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Official journal of Pakistan Society of Nuclear Medicine

Qaisar Hussain Siraj

Dr Khalid NawazDr Ahmad QureshyDr Abida RazaDr Shoaib Shah

Dr Maseeh uz ZamanDr Akhtar AhmedDr M Babar ImranDr Sadiq Hussain Nohario

Pakistan Journal ofNuclear Medicine

Prof A H Elgazaar, KuwaitProf S Rasoul Zakavi, IranProf Durval C Costa, PortugalProf Henry Bom, S KoreaProf Ajit K Padhy, SingaporeDr Kottekatu K Balan, UKProf G S Pant, Saudi ArabiaProf Omar Alonso, UruguayDr John R Buscombe, UK

Dr Frederic Fahey, USAProf Giuliano Mariani, ItalyDr G M Shah, Saudi ArabiaDr Thomas Pascal, PhilippinesProf Ali Nawaz Khan, UKDr Michael A Masoomi, UKDr Jamshed B Bomanji, UKProf Richard Underwood, UKProf A J B McEwan, Canada

Dr Humayun BashirDr Saima HaiderDr Nasir MahmoodDr H Ghulam AbbasDr Mujahid Khalid AliDr Riffat HussainDr Syed Shahid IqbalDr Shahab Fatimi

Dr Mohammad SohaibDr Mohsin Saeed SheikhDr Amjad Aziz KhanDr M Numair YounisMr Asdar ul HaqMr Farrukh HameedDr M Adnan SaeedDr Saima Riaz

Dr Ghazal Jameel (Publication Secretary)

P JNMQaisar Hussain SirajDurr-e-Sabih

REVIEW ARTICLE

Paving the way for modality choice of the future: challenges and expectations of the firstsimultaneous wholebody PETMRI molecular imaging in the UK Michael Masoomi, GeorgiosNtentas and Lawrence Foulsham

ORIGINAL ARTICLES

Efficacy of motioncorrection in absolute quantification of colonic PETCT for drugresponse therapy Michael Masoomi, Andy Robinson, Yassine Bouchareb, Seyedali Hejazi andNicholas M Spyrou

Exposure rate patterns in 131I therapy inpatients at NIMRA Jamshoro: an 08year studySajjad A Memon, Naeem A Laghari, Sadaf T Qureshi, Fayaz Ahmad, Atif Masood and Shahid Iqbal

Study of normal biodistribution and uptake patterns of novel anticancerradiopharmaceutical complex 99mTcMethotrexate Rashid Rasheed, Muhammad Javed,FayyazAhmad, Asima Sohail, Sohail Murad, Misbah Masood, Shahid Rasheed, Saqib Rasheed, Babar Imranand Simab Shaheen

Assessment of regional cerebral blood flow in major depressive illness by radionuclidebrain perfusion SPECT Saima Riaz, Fida Hussain, Amin Waqar, MK Ali and F Minhas

CASE REPORTS

Movahed's sign in chronic thromboembolic pulmonary embolism Humayun Bashir andGregory Shabo

A case of left Bochdalek hernia Qaisar H Siraj, Rasha M AlShammeri and Osama Ragab

A case of right Bochdalek hernia DurreSabih and Kashif Rahim

SPECTCT of an unsuspected ischial tuberosity avulsion fracture. Rasha AlHusseini and Qaisar H Siraj

SPECTCT of peritonealscrotal leakage in patients on continuous ambulatory peritonealdialysis Anwar AlBanna, Qaisar H Siraj, Uzma Afzal and Eiman AlAwadi

Mediastinal spread of medullary thyroid carcinoma imaged by locally formulated99mTc DMSA (V) Aakif Ullah Khan, Hameedullah*, Aamir Bahadur, Muhammad Rauf Khattak andAbdus Saeed ShahIMAGING GAMUTSMyocardial uptake of 99mTcMDP in infective endocarditis Hasan Raza, Zafar Nasir* andShahid Kamal

SPECTCT diagnosis of temporomandibular joint infection secondary to otitis externaAmir Javaid, Rasha M AlShammeri, Qaisar H Siraj and Anwar AlBanna

Unilateral decreased gallium limb uptake in poliomyelitis Eiman AlAwadi*and Qaisar H Siraj

The 'signet ring� sign on 99mTcMAG3 renal scan Anthony D'Sa*, Marina Easty and LorenzoBiassoni

Multiple osteomyelitis with septic arthritis on a 3phase bone scanMasha Maharaj, Alexandra Frankl, Elise Kuwa, Xolani Mqhayisa, Farzana Rasool, Jacob Manamela andElizabeth Kgakgudia

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Paving the way for modality choice of thefuture: challenges and expectations of the firstsimultaneous wholebody PETMRI molecular

imaging in the UKMichael Masoomi1,3,*, Georgios Ntentas2,3,

Lawrence Foulsham4

1Department of Nuclear Medicine, Farwania Hospital, Kuwait2Department of Medical Physics, Kings College Hospital, London, UK3Department of Medical Physics, University of Surrey, Guildford, UK4Imaging and Oncology Systems, Siemens Healthcare Solutions, UK

REVIEW ARTICLE

*Correspondence

Dr Michael A Masoomi Department of Nuclear Medicine Farwaniya Hospital PO Box 18373, Kuwait 81004 Email: [email protected]

Abstract Following the success of PETCTin the last decade, there have been highexpectations regarding the development ofnew hybrid imaging modalities such as PETMRI. After years of development, the firstsimultaneous, fully integrated, wholebodyPETMRI scanner has been released and firstclinical results have been published.

PETMRI offers numerous advantages such asexcellent softtissue contrast, significantlylower radiation dose than PETCT and a widevariety of functional MR imaging combinedwith PET. However, there are some technicaland operational challenges to be addressed.The main objectives of this study were toreview the challenges and expectations in theinstallation, siting, and patient serviceprovision of the Biograph mMR, the firstsimultaneous wholebody PETMRI systeminstalled in the UK and to underline the variousfeasible solutions.

The paper incorporates an extensive literaturereview, several visits to the installation siteand productive discussions with associatedscientists and Siemens Healthcare (BiographmMR manufacturer). With regards to roomshielding and siting requirements, severalunique characteristics were observed as theyhad to meet the local regulations for both thePET and the MRI components. Local patientservice provision requirements wereaddressed through developing new clinicalexamination protocols and through additionalsafety considerations. Further research will benecessary for optimising these proceduresand to ensure widespread clinical adoption ofthe PETMRI imaging system.

Key words: Simultaneous PETMRI,Biograph mMR, integrated PETMRI system

Introduction

The last decade has seen remarkable developmentsin hybrid medical imaging technology. The scientificcommunity and the healthcare industry have bothshown an increasing interest in research in the fieldand serious investments have been made in orderto produce cuttingedge multimodality imagingsystems.

PJNM 2013, 3:121 331691 © 2013 Pakistan Society of Nuclear Medicine

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PJNM 2013, Volume 3, Number 1 2

Imaging modalities such as computedtomography (CT), singlephoton emissioncomputed tomography (SPECT), positronemission tomography (PET), and magneticresonance imaging (MRI) are well known fortheir unique role in current diagnosticmedicine. Integration of these imagingmodalities in hybrid imaging systems cansignificantly improve the diagnostic yield. Theoverwhelming success of PETCT is evidencedby the fact that the hybrid PETCT has nowdisplaced the standalone PET systems [1].Although PETCT provides extremely usefulclinical data, it has some limitations anddrawbacks such as a high radiation dose andpoor softtissue contrast. Consequently, theidea of combining PET with MRI, for thelatter's null ionising radiation dose andexcellent softtissue contrast was conceivedso as to overcome these limitations. It wasfirst proposed at approximately the same timeas PETCT, i.e. early 1990s [2].

The combination of PET with MRI has anumber of advantages over other hybridimaging modalities. The superior diagnosticinformation regarding softtissue analysis,tissue characterisation, tumour staging andsome functional imaging that MRI provides,combined with the high sensitivity offunctional imaging of PET, offers an excellentdiagnostic tool. However, its technicaldevelopment and clinical application is stillvery challenging. Various aspects such asattenuation correction, bodymotion, MRcompatible detection systems and installationand workflow challenges need furtherresearch and innovative solutions beforePETMRI will be fully introduced forwidespread clinical practice.

This study initially provides a generaltheoretical background regarding hybridimaging and in particular, PETMRItechnology, and identifies and presents theadvantages and the challenges of thisadvanced technology in the delivery of clinicalservices of the first fullyintegrated andsimultaneous PETMRI system in the UK.

Hybrid imaging

In diagnostic imaging, there is a strongreliance on anatomically based techniquessuch as Xrays, MRI, ultrasound and CT,whereas this is not always the case formolecular or functional imaging techniques.Clinicians often tend to describe nuclearmedicine techniques using the popular epithetof 'unclear medicine� [3] which is due in partto the poor spatial resolution of functionalimaging, giving the impression that it issomehow less valid than radiologicaltechniques. Additionally, the complexity of theprinciples behind functional imaging such ascompartmental models, timeactivity curvesand deconvolutional analysis might be beyondcommon understanding. However, molecularand functional imaging provides significantdiagnostic information regarding radioisotopeuptake, actual tumour volume, etc., which iscrucial for accurate diagnosis and treatmentplanning. Hybrid imaging is an integration ofboth functional and anatomical imagingtechniques in the same modality and itrepresents the various advantages of bothmodalities. The combined devices in anintegrated system complement each othertechnically and clinically. The acquired imagesmatch significantly better than software fusionof images acquired on separate devices, theclinical workflow is improved and most of theintegrated systems have longterm financialadvantages over separate systems [4].

Recent developments in hybrid imaging

The main and most recent developments inhybrid imaging technology are SPECTCTPETCT, and PETMR. Other imaging systemsare also under design or in the exploratoryphase. Developments such as small animalSPECTMR and less obvious combinationsincluding CTMR and PEToptical are alsobeing studied [5].

The success of PETCT in replacing the standalone PET, demonstrates the potential ofintegrated technology in replacing theconventional systems. Significant investmentshave been made in instrumentation and R&D,which has facilitated manufacturing of thenew hybrid systems.

331691 © 2013 Pakistan Society of Nuclear Medicine Pak J Nucl Med 2013;3:121


PETCT has revolutionized the way thatclinicians perceive molecular imaging. Fusedimages are becoming the preferred diagnostictool as they increase the accuracy in localisingthe abnormalities and thus the clinicians'confidence in treatment planning. PETCT hasrapidly improved PET acquisition times frommore than one hour to less than 20 minutes. Asa consequence, patient tolerance has improved,a larger number of scans are being undertaken,and there is more efficient use of radiotracerswith rapid radioactive decay, together with moreproductive use of medical staff, with a resultantreduction in the overall costs [3].

Using CT to obtain attenuation correction mapshas been extremely beneficial and has not onlyimproved the quality of the PET scan but hasalso replaced the timeconsuming transmissionscans using radioactive sources. Since theattenuation characteristics of xrays aresignificantly different from the annihilationphotons, correction factors are required toconvert from a CT attenuation map to anappropriate 511 keV map, which can lead todiscordances.

Although the combination of CT with SPECT andPET for hybrid imaging is currently being utilizedin many studies with promising results, thereare some issues remaining to be addressed. Asdata acquisition is not simultaneous butsequential, patientmovement or respirationmay influence the images and introduce bodymotion artifacts. Various solutions have beenproposed to address these issues through anumber of ongoing research projects. There arealso some shortcomings in the use of CT as acomplementary modality which include a highradiation dose (especially significant for youngpatients) and poor softtissue contrast. Thesetwo limitations however do not apply to MRI,and unlike PETCT, simultaneous acquisition isfeasible with an integrated PETMRI system.

Positron emission tomography

In clinical PET imaging, a positron emitterradiolabelled molecule is administered to apatient via injection (Table 1). The positron aftera few millimeters random walk within the tissue,annihilates with an electron and two 511 keV

gammarays are emitted in almost oppositedirections. These gammarays are detected ascoincidence events when registered within ashorttime window and assigned to a line ofresponse (LOR). With coincident detection, theresolution along the LOR remains quite constantproviding significantly greater efficiency andimproved uniformity of spatial resolution about100 times that of SPECT [3]. Furthermore, thehigher sensitivity of PET enables identificationdelivery of pictogram quantities ofradiochemical compound, i.e. toxic cocktail, totarget organs for oncology purposes [7].

The detection of 511 keV photons has someminimum requirements such as good timing andenergy resolutions (~3ns and ~13% FWHMrespectively), high coincidence photo peakefficiency (~41%) and fast scintillation decayconstant (<300 ns) [7]. The commonly usedscintillation materials are bismuth germinate(BGO), ceriumactivated lutetiumoxyorthosilicate (LSO), ceriumactivated gadolinium oxyorthosilicate (GSO) and thalliumactivated sodium iodide (NaI). In the design ofthe current PETCT systems, scintillation blocksare attached to photo multiplier tubes (PMTs),whereas in integrated PETMRI systems,avalanche photodiode detectors (APDs) areutilized as PMTs are not able to function in ahigh magnetic field.

Due to the high penetration of the 511 keVannihilation photons of the PET radiotracers,which make the patient a high source ofradioactivity, it is necessary to carefully designthe radiation shielding to protect both the staffand the general public. One has to consider thetype and the amount of the radioisotope thatwill be administered, the length of time thatpatient will remain at the facility, the locationof the facility as well as the general environment[10]. The principal aim of radiation protectionis to maintain the dose to both radiation workersand the public as low as reasonably asachievable (ALARA). Highdensity materialssuch as lead, steel and concrete can be used forradiation shielding. The appropriate shieldingthicknesses (x) can be calculated fortransmitted radiation intensity (I) through anabsorbing material [9].



The appropriate buildup function for theshield geometry should be used:

where, Io is incident intensity, b(µx) is buildup function, µ is the linear attenuationcoefficient and x is the thickness of theshielding material.

Magnetic resonance imaging

Magnetic resonance imaging (MRI) does notrely on ionizing radiation (as CT andconventional radiography do), nor does itdepend on the transmission of energy throughtissue (unlike ultrasound imaging), rather ittakes advantage of an entirely differentphysical principle, i.e. the interaction of atomicnuclei with imposed magnetic fields, whichcauses radiofrequency NMR signals. Thesesignals provide unique information abouttissue chemistry, and MRI images reflect thisinformation that is altered depending on thetissue type and its characteristics. Figure 1,shows a schema of a complete MRI systemconsisting of a large bore magnet, stablepower supplies, RF transmitterreceiverelectronics, small fieldofview receiving coilsfor specific anatomy, moving patient tablewith embedded the associated computer andarray processor with fast Fourier transform[7].

The various MRI techniques provide theclinicians with very high diagnostic qualityimages and excellent softtissue contrast withno exposure to ionizing radiation. MRI cansuccessfully display chemical differences ofvarious tissue types (on a grayscale) andblood flow (as a highintensity image). Thefunctional MRI (fMRI) technique enablesstudying of the transit through the brain inreal time (using echo planar imaging) andmaps blood volume during brain activity [5].

Diffusionweighted MR (DWMR), where themagnetic field with different gradients is usedto map phase differences in the MRI signalcaused by diffusing molecules, can be used tostudy functional processes in living subjects.DWMR has clinical applications including fiber


I=Iob(µx)eµx

Table 1 PET radiotracers and some of their propertiesNuclide Halflife Decay

modePositron

max energy(MeV)

Photonemission(keV)

Dose rateconstraint

(µSv/m2/MBq/h)

1 hour integrateddose

(µSv/m2/MBq)

11C 20.4 min β+ 0.96 511 0.148 0.063

13N 10.0 min β+ 1.19 511 0.148 0.034

15O 2.0 min β+ 1.72 511 0.148 0.007

18F 109.8 min β+, EC 0.63 511 0.143 0.119

64Cu 12.7 h β, β+, EC 0.65 511, 1346 0.029 0.024

68Ga 68.3 min β+, EC 1.9 511 0.134 0.101

82Rb 76 s β+, EC 3.35 511, 776 0.159 0.006

124I 4.2 d β+, EC 1.54, 2.17 511,603,1693 0.185 0.184

Figure 1 A complete MRI system(courtesy Siemens Healthcare)


tracking, diagnosing Alzheimer's disease, characterization of tissue structure, cancer detection, andevaluation of ischaemia and multiple sclerosis.Magnetic resonance spectroscopy (MRS), whichapplies selective radiofrequency excitation pulses,is used to analyze molecular composition of tissuesand to define biopsy targets by separating areasof active tumour from inflammation, necrosis orfibrosis [12].

PETMRI: potential advantages

The idea of combined PET and MRI wasexpressed in the 1990s (earlier than proposalfor the combined PETCT). Simon Cherry andPaul Marsden [11] observed the potential ofsuch modality, but there were many technological challenges to overcome before the firstclinical PETMRI could be launched. Theadvantages of this hybrid imaging arenumerous with high commercial interests.PETMRI is a combination of excellent softtissue contrast, high spatial resolution,functional imaging and high sensitivity, whichenables assessment of metabolic abnormalitiesand changes in mass lesions, well beforetumour size changes can be measured.

Another essential advantage of PETMRI is thelower radiation exposure with significantly loweroverall examination doses in comparison toPETCT. A wholebody 18FPETCT doseestimation study of a male patient,demonstrated that the effective total doses (forthree different CT scanning protocols) were13.65, 24.80 and 32.18 mSv, whereas the PETcomponent dose contribution was only 6.23mSv. It is quite clear that CT is responsible forthe greatest amount of radiation dose.Replacing the CT with MRI considerably lowersradiation doses from 54% up to 83% [13]. Thisadvantage is of great importance in imagingchildren and young adults with potentiallycurable oncological diseases, patients withnononcological indications, in repeatedexaminations, and dynamic contrastenhancedstudies, though this may be of less importancein patients with limited life expectancy.

The high sensitivity of PET is complementingthe poor signal strength inherent in currentfunctional MRI imaging, whereas the MRI

strong magnetic field is improving PETresolution as it limits the positron range priorto annihilation [15]. For simultaneous dataacquisition, PETMRI not only allows highspatial overlay accuracy, but also allowsexceptional temporal coregistration, whichenables MRbased PET image motioncorrection for precise cardiac and abdominalimaging [12].

In theory, MRI appears to be a perfectanatomical complement to PET preferred forabdominal and pelvic imaging whereas PETCTis still the preferred choice for thoracictumours [12]. Coregistered anatomy andmetabolic images can enable better lesionidentification and staging in a variety ofmalignancies such as liver, bone metastases,brain tumours, rectal, prostate, breast,gynaecological and head and neck oncologicalstudies.

In the detection of bone metastases, FDGPETCT has been shown to provide falsenegative results, especially in earlymetastases, as FDG metabolism might not bevisualized due to the normal bone marrowuptake. On the contrary, MRI has proven toimage bone marrow itself, and thereforePETMRI holds the potential to demonstratethese secondary manifestations [12].Nonetheless, the diagnostic and clinical valueof the PETMRI is yet to be provenunequivocally despite its uniqueness andsuperiority over other hybrid modalities inseveral aspects. The clinical results shouldjustify the longer examination times and thehigh capital maintenance and the workflowcosts. It also needs to be proven that anintegration of the both modalities iseconomically superior to two individualsystems. The main argument for theintegration of PET and MRI examinations, inaddition to the earlier stated benefits, is toreduce the duration of the subsequent imagingwhich is extremely unpleasant for patients.

PETMRI: clinical expectations

The clinical success of PETCT has paved theway for the development of integrated PETMRmultimodality imaging system with high clinical



expectations. However, it is anticipated thatfully comprehensive clinical applications of theintegrated PETMR imaging system, willrequire some time as it has been mostlyutilized in research environment. Given thefact that research has been undertakensequentially in various modalities and withsimultaneous BrainPETMRI prototype in therecent years, there are strong indications thathardwarefusion PETMRI has the potential toprovide clinicians with various applicationsmainly in the following subspecialties

NeurologyThe human brain is the most investigatedclinical area with PETMRI so far. Variousstudies [5, 16, 17] have shown that brainimaging could greatly benefit from theadditional morphological and functionalinformation that is provided by PETMRI. Itenhances the diagnostic sensitivity for gliomasand can thus improve the 'waitandsee'approach for lowgrade gliomas with regardsto extent and timing of surgery. Furthermore,simultaneous BrainPETMRI (11Cmethionineor 68GaDOTATOC) demonstrates its usefulness for intracranial tumour assessmentand image quality similar to that using PETCT[18]. Simultaneous PETMRI also appears tohave a great potential in neuroscienceresearch, predominantly for the imaging ofmolecular processes such as cell transplantation, gene transfer and for multiparametric analysis of functions in neutralnetworks [5].

Head and neckMany tumours in the head and neck area arevery sensitive to radiotherapy and the highersofttissue contrast of MRI can be especiallyuseful and crucial in the accurate localizationof tumours and followup radiotherapytreatment planning. Recent studies haveshown that simultaneous PETMRI is feasibleand that there is no notable degradation inMRI or PET image quality seen [19]. Betterassessment of skull base infiltration, improveddetection of lymph node metastases and moreexact delineation of metabolically activetumours results from the excellent softtissuecontrast of MRI, the improved spatial resolution

of the PET component of the BrainPET and itssmaller diameter compared to a conventionalPETCT [19]. Although, small streak artifactswere observed, it did not significantlyinfluence tumours evaluation. Further studiesand developments aim to prove the superiorityof PETMRI in head and neck examinations.

CardiologyPETMRI cardiac imaging may introduce a newlevel of diagnosis. The variety of possiblecombinations for molecular imaging isincredibly wide and of great clinical interest.Cardiac MRI or wholebody MRI angiographycombined with PET could provide improveddifferentiation and detection of vulnerableplaques. PETMRI cardiac stress examinationsor lateenhancement MRI with FDGPET mayexpand the clinical view of current cardiacimaging as well. Dual functional studies suchas perfusion in PET with radioactive water orammonia and perfusion in MRI using arterialspin labelling or MRI contrast agents can becarried out to correlate and compare the sameparameters. PET perfusion can be alsocorrelated with the MRI BOLD (Blood OxygenLevel Dependent) effect [5]. Simultaneouslyacquired cardiac PETMRI will allow accuratebody motion correction and thus very preciseimaging. Figure 2 shows a cardiac image fromthe first integrated PETMRI system (BiographmMR).


Figure 2 Cardiac imaging, mMRtechnology eliminates motion effects andPET image degradation, whilst gating andtriggering tools deliver excellent MRIimages (courtesy Siemens Healthcare)


OncologyPETMRI may be useful in extracerebraloncology applications. A recent summarizedreview by Antoch and Bockisch [21] claimsthat PETMRI could be more accurate andperform better than PETCT for Tstaging foroncological examinations. Both systems showsimilar accuracies for Nstaging, whereasPETMRI may provide better accuracy forMstaging than PETCT depending on the areaof metastases. PETMRI may also provide abetter diagnosis in patients with osteomyelitisincluding those with diabetic foot disease,since MRI detects abnormalities within bonystructure (e.g. marrow). FDGPET is usefulfor the diagnosis of acute infections and canalso exclude the diagnosis of osteomyelitis. Inaddition, PETMRI holds a great potential forreplacing PETCT in evaluating treatmentresponse for chronic diseases that requirerepeated examinations.

PETMR system designs

Sequential configurationSequential design, where both systems wereplaced in tandem and physically separatedwas one of the first approaches inconfiguration of a clinical wholebody PETMRsystem. The advantage of this configurationis that it can be constructed with a minimumadjustment of the already existing individualsystems and software packages, which couldlead to a quick product development.Furthermore, the separation between the twomodalities demands a less complicatedelectromagnetic shielding for the PETcomponent and intrinsic problems can beavoided. Moreover, it is a way to improvephysical access to the patient and reducepatient claustrophobia. The disadvantages ofthis design concept include accommodatinglong examination times and an inability toacquire simultaneous imaging, and thereforecoregistration errors could occur leading toimage quality degradation. The spaceavailability and associated cost can also be alimiting factor [22].

Insert architectureThe recent approach of building a removableMRcompatible PET insert and placing it within

a conventional MRI system was the firstattempt at simultaneous PETMRI dataacquisition known as BrainPETMRI prototypesystem (Figure 3). The development wascarried out by a collaborative team of theGerman and US researchers from theUniversities of Tubingen and Tennessee, aswell as the Siemens Healthcare [23]. Thesimultaneous acquisition, not only offers areduction in the overall acquisition time andexcellent geometrical coregistration, but alsoopens the way to a wide variety of innovativeapplications such as kinetic studies, functionalMRI, etc. Furthermore, medical centers withaccess to the inhouse MRI can easily acquirea flexible and nondedicated PETMR systemwith a relatively costeffective approach.However, due to the small bore diameter, thisarchitecture is limited to brain studies [22].


Figure 3 BrainPETMRI prototype witha MRcompatible PET insert is placed withina Siemens MAGNETOM Trio MR scanner(courtesy Siemens Healthcare)

Figure 4 Biograph mMR, a fully integrated,simultaneous wholebody PETMRI system(courtesy Siemens Healthcare)


Integrated ArchitectureThe approach describes a complete integrationof a PET detector and electronics within a MRIscanner, which is the most challenging andsophisticated solution (Figure 4).

