f r o m t h e l i t e r a t u r e

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FROM THE LITERATURE Each month the editor of Newsline selects articles on diagnostic, therapeu- tic, research, and practice issues from a range of international publications. Most selections come from outside the standard canon of nuclear medicine and radiology journals. These briefs are offered as a monthly window on the broad arena of medical and scientific endeavor in which nuclear medicine now plays an essential role. We have recently added a special section on molecular imaging, including both radionuclide-based and other molecular imaging efforts, in recognition of the extraordinary activity and promise of both diagnostic and therapeutic prog- ress in this area. The lines between diagnosis and therapy are sometimes blurred, as radiolabels are increasingly used as adjuncts to therapy and/or as active agents in therapeutic regimens, and these shifting lines are reflected in the briefs presented here. DIAGNOSIS –––––––––––––––––––– 99m Tc-DMSA Scintigraphy in Pediatric UTI Two articles e-published in October ahead of print focused on the conse- quences of pediatric urinary tract in- fections (UTIs) and efforts to assess risk factors for recurrence and complications. Both used 99m Tc-dimercaptosuccinic acid ( 99m Tc-DMSA) scintigraphy in exploring the characteristics of UTI in infants and children. Kotoula et al. from the Democritus University of Thrace School of Medicine (Alexandroupolis, Greece) reported on October 3 in International Urology and Nephrology on a study designed to establish the most reliable markers for identifying renal parenchymal involvement in UTIs in a group of 57 children (ages, 2–108 mo) admitted for a first episode of UTI. Among the markers evaluated were clinical features, admission leu- kocyte count, erythrocyte sedimenta- tion rate, C-reactive protein, and serum procalcitonin. Results were compared with the presence (27 children) or absence (30 children) of renal paren- chymal involvement as determined by 99m Tc-DMSA imaging. The authors found that serum procalcitonin had the best performance as an early predictive marker of renal parenchymal involve- ment, with sensitivity, specificity, and positive and negative predictive val- ues of 89%, 97%, 96%, and 91%, respectively. Shim et al. from the Ewha Womans University School of Medicine (Seoul, Korea) reported online on October 2 in Pediatric Nephrology on a study assess- ing risk factors for recurrent UTIs and subsequent renal scarring in infants with normal urinary systems. The study in- cluded 190 infants diagnosed with a first UTI. Along with UTI recurrence and other clinical features, the researchers gathered data on sex, age, phimosis, vaginal reflux, and acute pyelonephritis as assessed by 99m Tc-DMSA scintigra- phy. The recurrence rate within 1 y was 21.1%, with a significantly higher rate among children ,6 mo old (25.8%) than among those older (7.7%). In an in- cidental finding, the authors noted that recurrent UTI was seen in 34.0% of male infants with persistent nonretractile pre- puces, a percentage significantly higher than the 17.6% recurrence rate in other male infants. The authors concluded that for infants with normal urinary tract systems, the most significant factors for recurrence of a first UTI were age ,6m and the presence of a nonretractile pre- puce and/or acute pyelonephritis in males. They suggested that ‘‘nonretrac- tile prepuces should be adequately treated to become retractile in young male infants with acute pyelonephritis.’’ International Urology and Nephrology Pediatric Nephrology Recurrence Patterns in PET-Staged Colorectal Metastases Finkelstein et al. from Washington University in St. Louis (MO) and the affiliated Barnes-Jewish Hospital re- ported in the September issue of the Journal of Hepato-Biliary-Pancreatic Surgery (2008;15:483–487) on addi- tional data stemming from a previously reported study showing excellent 5-y survival rates in patients staged with 18 F-FDG PET before liver resection for metastatic colorectal cancer (Ann Surg. 2004;240:438–447). The current study focused on site- and time-specific patterns of recurrence in these patients and compared the results with control data derived from a literature search of all published case series of convention- ally staged patients. The study included 100 patients who underwent 18 F-FDG PET before hepatic resection for co- lorectal cancer metastases. Of these, 48 patients had no evidence of recurrence, 30 had recurrence within 1 y of re- section, and 22 had recurrence after 1 y. Of those who had recurrence within 1 y, 70% experienced intrahepatic recur- rence, whereas 86% of patients with recurrence .1 y after resection had extrahepatic recurrence, a pattern that was not to be found in reports of conventionally staged patients. The authors posited 2 potentially converging factors to explain the difference in pattern results in PET and conventional staging: (1) that 18 F-FDG PET more effectively detects extrahepatic disease than conventional staging; and (2) that liver resection may contribute to a growth spurt in hepatic metastases. Journal of Hepato-Biliary-Pancreatic Surgery Prestransplant PET in Aggressive B-Cell NHL In an article e-published on October 2 ahead of print in Cancer , Derenzini et al. from the University of Bologna (Italy) reported on a study designed to identify the main determinants of prog- nosis in patients with aggressive B-cell non-Hodgkin’s lymphoma (NHL) who undergo autologous stem cell transplan- tation. Among the factors considered were pretransplantation 18 F-FDG PET, secondary age-adjusted International Newsline 31N NEWSLINE

