istituto italiano di tecnologia surgery: from the design to the first ...€¦ · • radioguided...
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A β- probe for radioguided surgery: from the design
to the first preclinical tests
Università di Roma
Sezione di Roma
PhD Candidate: Andrea Russomando!Supervisor: Riccardo Faccini
Istituto Italiano di Tecnologia
La Sapienza, Università di Roma Dottorato di Ricerca in Fisica, XXVIII Ciclo
Russomando- PhD 2015
Outline• Radio-Guided Surgery (RGS)
• New technique exploiting β- radiotracers
• Clinical cases of interest
• Brain and Neurendocrine tumors
• Detector development
• Crystal characterization
• The final prototype
• Phantoms’ techniques
• Test on ex-vivo specimens
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Russomando- PhD 2015
Overview• Surgery remains the most frequently technique undertaken in
cancer treatment
• Imaging techniques (CT/PET/NMR) provide very clear and precise images of tumors before surgery
• The identification during the operation is far from being trivial
• The tumor mass may slightly change its position during the surgery(e.g. after craniotomy since the brain is not a rigid tissue)
• Necessity to identify the tumor during the operation
• Neuronavigation systems, Intraoperative NMR, Fluorescence-Guided Surgery
• RadioGuided surgery
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Russomando- PhD 2015
Radio-Guided surgery• Radio-guided surgery is a technique that enables the surgeon
to perform complete tumor resections (mass and remnants)
• A radio-marked tracer is administered to the patient before surgery
• The tracer temporally transforms the tissue in a radiations source allowing to identifytumor masses
• Each tumor requires an its own tracer and implies different problematics
• There is an uptake of the tracer from thesurrounding health tissue
!• After bulk removal, a specific probe system allows the
detection of the emissions released by the remnants (0.1 ml) in real time
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Russomando- PhD 2015
Gamma probe
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• Commercially available
• ɣ tracer emitter
• 99mTc, Eɣ ~ 140 keV
• Long range of photons (~1/3 of gammas traverses 8 cm)
• Exposure of medical personnel
Established Technique
Neoprobe model 2300!
Russomando- PhD 2015
Gamma probe
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• ɣ tracer emitter
• 99mTc, Eɣ ~ 140 keV
• Long range of photons (~1/3 of gammas traverses 8 cm)
• Tumor not tumor ratio (TNR)
• High background from nearby healthy organs (S/N)
• Necessity of a shield
• Used for:
• Thyroid carcinoma lymph-node recurrence, sentinel-node mapping for breast cancer and melanoma
Established Technique
Ɣ
Russomando- PhD 2015
ß- probe
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ß-
Change in paradigm
• Lower penetration power (~ 1 cm)
• Avoid the background of γ
• No need background subtraction
• Extension to different types of cancer (abdomen, brain, pediatric)
• Radio-tracer marked with ß-
• Need to develop specific radio tracers
• 90Y-DOTATOC, Emax 2.3 MeV
E. Solfaroli Camillocci, A. Russomando et al, Sci. Repts. 4,4401 (2014)
Russomando- PhD 2015
Outline• Radio-Guided Surgery (RGS)
• New technique exploiting β- radiotracers
• Clinical cases of interest
• Brain and Neurendocrine tumors
• Detector development
• Crystal characterization
• The final prototype
• Phantoms’ techniques
• Test on ex-vivo specimens
8
Russomando- PhD 2015
Radiotracer uptake• Studies on existing radio tracers
• DOTATOC: Somatostatine analogue marked with 90Y used for radio-metabolic treatment
• Clinical cases: Neurendocrine tumors and brain tumors (Meningiomas and Gliomas)
• Neurendocrine tumors (liver) Annual incidence 2.5-5 /100.000 people5-year survival 17%
• Meningiomas Annual incidence 3-4 /100.000 peopleUsually benign in nature (90%, 3y survival 86%)
• Gliomas infiltrations are difficult to detectAnnual incidence 6-7 /100.000 peopleHigh-grade glioma median survival 1 year
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End point 2.28MeV
90Y→90Zr+e-+νe τ1/2=64.1h <E(e-)>=0.93MeV
Russomando- PhD 2015
Expected background• TNR estimated from
• PET 68Ga-DOTATOC (brain)SPECT 177Lu-DOTATOC (liver)
• Background is the result of theuptake from the healthy tissues near the lesion
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10
TNR: specific activity ratio
1
11
1
ID LESION
TNR Meningiomas
11 patients
10
40
F. Collamati, A. Russomando et al, Towards a Radio-guided Surgery with b- Decays: Uptake of a somatostatin analogue (DOTATOC) in Meningioma and High Grade Glioma. J Nucl Med 56 (2015) 3-8
Russomando- PhD 2015
Outline• Radio-Guided Surgery (RGS)
