1. A. di Gaeta, A.A. Diano, P. Vassallo, E. Capobianco, M. Muto Neuroradiology unit A.O.R.N. “A. CARDARELLI” - Napoli Single voxel spectroscopy in the follow-up of low grade gliomas

2. From january 2003 until november 2009 we studied 24 low-grade astrocytoma with six years follow-up 24 low-grade astrocytoma with six years follow-up  16 hemisferic astrocytoma  2 gliomatosis  2 pylocitic astrocytoma (FCP)  2 trunk glioma  2 well differenziated oligodendrogliomas In 9 lesions we performed hystopathologic analysis surgery in six stereotactic biopsy in three

3. METHODS sequences sequences for volume sampling -PRESS (point resolved spectroscopy) The most clinically sequence used for its speedy and better S/R ratio(Pattany and all AJNR 27:1070-1073,May 2006) technique used “SINGLE VOXEL” (SVS) narrow study field Easily available in the majority of RM systems, rapid acquisition (5min.), but narrow study field even if better than multivoxel (Brandao Lara A. “MR spectroscopy of the brain “ pag 164 2002) in posterior fossa,in sovrasellar region and in regionsadjacent to skull base. The decision of which sequences(SVS or multivoxel ) and which parameters ( TE or TR) to use depends on the location of the lesion and the choice of the brain metabolites the investigator wants to evaluate Sundgren P.C. Mr spectroscopy in radiation injury AJNR 30:1469-1476 sep 2009 - RM magnet 1,5T, “head-coil” square, basic sequences (SE T1, T2 e flair) with and without contrast Standard RM spectroscopy

4. SPECTROSCOPIC DATA EVALUATION Spectrum visual analysis (peak height) Ratio NAA (marker neuronal integrity)/Cho ( increase in high grade tumors) Ratio NAA/Cr (reduced in high grade tumors ) Ratio Cho/Cr (increase in high grade tumors) Lactate and lipids evidence (ratio Lactate/Cr) Intermediate echo time (135) ideal to evaluate lactate and choline peaks (Brandao Lara A “MR Spectroscopy of the brain” pag 5,2002 Lippincott)

5. SPECTROSCOPIC DATA EVALUATION NAA/Cho = 1,8831 NAA/Cr = 1,7935 Cho/Cr = 0,9523

6. ASTROCITOMA “LOW-GRADE spectrum example” Case 31 R.M., femm a.28 NAA/Cho = 0,4525 NAA/Cr = 0,5023 Cho/Cr = 1,6574

7. Evaluation criteria Ratio NAA/Cho Lip/Lac peak remarks more than 20% variations in comparition to first examination Appearing or increase in comparition to first examination To remember that low grade gliomas spectrum could be similar to normal parenchyma (Brandao Lara A. pag 142 ;2002) Only in cases not treated

8.  Doesnt exist a real cut-off value of NAA/Cho ratio (Cha AJNR 27:475-487, March 2006).Indeed it is possible only differenziate tumour lesion from pseudotumoral lesion. (Majos “Proton MR spectroscopy improves discrimination between tumor and pseudotumoral lesion in solid brain masses AJNR 30:544- 551, March 2009) that is 0.5 82 % diagnostic accuracy  we have not evaluated lipids and lactate in treated gliomas because their values are always elevated and don’t show a good correlation with histologic grade of the lesion.  Lipids are present almost exclusively in high grade gliomas whereas lactate could be found in both low grade and  high grade gliomas. (Xiaojuan Li AJNR 26:760-769, April 2005) PRELIMINAR GENERAL CONSIDERATIONS

9. The use of NAA/Cho ratio allowed a correct retrospective classification in 80% of the cases in differenziating recurrent tumour from radiation injury with SVS(single Voxel spectroscopy) Schlemmer HP,Bachert P, Herfarth K Proton Mr spectroscopic evaluation of suspicious brain lesion after stereotactic radiotherapy AJNR 2001;22 :1316-1324 The most effective method of spectrum evaluation in SVS is the NAA/ Cho ratio. MR Spectroscopy in radiation injury Sundgren P.C.AJNR 30:1469-1476 september 2009