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Page 1: F R O M T H E L I T E R A T U R E

F R O M T H E L I T E R A T U R E

Each month the editor of Newslineselects articles on diagnostic, therapeu-tic, research, and practice issues froma range of international publications.Most selections come from outside thestandard canon of nuclear medicine andradiology journals. These briefs areoffered as a monthly window on thebroad arena of medical and scientificendeavor in which nuclear medicinenow plays an essential role. We haverecently added a special section onmolecular imaging, including bothradionuclide-based and other molecularimaging efforts, in recognition of theextraordinary activity and promise ofboth diagnostic and therapeutic prog-ress in this area. The lines betweendiagnosis and therapy are sometimesblurred, as radiolabels are increasinglyused as adjuncts to therapy and/or asactive agents in therapeutic regimens,and these shifting lines are reflected inthe briefs presented here.

DIAGNOSIS ––––––––––––––––––––

99mTc-DMSA Scintigraphyin Pediatric UTI

Two articles e-published in Octoberahead of print focused on the conse-quences of pediatric urinary tract in-fections (UTIs) and efforts to assess riskfactors for recurrence and complications.Both used 99mTc-dimercaptosuccinicacid (99mTc-DMSA) scintigraphy inexploring the characteristics of UTI ininfants and children. Kotoula et al. fromthe Democritus University of ThraceSchool of Medicine (Alexandroupolis,Greece) reported on October 3 inInternational Urology and Nephrologyon a study designed to establish themost reliable markers for identifyingrenal parenchymal involvement inUTIs in a group of 57 children (ages,2–108 mo) admitted for a first episodeof UTI. Among the markers evaluatedwere clinical features, admission leu-kocyte count, erythrocyte sedimenta-tion rate, C-reactive protein, and serumprocalcitonin. Results were compared

with the presence (27 children) orabsence (30 children) of renal paren-chymal involvement as determinedby 99mTc-DMSA imaging. The authorsfound that serum procalcitonin had thebest performance as an early predictivemarker of renal parenchymal involve-ment, with sensitivity, specificity, andpositive and negative predictive val-ues of 89%, 97%, 96%, and 91%,respectively.

Shim et al. from the Ewha WomansUniversity School of Medicine (Seoul,Korea) reported online on October 2 inPediatric Nephrology on a study assess-ing risk factors for recurrent UTIs andsubsequent renal scarring in infants withnormal urinary systems. The study in-cluded 190 infants diagnosed with a firstUTI. Along with UTI recurrence andother clinical features, the researchersgathered data on sex, age, phimosis,vaginal reflux, and acute pyelonephritisas assessed by 99mTc-DMSA scintigra-phy. The recurrence rate within 1 y was21.1%, with a significantly higher rateamong children ,6 mo old (25.8%) thanamong those older (7.7%). In an in-cidental finding, the authors noted thatrecurrent UTI was seen in 34.0% of maleinfants with persistent nonretractile pre-puces, a percentage significantly higherthan the 17.6% recurrence rate in othermale infants. The authors concluded thatfor infants with normal urinary tractsystems, the most significant factors forrecurrence of a first UTI were age ,6 mand the presence of a nonretractile pre-puce and/or acute pyelonephritis inmales. They suggested that ‘‘nonretrac-tile prepuces should be adequatelytreated to become retractile in youngmale infants with acute pyelonephritis.’’

