US20100010343A1 - Detection of radiation labeled sites using a radiation detection probe or camera incorporating a solid state photo-multiplier - Google Patents
Detection of radiation labeled sites using a radiation detection probe or camera incorporating a solid state photo-multiplier Download PDFInfo
- Publication number
- US20100010343A1 US20100010343A1 US11/784,854 US78485407A US2010010343A1 US 20100010343 A1 US20100010343 A1 US 20100010343A1 US 78485407 A US78485407 A US 78485407A US 2010010343 A1 US2010010343 A1 US 2010010343A1
- Authority
- US
- United States
- Prior art keywords
- beta
- radiation
- probe
- camera
- solid state
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000000523 sample Substances 0.000 title claims abstract description 146
- 230000005855 radiation Effects 0.000 title claims abstract description 76
- 239000007787 solid Substances 0.000 title claims abstract description 36
- 238000001514 detection method Methods 0.000 title abstract description 62
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims abstract description 31
- 229910052710 silicon Inorganic materials 0.000 claims abstract description 31
- 239000010703 silicon Substances 0.000 claims abstract description 31
- 230000002159 abnormal effect Effects 0.000 claims abstract description 8
- 238000003384 imaging method Methods 0.000 claims description 49
- 239000004033 plastic Substances 0.000 claims description 48
- 229920003023 plastic Polymers 0.000 claims description 48
- 238000001574 biopsy Methods 0.000 claims description 33
- 230000002285 radioactive effect Effects 0.000 claims description 25
- 230000003287 optical effect Effects 0.000 claims description 20
- 210000004881 tumor cell Anatomy 0.000 claims description 9
- 239000000463 material Substances 0.000 claims description 8
- 239000012528 membrane Substances 0.000 claims description 8
- 238000012545 processing Methods 0.000 claims description 8
- 230000000007 visual effect Effects 0.000 claims description 7
- 230000005540 biological transmission Effects 0.000 claims description 4
- 239000003292 glue Substances 0.000 claims description 4
- 230000002792 vascular Effects 0.000 claims description 4
- 230000004888 barrier function Effects 0.000 claims 10
- 238000000034 method Methods 0.000 abstract description 42
- 230000035945 sensitivity Effects 0.000 abstract description 36
- 230000002708 enhancing effect Effects 0.000 abstract description 2
- 206010028980 Neoplasm Diseases 0.000 description 144
- 210000001519 tissue Anatomy 0.000 description 94
- AOYNUTHNTBLRMT-SLPGGIOYSA-N 2-deoxy-2-fluoro-aldehydo-D-glucose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](F)C=O AOYNUTHNTBLRMT-SLPGGIOYSA-N 0.000 description 70
- 201000011510 cancer Diseases 0.000 description 56
- 238000002600 positron emission tomography Methods 0.000 description 53
- 210000004027 cell Anatomy 0.000 description 31
- 238000001356 surgical procedure Methods 0.000 description 27
- 230000003902 lesion Effects 0.000 description 24
- 206010006187 Breast cancer Diseases 0.000 description 22
- 208000026310 Breast neoplasm Diseases 0.000 description 22
- ZCXUVYAZINUVJD-AHXZWLDOSA-N 2-deoxy-2-((18)F)fluoro-alpha-D-glucose Chemical compound OC[C@H]1O[C@H](O)[C@H]([18F])[C@@H](O)[C@@H]1O ZCXUVYAZINUVJD-AHXZWLDOSA-N 0.000 description 19
- KRHYYFGTRYWZRS-BJUDXGSMSA-N ac1l2y5h Chemical group [18FH] KRHYYFGTRYWZRS-BJUDXGSMSA-N 0.000 description 19
- 238000005259 measurement Methods 0.000 description 17
- 201000001441 melanoma Diseases 0.000 description 17
- 210000002307 prostate Anatomy 0.000 description 16
- 206010060862 Prostate cancer Diseases 0.000 description 15
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 15
- 230000000694 effects Effects 0.000 description 13
- 230000003143 atherosclerotic effect Effects 0.000 description 12
- 230000008901 benefit Effects 0.000 description 12
- 238000012360 testing method Methods 0.000 description 11
- 238000010176 18-FDG-positron emission tomography Methods 0.000 description 10
- 210000004556 brain Anatomy 0.000 description 10
- 239000013307 optical fiber Substances 0.000 description 10
- 206010027476 Metastases Diseases 0.000 description 9
- 241000283973 Oryctolagus cuniculus Species 0.000 description 9
- 210000000709 aorta Anatomy 0.000 description 9
- 238000005516 engineering process Methods 0.000 description 9
- 239000011888 foil Substances 0.000 description 9
- OHSVLFRHMCKCQY-NJFSPNSNSA-N lutetium-177 Chemical compound [177Lu] OHSVLFRHMCKCQY-NJFSPNSNSA-N 0.000 description 9
- 210000005036 nerve Anatomy 0.000 description 9
- 238000002271 resection Methods 0.000 description 9
- 229910001220 stainless steel Inorganic materials 0.000 description 9
- 239000010935 stainless steel Substances 0.000 description 9
- 238000013459 approach Methods 0.000 description 8
- 230000005250 beta ray Effects 0.000 description 8
- 238000002591 computed tomography Methods 0.000 description 8
- 201000010099 disease Diseases 0.000 description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
- 230000009977 dual effect Effects 0.000 description 8
- 230000001965 increasing effect Effects 0.000 description 8
- 238000007726 management method Methods 0.000 description 8
- 241000700159 Rattus Species 0.000 description 7
- VWQVUPCCIRVNHF-OUBTZVSYSA-N Yttrium-90 Chemical compound [90Y] VWQVUPCCIRVNHF-OUBTZVSYSA-N 0.000 description 7
- 238000000211 autoradiogram Methods 0.000 description 7
- 230000002596 correlated effect Effects 0.000 description 7
- 238000013461 design Methods 0.000 description 7
- 238000011161 development Methods 0.000 description 7
- 230000018109 developmental process Effects 0.000 description 7
- 238000003745 diagnosis Methods 0.000 description 7
- 238000001727 in vivo Methods 0.000 description 7
- 210000001165 lymph node Anatomy 0.000 description 7
- 210000002540 macrophage Anatomy 0.000 description 7
- 210000004379 membrane Anatomy 0.000 description 7
- 206010058314 Dysplasia Diseases 0.000 description 6
- 206010027480 Metastatic malignant melanoma Diseases 0.000 description 6
- 230000005856 abnormality Effects 0.000 description 6
- 238000009825 accumulation Methods 0.000 description 6
- 210000000481 breast Anatomy 0.000 description 6
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 6
- 210000003238 esophagus Anatomy 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 208000021039 metastatic melanoma Diseases 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000011282 treatment Methods 0.000 description 6
- 208000037260 Atherosclerotic Plaque Diseases 0.000 description 5
- 206010061218 Inflammation Diseases 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 238000012937 correction Methods 0.000 description 5
- 230000006378 damage Effects 0.000 description 5
- 239000000835 fiber Substances 0.000 description 5
- 230000002962 histologic effect Effects 0.000 description 5
- 230000004054 inflammatory process Effects 0.000 description 5
- 238000002595 magnetic resonance imaging Methods 0.000 description 5
- 230000004044 response Effects 0.000 description 5
- 238000002604 ultrasonography Methods 0.000 description 5
- VRYALKFFQXWPIH-PBXRRBTRSA-N (3r,4s,5r)-3,4,5,6-tetrahydroxyhexanal Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)CC=O VRYALKFFQXWPIH-PBXRRBTRSA-N 0.000 description 4
- 102100041003 Glutamate carboxypeptidase 2 Human genes 0.000 description 4
- 101000892862 Homo sapiens Glutamate carboxypeptidase 2 Proteins 0.000 description 4
- 208000035346 Margins of Excision Diseases 0.000 description 4
- 206010054949 Metaplasia Diseases 0.000 description 4
- 238000012879 PET imaging Methods 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 230000008878 coupling Effects 0.000 description 4
- 238000010168 coupling process Methods 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 238000002405 diagnostic procedure Methods 0.000 description 4
- 238000002224 dissection Methods 0.000 description 4
- 238000001861 endoscopic biopsy Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 230000036210 malignancy Effects 0.000 description 4
- 230000004060 metabolic process Effects 0.000 description 4
- 206010061289 metastatic neoplasm Diseases 0.000 description 4
- 238000011471 prostatectomy Methods 0.000 description 4
- 238000011472 radical prostatectomy Methods 0.000 description 4
- 230000000306 recurrent effect Effects 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 238000012384 transportation and delivery Methods 0.000 description 4
- AOYNUTHNTBLRMT-MXWOLSILSA-N 2-Deoxy-2(F-18)fluoro-2-D-glucose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H]([18F])C=O AOYNUTHNTBLRMT-MXWOLSILSA-N 0.000 description 3
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 3
- 102000005548 Hexokinase Human genes 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 229920005479 Lucite® Polymers 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 108091006296 SLC2A1 Proteins 0.000 description 3
- 208000027418 Wounds and injury Diseases 0.000 description 3
- 238000003491 array Methods 0.000 description 3
- 238000007469 bone scintigraphy Methods 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- 235000012000 cholesterol Nutrition 0.000 description 3
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 3
- 230000034994 death Effects 0.000 description 3
- 231100000517 death Toxicity 0.000 description 3
- 230000003111 delayed effect Effects 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 208000014674 injury Diseases 0.000 description 3
- 208000030776 invasive breast carcinoma Diseases 0.000 description 3
- 230000004807 localization Effects 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 239000004926 polymethyl methacrylate Substances 0.000 description 3
- 230000002980 postoperative effect Effects 0.000 description 3
- 238000005070 sampling Methods 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 201000001320 Atherosclerosis Diseases 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 206010061819 Disease recurrence Diseases 0.000 description 2
- 208000032612 Glial tumor Diseases 0.000 description 2
- 206010018338 Glioma Diseases 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 108091052347 Glucose transporter family Proteins 0.000 description 2
- 102000042092 Glucose transporter family Human genes 0.000 description 2
- 108700040460 Hexokinases Proteins 0.000 description 2
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 2
- 206010033128 Ovarian cancer Diseases 0.000 description 2
- 208000007660 Residual Neoplasm Diseases 0.000 description 2
- 210000001744 T-lymphocyte Anatomy 0.000 description 2
- 108010076830 Thionins Proteins 0.000 description 2
- 208000035868 Vascular inflammations Diseases 0.000 description 2
- 210000001015 abdomen Anatomy 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 238000011888 autopsy Methods 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 230000000747 cardiac effect Effects 0.000 description 2
- 239000000919 ceramic Substances 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 230000000875 corresponding effect Effects 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- 201000004101 esophageal cancer Diseases 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 235000013312 flour Nutrition 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 239000004519 grease Substances 0.000 description 2
- 201000001881 impotence Diseases 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 210000004969 inflammatory cell Anatomy 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 238000003780 insertion Methods 0.000 description 2
- 230000037431 insertion Effects 0.000 description 2
- 238000009413 insulation Methods 0.000 description 2
- 230000033001 locomotion Effects 0.000 description 2
- 230000003211 malignant effect Effects 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000009401 metastasis Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000009206 nuclear medicine Methods 0.000 description 2
- 238000012335 pathological evaluation Methods 0.000 description 2
- 230000007170 pathology Effects 0.000 description 2
- 230000035515 penetration Effects 0.000 description 2
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 2
- 229920001481 poly(stearyl methacrylate) Polymers 0.000 description 2
- 238000004393 prognosis Methods 0.000 description 2
- 238000001959 radiotherapy Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000004065 semiconductor Substances 0.000 description 2
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 2
- 210000004872 soft tissue Anatomy 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000009121 systemic therapy Methods 0.000 description 2
- ANRHNWWPFJCPAZ-UHFFFAOYSA-M thionine Chemical compound [Cl-].C1=CC(N)=CC2=[S+]C3=CC(N)=CC=C3N=C21 ANRHNWWPFJCPAZ-UHFFFAOYSA-M 0.000 description 2
- CEGXZKXILQSJHO-KODRXGBYSA-N (3r,4s,5r)-3,4,5,6-tetrahydroxyhexanoyl fluoride Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)CC(F)=O CEGXZKXILQSJHO-KODRXGBYSA-N 0.000 description 1
- RNAMYOYQYRYFQY-UHFFFAOYSA-N 2-(4,4-difluoropiperidin-1-yl)-6-methoxy-n-(1-propan-2-ylpiperidin-4-yl)-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-4-amine Chemical compound N1=C(N2CCC(F)(F)CC2)N=C2C=C(OCCCN3CCCC3)C(OC)=CC2=C1NC1CCN(C(C)C)CC1 RNAMYOYQYRYFQY-UHFFFAOYSA-N 0.000 description 1
- 238000011350 2-deoxy-2-(F-18)fluoro-D-glucose positron emission tomography Methods 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 208000036764 Adenocarcinoma of the esophagus Diseases 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 206010003178 Arterial thrombosis Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 208000023514 Barrett esophagus Diseases 0.000 description 1
- 208000023665 Barrett oesophagus Diseases 0.000 description 1
- 229920002799 BoPET Polymers 0.000 description 1
- 208000020084 Bone disease Diseases 0.000 description 1
- 206010006223 Breast discharge Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229910004613 CdTe Inorganic materials 0.000 description 1
- 229910004611 CdZnTe Inorganic materials 0.000 description 1
- NBSCHQHZLSJFNQ-GASJEMHNSA-N D-Glucose 6-phosphate Chemical compound OC1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H](O)[C@H]1O NBSCHQHZLSJFNQ-GASJEMHNSA-N 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- 208000007659 Fibroadenoma Diseases 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- VFRROHXSMXFLSN-UHFFFAOYSA-N Glc6P Natural products OP(=O)(O)OCC(O)C(O)C(O)C(O)C=O VFRROHXSMXFLSN-UHFFFAOYSA-N 0.000 description 1
- 102000058063 Glucose Transporter Type 1 Human genes 0.000 description 1
- 101150026303 HEX1 gene Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 208000007433 Lymphatic Metastasis Diseases 0.000 description 1
- 201000011055 Lymphocele Diseases 0.000 description 1
- 206010025282 Lymphoedema Diseases 0.000 description 1
- 229920000134 Metallised film Polymers 0.000 description 1
- 206010027452 Metastases to bone Diseases 0.000 description 1
- 206010027458 Metastases to lung Diseases 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 239000005041 Mylar™ Substances 0.000 description 1
- 206010028851 Necrosis Diseases 0.000 description 1
- 208000003788 Neoplasm Micrometastasis Diseases 0.000 description 1
- 101001083189 Neosartorya fumigata (strain ATCC MYA-4609 / Af293 / CBS 101355 / FGSC A1100) Hexokinase-1 Proteins 0.000 description 1
- 206010030137 Oesophageal adenocarcinoma Diseases 0.000 description 1
- 206010050171 Oesophageal dysplasia Diseases 0.000 description 1
- 241000283977 Oryctolagus Species 0.000 description 1
- 101000840556 Oryza sativa subsp. japonica Hexokinase-4, chloroplastic Proteins 0.000 description 1
- 101000840634 Oryza sativa subsp. japonica Hexokinase-5 Proteins 0.000 description 1
- 208000007571 Ovarian Epithelial Carcinoma Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000010378 Pulmonary Embolism Diseases 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 208000016247 Soft tissue disease Diseases 0.000 description 1
- 102100023536 Solute carrier family 2, facilitated glucose transporter member 1 Human genes 0.000 description 1
- 206010049418 Sudden Cardiac Death Diseases 0.000 description 1
- 206010042434 Sudden death Diseases 0.000 description 1
- 239000004809 Teflon Substances 0.000 description 1
- 229920006362 Teflon® Polymers 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 206010047249 Venous thrombosis Diseases 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 238000011366 aggressive therapy Methods 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 210000003484 anatomy Anatomy 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 238000002583 angiography Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 210000000702 aorta abdominal Anatomy 0.000 description 1
- 230000000712 assembly Effects 0.000 description 1
- 238000000429 assembly Methods 0.000 description 1
- 230000007214 atherothrombosis Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000011956 best available technology Methods 0.000 description 1
- 239000000090 biomarker Substances 0.000 description 1
- 229910052797 bismuth Inorganic materials 0.000 description 1
- JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 238000011088 calibration curve Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000007211 cardiovascular event Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 210000000038 chest Anatomy 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000001010 compromised effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002586 coronary angiography Methods 0.000 description 1
- 208000002528 coronary thrombosis Diseases 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 239000006059 cover glass Substances 0.000 description 1
- 208000030381 cutaneous melanoma Diseases 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 238000005695 dehalogenation reaction Methods 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 238000006209 dephosphorylation reaction Methods 0.000 description 1
- 239000010432 diamond Substances 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000004980 dosimetry Methods 0.000 description 1
- 238000000295 emission spectrum Methods 0.000 description 1
- 230000002996 emotional effect Effects 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 208000028653 esophageal adenocarcinoma Diseases 0.000 description 1
- 210000003195 fascia Anatomy 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000005251 gamma ray Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 150000002303 glucose derivatives Chemical class 0.000 description 1
- 230000004153 glucose metabolism Effects 0.000 description 1
- 230000002414 glycolytic effect Effects 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 208000016356 hereditary diffuse gastric adenocarcinoma Diseases 0.000 description 1
- 230000003118 histopathologic effect Effects 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 239000012212 insulator Substances 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 210000004347 intestinal mucosa Anatomy 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 230000002601 intratumoral effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 208000023418 invasive ductal and lobular carcinoma Diseases 0.000 description 1
- 206010073095 invasive ductal breast carcinoma Diseases 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000009533 lab test Methods 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 238000002357 laparoscopic surgery Methods 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 208000010949 lymph node disease Diseases 0.000 description 1
- 230000001926 lymphatic effect Effects 0.000 description 1
- 208000002502 lymphedema Diseases 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000007102 metabolic function Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 210000004088 microvessel Anatomy 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 230000000394 mitotic effect Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 210000003928 nasal cavity Anatomy 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 230000001338 necrotic effect Effects 0.000 description 1
- 238000013188 needle biopsy Methods 0.000 description 1
- 238000011587 new zealand white rabbit Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 230000010355 oscillation Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 210000004197 pelvis Anatomy 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- 230000008447 perception Effects 0.000 description 1
- 238000009520 phase I clinical trial Methods 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 238000013439 planning Methods 0.000 description 1
- 229910021420 polycrystalline silicon Inorganic materials 0.000 description 1
- 229920005591 polysilicon Polymers 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000002250 progressing effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 238000011555 rabbit model Methods 0.000 description 1
- 239000000700 radioactive tracer Substances 0.000 description 1
- 238000011127 radiochemotherapy Methods 0.000 description 1
- 239000012217 radiopharmaceutical Substances 0.000 description 1
- 229940121896 radiopharmaceutical Drugs 0.000 description 1
- 230000002799 radiopharmaceutical effect Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 210000001625 seminal vesicle Anatomy 0.000 description 1