10.  A correlative study between spettroscopy and perfusion(CBF) show a good care sampling of the metabolites in more hyperfused areas ( higher Cho and increased lipids-lactate/creatina ratio ) in the high grade lesions in comparition to low grade lesions. (Chawla AJNR 28:1683-1689, October 2007)  Also a MET– PET correlative study has shown a good reliability showing the turn over a more aggressive behaviour ( metionina high uptake) in comparision to a more quiescent behaviour (low uptake). (Kato “Analysis of C-methionine uptake in low-grade gliomas and correlation with proliferative activity” AJNR 29 :1867-1871, 2007)  Morever has been demonstrated that the low TE (30) myoinositol sampling has shown a remarkable accuracy in discerning low grade gliomas (high MI/Cr ratio )from high grade gliomas(MI/Cr low ratio) (Castillo M AJNR 21:1645-1649, 2000) RELATED PAPERS OF TURNING OF LOW GRADE LESIONS TO HIGH GRADE LESIONS  A good correlation of trasformation from grade 2 gliomas to grade 3 anaplastic astrocytoma was found monitoring a gradual increase of the choline and the creatine (Majos Eur Radiology 13(3):582-591, March 2003)

11. Some examples

12. 6° 30 months later 6° examination 17/03/2006 30 months later 4° 4° spectroscopic examination 13/05/2005 NAA/Cho = 0,3876 NAA/Cr = 0,6070 Cho/Cr = 1,5495 NAA/Cho = 0,2764 NAA/Cr = 0,5208 Cho/Cr = 1,883 NAA/Cho = 0,1414 NAA/Cr = 0,2873 Cho/Cr = 2,9500 1 spectroscopic examination 01/09/2003 TE 135 TE 35 TE 135

13. 3a. e 10m.after 1°examination 4° examination - 29/12/2006 – 3a. e 10m.after 1°examination NAA/Cho = 0,0871 NAA/Cr = 0,2626 Cho/Cr = 3,0188 NAA/Cho = 0,1535 NAA/Cr = 0,4509 Cho/Cr = 2,3057 1° 1° spectroscopic examination - 16/02/2003 NAA/Cho > 20%

14. 1° examination - 19/01/2006 NAA/Cho = 0,8306 NAA/Cr = 0,8127 Cho/Cr = 0,9705 4° esame - 26/02/2007 – 13 months after first examination NAA/Cho = 0,6491 NAA/Cr = 0,6968 Cho/Cr = 1,0733

15. “LOW-GRADE” astrocytoma spectroscopic follow-up Case N.95. S.G. 30 a. 1° examination january 2005 CT performed for seizure after minor trauma ( face injury playing soccer)

16. june 2005 2° examination (six months later). june 2005. RM spectroscopy NAA/Cho = 0,4538 NAA/Cr = 0,8505 Cho/Cr = 1,8741 “LOW-GRADE” ASTROCYTOMA SPECTROSCOPIC FOLLOW’UP

17. “LOW-GRADE”astrocytoma spectroscopic follow-up 3° examination ( 4 months later) October 2005 NAA/Cho = 0,1999 NAA/Cr = 0,4130 Cho/Cr = 2,0656

18. 2months later 4° examination 2months later (december 2005) NAA/Cho = 0,4680 NAA/Cr = 0,8297 Cho/Cr = 1,7726 NAA/Cho = 0,3522 NAA/Cr = 0,7553 Cho/Cr = 2,1445

19. NAA/Cho = 0,2511 NAA/Cr = 0,5712 Cho/Cr = 2,2747 months later (March 2006). Voxel positioned at the core lesion 5° examination 3 months later (March 2006). Voxel positioned at the core lesion ASTROCITOMA “LOW-GRADE”spectroscopy follow-up

