 0.009). While neither EGFR amplification nor MGMT promoter methylation was significantly associated with survival, high AMT tumor/cortex uptake ratios on PET were strongly prognostic for longer survival (hazards ratio, 30; P = 0.002). Estimated mean overall survival was 26 months in patients with high versus 8 months in those with low tumoral AMT uptake ratios.

CONCLUSIONS:

The results demonstrate specific MRI and amino acid PET imaging characteristics associated with EGFR amplification and MGMT promoter methylation in patients with primary glioblastoma. High tryptophan uptake on PET may identify a subgroup with prolonged survival.

PMID:
28195901
PMCID:
PMC5380523
DOI:
10.1097/RLU.0000000000001577
[Indexed for MEDLINE]
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16.
Pediatr Neurol Briefs. 2016 Nov;30(11):43.

Predicting and Preventing Epilepsy in Sturge-Weber Syndrome?

Author information

1
Department of Pediatrics and Neurology, Wayne State University School of Medicine, Children's Hospital of Michigan, Detroit, MI.

Abstract

Investigators from the University of Montreal studied potential predictors of epilepsy in young patients with Sturge-Weber syndrome (SWS).

KEYWORDS:

Developmental Venous Anomaly; Epilepsy; Sturge-Weber syndrome

17.
Neurology. 2017 Jan 3;88(1):103-105. doi: 10.1212/WNL.0000000000003455. Epub 2016 Nov 18.

Enlargement of deep medullary veins during the early clinical course of Sturge-Weber syndrome.

Author information

1
From Wayne State University (V.K.P., H.T.C., C.J.); Children's Hospital of Michigan (V.K.P., H.T.C., C.J.), Detroit; and Nemours/Alfred I. DuPont Hospital for Children (H.T.C.), Wilmington, DE.
2
From Wayne State University (V.K.P., H.T.C., C.J.); Children's Hospital of Michigan (V.K.P., H.T.C., C.J.), Detroit; and Nemours/Alfred I. DuPont Hospital for Children (H.T.C.), Wilmington, DE. juhasz@pet.wayne.edu.
PMID:
27864521
PMCID:
PMC5200860
DOI:
10.1212/WNL.0000000000003455
[Indexed for MEDLINE]
Free PMC Article
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18.
J Nucl Med. 2017 Feb;58(2):208-213. doi: 10.2967/jnumed.116.179994. Epub 2016 Oct 20.

Assessment of Tryptophan Uptake and Kinetics Using 1-(2-18F-Fluoroethyl)-l-Tryptophan and α-11C-Methyl-l-Tryptophan PET Imaging in Mice Implanted with Patient-Derived Brain Tumor Xenografts.

Author information

1
Department of Neurosurgery, Wayne State University, Detroit, Michigan.
2
Department of Pediatrics, Wayne State University, Detroit, Michigan.
3
Department of Radiology, Wayne State University, Detroit, Michigan.
4
PET Center and Translational Imaging Laboratory, Children's Hospital of Michigan, Detroit, Michigan.
5
Department of Oncology, Wayne State University, Detroit, Michigan.
6
Karmanos Cancer Institute, Detroit, Michigan.
7
Department of Radiology and Advanced Imaging Research Center, University of Texas Southwestern, Dallas, Texasand.
8
Department of Neurology, Wayne State University, Detroit, Michigan.
9
Department of Neurosurgery, Wayne State University, Detroit, Michigan smittal@med.wayne.edu.

Abstract

Abnormal tryptophan metabolism via the kynurenine pathway is involved in the pathophysiology of a variety of human diseases including cancers. α-11C-methyl-l-tryptophan (11C-AMT) PET imaging demonstrated increased tryptophan uptake and trapping in epileptic foci and brain tumors, but the short half-life of 11C limits its widespread clinical application. Recent in vitro studies suggested that the novel radiotracer 1-(2-18F-fluoroethyl)-l-tryptophan (18F-FETrp) may be useful to assess tryptophan metabolism via the kynurenine pathway. In this study, we tested in vivo organ and tumor uptake and kinetics of 18F-FETrp in patient-derived xenograft mouse models and compared them with 11C-AMT uptake.

METHODS:

Xenograft mouse models of glioblastoma and metastatic brain tumors (from lung and breast cancer) were developed by subcutaneous implantation of patient tumor fragments. Dynamic PET scans with 18F-FETrp and 11C-AMT were obtained for mice bearing human brain tumors 1-7 d apart. The biodistribution and tumoral SUVs for both tracers were compared.

RESULTS:

18F-FETrp showed prominent uptake in the pancreas and no bone uptake, whereas 11C-AMT showed higher uptake in the kidneys. Both tracers showed uptake in the xenograft tumors, with a plateau of approximately 30 min after injection; however, 18F-FETrp showed higher tumoral SUV than 11C-AMT in all 3 tumor types tested. The radiation dosimetry for 18F-FETrp determined from the mouse data compared favorably with the clinical 18F-FDG PET tracer.

CONCLUSION:

18F-FETrp tumoral uptake, biodistribution, and radiation dosimetry data provide strong preclinical evidence that this new radiotracer warrants further studies that may lead to a broadly applicable molecular imaging tool to examine abnormal tryptophan metabolism in human tumors.

KEYWORDS:

brain metastasis; glioblastoma; indoleamine 2,3-dioxygenase

PMID:
27765857
PMCID:
PMC5288739
DOI:
10.2967/jnumed.116.179994
[Indexed for MEDLINE]
Free PMC Article
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19.
Childs Nerv Syst. 2016 Oct;32(10):1823-32. doi: 10.1007/s00381-016-3125-z. Epub 2016 Sep 20.

PET and SPECT studies in children with hemispheric low-grade gliomas.