- 238000011270 sentinel node biopsy Methods 0.000 description 1
- 201000003708 skin melanoma Diseases 0.000 description 1
- 210000001154 skull base Anatomy 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 210000003708 urethra Anatomy 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 201000010653 vesiculitis Diseases 0.000 description 1
- 238000011179 visual inspection Methods 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
- A61B17/34—Trocars; Puncturing needles
- A61B17/3403—Needle locating or guiding means
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B6/00—Apparatus for radiation diagnosis, e.g. combined with radiation therapy equipment
- A61B6/02—Devices for diagnosis sequentially in different planes; Stereoscopic radiation diagnosis
- A61B6/03—Computerised tomographs
- A61B6/037—Emission tomography
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B6/00—Apparatus for radiation diagnosis, e.g. combined with radiation therapy equipment
- A61B6/40—Apparatus for radiation diagnosis, e.g. combined with radiation therapy equipment with arrangements for generating radiation specially adapted for radiation diagnosis
- A61B6/4057—Apparatus for radiation diagnosis, e.g. combined with radiation therapy equipment with arrangements for generating radiation specially adapted for radiation diagnosis by using radiation sources located in the interior of the body
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B6/00—Apparatus for radiation diagnosis, e.g. combined with radiation therapy equipment
- A61B6/42—Apparatus for radiation diagnosis, e.g. combined with radiation therapy equipment with arrangements for detecting radiation specially adapted for radiation diagnosis
- A61B6/4208—Apparatus for radiation diagnosis, e.g. combined with radiation therapy equipment with arrangements for detecting radiation specially adapted for radiation diagnosis characterised by using a particular type of detector
- A61B6/4233—Apparatus for radiation diagnosis, e.g. combined with radiation therapy equipment with arrangements for detecting radiation specially adapted for radiation diagnosis characterised by using a particular type of detector using matrix detectors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B6/00—Apparatus for radiation diagnosis, e.g. combined with radiation therapy equipment
- A61B6/42—Apparatus for radiation diagnosis, e.g. combined with radiation therapy equipment with arrangements for detecting radiation specially adapted for radiation diagnosis
- A61B6/4208—Apparatus for radiation diagnosis, e.g. combined with radiation therapy equipment with arrangements for detecting radiation specially adapted for radiation diagnosis characterised by using a particular type of detector
- A61B6/4258—Apparatus for radiation diagnosis, e.g. combined with radiation therapy equipment with arrangements for detecting radiation specially adapted for radiation diagnosis characterised by using a particular type of detector for detecting non x-ray radiation, e.g. gamma radiation
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B6/00—Apparatus for radiation diagnosis, e.g. combined with radiation therapy equipment
- A61B6/50—Clinical applications
- A61B6/508—Clinical applications for non-human patients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B90/00—Instruments, implements or accessories specially adapted for surgery or diagnosis and not covered by any of the groups A61B1/00 - A61B50/00, e.g. for luxation treatment or for protecting wound edges
- A61B90/39—Markers, e.g. radio-opaque or breast lesions markers
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01T—MEASUREMENT OF NUCLEAR OR X-RADIATION
- G01T1/00—Measuring X-radiation, gamma radiation, corpuscular radiation, or cosmic radiation
- G01T1/16—Measuring radiation intensity
- G01T1/161—Applications in the field of nuclear medicine, e.g. in vivo counting
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01T—MEASUREMENT OF NUCLEAR OR X-RADIATION
- G01T1/00—Measuring X-radiation, gamma radiation, corpuscular radiation, or cosmic radiation
- G01T1/16—Measuring radiation intensity
- G01T1/20—Measuring radiation intensity with scintillation detectors
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01T—MEASUREMENT OF NUCLEAR OR X-RADIATION
- G01T1/00—Measuring X-radiation, gamma radiation, corpuscular radiation, or cosmic radiation
- G01T1/29—Measurement performed on radiation beams, e.g. position or section of the beam; Measurement of spatial distribution of radiation
- G01T1/2914—Measurement of spatial distribution of radiation
- G01T1/2985—In depth localisation, e.g. using positron emitters; Tomographic imaging (longitudinal and transverse section imaging; apparatus for radiation diagnosis sequentially in different planes, steroscopic radiation diagnosis)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
- A61B17/00234—Surgical instruments, devices or methods, e.g. tourniquets for minimally invasive surgery
- A61B2017/00238—Type of minimally invasive operation
- A61B2017/00274—Prostate operation, e.g. prostatectomy, turp, bhp treatment
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
- A61B17/34—Trocars; Puncturing needles
- A61B17/3403—Needle locating or guiding means
- A61B2017/3413—Needle locating or guiding means guided by ultrasound
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
- A61B2018/00315—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body for treatment of particular body parts
- A61B2018/00547—Prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B90/00—Instruments, implements or accessories specially adapted for surgery or diagnosis and not covered by any of the groups A61B1/00 - A61B50/00, e.g. for luxation treatment or for protecting wound edges
- A61B90/39—Markers, e.g. radio-opaque or breast lesions markers
- A61B2090/392—Radioactive markers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B90/00—Instruments, implements or accessories specially adapted for surgery or diagnosis and not covered by any of the groups A61B1/00 - A61B50/00, e.g. for luxation treatment or for protecting wound edges
- A61B90/39—Markers, e.g. radio-opaque or breast lesions markers
- A61B2090/3937—Visible markers
- A61B2090/395—Visible markers with marking agent for marking skin or other tissue
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B34/00—Computer-aided surgery; Manipulators or robots specially adapted for use in surgery
- A61B34/20—Surgical navigation systems; Devices for tracking or guiding surgical instruments, e.g. for frameless stereotaxis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B6/00—Apparatus for radiation diagnosis, e.g. combined with radiation therapy equipment
- A61B6/44—Constructional features of apparatus for radiation diagnosis
- A61B6/4423—Constructional features of apparatus for radiation diagnosis related to hygiene or sterilisation
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B6/00—Apparatus for radiation diagnosis, e.g. combined with radiation therapy equipment
- A61B6/44—Constructional features of apparatus for radiation diagnosis
- A61B6/4488—Means for cooling
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B6/00—Apparatus for radiation diagnosis, e.g. combined with radiation therapy equipment
- A61B6/50—Clinical applications
- A61B6/506—Clinical applications involving diagnosis of nerves
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B6/00—Apparatus for radiation diagnosis, e.g. combined with radiation therapy equipment
- A61B6/58—Testing, adjusting or calibrating apparatus or devices for radiation diagnosis
- A61B6/582—Calibration
- A61B6/583—Calibration using calibration phantoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B90/00—Instruments, implements or accessories specially adapted for surgery or diagnosis and not covered by any of the groups A61B1/00 - A61B50/00, e.g. for luxation treatment or for protecting wound edges
- A61B90/36—Image-producing devices or illumination devices not otherwise provided for
- A61B90/361—Image-producing devices, e.g. surgical cameras
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medical Informatics (AREA)
- Engineering & Computer Science (AREA)
- Physics & Mathematics (AREA)
- Molecular Biology (AREA)
- Surgery (AREA)
- General Health & Medical Sciences (AREA)
- Biomedical Technology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- High Energy & Nuclear Physics (AREA)
- Pathology (AREA)
- Animal Behavior & Ethology (AREA)
- Heart & Thoracic Surgery (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Optics & Photonics (AREA)
- Radiology & Medical Imaging (AREA)
- Biophysics (AREA)
- General Physics & Mathematics (AREA)
- Spectroscopy & Molecular Physics (AREA)
- Oral & Maxillofacial Surgery (AREA)
- Dentistry (AREA)
- Mathematical Physics (AREA)
- Nuclear Medicine (AREA)
Abstract
Description
- This application claims benefit of
Provisional Application 60/855,829, filed Oct. 31, 2006 andProvisional Application 60/809,639 filed May 30, 2006 and is a Continuation-In-Part of U.S. application Ser. No. 11/270,906 filed Nov. 10, 2005, which claims benefit of U.S. Provisional Application Ser. No. 60/656,565 filed Feb. 25, 2005. - The present invention is directed to the uses of solid state or silicon photomultiplier (SSPM, or SiPM) devices to provide safe, highly sensitive and compact beta and gamma probes or cameras for use for locating radiation labeled sites within the human body. These instruments are intraoperative radiation detection probes for use in surgical procedures to aid in the location, detection and removal of detected cancer cells, as a part of biopsy devices or catheters, configured for delivery through or with a laparoscope for locating and treating abnormal labeled sites within the body, or for examining excised tissue.
- Surgery is the only certain cure for cancer; however, its curative ability is compromised by the potential of leaving behind microscopic traces of the tumor, known as margins. In breast cancer, for example, there is a 20% recurrence rate after breast-conserving surgery (lumpectomy) due to missed margins. A beta camera capable of surveying the tumor bed, intraoperatively, and imaging visually undetectable, minute amounts of cancer cells, could significantly reduce recurrence rate of many cancers and increase survival. In addition, this beta camera may enable more breast cancer patients to become candidates for breast saving lumpectomies and improve the psychological recovery from breast cancer.
- Surgery is an important mode of treatment of prostate cancer. However, several problems remain. Complete local resection of cancerous tissue is not possible in some cases since normal and prostate cancer tissues are not visually distinguishable. In approximately 30% of cases the margins of resection are involved (or positive). Unfortunately, this finding is currently made by the pathologist from the resected prostate, well after the surgery, when there is little that can be done to rectify the situation. Further, assessment of lymph nodes is important in staging the cancer. This is done by multiple node dissections and pathological evaluations in the vast majority of patients, which results in increased morbidity, operative time, and cost. Currently, trans-rectal biopsies, in post-prostatectomy patients with elevated PSA, are done with ultrasound guidance. However, often no suspicious lesion is seen and biopsies are little more than random samples. As a result, there is a low sensitivity rate.
- Vulnerable atherosclerotic plaques are the major cause of sudden cardiac death. Detection of this type of plaques is a major challenge in cardiology. Various radiopharmaceuticals have been developed to this date with preferential uptake in vulnerable plaques. Vulnerable plaque (VP) is atherosclerotic plaque that is prone to disruption, causing thrombosis, which often leads to a clinical event. Autopsy studies have demonstrated that the majority of cases of sudden death are caused by occlusive coronary thromboses that are associated with an underlying ruptured plaque. From such autopsy studies, much has been learned about the morphological features that are common to VP. Those histologic characteristics include a thin fibrous cap, an underlying lipid pool, and an abundance of inflammatory cells.
- Even with today's best available technology an unacceptably high incidence of cardiovascular events remains even after aggressive therapy. Novel approaches to prevent myocardial infarctions are therefore needed. It is proposed that one of the most effective methods to prevent MI would be to stabilize vulnerable plaque before they rupture. However, currently available systemic therapies are able to lower the risk of plaque rupture by only 20-40%, leaving the vast majority of vulnerable plaques ripe for rupture. As such, it is crucial that vulnerable plaques are localized such that local plaque-stabilizing therapies can be delivered. However, currently available technologies are not able to detect vulnerable plaques. This may be due to the fact that available technologies rely on identifying structural criteria to differentiate the common stable plaque from the rupture-prone vulnerable plaque. Indeed, the most commonly employed method for plaque characterization is coronary arteriography, a method which qualifies plaques based on the degree to which they impinge on and thus narrow the vessel lumen. Multiple angiographic studies that have examined ruptured plaques have found that they are most often associated with insignificant luminal narrowing prior to their rupture. Therefore, technologies that rely on identifying luminal narrowing are not able to identify vulnerable plaques with acceptable sensitivity.
- Further, inflammation is particularly important in the development and progression of atherothrombosis. It is now well-established that atherosclerosis is an inflammatory disease. Histopathological data has confirmed the critical association of plaque inflammation and rupture. Numerous studies demonstrate an abundance of inflammatory cells (T cells and macrophages) within ruptured plaques. Moreover, several large studies have shown a strong association between inflammatory biomarkers and subsequent events. Positron emission tomography (PET) may represent the most promising non-invasive imaging technology for the detection of inflammation in humans. PET imaging with 18F-Flurodeoxyglucose (FDG) has been used extensively in humans to detect metabolically active tissues such as neoplasms, autoimmune disease, and infection. Numerous studies demonstrate that FDG uptake is increased in inflamed tissues such as tumors and infectious foci. Autoradiographic studies show that FDG localizes to macrophage-dense regions within chronic inflammatory lesions and within macrophages surrounding malignant foci.
- F-18 atoms emit positrons (beta rays) that in turn generate gamma rays. Gamma rays travel tens of cm in tissue, while beta rays have a range of ˜2 mm. Beta emitting isotopes are ideal for intraoperative imaging since background radiation will not interfere with the identification of margins. Until now, beta cameras have suffered from serious flaws that prevent their general use in cancer surgery or in vivo diagnostic procedures. The thin shielding required for positron detection provides insufficient insulation from the high voltage photomultiplier tubes (PMTs) and the long fiber-optic coupling used to separate the high voltage from the patient can greatly reduces sensitivity.
- Numerous studies have demonstrated PET's enhanced sensitivity and specificity for identifying tumors as compared to more conventional techniques (Finkelstein S E, Carrasquillo J A, Hoffman J M, Galen B, Choyke P, White D E, Rosenberg S A, Sherry R M. “A Prospective Analysis Of Positron Emission Tomography And Conventional Imaging For Detection Of Stage IV Metastatic Melanoma In Patients Undergoing Metastasectomy”, Ann Surg Oncol, 11, p731-738 (2004); Gulec S A, Faries M B, Lee C C, Kirgan D, Glass C, Morton D L, Essner R. “The Role Of Fluorine-18 Deoxyglucose Positron Emission Tomography In The Management Of Patients With Metastatic Melanoma: Impact On Surgical Decision Making”, Clin Nucl Med, 28 p961-965 (2003); Benard F, Turcotte E. “Imaging In Breast Cancer: Single-Photon Computed Tomography And Positron-Emission Tomography”, Breast Cancer Res, 7, p153-162, (2005)). Usually, PET is performed after IV injection of F-18 labeled fluorodeoxy-glucose (FDG), a glucose analog that is transported into cells but can't complete its metabolism like glucose, and hence accumulates in the cells. Cancer cells accumulate more FDG than normal cells; therefore they become more radioactive than the surrounding normal tissue. The positrons that are emitted by F-18 travel a short distance in tissue (˜1 mm) and then pair up with an electron and annihilate to two high-energy gamma rays. These high-energy gamma rays each have 511 keV energy, and are emitted simultaneously and back-to-back (at a 180 degree angle to each other). The coincidence detection of these emissions by detectors of a PET scanner determines a line along which the F-18 decay occurred (called the line of response). During the PET scan, a collection of these lines will accumulate in the computer of the PET scanner. Using a tomographic algorithm, a distribution map of FDG accumulation is generated by the collection of lines of responses.
- A prerequisite for the accurate identification of cancer with PET is the ability of the radiation source to localize within the tumor, with only minimal or no uptake in adjacent normal tissue, necrotic tissue, or healing tissue. A large number of radioisotopes emit positrons. Notable among them are radioisotopes of carbon, nitrogen, oxygen and fluorine (substituted for hydrogen in many compounds). These are the building blocks of biologic matter. Therefore, the choice for making positron emitting radioisotopes is large. To date, more than 500 radiochemicals have been developed with positron emitting radioisotopes (Quon A, Gambhir S S. “FDG-PET And Beyond: Molecular Breast Cancer Imaging”, J Clin Oncol, 23, p1664-1673 (2005)). Although there are a variety of radioisotopes that would be useful for PET imaging based on metabolic properties of malignancy, so far only FDG has gained universal acceptance as a cancer-seeking agent. The use of FDG is based on the concept that tumor tissues grow generally faster than normal tissues, and thus have an increased rate of glucose metabolism. The FDG molecule is transported into cells by facilitative glucose transporters, such as GLUT-1, and is phosphorylated to PDG-6 phosphate by hexokinase (Luigi A, Caraco C, Jagoda E, Eckelman W, Neumann, Ronald. Glut-1 And Hexokinase Expression: Relationship With 2-Fluoro-2-Deoxy-D-Glucose Uptake In A431 And T47d Cells In Culture”, Cancer Res, 59, p4709-4714 (1999)). Some cancers also have reduced rates of glucose-6-phosphate metabolism accentuating the phosphorylated deoxyglucose into tumor tissue (Chung J K, Lee Y J, Kim S K, Jeong J M, Lee D S, Lee M S. “Comparison Of [18F]Fluorodeoxyglucose Uptake With Glucose Transporter-1 Expression And Proliferation Rate In Human Glioma And Non-Small-Cell Lung Cancer”, Nucl Med Commun, 25, p11-17 (2004); Pugachev A, Ruan S, Carlin S, Larson S, Campa J, Ling C, Humm J. “Dependence Of FDG Uptake On Tumor Microenvironment”, Int J Rad Oncol Biol Phys, 62, p545-553 (2005)). This intermediary is trapped in cancer cells because the dephosphorylation reaction is either slow or absent.
- The greater uptake of FDG and lower levels of metabolism in more aggressive tumors lead to improved imaging of particular cancers; i.e., more accurate staging. FDG avidity is determined by glycolytic activity of the tumor and the viable tumor volume. Individual cancer types may show significant variability in terms of FDG avidity. Even in the same patient, different lesions may have different degrees of FDG uptake. FDG metabolism and clearance occurs at a much faster rate in normal tissues than tumor tissue, and thus tumor-to-background ratios improves with time resulting in better lesion detection when imaging is delayed. Boerner et al. have shown that tumor-to-non-tumor and tumor-to-organ ratios were significantly higher for the images taken at 3 hours post-injection than for the 1.5-hour images, and lesion detectability was 83% in 1.5-hour images compared to 93% in 3-hour images in breast cancer patients. Although more delayed intervals between FDG injection and imaging might compromise image quality due to lower count rates, this is much less of an issue with an FDG sensitive probe. Longer intervals may accentuate the tumor to background ratios, and further improve FDG detection. Important contributors to the background radiation are the sites of physiologic FDG uptake. The in situ tumor to background ratios is strongly affected by the surrounding areas of physiologic uptake or accumulation. The brain uptake in the head and neck region, cardiac uptake in the chest, kidney uptake and the accumulation inside the bladder in abdomen and pelvis affect the in situ tumor to background ratios.