• New technique exploiting β- radiotracers
• Clinical cases of interest
• Brain and Neurendocrine tumors
• Detector development
• Crystal characterization
• The final prototype
• Phantoms’ techniques
• Test on ex-vivo specimens
11
Russomando- PhD 2015
S.V.Budakovsky et al., Functional Materials 16, 1
(2009)
Para-Terphenyl• Scintillator based on
para-terphenyl doped with 0.1% diphenylbutadiene
• Organic scintillator with crystalline structure
• Non-hygroscopic
• Light material (low ρ=1.16 g/cm3)
• Scarce sensitivity to γ (Bremsstrahlung)
• High Light Yield
• Suitable for detection of non-penetrating low energy radiation
• Light Attenuation Length λ∼5 mm
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aromatic hydrocarbon
isomer C18H14
Aromatic hydrocarbon isomer
C18H14
M. Angelone, A. Russomando et al, Properties of P-Terphenyl as detector for a, b, and g radiation, IEEE Trans. on Nucl. Sci. 2014; 61: 1483-7
Russomando- PhD 2015 y
[mm
]
Material characteristics• The properties of the
material were characterized
• Active volume optimization
• Estimation of the light attenuation length
• Photon sensitivity
• Bremsstrahlung peaked at 100 keV
• Expected sensitivity lower than 0.1%
• Diffusion
• Effect of different wrappings
• Possibility of imaging13
Sensitivity"to photons
0.1 %133Ba (ɣ 30-350 keV)
Shield thickness
Sens
itivi
ty [%
]
60Co (ɣ 1.2 MeV)
137Cs (ɣ 660 keV)
x [mm]
Russomando- PhD 2015
• Core: cylindrical scintillator of p-terphenyl
• d=5 mm, h=3.1 mm
• Direct coupling with a SiPM (sensL B-series 10035)
• Probe characteristics:
• Aluminum body for easy handling
• Tip: PVC ring to mechanical support resulting in a lateral shielding10µm Al sheet to reduce the thickness of electrons entrance window
• Portable (battery), no need of HV (increase patient’s safety)
• Result of a systematic optimization work
• Different configurations were tested: crystal wrappings, optical fibres, PMT …
β- probe prototype
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20cm
Russomando- PhD 2015
Field of view• 90Sr ➙ 90Y
ß-, t1/2 28.8 y, Emax=0.55 MeV
• 90Y (ß-, t1/2 64 hours, Emax=2.28 MeV)
• Profiles reconstructed by the probe on sealed beta sources
• Air / Water
• Equivalence human body ⟷ water
• σ = 2.2 mm, depthmax =9.3 mm
• This is the maximum distance from which the probe identifies a point size residual during the operation
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90Sr Point source
90Sr Diffuse "source
Rat
e [H
z]R
ate
[Hz]
10 11 12 13
Russomando- PhD 2015
Expected performance• Including in FLUKA simulation TNR from
PET/SPECT DICOM images and results oflaboratories tests performance of the β- RGS were estimated:
• tmin minimum time needed by the probe to identify a 0.1ml tumor residual after administration of 3MBq/kg (95% C.L.)
• 0.1 ml is the minimal residual well identified by diagnostic imaging
• 3MBq/kg is comparable with activity for diagnostic (PET exam)
• Probability of False Positive FP<1% ; Probability of False Negative FN<5%
• Nets Liver: Less than 1s administering 3MBq/kgMeningiomas: Good sensitivity to 0.1ml residuals within 1sGliomas: Lower uptake, the time needed is ~5s, till acceptable
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F. Collamati, A. Russomando et al, Towards a Radio-guided Surgery with b- Decays: Uptake of a somatostatin analogue (DOTATOC) in Meningioma and High Grade Glioma. J Nucl Med 56 (2015) 3-8
Russomando- PhD 2015
Outline• Radio-Guided Surgery (RGS)
• New technique exploiting β- radiotracers
• Clinical cases of interest
• Brain and Neurendocrine tumors
• Detector development
• Crystal characterization
• The final prototype
• Phantoms’ techniques
• Test on ex-vivo specimens
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Russomando- PhD 2015
Phantom factory
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• Liquid radio-tracer (saline solution of 90Y)
• Created “ad hoc” phantoms to simulate tumor remnants
• Sponge material (65% cellulose and 35% cotton fibres)
• Easy to cut
• Different activities changing 90Y dilutions
• Differences in activity between phantoms lower than 5%
Russomando- PhD 2015
Typical assembly
• Simulation of a tumor embedded in healthy tissue
• Typical assembly: spot (high uptake) inserted intoa torus (low uptake) over a disk (low uptake)
• Allow exploration of different patterns
• Different TNR realized whit diluted 90Y solution
• Static and dynamic situations were studied
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20 mm
5 mm
2,5 mmV=0,049 ml
V=0,736 ml
V=0,785 ml
10 - Tumor"1 - Healthy"0 - Necrotic
Russomando- PhD 2015
Automated set-up "
Active spot identification
Lines represent the discovery potential of the probe with different acquisition times