International Urology and NephrologyPediatric Nephrology

Recurrence Patterns inPET-Staged ColorectalMetastases

Finkelstein et al. from WashingtonUniversity in St. Louis (MO) and theaffiliated Barnes-Jewish Hospital re-

ported in the September issue of theJournal of Hepato-Biliary-PancreaticSurgery (2008;15:483–487) on addi-tional data stemming from a previouslyreported study showing excellent 5-ysurvival rates in patients staged with18F-FDG PET before liver resectionfor metastatic colorectal cancer (AnnSurg. 2004;240:438–447). The currentstudy focused on site- and time-specificpatterns of recurrence in these patientsand compared the results with controldata derived from a literature search ofall published case series of convention-ally staged patients. The study included100 patients who underwent 18F-FDGPET before hepatic resection for co-lorectal cancer metastases. Of these, 48patients had no evidence of recurrence,30 had recurrence within 1 y of re-section, and 22 had recurrence after 1 y.Of those who had recurrence within 1 y,70% experienced intrahepatic recur-rence, whereas 86% of patients withrecurrence .1 y after resection hadextrahepatic recurrence, a pattern thatwas not to be found in reports ofconventionally staged patients. Theauthors posited 2 potentially convergingfactors to explain the difference inpattern results in PET and conventionalstaging: (1) that 18F-FDG PET moreeffectively detects extrahepatic diseasethan conventional staging; and (2) thatliver resection may contribute to agrowth spurt in hepatic metastases.

Journal of Hepato-Biliary-PancreaticSurgery

Prestransplant PET inAggressive B-Cell NHL

In an article e-published on October2 ahead of print in Cancer, Derenziniet al. from the University of Bologna(Italy) reported on a study designed toidentify the main determinants of prog-nosis in patients with aggressive B-cellnon-Hodgkin’s lymphoma (NHL) whoundergo autologous stem cell transplan-tation. Among the factors consideredwere pretransplantation 18F-FDG PET,secondary age-adjusted International

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Prognostic Index score, histology, andprevious response to first-line chemo-therapy. The study included 75 patientswith diffuse, large B-cell lymphoma orgrade 3 follicular lymphoma who weretreated with second-line chemotherapyfollowed by autologous stem cell trans-plantation(inonly72patients).Allpatientsunderwent PET imaging after 1–3 coursesof chemotherapy and before stem celltransplantation. Subsequent analyses de-termined that pretransplantation PETwas the only significant independentprognostic factor for progression-freesurvival and overall survival.

Cancer

11C-Methionine PET inLiver Transplantation

Otsuki et al. from the National Chiba-East Hospital (Japan) reported in theOctober issue of Transplantation Pro-ceedings (2008;40:2562–2564) on theutility of 11C-methionine PET for theevaluation of segmental pancreatic func-tion before and after distal pancreatec-tomy in patients with pancreatic diseaseand in living donors for pancreas trans-plantation. In each individual, traceruptake by the pancreatic head was ex-pressed as a standardized uptake value(SUV), with comparisons between pre-and postsurgical SUVs. Before distalpancreatectomy, the SUVs of the pancre-atic head in patients and donors were15.3 6 6.0 and 16.1 6 1.0, respectively.These respective SUVs were 18.2 6 2.4and 14.7 6 1.4 after surgery. Although nosignificant differences were noted aftersurgery in either group, the SUVs of theresidual pancreatic head were elevated in80% of patients and 50% of donors. Theauthors concluded that these data suggestthat ‘‘the function of the pancreatic headmay be maintained or improved afterdistal pancreatectomy’’ and that 11C-methionine PET may become ‘‘a potentmodality to evaluate segmental pancreaticfunction for a safe living donor operation.’’