- Gritters and colleagues (Gritters L S, Francis I R, Zasadny K R, Wahl R L. “Initial Assessment Of Positron Emission Tomography Using 2-Flourine-18-Flouro-2-Deoxy-D-Glucose In The Imaging Of Malignant Melanoma”, J Nucl Med, 34, p1420-1427 (1933)) found PET to be highly accurate for identifying cutaneous melanoma metastases. A number of other investigators have also found PET to be both sensitive and specific for metastatic melanoma. For distant metastases, numerous studies have shown PET to have equal or superior sensitivity to CT, MRI, and ultrasound (Schwimmer J, Essner R, Patel A, Jahan S A, Shepherd J E, Park K, Phelps M E, Czernin J, Gambhir SS. “A Review Of The Literature For Whole-Body FDG PET In The Management Of Patients With Melanoma”, Quarterly J Nucl Med, 44, p153-167, (2000); Finkelstein, SE, Carrasquillo J A, Hoffman J M, Galen B, Choyke P, White D E, Rosenberg S A, Sherry R M. “A Prospective Analysis Of Positron Emission Tomography And Conventional Imaging For Detection Of Stage IV Metastatic Melanoma In Patients Undergoing Metastasectomy”, Ann Surg Oncol, 11, p731-738 (2004); Kaleya R N, Heckman J T, Most M, Zager J S. “Lymphatic Mapping And Sentinel Node Biopsy: A Surgical Perspective”, Semin Nucl Med. 35, p129-134, (2005)). While melanoma is more likely to metastasize to the brain, lung, or liver, the pattern is unpredictable and so whole-body functional imaging is most suitable. Numerous studies have shown the value of PET in the management of patients with advanced melanoma, with treatment plan changing in 15-50% of cases (Gulec S A, Faries M B, Lee C C, Kirgan D, Glass C, Morton D L, Essner R. “The Role Of Fluorine-18 Deoxyglucose Positron Emission Tomography In The Management Of Patients With Metastatic Melanoma: Impact On Surgical Decision Making”, Clin Nucl Med, 28, p961-965 (2003); Damian D L, Fulham M J, Thompson E, Thompson J F. “Positron Emission Tomography In The Detection And Management Of Metastatic Melanoma”, Melanoma Res, 6, p325-329 (1996); Tyler D S, Onaitis M, Kherani A, Hata A, Nicholson E, Keogan M, Fisher S, Coleman E, Seigler H F. “Positron Emission Tomography Scanning In Malignant Melanoma—Clinical Utility In Patients With Stage III Disease”, Cancer, 89, p1019-1025 (2000); Jadvar H, Johnson D L, Segall G M. “The Effect Of Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography On The Management Of Cutaneous Malignant Melanoma”, Clin Nucl Med, 25, p48-51 (2000; Stas M, Stroobants S, Dupont P, Gysen M, Van Hoe L, Garmyn M, Mortelmans L, De Wever I. “18-FDG PET Scan In The Staging Of Recurrent Melanoma: Additional Value And Therapeutic Impact”, Melanoma Res, 12, p479-490, (2002); Wong C S, Silverman D H, Seltzer M, Schiepers C, Ariannejad M, Gambhir S S, Phelps M E, Rao J, Valk P, Czernin J. “The Impact Of 2-Deoxy-2[18F] Fluoro-D-Glucose Whole Body Positron Emission Tomography For Managing Patients With Melanoma: The Referring Physician's Perspective”, Mol Imaging Biol, 4, p185-190 (2002)). CT is, however, superior to PET in the detection of small pulmonary metastases, possibly due to respiratory motion (Gritters et al, ibid; Kumar et al, ibid; Rinne D, Baum R P, Hor G, Kaufmann R. “Primary Staging And Follow-Up Of High Risk Melanoma Patients With Whole-Body F-18-Fluorodeoxyglucose Positron Emission Tomography—Results Of A Prospective Study Of 100 Patients”, Cancer, 82, p1664-1671, (1998)). Neither lab tests nor imaging have been shown to be useful in detecting recurrence in asymptomatic patients. In patients with known recurrence PET has been shown to detect additional metastases and alter treatment planning. Stas et al. (Stas M, Stroobants S, Dupont P, Gysen M, Van Hoe L, Garmyn M, Mortelmans L, De Wever I. “18-FDG PET Scan In The Staging Of Recurrent Melanoma: Additional Value And Therapeutic Impact”, Melanoma Res, 12, p479-490 (2002) found the sensitivity, specificity, and accuracy of PET to be 85%, 90%, and 88%, respectively as compared to 81%, 87%, and 84% with conventional imaging. Fuster et al (Fuster D, Chiang S, Johnson G, Schuchter L M, Zhuang H M, Alavi A. “Is F-18-FDG PET More Accurate Than Standard Diagnostic Procedures In The Detection Of Suspected Recurrent Melanoma?” J Nucl Med. 45, p1323-1327 (2004)) studied 156 patients with known or suspected recurrence and found the sensitivity, specificity, and accuracy of PET to be 74%, 86%, and 81% respectively compared to 58%, 45%, and 52% for conventional imaging.
- FDG-PET imaging is becoming the method of choice for staging of breast cancer as well as for the detection of recurrent disease (Quon A, Gambhir SS. “FDG-PET And Beyond: Molecular Breast Cancer Imaging”, J Clin Oncol, 23 p 1664-1673 (2005)), the location of metastases (Lonneux M, Borbath I, Berliere M, et al. “The Place Of Whole-Body PET FDG For The Diagnosis Of Distant Recurrence Of Breast Cancer”, Clin Positron Imaging, 3, p45-49 (2000)), and the monitoring of responses to radiation and chemotherapy. It is not yet widely used in primary diagnosis, though, due to significant variation in FDG avidity based on tissue pathology and tumor size (Luigi et al, ibid). Noninvasive breast cancer has been previously shown to be poorly imaged by FDG-PET (Wu D, Gambhir SS. “Positron Emission Tomography In Diagnosis And Management Of Invasive Breast Cancer: Current Status And Future Perspectives”, Clin Breast Cancer, 4(Suppl 1), pS55-S63, (2003)) and the majority of FDG-PET research studies in the literature have been performed on patients with invasive breast cancer. There are significant variations between studies. The overall specificity of FDG-PET is relatively high, but false-positives do occur in some benign inflammatory conditions and fibroadenomas (Pelosi E, Messa C, Sironi S, et al. “Value Of Integrated PET/CT For Lesion Localization In Cancer Patients: A Comparative Study”, Eur J Nucl Med Mol Imaging, 31, p932-939 (2004); Avril N, Rose C A, Schelling M, et al. “Breast Imaging With Positron Emission Tomography And Fluorine-18 Fluorodeoxyglucose: Use And Limitations.” J Clin Oncol, 18, p3495-3502 (2000)).
- Invasive breast cancer includes multiple histologic types including infiltrating ductal, infiltrating lobular, and combined infiltrating ductal and lobular carcinoma. Infiltrating ductal carcinoma has a higher level of FDG uptake and therefore is detected at a significantly higher sensitivity than infiltrating lobular breast cancer (Zhao S, Kuge, Y, Mochizuki T, Takahashi T, Nakada K, Sato M, Takei T, Tamaki N. “Biologic Correlates Of Intratumoral Heterogeneity In 18F-FDG Distribution With Regional Expression Of Glucose Transporters And Hexokinase-II In Experimental Tumor”, J Nucl Med, 46, p675-682 (2005); Amthauer H, Denecke T, Rau B, Hildenbrandt B, Hunerbein M, Ruf J, Scheider U, Gutberlet M, Schlar P M, Felix R, Wust P. “Response Prediction By FDG-PET After Neoadjuvant Radiochemotherapy And Combined Regional Hyperthemia Of Rectal Cancer: Correlation With Endorectal Ultrasound And Histopathology”, Eur J Nucl Med Mol Imaging, 31, p811-819 (2004)). This suggests that tumor aggressiveness is not the sole determinant of FDG uptake but that the mechanism of the variable FDG uptake by breast cancer cells is likely modulated by multiple factors including glucose transport-1 (GLUT 1) expression, hexokinase I (Hex-1) activity, tumor microvessel density, amount of necrosis, number of lymphocytes, tumor cell density, and mitotic activity index (Bos R, van Der Hoeven J J, van Der Wall E, et al. “Biologic Correlates Of [F18]Fluorodeoxyglucose Uptake In Human Breast Cancer Measured By Positron Emission Tomography”, J Clin Oncol, 20, p379-387, (2002)).
- Image-guided core biopsy has the advantage of being the least invasive, most comfortable for the patient, and least costly method to determine the nature of image-detected abnormalities. The issue of a benign finding that apparently is not consistent with the clinical and radiographic findings has been most carefully studied in the management of breast abnormalities, which may be palpable or only observed by various imaging techniques. When a benign histologic diagnosis appears to be consistent with both the clinical findings and the radiographic features (the “triple test”) the likelihood of missing malignant disease is minimized and follow-up examinations rather than surgical biopsy are recommended.
- In the increasingly frequent scenario of pre-clinical, image-detected lesions, physical examination is not helpful in determining concordance; thereby leading to considerable uncertainty as to whether the area of interest has been appropriately sampled. Detecting radioactivity in the core sample obtained from a PET-positive abnormality would be a great advance in confirming accurate sampling, and therefore, definitive histologic diagnosis. The increasing sensitivity of imaging modalities, including magnetic resonance (MRI), computed tomography (CT), and positron emission tomography (PET) has resulted in the identification of abnormalities prior to the development of clinical manifestations. The nature of such abnormalities, which may represent primary tumors or metastatic lesions, must be determined. Minimally invasive, image-guided, core-needle biopsies are generally the first diagnostic approach. If a benign diagnosis is rendered, the clinician, in consultation with the radiologist and pathologist, must determine whether the finding is concordant with the clinical history and the configuration of the image-detected abnormality. Non-concordance implies the possibility of a sampling error, which often leads to a recommendation for open, surgical biopsy.
- Examples of probes for intraoperative radiation detection which might be used in the procedures described herein include:
- Scintillator-PMT systems, that use vacuum tube PMTs and scintillation crystals such as NaI(T1),
- Scintillator-PIN diode systems that use PIN diodes as light detectors and then couple them to a scintillator with emissions around ˜500 nm wavelength (such as CsI). The PIN diode has a gain of one (1) and therefore needs very low noise and high gain amplifiers,
- Cd—Te semiconductor detectors, that convert the energy from radiation directly to an electronic pulse, or
- Zn—Cd—Te semiconductor detectors that convert the energy from radiation directly to an electronic pulse.
- Applicant's existing beta camera, developed in the early 1990s utilizes a position-sensitive photomultiplier tube (Hamamatsu 8520-00-12) that is optically coupled directly to a 1 mm thick sheet of plastic scintillator. A thin foil of aluminum Mylar (50 micron thick) is used to cover the front of the scintillator, to make it light-tight, while allowing positrons to enter the scintillator. This camera operates at 1200 Volts (F. Daghighian, P. Shenderov, B. Eshagian. “Interoperative Beta Cameras”. J. Nucl. Med., 446 (May 1995). Although the whole camera is well insulated electrically for ex-vivo use, to provide the level of insulation needed for its safe use in the surgical site is an impossible task. An improvement to the electrical safety was accomplished by building a flexible beta camera comprising a 2×1.5×150 cm3 imaging grade array of optical fibers (each 100 microns thick) located between the sheet of plastic scintillator and the position sensitive PMT. The optical fibers act as an insulator, but light loss in this fiber bundle is large and degrades the sensitivity. A sub-millimeter resolution with a sensitivity of 4000 cps/microCi is achievable with this camera. Tornai et al. (M. P. Tornai, L. R. MacDonald, C. S. Levin, S. Siegel, E. J. Hoffman, “Design Considerations And Initial Performance Of A 1.2 Cm2 Beta Imaging Intra-Operative Probe.” IEEE Trans. Nuc. Sci., 43 (4), p2326 (1996)) built a similar flexible beta camera and measured a line spread function of 0.5 mm for their 1.08 cm FOV camera, and a transmission image consisting of 0.5 mm holes 0.6 mm apart was successfully imaged. However, the sensitivity of this camera was not acceptable for surgical procedures. Yamamoto and colleagues built cameras with 10 and 20 mm diameters, and measured 0.8 mm and 0.5 mm FWHM, respectively (S. Yamamoto, C. Seki, K. Kashikura, H. Fujita, T. Matsuda, R. Ban, I. Kanno, “Development of a High Resolution Beta Camera for a Direct Measurement of Positron Distribution on Brain Surfaces.” IEEE Trans. Nuc. Sci. 44 (4) p1538 (1997)
- Various solid state detectors have been proposed. Tornai and colleagues developed a prototype silicon strip detector, though this was never incorporated into a surgical device (M. P. Tornai, B. E. Patt, J. S. Iwanczyk, C. R. Tull, L. R. MacDonald, E. J. Hoffman, “A Novel Silicon Array Designed For Intraoperative Charged Particle Imaging.” Medical Physics, 29 (11), p2529 (2002)). Janacek et al. developed a positron-sensitive intravascular probe which incorporated a multi-element linear silicon array (M. Janacek, E. J. Hoffman, C. R. Tull, B. E. Patt, J. S. Iwanczyk, L. R. MacDonald, G. J. Maculewicz, V. Ghazarossian, H. W. Strauss, “Multi-Element Linear Array Of Silicon Detectors For Imaging Beta Emitting Compounds In The Coronary Arteries.” Proc. IEEE NSS/MIC (2002). The disadvantage of silicon based beta cameras is that they do not have internal gain as does an SSPM, and they bring the electrical charge onto the surface of the beta camera. Therefore they are not electrically safe. A shortcoming of using CdTe or CdZnTe for constructing a beta camera is that they have high atomic numbers and high densities; therefore, they are more sensitive to unwanted background gamma rays than plastic scintillators (density of 1 and atomic number of 6).
- Introduced in 2002, solid state photomultipliers have been used primarily in high energy and astrophysics experiments where very high sensitivity light detection is required (P. Buzhan, B. Dolgoshein, A. Ilyin, V. Kantserov, V. Kaplin, A. Karakash, A. Pleshko, E. Popova, S. Smimov, Yu. Volkov, L. Filatov, S. Klemin, F. Kayumov, “The Advanced Study of Silicon Photomultiplier”, ICFA Instrumentation Bulletin, 23 (Fall 2001); Buzhan P, Dolgoshein B, Filatov L et al. “Silicon Photomultiplier And Its Possible Applications”, Nuclear Instruments and Methods in Physics Research A, 504 p48-52 (2003). A silicon photomultiplier is a large assembly of avalanche photodiodes operating in Geiger mode. Each detector, which can be as small as 1 mm×1 mm, consists of an array of (˜600) micropixels connected in parallel (
FIG. 1 )). The micropixels act individually as binary photon detectors, in that an interaction with a single photon causes a Geiger discharge. Each micropixel “switch” operates independently of the others, and the detector signal is the summed output of all micropixels within a given integration time. When coupled to a scintillator, such as by an optical glue, the SSPM detects the light produced in the scintillator by incident radiation, giving rise to a signal proportional to the energy of the radiation. - A recent development is a solid state or silicon photomultiplier (SSPM, or SiPM) developed by a team from the Moscow Engineering and Physics Institute (B Dolgoshein Int. Conf. on New Developments in Photodetection (Beaune, France) June 2002) together with Pulsar Enterprise in Moscow. The device comprises a large number of microphoton counters (1000/mm2) which are located on a common silicon substrate and have a common output load. Each photon counter is a small (20-30 μm square) pixel with a depletion region of about 2 μm. They are decoupled by polysilicon resistors and operate in a limited Geiger mode with a gain of approximately one million. This means that the SiPM is sensitive to a single photoelectron, with a very low noise level. Each photon counter operates digitally as a binary device. However the assembly of multiple SiPM is an analogue detector with the capability to measure light intensity within a dynamic range of about 1000/mm2 and has high photon capability.
- The photon detection efficiency of the SSPM is at about the same level as photomultiplier tubes (PMTs) in the blue region (20%), and is higher in the yellow-green region. The device has very good timing resolution (50 ps r.m.s. for one photoelectron) and shows good temperature stability. It is also insensitive to magnetic fields. These characteristics mean that the SSPM can be used in place of other known photodetectors (e.g., PMT, APD, HPD, VLPC). The main advantage of the SSPM is its small size (1×1 mm) and its low operating voltage of ˜60 V. These characteristics render SSPM ideal for use in intraoperative and intra-luminal radiation detection probes and cameras.
- One currently proposed medical applications for SSPM is in a small field of view PET scanner that can work in high magnetic fields of an MRI scanner (Rubashov, I. B., U.S. Pat. No. 6,946,841).
- The present invention is directed to instruments and instrumental techniques for locating radio-labeled sites which utilize a radiation detector for locating the position of the radiation tagged sites, for example in cancerous tumors or vulnerable plaque. Also described are unique new intraoperative radiation detection probes and cameras for use in these techniques. The instruments and instrumental techniques facilitate the surgical removal of labeled cancerous cells or plaque and the delivery of materials to treat the tumor or plaque to, for example, retard, stop or reduce the growth and spread of the cancer or plaque once the radiation labeled cancer cells or plaque is located.
