Gamma Ray and Beta Ray Probes Larry MacDonald Imaging Research Laboratory University of Washington Radiology http://depts.washington.edu/nucmed/IRL/ 23 Oct. 2007

Gamma Ray and Beta Ray Probes “Probe” implies hand-held device provides  positioning flexibility  real-time response Most relevant arena for probes is the operating room  OR compatible Expand the probe idea functionality (above points) to larger imaging systems

Properties of Gamma Rays and Beta Rays massless photons travel potentially long distances in body  penetration is exponential: N=N0e-(mat.,E)*x  typical ~ cm-m penetration, no maximum  difficult to collimate  mono-energetic (allows energy discrimination) Beta Rays (e- & e+) massive charged particles undergo many interactions in body  penetration between exp.&linear  typical ~ mm penetration, max. exists  easy to collimate  continuous distribution of energies up to a maximum (does not allow energy discrimination)

Probe Application Requirements Procedure efficacy depends on measurement system consisting of Labeled compound extracted from blood into tumor/ROI high tumor-to-background remain in tumor for a time consistent with surgery and T1/2 Radioisotope chemical properties for stable label appropriate half-life (T1/2) emission compatible with the detector and patient safety Radiation detector efficient to radiation insensitive to background (or discrimination capability) good energy resolution (eliminate background and scatter) adequate collimation spatial resolution

First Applications, Probes, Isotopes First application: tumor localization pre- & intra-operative First probe: Geiger-Muller gas filled low sensitivity no energy resolution First isotope used with probe: 32-P (-) Emax = 1.7 MeV --> ~ 7-8 mm range in tissue T1/2=14d --> dosimetry issues

Available Tracers In principle any Nuc. Med. () / PET (+) agent + easy to collimate short range --> good localization confounding presence of 511 keV annihilation photons  difficult to collimate

Contemporary Applications, Probes, Isotopes Clinical Sentinel lymph nodes (SLN) replace complete axillary LN dissection with excision of selective SLN Scintillation and solid-state “pencil” detectors non-imaging small point detectors 99m-Tc labeled colloids designed to flow through lymph systems - not biologically active Research Sentinel lymph nodes - add imaging capability, expand disease base Brain tumor margins - scint./solidstate/combo imaging probes - +(PET) Arterial vulnerable plaque - “imaging” catheters - +(PET)

SLN Procedure: Evaluate Spread of Cancer Applied to melanoma, breast cancer. Other cancers being investigated. Pathology of first downstream lymph nodes (Sentinel node(s)) is indicative of disease spread. Removal of only Sentinel node(s) avoids complications of complete node basin dissection. 99m-Tc labeled colloid injected near primary tumor – drains through lymphatics. NO BACKGROUND, except injection site ~ 100X node act. ---> HIGH CONTRAST at nodes; nCi sensitivity Pre-operative imaging in Nuc. Med. with conventional camera is not universal. Non-imaging gamma probes are used to find nodes during surgery. Atlanta VA Protocol - breast Injections Tc-99m sulfur colloid (0.22 µm filtered) 2 peri-tumoral (125 µCi in 1.0 cc each – syringes shaken) 1 subdermal (250 µCi in 0.3 cc – syringe shaken) massage (1-5 min) Preoperative Imaging patient position (arm extended – surgical position) time-course acquisition (for order of SLN visualization) transmission source (for body contour definition) anterior, lateral, oblique (for oblique, rotate patient, not camera) breast positioning (to minimize attenuation effects) anterior & lateral marking (for guidance in surgery) Intraoperative Counting pre-incision, post-excision

SLN Detection Technical Issues and Protocol Variations Probe - all quite similar Tracer - colloid particle size Injection site - subdermal / peritumorial / intratumorial / subcutaneous Number of injections Injection volume and activity Massage injection site? Injection - detection timing Detection mode: blue dye / gamma probe / preoperative imaging Dynamic imaging / early imaging / early+late imaging Number of nodes to remove Pathology Requirements - H&E staining / IHC /Cytology

SLN Theoretical Basis Patients present with earlier stage of disease Lymph flow is orderly and predictable Tumor cells disseminate sequentially The “sentinel” node is the first node encountered by tumor cells Sentinel node status predicts distant basin status Basin involvement is less frequent

Commercial SLN Probes Non-imaging Tyco healthcare Navigator GPS cadmium telluride (CdTe) semiconductor detector Battelle Healthcare Products Neo2000® cadmium zinc telluride (CZT) semiconductor detector Non-imaging Carewise Medical Products, Inc. C-Trak® scintillation crystal (?)