Transplantation Proceedings

PET in NHL Bone MarrowInvolvement

In the October issue of the AmericanJournal of Clinical Oncology (2008;31:

409–412), Muslimani et al. from theCleveland Clinic at Fairview Hospital(OH) reported on the use of 18F-FDGPET to accurately assess the presenceof bone marrow involvement in non-Hodgkin’s lymphoma (NHL). The studyincluded 97 patients with histologicallyproven NHL. Each patient underwent18F-FDG PET imaging for initial stag-ing, as well as unilateral posterior iliaccrest bone marrow biopsy. The authorsfound an overall sensitivity and speci-ficity for 18F-FDG PETof 79% and 91%,respectively, in detecting bone marrowinvolvement, regardless of the typeof NHL (indolent or aggressive/highlyaggressive). They concluded that18F-FDG PET shows potential for theroutine detection of bone marrow in-volvement in NHL. They noted thatimage-guided repeat bone marrow bi-opsy should be considered in patientswith negative initial iliac crest bonemarrow biopsy and whose PET scansshow bone marrow involvement ina different site.

American Journal of ClinicalOncology

PET in Oral CavitySquamous Cell Carcinoma

Liao et al. from Chang GungMemorial Hospital and Chang GungUniversity (Taoyuan, Taiwan) reportedon October 2 ahead of print in theInternational Journal of RadiationOncology, Biology, Physics on thecapabilities of primary tumor standard-ized uptake values (SUVs) obtained onpreoperative 18F-FDG PET imaging topredict outcomes in patients with oralcavity squamous cell carcinoma andpathologically positive lymph nodes.The study included 109 such patientswho underwent 18F-FDG PET imagingwithin 2 wk before surgery and neckdissection, with 24-mo follow-up ordeath within that period as endpoints(26-mo median follow-up for all pa-tients; 39 mo for surviving patients). AnSUVmax of 19.3 and tumor depth $12mm provided the greatest prognosticinformation for the 5-y local controlrate. The authors found that the 8patients with both an SUVmax $19.3

and tumor depth $12 mm had signif-icantly poorer 5-y local control, dis-ease-free, disease-specific, and overallsurvival rates than other patient groups.They concluded that the combination ofprimary tumor SUVmax and pathologictumor depth was able to identify ‘‘asubgroup of oral cavity squamous cellcarcinoma patients at greatest risk ofpoor local control and death.’’

International Journal of RadiationOncology, Biology, Physics

PET and Laparoscopy inRecurrent Ovarian Cancer

In an article published in the October1 issue of Oncology (2008;75:152–158),Fagotti et al. from the Catholic Univer-sity of the Sacred Heart (Rome, Italy)reported on a study investigating theroles of 18F-FDG PET/CT and laparos-copy in optimal diagnostic and stagingstrategies for recurrent ovarian cancer.The study included 70 patients withrecurrent ovarian cancer who underwentboth PET/CTand laparoscopy. Negativeand positive predictive values, specific-ity, sensitivity, and accuracy rates witheach technique were compared, as werethe numbers of nodules accuratelyidentified. The negative and positivepredictive values, specificity, sensitivity,and accuracy of PET/CT were 83.3%,76.9%, 55.6%, 93.0%, and 78.6%,respectively. Corresponding respectivevalues for staging laparoscopy were88.9%, 64.0%, 80.8%, 95.0%, and83.1%. Combined, the 2 techniquesshowed negative and positive predictivevalues of 88.9% and 78.8%, respec-tively, and specificity, sensitivity, andaccuracy of 59.3%, 95.3%, and 81.4%,respectively. Staging laparoscopy wasmore capable than PET in identifyinginvolved nodules (50.0% and 40.3%,respectively). The authors concludedthat the combination of PET/CT andstaging laparoscopy ‘‘has a significanteffect on the multimodal approach to thepopulation of patients with recurrentovarian cancer’’ and that ‘‘such techni-ques should be considered complemen-tary’’ because of the potential of each indifferent settings of the disease.