PETMR: technological challenges anddrawbacks

As with any new and innovative technology,various problems and challenges alsomaterialized in the construction, installationand operation of the combined PETMRI. Inthe late 1990s, when the idea was firstlyconceived, the construction of a simultaneouswholebody PETMRI appeared to be unlikely,whereas the fully integrated PETMR systemis now not only a reality but the initial clinicalresults are being published [25].

MRcompatible PET detectorsThe main detection technology that isembedded in clinical PET and PETCT scannersis based on the light sharing and mappingmany small scintillation crystals to the lightdetectors (PMTs). The intense MR magneticfield severely affects the function of PMTs andimage quality (Figure 5). To tackle thislimitation, a sequential PET and MRIacquisition has been proposed, although thistechnique does not allow simultaneousacquisition and is associated with the bodymotion risks and the long examination times.

Another solution proposed the use of opticalfibers to lead the light signal from thescintillation crystals outside the magnetic fieldin order to minimize the interference. Splitmagnets, with a PET detector positionedbetween the two magnet halves, andconnected with the optical fibers, have alsobeen proposed [1]. However, the long opticfibers cause signal degradation and inferiorPET performance. A recent study by Mackewnet al. [26] has also shown that the proposedsystems suffers from a reduced PETSNR as aresult of the light attenuation in the opticalfibers (3.5 meters long), which can in part beovercome by the MRcompatible gammashields. The gamma shields significantlyreduces the scatter ratio and improves thequality of the image. However, the limitedaxial coverage coupled with practicaldisadvantages such as space requirementsand higher cost has hampered this solution.The most realistic and accepted solution is toreplace the PMTs with avalanche photodiodedetectors (APDs), which are thesemiconductor equivalent of PMTs and canfunction in strong magnetic fields (Figure 5).

Unlike PMTs, APDPET systems can be easilyswitched on and off without requiring longwarmingup times and unlike PMTs does notrequire a large space. This principle wassuccessfully demonstrated in the prototypeBrainPETMR system in 2006 and variousstudies have proved the feasibility of theconcept [16, 27]. The proposed PET assemblycomprised of 192 LSO detector blocksarranged in six rings. Each block has a 12 x12 matrix of 2.5 x 2.5 x 20 mm3 crystals withan axial field of view (FOV) of 19.25 cm, whichis coupled to a compact 3 x 3 APD array. ThePET system has a 5.6% point sourcesensitivity and 2.1 mm spatial resolution inthe center of the FOV [5].

Based on the success of the APD detectiontechnology, a dedicated wholebody PETMRIsystem, the Biograph mMR, has beendeveloped (Figure 6). The mMR hybrid systemhas 64LSOAPD detector blocks, each with ablock area of 32 x 32 mm2 which form one PETdetector ring. The PET detector unit has 8rings in total, with an axial FOV of 25.8 cm.


Figure 5 Schematic diagrams of thedetection process (top); conventional PET(bottom left) and APDbased (bottomright) detectors response to magnetic field


The size of the each LSO crystal is 4 x 4 x 20mm3, which is the finest crystal dimension inthe current market [28]. However, the APDPET systems are still slower than theconventional PMTsPET modalities. Researchon the development of dedicated siliconphotomultipliers (SiPM) is currentlyundertaken, which can increase the PETeffective sensitivity up to 10 times, when it issupported with the TimeofFlight PET and theshort coincidence time resolution (<200ns)[29]. The proposed time resolution can onlybe measured by having a scintillation detectorwith appropriated characteristics andadequate electronics. The scintillationmaterials such as LaBr3 and Lul2 arepromising.

MRbased attenuation correction

Another critical question in the developmentof an integrated and simultaneous PETMRimaging system is the provision of the MRIattenuation map for the correction of the PETreconstructed images, due to the attenuationand scattering of 511 keV in the body and thehardware (e.g. RF coils and moving tables).Traditionally, for the standalone PET systems,topography of attenuation values (μmap)could be reconstructed by rotation of aradioactive 68Ge 511 keV source around thepatient. This technique is timeconsuming asthe source has to rotate slowly in order toachieve a higher count rate. For the currentPETCT systems, the CT scans are used toestimate the expected attenuation, byconverting the attenuation values from the

70120 keV to 511 keV, which provides areliable and quick attenuation correctionμmap of the patient and the hardware in thePETFOV.

MR imaging is based on photon densities andT1 and T2 relaxation times which providestissue typeclass information rather than thephoton absorption information and therefore,unlike CT, it is not able to measure physicalquantities that would allow a direct derivationof μmaps [30]. Various MRIbased attenuationcorrection methods such as atlasbasedmethods or imagesegmentationbased efforts,have been proposed to overcome the problem[3032]. A recent study by Moller et al. [31]has shown that segmentation of theattenuation map in 4 classes (background,lungs, fat and softtissue) appears to be validand practical for MRIbased attenuationcorrection. A CT attenuation correction methodwas used as a gold standard in order toquantify the effects of segmentation on thestandardized uptake values (SUV). Thesegmentation effects showed a slight decreasein the SUV value, particularly in bone lesions(13.1%), whereas the decrease for the neckand the lung lesions was minor (≤8%). Incomparison to the CT based attenuation map,the variations observed in the segmentedmethod, were not adequate to deter the useof the technique in a PETMRI scan. Althoughthe impact of the attenuation on the pelviclesions is higher, due to the fact that bonescannot be segmented in wholebody MRimaging, it does not lead to clinicalmisinterpretations. The impact however ismore noticeable and introduces bias inneurology and more specifically in brain studiesand therefore the segmented attenuation mapis not suitable for neurologic PET andconsequently different methods need to beapplied [31].

An alternative approach for MRIbasedattenuation correction which takes bone intoaccount is the atlas based registration [33].This technique captures global variation ofanatomy to predict pseudoCT image from agiven MR image, and then use the images tocreate attenuation maps as it would beperformed in a PETCT examination. A study


Figure 6 APDbased PET detector used inmMR (courtesy Siemens Healthcare)


of human brain by Hofmann et al. [33] whichcombines local pattern recognition with theatlasbased registration, has demonstratedthat an estimation of pseudoCT images canbe performed successfully. It has also enabledPET quantification, with a mean error of 3.2%in comparison to the CTbased correctionutilizing the predefined ROI. The resultsdemonstrate that atlas MRIbased attenuationcorrection is a feasible method, with highaccuracy for brain imaging, but furtherresearch is needed to validate the method forwholebody imaging.

A novel dualecho ultrashort echo time(DUTE) MRI sequence proposed by Catana etal. [27] suggested that the method couldpotentially be useful for neurologic PETMRIstudies and it even appeared to be superiorto the atlasbased methods, for patients withmodified bone anatomy [27]. An alternativereliable MRbased method, which targetspatientspecific quantitative analysis in timeofflight PETMRI, was proposed by Salomonet al. [34]. The possibility of introducing atransmission scanner to the PETMRI systemwas also considered but various issues suchas interference, additional radiation dose,considerable development effort, andadditional cost have to be considered [35].The lack of MRI attenuation information inpatient imaging appears to be a drawback incombined PETMR imaging although variousMRbased AC methods have been proposedand are appearing to be robust enough to beused in clinical applications.

MRbased motion correction

PET provides an estimation of radiotracerconcentration, but its degradation in quantitative accuracy and spatial resolution isinevitable due to subject motion. The motioncorrection technique can be developed insimultaneously PETMR imagining, by takingadvantage of the MRI as it has been shown inthe recent studies [3637].

Motioncorrection is more crucial in wholebody imaging than in brain studies, as thesubject motion in brain can be estimated wellby using external motion tracking devices and

the image processing techniques. However,in wholebody imaging, the complexdeformations and the image degradation mayoccur due to the respiration, peristalsis,cardiac contraction and the arbitrary patientmovement [38]. Tsoumpas et al. [37]compared PET and MR based motioncorrection techniques and concluded that theperformance of the latter is superior to thePETbased motion correction as PET systemshave limited FOV and therefore cannotmeasure motion at the edges. Moreover, thePET images are too noisy to employ nonrigidregistration, and due to the rapid tracerkinetics, the activity varies significantly withtime and with the patient's physiologicalresponse. On the contrary, MRI provides theexcellent softtissue contrast and thus it is anextremely useful tool for the estimation ofmotion in human anatomy.

The use of novel MRI techniques may providecontinuous and synchronous motionmonitoring during the PET acquisition whichcould be proven to be the ideal solution toback the arguments for an integrated andsimultaneous PETMRI system. However, fastMR sequences and an image processing toolto characterize the motion is required.Moreover, there are many other issues suchas eddy current artifacts, degradation ofgradient coil performance, RF noise or signalloss and uniformity of magnetic fields, whichcould degrade the overall performance of thesystem. In addition, although minimizing thecurrent lengthy PETMRI examination times ischallenging but is necessary to avoid imagedegradation as a result of body motion.

Fully integrated PETMR system:installation challenges

Technical Specifications

The Biograph mMR (Figure 4) is the first fullyintegrated PETMRI system. It is anintegration of a 3Tesla (3T) wholebody MRIsystem with an incorporated isocenter PETdetector. Diameter of the patient bore is 60cm, the magnet length is 163 cm, and thesystem covers 199 cm length which enableswholebody imaging.




The magnet type is NiobiumTitanium and itsweight including cryogens is 6300 kg. Themagnetic field shimming, i.e. the process ofimproving field homogeneity by compensatingfor imbalances in the main magnetic field ofan MRI system, is approximately 20 sec. TheBiograph mMR incorporates zeroheliumboiloff technology and the helium capacity isapproximately 1500 litres. The maximumacoustic noise level is 115 dB and the MRIresolution in the FOV varies from 5 mm to 500mm [40]. The PET detector assembly is acombination of LSO crystals (4x4x20 mm3 percrystal) and APD which can detect gammarays in strong magnetic fields. Each PETdetector ring consists of 64 detector blocks

with 32x32 mm2 area per block. The full PETdetector unit consists of 8 rings which forman axial FOV of 25.8 cm. It is larger than theconventional current PET/CT systems whichusually have a 2022 cm axial FOV.

SitingVarious unique parameters have to beconsidered in relation to siting a PETMRIhybrid imaging modality. Since thecombination of MR with PET in the same roomis a technology at early stage, routineinstallation protocols and thorough design forfacilities and workplace requires to bedeveloped. This review underlines theproposed solutions.

Minimum distances magnet magnet (SIEMENSE)0.2T 0.35T 1.0T 1.5T 3.0T

0.2T 10 10 5 6 10 0.35T 10 10 5 6 101.0T 5 5 4.5 5 61.5T 6 6 5 5 63.0T 10 10 6 6 6

Object Minimum clearance Max. weight

radial (X/Y) axial (Z)

Guidelines for Water cooling system 4.0 m 4.0 m

minimum Wheelchairs up to approx. 50 kg 5.5m 0.5 m

clearances Calls up to approx. 200 kg 6.0 m 7.0 m

and Transformers < 10D0 kVA 14.3 m 15.0 m

maximum High voltage cables < 1000 A 12.0 m 5.0 m

weights Cars up to approx. 900 kg 0.5 m B.0 m

Trucks up to approx. 4500 kg, Lifts 7.0 m 9.5 m

Street cars, trams 40.0 m 40.0 mAngiography systems with magneticnavigation 30.0 m 30.D m

Reinforcement steer in the floor > 1.25 m below magnet centre ≤ 100 kg /m2

Iron beam mass in the floor > 1.25 m below magnet centre ≤ 100 kg / m

Table 2 Guidelines for a minimum distances between the magnet isocenter anddifferent objects including maximum weights for metallic materials



Figure 7 The detailed floor plan of the PETMRI facilities and magnetic field extend. Patientspreparation rooms, toilet, dispensary, storing space, equipment and control rooms andadjacent noncontrolled area are shown above (couretsy Siemens Healthcare)


Magnetic field shieldingMRI uses high magnetic field (3T for the mMR)and therefore, magnetic shielding is crucial forboth safety and field homogeneity.

Protecting the immediate environment fromthe effect of the magnetic field is significantfor the various followup reasons: a) it candisrupt pacemakers or insulin pumps function;b) a great potential health hazard is associatedwith ferromagnetic objects such as scissors,knifes or oxygen cylinders that are accelerated

in the field and can become dangerousprojectiles; c) has serious impact on functionof computers, other medical devices, camerasand a wide variety of other electronic devices[42]. Moreover, the homogeneity of themagnetic field itself can also be affected bythe ferromagnetic objects which can lead tothe image degradation and artifacts, andtherefore, guidelines for a minimum distancesbetween the magnet isocenter and otherdevices or ferromagnetic objects should befollowed (Table 2).


Figure 8 The crosssection of the PETMRI facilities showing the extent of the magneticfield above and underneath the mMR floor (courtesy Siemens Healthcare)


The official regulations require magnetic fieldsup to 0.5mT to be restricted in a controlledarea, posing any threat. Figures 7 & 8 describethe floor plan and crosssection of the wholemMR facility, showing the strength of themagnetic fields in various distances from themagnet isocenter and how the 0.5mT field isrestricted almost completely within theexamination room. The noncontrolled areaon the right side of the mMR examinationroom had to be protected from the 0.5mTmagnetic field as the patient rooms werelocated here and therefore, 6 mm thick carbonsteel plates had to be placed on the wallbetween the mMR examination room and thenoncontrolled area (Figure 7). In addition, forthe protection of the noncontrolled areaunderneath, a carbon steel plate of 7x4 m2 insurface area and 10 mm in thickness wasplaced on the either side of the floor slab ofthe mMR examination room. The minimumdistance that ferrous components can beplaced below the magnet field strength is300400 mm, and since the thickness of thefloor slab below the magnet is 400 mm, nointeractions between the magnet and the steelplate are expected [43].

Radiofrequency shieldingThe examination area should be shielded toprovide a reduction of radiofrequency wavesoriginating from external transmitters, and toprotect the environment from the internal RFwaves originating from the MRI. A copper RFcabin (Faraday cage) was installed in theexamination room in order to provide therequired attenuation (90 db) of the radiofrequency in the range of 15128 MHz [43].

The PET electronics and cables are vulnerableto radiofrequencies, causing downgrading ofperformance and therefore, an extra RF filterpanel is required for the PETMRI installation.Moreover, the MRI cable trays must beseparated from the PET cable trays with aminimum distance of 800 to 1000 mm, andthe cables which connect the PET electronicequipment to the PET detector should be alsorouted via a cable handler and should bemounted above the ceiling of the RF cabin witha minimum clearance of 255 mm [43]. Inorder to avoid electromagnetic interactions,

optical glass fibers could be a feasiblealternative to the conventional coaxial cablesthat are currently used for the MRI and PETinterconnections. Optical glass fibers onlytransmit optical signals and they are totallyimmune to the electromagnetic interferences.In addition they are able to carry hugeamounts of data and have exceptionally stablesignal intensity and flexible small crosssections. The recent study by Yuan et al. [44]demonstrated that the optical glass fibers area feasible solution for MRI and PETMRIsystems. Future research and development ofless expensive optical fiber materials, mayfurther support the use of this technology inmedical imaging systems.

Ionizing radiation shieldingIn addition to the magnetic and RF shieldingfor PETMRI facilities, radiation shielding dueto the ionizing radiation of 511 keV gammarays is also required. For the Biograph mMRfacilities lead chevrons were placed as themain radiation shielding in addition to thebuilding concrete walls and the steel plates ofthe magnetic shielding. Figure 9 illustrates thelead shielding for sections of the room, where21 mm lead chevrons were installed on thewall between the examination room and theadjacent noncontrolled area and 11 mm leadwere placed between the control room and theexamination area. The control room windowwas shielded with RF and a radiation absorbinglead glass. Since, the thickness of the concrete(400mm) was adequate to attenuate all theemitted radiation, lead was not placed on thefloor and on the ceiling. The rest of the wallswere not shielded with lead as the adjacentareas (toilets and preparation rooms) hadtheir own lead shielding [43].

Additional considerationsThe loading capacity of the floor must bedesigned in order to support the weight of:PETMR system (up to 10,500 kg); the RFcabin, the iron and the radiation shielding; theload of the electronic equipment of bothmodalities (approximately 4000 kg) and theadditional load for service purposes (up to1000 kg). In addition, the mass of the floorshould be adequate enough to isolate soundand vibrations in order to prevent




prevent inhomogeneity in the magnetic fieldand in the image quality [43].

For conventional MRI, a chilled water systemis required at all times to cool the head andthe gradient systems. For the PETMRI, the

cooling system can be also used to cool downthe additional PET equipment. Therecommended piping materials should bestainless steel, nonferrous metal (copper orbrass) and synthetic materials such as plastic.Materials, such as aluminum, iron, carbon

Figure 9 Biograph mMR floor plan (courtesy Siemens Healthcare)

21mm of leadchevron wasplaced on thisside

11mm of leadchevron wasplaced on thisside

Section thatmMR deliverywill take placethrough

Noncontrolledarea

Green line: leadshielding


steel, zinc and standard steel pipes may causedamage to the cooling system and should beavoided.

Rust and flakes may be produced within thepipes as a result of oxidation processes, whichcan destroy the electronic equipment. For thecurrent PETMRI facilities, piping materials ofcarbon steel has been used and therefore abarrier filter has to be placed to filter out allthe rust and the flakes. Cautious monitoringof the filter is required as it can get cloggedwith debris resulting in slowing down of thecold water supply and can eventually causethe cryogens to boil off (quench). The powersupply, the heat dissipation and the watersupply requirements of the mMR are 30%higher than those of a conventional 3TMRsystem [43].

PETMR service delivery challenges

Potential risk and safety aspects

The ionizing and nonionizing radiation safetyaspects of PET and MRI are well known andthe established safety protocols have beenfollowed in medical imaging departments.However, for PETMRI examinations, there areadditional safety considerations that shouldbe evaluated.

During PET examinations, various equipmentsuch as injection systems, syringes,radioactive source containers and otherroutinely used equipment, may pose a hazardto patients due to the high magnetic field ofMRI. PETMRI examinations should be avoidedfor patients with passive implants such ascatheters, heart valve prostheses, orthopaedicprostheses, vascular clips, sheets and screwsor for patients with active implants such asheart pacemakers and defibrillators, electronicdrug infusion pumps, cochlear implants andother objects made of ferromagnetic materialssuch as bullets or pellets [42]. In order toeliminate or to minimize the impact of thehazardous situations, careful interview of thepatients and the provision of metal detectorsin the entrance of the PETMRI facilities arenecessary.

Some studies have demonstrated that mild

hyperthermia caused by the RF fields has aradiosensitizing effect in tumours and lowfrequency or static magnetic fields mayenhance the genotoxic potential of ionizingradiation. Although, pregnant women areallowed to undertake MRI examinations in thefirst trimester for special medical conditions,PETMRI examinations should be avoided dueto the effect of additional ionizing radiation ofPET imaging which could seriously damage thefoetus [42].

Examination timesThe PET and MRI imaging techniques bothrequire relatively long examination times,although the simultaneous acquisition of theBiograph mMR dramatically reduces theoverall imaging time, however furtherreduction in the simultaneous imageacquisition period remains a clinical challenge.Lengthy examination times (2050 min) causevarious problems such as patient discomfort,claustrophobia and image artifacts as a resultof volunteer or nonvolunteer body motion. Inparticular, reducing the imaging time inpediatric oncology is crucial. The examinationtimes are driven mainly by the MRI andtherefore there is a need for development ofa faster MRI sequences.

New clinical protocolsThe objectives of clinical protocols are tostandardize and to raise quality of medicalcare for reducing patients' health risk and toensure the cost effective medical procedures.As such, either a new optimized imagingprotocol should be developed for the PETMRIstudies or the already existing PET and MRIprotocols modifed by taking into theconsiderations all the specificities of the newmodality. The need for modifying ordeveloping a protocol for 82RbPETMRmyocardial perfusion imaging is a clearexample that appears to be difficult andchallenging. 82Rb is a generator product witha physical halflife of 75 seconds, which has asignificant advantage of having no need foronsite cyclotron [46]. The 82Rb generatorinjection system is placed beside theconventional PET or the PETCT systems forinjecting the 82Rb radiopharmaceutical directly



into the patients. This approach is not feasiblein MRI environment, due to the ferrousmaterials of the 82Rb generator. A proposedsolution is to place the 82Rb generator outsidethe examination room and to inject theradiopharmaceutical remotely, using a longerinjection system supported by a pump.However, the proposal might face somedrawbacks and consistent radiotracer deliverymay not be guaranteed. Provision of a MRIcompatible generator can be a potentialsolution, although as with any other MRIcompatible medical equipment, the cost could beup to three times higher. Moreover, during thereststress 82RbPETMR myocardial perfusionstudies, unlike the 82RbPETCT, a clinician cannotbe in the examination room, especially during theonline injection, and the possibility of immediateintervention in health risk situations needs to beaddressed by developing remote and automatedmonitoring systems.

Scientific teams "fusion"Another practical but major challenge is to puttogether two scientific teams with a verydifferent background knowledge. PETscientists need to deeply understand thecomplex MRI physical principles, workingprocedures and safety aspects and vice versa.Hence, new training programs should bedeveloped in order to prepare a newgeneration of PETMRI specialists.

New tracersAdditional field of research with a potentiallyhigh interest is the development and productionof tracers, which can simultaneously generatesignals for the both PET and MRI imaging. Thestudy by the Lee et al. demonstrated theproduction of polyaspartic acid particles, whichwere coated with the cyclic RGD peptide via apolyethylene glycol spacer and DOTA. It notonly has excellent magnetic properties for MRIbut at the same time it could be efficientlylabelled with 64Cu for the PET imaging [48].

Discussion

The current development of the new hybridPETMRI imaging technology may open a new

horizon in diagnostic imaging and establishesa modality of choice for a variety of studies.

The potential advantages and clinicalapplications of PETMRI are numerous. Theexcellent softtissue contrast, high spatialresolution and functional imaging (fMRI,DWMRI, MRS) of MR, in combination with thehigh sensitivity functional imaging of PET,enables the assessment of metabolicabnormalities and changes in mass lesionsbefore the tumour size changes can bemeasured and therefore, facilitates andenhances cancer diagnosis to reach new levels.

The lower radiation dose of PETMRI incomparison to the PETCT dose (54% to 83%lower dose) is another considerable crucialadvantage, especially while imaging childrenand patients with potentially curableoncological diseases [13]. Moreover, thestrong magnetic field of the MRI may improvethe PET resolution, as it limits the positronrange prior to the annihilation [15]. Forsimultaneous data acquisition, PETMRI notonly allow for high spatial overlay accuracy,but the exceptional temporal coregistrationalso enables the MRbased PET image motioncorrection for precise cardiac and abdominalimaging [12]. In addition the simultaneousacquisition significantly reduces the overallexamination time of the individually acquiredPET and MRI.

Considering the above factors, MRI appearsto be a perfect anatomical complement to PETalthough, there are remaining disadvantagesand drawbacks in PETMRI technology thatneeds to be overcome.

One of the main identified challenges and thefollowup solutions was to develop a MRcompatible PET detector and to replace theassociated PMTs with APDs capable offunctioning within strong magnetic fields.Various studies [5, 16, 25, 27] and Siemens'choice of APDs, for the construction of theBiograph mMR, demonstrated the superiorityof this solution.

Development of a MRIbased attenuationcorrection map for combined PETMRI is



another challenge especially for the wholebody imaging. Various studies [3033] haveindicated the atlas MRIbased attenuationcorrection as the preferred method for headand neck imaging, whereas the segmentationbased methods perform better for the rest ofthe body. The results show that the MRIbasedattenuation correction is feasible with nosignificant effects on the clinical analysis,though further research is needed to validatethese methods and to achieve a superiorquality of the CTbased attenuation correctionmaps. The various drawbacks such as motioncorrection and electromagnetic interactionsbetween the PET and MRI systems (eddycurrents artifacts, RF noise, signal loss anddegradation of gradient coil performance)need to be addressed although, it appears thatthe issues can be successfully overcome withno significant effect on the overallperformance of an integrated PETMRI system[28, 37].

The use of iron shielding to restrict the 0.5mTmagnetic field within the mMR room, is shownin Figures (78). A copper RF cabin wasinstalled to provide attenuation of 90 db in thefrequency range of 15128 MHz. As the PETelectronics and cables are vulnerable toradiofrequencies, an extra RF filter panel wasplaced to shield the PET electronics in theequipment room. The PET and the MRI cabletrays should be separated by a minimum of800 to 1000 mm in order to avoid any crossinterferences. The connection between PETdetectors and their electronic equipmentshould be routed via a cable handler andshould be mounted above the ceiling of the RFcabin with a minimum clearance of 255 mm.The cooling system should be able to cooldown the PET and the MRI equipment. Thepower supply, the heat dissipation and thewater supply requirements are 30% higherthan for a conventional 3TMR system.