20. NAA/Cho = 0,4538 NAA/Cr = 0,8505 Cho/Cr = 1,8741 NAA/Cho = 0,2511 NAA/Cr = 0,5712 Cho/Cr = 2,2747 june 2005 1° spectroscopic examination june 2005 9months later (March 2006) 4° spectroscopic examination 9 months later (March 2006) NAA/Cho > 20% Lip

21. FUNCTIONAL MRI” april 2006

22. surgery Hystologic data : Macroscopic report: “fragments of whitish, homogenous… tissue ” Microscopic report : “glial tumour fairly cellular, mainly microcistic, composed by monomorfe cells, ” Diagnosis: Oligoastrocitoma (grado II WHO)

23. january 2007 1° spectroscopic control after surgery. january 2007

24. 2007 2° spectroscopic control after surgery. April 2007

25. 2009 3° spectroscopic control after surgery. April 2009

26. 2009 4° spectroscopic control after surgery. Nov 2009

27. OLIGODENDROGLIOMA spectroscopy follow-up 1° Case 106. D’A.G. A. 43 women. Operated 4 years before : “oligondendroglioma well differenziated” 1° spectroscopic examination 05/01/2006 NAA/Cho = 0,1551 NAA/Cr = 0,3696 Cho/Cr = 2,3825

28. OLIGODENDROGLIOMA spectroscopy follow-up 2°5 2° spectroscopic examination 12/05/2006. 5 months later NAA/Cho = 0,2320 NAA/Cr = 0,5166 Cho/Cr = 2,2263

29. OLIGODENDROGLIOMA spectroscopy follow-up 3° 3°spectroscopic examination 16/01/2007. 7 months.later 1 year after 1° spectrum NAA/Cho = 0,2047 NAA/Cr = 0,6040 Cho/Cr = 2,9497

30. NAA/Cho = 0,1551 NAA/Cr = 0,3696 Cho/Cr = 2,3825 NAA/Cho = 0,2320 NAA/Cr = 0,5166 Cho/Cr = 2,2263 1° 1° MRs 05/01/2006 2° 2° MRs 5 months later 3° 3° MRs 1 year later NAA/Cho = 0,2047 NAA/Cr = 0,6040 Cho/Cr = 2,9497

31. 4°1 4°examination 18/06/2008. 17 months later 2 years and half from 1 spectrum OLIGODENDROGLIOMA spectroscopy follow-up

32. 5°3 5°examination 30/09/2008. 3months later2 years and half from 1° spectrum OLIGODENDROGLIOMA spectroscopy follow-up

33. Results  In 20 patients good correlation between variation of NAA/Cho ratio and appearing or increase of lipid/lactate peaks and clinical-morfologic pattern (stable or progressive)  In 4 hemisferic operated astrocytomas and in a trunk glioma irradiated: disagreement between clinical-morphological pattern (in stable resolution) and spectroscopic pattern (persistent inversion of the NAA/Cho e Cho/Cr ratio)  In 2 of these patients restart of the disease at the subsequent controls  The appearing of a spectroscopic alteration could anticipate of about 1-2months contrast enhancment with standard RM(Brandao Lara A. “MR Spectroscopy of the Brain” pag 158. Lippincott)

34. Conclusions 2 are the more interesting clinical applications of the spectroscopic SVS follow-up of the brain neoplasm not operated lesions turn“surveallance” of the not operated lesions and possibility of evaluate an initial “turn ” from “low- grade” to high grade lesions. evaluation after surgery and sometimes after RT of the beginning of the neoplastic relapse But the effort to separate tumor recurrence from pure radiation damage might be more problematic when using SVS compared with using multivoxel spectroscopy.Sundgren P.C. Mr spectroscopy in radiation injury AJNR 30:1469-1476 September 2009

35. Thank you