El 14 de noviembre de 2016, la Fundación Ramón Areces organizó un Simposio Internacional sobre tecnología aplicada al mundo de la medicina de la mano del Instituto Tecnológico de Massachusetts (MIT) y de la Fundación mVision. Este encuentro llevó por título 'La visión computacional se encuentra con la medicina'. Durante esta jornada, se analizó el impacto que están teniendo las nuevas técnicas de imagen en alta resolución para el diagnóstico de todo tipo de enfermedades.

1. Imaging in Oncology:
Adding light to the dark
side
Francisca Mulero MD, PhD
Molecular Imaging Unit, CNIO
fmulero@cnio.es

2. The only MD able to diagnose using
only the stethoscope exist only in
movies…

3. Tumour Hypoxia
Pathological condition, tissues lack Oxygen
Up 50-60% tumours exhibit hypoxic/anoxic areas
Tumours often adapt to hypoxic environments by
upregulation of a transcription factor, hypoxia-inducible
factor 1 (HIF-1)
Tumours have rapid proliferation and vascular
abnormalities
Perfusion limited O2 delivery
Tumoral vessels with structural abnormalities
Dilated, sacular, tortuous
Heterogeneous spatial distribution

4. Image from Kabbinavar, 2006, Peer Review Press. Adapted from Bergers G. Benjamin LE, Nat Rev Cancer 2003
Tumour Not well perfused. Drugs not good access.
Hypoxia adaptation slow proliferation rates.
Conventional Chemo drugs are antiproliferative agent.
Angiogenic inhibitors new treatments for cancer
Radiotherapy cytotoxicity depends on intracellular O2
Tumour Hypoxia

5. Tumour Hypoxia Diagnosis

6. Patients with hypoxic tumors often have a
poor prognosis and decreased overall survival
rate
Knowing degree and extent of hypoxia prior
to the initiation of treatment will be invaluable
in treatment planning
Tumour Hypoxia Diagnosis

7. Measuring hypoxia
 Polarographic needle electrode Eppendorf®
 Gold standard, accurate measurement
 Partial information, invasive
 Optical imaging techniques
 Phosphorescence imaging by phosphorescent nanosensors (in vivo mycroscopy)
 NIR spectroscopy spectral changes by hemoglobin
 Both: low spatial resolution, light scattering, limited path length and clinical
translation
 MRI, BOLD, EPR and 19F
 Indirect (exogenous and endogenous markers)
 Measure molecular reporters of O2 (pO < 10 mmHg)
 PET with Nitroimidazole derivatives, CaIX ligands
 IHC staining antibodies against pimonidazole
 Biopsy specimens

8. Advantage:
3D & non invasive
 Compared IHQ, genes-miRNA
signatures
 Tumour spacially heterogeneous
Courtesy of B. van der Kogel
Disadvantage:
O2 voxel distribution
 pO2 in a voxel is the average of pO2o of cells
inside it
 Each voxel contains a mixture of cells with
different O2 concentrations
Hypoxia Imaging
Courtesy of B. van der Kogel

9. PET
Positron Emission Tomography
 Molecule is labelled with a positron emitting
radioisotope.
Non-pharmaceutical trace quantities.
High Sensitivity and quantitative.
Independent of the depth.
Real translational approach.

10. PET-CT & PET-MR
CT
MR
PET
PET-CT
PET-MR

11.  CT is the first imaging test of choice in most cases
 18F-FDG PET-CT is more accurate than CT alone
• Characterizing lesions difficult to biopsy
• Detecting occult cancer
• Determining extent of cancer and response to therapy
 F18-FDG metabolism marker. Beyond FDG…
 FDG PET-CT changes management 36%
PET-CT in Oncology

12. PET-CT with 18F-FDG

13. Lesion Characterization
PET-CT with 18F-FDG

14. Lesion Characterization
PET-CT with 18F-FDG

15. Enhanced Detection
PET-CT with 18F-FDG

16. PET beyond 18F-FDG
Imaging of hypoxia
 18F/Nitroimidazole derivatives
 Reduced by nitroreductase enzymes in a hypoxic environment and trapped
in hypoxic tumor cells pO2 < 10 mmHg.
 Pimonidazole IHC analysis is invasive and 2D qualitative method PET
imaging can quantitatively evaluate 3D hypoxia regions
 Tumour hypoxia is heterogeneus in space
 124I/89Zr Antibodies
 CAIX
 Preclinical studies
 64Cu-ATSM diacetyl-bis (N4-methylthiosemicarbazone)
 The exact mechanism of retention still not completely understood.
 It has been shown to have high membrane permeability and fast tumour
uptake
 It seems to be affected by mechanisms other than hypoxia per se

17. PET Imaging of hypoxia
 18F/Nitroimidazole derivatives
 Reduced by nitroreductase enzymes in a hypoxic environment and trapped
in hypoxic tumor cells pO2 < 10 mmHg.
 Pimonidazole IHC analysis is invasive and 2D qualitative method PET
imaging can quantitatively evaluate 3D hypoxia regions
 Tumour hypoxia is heterogeneus in space
 124I/89Zr Antibodies
 CAIX
 Preclinical studies
 64Cu-ATSM diacetyl-bis (N4-methylthiosemicarbazone)
 The exact mechanism of retention still not completely understood.
 It has been shown to have high membrane permeability and fast tumour
uptake
 It seems to be affected by mechanisms other than hypoxia per se