The prospective hazards of PET examinationequipment made from ferrous materials (e.g.injection systems, syringes, radioactive sourcecontainers, etc.) have to be addressed andtherefore, nonferrous materials should be usedin order to avoid potential health risks. PETMRI examination times have been estimatedto be 2050 minutes, which are relatively long,

in particular for paediatric studies. However,the ability to simultaneously acquire PET andMRI data is extremely valuable and itspotential clinical benefits appear to justify theprolonged examination times.

Future considerations

MRbased attenuation correction: Moreresearch in MRbased attenuation correction,especially for the wholebody scans is needed.Although, some alternative methods such asnovel eualecho ultrashort time echo MRIsequences or timeofflight PETMRI havebeen proposed by Catana et al. and Salomonet al. [27, 34].

APDs: Further development in APDs although,Silicon Photomultipliers (SiPMs) might be afeasible alternative solution in the near futureto achieve a better time resolution [29].

Bore and FOV: A larger bore and FOV whichreduce artifacts and improve patients comfort(the current system has a bore diameter of 60cm). The need for imaging large patients isgrowing.

New dualfunction agents: Agents which canbe used simultaneously as contrast agents forMRI and specific tracers for PET.

Protocol optimization: An optimized and fasterprotocols for MR imaging (e.g. fastspinechoes) to reduce the overall examinationtimes.

Monitoring Systems: The production ofautomated monitoring systems or MRcompatible medical equipment. The Lack ofspecific equipment such as 82Rb generators,could pose a drawback for future studies.

Conclusions

The longawaited simultaneous wholebodyPETMR imaging modality has finally enteredthe realms of practical nuclear medicine. As isthe case with the early years of every cuttingedge technology, it must prove its worth andtranslate its technologic advances into theclinical benefits. Various challenges have beenidentified whilst some are still pending



solution. The Biograph mMR (and every otherintegrated PETMRI system) still needs toaddress the question, as to whether thisclinical tool can offer something unique andexpand the boundaries of medical imaging.The first clinical results are extremelypromising and it is very likely that PETMRIwill be the imaging modality of choice for thenext decade.

Acknowledgement

The authors would like to thank WendyWaddington (UCLH) for useful discussion, theSiemens installation team (UK) for provisionof the technical data and Dr Seyedali Hejazi(Harvard Medical School) for informativeclinical discussion.

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331691 © 2013 Pakistan Society of Nuclear Medicine 222210288(201307/01)3:1<01:PTFMCO>2.0.TX;2M

Efficacy of motioncorrection in absolutequantification of colonic PETCT for drug

response therapyMichael A Masoomi1,2,4,*, Andy Robinson2, YassineBouchareb3, Seyedali Hejazi5, Nicholas M Spyrou4

1Department of Nuclear Medicine, Farwaniya Hospital, Kuwait2Nuclear Medicine Physics, Queen Alexandra Hospital, UK

3Barts Health NHS Trust, London, 4University of Surrey, Guildford, UK5Harvard Medical School, Boston, USA

ORIGINAL ARTICLE

*Correspondence Dr Michael M Masoomi Department of Nuclear Medicine Farwania Hospital PO Box 18373, Kuwait 81004Email: [email protected]

Abstract

Aims The study aimed at: a) characterizingand correcting bowelmotion induced artefactswhilst imaging the region in pre and postdrug therapy 18FFDG scans; b)developing amotion model of the gut using a fully 3Dnonrigid registration technique for applyingto NACT digitised images.

Methods A motion correction technique forPETCT scans, particularly those of theabdomen and colon was developed.Attenuation and activity image volumes weregenerated at different points in the respiratorycycle using the Nonuniform Rational BsplineCardiac Torso (NCAT) anthropomorphicphantom. The movement of the abdomen wascharacterised as part of the image registrationprocess and assessment of the motioncorrection technique was performedquantitatively with Region of Interest (ROI),image fidelity, and image correlationtechniques; semiquantitatively with lineprofile analysis; and qualitatively by overlaying

nonmotioncorrected and motioncorrectedimage frames.

Results Motion correction was successful forframes that were substantially different to thereference (large motion); these frames hadconsiderable differences between the ROIactivities in the nonmotion corrected andreference frames. Large motion correctionresulted in an improvement in image fidelityfactor (from 0.848 to 0.976).

Conclusion In principle, PETCT motioncorrection of the colon can be performedusing image registration between differentframes in the respiratory cycle. Clinically,frames at different points in the respiratorycycle can be obtained by respiratory gatingduring PET image acquisition. Future workcan concentrate on developing this techniqueso that it can be applied to clinical data.

Key words: Motioncorrection, NCAT,Quantitative measurement

Introduction

Physiological motion significantly affects thequality of the medical imaging scan: it notonly causes artefacts on hybrid functionalstructural scans such as the PETCT, but also


www.pjnm.net 22210288(201307/01)3:1<22:EOMCIA>2.0.TX;2M


reduces the accuracy of uptake parameters,which are based on the measurement ofradionuclide uptake. Accurate measurementof radionuclide concentration within organsprovides an accurate assessment of diseaseseverity and can therefore be used to measurethe response of various drug therapies. Oneapplication, where this is particularly useful,is the diagnosis and assessment ofinflammatory bowel disease (IBD) inpaediatric patients. Due to the nature of drugtherapies for this disease, an accurateassessment of disease severity is importantfor correct dosing of current drug therapies some of which have undesirable side effectsand varying toxicities. Drug companies investheavily in drug development and manyexperimental drugs never make it to market[4]. An accurate quantitative method ofmeasuring radionuclide uptake in pathologicaltissues would not only provide an accurateway of assessing the clinical severity ofdisease, but would also provide a quantitativemethod for assessing the effectiveness ofdevelopmental drugs [8]. Endoscopy is asuseful for direct visualisation of the lesion as

for biopsy. However, biopsy of the diseasedbowel is not always possible in proximal smallbowel disease or in the presence of strictures,and it may be uncomfortable orcontraindicated in very active disease.Therefore, a less invasive approach is needed,particularly for the assessment of theresponse to drug therapy in paediatric IBD.

Most current motioncorrection techniquesfocus on the correction of motion within thelungs and the upper abdomen: these are twoareas where motion is a particular problem.To the authors' knowledge there has been nowork to quantify the motion associated withthe movement of the ascending,transverse, or descending colon or on amethod to correct for this motion.

We have proposed a motioncorrectiontechnique based on the registration ofreconstructed images acquired at differenttime points within the respiratory cycle. Themotioncorrection technique developed inthis work is likely to be applicable toapplications other than those concerningmeasurement of the response to drug


Figure 1 Sketch of the motioncorrection methodology used in this study to estimate theinterframe 3D motion parameters (T21, T31, T41 and T51); T21 is the transformationwhich aligns frame 2 (50% inspiration) to the endexpiration frame (reference frame);T31 is the transformation describing the 3D motion between frame 3 (fullinspiration) andthe reference frame, and so on.


therapies or assessing IBD; however, theprinciples will generally be the same.

Materials and Methods

An imagebased motioncorrection approachusing a voxelintensitybased and multiresolution multioptimisation (MRMO)algorithm, first described by Bouchareb et al.[1, 6] was adopted as the motioncorrectiontechnique presented in this study. The 3Dmotiongenerated parameters (through arespiratory cycle) were coregistered to areference frame using a time efficient scheme.The reference frame is considered to be theendexpiration frame because it's the mostreproducible phase in breathing cycles (seeFigure 1).

This work utilised the NCAT phantomdeveloped by Segars et al. [2]. The NCATphantom is dynamic anthropomorphicdigitised phantom capable of generatingseveral sets of image data (called frames) atdifferent points in the respiratory or cardiaccycle. The air inside the small intestine andcolon was set to a background of 100counts/second/pixel and the activity outsidethe phantom was set to 0 counts/second/pixel. The organtobackground activityratios were set at 26:1. In each imagevolume, a set of five lesions of varyingdiameters (5, 10, 15 & 20 mm) with activitytobackground ratios of 10:1 were generated.

The properties of the image registrationsoftware used in this work are such that if itis applied to image sets generated by theNCAT phantom at different points in therespiratory cycle, the motion between thetwo image sets can be quantified by thetransformation parameters alreadydescribed. To simulate the effects of the pointspread function (PSF) of a real PET scanner,on the activity images, each image volumewas convolved with a Gaussian kernel.

Abdomen and colon motion was characterisedthrough translation, rotation, scaling andshearing parameters. Quantitative and

qualitative parameters including imagecomparison, ROI staticframe analysis, longframe analysis and lesion analysis, wereevaluated.

Results & Discussion

Characterisation of abdomen and colonmotion

Translation parameters

The largest translations estimated to registerthe different respiratory frames to thereference, were found to be in the Zaxis orheadtofeet (Figure 2a). There was anextremely small, if not zero, Xaxis translationcomponent. Translations below 3 mm arelikely to be below the resolution of a typicalPET scanner, therefore correction parametersbelow this are not likely to be clinicallybeneficial.

Rotation parameters

The largest rotation estimated to register thedifferent respiratory frames to the referenceframe was found to be about the Xaxis(Figure 2b). As we breathe in, the chestrotates upwards, and this compliments thetranslation in the Y direction. The remainingrotations about the Z and Y axes are smallerin magnitude.

Scaling parameters

Scaling parameters follow a similar trend tothe translation parameters. The predominantscaling is in the Zaxis, followed by the Yaxis,and with no scaling required in the Xaxis(Figure 2c).

Shearing parameters

Shearing is the final and the most complicatedtointerpret motion parameter. It forms thefinal level of optimisation. The X shearingcomponent is approximately linear. The Yshearing component has a parabolic nature,and the Z shearing component has a lessintuitive relationship (Figure 2d).



Image Comparison

Image comparison was performed quantitatively with image fidelity, Qf (Equation 1),and correlation measurements, Qc, (Equation2), and with ROI analysis [3, 5]

Equation 1

Equation 2

It can be seen from Figure 3 that the fidelityof the images is greatly increased aftercorrection of motion between the imageframes and the reference frame, with the

lowest value after correction being 0.976.

ROI staticframe analysis

Assessment of the motion correctiontechnique was also performed with ROI


Figure 2 Translation (a), rotation (b), scaling (c) and shearing (d) registration parameters

a b

c d

[ ]2

2

)],(*[),(*),(

1jiP

jiPjiPQ

ji

jif åå

-åå-=

[ ]2

2

)],(*[),(*),(

jiPjiPjiP

Qji

jic åå

´åå=

Figure 3 Fidelity and correlation factors fornonmotion and motion corrected frames asa function of chest position


analysis of the activities within regions of theemission images (Figure 4). Four ellipticalROIs were drawn: 1) in the tissue at the topof the transverse colon; 2) the loop betweenthe ascending and the transverse colon; 3)transverse colon in various orientations(transverse, coronal, sagittal) and 4) in thelumen of the transverse colon. It was noticedthat for small lung volumes, the motioncorrection actually reduces the activity in ROI1 to below both the reference and nonmotioncorrected frames (Figure 5a). At chest position(intermediate lung volume), the discrepancybetween nonmotion corrected frames and thereference, starts to become apparent (Figure5b). However, it can be seen from the motioncorrected frames that this discrepancy islower. At large displacements exhibited byrespiratory frames further away from thereference (large lung volumes), the differencebetween reference and nonmotion correctedROIs is large (Figure 5c), whereas thedifference between the reference and motioncorrected ROIs is significantly reduced.

Longframe analysis

Figure 6 shows the ROI activities for images,which are the sum of all the individualmotioncorrected frames, nonmotion corrected

frames, and a larger time period referenceframe (long frames). There appears to be alarge difference between the reference andthe nonmotion corrected frames, and a smalldifference between the reference and motioncorrected frames. This situation moreaccurately represents how an ungated clinical


Figure 4 Elliptical ROIs as perdescription

b

a

c

Figure 5 Motion correction for small(a), intermediate (b) and large (c) lungvolumes



image would look. For ROI 2, even though thisROI is supposed to be in an area ofbackground activity, it can be seen that theactivity is significantly more than backgroundin the noncorrected mage.

Lesion activities

ROIs were created around each of the lesionsin the same way as before. Figures 7 showsthe motioncorrected and nonmotioncorrected lesion activities for small,intermediate and large lung volumes. For thesmallvolume (Figure 7a), it can be seen thatthe measurements in each lesion are virtuallythe same, which suggests that there is littledifference between the reference and themotioncorrected and the nonmotioncorrected images. As for Figure 7b, it displaysthe same behaviour as in Figure 7a, althoughthe difference is much more pronounced. Withreference to Figure 7c, the measurements ineach lesion are virtually the same for thereference and motioncorrected frames, with

Figure 7 Lesion activities for small(a), intermediate (b), and large (c) lungvolumes

Figure 6 Motioncorrection for longframe Figure 8 (a) Frame 5 overlaid onto

reference frame. Areas displayingmismatch in alignment due torespiratory motion are the kidneys,liver, transverse colon, and areas of thesmall intestine; (b) Motioncorrectedframe 5 overlaid onto reference frame.Areas where motioncorrection has beenparticularly successful and mismatchlargely reduced are the kidneys, liver,transverse colon, and the small intestine

a

b

a

b

c


the exception of lesion 1. The anomaly for ROI1 could be caused by the movement of tissuewith a similar activity in the lesion moving intothe ROI. This suggests that for large amountsof motion, motioncorrection is particularlyeffective in yielding a correct lesion activityfor lesions of sizes ≥10 mm.

Conclusions

The motioncorrection technique adopted isespecially effective at correcting for motionbetween 25100% from the full expirationreference (i.e. chest positions correspondingfrom ¼ inhale to full inhale). For lesions sizes≥10 mm, motioncorrection appeared to besuccessful for lesions in various positions inthe ascending and transverse colon. It couldnot be established whether motion correctionof lesions <10 mm was successful or not, andthis is something that requires furtherinvestigation. For normal inspiration (used inthis work), the maximum diaphragmmovement is set to 2 cm and the maximumanteriorposterior expansion is set to 1.2 cm.Motioncorrection will reduce artefacts,improve accuracy of assessing severity andefficacy of a given treatment quantitatively(Figure 8). Another extension of this workwould be to include local motion due to thetransit of a bolus through the colon or fromother stimuli [7].

Acknowledgment

Authors would like to thank Dr William Ryderfor his assistance in implementing an analysistool developed during the course of thisproject.

References

1. Bouchareb Y, Janka R, Kalendar WA.Generation of multiphase (4D) CT databased on a nonrigid registration approachand MR breath hold scans, Medical ImageUnderstanding and Analysis ConferenceProceedings; 2004:236239.

2. Segars WP. Development of a new dynamicNURBSbased cardiac torso (NCAT)phantom, PhD Thesis (The University ofNorth Carolina, USA) 2001.

3. Masoomi MA. Quantitative and qualitativeimaging in single photon emissiontomography for nuclear m e d i c i n eapplications, PhD Thesis, (University ofSurrey, UK) 1990.

4. Lammertsma A. Role of human and animalPET studies in drug development. InternatCong Series 2004; 1265:311.

5. Masoomi MA, Bouchareb Y, Robinson A,Spyrou NM. PET/CT motion correction inpaediatric gut inflammation drug responsetherapy (invited presentation), Am NuclSoc Trans, Washington, 2007; 97:241.

6. Bouchareb Y , Roemer W , Platsch G,Kalender WA. Normalised m u t u a linformation based nonrigid registration(fusion) approach for FDGPET and CTscans. RSNA 2003 Proceedings: 328329.

7. Scott M. Wingate Institute of neurogastroenterology (London, UK), PrivateCommunication.

8. Weldon MJ, Masoomi MA, Britton, Gane J,Finlayson CJ, Joseph AEA, Maxwell JD.Quantification of inflammatory boweldisease activity using technetium99mHMPAO labelled leucocyte single photonemission computerised tomography(SPECT), Gut 1995; 36:243250.

331691 © 2013 Pakistan Society of Nuclear Medicine 22210288(201307/01)3:1<22:EOMCIA>2.0.TX;2M

Exposure rate patterns in 131I therapy inpatientsat NIMRA Jamshoro: an 08year study

Sajjad Ahmed Memon*, 1, Naeem Ahmed Laghari1, SadafTabasum Qureshi2, Fayaz Ahmad3, Atif Masood4,

Shahid Iqbal11Nuclear Institute of Medicine and Radiotherapy (NIMRA) Jamshoro,

2University of Sindh, Jamshoro, Pakistan3Pakistan Atomic Energy Commission, Islamabad, Pakistan

4Karachi Institute of Institute of Radiotherapy &Nuclear Medicine, Karachi, Pakistan

ORIGINAL ARTICLE

*Correspondence Sajjad Ahmed Memon, Nuclear Institute of Medicine & Radiotherapy Jamshoro, Pakistan Tel: +9222921338184 Fax:+92229213386 Email:[email protected]

Abstract

Aims Therapeutic use of unsealed radioisotopes with an objective of providingradiation dose to the target or affected tissuehas been in clinical practice for more than 70years. Oral administration of radioiodine is anestablished therapy for the treatment ofdifferentiated thyroid cancers. To avoidunacceptably high radiation exposures topatients' family members and other relatedpeople by applying ALARA (as low asreasonable achievable) principle, patients whoadministered the therapeutic dosage of 131Iare required to be hospitalized for some perioduntil the retained radioactivity in the body orthe exposure rate at one meter falls toacceptable levels according to national andinternational limits. The main aim of this studywas to investigate the exposure rate patternsof inpatients administered with therapeuticradioiodine and discuss the associatedradiation safety issues.

Methods This work presents the exposurerate patterns in patients treated with 131I atour institute from 2004 to 2011. A total of 83patients with thyroid cancer treated withdifferent activities of 131I ranging from 50 to150 mCi were included in this study. 76% ofthe patients were females and 24% male withan age range of 17 to 70 years.

Results The majority of patients (77.11%)were discharged at the exposure rate of lessthan 02 mR/hr (milliRoentgen/hour),whereas only 22.89% patients weredischarged at the exposure rate between 02mR/hr and 05 mR/hr. Only 1.2% of totalpatients discharged after first 24 hoursfollowing 131I administration whereas 33.73%,25.3% and 21.67% patients were dischargedafter 48, 72 and 96 hours after the doseadministration. Only 1.2% of the patientsstayed the longest duration in isolation (264hours or 11 days) at the hospital.

Conclusion With proper radiation safetymeasurements and pursuance of instructions,reduction in exposure to family members ofpatients and public can be suitably achieved.

Key words: ALARA, exposure rate,isolation room, radioiodine, I131


www.pjnm.net 22210288(201301/01)3:1<29:ERPIIT>2.0.TX;2M


Introduction

131I is a ßemitting radionuclide with a physicalhalflife of 8.1 days. Ernest O. Lawrence in 1931first constructed the cyclotron, which was laterin 1934 used for radiosodium production byEnrico Fermi through bombardment of neutronson stable iodine [6]. The primary emissions of131I are ß particles of a maximal energy of 610keV followed by a gamma rays emission of 364keV [13]. Sodium iodide (131I) was first usedin January 1941 by Saul Hertz and ArthurRoberts for treating hyperthyroidism [4] andsince then has become a popular treatmentoption for patients with thyroid cancer. It is asafe and a relatively inexpensive treatment ofchoice [4, 1, 5].

Patients treated with therapeutic dosages of131I are potential sources of unacceptablehigh radiation exposure to other individuals,particularly their close family members.Several standards and policies have beenestablished to regulate the discharge ofhospitalized patients receiving radioactivetreatment. Generally, the patient ishospitalized until the measured exposurerate at one meter from the patient�s bodysurface falls to acceptable levels [79] as perthe ALARA principle [10]. The criteria forreleasing patients are set to ensure that noone receives exposures above the regulatorydose limits for the general public [7, 1115].The main aim of this study was to discuss indetail the issues related to the patientsadministered with radioiodine as well as thesite where the activities of 131I wereadministered.

Patients and methods

Exposure rate measurement is a crucial factorin discharging patients administered withradioiodine therapy. The exposure ratemeasurement aims at keeping the radiationexposure to others as low as reasonableachievable [10, 16]. If the administeredactivity to the patient is more than 30 mCi orif the emitting exposure rate more than 5

mR/hr at one meter from the patient,hospitalization in a special isolation room untilthe residual activity is reduced to less than 30mCi or the exposure rate decreases to lessthan 5 mR/hr is necessary [17, 18].

A total of 83 patients, 63 (76%) women and20 (24%) men, were administered radioiodineat Nuclear Institute of Medicine andRadiotherapy (NIMRA) Jamshoro. Thepatients' ages ranged from 17 to 70 years. Allthe administered 131I activities ranged from50 mCi to 150 mCi. The dose to individualpatient was determined according to apatient's therapeutic requirements. Patients'personal data such as age, sex, administeredactivity, date and time of administration wererecorded. Initial exposure measurementswere recorded at the time of administrationof activity with daily exposure ratemeasurements at a distance of one meterincluding the day of discharge of the patientfrom hospital [12, 13, 19]. VictoreenMinimonitor II, model 05571, calibrated atSecondary Standard Dosimetry Laboratory,Pakistan Institute of Science and Technology,Islamabad, was used for exposure ratemeasurements.

Each patient was briefed about the procedureand written consent obtained [11]. Oral andwritten instructions relevant to the patient'sisolation and stay at home were provided toevery patient in order to minimize the doseto others [12, 20, 7, 21, 22]. The instructionsincluded: i) keeping the patient alone in theisolation room during stay at the hospital; ii)allowing caregivers/family members for veryshort periods to provide meals and water tothe patient; iii) ensuring plentiful intake ofliquids; iv) oral lemon/orange candies tominimize the dose to salivary glands; v)advising lactating mothers to stop nursingtheir babies immediately to prevent the babiesfrom ingesting radioiodine excreted into thebreast milk; vi) recommending avoidance ofpregnancy for a period of 46 months afterthe administration of 131I; vii) instructing thepatients to maintain safe distance betweenthemselves and their family members andgeneral public, ensuring separate sleeping



arrangements, avoiding travel by public transportand avoiding visiting public places such as grocerystores, shopping centers, theatres, restaurantsand public events; viii) instructing patients andtheir caregivers to comply with the same set ofinstructions at home after discharge from hospitalfor one to two weeks as maintained in isolationroom to reduce dose to caregivers/close familymembers.

The releasing criteria for the patients fromisolation was based on the local, national andinternational regulatory agencies [7, 14, 15]. USNuclear Regulatory Commission regulatory guide8.39 [23] explains various options includingrelease of patients based on measured exposurerate of 7 mR/hr at one meter [11, 16, 18, 24, 25].

It has been agreed that the patients may bereleased when their measured exposure rate isless than 5 mR/hr at one meter [26] and this limitis the regulatory requirements set by PNRA [7];however, at our institute, most patients were notdischarged from the hospital until their exposurerate was 02 mR/hr or even less to avoidunacceptable radiation exposure to familymembers.

Results

Out of 83 patients, only 1 patient (1.2%) wasdischarged after first 24 hours after 131Iadministration, with 28 (33.73%), 21 (25.3%)and 18 (21.67%) patients discharged respectivelyafter 48, 72 and 96 hours after doseadministration (Figure 1). One (1.2%) patientstayed 11 days (264 hours) due to radioactivityin the patient's enlarged neck nodes. Figure 2shows that the majority of patients (64 (77.11%))were discharged at the exposure rate≤02 mR/hr,whereas only 19 (22.89%) patients weredischarged at the exposure rate ranging from02mR/hr to 05 mR/hr.

Daily decrease in exposure rate shows theelimination of radioiodine from the patients andwe have a mixed pattern of patients' exposurerates treated at our Institute. In the first 24 hours,the exposure rate of 67 (80.72%) radioiodinetherapy patients dropped to approximately 50%of the initial exposure rate, and after eachconsecutive 24 hour period, the exposure ratesfell to 14.95%, 10.32% and 8.66% as indicatedin Figure 3. Overall, there was more than 75%fall in the initial exposure rate during stay of thepatients at the hospital. The doses tocaregivers/family members during patients' stayat hospital (through providing meals and water


Figure 1 Percentage of patients releasedat 24, 48, 72 and 96 hours at NIMRA

Figure 2 Exposure rate of patients beingreleased from NIMRA


to patients in a short time span) were estimatedfrom the daily exposure rate measurements,which ranged from 0.0321 to 0.235 mSv andfrom this set of data it was estimated that themajority of caregivers (more than 70%) receiveddoses between 0.05 mSv and 0.10 mSv.

The results of this study show that with goodradiation safety precautions and radiationprotection measures and complying withinstructions given to patient administered with131I, the exposure to family members of patientsand general public can be minimized.

Discussion

It is important to consider all matters related topatients administered with 131I at the instituteincluding: activity administered and its eliminationfrom the patient, releasing of patients fromisolation, exposure rate and its decreasingpattern, dose received by caregivers/close familymembers of patients, radiation doses to thegeneral public, and financial burden on thepatients and the medical institution where thepatients are treated as inpatients.

