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Spectroscopic Window on Tumor Metabolism Michael Garwood, Ph.D. Univ. of Minnesota

Spectroscopic Window on Tumor Metabolism Michael Garwood, Ph.D. Univ. of Minnesota. Role of MRS in the Clinical Management of Cancer. Diagnosis: guide biopsy avoid unnecessary/risky biopsies ascertain aggressiveness/stage/prognosis Treatment: guide choice of treatment

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Spectroscopic Window on Tumor Metabolism Michael Garwood, Ph.D. Univ. of Minnesota

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  1. Spectroscopic Window on Tumor MetabolismMichael Garwood, Ph.D.Univ. of Minnesota

  2. Role of MRS in the Clinical Management of Cancer • Diagnosis: • guide biopsy • avoid unnecessary/risky biopsies • ascertain aggressiveness/stage/prognosis • Treatment: • guide choice of treatment • identify non-responders early → alter treatment regime • tool for follow up

  3. High Res 1H MRS of Cells Malignant cells Non-Malignant cells extract in vitro Ackerstaff et al., J Cell Biochem 2003 GPC → PCho switch Aboagye et al., Cancer Res 1999

  4. H H H C H - + H -C - H C H H H Choline-containing compounds R-CH2-CH2-N

  5. In vivo 1H MRS of breast cancer First reported studies: Roebuck et al, Radiol 1998; Gribbestad et al, JMRI 1998 1H MRS MRI suppressed water lipids Choline compounds (tCho) lipid invasive ductal carcinoma Frequency (ppm) CMRR 4 Tesla

  6. P < 0.0008 Infiltrating ductal carcinoma Benign Focal Fibrosis Jacobs MA, Barker PB, et al. Proton magnetic resonance spectroscopic imaging of human breast cancer: a preliminary study. J Magn. Reson Imaging. 2004 Jan;19(1):68-75

  7. Membrane Choline Phospholipid Metabolism Lysophosphatidic acid Adapted from Aboagye EO, Bhujwalla ZM. Cancer Res 59:80-84 1999

  8. Mechanisms of increased PC in cancer: • Increased expression and activity of choline kinase [Ramirez de Molina et al., Oncogene 2002] • Higher rate of choline transport [Katz-Brull & Degani, AntiCancer Res. 1996] • Increased PLD activity [Noh et al., Cancer Lett. 2000] • Increased PLA2 activity [Guthridge et al., Cancer Lett. 1994]

  9. Right T1 FLAIR Cho Cho Cr NAA NAA Lac Left PPM 4.0 3.0 2.0 1.0 Glioblastoma Multiforme (High Grade Tumor) slide courtesy of Peter Barker, Johns Hopkins U

  10. Cheng LL, FEBS Lett. 2001 Prostate Cancer Normal human prostate Tumor-bearing prostate

  11. MR targeted TRUS guided biopsy positive 5 5 5 5 5 MRI/MRSI Targeted, TRUS-Guided Biopsies courtesy of J.Kurhanewicz, UCSF PSA - 12 ng/ml Two prior negative biopsies The sensitivity of TRUS guided biopsy is reduced in large prostates and when the cancer is located in difficult locations such as the apex or in the anterior or lateral aspects of the prostate. The accuracy of cancer detection of MRI/MRSI targeted biopsy in men with prior negative biopsy ≈80%. (Yuen et al, J. Urol. 2004; Prando et al, Radiology 2005) Journal Urology 2000, 164(2) 400-404

  12. Broadband pulses DF DF DF 90 180 180 RF Gradients X Y Z Chemical Shift: Minimized with higher BW pulses Spectrum Standard pulses 900 1800 Center Frequency (-235 Hz) %CS : DF / BWRF Courtesy of: G. Metzger

  13. OVS with over-prescription Courtesy of: G. Metzger

  14. Prostate Spectroscopy at 3T: Single Voxel Echo Time, Coupling and SNR TE = 260 ms TE = 100 ms Courtesy of: P. Choyke & G. Metzger

  15. Case Study: Slice 5 Cho Cre Cit Sp Courtesy of: P. Choyke & G. Metzger

  16. Quantification • Metabolite ratios (eg, tCho/NAA, (tCho+Cr)/Cit) • External reference (eg, phantom of known conc) • Reference to tissue water signal

  17. 3 Tesla Normal breast MRI Devices 4-ch coil 3x3x3 cm voxel LASER Localization TE Averaging (60-300ms in 128 increments) NEX=2 a) tCho b) 6 5 4 3 2 1 0

  18. Breast Anatomy Lobules Tavassoli, 1999 Stroma Fat Adipose tissue • Anatomy varies greatly • Tissues are distributed heterogeneously •  Intravoxel lipids are inevitable Fibroglandular tissue Netter, 1997