Oncology

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Post-RT PET in Head andNeck Cancer

Yao et al. from the UniversityHospitals Case Medical Center (Cleve-land, OH) reported on October 16 in theInternational Journal of Radiation On-cology, Biology, Physics on the accuracyand long-term prognostic abilities of18F-FDG PET in squamous cell carci-noma of the head and neck after ra-diation therapy. The study includeda retrospective review of the records of188 patients with head and neck squa-mous cell carcinoma who had under-gone PET imaging within 1 y ofintensity-modulated radiation therapy(128 with definitive and 60 with post-operative intensity-modulated therapy).Median follow-up times after radiationtherapy and PET imaging were 32.6 and29.2 mo, respectively. PET findings inthe neck were negative in 171 (2 false-negative) and positive in 17 (12 true-positive) patients. Sensitivity, specificity,and positive and negative predictivevalues in assessment of treatment re-sponse in the neck were 86%, 97%,71%, and 99%, respectively. PET find-ings in the primary site were negative in151 patients (2 false-negatives)and pos-itive in 37 patients (12 true-positives).Sensitivity, specificity, and positive andnegative predictive values in assessmentof treatment response in the primarysite were 86%, 86%, 32.4%, and 98.7%,respectively. Patients with positive PETfindings after radiation therapy hadsignificantly worse 3-y overall survivaland disease-free survival rates. Theauthors concluded that these results sug-gest that PET has a high negative pre-dictive value and ‘‘can provide guidancefor the management of head-and-neckcancer after definitive treatment.’’

International Journal of RadiationOncology, Biology, Physics

THERAPY –––––––––––––––––––––

Derlin-1 Role in Tumor-Targeting Therapy

Ran et al. from the Peking UnionMedical College (Beijing, People’sRepublic of China) reported in the

October 15 issue of Clinical Cancer Re-search (2008;14:6538–6545) on a studyof the potential role of the channel-likeprotein derlin-1 in antibody-mediatedtumor targeting therapy. The authorsfirst demonstrated the cell surface ex-pression of derlin-1 with immunofluo-rescent analysis of nonpermeabalizedcells and Western blotting of fractionalproteins of tumor cells. Immunochem-istry confirmed derlin-1 expression incancerous tissues. After the protein wasradiolabeled with 125I, biodistributionanalyses and scintigraphy were per-formed in injected isogenic mice mod-els. Tumor-bearing mice were treatedwith anti-derlin-1 poly- and monoclo-nal antibodies. Although robust cyto-plasmic and membrane expression ofderlin-1 was detected in various typesof human cancer tissues, this was notcorrelated with the clinicopathologicfeatures of pancreatic cancer. Derlin-1–directed antibodies successfully tar-geted colon tumors and significantlysuppressed tumor growth. The authorsconcluded that these preclinical datashowed ‘‘that derlin-1 protein is a func-tional molecular target expressed on thetumor cell surface and is a candidatetherapeutic target that may be trans-lated into clinical applications.’’

Clinical Cancer Research

Enhancing 177Lu-Based RITin Protate Cancer

In an article e-published on October21 ahead of print in Prostate, Kelly et al.from the Austin Hospital (Heidelberg,Australia) reported on a study explor-ing the biodistribution and therapeuticefficacy of 177Lu-labeled anti-Lewis Ymonoclonal antibody hu3S193 radio-immunotherapy (RIT) in mice bearingprostate cancer xenografts. In addition,potential enhancements provided bythe epidermal growth factor receptor(EGFR) tyrosine kinase inhibitorAG1478 and by docetaxel chemother-apy were assessed. The cytotoxicity ofthe radiolabeled agent was assessedusing proliferative assays in Lewis-Ypositive DU145 prostate cancer cells,and induction of apoptosis was mea-sured by enzyme-linked immunosorbent