Since patients administered with therapeuticdoses of 131I are a source of radiation exposureand a possible radiation hazard to surrounding

individuals, it is particularly important to avoidunacceptably high radiation exposure of closefamily members of the patients. Therefore, forradiation protection purposes, the radioactivepatients are required to be hospitalized for aperiod of 13 day or more until the radioactivityin their body or the exposure rate at one meterparallel to the thyroid, falls to acceptable levels[12, 23].

US Regulatory Guide 8.39 [24] describes thecriteria for releasing patients from isolation whohave been given 131I therapy doses. Acceptableradiation burden for release include a totalbodyactivity of less than 30 mCi (or an administereddose of <30 mCi) or exposure rates of thepatients at one meter at below 5 MR/hr. Whenone of the criteria is met, the patient may bedischarged to home. Since the exposure ratedecreases with passing time due to the decay ofingested activity as well as biological clearance,daily surveys are essential. Most of the activity isexcreted from the body in urine during the firsttwo days after the radioiodine administration [1,2, 27, 28]. Uptake and retention of radiationvaries from patient to patient. From a safety pointof view of the patients' family members andgeneral public, the exposure rate must beconsidered along with the socioeconomicconditions of patients as many of our patientsare financially poor and the resources availableto the institution where the patients are beingtreated are very limited [2]. The radiologicalprotection webpage of the IAEA, prescribes 8490percent of the dose of 131I (used for treatment ofthyroid disorders) as allowed to be dischargedinto the public sewer. The site also sets thehospital discharge criteria for patient dischargeat 30 mCi or less than 5 mR/hr [8]. In Japanhowever, the level set level for the same is 14mCi or less than 3 mR/hr. ARPNSA has set thedischarge levels for radioiodine patients at 0.54mR/hr at one meter and also indicated that about80% of the administered activity are eliminatedwithin the first 48 hours [20].

Culver and Dworkin [26] reported that 26% ofthe treated patients were released after one dayfrom hospital whereas 67% and 7% were


Figure 3 Exposure rate patterns in ourpatient population


with residual activity of 27.0 ±6.3 mCi and themean exposure rate of 4.0 ±0.9 mR/hr at onemeter from the patient. Table 1 summarizes theresults of the different studies on percentageclearance of 131I activity from patients. RegulatoryGuide 8.39 [23] as well as Culver and Dworkin[26] prescribed that the patients may be releasedas the patients' measured exposure rate is lessthan 5 mR/hr at one meter, but at our institutemost patients were kept until their exposure ratebecome 02 mR/hr or even less. In a study carriedout by AlMaskery and Bererhi [24] it was shownthat the radiation exposure levels received by thefamily members including spouses range from1.3 to 4.2 mR/hr at one meter from the patients,which are in the range of permissible limits.Bererhi and Constable suggested that the patientsmay be treated as outpatients for reduction infinancial burden in the hospital [33].

Tonnonchiang et al. studied the cumulative dosesof patients' caregivers/close family members andreported that the dose to caregivers/close familymembers were less than annual limit to generalpublic which is 1 mSv [34] whereas Grigsby et al.evaluated the dose to family members of patientswhich reportedly ranged from 0.011.09 mSv[18]. Rutar et al. reported the radiation doses tocaregivers/close family members to range from0.17 to 4.09 mSv [35]. Marriott et al. in theirstudy described the maximum penetrating doseto caregivers/close family members in order of0.283 mSv [36].

Pant et al. suggested that patients may bereleased if the captured activity in the patientdrops to less than 16 mCi or the exposure rate atone meter from the patient is 3 mR/hr or less[37]. Muhammad et al. discussed the releasecriteria of radioiodine patients being treated indeveloping countries like Pakistan andrecommended that the limits might be set forreleasing patients from isolation as 10 mCi or 1mR/hr instead of 30 mCi or 5 mR/hr. Theyunderscored the importance of considering boththe financial situation of the treating institutionand the patient's background into considerationby weighing in such factors as the socioeconomiccondition, literacy rate, family situation of thepatients, etc. [38]. Panzegrau et al. [39]compared the costs of inpatient versus outpatienttreatment with same doses along with minimizingexposure to the general public and concluded thatthe average cost for outpatient treatment wasmuch less than the cost for inpatient treatmentwhich findings were also supported by Zaman etal. who reported a 60%86% reduction in cost ofoutpatient as compared with inpatient treatment[40]. These studies also imply that in the thirdworld countries it is quite important to considerthe economic burden on the hospitals providing131I treatment to the patients.

Conclusions

The results of this study as that of many otherstudies suggests that radioiodine is a very safeand effective treatment with good radiation safety


Study Percentage clearance of 131I activity from patients

24 hours 48 hours 72 hours 96 hoursThompson [18] _ 80 _ _Massimiliano et al. [29] _ 80 _ _Driver and Packer [13] 51 68 76.5 81.5Tuntawiroon et al. [30] 3075 _ _ _Parthasarathy and Crawford [31] 3075 _ _ _Tavakoli [32] 70 90 96 _Current study 50 65 75 84

Table 1 Summary of different studies on percentage clearance of 131I activity from patients


record when instructions given to patients andtheir close family members during and aftertreatment are followed so that the exposure tofamily members of patients and the general publiccan be minimized. Outpatient treatment incursmuch lower cost compared with inpatienttreatment [39, 40]. Like several other researchers[18, 24, 3436], our study has also shown thatthe radiation dose levels received by the familymembers of patients given outpatient 131Itreatment are within permissible limits andtherefore this obviates the need for admission ofpatients to isolation rooms to avoid unnecessaryexposure to close family members. Asrecommended by the International Commissionon Radiological Protection, it is important to tobe guided by the ALARA principle butconsideration should be give to the economic andsocial factors [10, 41] when considering patientdischarge outside the limits set by the regulatorybodies [79] in order to minimize the financialburden on the patients and their families as wellas on the treating hospitals. We thereforerecommend a relaxation in criteria for releasingof inpatients from hospitals.

Acknowledgements

The authors wish to thank Asrar Ahmad (SeniorScientist) and Nasurrullah (Receptionist) fromNIMRA, the Hot Lab technicians (especially KhalidHussain), the ward staff, and staff of computersection (especially Fawad Mehdi and MuhammadArshad) for their help and assistance, withoutwhich this study could not be commenced andsuccessfully completed.

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36. Marriott CJ, Webber CE, Gulenchyn KY.Radiation exposure for caregivers duringhighdose outpatient radioiodine therapy.Radiat Prot Dosimetry 2007;123(1):627.

37. Pant GS, Sharma SK, Bal CS et al. Radiationdose to family members of hyperthyroidismand thyroid cancer patients treated with 131I.Radiat Prot Dosimetry 2006;118:227.

38. Muhammad W, Faaruq S, Matiullah et al.Release criteria from hospitals of 131Ithyrotoxicosis therapy patients in developingcountries: case study. Radiat Prot Dosimetry2006;121(2):1369.

39. Panzegrau B, Gordon L, Goudy GH. Outpatienttherapeutic 131I for thyroid cancer. J Nucl MedTechnol 2005;33:2830.

40. Zaman M, Fatima N, Sajjad Z et al. HighdoseI131 therapy on outpatient basis: Imperativeand no more a desire. Pak J Nucl Med 2012;2:927.

41. Jonsson H, Mattsson S. Excess radiationabsorbed doses from nonoptimisedradioiodine treatment of hyperthyroidism.Radiat Prot Dosimetry 2004;108(2):10714.

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PJNM 2013;3:3743 331691 © 2013 Pakistan Society of Nuclear Medicine

Study of normal biodistribution and uptake patternsof novel anticancer radiopharmaceutical complex

99mTcMethotrexate

Rashid Rasheed1,*, Muhammad Javed1,Fayyaz Ahmad1, AsimaSohail1, Sohail Murad1, Misbah Masood2, Shahid Rasheed3,

Saqib Rasheed4, Babar Imran5, Simab Shaheen6

1Gujranwala Institute of Nuclear Medicine (GINUM), Gujranwala2Institute of Nuclear Medicine & Oncology Lahore (INMOL), Lahore3National University of science and technology (NUST), Rawalpindi

4QuaideAzam University (QAU), Islamabad5Punjab Institute of Nuclear Medicine (PINUM), Faisalabad

6University of Punjab, Lahore

ORIGINAL ARTICLE

Abstract

Objective Methotrexate (MTx) is an anticanceragent used in the treatment of various cancers.The objective of this study was to document thebiodistribution of 99mTclabelled Mtx (99mTcMTx)in normal subjects and patients with breastcancers.

Methods We prepared the 99mTcMTx kit by adirect labelling method and studied itsbiodistribution in volunteer subjects and patientswith breast carcinoma breast. This clinical studywas preceded by animal trials [1].

Results The normal biodistribution pattern inhumans was characterized by nonspecificuptake in the body with the 99mTcMTxbehaving like a blood pool agent with noevidence of specific organ uptake. The kidneyswere seen to be the main route of excretion.Biodistribution data of patients with carcinomabreast showed excellent tracer uptake in thetumour and showed no other nonspecifictracer uptake.

Conclusion This initial clinical trial showed that99mTclabelled anticancer drug can be successfullyused for tumour scintigraphy, which appears tobe a major breakthrough as this method oflabelling and scanning may be useful in futuretumour staging, calculating the sensitivity oftumours to certain anticancer agent and responseevaluation during chemotherapy.

Key words: 99mTcmethotrexate, biodistribution, breast cancer

*Correspondence Dr Rashid Rasheed Dept of Nuclear Medicine GINUM Cancer Hospital Gujranwala, Pakistan Email: [email protected] Tel: +923336523396 Fax: +92553493379

www.pjnm.net 22210288(201307/01)3:1<37:SONBAU>2.0.TX;2M


Introduction

The drug methotrexate (MTx) is a chemotherapeutic agent used in the treatment ofbreast cancers, head and neck cancers,leukaemia, lymphoma, lung cancers, osteosarcomas, bladder cancers, etc. [2]. In breastcancer, the drug is being used as an adjuvantand neoadjuvant chemotherapeutic agent [3].Cancer causes abnormal growth of cells bymultiple changes in gene expression leadingto deregulation in the balance of cellproliferation and cell death and ultimatelyevolving into a population of cells that caninvade tissues and metastasize to distant sitescausing significant morbidity and, if untreated,death of the host [4].

Methotrexate has been previously labelled with99mTc using a conjugate mercaptoacetyl triglycine(MAG3) and its gamma scintigraphic propertieshave been studied in animal models of tumour [1,5, 6]. Recently published animal studies also used99mTcMAG3MTx complex as a tumour imagingagent in animals [6]. However, the use of conjugatemakes the kit costly and more difficult to preparedue to the complexity of the labelling procedure andheating of the compound for proper labelling. It istherefore desirable to explore new methods fordirect and simple labelling of the anticancer agentsalong with preservation of the chemicalcharacteristics of the agent without increasing its invivo toxicity. This study aimed at direct labelling of99mTc with Methotrexate and studying thebiodistribution in normal human subjects andpatients with breast cancer following an animalmodel study [1].

Materials and Methods

Several chemicals used in this research werepurchased from Aldrich, USA (Methotrexate,stannous chloride ascorbic acid and sodium citrate),with normal saline procured from Ostuka, Pakistan.The technetium99m generator was purchased fromPakistan Institute of Nuclear Science and Technology(PINSTECH).

MTx kit formulation was carried out bymodified method published by our team [1].

20 mg of MTx was dissolved in 18 ml of D/D(double distilled) water by using few drops of1N NaOH. Ascorbic acid (30 mg) and sodiumcitrate (20 mg) were added in the stirredsolution. Next, 2 ml of stannous tartrate (5mg/ml) in pyrophosphate (5 mg/ml) solutionwere added with constant stirring and pHadjusted to 8.08.5 and a fraction of 1 ml wasdispensed in a 10 ml serum vial after passingthrough 0.22 µm membrane filter. Sodiumpertechnetate (925 MBq) eluted fromPakgen® generator from PINSTECH wasadded into the vial and incubated for 15 minat room temperature.

In vitro stability of the 99mTcMTx radiometalcomplex was estimated for various intervals oftime up to 5h. To assess the dissociation of thelabelled complex at room temperature, aliquotsat different time intervals were applied on 3mm chromatography paper (PC) and ITLCSGstrips. The PC strips were developed in acetoneand the ITLCSG strips in saline. Thepercentage dissociation of the complex at aparticular time interval was detected by thepercentage of free pertechnetate at that time.In case there was a significant loss of metalcomplex stability, it was advised to not use theradiopharmaceutical for clinical applications.Free pertechnetate in radiometal complex wascalculated using PC up to 5 hours and it wasfound to be 0.258% at any time, which waswithin acceptable limits.

The radiopharmaceutical kit was synthesizedunder sterile conditions. Laminar flow hood wassterilized with methylated spirit under UV lightexposure for 24h. Apparatus used for the kitformulation was sterilized in a preheated oven at200oC for 2h. The doserelated toxicity wasinvestigated in a group of three rabbits for fiveconsecutive days by injecting 100 mg/kg of 99mTccomplex. No signs of toxicity were observed until72h after the last i.v. injection. The animal toxicitystudy was performed in accordance with thecurrent rules of INMOL Hospital, Lahore, Pakistan.99mTcMTx complex has been tested in the animalmodels using mice by Dar et al. who demonstratedsignificant tumour uptake as compared to thenormal organs confirming that MTx is morespecific and therefore effective at tumour level



rather than in the normal tissues [1].

The study was approved by the Ethical ReviewBoard of the Gujranwala Institute of NuclearMedicine and Radiotherapy (GINUM). Threefemale patients with proven breast cancer andone female normal volunteer were studied.The subjects were fully informed of theprocedure and written consent obtained.

Before starting imaging studies, routine bloodand biochemical lab tests of all subjectsincluding a complete blood count (CBC), liverfunction tests (LFT), urea and creatinine weredetermined. Besides these clinical investigations, blood pressure and blood sugar of allsubjects were also monitored along with ER,PR, Her2Neu status of tumour receptors.Urine samples were collected for routinechemical and microscopic examination. Allthese investigations were considered asbaseline. A dose of 555 MBq of 99mTcMTx wasgiven i.v. in 30s to acquire dynamic imagesof both breasts. During the study, vital signswere monitored for any significant changefrom baseline. Scintigraphic results werecoevaluated with ultrasonography (USG) ofthe breasts, mammography and the diagnosiswas verified by biopsy of the cancerousspecimen.

Imaging protocol comprised of a dynamicacquisition of ten 60sec frames. Anterior andposterior wholebody images were acquiredat 30, 60, and 120 min postinjection. Toobtain clear visualization of the tumour, staticimages were additionally acquired in variouspositions (anterior, posterior, left lateral, rightlateral). Images were recorded by a largefieldofview (LFOV) dualheaded gammacamera (ECAM® by Siemens�, Germany),equipped with a lowenergy, allpurposecollimator for acquisition. Data processing wasdone on ECAM® work station using ESOFT®by SYNGO�.

Pharmacokinetics and biodistribution wasstudied by regionofinterest (ROI) analyses.An ROI was drawn around the wholebody onanterior and posterior views, and counts withgeometric mean method were considered

100% of the injected dose at that particulartime. ROIs were also drawn around otherimportant organs including the tumour, thekidneys, the heart and the bladder. Thebackground regions were placed close to theprimary ROIs for background correction.Scans were also analysed qualitatively. Thestudy population was much too small to allowfor statistical analyses (e.g. sensitivity,specificity and accuracy); however, correlationwith the diagnostic results from radiology andpathology was crucially undertaken andproved to be accurate.

Protein binding of 99mTcMTX was investigatedby taking a 1.6 ml blood sample andcentrifuging it at 3000rpm for 10 minutes toobtain a layer of blood cells and a layer ofserum. The blood cell layer was wasted and 2ml labelled kit was added to 0.3 ml of serumand incubated for one hour at 37oC. Next, anequal volume of trichloroacetic acid (10%)was added to the tube and shaken for tenminutes. The tube was again centrifuged at3000rpm for 10 minutes for obtainsupernatant solution and the residue. The twolayers were separated and their activitiesmeasured. The percentage of supernatant andresidue were calculated from the formula:

supernatant counts% supernatant = �� x 100 supernatant + residue counts

residue counts% residue = �� x 100 supernatant + residue counts

In vitro stability in blood was determined byadding 0.2 ml of the labelled kit to a 0.4 mlaliquot of blood and incubating at 37oC for 30min and hourly QC was performed.

In vitro stability in serum was determined bycentrifuging 5 ml aliquot of blood for 10minutes at 3000rpm. The serum wasseparated in a sample vial and blood cell layerwas wasted. Labelled kit (0.2 ml) was addedto the serum (0.2 ml) and incubated at 37oCfor 30 min and hourly QC performed.



Results

During labelling process of MTx with 99mTcdifferent species were formed including boundreduced 99mTc with drug, free pertechnetate(99mTcO4) and hydrolyzed 99mTcO2, which were

separated by PC and ITLC using acetone andsaline as mobile phase. In PC, 99mTcO4 had anRf of 0.80.9, while the 99mTcMTx and thehydrolyzed 99mTcO2 appeared at Rf=0.000.01.The hydrolyzed fraction was separated fromthe other two fractions by using saline asmobile phase by ITLC Silica Gel (SG). In thiscase the 99mTcMTx complex appeared at Rf =0.91.0, and the 99mTcO2 was detected atRf=0.000.01. The overall labelling yield ofthe 99mTcMTx complex was more than95.0±1.5% as shown in Figures 1 and 2.

The three patients as well as the normalcontrol remained well and no adversereactions were reported following i.v. injectionof 99mTcMTx. Subject�s blood pressure, heartrate, respiratory rate and body temperaturewere recorded before injection and at 4h afterinjection of 99mTcMTx. WBC and RBC countsand ER, PR, Her2 Neu were also examined.USG of the breasts, mammography and biopsyof the cancerous specimen were supportingdiagnostic tools. All tests including both theclinical and the laboratory investigations afterthe 99mTcMTx matched well with the baselinetests data. The subjects� vital signs, ECG andblood tests of were monitored during and afterthe injections and no signs of toxicity werenoticed up to three days.

The pharmacokinetics in the single subjectwith breast cancer was studied. The agentwas injected with the patient lying on theimaging table positioned under the SPECTgamma camera. The wholebody and staticscan images of the subject showing normalbiodistribution of radiotracer are shown inFigure 3.

Discussion

Our study provides the first clinical evidenceof the normal biodistribution of 99mTcMTx inhumans as a possible breast cancer imagingagent. We have modified the radiolabellingprocedure previously used in animals [1]. Thequality control of 99mTcMTx was performed by


Figure 1 Paper chromatography patternof 99mTcmethotrexate. Free pertechnetatemigrated toward the solvent front whilelabelled 99mTc remained at the origin of paper

Figure 2 ITLCSG pattern of 99mTcmethotrexate. The hydrolyzed componentremained at the origin of paper and labelled99mTc moved towards the solvent front


using paper and instant thin layer chromatography (ITLC). Results showed that95%±1.5% of the drug was radiolabelled. Invitro stability of 99mTcMTx was studied up to24 hours in fresh sample of blood and serum.No significant dissociation of 99mTcMTx wasobserved. The scintigraphic procedure wasused to evaluate the biodistribution andbiokinetics of the radiopharmaceutical.

Clinical safety trial tests are essential for anydrug before it is widely used. The project wasapproved by the Ethical Review Board and allrelevant safety consideration were taken intoaccount including the preparation of theradiopharmaceutical under sterile conditionsand animal studies with appropriatemonitoring for 72h. On completion of theanimal studies and following publication of thefindings of the study [1], we proceeded withthe human studies as outlined in this paper.Normal biodistribution study in the controlsubject showed prompt distribution of thetracer in the blood and excretion from thekidneys and urinary bladder (Figure 3).Normal blood pool is seen in the heart andmild uptake in the liver and spleen is alsoappreciable but this is apparently blood poolactivity only. No other nonspecific uptake wasnoted, which is reassuring and was theexpected finding. Main route of excretion arethe kidneys. Scintigraphy in the patient withbreast cancer showed prompt uptake ofradiotracer by the primary tumour (Figure 4)with gradual increase in the concentration ofradiotracer in the tumour with maximumtumour uptake seen at 1 hour postinjection.The maximum uptake of injected dose was inthe kidneys and the urinary bladder and wasseen to increase with time. An importantfeature was the lack of nonspecific uptake of99mTcMTx at any other body site. The mainroutes of excretion of tracer were from kidneysthough there is nonspecific blood pool activityin the liver and spleen (see Figure 4). Ourstudy also showed marked tumour uptakeimmediately after injection which increasedwith time. This specific uptake of 99mTcMtxwas also previously evidenced and reportedin animals [1].


Figure 3 Normal biodistribution of 99mTcMTx in the control subject: wholebodyscans at 1hour in the anterior (a) andposterior (b) projections followed by statictrunk views in the right lateral (c) and theleft lateral (d) projections showing the rightand the left breasts with the patient lyingprone

Figure 4 Biodistribution of 99mTcMTx in apatient with left breast cancer (arrows):wholebody scans at 1hour in the anterior(a) and posterior (b) projections followedby static trunk views in the right lateral (c)and the left lateral (d) projections showingthe right and the left breasts with thepatient lying prone


Our work is well supported by previouslypublished studies [56], which demonstratedgood uptake of the 99mTclabelled MAG3MTxcomplex in breast cancer in animal modelstogether with excretion of the radiopharmaceutical by the the kidneys. Ourmethod appears to have a distinct advantageover some other reported animal studieswhere 99mTc labelled MAG3MTx was seen tobe mainly excreted through faeces via liver[7]. The direct labelling of MTx has theadvantage of predominant renal excretion,which is clinically important because nonspecific hepatic uptake can cause difficulty inevaluation of liver lesions. The otheradvantage of the direct labelling method is thelow cost of the kit and the simplifiedformulation.

When compared to other studies, 99mTcMTxhas three distinct advantages including: 1) itis a tumourspecific agent which can be usedfor diagnostic imaging and as well as therapyand followup; 2) the targetto backgroundratios are high with 99mTcMTx as the liveractivity is almost near background whencompared to 99mTcMIBI; and c) 99mTcMTx canalso be used in monitoring response to neoadjuvant chemotherapy in breast cancer.

99mTcMTx can potentially be used not only fordiagnostic imaging and tumour staging butalso for followup studies performed formonitoring the response of chemotherapy inbreast cancer in an analogous fashion toFDGPET in lymphomas and other tumours. Itis quite plausible that 99mTcMTx may be thefirst ever SPECT anticancer radiopharmaceutical that may be introduced inoncology for staging of breast carcinoma.

Conclusion

We have demonstrated that the directlabelling methodology of 99mTcMTx is a costeffective, simpletoperform and a timeefficient method. The patient data showssufficient uptake in tumour cells with very lowuptake in normal tissues, which indicates its

potential for use as an imaging agent inbreast carcinoma. The subjective data fromour study indicates that 99mTcMTX in theabsence of a breast tumour behaves like bloodpool agent. Renal excretion is the normaldominant route of excretion. Remarkableuptake in breast cancer tissue showed thatthis technetium labelled anticancer agent canbe used for tumour scintigraphy. The initialresults of the our study in humans with thenew direct labelling method has underscoredthe potential of labelling and imaging ofanticancer drugs with technetium for tumourimaging and monitoring the response tochemotheray. However, more work is neededto explore the full potential of this new method.

Acknowledgements

This research work was carried out by Nuclearmedicine department GINUM and PunjabUniversity, Lahore. We acknowledge theefforts of Majid Raza, Shehla Akhtar,Muhammad Zubair, Muhammad Taqi andMuhammad Tariq with thanks. Special thanksto Dr Abdul Qadir, PhD, (Punjab University)for technical support to the project. Theproject was funded by Dr Rashid Rasheed,Consultant Nuclear Medicine Physician andMuhammad Javed, Dty Chief scientist, GINUM.

References

1. Dar UK, Khan I. Preparation and biodistribution in mice of a newradiopharmaceutical technetium99mlabeled methotrexate, as a tumordiagnostic agent. Hell J Nucl Med 2012;15(2):120124.

2. http://www.drugs.com/pro/methotrexate.html;Methotrexate Clinical Pharmacology,updated Sep 4th, 2012.

3. Werkheiser WC. The Biochemical, cellular,and pharmacological action and effects ofthe folic acid antagonists. Cancer Res1963;23:12771285.

4. Padmanabhan N, Howell A, Rubens RD.Mechanism of action of adjuvant chemo



therapy in early breast cancer. Lancet1986;2(8504):4114.

5. Okarvi SM, Jammaz IA. Preparation and invitro and in vivo evaluation of technetium99mlabeled folate and methotrexateconjugates as tumor imaging agents.Cancer Biother & Radiopharm 2006;21(1):4960.

6. Jain RK, Wei J, Pietro M, Gullino.Pharmacokinetics of methotrexate in solidtumors. J Pharmacokin & Biopharm 1979;7(2):181194.

7. Ahmad N, Fatima S, Irfan J, Saeed S.Modified method for methotrexateTc99m labeled radiopharmaceutical, synthesis andevaluation. J Nucl Med 2012; 53(S1):1754.