  19. Internal Referencing with Water • NOT assuming constant water concentration • Assuming a two-compartment model (water & fat) and all tCho is in the aqueous compartment [tCho] expressed in molal units (mmol tCho/kg water) No assumptions about volume or density Bolan et al., MRM 2003

  20. Spectral Fitting • Adapted TDFDFit (Slotboom et al., MRM 1998) • Time-Domain Model: • Minimize residuals in frequency-domain over narrow (0.4 ppm) band model • Fit 3 peaks independently: tCho, water, 1.3 ppm lipid • Errors from Cramer-Rao Minimum Variance Bound; used for detection threshold data residual 6 4 2 0 ppm Bolan et al., MRM 2003

  21. Normal gland (Presumed) [tCho] = 0.75 ± 0.07 mmol/kg volume = 13.0 mL lipid fraction = 3.5% Invasive Ductal Carcinoma [tCho] = 6.8 ± 0.1 mmol/kg volume = 6.8 mL lipid fraction = 8% Atypical Hyperplasia [[tCho] = 1.5 ± 0.8 mmol/kg volume = 1.1 mL lipid fraction = 15% Bolan et al., MRM 2003

  22. invasive ductal carcinoma no Cho Frequency (ppm)

  23. Reason for false negative? Spurious lipid sideband peaks! invasive ductal carcinoma Frequency (ppm)

  24. Sideband Artifacts water sidebands sidebands 57 • Antisymmetric side peaks • Amplitude >1% • Caused by B0 oscillation TE (ms) 45 -100 -300 100 300 -500 -500 Hz Sidebands have coherent, TE-dependent phase Averaging causes destructive interference Bolan et al., MRM 2002

  25. Echo-time Averaging tCho? NEX=64 TE=45ms Conventional single TE No tCho TE=45-196ms 64 increments TE averaging 2 8 6 4 0 -2 ppm Bolan et al., MRM 2002

  26. In vivo 1H spectrum of a voxel containing mainly adipose tissue

  27. Day 127 (AC x 4 followed by Taxotere x 3) size = 3.0 x 2.7 x 3.0 cm3 [Cho] = 0.642 mmol/kg Voxel of just the non enhancing region [Cho] = 0.910 mmol/kg Voxel of just the enhancing region [Cho] = 0 mmol/kg

  28. Invasive Ductal Carcinoma Precontrast Postcontrast Subtraction 4 H2O Lipid 3 Lipid Lipid 2 SI tCho 1 0 0 0 1 2 3 4 5 7 6 5 4 3 2 1 0 -1 ppm time (min) time (sec) All 4 readers maintained their decision to biopsy [tCho] = 0 ± 1.73 Meisamy et al, Radiology 2005

  29. Conclusions about MRS for breast cancer diagnosis: • Adding quantitative 1H MRS to breast MRI improves sensitivity, specificity, and accuracy, over MRI alone • Quantitative 1H MRS is particularly useful in cases where lesion morphology and time-intensity curves are indeterminate Meisamy et al, Radiology 2005

  30. Treatment Planning and Monitoring

  31. MRSI for Radiation Treatment Planning of Brain Tumor MRSI-based radiation dose painting using the IMRT method Thakur, Chang, Huang, Koutcher, Narayana Memorial Sloan-Kettering Cancer Center

  32. Models of tCho response Jordan et al., NMR Biomed 2006 Al-Safar et al., Cancer Res 2006 cell density Measured acute response to PX-478 (inhibits HIF1-alpha production) in mouse xenografts of HT-29 (colon) Methods: in vivo MRS at 4.7T, ex vivo validation Results: tCho dropped significantly at 12 and 24 hrs PCho CK Measured acute response to MN58b (inhibits CK) in mouse xenografts of MDA-MB-231 (breast) and HT-29 (colon) Methods: in vivo MRS at 4.7T, ex vivo validation Results: tCho dropped significantly at 48hrs in both models

  33. Treatment Monitoring in Breast Cancer • Neoadjuvant chemotherapy (primary systemic therapy, PST) is the preferred treatment for locally advanced breast cancer (Fisher et al. J Clin Oncol 1997, 1998) • Advantages: • Tumor shrinkage; possible breast conserving procedures • In vivo monitoring of chemo-sensitivity (customize Tx  complete pathologic response)

  34. 4T Tx Monitoring in Breast Cancer: Results to Date Responders Non-Responders • 14/18 Responders had a decrease in [tCho] at Day 1 • 9/10 Non-responders had a increase in [tCho] at Day 1 • Day 1 Rule: 82% accuracy in 28 subjects 9 9 8 8 7 7 6 6 5 5 [tCho] (mmol/kg) [tCho] (mmol/kg) 4 4 3 3 2 2 1 1 0 0 Baseline Day 1 Baseline Day 1 Meisamy et al, Radiology 2004