-
FIG. 1 is a schematic drawing showing a two dimensional array of SSPM assembled with a sheet of plastic scintillator. -
FIG. 2 is a schematic drawing showing a single-detector module with a small plastic scintillator coupled to a SSPM for use in a beta probe or as an element of a beta camera. -
FIG. 3 is a schematic diagram of a dual-detector module for a beta probe or camera having a first detector and a second detector, the second detector for counting only the spurious gamma rays. -
FIG. 4 is perspective drawing schematically showing a beta camera which can include the two-dimensional array of single-detectors ofFIG. 2 or the dual-detectors ofFIG. 3 . -
FIG. 5 is a schematic drawing of a two-dimensional array of SSPM/scintillator modules on a flexible membrane. -
FIG. 6 is a graph showing the energy spectrum of the beta rays from an F-18 isotope received by a particular single-detector SSPM assembly with a plastic scintillator. -
FIG. 7 is a schematic drawing of a further embodiment of an assembly having a sheet of plastic scintillators coupled to a one-dimensional or two-dimensional array of SSPMs. -
FIG. 8 is a schematic drawing of a first embodiment of a scintillator/SSPM assembly for use in the assembly ofFIG. 1 orFIG. 7 . -
FIG. 9 is a schematic drawing of a second embodiment of a scintillator/SSPM assembly for use in the assembly ofFIG. 1 orFIG. 7 . -
FIG. 10 is a schematic drawing of a third embodiment of a scintillator/SSPM assembly for use in the assembly ofFIG. 1 orFIG. 7 . -
FIG. 11 is a schematic representation of a test apparatus used to determine the capability of a beta probe or camera incorporating features of the invention to detect and record the level of radiation emitted from simulated tumors. -
FIG. 12 is a graph which correlates the counts measured versus the number of labeled cells using the test apparatus ofFIG. 11 . -
FIG. 13 shows a section of a rat's brain histologically stained with thionin along with the scan direction of a beta probe incorporating features of the invention. -
FIG. 14 is a graph showing the count profiles from the probe incorporating features of the invention obtained by scanning the upper one fourth of the coronal surface of a rat with a labeled tumor. -
FIG. 15 is a PET scan of a patient with melanoma on the neck. -
FIG. 16 is a graph showing radiation counts of a beta and a gamma detector on the residue of cancerous tissue after removal of the neck melanoma shown inFIG. 15 . -
FIG. 17 is an expanded schematic view of a detector assembly incorporating features of the invention, for use in building very small beta probes, for example on the order of one millimeter diameter, or one-dimensional cameras. -
FIG. 18 is a side view of a biopsy probe incorporating the detector assembly ofFIG. 17 . -
FIG. 19 is a side view of a catheter incorporating the detector assembly ofFIG. 17 . -
FIG. 20 is a side cut away view of a mini-gamma imaging probe with nine detector modules. -
FIG. 21 is a top view of the mini-gamma imaging probe ofFIG. 20 showing the nine detector modules. -
FIG. 22 is a second embodiment of a small gamma camera with a plate of scintillators coupled to an array of SSPM's. -
FIG. 23 shows an array of SSPMs on the exterior surface of a scope, such as an endoscope, for insertion in a body orifice. -
FIG. 24 is a modification of the dual detector module ofFIG. 3 , including two SSPM's collecting the signals generated by beta rays in a single scintillator. -
FIG. 25 is a schematic diagram of a coincidence circuit used to sum the signals from the two beta detectors (SSPMs) shown inFIG. 24 . -
FIG. 26 is an expanded schematic view of a probe embodiment that includes scintillators over the end and side of the probe tip. -
FIG. 27 is a variation of the array assembly ofFIG. 1 including suction ports, position marking devices and a digital imaging camera. - In 2005, there was an estimated 415,000 new cases of melanoma, breast, and colon cancers in the United States. Approximately 138,000 will ultimately develop metastases or have locally advanced disease. At least 10% should be eligible for surgical resection. If the probes (camera) can reduce the incidence of positive margins or subsequent local recurrence by 10-20%, then the incidence of re-operations could be reduced by 2,000-4,000 patients per year. Both the financial and emotional costs to patients would also be reduced.
- Breast cancer usually recurs in the breast because the original primary tumor was not completely resected and the remaining cells were not destroyed by adjuvant radiation or systemic therapy. The accurate assessment of margins has assumed great importance in the conduct of lumpectomy. Various techniques have been used to assess margins postoperatively, including cytologic and histopathologic techniques. These techniques suffer from sampling problems and the fact that the results are delayed, requiring re-operation in approximately 20% of patients treated with lumpectomy. The ability to intraoperatively detect true involvement at the margins of resection within the lumpectomy bed would enable the surgeon to complete the successful lumpectomy by resecting all involved tissue in one operation. This would avoid a second operation in thousands of women annually and avoid recurrences in an unknown but probably large number. Numerous radioactive compounds for targeting and tagging particular body tissue and particularly different cancerous lesions are known in the art. Fluorine-18 deoxyglucose (FDG) has been particularly identified as having a high uptake in breast cancer tissue (Quon et al, ibid; Bos R, van Der Hoeven J J, van Der Wall E, et al. “Biologic Correlates Of [F18]Fluorodeoxyglucose Uptake In Human Breast Cancer Measured By Positron Emission Tomography'” J Clin Oncol, 20, p379-387 (2002)). Positrons emitted from 18F in FDG can guide the beta probe to detect these residual tumor cells. Therefore the probe described herein and its use is of major importance in avoiding second operations and preventing recurrences in women with breast cancer who are undergoing breast-conserving therapy. An improvement of even 10 percent, that is, a >30-40 percent reduction in finding postoperative, cancer-positive margins, provides meaningful reduction in the re-operative rate for breast cancer patients across the nation.
- An important objective of cancer surgery is to insure complete removal of all cancerous tissue. Tumor-positive margins dilute the benefits of surgery. Milligram deposits of cancer cells can be localized with a beta camera that can image the distribution of F-18 labeled fluorodeoxyglucose (FDG). However, the short (˜1 mm) range of positrons in tissue requires the camera to be as close as possible to, and preferably in direct contact with, the open surgical field. Existing experimental beta cameras use high voltage detectors which are unsafe for in vivo use. The solution has been to use fiber optic coupling to keep the high voltage parts safely removed from the patient, but this approach significantly reduces sensitivity.
- Set forth herein is a beta camera with the resolution and sensitivity to detect cancer deposits at least as small as 5 mg. Through the evaluation of various configurations of SSPMs and scintillators as shown and described herein, it has now been demonstrated that SSPMs have higher sensitivity than photomultiplier tubes and can operate at ˜50 volts. They are also very small (1×1 mm). An absolute efficiency of at least 15% has been shown for a small plastic scintillator directly coupled to an SSPM as opposed to 0.2% for an identical scintillator coupled by fiber optics to a PMT. A first embodiment of beta camera, incorporating features of the invention, comprises a sheet of red plastic scintillator and a 2 dimensional array of SSPMs, including means to compensate for temperature variance ranging from 25 to 37° C.
- The use of solid state photomultiplier (SSPM) which operates at very low voltages allows direct intraoperative use while performing at least as well as or better than prior art devices. Described herein are new beta cameras based on SSPM technology that surgeons can use to detect tumor margins with unprecedented sensitivity and in turn to reduce local relapse rates from the resected field.
- Since 2002, solid state photomultipliers have been utilized in high energy physics laboratories. They have a gain of about 1 million, a working voltage of about 50 Volts, a size of about 1×1×0.5 mm and a low noise at ambient temperatures (20° to 40° C.). These properties were found to be favorable for constructing a intra-operative beta probe as set forth herein. Several variations of these detectors have been assembled into new devices for use in intraoperative procedures in the field of nuclear medicine.
- A first embodiment of the SSPM beta camera incorporating features of the invention has a 10×10
array 10 of SSPM's 12 optically coupled to aplastic scintillator sheet 14 as shown schematically inFIG. 1 .FIGS. 20 and 21 show a cutaway and end view of a probe including such an assembly. In a representative assembly, the size of eachSSPM 12 is 2×2 mm and the size of thescintillator portion 14 is 20×20 mm. The unique advantage of such a probe is that by using an SSPM, a gamma probe is built with a typical dimension of 5 mm diameter and 10 mm long, that operates at a low voltage of 50 V and has a high sensitivity and gain. Each detector module is made by optically coupling a heavy scintillator, such as GSO, NaI(T1) or BGO, to an SSPM. The total dimension of such a gamma imaging probe is 10×10 mm on the sides and about 12 mm long. This small size enables its use in laparoscopic and other endo-surgical applications or applied to the tip of surgical tools or mounted on the finger of the surgeon, for example, in the finger of the surgical glove. EachSSPM 12 is connected by a digital signal conduit (lead) 254 to its own electronic processors (not shown). Beta rays from a radiation source strike the scintillator generating scintillation light which is detected by the SSPMs which in turn generate a digital signal. The digital signals are used to generate an image on ascreen 42, similar to Anger logic. The beta rays do not need a collimator since they have short ranges.FIG. 22 is a further embodiment of a small gamm camera including a plate ofscintillators 14, such as bismuth germanate (BG0), GSO (Gd2S1O5), or NaI(T1) coupled to an array ofSSPMs 12, which includes acollimator 260 for the gamma rays. - Gamma rays travel several centimeters in tissue; therefore a detector that is sensitive to gamma rays would be susceptible to spurious gamma rays emitted by distant organs and background tissue. This background radiation may obscure the tumor margins. One limitation of gamma probes in surgery or other medical procedures is their inability to distinguish between the signal and the background radioactivity which obscures the ability to localize small tumors with low tumor/background uptake ratios. On the other hand, beta rays travel only a couple of millimeters and so a beta detector senses only the local radioactive concentration. Beta
sensitive probes 16, 18 shown inFIGS. 2 and 3 , which incorporate features of the invention, can be used to detect radiation labeled tissue, particularly to detect FDG-avid cancer cells. In the single-detector beta probe module 16 shown inFIG. 2 a firstplastic scintillator 14 connected to aSSPM 12 is used in theBeta detection assembly 20 to selectively detect beta over gamma rays. Althoughplastic scintillator 14 is selected to be relatively insensitive to gamma rays, it still detects some. These spurious gamma rays become significant when the background radioactivity is high. One way to avoid counting these spurious gamma rays is to raise the energy threshold of the detector and therefore loose some of the real beta count that results in low sensitivity. One remedy to this problem is the use of a reference gamma ray detector such as set forth in a dual-detector beta probe module that was proposed by the applicant in a prior patent (Mazziotta et al., U.S. Pat. No. 5,008,546). In this prior disclosed dual detector beta probe fiber optics were used to transmit the scintillation light to two PMTs which resulted in a significant loss of the level of the signal. That device also had the problem of asymmetric counting of the spurious gamma rays as a result of geometrical limitations that the fiberoptics placed on the design. Furthermore, optical fibers cause light-loss and therefore loss of signal. These problems are resolved in the dual-detector modules 18 disclosed in this application by the use of SSPM's and stacking thebeta detector assembly 20 on top of agamma detection assembly 22 which preserves symmetry (FIG. 3 ). Thegamma detector assembly 22, comprising ascintillator 114 and aSSPM 112, which is also referred to as a reference detector, placed behind thebeta detection assembly 20 detects only the gamma rays because a 1 mmthick aluminum plate 24 is placed on the exposed surface thereof to shield the beta rays from reaching the detector in the shielded area. In thesystem electronics 32, counts from thisreference detector 22 are subtracted from those of thebeta detector 20 to determine the pure beta count rate. Both thebeta detector assembly 20 and the reference detector, as discussed below, can also include atemperature sensor 26 and a cooling orheat source 28, such as a Peltier cooler, and acontrol circuit 30 to maintain a fixed standard temperature. Acircumferential metal shield 40 may also be included so that beta rays do not enter the gamma detector from the side. This beta probe is ideal for the detection of minute tumor remnants which, due to the short penetration range of beta rays in tissue, are not obscured by the radioactivity accumulated in normal tissues. - Further, because each
individual Beta detector 20 has its own independent electronic noise pattern, low-energy beta rays may generate signals that are smaller than the electronic noise. Energy thresholding above the electronic noise level can cause these low-energy betas to be ignored. Therefore it is important that procedures be undertaken to eliminate or hide the detector electronic noise or to amplify the beta probe output. In order to count the low energy beta rays using a beta probe and increase its sensitivity, the design ofFIG. 3 is modified to have twoSSPMs 12 such as shown inFIG. 24 . The beta rays incident on thebeta detector 20 generate light in thescintillator 14 which is counted by the two SSPMs simultaneously. As shown inFIG. 25 acoincidence circuit 300 is used to open thegate 302 of a summingcircuit 304. The discriminator levels are set below the highest electronic noise levels, to reduce the electronic noises but not eliminate them completely. If the noise pulses of the two SSPM detectors do not happen in coincidence, the gate will stay closed and no event will be counted. On the other hand, if there is a low scintillation light burst due to a low energy beta ray hitting the scintillator, then both SSPM detectors will generate signals in coincidence. The gate will open, and the summed pulses indicate the existence of real scintillation signals, and they are counted. This technique of coincidence-noise-reduction allows the energy threshold on each one of the detectors to be lower and the low energy beta counts that previously would have been below the energy threshold, and consequently not counted, are now countable. - This method of coincidence noise reduction and increase in the sensitivity is implemented in the dual detector beta probe as shown schematically in
FIG. 24 , where the first andsecond SSPM 12 are partially staggered to allow packing in a 5 mm diameter tube. A third “reference gamma detector” 22 is also used as discussed herein above. In a beta camera such as shown inFIGS. 8 , 9, and 10 one or more adjacent detectors can be paired to achieve coincidence noise reduction and increase the sensitivity. As a result a probe can be built to detect the presence of beta radiation or low energy gamma radiation emitted from labeled sites in the human body comprising a scintillator coupled to two or more solid state photomultipliers. Signals generated by the photomultipliers are fed into a coincidence circuit that delivers a signal only if the two signals fed thereto are within a pre-set time window, said delivered signal being used to trigger counting of the signals of one or more of the solid state photomultipliers and prevent the electronic noise pulses from being counted as beta rays. -
FIG. 26 shows an embodiment incorporating features of the invention which comprises aprobe 310 in which thetip 312 of theprobe 310 as well as about 0.5 inches of the length of thelateral side 314 of the probe's cylindrical surface adjacent thetip 312 is covered by SSPMlight detectors 12. Theselight detectors 12 are optically connected to two plastic scintillator pieces, namely acylindrical collar 316 and atip cover 318. A sheet of BC-430 scintillator (Saint-Gobain Crystals, Newbury, Ohio), wrapped in 2 layers of Teflon tape on the sides and top was used. Thisprobe 310 uses “solid state photomultipliers” or “Silicon Photomultipliers” 12 for detection of scintillation light. The signals are digitized using multiple LabView-conrolled 8-channel data acquisition boards, and then are used to generate an image. - For accurate beta ray measurements and imaging, it is preferred that the detector be brought into direct contact with the tissue under investigation and stay stationary with respect to tissue during the image acquisition period. The proposed device provides this capability. To assist in obtaining good contact with the tissue surface and stay fixed, suction can be applied to the tissue surface through or around the probe.
FIG. 27 , a modification ofFIG. 1 , shows one such device where multiple suction holes ortubes 320 are placed on the surface of the camera. The operator has the option to control the negative pressures and turn the vacuum on and off at each of these holes. - The beta camera of
FIG. 27 also includes a centrally located visible-lightdigital camera 322 within the array of SSPM's and the scintillator so that a digital photograph of the tissue and the radioactive image can be superimposed. The system also includes aposition marking device 324, preferable mounted within or adjacent thesuction tubes 320. Examples of suitable marking devices are a laser beam marker or an inkjet dispenser. Technology such as used on inkjet printers can be incorporated within the probe tip. Inkjet technology uses a Piezoelectric crystal at the rear of the ink reservoir. This crystal flexes when an electric current is applied to it. To place a marking dot on the tissue being imaged, a current is applied to the Piezo element which then flexes and, in so doing, forces a drop of ink out of the nozzle on to the adjacent tissue. Preferred colors are blue, green or black but other colors readily imaged on the tissue, which is red in color, can be suitable. - A visual image of the surgical field can be acquired by lifting the beta camera off of the tissue surface, for example by about 0.5 inch. A flash of light is used to brighten the field and the four corners of the field of view which have been marked by a laser or ink spots. A beta ray image of the field is also generated and the visual image and the beta ray image can be digitally stored and displayed on the same screen. A software program within the image receiving electronics uses the laser or ink spot to automatically superimposes the corners of the beta image with the visual image.
- Further, it is important that the radioactive tissue with higher uptake, or hot spot, once located, be marked. In prior devices, after observing a hot-spot on the image screen, the corresponding location on tissue could not be accurately found after the camera was removed from the tissue surface. This is particularly critical in endo-surgical applications of the beta camera. A marking mechanism described herein used in conjunction with the devices described addresses this major deficiency of the prior art.
-
FIG. 4 is a schematic diagram of abeta ray camera 34 incorporating the SSPM and a scintillator film assembly as shown inFIG. 2 orFIG. 3 . Thebeta camera 34 is shown to include thedual detector module 18 ofFIG. 3 , thesignal processing electronics 32 and adisplay screen 36 to provide a visual display of the beta counts detected. To meet the UL electrical safety requirements for surgical instruments, novel arrays of solid-state photomultipliers (SSPM, Photonique SA, Geneva, Switzerland), that operate at 50 Volts have been utilized in the probes described herein. A thin stainless steel foil 34 (5 microns thick obtained from Goodfellow Inc., Devon, Pa.) is wrapped around the circumference of the assembly to prevent ambient light from entering the camera and interfering with positrons entering through thecontact end 36 of thescintillator 14. Software provided in adata processing unit 32 generates uniformity look-up tables and other corrections necessary to enable the data generated by thecamera 34 to process and display the images on thedisplay 36. The device satisfies the U.S. and international standards IEC60601-1, EN60601-1, UL2601-1, CSA C22.2 No. 601.1 for surgical instruments. Thescintillator 14 of choice for the selective detection of beta rays over gamma rays is a plastic scintillator, due to its low atomic number which reduces its sensitivity to background gamma rays. Each SSPM is coupled to a piece of Bicron BC-430 plastic scintillator. TheSSPM 12 is also mounted on a ceramic substrate and has compact dimensions of 3×3 mm and 1 mm thickness. The scintillator, as shown inFIGS. 2 and 3 , is machined to have a truncated base maximizing the light transmission to the sensor. A 5 micron thick stainless steel foil may be shaped into a cap and glued to the ceramic base of the SSPM using bio-safe glue. This foil also acts as a reflector of scintillation light. - In a second method, instead of using a single sheet of plastic scintillator coupled to multiple SSPM's, each
SSPM 12 is coupled to itsown scintillator 14 to form a SSPM/scintillator module 250. The multiple SSPM/scintillator modules 250 are mounted on aflexible membrane 252 and theleads 254 from eachmodule 250 is fed through themembrane 252 to thesystem electronics 32. This flexible-detector arrangement 256 is shown inFIG. 5 . These modules can then be packed in one dimensional or two dimensional arrays to form a beta camera or molded to different shapes such as a trough or the surface of a tube. - Gamma rays travel several centimeters in tissue. Therefore a detector that is sensitive to gamma rays is susceptible to spurious gamma rays emitted by distant organs and background tissue. This background radiation may obscure the tumor margins. On the other hand, beta rays travel only a couple of millimeters and therefore a beta detector senses only the radioactive concentration adjacent to the
contact end 36 of thecamera 34. All positron-emitting radioisotopes emit beta (the positrons are a form of beta rays) as well as 511 keV gamma rays. Therefore in order to detect a small superficial tumor, a beta detector should be used. Further, since beta rays travel only a very short distance in solids, it is preferred that the detector and the tissue should come in contact with each other. Athin membrane 38 is preferably provided to separate the detector from the tissue. Also, the detector operates under low voltages in order to ensure electrical safety. - Positron emitting isotopes, for example F-18, are used for PET scanning. In tissue, positrons emitted from the F-18 containing compounds travel a couple of millimeters before they convert to high-energy gamma rays of 511-keV energy.