assay. Results showed that 177Lu-hu3S193 mediated significant inductionof cytotoxicity and apoptosis. Bothbiodistribution and tumor localizationof the agent were studied in mice bearingDU145 tumor xenografts, with a doseescalation study used to assess efficacyand maximum tolerated dose. Thesemouse studies showed specific targetingof DU145 prostate cell xenografts, withmaximum tumor uptake of 33.2 6 3.9%ID/g at 120 h after injection. 177Lu-hu3S193 caused specific and dose-dependent inhibition of prostate cancertumor growth, with a maximum toler-ated dose of 350 mCi. When eitherEGFR inhibitor AG1478 or docetaxelchemotherapy was administered at sub-therapeutic doses with RIT, efficacy wassignificantly improved. The authorsconcluded that ‘‘177Lu-hu3S193 RITis effective as a single agent in thetreatment of Lewis-Y positive prostatecancer models’’ and that the ‘‘enhance-ment of RIT by AG1478 or docetaxelindicates the promise of combinedmodality strategies.’’

Prostate

MOLECULAR IMAGING –––––––

Imaging T–B CellInteractions

Qi et al. from the National Instituteof Allergy and Infectious Diseases(Bethesda, MD) reported in the October9 issue of Nature (2008;455:764–769)on a study using 2-photon intravitalimaging to explore the mechanismsunderlying defects in germinal centerformation, a crucial element in thegeneration of long-term antibody-mediated immunity that involves co-operation between antigen-specific Tand B lymphocytes. Molecular imagingindicated that loss-of-function muta-tions in the signaling lymphocyte ac-tivation molecule–associated proteinand resulting deficiencies selectivelyimpaired the ability of T cells to stablyinteract with cognate B cells but notwith antigen-presenting dendritic cells.These loss of function mutations arecommon in human X-linked lympho-proliferative disease and the gene-

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targeted mouse model explored in thisstudy, and result in a failure of antigen-specific B cells to receive adequatelevels of contact-dependent T-cell helpto expand normally. In addition, thelack of stable interactions with B cellsrenders signaling lymphocyte activationmolecule–associated protein T cellsunable to be efficiently recruited to andretained in a nascent germinal center aspart of the germinal center reaction. Theauthors concluded that these results‘‘offer an explanation for the germinalcenter defect due to signaling lympho-cyteactivationmolecule–associatedpro-tein deficiency and provide new insightsinto the bidirectional communicationbetween cognate T and B cells in vivo.’’

Nature

MR and Integrin-TargetedNanoparticles inAngiogenesis

Waters et al. from the WashingtonUniversity School of Medicine (St.Louis, MO) reported on September25 ahead of print in the Journal ofCardiovascular Magnetic Resonanceon a study of the specific binding ofanb3 integrin–targeted nanoparticles toneovasculature in a rabbit model ofaortic valve disease. The study alsofocused on the ability of fluorine-labeled MR techniques to detect andquantify neovasculature in excisedvalve leaflets. The experiment included16 New Zealand white rabbits that werecholesterol fed for ;6 mo to promotethe development of aortic valve thick-ening, inflammation, and angiogenesismimicking early human aortic valvedisease. Ten animals were treated withanb3 integrin–targeted perfluorocarbonnanoparticles, and 6 controls weretreated with untargeted perfluorocar-bon nanoparticles. At 2 h after treat-ment, the aortic valves were removedfrom 6 of the integrin-targeted animalsand all 6 of the control animals. Thevalves were imaged with 19F MRspectroscopy. The remaining 3 rabbitstreated with anb3 integrin–targetednanoparticles underwent 19F MR spec-troscopy on a clinical scanner. Allresults were compared with angiogen-

esis determined by immunohistochem-istry. The researchers found that thevalves of animals treated with targetednanoparticles had 220% more fluorinesignal than those of animals treatedwith untargeted nanoparticles. Nano-particles were also successfully de-tected in all samples scanned on theclinical scanner. Immunohistochemis-try confirmed the presence of angio-genesis in all sampled valves. Theauthors concluded that because theseintegrin-targeted nanoparticles specifi-cally detect early angiogenesis insclerotic aortic valves of cholesterol-fed rabbits, these techniques ‘‘may beuseful for assessing atheroscleroticcomponents of preclinical aortic valvedisease in patients and could assist indefining efficacy of medical therapies.’’They added that although questionsremain about specifically what to imageas meaningful biomarkers of earlyvalve disease, a variety of moleculesand cell types are potentially targetableand may prove complementary inelucidating complex pathologies.