Important Operating Properties of Probes Sensitivity (counts/sec./inj. activity) detector material detector size (depth) radiation type () and energy Spatial resolution (resolving small nearby nodes) detector size (width / diameter) collimator opening Energy resolution (reject scatter) detector type (scintillation / semiconductor)

SLN Probe Design NaI(Tl) / CsI(Na) / BGO (scintillation crystal) OR CdTe / CdZnTe (semiconductor) field of view, spatial resolution dependent on detector size and collimator geometry --- multiple collimators available -ray shielding cable to console ergonomic handle electronics PMT for scintillators low noise amps./buffers

SLN Probe Detector Materials SUPERIOR ENERGY RESOLUTION POSSIBLE! Scintillation crystals Indirect detection method high voltage ~ 1000V Semiconductors Direct detection method low voltage ~ 50V  visible light photosensor e.g. PMT, photodiode  energy (photo)electron (atomic ionizations)  semiconductor material e.g. Si, CdTe, CZT, Ge, HgI2 scintillation crystal e.g. NaI(Tl), BGO, CsI(Tl) atomic excitations scintillation photons photosensor conversion (photoelectron…) current electron-hole pairs current SUPERIOR ENERGY RESOLUTION POSSIBLE!

Current common clinical applications Melanoma Breast cancer SLN Probe Uses Current common clinical applications Melanoma Breast cancer Active research application areas (oncology) Colon Head and neck Cervical / Reproductive Lung

Intra-Operative Imaging of Sentinel Lymph Nodes Harbor Seven patients (breast cancer = 6; melanoma = 1). No conventional lymphoscintigraphy. 30 MBq (0.8 mCi) 99mTc sulphur colloid and isosulphan blue injected in the O.R. LNs localized using probe and blue dye. GammaCAM/OR used immediately after injection & massage, prior to patient preparation. No post-excision imaging. Image acquisition times averaged 89.5 sec (range: 47 – 139 sec). JWCI 19 patients (melanoma = 10; parathyroid = 7; colon = 2). Conventional lymphoscintigraphy is performed. 99mTc injection in N.M.; 0.5 mCi filtered sulfur colloid for melanoma in O.R.; 0.5 mCi filtered sulfur colloid for colon cases In N.M.; 15+ mCi Sestamibi in the parathyroid cases Isosulphan blue injected in the O.R. LNs localized using probe and blue dye and lymphoscint. GCOR images acquired pre- and post-incision. Typical acquisition times ~ 60 sec.

Introduce a compact high-resolution gamma camera into the operating room Goals: Reduce time of surgical procedures/node search. Increase confidence that all implicated nodes are removed. Identify nodes near injection site. Find additional hot nodes hidden by attenuation. Advantages: Display isotope distribution live-time in O.R. Rapidly assay secondary node basins. Faster learning curve. Reduce surgical incision size & morbidity due to node removal. Quantifiable measure of activity in nodes.

Intra-Operative SLN Imaging: Hand-Held Gamma Camera The Hand-Held Camera can be used pre-operatively and intra-operatively Simultaneous image and audible count rate indicator 1 mm intrinsic spatial resolution 2 cm square intrinsic FOV Multiple collimators dictate a range of imaging parameters. Smart algorithms identify activity concentrations in low statistics distributions

Intra-Operative SLN Imaging: LumaGEM™ in the Operating Room Articulating arm Protocols vary widely Degree of pre-OR imaging varies None Passive NM participation Active NM participation Nuclear medicine in the OR requires logistical coordination between NM & Surgery Image acq./ processing PC The camera was developed at Gamma Medica/Photon Imaging through an SBIR grant from the NIH. Very first studies conducted at Harbor Ucla Medical Center. Only pre-incision/pre-patient prep studies were performed there. Both pre- and post-incision imaging performed at JWCI. Studies are also being conducted at the Atlanta VA/Emory Univ. (those results are presented in the next talk.) LumaGEM™ Monitor on back of gamma cam. (not shown) displays images in View-Thru format. ~ 1 m2 footprint wheel base

Nuc. Med. Dept. image showed one focus in axilla Intra-Operative SLN Imaging: Extreme Color Scale Thresholding to Visualize Low Activity Nodes Color Scale Threshold 100% (same image) 0.4% Nuc. Med. Dept. image showed one focus in axilla No Primary: Primary had been previously removed 58 sec. Pre-Prep OR image: Axilla. ROI activity: 4.5 kBq (0.12 mCi) INJ INJ 19 patients (melanoma = 10; parathyroid = 7; colon = 2). Conventional lymphoscintigraphy is performed. 99mTc injection in N.M.; 0.5 mCi filtered sulfur colloid for melanoma in O.R.; 0.5 mCi filtered sulfur colloid for colon cases In N.M.; 15+ mCi Sestamibi in the parathyroid cases Isosulphan blue injected in the O.R. LNs localized using probe and blue dye and lymphoscint. GCOR images acquired pre- and post-incision. Typical acquisition times ~ 60 sec. JWCI 2002-11-11-1000 Docs worried about this case b/c there was no primary. PRE-incision image. 58 sec. Illustrated here is the degree to which the color scale threshold must be reduced in order to visualize the node, which can be 100s of times less radioactive than the primary/injection site. ROI activity of 4.5 kBq does NOT account for attenuation, which is a factor. superior axilla node ROI pre-incision Melanoma on RT ant. shoulder JWCI 2002-11-11-1000