- It is estimated that in 2005, approximately 232,090 men in the United States were diagnosed with prostate cancer and 30,350 men died from the disease. Within the next 15 years, prostate cancer is predicted to be the most common cancer in men. Annually, surgical treatment is offered to over 70,000 men. Radical prostatectomy is considered the gold standard of treatment for clinically localized prostate cancer. This involves removal of the prostate, seminal vesicles, surrounding fascia and often regional lymph nodes.
- While surgery is safe, it is often associated with postoperative impotence and some times residual cancer around the nerves (positive margins). This is due to the close proximity of nerves, poor differentiation from surrounding tissue and the lack of clear planes of demarcation between nerves and cancerous tissue. The goal of prostate cancer surgery is to remove the cancer harboring prostate gland with minimal damage to the surrounding structures (i.e. nerves for erection and continence). These two goals are mutually competing as nerves for erection often travel very close to the prostate enclosed within layers of tissue. Not only are the nerves almost hugging the prostate, they are very tiny and often invisible to the unaided eye because of obstruction. This technical challenge sometimes results in either incomplete removal of the cancer with positive surgical margins near the nerves or postoperative impotence due to the damage or excision of these nerves.
- The incidence of positive surgical margins in patients who have RRP for clinically localized prostate cancer has ranged from 14% to 46%. Cancer in the surgical margin has been shown to be a significant independent adverse factor associated with a greater risk of biochemical disease recurrence, local disease recurrence in the prostatic fossa, and systemic progression with death from prostate cancer.
- The diagnosis of positive margins is usually made postoperatively by the pathologist when a tumor is detected at the surgical resection surface. To date there is no method by which tumor cells can be detected by visual inspection. Intraoperative visualization of cancer cells during radical prostatectomy would result in precise delineation of boundaries of malignancy and have far reaching implications in other surgical specialties.
- An important objective of cancer surgery is to insure complete removal of all cancerous tissue. Further, tumor-positive margins dilute the benefits of surgery. To address these issues a monoclonal antibody that specifically binds to an external epitope of the prostate specific membrane antigen PSMAext1 (such as monoclonal antibody J591) has been produced and labeled with radioactive isotopes In-111. Lu-177 and Y-90. When injected into the patient it migrates to the tumor cells in the prostate as well as the surrounding tissue if the cancer has spread.
- J591 is an anti-PSMA mAb that binds with 1-nM affinity to the extracellular domain of PSMA. Murine J591 antibody has been deimmunized using a method involving specific deletion of human B- and T-cell recognized epitopes. In vitro and animal studies of radiolabeled J591 has demonstrated the superiority of radiometals Yttrium-90 (90Y) and Lutetium-177 (177Lu), presumably due to their longer intracellular half-life (t1/2), as compared with the rapid dehalogenation and washout of 131I-J591. The 90Y and 177Lu, both beta emitters, have very different physical properties. The 90Y has a shorter half life (2.7 vs 6.7 days), a higher energy (max, 2.3 v 0.5 MeV), and a longer range (max, 12.0 v 2.2 mm) than 177Lu. As a pure beta emitter, 90Y cannot be used for imaging and requires the use of 111Indium as a surrogate label for scintigraphy and dosimetry calculations. In contrast, 177Lu emits 15% of its energy as a gamma emission in addition to the beta emissions, and can be imaged directly using a gamma camera. Bander et al. elected to evaluate both 90Y- and 177Lu-J591 in two independent phase I clinical trials. As to the phase I dose escalation trial of 177Lu-J591 in patients with progressing androgen-independent PC it was found that among the 35 patients receiving 177Lu-J591, 30 (86%) had metastatic disease detected on screening imaging studies. Specifically, 21 (60%) patients had bone-only metastases, six (17%) had soft tissue-only metastases, and three (9%) had both bone and soft tissue disease. In all of these 30 patients, all known sites of metastatic disease were successfully imaged by 177Lu-J591 scintigraphy. One patient with bone metastases had many more lesions visible on antibody scan than on bone scan. Another patient with a negative bone scan had a positive antibody scan that was confirmed positive by MRI. The bone scan of both patients later converted to positive in sites presaged by their antibody scans
- Gamma and beta cameras incorporating the invention described herein were used for detection of the cancer tissue in the prostate, which has high uptake of the radioactive labeled J591 Mab. Very small deposits of cancer cells in the margin of the resected prostate can be localized with the beta camera designed to image the distribution of the Lu-177 labeled J591 Mab. In addition, gamma rays from lymph nodes that are infected by cancer can be detected by the small gamma imaging probe or gamma camera of this invention.
- Pelvic lymphadenectomy (PLND) provides important information on tumor stage and prognosis that can not be matched by any other procedures to date. However, consensus has not been reached concerning the indication for, nor the extent of pelvic lymphadenectomy needed for exact staging of prostate cancer. The presence of lymphatic metastases markedly increases the risk of progression to metastatic disease and death. PLND may thus have a therapeutic benefit rather than solely being a diagnostic procedure.
- Currently used preoperative nomograms such as the Partin tables are inadequate to accurately predict occult pelvic lymph node disease. Imaging techniques such as CT scan. MRI and PET scan have not proven beneficial in identifying smaller pelvic nodes. (<5 mm) in which metastasis are predominantly found in prostate cancer. PLND, however, can add to the morbidity of any surgical procedure. Complications associated with lymph node dissection are lymphoceles, lymphedema, venous thrombosis and pulmonary embolism. An accurate intraoperative tool for visualizing micrometastasis would allow identification of patients with nodal involvement who would benefit from a PLND. A gamma probe or small gamma camera that is small enough to be incorporated into a laparoscopic or robotic surgical setting, such as the assemblies described in this invention, help in these types of cases as well as the detection of cancerous lymph nodes.
- The inherent morbidity associated with conventional open radical prostatectomy has led to the search for less invasive options. One of these options is robotic radical prostatectomy. This specialized surgery for prostate cancer has been developed in the last 5 years. More than 18,000 robotic prostatectomies were performed in 2005 alone. This procedure uses a state of-the-art daVinci™ surgical system, through which the surgeon uses a three-dimensional computer vision system to manipulate robotic arms. These robotic arms hold special surgical instruments that are introduced into the abdomen through tiny incisions. A stereoscopic camera—a long, thin, lighted telescope—is inserted and connected to the computer monitor that allows the surgeon to see inside the body. The vision is stereoscopic and magnifies the three-dimensional anatomy. The stereoscopic magnification helps the surgeon find the delicate nerves and muscles surrounding the prostate. The depth perception allows precision during the surgery and helps in meticulous surgical dissection. The magnification is 10- to 15-fold and the prostate and its surrounding structures are visible through a clear illuminated camera. Every structure is identified and precisely separated from prostate. This small camera can be negotiated into very narrow corners of the body that may normally be invisible to the surgeon when looking directly inside the body. The robotic arms can rotate a full 360 degrees allowing the surgeon to manipulate surgical instruments with greater precision and flexibility.
- These instruments are mounted at the tip and thus can be controlled with high fidelity and dexterity. This ability to move small instruments in any possible direction helps tremendously in performing delicate surgical moves which involve the ability to rotate, turn, flex, extend, push, twist, abduct and adduct while performing complex surgical tasks. An embodiment of the current beta camera invention having a width less than 12 mm allows its entrance through the port on a laparoscope and can be used in robotic procedures, such as prostectetomy surgeries, for detection of margins. Also, a gamma probe or camera described herein can be inserted to detect cancerous metastasis, for example, in lymph nodes.
- Surgery is an important mode of treatment of prostate cancer. However, the following problems remain:
- Complete local resection of cancerous tissue is not possible in some cases since normal and prostate cancer tissues are not visually distinguishable. In approximately 30% of cases the margins of resection are involved (or positive). Unfortunately, this finding is currently made by the pathologist from the resected prostate, well after the surgery, when there is little that can be done to rectify the situation.
- Assessment of lymph nodes is important in staging the cancer. This is done by multiple node dissections and pathological evaluations in the vast majority of patients, which results in increased morbidity, operative time, and cost.
- Currently, trans-rectal biopsies, in post-prostatectomy patients with elevated PSA, are done with ultrasound guidance. However, often no suspicious lesion is seen and biopsies are little more than random samples. As a result, there is a low sensitivity rate.
- As a feature of the invention described herein applicant addresses these problems by using a monoclonal antibody (such as J591) which has been produced and labeled with radioactive isotopes In-111. Lu-177 and Y-90. J 591 specifically binds to an external epitope of the prostate specific membrane antigen PSMAext1. Gamma and beta cameras described herein are used for the detection of cancer tissue that has high uptake of the radioactive labeled J591 Mab.
- An important objective of prostate surgery is to insure complete removal of all cancerous tissue. Tumor-positive margins dilute the benefits of surgery. Very small deposits of cancer cells, such as 1 mg in size, can be localized with a beta camera that can image the distribution of Lu-177 labeled J591 Mab. However, the short (˜1 mm) range of beta rays in tissue requires the camera to be as close as possible to, and preferably in direct contact with the open surgical field. Existing experimental beta cameras use high voltage detectors, which are unsafe for in vivo use. A prior approach has been to use fiber optic coupling to keep the high voltage parts safely removed from the patient, but this approach reduces sensitivity significantly.
- Applicant utilizes a solid state photomultiplier (SSPM) assembly described above to solve this problem. The SSPM operates at very low voltages and yet performs as well as conventional devices, and allows direct intraoperative use. Applicant has developed a new beta camera based on SSPM technology that surgeons can use in detecting tumor margins with unprecedented sensitivity, providing the potential to reduce local relapse rates from the resected field.
- The beta probe 16, and particularly the beta probe with
reference detector 18, is particularly sensitive to short-range positrons emitted by FDG and therefore it is highly sensitive to minute amounts of cancer cells that may be located within a millimeter of the surgical margin and effective in detecting small amounts of tumor at the margin of resection. As shown inFIG. 3 , the dualdetector beta probe 18 comprises two detectors, afirst detector 20 that detects (counts) both positrons and gamma rays and asecond detector 22 that detects (counts) only gamma rays. These counts are then transmitted to first andsecond SSPMs 12. Because gamma rays travel several centimeters in tissue, both detectors register counts emanating from distant tissues and not solely from the tissue under examination. Using electronic or software techniques the counts of thesecond detector 22 are subtracted from the counts from thefirst detector 20 so that only the counts generated by the positrons remain. Because positrons can travel only a couple of millimeters, this corrected count is an indication of local concentration of FDG. Counts, updated each second, are then passed through adata processor 32 where they are electronically processed and displayed on a visual screen or monitor 42 so that the surgeon can identify, isolate and remove the labeled cells. - The beta probe described herein circumvents this limitation of traditional gamma probe technology. Many radioisotopes used in nuclear medicine emit electrons or positrons. Since beta rays have short depth of penetration in tissue (˜1 mm), a beta sensitive probe is not affected by the background gamma radiation.
- The
beta camera 34 described herein which can be hand held or built into a probe or catheter provides real time imaging of positron emissions. Thisbeta camera 34 is capable of providing an image of the radioactive concentrations near the surface of the surgical field as well as ex-vivo imaging of resected tumors, for locating cancer on the margins. Scanning the surgical field with prior available probes can result in minute quantities of cancerous tissues being missed. Theintra-operative beta camera 34 described herein provides an image of the surgical field as well as enables the surgeon to detect any focal concentration of radioactivity. Detection of minute cancer remnants on or near the surface of the surgical field is less time-consuming with this beta camera than with prior beta probes, and is more reliable in surveying the entire resected tumor bed. Real-time imaging of beta emitting tumor tracers alleviates many uncertainties that presently exist in cancer surgery. - SSPMs have many advantages over photomultiplier tubes, the current standard for scintillation-based detection of radiation. Perhaps most importantly, the operating voltage for SSPMs is around 50 V, as opposed to the kilovoltages required for PMTs, and therefore SSPMs have superior electrical safety when used inside the body. SSPMs are also extremely small. A 1×1 mm2 detector performs comparably to a PMT with a 1 cm diameter and 5 cm length. SSPMs demonstrate extremely fast signal rise time (˜40 ps), high gain (˜107), good quantum efficiency at 450 nm (>20%), high stability, and low noise at room temperature. They are also completely insensitive to magnetic fields encountered in medical environments.
- A set of SSPMs (SSPM-050701GR) obtained from Photonique Inc. (Geneva, Switzerland) had a sensitive area of 1×1 mm and overall size of 3×3 mm. A 2×2 mm device is also available. The best quantum efficiency of these SSPM is in the green region of the spectrum. Therefore, a green plastic scintillator sheet, obtained from Saint Gaubain Inc., was coupled to the SSPM using optical grease. A positron source of F-18 placed next to the scintillator, using a bias voltage of 51 Volts, produced the energy spectrum shown in
FIG. 6 . The sensitivity of this configuration was compared with the conventional method of using a 5 mm long plastic scintillator coupled to a 400 mm long clear optical fiber to connect the plastic scintillator to a PMT. The prior devices used the optical fiber to provide electrical isolation and safety between the tissue and 1200 vols that is present in the PMT. The plastic scintillator was sheathed using a five micron thick stainless steel foil. A point source of F-18 was made by soaking a 1 mm piece of tissue paper soaked with a solution of F-18 FDG, dried and sandwiched between two layers of Scotch tape placed in a well. Measurement of the counts from that sample was made using each assembly and compared using a dose calibrator of 10 microCi. When the plastic scintillator was brought into contact with the test source 50,000 counts per second were measured using the SSPM, yielding a sensitivity of 5000 counts/sec for 1 microCi of activity. The value obtained for the optical fiber-PMT configuration was 100 cts/s/microCi. This experiment demonstrate that SSPM assembly described herein is superior to PMT-optical fiber configuration for detection of beta emitting radiotracers in vivo. Additionally, a uniformity correction can be built into the device by acquiring an image of a flat source over an extended acquisition time and using the information obtained to generate a look-up table for uniformity correction of future acquired images. -
FIG. 7 is a schematic of a further embodiment of adetector assembly 43 having thescintillator 14 coupled to an array ofSSPM 12 with anelectronic circuit board 44 mounted to theSSPMs 12. The assembly is enclosed in acapsule 46 formed from 5 micron thick stainless steel foil. The foil is mechanically strong and enables the camera to be cleaned as well as gas sterilized. Threevariations SSPM portion 47 ofFIG. 7 are shown inFIGS. 8 , 9 and 10. The first variation 52 of the scintillator/SSPM portion 47 shown inFIG. 8 is substantially the same variation as incorporated in the assembly ofFIG. 7 .FIG. 8 shows aflat scintillator sheet 14 with a plasticlight guide 48 between thescintillator sheet 14 and theSSPMs 12, the plasticlight guide 48 having approximately the same dimensions as thescintillator 14. A thinstainless steel membrane 50, which is a part of thestainless steel capsule 46, is shown covering the lower surface of thescintillator 14.FIG. 9 shows aflat scintillator sheet 14 with thelight guide 148 having a first surface in contact with, and of substantially the same dimension as thescintillator 14. The opposite surface has multiple taperedportions 58, each being connected to anSSPM 12, to direct maximum scintillation light to theindividual SSPMs 12.FIG. 10 utilizes ascintillator sheet 114 with discretetapered zones 60 which taper down toward the attached SSPM. In this instance theindividual SSPMs 12 are each attached directly to the end of one of the discretetapered zones 60 of thescintillator 14. Referring toFIG. 7 , the output from each of the SSPM in each of thevariations FIGS. 8-10 is feed to theelectronic circuit board 44 attached thereto for further processing and display. - Following are several tests performed using a beta probe as described therein. A disposable pre-sterilized plastic camera drape (which may be used in some surgical procedures) was not used since it attenuates the beta rays of F-18 by 30%.
- A prostate cancer cell line (LNCaP, CRL-1740, ATCC, Manassas, Va.) was used to establish the limits of detectability in terms of milligram of tumor. The radioisotope used, I-131, emits both gamma and beta rays similar to F-18. Cells were incubated with I-131 labeled J591 (antibody to prostate specific membrane antigen) for 2 hrs, then washed and the radioactivity was determined. In order to simulate tumors, as shown in
FIG. 11 , five small containers comprising 2 mmcylindrical recesses 62 were formed in aLucite slab 64, (2 with diameters of 2 mm and 3 with diameters of 4 mm). Theserecesses 62 were then filled with labeled cells (simulated tumor) 66 and were covered by a thin plastic tape to allow beta rays to penetrate. Radioactivity counts were determined using a well counter, and the mass of eachsimulated tumor 66 was determined. A beta probe 16 incorporating thedetection assembly 20 as described herein was placed on top of eachsimulated tumor 66 in the manner as shown inFIG. 11 . Counts were collected for 5 sec and recorded in triplicate. This experiment was repeated 3 times with background sources of 0.63, 1, and 2.2 mCi of I-131 placed beneath the tumors.FIG. 12 is a graph showing data collected, demonstrating that a 5 mg tumor was detectable in presence of significant background radiation. - There were 20 nCi per one million cells. The 2 mm diameter containers contained 6 mg of tumor cells, and the 4 mm diameter containers contained 23, 37 and 57 mg of tumor cells, respectively. The beta probe counts in 5 sec were 180±40, 498±43, 641±38, and 762±65, respectively. These counts were not affected by the background gamma rays. The background gamma rays generated 39 counts in 5 sec when 2.2 mCi of source was present 5 mm below the beta probe. These studies demonstrated that superficial tumors as small as 6 mg are detectable even in presence of gamma rays from a nearby 2 mCi source of I-131, thus demonstrating that the beta probe described herein is ideal for detection of small tumor residues utilizing FDG.
- Monoclonal antibody MX35 reacted with epithelial ovarian cancer was labeled with I-131. The labeling efficiency of the radioantibody was determined to be 92.6%. Six week old mice (n=3) (balb c/nu/nu) were injected intraperitoneally and subcutaneously with the human ovarian cancer cell line PR-428 (CRL-11732, ATCC). This cell line immuno-histologically expressed the MX35 antigen. The tumors weighed from about 0.5 to 2.0 grams. 25 mCi per 25 mg of labeled antibody were injected intravenously into the tail vein of each mouse. Probe counting was conducted 2, 5, and 7 days after Mab injection. Pentobarbital anesthesia was used and the tip of the probe 16 was placed on the surface of the skin at different locations on the body for the duration of 2 seconds per count.