18. Nitro-imidazoles mechanism of uptake
 Intitial distribution dependent of perfusion
 Retention < 10 mm Hg de pO2
RNO2
necrotic
RNO2
-
e- reduction
normoxic
RNH2
e- reduction
hypoxic
retention
metabolites
Vascular Space Cellular compartment
Mechanism of Action 18F-MISO
RNO2
18F-MISO

19. Genetically modified mouse models
 Spontaneous tumors
 Orthotopic location
-Lung, pancreas, breast, liver, bone etc.
Xenograft mouse models
 Implanted tumours
 Subcutaneous or Orthotopic location
Patients
 Clinical Trials
 Phase I&II
-PDAC, and breast carcinoma.
CNIO Hypoxia experience
qqqqqqq

20. Molecular
Imaging Unit
Location
CNIO
DeXa
IVIS
Spectrum
microCTIVIS 200
Analysis & Process
microPET-CT
Ultrasound
Thermography
Clinical PET-CT
Clinical 3T MRI
Hospital FuenlabradaHR microCT
3T MRI

21. Normal DNA
(Blood)
Tumor
Genomic profiling
Detecting Biomarkers
RESISTANTSENSITIVE
Potential drugs
based on Genomic
profiling
Drug Response in
Avatar mouse
Identify drug sensitivity based on
tumor genomics alterationsPersonalizeddrugtherapy
Patient 1
Custom
Database with
Response
Biomarkers
Genomic profiling
Predictive & Prognostic
Tumor
Personalized tumorgraft: Avatar
Exome sequencing
Imaging
Monitoring
(PET)

22. Vehicle
Antiangiogenicdrug PET 18F-MISO GEMM breast carcinoma
2 weeks 4 weeks

23. Hypoxia volume and
background correction

24. PET 18F-MISO

25. Clinical trial: PET 18F-MISO in
neoadjuvancy treatment evaluation

26. Clinical trial: PET 18F-MISO in
neoadjuvancy treatment evaluation

27. Clinical trial: PET 18F-MISO in
neoadjuvancy treatment evaluation

28. PET 18F-MISO

29. PET 18F-MISO

30. PET 18F-MISO

31. PET 18F-MISO

32. PET 18F-MISO
Ratio Tumor/Muscle cut-off 1,2-1,4

33. Delineation: Quantification
Absolute thresholds
▫ SUV = 1.2 or 1.4
Relative thresholds
▫ 40 or 50% of SUV max
Adaptative thresholds
▫ tumor > 1.0, 1.2 or 1.3 x background
Breast > 1.2 H&N > 1.24 RT= 1.3 NSCLC= 1.4 Average
1.25

34. PET 18F-MISO

35. Pre Treatment
Post Treatment
PET 18F-MISO

36. Pretreatment
Postreatment
PET 18F-MISO

37. Subcutaneous injection of
human tumor specimen
Albumin quantification
from imaging
Analysis for
[albumin]
Discriminate pancreatic tumors with
different stromal content 18FMISO PET-MRI

38. F18-MISO PET-MRI
Courtesy of Dr. Cañamaque and Dr. Carreras

39. MERGED MISO/FDG
F18-FDG F18-MISO

40. F18-FDG F18-MISO

41. Hypoxia Guided IMRT:
dose escalation in hypoxic areas
Dose Painting by Contours
Dose Painting by Numbers
0.4
0.6
1.1
1.9
2.7
2.9
Proof-of-concept using Cu-ASTM
KSC Chao, IJROBP 2001, 49, 1171
Theoretical feasibility
using 18F-FMISO
Dose prescription
based on tumor hypoxia
D. Thorwarth, IJROBP 2007, 68, 291
Z. Lin, IJROBP 2008, 70, 1219
NY Lee, IJROBP 2008, 70, 2
I. Toma-Dasu, Acta Oncol. 2009, 48, 1181
W. Choi, Radiother. Oncol. 2010, 97, 176

42. Hypoxia Guided IMRT:
dose escalation in hypoxic areas
Dose Painting by Contours
Dose Painting by Numbers
0.4
0.6
1.1
1.9
2.7
2.9
Proof-of-concept using Cu-ASTM
KSC Chao, IJROBP 2001, 49, 1171
Theoretical feasibility
using 18F-FMISO
Dose prescription
based on tumor hypoxia
D. Thorwarth, IJROBP 2007, 68, 291
Z. Lin, IJROBP 2008, 70, 1219
NY Lee, IJROBP 2008, 70, 2
I. Toma-Dasu, Acta Oncol. 2009, 48, 1181
W. Choi, Radiother. Oncol. 2010, 97, 176

43. CONCLUSION
Hypoxia imaging allows better definition of a population that
would benefit from novel anti-hypoxia directed therapies.
 Selecting a cohort of patients who might respond better to
treatments.
Molecular Imaging, specially PET, beyond the role of tumour
detection to the role of tumour characterization.
Support of personalized medicine. Dose painting radiotherapy.
 PET tracers, especially nitroimidazoles, are probably the most
exact method, directly identify hypoxia, whereas those based
on blood perfusion are indirect and thus less specific.

44. Acknowledgments
Special mention:
Álvaro Leal
Imaging Team:
Cristina Penalva
Elka SanMartín
Gloria Visdomine
Guillermo Garaulet
Lucia de la Cueva
Silvia Leal
Tatiana Alvarez