Juhász C1,2,3,4, Bosnyák E5,6.

Author information

1
Departments of Pediatrics, Wayne State University, Detroit, MI, USA. juhasz@pet.wayne.edu.
2
Departments of Neurology, Wayne State University, Detroit, MI, USA. juhasz@pet.wayne.edu.
3
PET Center and Translational Imaging Laboratory, Children's Hospital of Michigan, Wayne State University School of Medicine, 3901 Beaubien Street, Detroit, MI, 48201, USA. juhasz@pet.wayne.edu.
4
Karmanos Cancer Institute, Detroit, MI, USA. juhasz@pet.wayne.edu.
5
Departments of Pediatrics, Wayne State University, Detroit, MI, USA.
6
PET Center and Translational Imaging Laboratory, Children's Hospital of Michigan, Wayne State University School of Medicine, 3901 Beaubien Street, Detroit, MI, 48201, USA.

Abstract

Molecular imaging is playing an increasing role in the pretreatment evaluation of low-grade gliomas. While glucose positron emission tomography (PET) can be helpful to differentiate low-grade from high-grade tumors, PET imaging with amino acid radiotracers has several advantages, such as better differentiation between tumors and non-tumorous lesions, optimized biopsy targeting, and improved detection of tumor recurrence. This review provides a brief overview of single-photon emission computed tomography (SPECT) studies followed by a more detailed review of the clinical applications of glucose and amino acid PET imaging in low-grade hemispheric gliomas. We discuss key differences in the performance of the most commonly utilized PET radiotracers and highlight the advantage of PET/MRI fusion to obtain optimal information about tumor extent, heterogeneity, and metabolism. Recent data also suggest that simultaneous acquisition of PET/MR images and the combination of advanced MRI techniques with quantitative PET can further improve the pretreatment and post-treatment evaluation of pediatric brain tumors.

KEYWORDS:

Amino acid; Glucose; Low-grade; MRI; Pediatric glioma; Positron emission tomography

PMID:
27659825
PMCID:
PMC5120676
DOI:
10.1007/s00381-016-3125-z
[Indexed for MEDLINE]
Free PMC Article
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20.
J Neurol Sci. 2016 Sep 15;368:97-103. doi: 10.1016/j.jns.2016.06.065. Epub 2016 Jun 29.

Cortical thickness asymmetries and surgical outcome in neocortical epilepsy.

Author information

1
Department of Pediatrics, Wayne State University, 3901 Beaubien St., Detroit, MI 48201, United States; PET Center and Translational Imaging Laboratory, Children's Hospital of Michigan, 3901 Beaubien St., Detroit, MI 48201, United States.
2
Department of Pediatrics, Wayne State University, 3901 Beaubien St., Detroit, MI 48201, United States; Department of Neurology, Wayne State University, Harper University Hospital, 3990 John R. St, Detroit, MI 48201, United States.
3
Department of Pediatrics, Wayne State University, 3901 Beaubien St., Detroit, MI 48201, United States; Department of Neurosurgery, Wayne State University, Harper University Hospital, 3990 John R. St, Detroit, MI 48201, United States.
4
Department of Pediatrics, Wayne State University, 3901 Beaubien St., Detroit, MI 48201, United States; PET Center and Translational Imaging Laboratory, Children's Hospital of Michigan, 3901 Beaubien St., Detroit, MI 48201, United States; Department of Neurology, Wayne State University, Harper University Hospital, 3990 John R. St, Detroit, MI 48201, United States. Electronic address: juhasz@pet.wayne.edu.
5
Department of Pediatrics, Wayne State University, 3901 Beaubien St., Detroit, MI 48201, United States; PET Center and Translational Imaging Laboratory, Children's Hospital of Michigan, 3901 Beaubien St., Detroit, MI 48201, United States; Department of Neurology, Wayne State University, Harper University Hospital, 3990 John R. St, Detroit, MI 48201, United States.

Abstract

PURPOSE:

We evaluated if cortical thickness measures were associated with surgical outcome in patients with non-lesional neocortical epilepsy.

METHODS:

Twenty-one young patients (age: 2.4-19.7years) with epilepsy of neocortical origin and normal MRI underwent two-stage epilepsy surgery with subdural EEG monitoring. Cortical thickness was measured on presurgical volumetric MRI using the FreeSurfer software. The prognostic value of hemispheric and lobar/regional cortical thickness measures for 1-year and 2-year post-surgical seizure outcome has been analyzed.

RESULTS:

At one-year follow-up, 14 patients (67%) were seizure-free. Hemispheric and frontal lobe cortical thickness showed no/minimal asymmetry in seizure-free patients but thinner cortex ipsilateral to the seizure focus in those with recurrent seizures (p=0.02). More robust differences were found in patients≥6years of age (p=0.006 for frontal asymmetries), whose cortical thickness asymmetries remained prognostic for 2-year post-surgical outcome (p=0.007). By using an optimal cutoff threshold based on a receiver operating characteristic analysis, mean hemispheric asymmetry predicted one-year seizure freedom with 93% sensitivity and 71% specificity in the whole group, and with 100% sensitivity and 92% specificity in patients≥6years of age.

CONCLUSION:

In patients with neocortical epilepsy and normal MRI, neocortical thinning in the epileptic hemisphere, particularly in frontal cortex, is associated with poor surgical outcome. Although these results require validation in a larger cohort prospectively, these data suggest that presurgical evaluation of cortical thickness may assist in identification of patients at high risk for surgical failure.

KEYWORDS:

Cortical thickness; Epilepsy; Epilepsy surgery; Frontal lobe; MRI; Surgical outcome

PMID:
27538609
PMCID:
PMC4996370
DOI:
10.1016/j.jns.2016.06.065
[Indexed for MEDLINE]
Free PMC Article
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