- I-131 labeled MX35 monoclonal antibody showed high accumulation in the tumors after 2 days post injection. The average beta probe count was 115 cps on top of the tumor, and from 10 to 30
cps 5 mm away from the tumors. This test showed that a tumor can be detected with the beta probe 16 even when there is intervening soft tissue covering the tumor. - C6 (CCL-107, ATCC) rat glioma cells (5−10×105) were implanted into the right hemisphere of Wistar rats. After 10-14 days of tumor growth, animals were fixed in a stereotactic frame, and FDG was then delivered as an intravenous bolus (5-20 mCi/kg). Sixty minutes latter the beta probe 16 was positioned perpendicular to the surface of both normal tissue and tumor implanted hemisphere. The counts over the tumor were consistently higher (120-140 counts/min/mCi injected, n=3 rats). The rats were sacrificed and the brains were removed and cut coronally at the center of the tumor along the same line that the probe 16 measurements were obtained. The upper ¼ of the coronal cut surface was then scanned and radioactive counts were recorded for one minute by the probe 16. Frozen sections of the brain (20 um) were then cut and thaw mounted on a gelatin-coated cover glass. Autoradiograms were generated, digitized and the optical densities were recorded by scanning the autoradiogram (1 mm sections).
FIG. 13 shows a section of the rat's brain, adjacent to the one autoradiograph, histologically stained with thionin. The pattern of the tumor shown and that in the autoradiogram are closely correlated. The area scanned by the probe is shown in the upper ¼ of the image. Autoradiogram of the rat's brain section tumor with high accumulation of F-18 labeled FDG is shown in the upper part of the picture. This autoradiogram was digitized and the profile of the optical density over the area scanned by the probe was calculated. The average size of the tumor was 2 mm in diameter and 5 mm in depth and was correlated with histologic site of the tumor. The count profiles from the probe, obtained by scanning the upper one fourth of the coronal surface, correlated with the profile of the optical density of digitized autoradiogram is shown inFIG. 14 . The profile of the radioactive counts obtained by horizontal scanning of the probe is shown by the diamonds. The profile of the optical density of the autoradiogram in the region scanned by the probe is shown by the squares. Both profiles showed the localization of the center of the tumor at 3 mm to the right to the midline of the brain and estimated the tumor width to be 3 mm. This test demonstrates that a small tumor ˜1 mm labeled with FDG can be located by the beta probe. -
FIG. 15 is a PET scan of a patient with melanoma on the neck. The bulk of the tumor was then removed from the patient and the resected margins were scanned using the beta probe 16. The beta probe 16 found occult cancerous tissue at the margins. Radiation counts were measured by both the gamma and the beta probe. The normal tissue had no positron activity, but there was activity at the margins of resection after removal of the tumor. In one area on the base of skull the beta probe registered high activity compared with the normal tissue (FIG. 16 ). Final pathology demonstrated microscopic-positive margins that would have otherwise not been identified by the surgeon. Only the use of the beta probe prevented this cancer tissue from being left behind. The active margins most probably would have evolved into a reoccurrence of cancer. - In use the probe will be exposed to body temperatures from about 25 to about 37° C. Therefore calibration curves were obtained at 37, 35, 33, 30, 27 and 25° C. to generate sensitivity and dark current plots. Four alternative methods were employed to achieve reliable count rates that are independent of the temperature of the field of operation. These methods are as follows:
- Method #1: A
small thermocouple 26 is mounted to the back of the module in contact with theSSPM 12 in order to measure the temperature in real time. A sensitivity plot vs temperature is then used to generate a look-up table for use in the probe operational software in thedata processing unit 32 to correct for the effect of the temperature in real time. - Method #2: Real-time measurement of temperature can be made while varying the voltage in order to achieve constant sensitivity in the 25 to 37° C. range. The detector with
temperature sensor 26 is inserted in a radioactive source at different temperatures and the working voltage is adjusted to achieve a constant output. Inclusion of this table into the software allows the working voltage to be controlled in real time. - Method #3: Real Time Variation of the Pre-amplifier's Gain can be made while the voltage is kept constant and the gain of the pre-amplifier is varied to achieve a constant count rate across a range of temperatures between 25° and 37° C.
- Method #4: an electronic cooler, such as a
Peltier chip 28, is placed in thermal contact with theSSPM 12 in order to lower the temperature of the SSPM 12 (seeFIGS. 2 and 3 ). Atemperature sensing device 26, such as a thermocouple is employed to measure the SSPM's temperature, and anelectronic feedback circuit 30 is used to maintain a constant temperature at, for example 15° C. - These techniques are believed to be suitable to result in a percent change of less than 10%. As an alternative approach, the detector module can include means to maintain the module at a fixed temperature. For example, the detector module can be enclosed in a jacket and held at the constant temperature of 37° C. or a
miniature Peltier chip 28 can be placed on the back of the SSPM to control the temperature of the module by using afeedback circuit 30 that reads the temperature and turns the cooler on and off to maintain a predetermined constant temperature. - A further embodiment comprises an array of 4 by 4 silicon photomultiplier devices (16 devices). A readout circuit encodes position information from
SSPM 12 devices into a 4-wire output. The four signals are then added together to provide energy information. TheSSPMs 12 were coupled to a sheet ofplastic scintillator 14 using an optical grease and irradiated with a Na-22 source. Output current pulses averaged about 0.1 ma. This relatively large output current pulse can be encoded using a charge division scheme consisting of resistor chains in the X and Y direction to encode position. The 16SSPMs 12 are connected to the resistor junctions. The proportions of the currents flowing to the corners of the array are then converted to a voltage using 4 transimpedance amplifiers. It is possible that the high capacitance of each device (35 pf) may slow the scintillation pulse to the point of degrading the signal when the 16 devices are read-out in this fashion. Also, the large resulting input capacitance at the input of each of the four transimpedance amplifiers may need to be compensated to eliminate amplifier instability resulting in oscillation. However, both of these conditions are eliminated by using a separate, high-speed transimpedance amplifier for each of the 16 devices, converting the outputs to currents, and then feeding these currents into the resistor network encoder scheme referred to above. Another factor taken into consideration is gain matching between the devices. Because this is not provided by the manufacturer of the SSPM, a variable and independent bias voltage can be applied to each device and then the gain of the whole array normalized. A further embodiment comprises a readout board for 10×10 SSPMs in place of the 4×4 SSPM. The intrinsic uniformity of the beta cameras described herein is measured by scanning a flat uniform source of F-18 solution contained in a shallow dish. The result generated is reported as the ratio of the difference of the maximum counts/pixel and the minimum counts/pixel, over the average counts per pixel. - The tests were repeated in presence of various amounts of background radioactivity. First a glass bottle was filled with 2 liters of F-18 solution (total activity of 100 microCi) and placed under the beta camera; the image was acquired in 15 minutes. The energy window was set above the electronic noise. After this image was acquired, the average counts per pixel were measured. The energy threshold was then raised to one third of the highest energy channel, and the test was repeated. The sensitivity flat source was then placed under the beta camera, the background source was removed, and the sensitivity at the new energy threshold was measured. This procedure was repeated five times with the energy threshold raised each time until the highest channel was reached.
- In order to determine the spatial resolution of the beta camera, expressed in terms of the smallest hole pattern visible on the image, a phantom was prepared comprising multiple 2 mm deep holes, with different diameters, drilled in a flat Lucite block. The diameters of the holes were 1, 2, 3 or 4 mm, with their center-to-center distance equal to twice their diameters. They were filled with I-131 in solution, and covered by thin plastic tape. A beta camera was placed on top of this phantom and images were acquired for different time durations (10, 30, 60, 300 seconds). A uniformity correction was then applied. This test was repeated at different specific activities (0.2, 0.5, 1, 2, uCi/ml). The same phantom was used to determine the fractional degree of deviation from straight line in the image pattern.
- In addition, a set of phantom were used to determine the limit of tumor detection with the beta camera. A phantom of the normal tissue was made with a low radioactive concentration using a mixture of flour and solution of F-18 FDG. The more radioactive lesions were made in the same fashion. A large rectangular plastic container (60×30×20 cm) was filled with F-18 FDG and flour, and mixed to form a large piece of dough in the form of the human torso. One (1) gram samples of different areas of this phantom were used to measure its radioactive concentration in a well counter. The goal was to achieve a concentration of 0.2 microCi/cc. Various spheres of tumor phantoms (with radioactive concentration of 1 microCi/g) were then placed on or near the surface of the normal tissue phantom, the beta camera was placed over the simulated tumor for 30 seconds and an image acquired. The diameters of the simulated tumors were set at 3, 5, 7, 10, 15 mm. and the radiation levels in the tumors were set at 0.4, 0.6, 0.8, 1.5, and 2 microCi/g. To study the effects of thin layers of normal tissue that may be covering a superficial tumor, these experiments were repeated with layers of different thickness plastic (0.5, 1, 1.5, 2, 3, 5 mm) placed between the camera and the Lucite phantom and the simulated surgical procedures with a phantom were repeated.
- Referring to
FIG. 17 , to prepare aprobe 200 as described herein for use in a biopsy or intra-vascular radiation detection procedures a 1 mm diameter SSPM 212 (Photonique SA, Geneva,) was attached to a 5 mm long red plastic scintillator 214 (1 mm diameter, BC-430 Saint Gobain). The spectrum of the scintillation of light emitted by this redplastic scintillator 214 matches well with the spectral response of theSSPM 212 attached thereto. The emission spectrum of the scintillator peaks fairly sharply at 580 nm, where the detection efficiency of the SSPM is about 20%. A thin and flexible coaxial cable 216 (such as W. L Gore Ribbonized Coaxial or equivalent) was connected to the two leads of theSSPM 212. Thiscable 216 can be passed through a conventionalcardiac catheter 218, such as shown inFIG. 19 approximately 160 mm long which is glued to the end of the SSPM using a bio-safe glue. An end-cap 220 of stainless steel, preferably 304 stainless, was attached to the scintillator end of the module and wrapped in 5 micron-thin stainless steel foil 222 (GoodFellow Corp.) (shown inFIG. 17 retracted so that the inner construction can be displayed). A preferred adhesive for attaching the foil to the stainless cap is a bio-safe epoxy such as Master Bond EP21LV or equivalent. In a preferred embodiment the diameter of the detector module is approximately 1.25 mm, and the length of the scintillator is about 5 mm. A biopsy probe 224 constructed as shown inFIG. 18 is inserted with or without thecatheter 218 through biopsy needle (not shown), such as the BioPince Core Biopsy Needle, which has a 1.25 mm inner diameter, the biopsy probe 224 being designed to fit within the needle. The length of the needle (cannula) is about 5 mm longer than the standard 120 mm needle, so that a sharpdistal end 226 on the detector 224 sticks out of the cannula during the exploration phase. While the construction such as shown inFIG. 2 is described, the dual probe such as inFIG. 3 can be used and any of the designs ofFIGS. 7-10 can be incorporated in the probe. The biopsy probe 224 is placed inside a cannula and they are fixed together by a Luer-Lok® 228 (or any other suitable locking structure) on the proximal end of the probe 224, to form a Coaxial Introducer Needle/Probe assembly. The tip of the probe/cannula assembly has a sharpstainless steel tip 226 to cut through tissue so that the whole probe can approach and pierce through the lesion. The advancement of the biopsy probe 224 is stopped when the detector registers the maximum count rate of the beta rays within the lesion, or the camera shows a focal point of radioactivity along its axis. A safety lock (not shown) can then be advanced over the outer surface of the cannula so it contacts the skin, the Luer-Lok® 228 is twisted open and the probe 224 is retracted from the lesion, leaving the cannula tip in the lesion. A biopsy stylet can then be inserted through the conduit and the sample of the labeled tissue removed. The removed tissue sample can be counted again, ex-vivo, utilizing the beta probe 224 to ensure that it contains higher radioactive concentration before the procedure is terminated. The cannula can also be used as a conduit for delivery of a treatment media directly to the lesion or in close proximity of the diseased tissue. In another embodiment a dual detector module (FIG. 3 ) is used, therefore increasing the sensitivity compare to the use of single-detector module. In yet another embodiment a one-dimensional array of single or dual detector modules are used for obtaining the distribution of the beta radiation profile. - Several groups have demonstrated that FDG accumulates in inflamed atherosclerotic specimens in rabbit models of atherosclerosis. In a study performed with Watanabe heritable hyperlipidemic (WHHL) rabbits, Ogawa, et al. showed that 18F-FDG uptake correlate with the number of macrophages within the atherosclerotic lesions (R=0.81, P<0001).
- Applicant has found that non-invasive FDG-PET measurements correlate strongly with inflammation in experimental atherosclerotic lesions. In that study, inflamed atherosclerotic lesions were induced in nine male New Zealand white rabbits via balloon injury of the aorta-iliac arterial segment and exposure to a high cholesterol diet. Ten rabbits fed standard chow served as controls. Three to six months following balloon injury, the rabbits were injected with FDG (1 mCi/kg) and 3 hours thereafter the aortic uptake of FDG was assessed. Biodistribution of FDG activity within aortic segments was obtained using standard well gamma counting. FDG uptake was also determined non-invasively in a subset of six live atherosclerotic rabbits and five normal rabbits, using PET imaging and measurement of standardized uptake values (SUV) over the abdominal aorta. Plaque macrophage and smooth muscle cell density were determined by planimetric analysis of RAM-11 and smooth muscle actin staining, respectively.
- Co-registered PET&CT images demonstrated increased uptake of FDG in atherosclerotic aortas compared to control aortas. Further, well counter measurements of FDG uptake was significantly higher within atherosclerotic aortas compared to control aortas (P<0.001). In parallel with these findings, FDG uptake, as determined by PET, was higher in atherosclerotic aortas (0.68±0.06 vs. 0.13±0.01, SUV atherosclerotic vs. control, P<0.001). Moreover, macrophage density, assessed histologically, correlated with well-counter measurements FDG accumulation (r=0.79, P<0.001) as well as the non-invasive in vivo (PET) measurements of FDG uptake, (r=0.93, P<0.0001). Importantly, FDG uptake did not correlate with either smooth muscle cell staining, vessel wall thickness, or plaque thickness of the specimens. These data show that FDG accumulates in macrophage-rich atherosclerotic plaques and demonstrate that vascular macrophage activity can quantified non-invasively with FDG-PET. As such, measurement of vascular FDG uptake with PET holds promise for the non-invasive characterization of vascular inflammation.
- An intravascular beta ray detection probe 230 offers several advantages over conventional PET imaging. The resolution of the probe is significantly better than PET (2 vs. 6 mm). Also, in contrast to PET, the intravascular detection of short-range positrons is not affected by myocardial uptake of FDG. This is attributed to the fact that the beta probe detects beta particles (which travel less than 2 mm), and therefore, myocardium-derived particles do not reach the probe. On the other hand, PET detects annihilation photons, which traverse many centimeters through tissue. An intravascular detector enables precise localization of VP during the same sitting as diagnostic coronary angiography. This enables the local delivery of plaque-stabilizing therapy in a way that non-invasive techniques do not.
- In order to prove this concept with a beta probe, a PMT-optical fiber designs, was built by the applicant and the PMT-optical fiber based beta-ray detector probe was used to examine the feasibility of intravascular detection. This earlier design of a flexible beta probe had a diameter of 1.6 mm and length of 40 cm. This probe was selectively more sensitive to positrons than gamma rays or annihilation photons. To construct this probe, a 1 mm diameter, 2 mm long plastic scintillator was optically connected to a PMT via a 1 mm diameter, 40 cm long optical fiber, and was covered by aluminized Mylar (thickness=100 microns) acting as a reflector of the scintillation light. A commercially available computerized data acquisition system (Node Seeker-720™, IntraMedical, Inc.) was used to collect and display the counts. The efficiency of that probe, measured by placing a point source of F-18 in touch with its sensitive tip, was only about 0.2%.
FIG. 19 shows a vascular probe 230 similar in design to the biopsy probe ofFIG. 18 . The intravascular probe 230 has anSSPM 212 which receives a light pulse from aplastic scintillator 214. The electrical output of thescintillator 214 is fed, by acable 216 threaded through acatheter 218, to adigital signal processor 22 and then to adisplay 42. Preliminary testing of the novel detector incorporating features of theinvention incorporating SSPMs 212 demonstrated significant improvement in efficiency (up to about 15% efficiency) for acatheter 218 of 160 cm length. This device also had the added safety of low-voltage bias. - To prove the concept of using the intravascular probe 230 to detect labeled plaque an animal model was used. Atherosclerotic lesions were induced in New Zealand rabbits with a balloon injury to the infradiaphragmatic aorta followed by a high cholesterol diet. At 10 weeks, 37 MBq/kg FDG was administered to 4 rabbits with atherosclerotic lesions as well as to 3 control rabbits. 3-4 hours after FDG, the rabbits were sacrificed, and aortas removed as a single segment. The flexible intravascular beta probe 230 described above was inserted into the aorta. Measurements were made in triplicate, (at 2 s/measurement), at sites of grossly visible plaque and at non-injured sites in the cholesterol fed rabbits, as well as in corresponding areas in the control aorta. The queried aortic segments were then excised and examined using standard well counting. Activity determined by the catheter correlated with well counting measurements, (r=0.89, P<0.001). Moreover, atherosclerotic plaques were readily distinguished from non-injured regions by the beta probe, (11.9±2.1 [n=9, range 9.7-15.3] vs. 4.8±1.9 [n=14, range 1.3-7.3], cps in atherosclerotic vs control regions, P<0.001).
- This animal study demonstrated that while applicant's prior art PMT-optical fiber based intra-vascular beta probe, together with FDG, had promise for the in vivo detection of vulnerable plaques, to be practical for effective use in humans it required higher sensitivity, better flexibility, and a greater efficiency. This has now been met by the intravascular probe 230 described herein above.
- In a related area, Shen et al. showed that optical detection of breast cancer in the milk duct can be performed using a fiberoptic ductoscopy (Shen, K-W, Wu J, Lu J-S, et al. “Fiberoptic Ductoscopy for Patients with Nipple Discharge”, Cancer, 89, pp 1512-1519 (2000). In addition to intra-vascular applications for finding atherosclerotic plaques described above, the intravascular probe 230 or other one dimensional beta cameras built with SSPMs as described above can be used for intra-ductal detection of cancer in the breast, after injecting the patient with F-18 FDG, or any other beta emitting radio-tracers used for cancer detection. In addition, this probe can be used in intra-vascular detection of cancer by insertion into tumor vasculature, its movement guided by x-ray or ultrasound. Other body cavities can be used as access ports for this flexible radiation detection probe for detection of abnormal tissue in other organs; For example, the bladder can be accessed through urethra; the brain can be accessed through the nasal cavity, etc.
- The beta probe or one-dimensional beta camera described above for use in biopsy examination or as an intravascular catheter, for passage through blood vessels to locate labeled plaque or vascular inflammation can also be passed through a 5 mm-12 mm port in a laparoscope to detect, or map a tumor being resected by laparoscopic surgery.