331691 © 2013 Pakistan Society of Nuclear Medicine 22210288(201307/01)3:1<37:SONBAU>2.0.TX;2M

PJNM 2013;3:4452 331691 © 2013 Pakistan Society of Nuclear Medicine

Assessment of regional cerebral blood flow in majordepressive illness by radionuclide brain

perfusion SPECT

Saima Riaz1,*, Fida Hussain2, Amin Waqar2, MK Ali2, F Minhas3

1Shaukat Khanum Memorial Cancer Hospital and Research Centre2Nuclear Medical Centre, AFIP, Rawalpindi

3Department of Psychiatry, Rawalpindi General Hospital, Rawalpindi

ORIGINAL ARTICLE

Abstract

Objective To assess the regional cerebralperfusion changes in patients with majordepressive illness, with or without suicidalbehavior by 99mTcHMPAO brain perfusion SPECT.

Methods 99mTc HMPAO brain SPECT wasperformed in 40 subjects including 10 controlsin Group A. There were 30 patients with majordepression meeting the DSMIV criteria scoring>17 on the Hamilton Rating Scale. The patientswere subclassified into groups B and C. Group Bincluded 16 patients suffering from majordepression. Group C included 14 patients withmajor depression and attempted suicide or whohad moderate to severe suicidal risk as assessedby Intent Score Scale. Semiquantitativeassessment of cerebral perfusion was perfromedthrough a brain quantification software program.The cortextocerebellum ratios were calculatedin 16 ROIs drawn on coronal section in all thepatients.

Results The scintigraphic evaluation of thecerebral perfusion in the Group B (nonsuicidal)showed significant hypoperfusion in theprefrontal (p<0.001), orbitofrontal (p<0.01),frontal motor (p<0.01) and the temporal lobes(p<0.01). In the Group C (suicidal), significanthypoperfusion was noticed in the prefrontal(p<0.001), orbitofrontal (p<0.01) and frontalmotor areas (p<0.001). The temporal lobeshowed hyperperfusion (p< 0.001).

Conclusion In major depressive illness, theprefrontal, the orbitofrontal and the frontal motorareas, are markedly hypoperfused. In severedepression not associated with any suicidalbehavior, there is hypoperfusion in the temporallobes, whereas the temporal lobes arehyperperfused in suicidal behavior, with thedegree of hyperperfusion related to the severityof the suicidal behaviour.

Key words: 99mTcHMPAO, brain perfusionSPECT, major depression, cerebral blood flow

Introduction

Major Depressive Disorder (MDD) or unipolardepression is defined as a state of intensesadness or despair that has advanced to thepoint of being disruptive to an individual'ssocial functioning and/or daily living activities.

*Correspondence Dr Saima Riaz Nuclear Medicine DepartmentShaukat Khanum Memorial Cancer Hospital andResearch Centre, Lahore, PakistanTel: 03465938557Email: [email protected]

www.pjnm.net 22210288(201307/01)3:1<44:AORCBF>2.0.TX;2M



An episode of MDD is characterized bydisturbance in mood, psychomotor activity,cognitive and vegetative behaviour [1].Suicide is a potential, tragic consequence ofuntreated depression. The term "suicidality"refers to the occurrence of suicidal thoughts(or suicidal ideation) or suicidal behaviour.Suicidal behaviour may include acts of selfharm with a fatal (suicide) or a nonfatal(attempted suicide) outcome [2].

Depressive illness is clinically diverse,overlapping symptomatically with otherpsychiatric syndromes. In clinical practice,the diagnosis of depressive disorders is basedon the Mental Status Examination, whichincludes observational assessment andneuropsychiatric interview as described in theDSMIV diagnostic criteria for majordepressive disorder [1]. Neuroimagingtechniques are employed for defining theneuroanatomy and the pathophysiology of thepsychiatric disorders.

99mTcHMPAO (hexamethylpropyleneamineoxime) brain perfusion SPECT is a functionalneuroimaging technique that allows threedimensional noninvasive study of physiologicand physiopathologic events in human brain.Brain perfusion SPECT contributes to theknowledge of the pathophysiologic basis ofneurological and psychiatric diseases. Theability of SPECT to detect regional cerebralblood flow (rCBF) variations in differentconditions have favoured the investigation ofsensory, motor, and cognitive activities(neuroactivation studies) and the centraleffects of central nervous system (CNS) drugsthrough pharmacological challenge, in boththe normal and the abnormal brains [3].Functional abnormalities in depressivedisorders have been assessed with singlephoton emission computed tomography(SPECT) and positron emission tomography(PET). Both physiologic modalities provideuseful data on rCBF [4].

In major depression, decreased regional CBFhas been reported in the left prefrontal andboth temporal regions, with the severity ofdepression correlating with the reduction in

CBF in the anterofrontal and left prefrontalcortex [5].

Cognitive disturbance with increased negativethinking and pessimism is one of the featuresof the depressive syndrome. There is arelationship between rCBF, depressivesymptoms and negative symptoms in patientswith major depressive illness, withhypofrontality, i.e. decreased perfusion in thefrontal cortex, reported to be associatedspecifically with severity of the negativesymptoms [6].

Suicidal behaviour is one of the cognitivedisturbances associated with the depressivedisorders [7]. Decreased prefrontal cortexactivity with increased or decreased temporallobe activity is often the most serious subtypeof the depression and it is associated withsadness, irritability and suicidal behaviour [8].

This study aimed at assessing regionalcerebral perfusion in patients with majordepressive illness, with or without suicidalbehaviour by 99mTcHMPAO brain perfusionSPECT.

Subjects and Methods

A normal database was created from a sampleof 10 normal subjects (6 males and 4 females;mean age 27.6 ± 4.3 years). The normalcontrols included subjects without aneurological or psychological disorder or anypsychiatric manifestations. The diseasesample comprised of 30 patients (mean age36.5 ± 9.47 years) with MDD, who fulfilled theDSMIV criteria with a Hamilton DepressionRating Scale (HAMD) score above 17. It wasa hospitalbased sample, including outdoorand indoor patients from the psychiatrydepartment.

The patients' diagnosis was establishedthrough detailed psychiatric, neurological andpsychomotor evaluation by a consultantpsychiatrist. The disease sample was furthercategorized into groups B & C. Group Bincluded 16 patients (38% male, 62% female;mean age 40.2 ± 8.92 years) with MDD but



without a history of suicidal behaviour, asassessed on the Intent Score Scale and theRisk of Repetition Scale. Group C included 14patients (all males; mean age 32 ± 8.6 years)with MDD associated with suicidal behaviour.Suicidal behaviour was rated as low, moderateor high suicidal risk as assessed by the IntentScore Scale and Risk of Repetition Scale (ISS).The study was approved by the hospital ethicscommittee.

All subjects were instructed to avoid caffeineand tobacco 12 hours prior to the scan butthe patients were not told to stopantidepressant medications. Prior to theexamination, informed consent was takenfrom all the patients and the procedure wasbriefed to relieve their anxiety. Intravenousaccess was secured at least 10 min prior toinjection with the patients lying in a quiet,dimly lit room. Ceretec� kit (HMPAO) by GEHealthcare Ltd. UK, was used for the brainperfusion imaging. The kit was labelled with99mTc according to the manufacturer'sprotocol [10]. A dose of 555 MBq (15 mCi)was injected into each subject within 30minutes from kit reconstitution. The subjectwas positioned supine with the canthomeatalline perpendicular to the face of the detectorand the head held straight [11]. A singleheaded ECAM gamma camera system(Orbiter, Siemens) fitted with a lowenergyhighresolution collimator interfaced withICON software (version 6.0.3) was employed.The data set comprised of 64projectionacquisition (30sec/view). For reconstructionof the raw images, 1pixelthick slices wereobtained and processed (Butterworth filter,cutoff 0.3 cycles/cm). Brain quantificationprogram in the ICON software was employedfor semiquantitative analysis. 3pixelthickslices were selected along the occipitofrontalplane. Coronal slices were selected forprocessing as this approach gives the bestseparation of cortical regions and bettervisualization of regions showing abnormalcerebral blood perfusion [12, 13]. The fifth(parietal and cerebellar regions), ninth (frontaland temporal regions) and twelfth (prefrontaland orbitofrontal regions) coronal slices wereselected. A total of 16 regionsofinterest

(ROIs) were generated on each slice. Themean value of average counts was calculatedin the ROIs representing the cerebellar region.In all the three slices, the average cortextocerebellum perfusion ratios were calculatedfor each ROI.

The results of the patients were comparedwith the normal controls. Statistical certaintyof 95% (± 2 SD) values in each ROI was setas criteria for categorizing the respective ROIas hypoperfused or hyperperfused in groupsB and C. The significance of the results wasevaluated by applying student's ttest [14].

Results

All of the semiquantitative data was assessedfor its distribution in the randomly selectedROIs from the control and disease groups.Figure 1 shows the brain perfusion images forthe subjects in groups A, B and C. Since thesample was parametric, the data was seen tofollow the normal distribution. In the controlgroup (Group A), cortextocerebellumperfusion ratios with 2 standard deviation(±2SD) values were calculated for each ROI.

In Group B (severely depressed patientswithout suicidal behavior), significanthypoperfusion was noticed in both theprefrontal areas (p<0.001 on both sides), theorbitofrontal areas (p<0.01 on the right,p<0.001 on the left), both frontal motor areas(p< 0.05 on the right, p<0.01 on the left),both temporal lobes (p<0.01 on the right,p<0.001 on the left). Figure 4 gives thegraphical representation of the overall hypoand hyperperfusion tendencies in the GroupB in each of the cerebral regions under study.

Group C (severely depressed patientsassociated with the suicidal behaviour)patients showed significant hypoperfusion inthe prefrontal (p<0.001 on both sides), theorbitofrontal (p<0.01 on the right, p<0.002on the left) and both frontal motor areas (p<0.001). Significant hyperperfusion (p<0.01)was observed in the temporal lobes bilaterally.Figure 5 is a graphical representation of theoverall hypoperfusion and hyperperfusion



Figure 1 Representative 99mTcHMPAO Brain Perfusion SPECT scan of a GroupA subject(normal control)

Figure 2 Representative 99mTcHMPAO Brain Perfusion SPECT scan of a GroupB subject(major depressive illness without suicidal behaviour)

Figure 3 Representative 99mTcHMPAO Brain Perfusion SPECT scan of a GroupB patient(major depressive illness with suicidal behaviour)



tendencies in the cerebral regions in Group C.

All the 30 subjects enrolled in the study wereevaluated for any correlation between thescintigraphic results and the clinical evaluationon the Mental Status Examination. Thecomparison of the regional cerebral perfusionratios in both the groups with the ISS scoreshowed significantly different results in thetemporal lobes. The lower score on the ISSpresented with hypoperfusion in the temporallobe, while hyperperfusion in the temporallobe was noticed in patients scoring high onthe ISS score, as presented in the Figure 6.

Discussion

The depressive disorders are one of the mostprevalent psychiatric conditions in the world.A recent study by the World HealthOrganization found major depression to be the

Figure 5 Cerebral perfusion pattern inGroupC (major depressive illness withsuicidal behaviour) showing hypoperfusionin the prefrontal, orbitofrontal and frontalmotor areas, with the temporal lobesshowing hyperperfusion

Figure 6 Intent Score Scale and Risk ofRepetition Scale (ISS score) versustemporal lobe perfusion ratios. Note that thehypoperfusion in the temporal lobecorresponds to the lower score on the ISS,whereas hyperperfusion in the temporal lobeis noticed in patients scoring high on the ISSscore

Figure 4 Cerebral perfusion pattern in theGroup B (major depressive illness) showinghypoperfusion in the prefrontal, orbitofrontal, frontal motor and the temporal



leading cause of disability worldwide. Suicideis the most dreadful complication of the majordepressive disorders with 80% of suicidescarried out by persons with depressiveillnesses. Although there is ongoing researchon mood disorders, there is however a paucityof data available on the suicidal behaviourespecially in this part of the developing world.

Biochemical, pharmacologic and brain imagingtechniques have all been used to study theneurobiology of mood disorders. However,because of the diverse clinical nature andoverlap of symptoms with other psychiatricsyndromes, the knowledge of the underlyingpathology in in mood disorders remainssketchy [15].

The aim of this study was to document thecerebral perfusion changes in majordepressive illness in order to determine therole of brain perfusion SPECT imaging forevaluating the underlying pathophysiology inthe major depressive illness.

Although a discontinuation of antidepressantsis desirable to rule out any drug effects on thecerebral blood flow. However, it wasn�tethically feasible to withdraw medications inour study population, given the risk ofdeterioration in symptoms in the severelydepressed patients, particularly in the thoseassociated with suicidal behaviour. A carefulrecord of the type, dosage and duration ofmedications being taken by the patients wasmade and the patient preparation instructionsensured that there was no intake of tea orcoffee and that the patient refrained fromsmoking 12 hours prior to the scan incompliance with the guideline procedure [16].

The gender distribution in Group B (nonsuicidal) was 37% males and 63% females(ratio 1:1.7). The almost double the numberof females is supported the high incidence ofdepression in the female gender [20].However, Group C (suicidal) showedpredominance of the male subjects (100%).This could be a biased sampling but alsoconsistent with the statistical genderdistribution in the violent behaviour. Genderis a very strong predictor of violent behaviour

and of suicide. Victimization surveys havegenerally supported the predominance ofmales committing suicide [18]. The averageage in the Group B was 40.2±8.92 SD with ayounger average age of 32±8.6 SD in GroupC.

In our study population, hypoperfusion in thefrontal cortex was seen in both groups withsevere depression, i.e. both without and withsuicidal behaviour. Likewise, temporal lobehypoperfusion was also seen in both thegroups. However, the the Group C patientswith associated suicidal behaviour showedtemporal lobe hyperperfusion in contrast. Thehypoperfusion in the prefrontal, the orbitofrontal cortex and the frontal motor cortex, isconsistent with the findings of previousstudies. Drevets [4] identified neurophysiological abnormalities in multiple areas of theorbital and medial prefrontal cortex, theamygdala and related parts of the striatumand thalamus in patients with mood disorders.

Yazici et al. also found decreased rCBF in theleft prefrontal and in both temporal regions inmajor depression, with the severity ofdepression correlating with the reduction inrCBF in the regions of the anterofrontal andleft prefrontal cortex [5]. Mozley et al. opinedthat the regional cerebral distribution of99mTcHMPAO demonstrates heightenedvariability in depressives. Asymmetries aremore pronounced in the regions of the limbicsystem [19].

The hypoperfusion in the frontal lobe can beexplained on the basis of the neurocircuitryinvolved in the depressive disorders. Reviewof the diagnostic criteria of DSMIV for majordepression shows that a large number ofsymptomatologic presentations are associatedwith brain areas involved with humanbehaviour, corresponding to circuits that beginin the prefrontal dorsolateral cortex, orbitofrontal cortex and anterior cingulate gyrus[14]. The dorsolateral prefrontal cortex alongwith its subcortical connections is defined asthe superior intelligence area. The prefrontalcortex is related to the control of pleasure,pain, anger, rage, panic, aggression (fight



flightfreeze responses) and basic sexualresponses [20]. Dysfunction of the subcorticalfrontal circuit is related with the appearanceof poor organizational strategies, inability tofeel and express emotions and difficulty forkeeping or changing behaviours [14]. Theorbitofrontal subcortical circuit relates withcharacteristics of personality. Because of itsfunctions in emotion and reward, the orbitofrontal subcortex is considered to be a part ofthe limbic system and has got afferences fromthe temporal lobe, thalamus, amygdala, andsubstancia nigra [14]. The orbitofrontal cortexis involved in controlling and inhibitingimpulsive actions, and lesions to this area mayresult in disinhibited aggressive or suicidalbehaviour [18] as seen in the suicidalbehaviour group in our study.

Cognitive disturbances with increasednegative thinking and pessimism are one ofthe features of the depressive syndrome. Astudy of the relationship between rCBF,depressive symptoms and negative symptomsin the patients with major depressive illnessshowed that hypofrontality, i.e. decreasedperfusion in the frontal cortex, is associatedspecifically with negative symptom severity[6].

The limbic system is called as the "emotionalbrain". It influences many aspects ofemotional behaviour via its connections withthe hypothalamus and with the autonomicsystem. It is known to be involved in thedepressive disorders along with a decrease inthe rCBF in the prefrontal cortex as well aspara limbic areas [21]. The only explanationto the hypoperfusion in the frontal motor areasis on the basis of the recent anatomic andfunctional data. It has been shown that eachfrontal motor area has a specific pattern ofanatomic connections with the prefrontal lobe,and the cingulate cortex (limbic system). Byvirtue of its specific connections with theprefrontal and the cingulate areas, it isinvolved in higherorder aspects of motorcontrol related to motivation, memory andcognitive functions that are disturbed in thedepressive disorders [22]. The temporal lobesharbour the two limbic structures within itsmedial part: the amygdala and the

hippocampus and control the emotionalstability [23]. This forms the basis ofhypoperfusion in the temporal lobe in thedepressive disorder.

Group C patients (depressed patients withassociated suicidal behaviour interestinglyshowed varying results in the temporal lobes.A few patients had marked hyperperfusion,while others had moderate hyperperfusion inthe temporal lobes. Out of 14 patients, only 5fulfilled the criteria of the high suicidal riskscoring >11 on ISS. On the scintigraphicperfusion assessment, significant hyperperfusion (p<0.01) was observed in thetemporal lobes bilaterally. The rest of 9patients with moderate suicidal risk (scoring410 on the ISS), showed moderate hyperperfusion (p<0.05) in the temporal lobes.These two categories were restricted to thesame group because of the limited number ofpatients in both the categories.

Decreased prefrontal cortex activity withincreased or decreased temporal lobe activityis often the most serious subtype ofdepression and is associated with sadness,irritability and suicidal behaviour [8]. In aPubMed database search (19922002), anincidental finding of increased perfusion inbilateral temporal lobes was reported indepressed patients with suicidal behaviour onthe resting state 99mTcHMPAO SPECT [9]. Noother specific data is available in this context.Furthermore, literature on aggression pointsto a dysfunction of parts of the limbic system,particularly the amygdala and thehippocampus. These two limbic structureswithin the temporal lobe modulate behaviour,and dysfuntioning of the limbic system resultsin moodiness, irritability, clinical depression,increased negative thinking, decreasedmotivation, flood of negative emotions andsocial isolation [18].

The presence of relatively greaterhypoperfusion in the left cerebral cortex canbe related to the dominant hemispherephenomenon, which controls handedness,language perception, speech and thebehaviour. As more than 90% of thepopulation is right handed, the left hemisphere



is dominant [24]. There is also evidence thatthe frontal and temporal abnormalitiesassociated with the violence may be expressedmore in the dominant hemisphere [18].

The perfusion differences in the cerebralregions between the severely depressedpatients and those with the associated suicidalbehaviour were compared. Both the groupshowed marked hypoperfusion in the prefrontal, the orbitofrontal and the frontal motorcortex. No significant difference was found inthese areas on the intergroup comparison. Thecomparison of temporal lobes exhibitedsignificant results (p<0.0001 on both sides).The result can be attributed to the behaviourof the limbic system harbouring the temporallobes as explained earlier. Hyperactivity wasobserved in the temporal lobes in suicidalbehaviour depending on the severity of thesuicidal risk. Whereas the severe depressionnot associated with any suicidal behaviourdemonstrated the hypoactivity in the temporallobes.

All the 30 subjects enrolled in the study wereevaluated for any correlation between thescintigraphic results and the clinical evaluationon the Mental Status Examination, i.e. IntentScore Scale and Risk of Repetition Scale (ISSscrore). Comparison of the regional cerebralperfusion ratios with the ISS score showedsignificantly different results in the temporallobes in the two groups. The lower score onthe ISS, presented with hypoperfusion in thetemporal lobe: the average ISS score in GroupB was 0. In contrtast, hyperperfusion in thetemporal lobe was noticed in patients scoringhigh on the ISS score (average score 8.71±4.04 SD), thus showing that thehyperactivity in the temporal lobe increaseswith the severity of the negative symptoms.

Conclusion

The results of our study show that in majordepressive illness (both with or withoutassociated suicidal behaviour), the prefrontal,the orbitofrontal and the frontal motor areas aremarkedly hypoperfused. In severe depressionwithout associated suicidal behaviour,

there is hypoperfusion in the temporal lobeswhereas temporal lobe hyperperfusion isobserved in severely depressed patients withassociate suicidal behaviour, with the degreeof hyperperfusion depending on the severityof the suicidal risk.

References

1. Akiskal HS. Mood Disorders: ClinicalFeatures. In; Kaplan HI, Sadock BJ, eds.Comprehensive Text Book of Psychiatry,6th edition. Baltimore: Williams & Wilkins;1995:11231130.

2. Heeringen K. The neurobiology of suicideand suicidality. Can J Psychiatry 2003;48:292300.

3. Catafau AM, Etcheberrigaray A, Perez delos Cobos J, et al. Regional cerebral bloodflow changes in chronic alcoholic patientsinduced by naltrexone challenge duringdetoxification. J Nucl Med 1999;40:1924.[Abstract]

4. Drevets WC. Neuroimaging studies ofmood disorders. Biol Psychiatry 2000;48(8):81329.

5. Yazici KM, Kapucu O, Erbas B, Varoglu E,Gulec C, Bekdik CF. Assessment ofchanges in regional cerebral blood flow inpatients with major depression using the99mTcHMPAO single photon emissiontomography method. Eur J Nucl Med 1992;19(12):103843.

6. Galynker II, Cai J, Ongseng F, et al.Hypofrontality and negative symptoms inmajor depressive disorder. J Nucl Med1998;39(4):60812.

7. Van Laere KJ, Audenaert K, et al."Reduced frontal 5Ht2a binding potentialin suicide attempters correlated topsychological profile".URL:h t t p : / / w w w . b r a i n p l a c e . c o m/bp/abstracts/abstract_detail.php?Abstract.

8. Brain SPECT imaging information andresources: Images of depression.


331691 © 2013 Pakistan Society of Nuclear Medicine 22210288(201307/01)3:1<44:AORCBF>2.0.TX;2M

U R L : h t t p : / / w ww . am e n c l i n i c s .com/bp/atlas/ch7.php.

9. Gardner A, Pagani M et al. A review ofSPECT in neuropsychiatric disorders:neurobiological background,methodology, findings and futureperspectives. Alasbimn Journal 2003;5(21):15.

10. Technical information; CeretecTM kit forthe preparation of Technetium [99mTc]Exametazime injection. GE HealthcareLtd, UK, 2006.

11. Morano GN, Seibyl JP. Technical overviewof brain SPECT imaging: improvingacquisition and processing of data. J NuclMed Technol 2003;31(4):191195.

12. Burns A, Philpot M, Costa DC, Ell PJ, LevyR. The investigation of Alzheimer'sdisease with single photon emissiontomography. J Neurol Neurosurg andPsych 1989;52: 248253.

13. Costa DC, Ell PJ, Burns A, Philpot M, LevyR. CBF Tomograms with 99mTcHMPAO inpatients with dementia (Alzheimer's typeand HIV) and Parkinson's disease initialresults. J Cereb Blood Flow Metab 1988;8:109115.

14. Prado C, Mena I. Basal and frontalactivation NeuroSPECT demonstratesfunctional brain changes in majordepression. Alasbimn J 1999;1(3):13.

15. Pearlson GD, Schlaepfer TE. Brainimaging in mood disorders.Neuropsychopharmacology 2000. URL:http://www.acnp.org/g4 /GN401000100/CH098.html.

16. Juni J E, Waxman AD, Devous MD, et al.Society of nuclear medicine procedureguideline for brain perfusion single photonemission computed tomography (SPECT)using Tc99m radiopharmaceuticals.Society of Nuclear Medicine ProcedureGuidelines Manual. 2002; version 2.0:113118.

17. Blazer D. Mood Disorders: Epidemiology.In; Kaplan HI, Sadock BJ, eds.Comprehensive text book of psychiatry,6th edition. Baltimore: Williams & Wilkins;1995:10801085.

18. Volavka J. The neurobiology of violence.J Neuropsychiatry 1999;11:307314.

19. Mozley PD, Hornig RM, Woda AM, et al.Cerebral HMPAO SPECT in patients withmajor depression and healthy volunteers.Prog Neuropsychopharmacol Biol Psychiatry 1996;20(3):44358.

20. Miller KE. An integrative theory ofprefrontal cortex function. Annual Reviewof Neuroscience 2001;24(1):167202.

21. Ito H, Kawashima R, Awata S, et al. Hypoperfusion in the limbic system andprefrontal cortex in depression: SPECTwith anatomic standardization technique.J Nucl Med 1996;37(3):410414.

22. Luppino G, Rizzolatti G. The organizationof the frontal motor cortex. News inPhysiological Sciences 2000;15(5):219224.

23. Grebb JA. Neural sciences: introductionand overview. In; Kaplan HI, Sadock BJ,eds. Comprehensive Text Book ofPsychiatry, 6th edition. Baltimore:Williams & Wilkins; 1995:8.