Journal of Cardiovascular MagneticResonance

IL-18–Binding Protein-FcTherapy

In an article in the October 1 issueof Clinical Cancer Research (2008;14:6137–6145), Cao et al. from theStanford University School of Medi-cine (CA) reported on a study designedto use multimodality molecular imag-ing to identify cell lines that are mostsensitive to standalone interleukin-18–binding protein (IL-18bp)-Fc treat-ment, to study the pharmacokineticsand tumor targeting efficiency ofIL-18bp-Fc, and to assess the efficacyof IL-18bp-Fc in treating experimentalbreast cancer metastases to the lung. Arange of murine cells were assayed todetermine that 4T1 cells had the great-est sensitivity to IL-18bp-Fc. 4T1 cellswere stably transfected with fireflyluciferase and injected into mice toestablish an experimental lung metas-tasis model. Animals underwent 64Cu-DOTA-IL-18bp-Fc PET to assess bio-distribution, pharmacokinetics, and

tumor targeting efficiency. Animalswere divided into 2 groups and admin-istered either intraperitoneal saline orIL-18bp-Fc daily. Animals then un-derwent bioluminescence imaging,18F-FDG PET, and CT imaging toassess treatment results. These resultswere compared with histopathologyand other ex vivo studies. The research-ers found that PET showed high andspecific IL-18bp-Fc accumulation inthe luciferase-injected 4T1 lung metas-tasis tumors and that all 3 imagingmodalities indicated that IL-18bp-Fctreatment was effective in inhibitinglung metastasis tumor progression. Theauthors concluded that IL-18bp-Fctherapy can inhibit experimental breastcancer lung metastasis and that ‘‘non-invasive multimodality molecularimaging is a powerful tool for evalu-ating the tumor targeting efficiency/pharmacokinetics of the drug andeffective monitoring of the therapeuticresponse.’’

Clinical Cancer Research

Imaging MMPs in VascularRemodeling

Zhang et al. from the Yale Univer-sity School of Medicine (New Haven,CT), the VA Connecticut HealthcareSystem (West Haven), and LantheusMedical Imaging (North Billerica, MA)reported on October 20 ahead of print inCirculation on a study of 111In-labeledmolecular imaging of activated matrixmetalloproteinases (MMPs) in vascularremodeling. RP782, a novel indium111In-labeled tracer with specificity foractivated MMPs, was used to detectinjury-induced vascular remodeling ina mouse model. Carotid wire injury wasinduced in 1 group of apolipoproteinE-/- mice, with sham surgery performedin controls. Carotid wire injury led tosignificant hyperplasia and remodelingover the following 4 wk. MMP activity,detected by in situ zymography, in-creased after injury, reaching a maxi-mum at 3–4 wk. Mice were imaged withRP782 microSPECT and CT angiogra-phy at 1, 2, 3, and 4 wk after carotidinjury or sham surgery. Focal uptake ofRP782 was seen in the injured artery on

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microSPECT at 2, 3, and 4 wk. Pre-treatment with excess nonlabeled tracersignificantly reduced RP782 uptake,indicating uptake specificity. Serialchanges in the vessel wall area corre-lated closely with RP782 uptake. Theauthors concluded that RP782 micro-SPECT can detect injury-induced MMPactivation in the vessel wall and track thehyperplastic process in vascular remod-eling, a technique with clinical promisefor tracking the remodeling processin vivo.