- Esophageal cancer is very deadly—the American Cancer Society estimates that in 2006 there will be 14,550 new cases and 13,770 deaths in the United States alone. Patients are often diagnosed only after they present with symptoms, at which point the cancer is usually well advanced. If the disease is caught in the early stages, however, the prognosis can be quite good. Early detection is most likely to occur in populations being screened for the development of esophageal neoplasms. Patients diagnosed with Barrett's esophagus, the precursor lesion for esophageal adenocarcinoma, typically undergo regular surveillance for the progression of their condition to cancer. Unfortunately, current diagnostic methods which generally comprise anatomically guided biopsy for histological analysis are not accurate at detecting early stage disease. Histopathology is the only way to distinguish between the first stages of progression and malignancy, and thus biopsies are taken essentially at random. Applicant has conducted preliminary studies on patients injected with FDG and biopsied for measurement of the FDG uptake in tumor, Barrett's cells and normal tissue. This study shows that FDG uptake is an indicator of grade of the disease. In light of this discovery, a further alternative of the beta cameras described herein, is to prepare the array of the
scintillators 14 as separate SSPM/scintillator units 250 and mounting them on the surface of aflexible membrane 252 to form aflexible detector arrangement 256 such as shown inFIG. 5 . Thismembrane 252 can then be wrapped around the external surface of ascope 258, such as endoscope, for example in the manner shown inFIG. 23 , so that diseased tissue in the esophagus can be located, removed and biopsied. The cancerous tissue can then be removed or various topical therapies can be applied directly to labeled tissue in the esophagus. - As a still further alternative, the imaging of metabolic function, as indicated by increased radiotracer uptake, is believed to be a more accurate method of detection early cancer and dysplasia, and therefore indicate appropriate regions to biopsy. Localized detection of 18FDG was conducted using an endoscopic-based beta camera, which was brought into direct contact with the tissue being surveyed. Using a single-channel probe (a single SSPM/scintillator modulator 250) the area that can be surveyed is limited by the size of the probe tip. Exploring the esophagus with such a probe is therefore time-consuming. However, because a beta camera combines counts from an array of detectors and produces a scan of a larger field of view the entire esophagus can be scanned relatively quickly. Further, a non-planar or curved imager is superior to a planar camera, because it will conform better to the curved wall of the esophagus or other body passage.
- The embodiment is not limited to use in the esophagus and can be inserted in other body orifices. For example, a beta camera array can also be introduced rectally to map a labeled prostate, aid in imaging the prostate and conducting a biopsy of the rectal wall as well as for post prostatectomy examination in patients with elevated PSA.
- We have developed endoscopic positron emission detectors for endoscopic imaging with PET radiotracers. The development of highly sensitive endoscopic based positron emission imaging coupled with clinically available PET radiotracers (e.g. 18 fluoro-2-deoxyglucose (FDG)) offers the potential for endoscopic molecular imaging. There are detectable differences in FDG uptake between normal, dysplastic and cancerous esophageal tissue and these differences are detectable using endoscopic based positron emission molecular imaging.
- To demonstrate the utility of the above described endoscopic procedure, immediately following FDG administration and performance of a PET scan, patients with esophageal malignancies were evaluated endoscopically along with the performance of multiple biopsies taken from normal and abnormal appearing esophageal tissue. FDG expression in the biopsy samples was measured using a well-counter (the standard measuring device for FDG expression in tissue samples) and a miniature flexible positron emission detector such as incorporated in the endoscopic positron-sensitive imaging system described herein. The decay corrected counts per minute per mg of tissue were calculated based on the Picounter reading, time from the initial FDG injection and the weight of the biopsy specimen. Endoscopic biopsies were classified blindly by an experienced esophageal histopathologist (WMW), as normal squamous esophageal mucosa, intestinal metaplasia, dysplasia or invasive cancer. All results were normalized using the normal esophageal squamous epithelium counts per minute per mg as the reference point and expressed as mean+/−standard error of mean. Decay corrected counts per minute were correlated with histology. For the purposes of analysis, intestinal metaplasia and dysplasia were grouped together as premalignant lesions. Endoscopic biopsy FDG level as measured using the well-count was correlated with the measurements of the same tissue using the miniaturized positron emission detector.
- Seven patients were studied with between 8-14 esophageal biopsies sampled per patient. Three patients (1 cancer, 2 dysplasias) with negative PET scans had evidence of elevated FDG expression in their abnormal biopsies as compared to normal tissue. Six of seven patients showed a significant difference between endoscopic biopsy FDG levels for normal, intestinal metaplasia (IM)-dysplasia and invasive cancer. There was a strong correlation between FDG levels in biopsies as measured by standard well-count and the miniaturized flexible positron emission detector (r=0.85). Based on the data collected it was demonstrated that there is a differential expression in FDG levels between normal, dysplastic and invasive esophageal cancer. In three patients in whom the PET scan was read as negative the direct measurement of positron emission was correctly able to identify cancer and dysplasia. This confirms the superiority of our endoscopic radio-detection approach to conventional PET scan. There is a strong correlation between biopsy FDG expression as measured by standard technique and the above described miniaturized flexible positron emission detector, supporting the utility of endoscopic positron emission molecular imaging for esophageal dysplasia and the endoscopic evaluation with a radiation detection probe, in conjunction with radionuclide markers for enhancing selective endoscopic biopsy.
- Beta camera arrays as described herein are not limited to use in vivo. They can also be formed, by a tiling technique or, applied to a flexible backing, formed into a trough or cup shape for use in examination of the margins of resected tumors or prostate tissue placed therein to determine, by the detection of beta-ray emitting labeled cells, if the tumor cells appear to be on or near the margin of the extracted tissue.
- Still further, the techniques and devices described herein are not limited to beta or gamma detection. One skilled in the art will recognize that other radioactive emissions, for example, alpha rays, can be detected using similar arrangement with alpha-sensitive photo emitters.
- In summary, applicant has disclosed various embodiments of radiation detection probes and radiation detection cameras which are capable of detecting minute quantities of radioactive-labeled sites within the body so these tissues can be located, removed, and verified in vitro, based on beta or gamma emissions from those labeled tissue. The system can include corrections or adjustments for temperature so that the readings are normalized. While examples are given for use in locating cancer cells, inflamed or modified tissue or vulnerable plaque the utility of the invention is not limited thereto and can be used to locate and map any site, any specific tissue or any abnormal tissue, within the body that can be selectively labeled with radiation emitting materials.
Claims (31)
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US11/784,854 US8068896B2 (en) | 2005-02-25 | 2007-04-09 | Detection of radiation labeled sites using a radiation detection probe or camera incorporating a solid state photo-multiplier |
US12/776,777 US8050743B2 (en) | 2005-02-25 | 2010-05-10 | Positron emission detectors and configurations |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US65656505P | 2005-02-25 | 2005-02-25 | |
US11/270,906 US7653427B2 (en) | 2004-11-12 | 2005-11-10 | Method and instrument for minimally invasive sentinel lymph node location and biopsy |
US80963906P | 2006-05-30 | 2006-05-30 | |
US85582906P | 2006-10-31 | 2006-10-31 | |
US11/784,854 US8068896B2 (en) | 2005-02-25 | 2007-04-09 | Detection of radiation labeled sites using a radiation detection probe or camera incorporating a solid state photo-multiplier |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US11/270,906 Continuation-In-Part US7653427B2 (en) | 2004-11-12 | 2005-11-10 | Method and instrument for minimally invasive sentinel lymph node location and biopsy |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US11/929,349 Continuation-In-Part US7750311B2 (en) | 2005-02-25 | 2007-10-30 | Positron emission detectors and configurations |
Publications (3)
Publication Number | Publication Date |
---|---|
US20100010343A1 true US20100010343A1 (en) | 2010-01-14 |
US20100198061A9 US20100198061A9 (en) | 2010-08-05 |
US8068896B2 US8068896B2 (en) | 2011-11-29 |
Family
ID=41505783
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US11/784,854 Expired - Fee Related US8068896B2 (en) | 2005-02-25 | 2007-04-09 | Detection of radiation labeled sites using a radiation detection probe or camera incorporating a solid state photo-multiplier |
Country Status (1)
Country | Link |
---|---|
US (1) | US8068896B2 (en) |
Cited By (43)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20100243865A1 (en) * | 2009-03-25 | 2010-09-30 | Olcott Peter D | Cross-strip charge multiplexing readout for differential detector arrays |
US20110250128A1 (en) * | 2010-04-12 | 2011-10-13 | Colin M Carpenter | Method for tissue characterization based on beta radiation and coincident Cherenkov radiation of a radiotracer |
US20120032086A1 (en) * | 2010-02-08 | 2012-02-09 | Farhad Daghighian | Hand-held gamma ray scanner |
US8502154B2 (en) | 2011-04-21 | 2013-08-06 | Kabushiki Kaisha Toshiba | Method and system for organ specific PET imaging |
US20130304409A1 (en) * | 2012-05-10 | 2013-11-14 | Board Of Regents, The University Of Texas System | Methods for validating plastic scintillating detectors and applications of same |
US20130324844A1 (en) * | 2012-05-30 | 2013-12-05 | Joshua G. Knowland | System for the detection of gamma radiation from a radioactive analyte |
US20140018673A1 (en) * | 2012-06-18 | 2014-01-16 | Empire Technology Development Llc | Ionizing radiation detector for use with endoscopic ultrasound |
WO2014041512A1 (en) * | 2012-09-13 | 2014-03-20 | Koninklijke Philips N.V. | Breast surgery guidance based on breast mr images and radioactive markers |
WO2014116953A1 (en) * | 2013-01-25 | 2014-07-31 | Dilon Technologies, Inc. | Radiation detection probe |
US8816292B2 (en) | 2010-04-01 | 2014-08-26 | Hybridyne Imaging Technologies, Inc. | Compact endocavity diagnostic probes for nuclear radiation detection |
US20140276035A1 (en) * | 2013-03-15 | 2014-09-18 | Wisconsin Alumni Research Foundation | System and Method for Evaluation of Disease Burden |
US20140363063A1 (en) * | 2012-01-16 | 2014-12-11 | Koninklijke Philips N.V. | Imaging apparatus |
US20150021489A1 (en) * | 2012-04-19 | 2015-01-22 | Canberra Industries, Inc. | Radiation Detector System and Method |
US20150144797A1 (en) * | 2013-11-22 | 2015-05-28 | General Electric Company | Active pulse shaping of solid state photomultiplier signals |
US20150257718A1 (en) * | 2012-09-28 | 2015-09-17 | The Regents Of The University Of California | Realtime imaging and radiotherapy of microscopic disease |
US9207333B2 (en) | 2011-04-21 | 2015-12-08 | Kabushiki Kaisha Toshiba | Geometry for PET imaging |
EP2951612A2 (en) * | 2013-01-29 | 2015-12-09 | Universita' Degli Studi di Roma "La Sapienza" | Intraoperative detection of tumor residues using beta- radiation and corresponding probes |
US9322929B2 (en) | 2011-04-21 | 2016-04-26 | Kabushiki Kaisha Toshiba | PET imaging system including detector elements of different design and performance |
US9445774B2 (en) | 2011-04-27 | 2016-09-20 | Koninklijke Philips N.V. | Energy application apparatus |
ITUB20152742A1 (en) * | 2015-07-31 | 2017-01-31 | Istituto Naz Fisica Nucleare | INTRAOPERATIVE PROBE |
US9606245B1 (en) | 2015-03-24 | 2017-03-28 | The Research Foundation For The State University Of New York | Autonomous gamma, X-ray, and particle detector |
US9696439B2 (en) | 2015-08-10 | 2017-07-04 | Shanghai United Imaging Healthcare Co., Ltd. | Apparatus and method for PET detector |
US20170261620A1 (en) * | 2016-03-09 | 2017-09-14 | Toshiba Medical Systems Corporation | Photon counting detector and x-ray computed tomography (ct) apparatus |
US9939533B2 (en) | 2012-05-30 | 2018-04-10 | Lucerno Dynamics, Llc | System and method for the detection of gamma radiation from a radioactive analyte |
US20180228424A1 (en) * | 2015-04-02 | 2018-08-16 | Eulji University Industry Academy Cooperation Foundation | Triple-fusion imaging device for sentinel lymphadenectomy during laparoscopic surgery |
WO2018184251A1 (en) * | 2017-04-05 | 2018-10-11 | 博睿泰克科技(宁波)有限公司 | Method and device for brain functional imaging and brain tissue component detection |
WO2019030507A1 (en) * | 2017-08-09 | 2019-02-14 | Lightpoint Medical, Ltd | Scintillator products, apparatuses and methods for use in autoradiographic imaging |
WO2019070616A2 (en) | 2017-10-02 | 2019-04-11 | Intuitive Surgical Operations, Inc. | Radiation finder tool |
US10473797B2 (en) | 2013-12-23 | 2019-11-12 | Johnson Matthey Public Limited Company | Radiation detection apparatus and method |
CN110520760A (en) * | 2017-03-13 | 2019-11-29 | 通用电气公司 | Pixel for radiation detector designs |
US20200297294A1 (en) * | 2017-12-15 | 2020-09-24 | Lightpoint Medical, Ltd | Direct detection and imaging of charged particles from a radiopharmaceutical |
US10795037B2 (en) * | 2017-07-11 | 2020-10-06 | Reflexion Medical, Inc. | Methods for pet detector afterglow management |
US10959686B2 (en) | 2008-03-14 | 2021-03-30 | Reflexion Medical, Inc. | Method and apparatus for emission guided radiation therapy |
US11007384B2 (en) | 2017-08-09 | 2021-05-18 | Reflexion Medical, Inc. | Systems and methods for fault detection in emission-guided radiotherapy |
US20210177260A1 (en) * | 2019-12-13 | 2021-06-17 | NU-RISE Lda | Urinary catheter for detecting radiation |
US20210236848A1 (en) * | 2019-12-13 | 2021-08-05 | NU-RISE Lda | Urinary catheter for detecting radiation |
US11164315B2 (en) * | 2018-12-05 | 2021-11-02 | Stmicroelectronics S.R.L. | Image processing method and corresponding system |
FR3113740A1 (en) * | 2020-08-31 | 2022-03-04 | Bertin Technologies | Beta particle detection device |
US11270600B2 (en) * | 2017-05-16 | 2022-03-08 | United States Department Of Energy | Method and device for passive detection of physical effects |
US11369806B2 (en) | 2017-11-14 | 2022-06-28 | Reflexion Medical, Inc. | Systems and methods for patient monitoring for radiotherapy |
US20220260730A1 (en) * | 2019-08-09 | 2022-08-18 | Kyungpook National University Industry-Academic Cooperation Foundation | Photosensor |
US11504550B2 (en) | 2017-03-30 | 2022-11-22 | Reflexion Medical, Inc. | Radiation therapy systems and methods with tumor tracking |
US11944344B2 (en) | 2018-04-13 | 2024-04-02 | Karl Storz Se & Co. Kg | Guidance system, method and devices thereof |
Families Citing this family (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8648287B1 (en) * | 2005-05-27 | 2014-02-11 | Rambus Inc. | Image sensor using single photon jots and processor to create pixels |
US20110167896A1 (en) * | 2010-01-11 | 2011-07-14 | General Electric Company | Estimation of reservoir permeability |
JP5680110B2 (en) * | 2010-02-01 | 2015-03-04 | クリア−カット メディカル エル・ティー・ディー | Stump evaluation of in vitro samples |
US8729471B2 (en) | 2010-07-30 | 2014-05-20 | Pulsetor, Llc | Electron detector including an intimately-coupled scintillator-photomultiplier combination, and electron microscope and X-ray detector employing same |
EP2487703A1 (en) * | 2011-02-14 | 2012-08-15 | Fei Company | Detector for use in charged-particle microscopy |
JP6215202B2 (en) * | 2011-08-05 | 2017-10-18 | パルセータ, エルエルシーPulsetor, Llc | Electron detector comprising one or more combinations of closely coupled scintillator-photomultiplier tubes and an electron microscope using the same |
US9405023B2 (en) | 2013-02-12 | 2016-08-02 | General Electric Company | Method and apparatus for interfacing with an array of photodetectors |
DE102013114617A1 (en) * | 2013-12-20 | 2015-06-25 | Endress + Hauser Gmbh + Co. Kg | Radiometric instrument for performing measurements in potentially explosive atmospheres |
KR102301229B1 (en) * | 2014-10-24 | 2021-09-10 | 삼성전자주식회사 | Method and apparatus for differentially detecting beta-rays and gamma-rays included in radioactive rays, and pakage comprising the apparatus |
GB2536650A (en) | 2015-03-24 | 2016-09-28 | Augmedics Ltd | Method and system for combining video-based and optic-based augmented reality in a near eye display |
JP6548565B2 (en) * | 2015-12-14 | 2019-07-24 | 浜松ホトニクス株式会社 | Scintillator panel and radiation detector |
GB201604246D0 (en) * | 2016-03-11 | 2016-04-27 | Univ Hull | Radioactivity detection |
US10234573B2 (en) | 2016-08-18 | 2019-03-19 | Radiation Monitoring Devices, Inc. | Digital probe |
US20200041666A1 (en) * | 2018-08-06 | 2020-02-06 | Wisconsin Alumni Research Foundation | Semiconductor membrane enabled hard x-ray detectors |
US11766296B2 (en) | 2018-11-26 | 2023-09-26 | Augmedics Ltd. | Tracking system for image-guided surgery |
