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

Transcript of Istituto Italiano di Tecnologia surgery: from the design to the first ...€¦ · • RadioGuided...

Page 1: Istituto Italiano di Tecnologia surgery: from the design to the first ...€¦ · • RadioGuided surgery 3. Russomando- PhD 2015 Radio-Guided surgery • Radio-guided surgery is

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

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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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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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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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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!

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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

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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)

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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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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

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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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TNR: specific activity ratio

1

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1

ID LESION

TNR Meningiomas

11 patients

10

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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

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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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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

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[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]

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• 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

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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

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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

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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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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%

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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

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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

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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]

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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]

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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

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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

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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

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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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WARNING !!!!NEXT SLIDE COULD SHOCK

YOUR SENSIBILITY

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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)

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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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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

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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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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]

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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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High Grande Gliomas

ID LESION

TNR

3

Radiotracer uptake

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ID LESION

TNR Meningiomas

11 patients

10

40

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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