24. McMinn MH. Central nervous system.Last's anatomy regional and applied.Britain: English Language Book Society;1990:579607.


Movahed's sign in chronic thromboembolicpulmonary embolism

Humayun Bashir1,*, Gregory Shabo2

1Shaukat Khanum Memorial Cancer Hospital and Research Centre,Lahore Pakistan, and 2Kent and Canterbury Hospital, Canterbury, UK

CASE REPORT

Abstract

A 63yearold lady presented with breathlessness of over five weeks. Lung perfusionscan illustrated bilateral mismatched perfusiondefects consistent with multiple pulmonaryemboli. Six months later, the patientpresented with dyspnoea and was assessedfor ischaemic heart disease with a myocardialperfusion SPECT scan. The scan images didnot show any evidence of ischaemia orinfarction. However, the scan showedprominent right ventricular uptake and aDshaped left ventricle (Movahed's sign).Repeat perfusion lung scan demonstratedpersistent bilateral pumonary embolism.Echocardiogram confirmed marked right heartenlargement, significant pulmonary hypertension with pulmonary artery pressure inexcess of 80 mmHg. This case illustratesdiagnostic value of left ventricular shape on amyocardial perfusion scan.

Key words: Dshaped left ventricle,Movahed's sign, pulmonary embolism,pulmonary hypertension, right ventriclehypertrophy

Introduction

Single photon emission computed tomography(SPECT) myocardial perfusion imaging (MPI)is one of the most frequently performednuclear medicine procedures. Its applicationsinclude diagnosis, prognosis and riskstratification for coronary artery disease.Myocardial perfusion SPECT studies areprimarily performed for the assessment of theleft ventricular perfusion and function.Observations and findings regarding the rightventricle (RV) are often limited due to the thinmyocardial mass of the RV. However, thereare findings on SPECT that correlate with RVdysfunction and need to be reported. Chronicthromboembolic disease is one of the maincauses of severe pulmonary hypertension andright heart failure [1]. This case illustratesthe significance of RV findings on SPECT andthe importance of recognition of Movahed'ssign [2, 3].

Case Report

A 63yearold lady presented with breathlessness of five weeks, precipitated by a longflight. The patient's past history includedhypertension, hypothyroidism, hysterectomyfor fibroids and she was on hormonereplacement therapy (HRT). Her ECG showedTwave inversion in the inferoanterior chestleads with RBBB. The Ddimers level was highbut TroponinT level was normal. She was

*Correspondence Dr Humayun Bashir Nuclear Medicine DepartmentShaukat Khanum Memorial Cancer Hospital andResearch Centre, Lahore, PakistanTel: 00924235905000 Ext 4200Email: [email protected]

www.pjnm.net 22210288(201307/01)3:1<53:MSICTP>2.0.TX;2M


referred to the nuclear medicine deparment withhigh clinical suspicion of acute pulmonaryembolism (PE). Ventilationperfusion (VQ) lungscan was performed using 99mTctechnegas forventilation and 99mTcmacroaggregated albumin(MAA) for perfusion. The VQ scan showed bilateralmismatched perfusion defects consistent with a

high probability of PE. The patient wascommenced on anticoagulation for 6 months.

Six months later, the patient was referredagain to the nuclear medicine department fora myocardial perfusion scan to investigatepossible ischaemic heart disease. The patient'sbreathlessness had continued despite theanticoagulation therapy. Her baselineechocardiogram was essentially normal withan ejection fraction of 60%. There was adegree of tricuspid regurgitation probablyrelated to a rise in pulmonary artery pressuresecondary to the multiple pulmonary emboli.Her dyspnoea had improved by 80% withFrusemide, even without clinical signs of leftventricular failure. As the patient was onhormone replacement therapy, which isassumed to be associated with a threefoldincreased risk of venous thrombosis, this wasgradually tapered off. Patient managed 3minutes of treadmill exercise test, which waslimited by shortness of breath. However, sheachieved 80% of her maximum predictedheart rate.

A stress myocardial perfusion scan wasperformed using a 2day protocol with astandard pharmacological stress withadenosine (156 ml infusion per hour for 6minutes). There were no significant ECGchanges during stress. The nongatedmyocardial perfusion scan images showednormal perfusion in the LV walls with no

Figure 1 99mTctechnegas ventilation (toprow) and 99mTcMAA perfusion scan (bottomrow) showing bilateral multiple pulmonaryemboli

Figure 2 99mTcSestaMIBI myocardialperfusion scan showing normal LVperfusion, a Dshaped LV and increaseduptake in the RV wall

Figure 3 Followup 99mTctechnegasventilation (top row) and 99mTcMAAperfusion scan (bottom row) showingchronic bilateral pulmonary embolism




evidence of ischaemia or infarction seen.However, the LV cavity was seen to beDshaped due to a flattened septum. Thisscintigraphic appearance of the LV on cardiacSPECT has been recognized in the literatureas Movahed's sign where septal flattening issuggestive of raised right ventricle pressuresecondary to pulmonary hypertension. Theright ventricular wall showed prominent traceruptake suggestive of hypertrophy. A repeatfollowup VQ lung scan demonstratedpersistent bilateral pulmonary embolism withno significant change since the initialdiagnostic scan. A repeat echocardiogramconfirmed marked right heart enlargement,significant pulmonary hypertension with acalculated pulmonary artery pressure in excessof 80 mmHg. These findings confirmed chronicthromboembolic pulmonary hypertension.

Discussion

A straightening of the interventricular septumand a Dshaped left ventricle on shortaxis,are helpful echocardiographic signs fordiagnosing RV volume and/or pressureoverload [4]. Recognition of similar featureson myocardial perfusion SPECT have beenreported in literature as Movahed's sign [2,3].The right ventricle (RV) is routinely faintlyvisualized on gated cardiac SPECT studiesprimarily because of the relatively smaller RVmyocardial mass and lower coronary flow tothe RV. An increase in the RV mass orworkload causes higher tracer uptake in theRV wall secondary to increase in RV wallthickness and higher coronary flow.Furthermore, increased RV volume or pressureload results in displacement of the septumtowards the left ventricle causing septalflattening and a Dshaped configuration of theLV, i.e. the Movahed's sign [5, 6]. Recognitionof the RV dysfunction is important as it hasbeen associated with increased morbidity andmortality in patients with congenital heartdisease, valvular disease, coronary heartdisease, pulmonary hypertension and heartfailure [7, 8]. In a prospective study Pengo etal. found chronic thromboembolic pulmonaryhypertension to be relatively common with 4%of patients developing it within two years of

first symptomatic PE [9]. Myocardial perfusionSPECT is one of the most frequently performednuclear medicine procedures. There has beena consistent effort on the part of the variousprofessional societies to introduce and adapta standardized cardiac reporting pattern.Whereas LV findings remains the prime focus,it is recommended that abnormal RV findingsshould be mentioned in an MPI report asillustrated in this case [10].

Conclusion

Dshaped left ventricle is representative ofhigh right ventricle pressure and warrantsrecognition on myocardial perfusion imaging.

References

1. Jenkins D, Mayer E, Screaton N, MadaniM. Stateoftheart chronic thromboembolic pulmonary hypertension diagnosisand management. Eur Respir Rev 2012;21:123, 3239.

2. Movahed MR, Hepner A, Lizotte P, Milne N.Flattening of the interventricular septum(D.shaped left ventricle) in addition tohigh right ventricular tracer uptake andincreased right ventricular volume foundon gated SPECT studies strongly correlateswith right ventricular overload. J NuclCardiol 2005;2:42834.

3. Murarka S, Movahed MR. Review ofMovahed's sign (D shaped left ventricleseen on gated SPECT) suggestive of rightventricular overload. Int J CardiovascImaging 2010;26(5):5537.

4. Rudski LG, Lai WW, Afilalo J, Hua L et al.Guidelines for the EchocardiographicAssessment of the Right Heart in Adults:A Report from the American Society ofEchocardiography: J Am Soc Echocardiogr2010;23:685713.

5. WeiJen Shih, Kitta Kousa, Bonnie Mitchell,WenSheng Huang. Permanently increasedbrightness of right ventricle (Dshaped leftventricle) on myocardial perfusion imaging


331691 © 2013 Pakistan Society of Nuclear Medicine 22210288(201307/01)3:1<53:MSICTP>2.0.TX;2M

in a patient with chronic cor pulmonale: Anautopsy correlation. J Nucl Cardiol2006;13:2946.

6. Otani H, Zhao QH, Guguchew PA, WexlerJP, Travin MI. Identification of severe rightventricular dysfunction and pressureoverload by stress radionuclide myocardialperfusion SPECT imaging with gating. JNucl Cardiol 1999;6:3756.

7. Galie N, Torbicki A, Barst R, Dartevelle P,Haworth S, Higenbotam T et al. Guidelineson the diagnosis and treatment ofpulmonary arterial hypertension. The taskforce on the Diagnosis and treatment ofpulmonary arterial hypertension of theEuropean Society of Cardiology. Eur HeartJ 2004;25:22432278.

8. PepkeZaba J, Delcroix M, Lang I, et al.Chronic thromboembolic pulmonaryhypertension (CTEPH): results from aninternational prospective registry.Circulation 2011;124:19731981.

9. Pengo V, Lensing AWA, Prins MH,Marchiori A, Davidson BL, Albanese FTP,Biasiolo A, Pegoraro C, Iliceto S, PrandoniP. Incidence of chronic thromboembolicpulmonary hypertension after pulmonaryembolism. N Engl J Med 2004; 350;225764.

10. Tilkemeier PL, Cooke CD, Grossman GB,McCallister Jr BD, Ward RP. AmericanSociety of Nuclear Cardiology informationstatement: Standardized reporting matrixfor radionuclide myocardial perfusionimaging. J Nucl Cardiol 2006;13(6):e15771.


A case of left Bochdalek herniaQaisar H Siraj*,1, Rasha M AlShammeri2, Osama Ragab1

Yovan Devadoss1

1Department of Nuclear Medicine, Farwania Hospital, Kuwait2Dasman Clinic, Sharq, Kuwait

CASE REPORT

Abstract

Thoracic kidney is a very rare form of renalectopia representing less than 5% of all ectopickidneys. Ealry visualisation through functionalradionuclide imaging, both pre and postsurgery, helps in assessing the function and thelocation of the organs involved. We present acase of a 7monthold boy with surgical closureof leftsided congenital diaphragmatic hernia.99mTcDMSA scan was performed to localise thekidney and estimate the split renal function anda 99mTcMAA lung perfusion scan was performedto assess the relative lung function. The DMSAscan confirmed the presence of the left kidneyin the left hemithorax and the perfusion lungscan showed reduced pulmonary perfusion onthe left secondary to the left diaphragmatic renalhernia.

Key words: Renal cortical scan, perfusion lungscan, intrathoracic kidney, Bochdalik hernia

Introduction

Intrathoracic renal ectopia denotes either apartial or a complete protrusion of kidney abovethe level of the diaphragm into the posteriormediastinum. Thoracic kidney is a very rare formof renal ectopia representing less than 5 percent

of all ectopic kidneys. We present renal corticalscintigraphy and pulmonary perfusion imagingin a case of a left sided renal diaphragmatichernia where the radionuclide imaging providedrelevant information on the organ function andlocation.

Case report

A 7monthold boy with prenatal diagnosis ofcongenital diaphragmatic hernia was operated 35days after delivery for surgical closure of leftsided congenital diaphragmatic hernia. Thepatient was referred to the nuclear medicinedepartment for a perfusion lung scan to assessindividual lung function and renal corticalscintigraphy to localize the kidney and to estimatethe split renal function. Perfusion lung scan wasperformed using a dualheaded gamma camerawith low energy general purpose collimators.Multiple static images of the chest were acquiredafter IV injection of 74 MBq of 99mTcmacroaggregated albumin (99mTcMAA). The perfusionlung scan showed severe diffuse reduction ofuptake affecting the left lung with the right lungshowing normal uptake (Figure 1). Next, a planarstatic renal cortical scan was performed in theanterior, posterior and posteriorobliqueprojection 2 hours after IV injection of 74 MBq99mTcDMSA (Figure 2). The DMSA renal scanconfirmed the presence of the left kidney in theleft hemithorax compressing the left lung butboth kidneys were seen to contribute equally tothe total renal function. An abdominal ultrasoundwas also performed as a part of the diagnosticworkup of the patient (Figure 3).

*Correspondence Dr Qaisar H Siraj Department of Nuclear Medicine Farwania Hospital PO Box 18373, Kuwait 81004 Email: [email protected]

www.pjnm.net 222210288(201307/01)3:1<57:ACOLBH>2.0.TX;2M


Discussion

Congenital diaphragmatic hernias are usuallya lethal birth defect, associated with a 3050%mortality rate [1]. Two types of congenital

hernias occur, anterior (Morgagni) andposterior (Bochdalek); both types can occuron either side but are more common on theleft. The canal on the right closes earlier andis also "plugged" by the liver on the right


Figure 1 99mTcDMSA scan in the anterior (right) and the posterior (left) projectionsshowing left kidney in the lower chest (arrows)

RLLLRL LL

Figure 1 99mTcMAA perfusion lung scan in the anterior (right) and the posterior (left)projections showing a normally perfused right lung (RL) and a hypoperfused left lung (LL)with a focal defect (arrows) corresponding to the herniated left kidney


accounting for hernias rarely occurring on theleft. In 1848, Bochdalek first described thefailure of fusion of the posterolateral foraminain the pleuroperiotnal folds and the resultantherniation. Most Bochdaleck hernias arediagnosed in neonates and children andpresent with acute respiratory symptoms.Since 1988, at least 140 cases with thoracickidney have been reported in the literaturewith an apparent leftsided predominance anda male to female ratio of 2:1 [2].

Intrathoracic renal ectopia results in either apartial or a complete protrusion of kidneyabove the level of the diaphragm into theposterior mediastinum. The renal vasculatureand the ureter enter and exit from the pleuralcavity through the foramen of Bochdalek. Theureter is elongated to accommodate theexcessive distance to the bladder. The lowerlobe of the adjacent lung may be hypoplasticsecondary to compression by the kidney mass[3]. Frequently CDH is associated withpulmonary hypoplasia involving the ipsilaterallung, which may lead to pulmonaryhypertension and associated complications[4]. CDH is a disease of impaired lungdevelopment associated with, but not causedby, a structural defect of the diaphragm. Inaddition to pulmonary hypoplasia, numerousother disorders (e.g. surfactant deficiency,decreased antioxidant activity, increasedvascular reactivity with decreased nitric oxide

and increased endothelin1 activity, and leftheart hypoplasia may be associated withimpaired lung development [5].. The diagnosisof pulmonary hypoplasia in patients with CDHis best diagnosed by a perfusion lung scan [6].

Both pre and postsurgical assessment of thefunction of the organs herniated kidney andthe affected lung is useful in patientmanagement and surgical intervention.Nuclear medicine techniques are invaluable inthe in vivo assessment of the function of theorgans affected by the diaphragmatic hernia.

Conclusion

The scan findings here reflected the failure ofthe surgery to close the left diaphragmatichernia after delivery, with a persistent ectopicleft kidney in the chest. The DMSA renalscan not only delineated the physical locationof the ectopic kidney but also confirmed thefunction integrity of the ectopic organ. Theperfusion lung scan demonstrated thephysiological sequelae of the diaphragmatichernia on the pulmonary vasculature andfunction.

References

1. Sumner TE, Volberg FM, Smolen PM.Intrathoracic kidney diagnosis byultrasound. Pediatr Radiol 1982; 12 (2):78 80.

2. Jefferson KP, Persad RA. Thoracic kidney:a rare form of renal ectopia. J Urol 2001;165 (2): 504.

3. Eroglu A, Alper F, Turkyilmaz A,Karaoglanoglu N, Okur A. Pulmonaryagenesis associated with dextrocardia,sternal defects, and ectopic kidney. PediatrPulmonol 2005; 40 (6):547 9.

4. Keijzer R, Liu J, Deimling J, Tibboel D, PostM. Dualhit hypothesis explains pulmonaryhypoplasia in the Nitrofen model ofcongenital diaphragmatic hernia. Am JPathol 2000; 156(4):12991306.


Figure 3 Ultrasound showing the leftkidney (LK) in the thorax

LK


5. Thébaud B, Mercier JC, DinhXuan AT.Congenital diaphragmatic hernia. A causeof persistent pulmonary hypertension ofthe newborn which lacks an effectivetherapy. Biol Neonate. 1998Nov;74(5):32336.

6. Siraj QH, Clarke SEM. DiaphragmaticHernia Producing a Perfusion Defect andDiffuse Pulmonary Vascular Hypoplasia onLung Imaging. Clin Nucl Med 1994;

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LK


A case of right Bochdalek herniaDurreSabih*, Kashif Rahim

Multan Institute of Nuclear Medicine and Radiotherapy (MINAR),Multan, Pakistan

CASE REPORT

Abstract

Congenital diaphragmatic hernias are mostcommonly diagnosed as lethal anomalies inneonates or infants. In adults, congenitalhernias can present as an incidental findingor may be associated with nonspecificsymptoms. The presence of a basal lung massdue to the presence of herniated abdominalcontents in the thoracic cavity can appeardramatic on imaging and the unwary can beled into making a wrong diagnosis. We reporta case of an incidentally diagnosed rightsidedBochdalek hernia in a young woman anddiscuss the developmental anomalies leadingto this pathology.

Key words: Adult diaphragmatic hernia,congenital diaphragmatic hernia, Bochdalekhernia

Introduction

Congenital diaphragmatic hernias (CDH) aremost commonly diagnosed as lethal anomaliesin neonates or infants [1]. In adults, CDH canpresent as an incidental finding or may beassociated with nonspecific symptoms. Chestxray can mimic a mass or pnemothorax andlead to treatment complications [2]. Right

sided Bochdalek hernias are very rare, wedescribe a patient where this entity wasdiagnosed incidentally when a routineabdominal ultrasound was unable to identifythe right kidney in its normal location.

Case report

A 21yearold woman underwent an ulrasoundas part of the workup for primary subfertility.The right kidney wasn�t visualised on theultrasound. The patient was referred to thenuclear medicine department for renal corticalscintigraphy to investigate the apparent renal�absence� and to determine if this was due torenal ectopia or renal agenesis. Scintigraphywas performed 2 hours after intravenousinjection of 120 MBq 99mTcDMSA. The DMSArenal scan showed the right kidney locatedat an unusually higher level as compared tothe left (Figure 1). A colloid liver scan wasnext performed 30 minutes after intravenousinjection of of 200 MBq 99mTcstannous colloid.This showed the right kidney lying above theright lobe of the liver (Figure 2). A repeatultrasound examination to look for the rightkidney was next performed, which showed aright kidney normal in size and appearancelocated above the diaphragm (Figure 3). Therewere echogenic areas next to kidney showingperistaltic activity, which were suspected torepresent loops of gut herniating with thekidney.

Computed tomography (CT) with oral contrastshowed the ascending and most of transversecolon in the right thorax along with the right

*Correspondence Dr DurreSabih MINAR Nishtar Hospital, Multan Tel: +92 61 9200 252 Email: [email protected]

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Figure 1 DMSA renal scan in the posteriorprojection showing the right kidney locatedat an unusually higher level as comparedto the left

Figure 2 The combined colloid liver scanand DMSA renal scan showing the rightkidney to be lying above the right lobe ofthe liver

kidney (Figure 5). A right sided Bochdalekhernia was diagnosed by the fact thatposteriorly located retroperional strucures hadherniated into the chest.

Discussion

The diaphragm forms from the fusion of theseptum transversum, two pleuroperitonialfolds, cervical myotomes and the dorsalmesentery. Development begins in the thirdweek of gestation and is complete by theeighth week [3]. Congenital diaphragmatichernias (CDH) are usually a lethal birthdefects, associated with a 3050% mortalityrate [4]. CDH are associated with severalother anomalies and more than one cause

Figure 3 Ultrasound showing a right kidneynormal in size and appearance but locatedabove the right lobe of the liver


aneuploidy may exist [5].

In 1848, Bochdalek first described the failureof fusion of the posterolateral foramina in thepleuroperitoneal folds and the resultantherniation. The foramina of Bochdalek areopenings in the posterior aspects of thediaphragm (pleuroperiontal canals) throughwhich the pleural and peritoneal cavitiescommunicate [6]. There are three distinctopenings in the diaphragm to allow thepassage of the aorta, the oesophagus and theinferior vena cava. Two types of congenitalhernias occur, anterior (Morgagni) and

posterior (Bochdalek), both types can occuron either side but are more common on theleft. The canal on the right closes earlier andis also "plugged" by the liver on the rightaccounting for hernias rarely occurring on theright. In fact only about 20 cases of right sidedBochkdalek hernia had been reported till 2007[7].

Most Bochdaleck hernias are diagnosed inneonates and children and present with acuterespiratory symptoms. In adults, the diagnosistends to be incidental as in our case, or madeduring workup for nonspecific gastrointestinal


Figure 5 CT with oral contrast showing the ascending and most of transverse colon inthe right thorax along with the right kidney


or respiratory symptoms [8]. Not all cases areasymptomatic and shortness of breath [6]respiratory failure [9], pain with colon necrosis[1] chest pain and even renal colic [10] havebeen described in case reports. Sometimes achest xray will show a lung mass, loops ofgut in the chest, an eventrated diaphragm orfluid with blunting on the costophrenic angle[11]. One child with Bockdalek hernia hasbeen reported to be misdiagnosed as a caseof pneumothorax on a chest xray [12].However, in our case a prior chest xraywasn�t performed but the scout film showeda right sided lung mass (Figure 7) that couldhave been misinterpreted had this diagnosisnot been already made and the cause ofapparent lung mass determined. This reportdescribes interesting imaging findings in a rarecase.

References

1. Kocakusak A, Arikan S, Senturk O, YucelAF. Bochdalek's hernia in an adult withcolon necrosis. Hernia 2005;9(3):2847.

2. Dalton AM, Hodgson RS, Crossley C.Bochdalek hernia masquerading as atension pneumothorax. Emerg Med J2004;21(3):3934.

3. Schwartz DS. Congenital diaphragmatichernias. 2009. http://emedicine. Medscape.com/article/426142 overview#a04.

4. Smith NP. Jesudason EC, Losty PD.Congenital diaphragmatic hernia. PaediatrRespir Rev 2002;3(4):33948.

5. Langham MR Jr, Kays DW, Ledbetter DJ,Frentzen B, Sanford LL, Richards DS.Congenital diaphragmatic hernia.Epidemiology and outcome. Clin Perinatol1996;23(4):67188.

6. Alam A, Chander BN. Adult Bochdalekhernia. Med J Armed Forces India 2005;61:284286.

7. Rout S, Foo FJ, Hayden JD, Guthrie A,Smith AM. Rightsided Bochdalek herniaobstructing in an adult: case report and

331691 © 2013 Pakistan Society of Nuclear Medicine 22210288(201307/01)3:1<61:ACORBH>2.0.TX;2M

Figure 7 Scout film showing right sidedchest mass


SPECTCT of an unsuspected ischial tuberosityavulsion fracture

Rasha AlHusseini*,Qaisar H SirajDepartment of Nuclear Medicine, Farwania Hospital, Kuwait

CASE REPORT

Abstract

Ischial tuberosity avulsion fracture usuallyoccurs between puberty and late adolescencewhere the ischial tuberosity apophysis remainsopen and nonossified. Avulsion commonlyoccurs in young athletes resulting fromsudden forcible contraction of the hamstringsduring sudden forceful physical activity orchronic repetitive traction. Misdiagnosingischial tuberosity avulsion is not uncommonsince the clinical presentation closely mimicsthat of a hamstring injury. Early recognitionof the fracture is important as this will enableproper management and prevent thedevelopment of chronic pain. However,occasionally, the diagnosis is missed on plainradiographs since the radiographic featuresmay be absent, suble or nonspecific. Wepresent such a case of an unsuspected ischialtuberosity avulsion fracture diagnosed onSPECTCT.

Key words: avulsion fracture, ischialtuberosity, Tc99m MDP bone scan, SPECTCT

Introduction

Early recognition of the ischial tuberosityavulsion fracture is important for propermanagement. However, occasionally, thediagnosis is missed on plain radiographs sincethe radiographic features may be absent,subtle or nonspecific. We present such a caseof an unsuspected ischial tuberosity avulsionfracture diagnosed on SPECTCT.