  35. Responder to AC Pre PST 24 hrs ACX 1 ACX 4 [tCho] = 0.9 LD = 1.7 cm [tCho] = 4.6 LD = 4.0 cm [tCho] = 3.7 LD = 4.0 cm Meisamy et al, Radiology 2004

  36. Responder to AC, but not Taxol Pre PST 24 hrs ACX 1 ACX 4 TaxolX 2 [tCho] = 0.9 LD = 1.7 cm [tCho] = 4.6 LD = 4.0 cm [tCho] = 3.7 LD = 4.0 cm [tCho] = 4.1 LD = 1.7 cm Meisamy et al, Radiology 2004

  37. Therapeutic Selection and Monitoring 5 years 1 year citrate choline Metabolic Atrophy Metabolic Atrophy Baseline courtesy of J.Kurhanewicz, UCSF

  38. Is it possible to predict response from baseline MRS data?

  39. Responders Non-Responders 9 9 8 8 7 7 6 6 5 5 [tCho] (mmol/kg) [tCho] (mmol/kg) 4 4 3 3 2 2 1 1 0 0 Baseline Day 1 Baseline Day 1 Treatment Prediction / Phenotyping Baseline [tCho] was higher in responders than in non-responders (p=0.03) Higher [tCho] @ baseline associated with higher grade & positive nodes Can MRS identify responders before starting treatment? • Inconsistent findings in brain MRS: • Tzika, Neuroradiology 2001 – responders had lower tCho • Preul, Neurosurgery 2000 – no difference • Lazareff, J Neurooncol 1999 – no difference

  40. Pretreatment PME/NTP ratio Preliminary results with 31P MRSI Pretreatment 31P spectrum from nodal disease of a HNSCC patient who experienced partial response Pretreatment PME/NTP ratios from tumors; complete responders were different from incomplete response group P<0.001 A. Shukla-Dave, et. al. Acad Radiol, 9:688-694, 2002

  41. 31P MRS in Bone Sarcoma Baseline spectrum Zakian, et. al., Cancer Research 2003 Dec 15;63(24):9042-7

  42. Baseline Energetics Predicts Outcome in Bone Sarcoma NTP/Pi predicts longer survival Zakian, et. al., Cancer Research 2003 Dec 15;63(24):9042-7

  43. Future: • More studies correlating with pathology, immunohistochemistry, and outcomes • Further studies to assess reliability/reproducibility • Results of multi-center trials • Combine with other metrics (DCE-MRI, ADC,…) → multiparametric analyses • 3T (and higher?)

  44. IMAPS (1.5T) Prostate spectroscopy at 1.5T with endorectal coil The axial T2-weighted image (A) is used for matching voxel locations to histopathological specimens (D). One of the spectral maps (B), partially expanded in (E), reflects the quality of the MRSI data throughout the slice. Deviations in the (Cho + Cr)/Ci metabolite ratio map in (C) largely correspond to the tumor location indicated with the blue line in (D). Courtesy of T. Scheenen and Prof. A. Heerschap, Radboud University Nijmegen Medical Center, Dept. of Radiology The IMAPS community

  45. Slide courtesy of Michael Jacobs, JHU

  46. Current Multiparametric (MRI/DTI/MRSI) Prostate Imaging Exam MRSI (0.3 cc) T2 weighted MRI Healthy Cancer Citrate Lipid Choline Creatine Creatine Polyamines Choline Diffusion weighted MRI ADC Map PPM 3.0 2.5 2.0 3.0 2.5 2.0 Slide courtesy J. Kurhanewicz UCSF Decreased Signal Intensity on T2 weighted Imaging Reduced water diffusion Elevated choline Reduced citrate Reduced polyamines

  47. Choline 3T MRSI vs 1.5T MRSI: Improved Detection of Residual Cancer 3T 1.5T Creatine 0.16 cc 0.34 cc Cho Cho Cho Cho Cho

  48. Acknowledgements • Thanks for Sending Slides • Arend Heerschap • Jason Koutcher • John Kurhanewicz • Michael Jacobs • Peter Barker • Wei Huang U of Minn Researchers Patrick Bolan Greg Metzger Sina Meisamy Adeka McIntosh Curt Corum Angela Styczynski Nate Powell Djaudat Idiyatullin Jang-Yeon Park Carl Snyder James Boyum Doug Yee Michael Nelson Tim Emory Lenore Everson Todd Tuttle Evin Gulbahce Tommy Vaughan Funding Sources National Institutes of Health (CA92004, RR08079)

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