US11607119B2 (en) * | 2018-12-17 | 2023-03-21 | Qatar University | Fluorescence lifetime spectroscopy based capsule endoscopy |
US11382712B2 (en) | 2019-12-22 | 2022-07-12 | Augmedics Ltd. | Mirroring in image guided surgery |
US11963808B2 (en) | 2021-05-21 | 2024-04-23 | Lucerno Dynamics, Llc | In vivo measurement system and method for the localized measurement of radiotracer concentration in the body |
US11896445B2 (en) | 2021-07-07 | 2024-02-13 | Augmedics Ltd. | Iliac pin and adapter |
WO2023212745A2 (en) * | 2022-04-30 | 2023-11-02 | The General Hospital Corporation | System for and method of zinc imaging for margin assessment during breast conserving surgery |
Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4005292A (en) * | 1974-01-24 | 1977-01-25 | G. D. Searle & Co. | Mass counting of radioactivity samples |
US5008546A (en) * | 1990-06-18 | 1991-04-16 | The Regents Of The University Of California | Intraoperative beta probe and method of using the same |
US5325855A (en) * | 1992-08-07 | 1994-07-05 | Memorial Hospital For Cancer And Allied Diseases | Flexible intraoperative radiation imaging camera |
US5744805A (en) * | 1996-05-07 | 1998-04-28 | University Of Michigan | Solid state beta-sensitive surgical probe |
US5952664A (en) * | 1997-01-17 | 1999-09-14 | Imaging Diagnostic Systems, Inc. | Laser imaging apparatus using biomedical markers that bind to cancer cells |
US20010056234A1 (en) * | 2000-04-12 | 2001-12-27 | Weinberg Irving N. | Hand held camera with tomographic capability |
US6671541B2 (en) * | 2000-12-01 | 2003-12-30 | Neomed Technologies, Inc. | Cardiovascular imaging and functional analysis system |
US20050236553A1 (en) * | 2004-04-08 | 2005-10-27 | Canon Kabushiki Kaisha | Solid-state image sensing element and its design support method, and image sensing device |
US6973163B2 (en) * | 2003-03-19 | 2005-12-06 | Fuji Photo Film Co., Ltd. | Radiography system and machine readable medium storing program |
US20060192128A1 (en) * | 2003-04-10 | 2006-08-31 | Benlloch Bavciera Jose M | Gamma ray detector with interaction depth coding |
-
2007
- 2007-04-09 US US11/784,854 patent/US8068896B2/en not_active Expired - Fee Related
Patent Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4005292A (en) * | 1974-01-24 | 1977-01-25 | G. D. Searle & Co. | Mass counting of radioactivity samples |
US5008546A (en) * | 1990-06-18 | 1991-04-16 | The Regents Of The University Of California | Intraoperative beta probe and method of using the same |
US5325855A (en) * | 1992-08-07 | 1994-07-05 | Memorial Hospital For Cancer And Allied Diseases | Flexible intraoperative radiation imaging camera |
US5744805A (en) * | 1996-05-07 | 1998-04-28 | University Of Michigan | Solid state beta-sensitive surgical probe |
US5952664A (en) * | 1997-01-17 | 1999-09-14 | Imaging Diagnostic Systems, Inc. | Laser imaging apparatus using biomedical markers that bind to cancer cells |
US20010056234A1 (en) * | 2000-04-12 | 2001-12-27 | Weinberg Irving N. | Hand held camera with tomographic capability |
US6671541B2 (en) * | 2000-12-01 | 2003-12-30 | Neomed Technologies, Inc. | Cardiovascular imaging and functional analysis system |
US6973163B2 (en) * | 2003-03-19 | 2005-12-06 | Fuji Photo Film Co., Ltd. | Radiography system and machine readable medium storing program |
US20060192128A1 (en) * | 2003-04-10 | 2006-08-31 | Benlloch Bavciera Jose M | Gamma ray detector with interaction depth coding |
US20050236553A1 (en) * | 2004-04-08 | 2005-10-27 | Canon Kabushiki Kaisha | Solid-state image sensing element and its design support method, and image sensing device |
Cited By (72)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10959686B2 (en) | 2008-03-14 | 2021-03-30 | Reflexion Medical, Inc. | Method and apparatus for emission guided radiation therapy |
US11627920B2 (en) | 2008-03-14 | 2023-04-18 | Reflexion Medical, Inc. | Method and apparatus for emission guided radiation therapy |
US8575534B2 (en) | 2009-03-25 | 2013-11-05 | The Board Of Trustees Of The Leland Stanford Junior University | Cross-strip charge multiplexing readout for differential detector arrays with capacitive row and column charge splitters |
US20100243865A1 (en) * | 2009-03-25 | 2010-09-30 | Olcott Peter D | Cross-strip charge multiplexing readout for differential detector arrays |
US20120032086A1 (en) * | 2010-02-08 | 2012-02-09 | Farhad Daghighian | Hand-held gamma ray scanner |
US8816292B2 (en) | 2010-04-01 | 2014-08-26 | Hybridyne Imaging Technologies, Inc. | Compact endocavity diagnostic probes for nuclear radiation detection |
US20110250128A1 (en) * | 2010-04-12 | 2011-10-13 | Colin M Carpenter | Method for tissue characterization based on beta radiation and coincident Cherenkov radiation of a radiotracer |
US9207333B2 (en) | 2011-04-21 | 2015-12-08 | Kabushiki Kaisha Toshiba | Geometry for PET imaging |
US8502154B2 (en) | 2011-04-21 | 2013-08-06 | Kabushiki Kaisha Toshiba | Method and system for organ specific PET imaging |
US9322929B2 (en) | 2011-04-21 | 2016-04-26 | Kabushiki Kaisha Toshiba | PET imaging system including detector elements of different design and performance |
US9445774B2 (en) | 2011-04-27 | 2016-09-20 | Koninklijke Philips N.V. | Energy application apparatus |
US10204415B2 (en) * | 2012-01-16 | 2019-02-12 | Koninklijke Philips N.V. | Imaging apparatus |
US20140363063A1 (en) * | 2012-01-16 | 2014-12-11 | Koninklijke Philips N.V. | Imaging apparatus |
US20150021489A1 (en) * | 2012-04-19 | 2015-01-22 | Canberra Industries, Inc. | Radiation Detector System and Method |
US9366768B2 (en) * | 2012-04-19 | 2016-06-14 | Canberra Industries, Inc. | Radiation detector system and method |
US20130304409A1 (en) * | 2012-05-10 | 2013-11-14 | Board Of Regents, The University Of Texas System | Methods for validating plastic scintillating detectors and applications of same |
US9939533B2 (en) | 2012-05-30 | 2018-04-10 | Lucerno Dynamics, Llc | System and method for the detection of gamma radiation from a radioactive analyte |
US9002438B2 (en) * | 2012-05-30 | 2015-04-07 | Lucerno Dynamics | System for the detection of gamma radiation from a radioactive analyte |
US20210055431A1 (en) * | 2012-05-30 | 2021-02-25 | Lucerno Dynamics, Llc | System and method for the detection of gamma radiation from a radioactive analyte |
US10852446B2 (en) * | 2012-05-30 | 2020-12-01 | Lucerno Dynamics, Llc | System and method for the detection of gamma radiation from a radioactive analyte |
US11668844B2 (en) * | 2012-05-30 | 2023-06-06 | Lucerno Dynamics, Llc | System and method for the detection of gamma radiation from a radioactive analyte |
JP2014182121A (en) * | 2012-05-30 | 2014-09-29 | Lucerno Dynamics Llc | System for detecting gamma radiation from radioactive analyte |
US20130324844A1 (en) * | 2012-05-30 | 2013-12-05 | Joshua G. Knowland | System for the detection of gamma radiation from a radioactive analyte |
US20140018673A1 (en) * | 2012-06-18 | 2014-01-16 | Empire Technology Development Llc | Ionizing radiation detector for use with endoscopic ultrasound |
WO2014041512A1 (en) * | 2012-09-13 | 2014-03-20 | Koninklijke Philips N.V. | Breast surgery guidance based on breast mr images and radioactive markers |
US20150257718A1 (en) * | 2012-09-28 | 2015-09-17 | The Regents Of The University Of California | Realtime imaging and radiotherapy of microscopic disease |
WO2014116953A1 (en) * | 2013-01-25 | 2014-07-31 | Dilon Technologies, Inc. | Radiation detection probe |
EP2951612A2 (en) * | 2013-01-29 | 2015-12-09 | Universita' Degli Studi di Roma "La Sapienza" | Intraoperative detection of tumor residues using beta- radiation and corresponding probes |
US20160100795A1 (en) * | 2013-03-15 | 2016-04-14 | Wisconsin Alumni Research Foundation | System and Method for Evaluation of Disease Burden |
US9161720B2 (en) * | 2013-03-15 | 2015-10-20 | Wisconsin Alumni Research Foundation | System and method for evaluation of disease burden |
US20140276035A1 (en) * | 2013-03-15 | 2014-09-18 | Wisconsin Alumni Research Foundation | System and Method for Evaluation of Disease Burden |
US9603567B2 (en) * | 2013-03-15 | 2017-03-28 | Wisconsin Alumni Research Foundation | System and method for evaluation of disease burden |
US20150144797A1 (en) * | 2013-11-22 | 2015-05-28 | General Electric Company | Active pulse shaping of solid state photomultiplier signals |
US9869781B2 (en) * | 2013-11-22 | 2018-01-16 | General Electric Company | Active pulse shaping of solid state photomultiplier signals |
US10473797B2 (en) | 2013-12-23 | 2019-11-12 | Johnson Matthey Public Limited Company | Radiation detection apparatus and method |
US9606245B1 (en) | 2015-03-24 | 2017-03-28 | The Research Foundation For The State University Of New York | Autonomous gamma, X-ray, and particle detector |
US9835737B1 (en) | 2015-03-24 | 2017-12-05 | The Research Foundation For The State University Of New York | Autonomous gamma, X-ray, and particle detector |
US20180228424A1 (en) * | 2015-04-02 | 2018-08-16 | Eulji University Industry Academy Cooperation Foundation | Triple-fusion imaging device for sentinel lymphadenectomy during laparoscopic surgery |
ITUB20152742A1 (en) * | 2015-07-31 | 2017-01-31 | Istituto Naz Fisica Nucleare | INTRAOPERATIVE PROBE |
US11782175B2 (en) | 2015-08-10 | 2023-10-10 | Shanghai United Imaging Healthcare Co., Ltd. | Apparatus and method for PET detector |
US11378702B2 (en) | 2015-08-10 | 2022-07-05 | Shanghai United Imaging Healthcare Co., Ltd. | Apparatus and method for PET detector |
US10877169B2 (en) | 2015-08-10 | 2020-12-29 | Shanghai United Imaging Healthcare Co., Ltd. | Apparatus and method for pet detector |
US9696439B2 (en) | 2015-08-10 | 2017-07-04 | Shanghai United Imaging Healthcare Co., Ltd. | Apparatus and method for PET detector |
US9835740B2 (en) | 2015-08-10 | 2017-12-05 | Shanghai United Imaging Healthcare Co., Ltd. | Apparatus and method for PET detector |
US10338012B2 (en) * | 2016-03-09 | 2019-07-02 | Toshiba Medical Systems Corporation | Photon counting detector and X-ray computed tomography (CT) apparatus |
US20170261620A1 (en) * | 2016-03-09 | 2017-09-14 | Toshiba Medical Systems Corporation | Photon counting detector and x-ray computed tomography (ct) apparatus |
CN110520760A (en) * | 2017-03-13 | 2019-11-29 | 通用电气公司 | Pixel for radiation detector designs |
US11904184B2 (en) | 2017-03-30 | 2024-02-20 | Reflexion Medical, Inc. | Radiation therapy systems and methods with tumor tracking |
US11504550B2 (en) | 2017-03-30 | 2022-11-22 | Reflexion Medical, Inc. | Radiation therapy systems and methods with tumor tracking |
WO2018184251A1 (en) * | 2017-04-05 | 2018-10-11 | 博睿泰克科技(宁波)有限公司 | Method and device for brain functional imaging and brain tissue component detection |
US11270600B2 (en) * | 2017-05-16 | 2022-03-08 | United States Department Of Energy | Method and device for passive detection of physical effects |
US11675097B2 (en) | 2017-07-11 | 2023-06-13 | Reflexion Medical, Inc. | Methods for PET detector afterglow management |
US10795037B2 (en) * | 2017-07-11 | 2020-10-06 | Reflexion Medical, Inc. | Methods for pet detector afterglow management |
US11287540B2 (en) | 2017-07-11 | 2022-03-29 | Reflexion Medical, Inc. | Methods for PET detector afterglow management |
WO2019030507A1 (en) * | 2017-08-09 | 2019-02-14 | Lightpoint Medical, Ltd | Scintillator products, apparatuses and methods for use in autoradiographic imaging |
US11511133B2 (en) | 2017-08-09 | 2022-11-29 | Reflexion Medical, Inc. | Systems and methods for fault detection in emission-guided radiotherapy |
US11007384B2 (en) | 2017-08-09 | 2021-05-18 | Reflexion Medical, Inc. | Systems and methods for fault detection in emission-guided radiotherapy |
EP3691557A4 (en) * | 2017-10-02 | 2021-06-23 | Intuitive Surgical Operations, Inc. | Radiation finder tool |
WO2019070616A2 (en) | 2017-10-02 | 2019-04-11 | Intuitive Surgical Operations, Inc. | Radiation finder tool |
WO2019070616A3 (en) * | 2017-10-02 | 2019-05-16 | Intuitive Surgical Operations, Inc. | Radiation finder tool |
US11452489B2 (en) * | 2017-10-02 | 2022-09-27 | Intuitive Surgical Operations, Inc. | Radiation finder tool |
US11369806B2 (en) | 2017-11-14 | 2022-06-28 | Reflexion Medical, Inc. | Systems and methods for patient monitoring for radiotherapy |
US20200297294A1 (en) * | 2017-12-15 | 2020-09-24 | Lightpoint Medical, Ltd | Direct detection and imaging of charged particles from a radiopharmaceutical |
US11944344B2 (en) | 2018-04-13 | 2024-04-02 | Karl Storz Se & Co. Kg | Guidance system, method and devices thereof |
US11164315B2 (en) * | 2018-12-05 | 2021-11-02 | Stmicroelectronics S.R.L. | Image processing method and corresponding system |
US20220260730A1 (en) * | 2019-08-09 | 2022-08-18 | Kyungpook National University Industry-Academic Cooperation Foundation | Photosensor |
US11815632B2 (en) * | 2019-08-09 | 2023-11-14 | Kyungpook National University Industry-Academic Cooperation Foundation | Photosensor |
US20210177260A1 (en) * | 2019-12-13 | 2021-06-17 | NU-RISE Lda | Urinary catheter for detecting radiation |
US20210236848A1 (en) * | 2019-12-13 | 2021-08-05 | NU-RISE Lda | Urinary catheter for detecting radiation |
US11896844B2 (en) * | 2019-12-13 | 2024-02-13 | NU-RISE Lda | Urinary catheter for detecting radiation |
US11903672B2 (en) * | 2019-12-13 | 2024-02-20 | NU-RISE Lda | Urinary catheter for detecting radiation |
FR3113740A1 (en) * | 2020-08-31 | 2022-03-04 | Bertin Technologies | Beta particle detection device |
Also Published As
Publication number | Publication date |
---|---|
US8068896B2 (en) | 2011-11-29 |
US20100198061A9 (en) | 2010-08-05 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US8068896B2 (en) | Detection of radiation labeled sites using a radiation detection probe or camera incorporating a solid state photo-multiplier | |
Van Oosterom et al. | Recent advances in nuclear and hybrid detection modalities for image-guided surgery | |
US7373197B2 (en) | Methods and devices to expand applications of intraoperative radiation probes | |
US8050743B2 (en) | Positron emission detectors and configurations | |
Gulec et al. | PET-Probe: evaluation of technical performance and clinical utility of a handheld high-energy gamma probe in oncologic surgery | |
US6740882B2 (en) | Dedicated apparatus and method for emission mammography | |
US5519221A (en) | Dedicated apparatus and method for emission mammography | |
Scheiber | CdTe and CdZnTe detectors in nuclear medicine | |
US20120068076A1 (en) | Portable pet scanner for imaging of a portion of the body | |
US10178979B2 (en) | Endorectal prostate probe composed of a combined mini gamma camera and ultrasound sensor | |
JP2004512502A (en) | Radiation radiation detector with position tracking system and its use in medical systems and procedures | |
US10568560B2 (en) | Endorectal prostate probe with combined PET and US modalities | |
US20080208044A1 (en) | Combined nuclear and sonographic imaging apparatus and method | |
WO1994003108A1 (en) | Flexible intraoperative radiation imaging camera | |
Strong et al. | A novel method to localize antibody-targeted cancer deposits intraoperatively using handheld PET beta and gamma probes | |
US5965891A (en) | Dedicated apparatus and method for emission mammography | |
Kogler et al. | Evaluation of camera-based freehand SPECT in preoperative sentinel lymph node mapping for melanoma patients | |
Bogalhas et al. | Development of a positron probe for localization and excision of brain tumours during surgery | |
Piert et al. | Probe-guided localization of cancer deposits using [^ sup 18^ F] fluorodeoxyglucose | |
Kaviani et al. | Development and characterization of a compact hand-held gamma probe system, SURGEOGUIDE, based on NEMA NU3-2004 standards | |
Curtet et al. | Prospective comparison of two gamma probes for intraoperative detection of 18 F-FDG: in vitro assessment and clinical evaluation in differentiated thyroid cancer patients with iodine-negative recurrence | |
US20140276019A1 (en) | PET Imaging With Partially Radiation-Transparent Probes-Inserts | |
Soluri et al. | Small field of view, high-resolution, portable γ-camera for axillary sentinel node detection | |
Zanzonico | Instrumentation for Intraoperative Detection and Imaging | |
Shestakova et al. | Feasibility studies of an emccd-based beta imaging probe for radioguided thyroid surgery |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: INTRAMEDICAL IMAGING, LLC, CALIFORNIA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:DAGHIGHIAN, FARHAD;DAGHIGHIAN, HENRY;REEL/FRAME:019209/0249 Effective date: 20070406 |
|
ZAAA | Notice of allowance and fees due |
Free format text: ORIGINAL CODE: NOA |
|
ZAAB | Notice of allowance mailed |
Free format text: ORIGINAL CODE: MN/=. |
|
STCF | Information on status: patent grant |
Free format text: PATENTED CASE |
|
REMI | Maintenance fee reminder mailed | ||
FPAY | Fee payment |
Year of fee payment: 4 |
|
SULP | Surcharge for late payment | ||
FEPP | Fee payment procedure |
Free format text: 7.5 YR SURCHARGE - LATE PMT W/IN 6 MO, SMALL ENTITY (ORIGINAL EVENT CODE: M2555); ENTITY STATUS OF PATENT OWNER: SMALL ENTITY |
|
MAFP | Maintenance fee payment |
Free format text: PAYMENT OF MAINTENANCE FEE, 8TH YR, SMALL ENTITY (ORIGINAL EVENT CODE: M2552); ENTITY STATUS OF PATENT OWNER: SMALL ENTITY Year of fee payment: 8 |
|
AS | Assignment |
Owner name: INTRAMEDICAL IMAGING, LLC, CALIFORNIA Free format text: CHANGE OF ADDESS OF ASSIGNEE;ASSIGNORS:DAGHIGHIAN, FARHAD;DAGHIGHIAN, HENRY;REEL/FRAME:057394/0680 Effective date: 20070406 |
|
FEPP | Fee payment procedure |
Free format text: MAINTENANCE FEE REMINDER MAILED (ORIGINAL EVENT CODE: REM.); ENTITY STATUS OF PATENT OWNER: SMALL ENTITY |
|
LAPS | Lapse for failure to pay maintenance fees |
Free format text: PATENT EXPIRED FOR FAILURE TO PAY MAINTENANCE FEES (ORIGINAL EVENT CODE: EXP.); ENTITY STATUS OF PATENT OWNER: SMALL ENTITY |
|
STCH | Information on status: patent discontinuation |
Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362 |
|
FP | Lapsed due to failure to pay maintenance fee |
Effective date: 20231129 |