*Correspondence Dr Rasha AlHusseini Department of Nuclear Medicine Farwania Hospital PO Box 18373, Kuwait 81004 Email: [email protected]

www.pjnm.net 22210288(201307/01)3:1<65:SOAUTT>2.0.TX;2M

Figure 1 2Phase Scan with bloodpool (toprow) and delayed 3hour bone scan (bottomrow) images of the pelvis in the anterior (leftcolumn) and posterior (right column)projections. There is increased blood poolactivity in the ischial region on the right inthe posterior projection with the planarimages showing focal increased uptake inthe right ischium (arrows)



Figure 2 Bone scan SPECT images in the coronal (left), sagittal (middle) and coronal(right) axes showing focal increased uptake in the region of the right ischial tuberosity withfeatures suggestive of exostosis

Figure 3 CT images (top row) and SPECTCT fusion images (bottom row) in the transaxial(left), coronal (middle) and sagittal (right) axes showing increased uptake at the site ofavulsion fracture in the right ischium



Case report

A 15yearold boy presenting with a historyof sports injury (twisted his ankle whilstplaying football) one year ago, withsubsequent pain in the posterior aspect of theright upper thigh and buttock. Xray takenfollowing the injury was negative. A 2phasebone scan with SPECTCT of the pelvis wasperformed. Blood pool images showed mildhyperemia in the ischial region on the right inthe posterior projection (Figure 1). The planarimages showed two foci of increased traceruptake in the right ischium on a backgroundof mild increased uptake in the bone (Figure1). The SPECTCT however showed a completefracture of the ischial tuberosity with increaseduptake in the region of fracture with featuressuggestive of oxostosis (Figure 2). The fusionimage showed increased uptake at the site ofthe avulsion (Figure 3).

Discussion

Avulsion fracture is a unique type of bonepathology that results from sudden forcefulmuscular contractions pulling a fragment ofthe bone away. The apophyses are the mostlikely portions of the bone to avulse. Avulsionfractures are highly prevalent amongadolescent males and are usually preceded byhistory of physical activity [1]. If not properlydiagnosed and treated, these injuries can bedebilitating to an adolescent athlete.

Patients suffering from avulsion fractures ofthe pelvis typically present as adolescentsengaging in physical activity that requiressudden and forceful muscular contraction thatresults in a popping sensation with local pain,tenderness and difficulty with ambulation. Acareful history and physical examination alongwith imaging are essential for an accuratediagnosis of avulsion fractures. Table 1provides clinical causation criteria for thediagnosis of ischial tuberosity avulsionfractures.

Plain radiographs, CT, MRI and bone scans allhelp in the diagnosis. Functional bone imaginghowever provides a sensitive and earlydiagnosis at an early stage when structuralchanges are minimal or not apparent. Thedegree and the pattern of uptake on serialbone scans also provides information on thehealing process (union) or lack thereof(nonunion) since a large proportion (around68%) of ischial tuberosity avulsion fracturesdo not reunite [2]. These fractures can betreated conservatively or surgically: thechoice of the treatment method also dependson the amount of displacement of the avulsedsegment with greater than 2 cmdisplacements considered for surgicaltreatment [3].

The SPECT bone scan is more sensitive andspecific than the planar bone scan. Theaddition of the CT component adds to thespecificity SPECT and also provides additional

Sex predilection Males (mostly)

Prime onset mechanism Physical activity

Commonest physical activity Soccer & gymnastics

Onset factor Sudden Forceful muscular contraction

Commonest site Ishial tuberosity

Commonest activity Running and kicking

Skeletal maturity Immature; adolescent

Table 1 Clinical causative criteria for the diagnosis of ischial tuberosity avulsion


331691 © 2013 Pakistan Society of Nuclear Medicine 22210288(201307/01)3:1<65:SOAUTT>2.0.TX;2M

structural information. The hybrid functionalstructural modality of SPECTCT is ideal forimaging patients with suspected ischialtuberosity avulsion fractures as it provides therequisite functional and structural informationnecessary for both diagnosis and subsequenttreatment.

This case highlights the importance of anawareness of the clinical causative criteria thatmay help in the appropriate diagnosisparticularly in the light of the fact thatalthough the patient fulfilled almost all theclinical criteria but the correct diagnosis wasn�testablished in a timely fashion. The case alsoillustrates the value of SPECTCT inestablishing the diagnosis of ischialapophyseal avulsion fractures. The case alsoillustrates the importance of an awareness ofthe radiographic and scintigraphic features ofthis pathology and its associatedcomplications such as exostosis formation andnonunion, which are crucial for correctmanagement. SPECTCT also providesinformation for instituting the appropriatetreatment and followup.

References

1. Mbubaegbu CE, O�Doherty D, ShenolikarA. Traumatic apophyseal avulsion of thegreater trochanter: case report and reviewof the literature. Injury 1998;29(8):647649.

2. Martin TA, Pipkin G. Treatment of avulsionof the ischial tuberosity. Clin Orthop RelatRes 1957;(10):10818.

3. Wood JJ, Rajput R, Ward AJ. Avulsionfracture of the greater trochanter of thefemur: recommendations for closedreduction of the apophyseal injury. InjuryExtra. 2005; 36:255258.


SPECTCT of peritonealscrotal leakage inpatients on continuous ambulatory

peritoneal dialysis Anwar AlBanna*,Qaisar H Siraj, Uzma Afzal, Eiman AlAwadi,

Ahmad Ashour

Department of Nuclear Medicine, Farwania Hospital, Kuwait

CASE REPORT

Abstract

Peritoneal scintigraphy is a useful radionuclidetechnique in assessing the drainage functionand for evaluating anatomical problems inpatients on CAPD. Occasionally a patient onCAPD will present with scrotal swelling whenradionuclide technique helps diagnose thecause of the swelling. We present a report ofperitoneal scintigraphy in two patients onCAPD with scrotal swelling where the planarand SPECTCT images demonstrated aconnection between the peritoneal cavity andthe peritesticular tunica vaginalis. This is thefirst report of a SPECTCT peritoneal scintigram.

Key words: Scrotal swelling, diasylateleakage, peritoneal scintigraphy

Introduction

Peritoneal scintigraphy is a useful radionuclidetechnique in assessing the drainage functionand for evaluating anatomical problems inpatients on Continuous Ambulatory PeritonealDialysis (CAPD).

The occasional association of CAPD and inguinal

hernia [1, 2] necessitates investigation ofpatients on CAPD who present with testicularswelling with peritoneal scintigraphy in orderto correctly identify the underlying cause ofthe scrotal swelling.

There are multiple causes of scrotal swelling,both systemic and local. However in patientson CAPD, additional factors such as diasylateleakage and volume retention, may contributeto the scrotal swelling. It is therefore essentialto determine the exact cause for the scrotalswelling in patients undergoing CAPD in orderto institute the appropriate treatment.Diagnosing diasylate leakage will requiresurgical repair, but if the leakage is excluded,increasing ultrafiltration will most probablyresolve the scrotal oedema.

Peritoneal scintigraphy is a valuable test fornot only diagnosing the presence of the leakbut also for identifying the source of theleakage [3, 4]. We present a report ofperitoneal scintigraphy in two patients onCAPD with scrotal swelling where the planarand SPECTCT images demonstrated aconnection between the peritoneal cavity andthe peritesticular tunica vaginalis. This is thefirst report of a SPECTCT peritoneal scintigram.

Case reports

Case 1 A 52yearold male with endstagerenal disease presented a week after startingCAPD with 1day history of scrotal swelling.

*Correspondence Dr Anwar AlBanna Department of Nuclear Medicine Farwania Hospital PO Box 18373, Kuwait 81004 Email: [email protected]

www.pjnm.net 22210288(201307/01)3:1<69:SOPSLI>2.0.TX;2M



Figure 1 99mTcNanocolloid peritoneal scanplanar static imaging performed immediatelypostinjection (top), supine post ambulationimage at 60min postinjection (middle)followed by imaging in the erect posture(bottom). Activity is seen in the proximal leftinguinal canal (arrow) in all the three images

Figure 2 99mTcNanocolloid planar peritonealscan images: immediate postinjection staticimage (top) and static images with cobalt57flood phantom preambulation (middle) andpostambulation (bottom). Activity is seen inthe left inguinal canal (arrow). The scrotaloutline is marked (chevrons)



Peritoneal scintigraphy was performed afterintraperitoneal instillation of 120 MBq of99mTcNanocolloid via the indwelling Tenckhoffcatheter. Static 5minute duration images ofthe abdomen and pelvis were obtained in thesupine posture, immediately after tracerinstillation followed by static imaging in theerect posture after ambulation. The imagesrevealed early visualization of a focus ofactivity in the proximal left inguinal canalwhich was seen to persist unchanged on thesubsequent images (Figure 1).

Case 2 A 55yearold male recently startedon CAPD due to endstage renal diseasereported with persistent bilateral scrotalswelling post CAPD. The patient had similarpresentation earlier following a previoussession of CAPD, which however had resolved

spontaneously. Peritoneal scintigraphy wasperformed after intraperitoneal instillation of130 MBq of 99mTcNanocolloid via theindwelling Tenckhoff catheter. Planarsequential images of the pelvis and scrotalregion were obtained with and without cobalt57 flood phantom, pre and postambulation(Figure 2). SPECTCT was additionallyperformed. The images show appearance ofthe activity in the left inguinal region whichappear to be in the left inguinal canal on CTcomponent (Figure 3).

Discussion

A chronic elevation in intraabdominalpressure in patients undergoing CAPDproduces an increased stress on the abdominalwall which compounded by several systemic

Figure 3 99mTcNanocolloid SPECTCT scan images in the transaxial (left column), sagittal(middle column) and the coronal (right column) axes with SPECT (top row), CT (middle row)and fused SPECTCT (bottom row) showing radioactive fluid in the left inguinal canal (arrows)


331691 © 2012 Pakistan Society of Nuclear Medicine 22210288(201307/01)3:1<69:SOPSLI>2.0.TX;2M

(uraemia, anaemia, transperitoneal proteinloss, etc.) and local predisposing factors(multiparity, prior abdominal surgery, patentprocesses vaginalis, etc.) increases thelikelihood of CAPDinduced hernias [57].

Scrotal swelling in a CAPD patient is a causefor concern since inguinal and ventral herniasboth, can cause leakage of the peritonealfluids into the scrotum. In inguinal hernias,fluid accumulates in the cavity of tunicavaginalis through a patent processus vaginalis,whereas in ventral hernias, fluid extravasatesfrom a peritoneal tear into the sacral tissue.Extraperitoneal leakage can also occur at thesite of the catheter tip or even from tornperitoneum within a hernial sac. The etiologyis further compounded by the fact thatoccasionally scrotal/penile oedema may resultfrom resorbtion of fluid from within a patentprocesses vaginalis despite an intactperitoneal lining.

Since the management of the these situationsdepends on an accurate diagnosis of the site,nature and extent of the leakage, an imagingmodality, which is able to provide the relevantfunctional and anatomical information can alterpatient management. Peritoneal scintigraphyenables tracking the radiotracer distributionand provides information on site and extentof the peritoneal leakage with the SPECTCTfusion images help accurately localize theexact anatomical route and plane.

In conclusion, combination functionalstructuralimaging technique of SPECTCT has theadvantage of accurately localizing the exactsite and extent of leakage as well asdifferentiating between the type and cause ofthe scrotal swelling in patients undergoingCAPD presenting with scrotal swelling. This isthe first report of a SPECTCT peritonealscintigram in a diagnosis of peritonealscrotaldiasylate leakage.

References

1. Cooper JC, Nicholls AJ, Simms JM, PlattsMM, Brown CB, Johnson AG. Genitaloedema in patients treated by continuousambulatory peritoneal dialysis: an unusual

presentation of inguinal hernia. Br Med J(Clin Res Ed) 1983;286(6382):19234.

2. Wetherington GM, Leapman SB, RobisonRJ, Filo RS. Abdominal wall and inguinalhernias in continuous ambulatoryperitoneal dialysis patients. Am J Surg1985;150(3):35760.

3. Walker JV, Fish MB. Scintigraphic detectionof abdominal wall and diaphragmaticperitoneal leaks in patients on continuousambulatory peritoneal dialysis. J Nucl Med1988;29(9):1596602.

4. Johnson J, Baum S, Smink RD, Jr.Radionuclide imaging in the diagnosis ofhernias related to peritoneal dialysis. ArchSurg 1987;122(8):952954.

5. O'Connor JP, Rigby RJ, Hardie IR, Wall DR,Strong RW, Woodruff PW, Petrie JJ.Abdominal hernias complicating continuousambulatory peritoneal dialysis. Am JNephrol 1986;6(4):2714.

6. Suga K, Kaneko T, Nishigauchi K, SoejimaK, Utsumi H, Yamada N. Demonstration ofinguinal hernia by means of peritoneal99mTcMAA scintigraphy with a loadproduced by standing in a patient treatedby continuous ambulatory peritonealdialysis. Ann Nucl Med 1992;6(3):2036.

7. Walker JV, Fish MB. Scintigraphic detectionof abdominal wall and diaphragmaticperitoneal leaks in patients on continuousambulatory peritoneal dialysis. J Nuc Med1988 Sep;29(9):1596602.


Mediastinal spread of medullary thyroidcarcinoma imaged by locally formulated

99mTc DMSA (V)Aakif Ullah Khan, Hameedullah*, Aamir Bahadur, Muhammad

Rauf Khattak, Abdus Saeed Shah

Department of Nuclear Medicine, Institute of Radiotherapy and NuclearMedicine (IRNUM), Peshawar

CASE REPORT

Abstract

Medullary thyroid carcinoma (MTC) is adistinct Ccell tumour of the thyroid gland thatproduces calcitonin in high quantities. Variousimaging techniques are available in nuclearmedicine to image MTC which include 131IMIBG and somatostatin receptor imagingagent 111InOctreotide. Due to thenonavailability of these agents in Pakistan, wetried using locally prepared 99mTclabelledpentavalent dimercaptosuccinic acid (99mTc(V)DMSA) in a patient suspected of advancedMTC. CT with contrast could not be performedin this patient due to raised serum urea andcreatinine levels indicating renal impairment.99mTc(V)DMSA was prepared by modificationof a locally formulated kit of renal DMSA.Significant accumulation of the tracer wasseen in the gross disease present in the neckand mediastinum. The resolution and goodphysical characteristics of 99mTc(V)DMSAmake it a useful agent for MTC imaging, whereother modalities are not available.

Key words: Medullary thyroid cancer, 131IMIBG, 111Inoctreotide, somatostatin receptorscintigraphy, 99mTc(V)DMSA scan

Introduction

Medullary thyroid carcinoma (MTC) is anuncommon tumour accounting for 310% of allthyroid malignancies [1]. According to theradiotherapy record of Institute of Radiotherapyand Nuclear Medicine (IRNUM), there are only65 cases of MTC from 1994 to 2011, whichcomprises about 12% of all neuroendocrinetumours and 0.08% of all malignant casesregistered in the hospital.

MTC arises from thyroid Ccells which producecalcitonin. Hence, an elevated serumcalcitonin level is a reliable marker of awelldifferentiated MTC [2, 3]. This tumour ismostly resistant to external beam radiationtherapy (EBRT) and chemotherapy in most ofthe cases [4]. The treatment of gross primaryand recurrent disease is surgery [5]. But fora successful surgical attempt, a knowledge ofthe extent of disease is very important. Effortsto delineate the disease has been made in thepast using various imaging techniques likeconventional xrays, computed tomography(CT), magnetic resonance imaging (MRI),abdominal and neck ultrasound. However,

*CorrespondenceMr HameedullahInstitute of Radiotherapy and Nuclear MedicineUniversity Campus, PeshawarTel: +9291921611417 Ext: 150Fax +92919216118Email: [email protected]

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these modalities pose some difficulties in thedetection of recurrent and metastatic MTC dueto the distortion of normal anatomy after thesurgery [6]. Bone scan is used to look forskeletal involvement in the disease process.The functional imaging tools commonlyemployed for the evaluation and visualizationof MTC are radioiodinated (123I ) or (131I)metaiodobenzylguanidine (MIBG), thalliumchloride (201TI), pentavalent 99mTcdimercaptosuccinic acid (99mTc(V)DMSA), and 111Inand 99mTclabelled octreotides [6, 7]. Out ofthese 111In and 99mTclabelled octreotides haveproved more useful but their high cost andnonavailability at most of the nuclear medicineinstitutes in our country are the majorhindrances in the way of their routine use [8,9]. Alternatively, 18FFDG PET and monoclonalantiCEA labelled antibodies also have provedto be advantageous, but their use in theroutine workup of MTC patients is also limitedbecause of the abovementioned reasons [1012].

Where conventional imaging techniques (US,CT and MRI) fail to localize the tumour or themetastatic lesion, radionuclide techniques arethe next diagnostic step in the evaluation of aMTC patient depending upon the availability ofthe method and experience of the professionalsin a nuclear medicine facility. Several authorsbelieve that imaging with 99mTc(V)DMSA is themost costeffective and timeefficienttechnique for MTC evaluation [11, 13].

Previously published work from this institutereports successful visualisation of MTC using99mTc(V)DMSA and 131I MIBG [14, 15]. Thepresent case is yet another example ofsuccessful diagnosis of MTC using locallyformulated 99mTc(V)DMSA where the scanyielded good quality images and providedimportant clinical information helpful insubsequent patient care.

Case Report

A 38yearold male was diagnosed four yearsago as a case of MTC after excision biopsies

from a neck mass. He was given EBRT (50 Gy)to the neck and superior mediastinum at thisinstitute but was subsequently lost to followupuntil 3 years ago when he reported withdyspnoea and chest tightness. At the time ofhis second presentation, his serum calcitoninwas very high at >2000pg/ml (normal range08.4). He had palpable lymph nodes in theneck but due to his severe chest tightness andbreathlessness, there was a clinical suspicionof advanced disease in the mediastinal lymphnodes. On routine checkup, his renal profilewas found to be deranged with high serumurea and creatinine values.

The case was discussed in the institutionaltumour board and then referred to nuclearmedicine department for somatostatin receptorImaging (SSR). However, due to nonavailabilityof this radiopharmaceutical, it was decided toperform 99mTc(V)DMSA scintigraphy usinglocally formulated radiopharmaceutical. Insome institutes, DMSA(V) is available in theform of a freezedried kit, which is thenreconstituted. We however prepared theradiopharmaceutical using renal DMSA vialwhich labels with 99mTc in +3 oxidation state(trivalent) at pH 34; this was converted toDMSA(V) with pH 8.5 (determined by pHindicator strips ) under aseptic conditions. Therenal DMSA kit (supplied by IPD, PINSTECHIslamabad, Pakistan) containeddimercaptosuccinic acid (1.0 mg), SnCl2.2H2O(0.35 mg), ascorbic acid (0.5 mg), andmannitol (20 mg). 1 ml of 0.167N solution ofNaHCO3 (which can be prepared by dissolving280 mg of analytical grade NaHCO3 in 20 ml ofdistilled water) was added to the vial to makethe medium alkaline. The pH of this DMSA viallies in the range of 8.4 to 8.5. 20 mCi (740MBq) of fresh elute of sodium pertechnetateobtained Mo/Tc Generator (PAKGEN providedby IPD, PINSTECH Islamabad, Pakistan) wasadded to this vial. The vial was incubated for15 minutes to complete the reaction. Qualitycontrol tests were performed by thinlayerchromatography (TLC); the radiochemicalpurity (RCP) was found to be more than 95%.

The preparation was then injected intravenously into the patient's antecubital veinthrough an indwelling intravenous cannula.



Early (1hour) and delayed (24hour) anteriorspot images of the head, neck, chest andabdomen were acquired using Siemens Orbitorgamma camera with lowenergy allpurpose(LEAP) collimator and energy window of 15%centered at 140 KeV photopeak.

The 1hour images were very sharp withexcellent resolution and showed goodradiopharmaceutical avidity by the tumour andseemed potentially useful determining andevaluating sites of metastases in the head,neck and chest region (Figure 1). The 24hour

post tracer injection images were additionallyacquired to see the tracer residence over aprolonged period of time and to look for anyredistribution (Figure 2).

Discussion

MTC is a rare and slowgrowing tumour butposes challenges in the management. Itoriginates from parafollicular Ccells andsecretes copious calcitonin; hence highcacitonin levels are used as a marker of disease

Figure 1 99mTc(V) DMSA scan 1hourimages in the anterior projection

Figure 2 99mTc(V) DMSA scan 24hourimages in the anterior projection



recurrence or residual disease. These tumoursdo not concentrate radioiodine and show poorresponse to chemotherapy and radiationtherapy. Surgery is therefore the only strategyfor potential cure; but for successful surgicalmanagement, early detection of recurrence isvery important. Conventional radiographicimaging modalities are often employed fordetecting the recurrence or the residue of thetumour. But the results of these techniques aresometimes negative in presence of elevatedcalcitonin levels because of the lower sensitivityof morphological imaging modalities in scarredor previously violated tissues or organs.Therefore, functional nuclear medicine imagingstudies such as radioiodinated (123I or 131I)metaiodobenzylguanidine (MIBG), thalliumchloride (201TI), pentavalent 99mTcdimercaptosuccinic acid (99mTc(V)DMSA), 111In and99mTclabelled octreotides, 18FFDG PET andmonoclonal antiCEA labelled antibodies, areexplored as a secondline options to detect MTCrecurrence. But all of these techniques haveassociated merits and demerits. Amongst them99mTc(V)DMSA has superior characteristics, suchas better physical properties, lower cost, wideavailability and less time delay betweenradiotracer injection and imaging, which makesit a better imaging agent for detection ofrecurrence and metastatic MTC.

In this particular case, where CT scan withcontrast was deemed unsuitable due to renalimpairment, we tried using 99mTc(V)DMSAfunctional imaging as the primary diagnostictest, and the technique provided excellentquality images with the uptake persisting in thetumour for many hours as indicated by the24hr images. We have previously imaged MTCimaged with 99mTc(V)DMSA and we think thatthis agent can also be used in future fortargetting these tumours with 188Relabelledpentavalent DMSA ( 188Re(V)DMSA) [14].

99mTc(V)DMSA is a radiopharmaceutical whichis used to evaluate, image and manage a largenumber of tumours, but the exact mechanismof 99mTc(V)DMSA uptake in tumours is stillunknown. One suggested mechanism is thepHsensitive character of 99mTc(V)DMSA which

is reported as a factor influencing itsaccumulation in cancer cells [16]. Severalreports from Papantoniou and colleaguessuggested that 99mTc(V)DMSA uptake by breasttumours is related to proliferative activity, whichis either directly related to tumour grade or tothe mitotic activity [17]. It is also thought thatthe mechanism of uptake of 99mTc(V)DMSA bedue to the structural similarity between 99mTc(V)DMSA core (phosphatelike ion TcO43) andPO43), which is avidly taken up by some cancercells, but some other studies suggest a morecell specific 99mTc(V)DMSA uptake than thephosphate localization. Our experience of avidand persistent 99mTc(V)DMSA uptake in all thetumour deposits in the neck and mediastinumhave encouraged us to explore its potentials andvarious clinical settings.

Conclusion

99mTc (V) DMSA is an economical and readilyavailable imaging agent for the detection of MTCin the clinical setting of recurrence detectionespecially in the head, neck and mediastinalregions.

References

1. Favia G, Iacobone M. Medullary thyroidcarcinoma: state of the art. G Chir 2005;26(1112):4059.

2. Ismailov SI, Piulatova NR. Postoperativecalcitonin study in medullary thyroidcarcinoma. Endocr Relat Cancer2004;11(2):35763.

3. Vierhapper H, Raber W, Bieglmayer C,Kaserer K, Weinhausl A, Niederle B. Routinemeasurement of plasma calcitonin innodular thyroid diseases. J Clin EndocrinolMetab 1997;82:15891593.

4. Pitt SC, Moley J F. Medullary, anaplastic,and metastatic cancers of the thyroid.Semin Oncol, 2010;37(6):567579.


331691 © 2013 Pakistan Society of Nuclear Medicine 22210288(201307/01)3:1<73:MSOMTC>2.0.TX;2M

5. Moley JF, Medullary thyroid carcinoma,Curr Treat Options Oncol 2003;4:33947.

6. Niafar M, Dabiri S, Bozorgi F, Niafar Fand Gholami N. Metastatic medullarythyroid carcinoma: a case report. J ResMed Sci. 2011;16(4):568573.

7. Lewington VJ, Clarke SE. Isotopicevaluation and therapy in patients withmalignant endocrine disease. Best PractRes Clin Endocrinol Metab 2001;15(2):22539.

8. Gabriel M, Decristoforo C, Donnemiller E,Ulmer H, Watfah Rychlinski C, Mather SJ,et al. An intrapatient comparison of99mTcEDDA/HYNICTOC with 111InDTPAoctreotide for diagnosis of somatostatinreceptorexpressing tumors. J Nucl Med2003;44(5):70816.

9. Czepczyñski R, Parisella MG, Kosowicz J,Miko³ajczak R, Ziemnicka K, GryczyñskaM, et al. Somatostatin receptorscintigraphy using 99mTcEDDA/HYNICTOC in patients with medullary thyroidcarcinoma. Eur J Nucl Med Mol Imaging2007;34(10):163545.

10. Rufini V, Castaldi P, Treglia G, Perotti G,Gross MD, AlNahhas A. Nuclear medicineprocedures in the diagnosis and therapyof medullary thyroid carcinoma.Biomed Pharmacother 2008;62(3):13946. Epub 2007 Aug 20.

11. Bozkurt MF, Uğur O, Banti E, GrassettoG, Rubello D. Functional nuclear medicineimaging of medullary thyroid cancer.Nucl Med Commun 2008;29(11):93442.