Circulation

Quantum Dot Nanosensorsand Protease Activity

In an article e-published on October16 ahead of print in Analytical Chemistry,Xia et al. from the Stanford UniversitySchool of Medicine and the StanfordNanocharacterization Laboratory (CA)reported on the development of a proteasesensing nanoplatform based on semi-conductor nanocrystals/quantum dotsand on the use of bioluminescence reso-nance energy transfer (BRET) to detectprotease activity in complex biologicsamples. The nanosensors function withbioluminescent proteins as the BRETdonor, quantum dots as the BRET ac-ceptor, and protease substrates betweenthe 2 as a sensing group. The authorsdescribe the use of an intein-mediated(protein slicing) conjugation strategy forsite-specific conjugation of proteins toquantum dots in these nanosensors. Aseries of quantum dot nanosensors weresynthesized for highly sensitive detectionof an important class of protease matrixmetalloproteinase (MMP) activity. Theyshowed that these nanosensors can detectMMP activity in buffers and in mouseserum with a sensitivity down to a fewnanograms per milliliter. The authorsalso showed the suitability of these

nanosensors for multiplex protease assay.The advantages of this approach overfluorescence-based quantum dot nano-sensors were reviewed, including smallsize and enhanced reliability and sensi-tivity. They concluded that this intein-mediated conjugation method shouldwork with other nanoparticles.

Analytical Chemistry

Real-Time Sensing ofInflammation inAtherosclerosis

Jaffer et al. from the MassachusettsGeneral Hospital Center for MolecularImaging Research (Boston) reportedon October 13 ahead of print inCirculation on the development ofa near-infrared fluorescence (NIRF)catheter-based strategy for sensingcysteine protease activity during vas-cular catheterization. The catheter de-sign was based on that of a clinicalcoronary artery guidewire and wastested in phantom studies and in a rabbitmodel of atherosclerosis. In rabbitsinjected with a cysteine protease-activatable NIRF imaging agent, cath-eter pullbacks through the blood-fillediliac artery detected NIRF signals 24 hlater. Saline flush-modulated NIRF sig-nal profiles also distinguished athero-mata from normal segments invivo, anda good correlation was seen betweenin vivo and ex vivo plaque target-to-background ratios. Histopathologicanalyses confirmed strong NIRF signalin plaques, a finding absent in plaquesfrom a control group not injected withthe protease agent. In addition, NIRFsignals colocalized with immunoreac-tive macrophages and the cysteineprotease cathepsin B. The authorsconcluded that because their intravas-cular fluorescence catheter can provide

real-time NIRF detection of cysteineprotease activity in vessels the size ofhuman coronary arteries, this strategycould aid in the clinical detection ofinflammation and high-risk plaques insmall arteries.

Circulation

1H/31P MRS Imaging inCarotid Stenosis

Hattingen et al. reported on October15 ahead of print in MAGMA on a studydesigned to determine whether com-bined 1H and 31P MR spectroscopic(MRS) imaging before and after treat-ment of severe internal carotid artery(ICA) stenosis can identify significantchanges in energy metabolism in thebasal ganglia of both hemispheres. Thestudy included 14 patients with high-grade ICA stenoses and 11 healthycontrols, all of whom underwent 2D 1Hand 3D 31P MRS imaging before andafter treatment. Data elements comparedin the 2 groups of subjects and in patientsbefore and after surgery included changesin phosphorylated metabolites, pH,N-acetyl-acetate, creatine, and choline-containing compounds. The researchersfound that patients had significantlyhigher adenosindiphosphate (ADP) inbasal ganglia ipsi- and contralateral tothe side of stenosis than controls. ADPof both hemispheres significantly de-creased (;20%) after treatment, as didphosphorylated metabolites. The au-thors concluded that these results in-dicate that unilateral high-grade ICAstenosis has an effect on cerebral high-energy metabolism in both hemi-spheres, an effect that is partiallyreversible after treatment. This sug-gests that ‘‘the restoration of blood flowin high-grade ICA stenosis recovers theimpaired energy balance of the brain.’’

MAGMA

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