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Activity 10 kBq/mlActivity 1 kBq/mlActivity 0 kBq/ml
TNR=10 step 1 mm/ 10 s
Rat
e [H
z]
5 mm
FP thresholds
Russomando- PhD 2015
Simulation of surgical operation
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20 mm
15 mm
4 mm
6 mm
5 mm
2.5 mm3 mm
Movement Probe Footprint
TNR 10:1
Position [mm]
Russomando- PhD 2015
Simulation of surgical operation
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• Progressive removal of the tumor tissue
20 mm
15 mm
4 mm
6 mm
5 mm
2.5 mm3 mm
Probe FootprintMovement
Position [mm]
Russomando- PhD 2015
Simulation of surgical operation
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• Progressive removal of the tumor tissue
20 mm
15 mm
4 mm
6 mm
5 mm
2.5 mm3 mm
Probe FootprintMovement
Russomando- PhD 2015
Simulation of surgical operation
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• Smallest volume detected 0.03 ml(benchmark 0.1 ml)
20 mm
15 mm
4 mm
6 mm
5 mm
2.5 mm3 mm
Probe Footprint
No more residuals
Position [mm]
Movement
Russomando- PhD 2015
Human perception• To evaluate the human factor, colleagues
were asked to simulate the surgeon
• The testers were equipped with different feedback
• Visual (blinking led)
• Acoustic (buzzer)
• Numeric (tablet)
• Sequentially each of the phantoms was randomly chosen by a microprocessor
• The testers were not able to take a decision in less than 2-3 s
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10 - Tumor"1 - Healthy"0 - Necrotic
Russomando- PhD 2015
Outline• Radio-Guided Surgery (RGS)
• New technique exploiting β- radiotracers
• Clinical cases of interest
• Brain and Neurendocrine tumors
• Detector development
• Crystal characterization
• The final prototype
• Phantoms’ techniques
• Test on ex-vivo specimens
26
WARNING !!!!NEXT SLIDE COULD SHOCK
YOUR SENSIBILITY
Russomando- PhD 2015
Brain tumor surgery
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1
2 3
Identification of"meningioma (bulk)
Bulk removalResidual?
Patient injected 24 h before the operation with 4 MBq/kg of
90Y-DOTATOC (renal dose 0.4Gy)
Russomando- PhD 2015
Ex-vivo specimens• Different samples were analyzed
• Type of tissue, uptake, surgeon rating (T = tumor, NT = not tumor, ? not sure)
• The results of the anatomo-pathologicalmeasures will define the nature of the samples (not yet available)
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5 mm
1 cm
Sample Weight [g] Surgeon Rate [Hz]
A 0.39 Dura - NT 5
B 0.23 Lesion - T 51
C 0.73 Lesion - T 45
D 4.84 Bulk - T 102
E 0.88 Dura - ? 3
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Russomando- PhD 2015
Summary• Aim of the thesis was to develop
• A β- probe for radioguided surgery
• No background from gammas allows for:
• Shorter time to have a response
• A smaller and more versatile detector
• Much reduced noise from nearby healthy organs
• To an effective use in clinical practice :
• A radiotracer and clinical cases of interested were identified
• A handy counter device was developed and characterized
• A phantom techniques for improved laboratory test was set up
• A first preclinical test confirmed the potentiality of the work
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BACK-UP
Russomando- PhD 2015
A.R.P.G. @ Sapienza (ROME)• A.R.P.G.
• Applied Radiation Physics Group
• ~ 20 people (collaboration with bio-engineers, nuclear medicine physicians, neurosurgeons)
• Collaboration of particle physicists for medical applications
• F. Collamati, R. Faccini, S. Morganti, L. Recchia, A. Russomando, E. Solfaroli.
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Russomando- PhD 2015
Active spot identification
Lines represent the discovery potential of the probe with different lasting times
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Activity 10 kBq/mlActivity 1 kBq/mlActivity 0 kBq/ml
TNR=10 step 1 mm/ 10 sR
ate
[Hz]
Russomando- PhD 2015
Simulation
• To evaluate the minimal energy an electron must have when entering the probe in order to be detected a 0.1mm scan was performed between 7 a 9 mm of water thickness
• Same configuration has been built in FLUKA (MonteCarlo simulation package)
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Russomando- PhD 2015
High Grande Gliomas
ID LESION
TNR
3
Radiotracer uptake
36
ID LESION
TNR Meningiomas
11 patients
10
40
10
F. Collamati et al, Towards a Radio-guided Surgery with b- Decays: Uptake of a somatostatin analogue (DOTATOC) in Meningioma and High Grade Glioma. J Nucl Med 56 (2015) 3-8
!
• Uptake and background from healthy tissues were estimated on 11 meningioma patients and 12 HGG patients
• Uptake of 90Y-DOTATOC in meningiomas was high in all studied patients
• Uptake in HGGs was lower but still acceptable for RGS