Intra-Operative SLN Imaging: Quickly Survey Secondary Node Basins OR imaging before patient preparation (patient anesthetized) - Familiarizes physician with count rates, node location Color Scale Threshold 5% Pre-incision imaging can be done under slightly less pressure that when the patient is open. These pre-incision images give an idea of not only where to look once the patient is open, but also how long one needs to image before expecting to see the node, what the nature/shape of the nodes are, etc. With this info post-incision imaging is facilitated and sped up. Shown here: negative supraclavcular region. Same patient as last slide. superior 62 sec. Pre-Prep OR image: Supraclavicular pre-incision INJ JWCI 2002-11-11-1000

Two nodes excised Re-image axilla Intra-Operative SLN Imaging: Post-Excision Findings Time sequence axilla: post-incision, pre-excision reference point source nodes #sec: 30 35 40 45 50 55 Same case: -Time sequence images. -Single focus on pre-op images (both Nuc Med and GCOR) shows up as two hot nodes on post-incision image. This could be due to colloid flow to a second node in the intervening time, or the reduced attenuation of imaging the node basin directly, or both. -The position of the two nodes are found by bringing a reference source into to FoV and over the hot spots. -After removing these two, axilla imaged again revealed a 3rd hot node. That was also removed. -Post excision of 3rd node: image (not shown here) was free of additional hot spots. -The surgeon placed the excised 3rd node back into the FoV to confirm that that was giving the signal seen above. That was found to be the case. Two nodes excised Re-image axilla axilla: post-excision of two hot nodes 3rd node #sec: 42 47 52 57 62 67 JWCI 2002-11-11-1000

Intra-Operative SLN Imaging: Summary Discussion Locate more hot nodes in less time Increases confidence Degree of pre-OR imaging varies None Passive NM participation Active NM participation Expanding beyond melanoma/breast Cost/Benefit Ratio Harbor Seven patients (breast cancer = 6; melanoma = 1). No conventional lymphoscintigraphy. 30 MBq (0.8 mCi) 99mTc sulphur colloid and isosulphan blue injected in the O.R. LNs localized using probe and blue dye. GammaCAM/OR used immediately after injection & massage, prior to patient preparation. No post-excision imaging. Image acquisition times averaged 89.5 sec (range: 47 – 139 sec). JWCI 19 patients (melanoma = 10; parathyroid = 7; colon = 2). Conventional lymphoscintigraphy is performed. 99mTc injection in N.M.; 0.5 mCi filtered sulfur colloid for melanoma in O.R.; 0.5 mCi filtered sulfur colloid for colon cases In N.M.; 15+ mCi Sestamibi in the parathyroid cases Isosulphan blue injected in the O.R. LNs localized using probe and blue dye and lymphoscint. GCOR images acquired pre- and post-incision. Typical acquisition times ~ 60 sec. Atlanta VA Protocol - breast Injections Tc-99m sulfur colloid (0.22 µm filtered) 2 peri-tumoral (125 µCi in 1.0 cc each – syringes shaken) 1 subdermal (250 µCi in 0.3 cc – syringe shaken) massage (1-5 min) Preoperative Imaging patient position (arm extended – surgical position) time-course acquisition (for order of SLN visualization) transmission source (for body contour definition) anterior, lateral, oblique (for oblique, rotate patient, not camera) breast positioning (to minimize attenuation effects) anterior & lateral marking (for guidance in surgery) Intraoperative Counting pre-incision, post-excision

Research Beta Ray Probes

 Probe Catheter for Unstable Plaque Technique Agent preferentially taken up in unstable plaque Label agent with  emitter Inject agent Insert detector catheter into artery Linear detector array locates labeled plaque along artery length Detectors: scintillators+fibers or silicon direct detection Beta ray imaging (short range localization, no -ray collimation possible) Two detector options: signal cables silicon detectors “Detector Identification Through Light Separation for Miniature Imaging Probe” Janecek et. al, IEEE Trans. Nucl. Sci., Vol. 51(3), 2004

Imaging  Probe for Brain Tumor Margins - Aid removal of tumor margins in the brain - Use 18F or other PET tracers - detect +, reject 511 keV ’s - Both scintillation and semiconductor versions developed - Phoswich detects + and 511 keV  in coincidence PHOSWICH: two scint. materials with distinct timing prop. allow pulse discrimination Not Phoswich independent det. Phoswich Phoswich continuous (gamma camera-like) discrete (PET-like)