12. Ozkan E, Soydal C, Kucuk ON, Ibis E,Erbay G impact of ¹⁸FFDG PET/CT fordetecting recurrence of medullary thyroidcarcinoma. Nucl Med Commun 2011;32(12):11628.

13. Guerra U, Pizzocaro C, Terzi A. The useof 99mTc (V) DMSA as imaging for the

medullary carcinoma. J Nucl Med AlliedSci 1988;32:242247.

14. Khan AU , Ahmad S, Manan A and KhanAA. Visualisation of medullary carcinomathyroid with locally formulated 99mTc(V)DMSA and comparison with 131IMIBG Scintigraphy. J Coll Physicians SurgPak 2001;11(6): 394396.

15. Khan AU, Thein TM, Khan AA, Khan SM.Role of locally formulated 131IMIBG inimaging of neuroendocrine tumors. J CollPhysician Surg Pak 2001; 11(10):61721.

16. Horiuchi K, Saji H, Yokoyama A. Tc(V)DMSA tumor localization mechanism: apHsensitive Tc(V)DMSAenhancedtarget/nontarget ratio by glucosemediated acidosis. Nucl Med Biol 1998;25(6):54955.

17. Papantoniou V, Christodoulidou J,Papadaki E. 99mTc(V)DMSAscintimammography in the assessmentof breast lesions: comparative study with99mTcMIBI. Eur J Nucl Med 2001;28(7):923�8.


Myocardial uptake of 99mTcMDP in infectiveendocarditis

Hasan Raza, Zafar Nasir*, Shahid Kamal

Atomic Energy Medical Centre, JPMC, Karachi

IMAGING GAMUT

Key words: Infective endocarditis, Tc99mMDP bone scan, SPECTCT

Background A 10yearold girl withcongenital heart disease was diagnosed withinfective endocarditis. The patient developedpain in her right hip region. Her chest and pelvicxrays were unremarkable. She was referredto the nuclear medicine department for a bonescan to investigate a musculoskeletal cause forthe pain.

Procedure Planar bone scintigraphy wasperformed 3 hours after an intravenous injectionof 370 MBq 99mTcmethylene diphosphonate(99mTcMDP). This was followed by a SPECTCTof the upper trunk.

Findings The planar bone scan showed focalsofttissue uptake in the left chest lateral to thesternum and adjacent to the anterior end of theribs in the 2nd intercostal space (Figure 1).SPECT images showed tracer uptake justposterior to ribs on the left side (Figure 2).Fused CTSPECT images revealed tracer uptakeat the upper lateral part of the heart (Figure 3).

Her Echocardiography showed patent ductusarteriosus (PDA) with lefttoright shunt andmitral and tricuspid regurgitation. There were

*Correspondence Dr Zafar Nasir Atomic Energy Medical Centre Jinnah Post Graduate Medical Centre Rafique Shaheed Road, Karachi Email: [email protected]

www.pjnm.net 22210288(201307/01)3:1<78:MUOTII>2.0.TX;2M

Figure 1 Bone scan images of the trunk inthe anterior (left column) and the posterior(right column) projections with focal softtissue uptake in the left chest region (arrow)

Figure 2 Bone SPECT images in the sagittal(left), axial (middle) and coronal (right)slices showing focal increased softtissueuptake (arrows)


331691 © 2013 Pakistan Society of Nuclear Medicine 22210288(201307/01)3:1<78:MUOTII>2.0.TX;2M

vegetations over PDA and thickened andprolapsing anterior mitral commissure.

Conclusion It was speculated that cardiaccalcinosis associated with vegetations over PDAor the thickened prolapsed mitral valve was thelikely cause of focal increased 99mTcMDP uptakeseen in this case as has been suggested in thepublished literature [1, 2].

Comments 99mTcMDP softtissue uptake can bedivided into five categories including dystrophiccalcification, metastatic calcification, metabolicuptake, compartmental sequestration and spurious orartifactual uptake. Dystrophic calcification occurs inpatients with normal Ca2+ and PO4 levels and refers toCa2+ deposition in tissues secondary to histologicdisruption caused by trauma, ischaemia or cellularnecrosis or in the enzymatic necrosis of fat. It isthought that calcium ion binds to phospholipidspresent in membrane bound vesicles, phosphatasesgenerate phosphate groups which in turn bind to the

calcium, and the cycle is repeated until localconcentrations are elevated and crystals begin to form[3]. Tissue damage from inflammation or infectionresults in calcium deposition based on theirpathophysiologic characteristics resulting in dystrophiccalcification [4].

There are several reports of myocardial uptake of MDPin the literature including uptake in amyloidosis,multiple myeloma and cardiac calcinosis inhaemodialysis patients [5, 6] but the case of of MDPcardiac uptake in infective endocarditis has not beenpreviously reported.

References

1. Inoue N, Ohkusa T, Katoh T, Esato K,Matsuzaki M. Infective endocarditis withextensive calcified granulation of mitralannulus and valve. Jpn Circ J 2000;64:990.

2. Eicher JC, De Nadai L, Soto FX, FalconEicher S, Dobsák P, Zanetta G, et al.Bacterial endocarditis complicating mitralannular calcification: a clinical andechocardiographic study. J Heart Valve Dis2004;13(2):21727.

3. Zuckier LS, Freeman LM. Nonosseous,nonurologic uptake on bone scintigraphy:atlas and analysis. Semin Nucl Med2010;40:242256.

4. Peller PJ, Ho VB, Kransdorf MJ.Extraosseous Tc99m MDP uptake: apathophysiologic approach. Radiographics1993;13:715734.

5. Eguchi M, Tsuchihashi K, Takizawa H,Nakahara N, Hagiwara M, Ohnishi H, et al.Detection of cardiac calcinosis inhemodialysis patients by wholebodyscintigraphy with 99mtechnetiummethylene diphosphonate. Am J Nephrol2000;20:278282.

6. Reitz MD, Vasinrapee P, Mishkin FS.Myocardial, pulmonary, and gastric uptakeof technetium99m MDP in a patient withmultiple myeloma and hypercalcemia. ClinNucl Med 1986;11(10):730.

Figure 3 Fused SPECTCT images in thecoronal (top left), sagittal (top right) andaxial (bottom) projection slices showingcardiac uptake (cross hair)


SPECTCT diagnosis of temporomandibular jointinfection secondary to otitis externa

Amir Javaid1,*,Rasha M AlShammeri2,Qaisar H Siraj1, Anwar AlBanna1

1Department of Nuclear Medicine, Farwanai Hospital, Kuwait2Dasman Clinic, Sharq Kuwait

IMAGING GAMUT

Key words: Temporomandibular jointinfection, bone scan, Gallium67 scan

Background A 61yearold man presentedwith a history of persistent pain in the left ear forthe last 6 months. He was clinically suspectedwith malignant otitis externa (MOE) and wastherefore referred to the nuclear medicinedepartment for bone and gallium scans toestablish the diagnosis.

Procedure A 2phase bone scan of the headincluding planar blood pool imaging in the

*Correspondence Dr Amir Javaid Department of Nuclear Medicine Farwania Hospital PO Box 18373, Kuwait 81004 Email: [email protected]

www.pjnm.net 22210288(201307/01)3:1<80:SDOTJI>2.0.TX;2M

Figure 1 Bone scan blood pool imagesshowing a commashaped area of increaseduptake on the left (arrows)

Figure 2 Planar bone scan images showingincreased uptake in the left mastoid region(arrow)



anterior, posterior, right lateral and left lateralprojections was acquired immediatelyfollowing injection of 876 MBq of 99mTcmethylene diphosphonate (MDP). Planardelayed bone scan images were acquired in

the same projections followed by a SPECTCTof the skull. A Gallium67 scan was additionallyperformed with planar imaging at 24hour and48hour postinjection together with a SPECTCT at 24hour.

Figure 3 CT (top row) and fused SPECTCTMDP bone scan images showing discreteincreased uptake in the lefttemporomandibular joint (arrows)

Figure 5 CT (top row) and fused SPECTCT24hour Gallium67 scan images showingincreased uptake in the softtissue overlyingthe left temporomandibular joint (arrows)

Figure 4 Planar Gallium scan images at24hour postinjection showing increasedactivity on the left (arrows)

Figure 6 CT (top row) and fused SPECTCT24hour Gallium67 scan images showingincreased softtissue uptake in the regionof the left auditory canal (arrows) consistentwith otitis externa


331691 © 2013 Pakistan Society of Nuclear Medicine 22210288(201307/01)3:1<80:SDOTJI>2.0.TX;2M

Findings The blood pool images of the headshowed a �commashaped� area of increasedactivity on the left side extending downwardsfrom the region of the ear (Figure 1). Thedelayed bone scan spot views (Figure 2)showed focal uptake in the region of the lefttemporal bone, which on SPECTCT was seento correspond the left temporomandibular joint(Figure 3). Gallium67 planar images (Figure4) showed an area of increased tracer uptakeon the left side of the head, which on SPECTCTwas seen to correspond to the softtissueoverlying the left temporomandibular joint(Figure 5). The SPECTCT images did not showany uptake in the temporal bone either on thebone or on the Gallium scan.

Conclusions The concordant increasedactivity seen on the bone scan blood poolimages and the planar Gallium67 scan imageswas indicative of left otitis externa together withsofttissue infection/inflammation. However,the bone SPECTCT precisely localised theincreased bone uptake to the lefttemporomandibular joint (TMJ). There washowever no evidence of increased bone uptakeseen in the left mastoid region or the petroustemporal region to indicate MOE on the bonescan. The Galllium67 SPECTCT scan showedincreased softtissue activity overlying the leftTMJ along with increased uptake in the externalauditory canal (Figure 6) without evidence ofsignificant increased TMJ uptake or anyevidence of skull base osteomyelitis.

Comments The 2phase bone scan withSPECT is the modality of choice for an accurateand sensitive diagnosis of MOE and isconsidered the firstline imaging modality. Bonescintigraphy should precede infection imagingfor the initial diagnosis of MOE, since a negativeresult obviates the need for infection imaging[1].

In investigation of MOE, CT is valuable indelineating the associated structural changesalthough technique is relatively insensitive inthe absence of structural change and may befalsenegative and is also not suitable forfollowup [1]. Nonetheless, dual modalitySPECTCT imaging provides a superiordiagnostic yield than single modality imaging

alone and should be the first modality of choicein institutions where diagnostic SPECTCT isavailable on site.

Gallium and bone scans are both sensitive inthe followup of the cases. The sensitivity of thebone scan however is higher than gallium butthe latter is preferable since increased osseousactivity may persist on a bone scan despiteresolution of active infection [1]. The galliumscan also better delineates the extent of softtissue infection as demonstrated in this case.

Cellulitis, abscess, MOE and TMJ infection aresome of the complications of otitis externa.Although the involvement of TMJ in nonmalignant otitis externa is very rare but fewcases are reported in literature [2, 3]. This caseunderscores the importance of combinedstructural and functional SPECTCT imaging foran optimum diagnostic yield as softtissueinvolvement is best delineated by combined CTand infection imaging and bone and jointinvolvement by combined CT and bonescintigraphy. Both the presence of otitis as wellas the adjacent softtissue spread of infectionare accurately depicted on a Gallium SPECTCTscan.

References

1. Okpala NC, Siraj QH, Nilssen E, Pringle M.Radiological and radionuclide investigationof malignant otitis externa. J Laryngol Otol2005;119(1):715.

2. Thomson HG. Septic arthritis of thetemporomandibular joint complicating otitisexterna. J Laryngol Otol: 1989Mar;103(3):31921.

3. MartinezRey C, RodriguezFramil M.Pseudomonas aeruginosa septic arthritis ofthe temporomandibular joint in a youngpatient without malignant otitis externa.Rev Med Chil 2011;139(1):1267.


Unilateral decreased gallium limb uptake inpoliomyelitis

Eiman AlAwadi*, Qaisar H Siraj

Department of Nuclear Medicine, Farwanai Hospital, Kuwait

IMAGING GAMUT

Key words: Poliomyelitis, Gallium67 scan,Bone scan

Background A 33yearold female had ahistory of poliomyelitis affecting her lowerright limb at the age of 5year. She presentedwith gradually increasing right knee pain andwas referred to the nuclear medicinedepartment for a bone scan for suspectedarthritis of the knee and other joints.

Procedure A 3phase bone scan of the kneestogether with a wholebody bone scan andSPECTCT were performed. To exclude thepossibility of septic arthritis, a gallium67 scanwas additionally performed with imaging at 24and 48 hours.

Findings The planar bone scan wasunremarkable except for mild arthritis in theright knee (Figure 1). The gallium scan showedgeneralised reduced activity in the right lowerlimb and relatively increased activity in the leftlower limb together with increased uptake inthe arthritic right knee (Figure 2).

Conclusions The bone scan findings wereconsistent with active arthritis in the right kneewith moderate arthropathy involving severallarge and small joints. The unilateral reducedgallium activity in the limb was attributed

to disuse atrophy of the right lower extremity,which was evidenced by less muscle mass onthe right side on CT scan (Figure 3).

Comments This case illustrates the patternof unilateral decreased gallium uptake in lowerextremity in poliomyelitis. The uptake patternwas characterized by decreased uptake in theaffected limb together with physiologicincreased uptake in the nonaffected limb. The

*Correspondence Dr Eiman AlAwadi Department of Nuclear Medicine Farwania Hospital PO Box 18373, Kuwait 81004 Email: [email protected]

www.pjnm.net 22210288(201307/01)3:1<83:UDGLUI>2.0.TX;2M

Figure 1 Wholebody bone scan showingincreased uptake in the right knee as wellas multiple large and small joints in the body


331691 © 2013 Pakistan Society of Nuclear Medicine 22210288(201307/01)3:1<83:UDGLUI>2.0.TX;2M

Figure 2 Gallium scan at 24 hours (toprow) and 48 hours (bottom row)postinjection

Figure 3 Axial CT at mid thigh level

cause of the reduced gallium uptake is relatedto disuse and has been reported previously ina patient with AVN of the femoral head [1].

Patterns of uptake on bone scans in patientswith poliomyelitis have also been reported [2].However, unilateral decreased uptake ofgallium in lower extremity in patient withpoliomyelitis has not been previously reported.

This case adds poliomyelitis to the differentialdiagnosis of unilateral decreased galliumuptake in the lower extremity.

References

1. Bhargava P, Charron M, Beauchemin D.Asymmetric lower extremity muscleactivity on a Gallium scan. Clin Nucl Med2005; 30(5):367.

2. Marafi FA, AlSaid A, Esmail AA, ElgazzarAH. Baseline patterns of bone scintigraphyin patients with established postpoliomyelitis paralysis. Skelet Radiol 2010;39(9):891895.

The 'signet ring� sign on 99mTcMAG3 renal scan

Anthony D'Sa*, Marina Easty, Lorenzo Biassoni

Department of Nuclear Medicine, Great Ormond StreetHospital for Children, London, UK

IMAGING GAMUT

Key words: Duplex renal system, reflux,paediatric, 99mTcMAG3

Background Ultrasonographic evaluation ofthe renal tract in a 2yearold boy revealedbilateral duplex renal systems, a leftureterocele and left hydronephrosis. Thepatient was previously diagnosed with a lefthydroureter on a routine antenatal anomalyultrasound scan.

Procedure The patient was referred to thenuclear medicine department for scintigraphicevaluation of renal function and excretion at

*Correspondence Dr Anthony D'Sa Department of Nuclear Medicine Great Ormond Street Hospital for Children Great Ormond Street London WC1N 3JH Email: [email protected]

www.pjnm.net 22210288(201307/01)3:1<85:TSRSOT>2.0.TX;2M


Figure 1 99mTc MAG3 dynamic renography regrouped images. In the early phase of thedynamic renography, there is a photopenic area in the lower portion of the right kidney,surrounded by a rim of uptake, as shown at 2 minutes (arrow). On the following frames,this area fills with tracer, but the tracer seems to predominantly concentrate laterally,suggesting that the renal pelvis may face the right anterolateral abdominal wall. Thephotondeficient nature of the lower portion of the right kidney is likely to be due to theposition of the lower portion of the right kidney further away from the gamma cameracompared to the upper portion; the dilated renal pelvis with nonradiolabelled urine withinit (as expected in the early phase of the renogram) contributed further to the photonattenuation


331691 © 2013 Pakistan Society of Nuclear Medicine 22210288(201307/01)1:1<85:TSRSOT>2.0.TX;2M

the age of 1 and 6 months. Dynamic renalscintigraphy was performed after intravenousinjection of 99mTcmercapto acetyltriglycine(99mTcMAG3) and the study processed togenerate summed images and renogramcurves for the right and the left kidneys.

Findings The composite summed image ofthe dynamic studye showed a photondeficientarea at the lower pole of the right kidney. Thefirst impression looking at this scan raised thepossibility that the features might representa duplex right kidney, with a better functioningupper moiety and a lower moiety with reducedfunction and hydronephrosis (Figure 1). Ofnote was the circumferential configuration ofuptake on all sides of the photopenic area. Anultrasound performed on the same day as the99mTc MAG3 was reviewed. It was deducedthat the photopenic area was in fact due tothe dilated renal pelvis being "seen" en facedue to kidney malrotation (Figure 2).

Comments We have quite frequentlynoticed the appearances described above inour clinical practice; another patient with amalrotated right kidney with hydronephrosisis displayed for comparison (Figure 3). Werefer to the 99mTcMAG3 image of a malrotatedkidney with an associated hydronephrosis asthe "signet ring" sign.

Figure 2 Ultrasound showing the renalhilum (arrow) closest to the probe onanterolateral images. There is dilatation ofthe right renal pelvis

Figure 3 99mTcMAG3 dynamic renographyearly parenchymal phase of the study. Thisshows a photopenic area surrounded byuptake in the lower portion of the rightkidney, with good tracer uptake in the upperpole (arrow). These findings were laterconfirmed to represent a malrotated kidneywith hydronephrosis


Multiple osteomyelitis with septic arthritis on a3phase bone scan

Masha Maharaj*, Alexandra Frankl, Elise Kuwa, Xolani Mqhayisa,Farzana Rasool, Jacob Manamela, Elizabeth Kgakgudia

Division of Nuclear Medicine, Polokwane Provincial Hospital, University ofLimpopo, Polokwane, South Africa

IMAGING GAMUT

Key words: Osteomyelitis, Septic arthritis,Bone scan

Background An 8yearold boy presentedwith 3 months history of left hip pain followingblunt trauma to the pelvis and abdomen. Initialxray of the pelvis was reported to be normal.All inflammatory markers were elevated.Biochemistry revealed an ESR of 130 (normal010 mm/hr), Creactive protein of 60 (normal05 mg/l). Skeletal scinitgraphy was indicatedto investigate possible musculoskeletal infection[1, 2].

Procedure A 3phase bone scan of the pelvisand femora together with a delayed wholebodybone scan in the anterior and posteriorprojections were performed following injectionof 99mTcmethylene diphosphonate.

Findings The 3phase bone scan imagesrevealed increased vascularity in the entire leftfemur and in the left hip with a large softtissuecomponent (Figure 1). There was moderate tointense heterogeneous uptake of tracerthroughout the left femur, the medial twothirdsof right clavicle and the entire left clavicle. Faint increased uptake was also seen in the proximal

onethird of the left humerus as well as in theproximal onethird of the left tibia. (Figure 2).The left femoral head was completelydisplaced superiorly and laterally. The leftfemoral neck appeared less intense. An'encapsulated' photopenic area in the left hipjoint space was noted inferior to the leftfemoral neck (Figure 3).

*Correspondence Dr Masha Maharaj Division of Nuclear Medicine Polokwane Provincial Hospital University of Limpopo, South Africa Email: [email protected]

www.pjnm.net 22210288(201307/01)3:1<87:MOWSAO>2.0.TX;2M

Figure 1 99mTcMDP blood flow (top) andblood pool (bottom) images showingincreased vascularity in the femur, hip andpelvis of the left


Conclusion The scan findings were consistentwith multifocal osteomyelitis, septic arthritisof the left hip together with a suspected fracturein the proximal left femur. The photopenic massseen in the region of the left hip joint raised thepossibility of an encapsulated abscess. Asubsequent CT scan showed multiple intra

and extraarticular rimenhanced lesions inleft hip joint space, consistent with a networkof abscesses with the largest measuring 3.5cmx 2.7cm x 2.5cm (HU=17). CT scan alsoconfirmed an intertrochanteric fracture. Thepatient was taken into theatre for incision,drainage and debridement. Pseudomonasaeruginosa was cultured from the biopsysample and the patient was treated with acourse of intravenous antibiotics.

Comment Radionuclide bone scintigraphy isparticularly useful for the diagnosis of multifocalosteomyelitis and septic arthritis asdemonstrated in this case. Also illustrated in thiscase is the use of complimentary anatomicalimaging (CT scan) in confirming and furthercharacterizing the left hip pathology. Imagingis essential for confirming the clinical diagnosisof osteomyelitis and also provides essentialinformation on the site and extent of theinfection, which helps the referring clinician inplanning medical or surgical treatment [3].

References

1. Riise OR, Kirkhus E, Handeland KS, FlatoB, Reiseter T, Cvancarova M, Nakstad B,Wathne KO. Childhood osteomyelitisincidence and differentiation from otheracute onset musculoskeletal features in apopulationbased study. BMC Pediatrics2008;8:45.

2. McCarville MB. The child with bone pain:malignancies and mimickers. CancerImaging. 2009;9:S115_S121.

3. Sia IG, Berbari EF. Osteomyelitis. BestPract Res Clin Rheumatol 2006;20:1065�1081.

331691 © 2013 Pakistan Society of Nuclear Medicine 2210288(201307/01)3:1<87:MOWSAO>2.0.TX;2M

Figure 2 99mTcMDP wholebody images inthe anterior (left) and posterior (right)projections

Figure 3 Pinhole images of the right (a)and the left (b) hip regions in the anteriorprojection

a b

Masoomi M, Ntentas G, Foulsham L. Paving the way for modality choice of the future: challenges andexpectations of the first simultaneous wholebody PETMRI molecular imaging in the UK. Pak J Nucl Med2013;3:121.

Masoomi M, Robinson A, Bouchareb Y, Hejazi S, Spyrou NM. Efficacy of motioncorrection in absolutequantification of colonic PETCT for drug response therapy. Pak J Nucl Med 2013;3:2228.

Memon SA, Laghari NA, Qureshi ST, Ahmad F, Masood A, Iqbal S. Exposure rate patterns in 131I therapyinpatients at NIMRA Jamshoro: an 08year study. Pak J Nucl Med 2013;3:2936.

Rasheed R, Javed M, Ahmad F, Sohail A, Murad S, Masood M, Rasheed S, Rasheed S, Imran B, ShaheenS. Study of normal biodistribution and uptake patterns of novel anticancer radiopharmaceutical complex99mTcMethotrexate. Pak J Nucl Med 2013;3:3743.

Riaz S, Hussain F, Waqar A, Ali MK, Minhas F. Assessment of regional cerebral blood flow in majordepressive illness by radionuclide brain perfusion SPECT. Pak J Nucl Med 2013;3:4452.

Bashir H, Shabo G. Movahed's sign in chronic thromboembolic pulmonary embolism. Pak J Nucl Med2013;3:5356.

Siraj QH, AlShammeri RM, Ragab O. A case of left Bochdalek hernia . Pak J Nucl Med 2013;3:5760.

DurreSabih, Rahim K. A case of right Bochdalek hernia. Pak J Nucl Med 2013;3:6164.

AlHusseini R, Siraj QH. SPECTCT of an unsuspected ischial tuberosity avulsion fracture. Pak J Nucl Med2013;3:6568.

AlBanna A, Siraj QH, Afzal U, AlAwadi E. SPECTCT of peritonealscrotal leakage in patients on continuousambulatory peritoneal dialysis. Pak J Nucl Med 2013;3:6972.

Khan AU, Hameedullah, Bahadur A, Khattak MR, Shah AS. Mediastinal spread of medullary thyroidcarcinoma imaged by locally formulated 99mTc DMSA (V). Pak J Nucl Med 2013;3:7377.

Raza H, Nasir Z, Kamal S. Myocardial uptake of 99mTcMDP in infective endocarditis. Pak J Nucl Med2013;3:7879.

Javaid A, AlShammeri RM, Siraj QH, AlBanna A. SPECTCT diagnosis of temporomandibular joint infectionsecondary to otitis externa. Pak J Nucl Med 2013;3:8082.

AlAwadi E, Siraj QH. Unilateral decreased gallium limb uptake in poliomyeliti. Pak J Nucl Med2013;3:8384.

D'Sa A, Easty M, Biassoni L. The 'signet ring� sign on 99mTcMAG3 renal scan. Pak J Nucl Med 2013;3:8586.

Maharaj M, Frankl A, Kuwa A, Mqhayisa X, Rasool F, Manamela J, Kgakgudia E. Multiple osteomyelitiswith septic arthritis on a 3phase bone scan. Pak J Nucl Med 2013;3:8788.

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