Edit Bosnyák1, David O Kamson1, Anthony R Guastella1, Kaushik Varadarajan1, Natasha L Robinette1, William J Kupsky1, Otto Muzik1, Sharon K Michelhaugh1, Sandeep Mittal1, Csaba Juhász1. 1. Department of Pediatrics, Wayne State University, Detroit, Michigan (E.B., D.O.K., O.M., C.J.); Department of Neurology, Wayne State University, Detroit, Michigan (C.J.); Department of Neurosurgery, Wayne State University, Detroit, Michigan (A.R.G., K.V., S.K.M., S.M.); Department of Oncology, Wayne State University, Detroit, Michigan (A.R.G., S.M.); Department of Radiology, Wayne State University, , Detroit, Michigan (N.L.R., O.M.); Department of Pathology, Wayne State University, Detroit, Michigan (W.J.K.); PET Center, Children's Hospital of Michigan, Detroit, Michigan (E.B., D.O.K., O.M., C.J.); Karmanos Cancer Institute, Detroit, Michigan (N.L.R., W.J.K., S.M., C.J.).
Abstract
BACKGROUND: Increased tryptophan metabolism via the kynurenine pathway (KP) is a key mechanism of tumoral immune suppression in gliomas. However, details of tryptophan metabolism in meningiomas have not been elucidated. In this study, we evaluated in vivo tryptophan metabolism in meningiomas and compared it with gliomas using α-[(11)C]-methyl-L-tryptophan (AMT)-PET. We also explored expression patterns of KP enzymes in resected meningiomas. METHODS: Forty-seven patients with MRI-detected meningioma (n = 16) and glioma (n = 31) underwent presurgical AMT-PET scanning. Tumoral AMT uptake and tracer kinetic parameters (including K and k3' evaluating unidirectional uptake and trapping, respectively) were measured, correlated with meningioma grade, and compared between meningiomas and gliomas. Patterns of KP enzyme expression were assessed by immunohistochemistry in all meningiomas. RESULTS: Meningioma grade showed a positive correlation with AMT k3' tumor/cortex ratio (r = 0.75, P = .003), and this PET parameter distinguished grade I from grade II/III meningiomas with 92% accuracy. Kinetic AMT parameters could differentiate meningiomas from both low-grade gliomas (97% accuracy by k3' ratios) and high-grade gliomas (83% accuracy by K ratios). Among 3 initial KP enzymes (indoleamine 2,3-dioxygenase 1/2, and tryptophan 2,3-dioxygenase 2 [TDO2]), TDO2 showed the strongest immunostaining, particularly in grade I meningiomas. TDO2 also showed a strong negative correlation with AMT k3' ratios (P = .001). CONCLUSIONS: PET imaging of tryptophan metabolism can provide quantitative imaging markers for differentiating grade I from grade II/III meningiomas. TDO2 may be an important driver of in vivo tryptophan metabolism in these tumors. These results can have implications for pharmacological targeting of the KP in meningiomas.
BACKGROUND: Increased tryptophan metabolism via the kynurenine pathway (KP) is a key mechanism of tumoral immune suppression in gliomas. However, details of tryptophan metabolism in meningiomas have not been elucidated. In this study, we evaluated in vivo tryptophan metabolism in meningiomas and compared it with gliomas using α-[(11)C]-methyl-L-tryptophan (AMT)-PET. We also explored expression patterns of KP enzymes in resected meningiomas. METHODS: Forty-seven patients with MRI-detected meningioma (n = 16) and glioma (n = 31) underwent presurgical AMT-PET scanning. Tumoral AMT uptake and tracer kinetic parameters (including K and k3' evaluating unidirectional uptake and trapping, respectively) were measured, correlated with meningioma grade, and compared between meningiomas and gliomas. Patterns of KP enzyme expression were assessed by immunohistochemistry in all meningiomas. RESULTS:Meningioma grade showed a positive correlation with AMT k3' tumor/cortex ratio (r = 0.75, P = .003), and this PET parameter distinguished grade I from grade II/III meningiomas with 92% accuracy. Kinetic AMT parameters could differentiate meningiomas from both low-grade gliomas (97% accuracy by k3' ratios) and high-grade gliomas (83% accuracy by K ratios). Among 3 initial KP enzymes (indoleamine 2,3-dioxygenase 1/2, and tryptophan 2,3-dioxygenase 2 [TDO2]), TDO2 showed the strongest immunostaining, particularly in grade I meningiomas. TDO2 also showed a strong negative correlation with AMT k3' ratios (P = .001). CONCLUSIONS: PET imaging of tryptophan metabolism can provide quantitative imaging markers for differentiating grade I from grade II/III meningiomas. TDO2 may be an important driver of in vivo tryptophan metabolism in these tumors. These results can have implications for pharmacological targeting of the KP in meningiomas.
Authors: Csaba Juhász; Zeina Nahleh; Ian Zitron; Diane C Chugani; Majid Z Janabi; Sudeshna Bandyopadhyay; Rouba Ali-Fehmi; Thomas J Mangner; Pulak K Chakraborty; Sandeep Mittal; Otto Muzik Journal: Nucl Med Biol Date: 2012-03-22 Impact factor: 2.408
Authors: Derek A Wainwright; Irina V Balyasnikova; Alan L Chang; Atique U Ahmed; Kyung-Sub Moon; Brenda Auffinger; Alex L Tobias; Yu Han; Maciej S Lesniak Journal: Clin Cancer Res Date: 2012-08-29 Impact factor: 12.531
Authors: Paul B Larkin; Korrapati V Sathyasaikumar; Francesca M Notarangelo; Hiroshi Funakoshi; Toshikazu Nakamura; Robert Schwarcz; Paul J Muchowski Journal: Biochim Biophys Acta Date: 2016-07-05
Authors: Edit Bosnyák; Sharon K Michelhaugh; Neil V Klinger; David O Kamson; Geoffrey R Barger; Sandeep Mittal; Csaba Juhász Journal: Clin Nucl Med Date: 2017-05 Impact factor: 7.794
Authors: Anthony R Guastella; Sharon K Michelhaugh; Neil V Klinger; Hassan A Fadel; Sam Kiousis; Rouba Ali-Fehmi; William J Kupsky; Csaba Juhász; Sandeep Mittal Journal: J Neurooncol Date: 2018-04-17 Impact factor: 4.130