EJNM NUCLEARMEDICINE EGYPTIANJOURNALOF. EGYPTIANSOCIETYOFNUCLEARMEDICINESPECIALISTS

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1 EGYPTIAN JOURNAL OF NUCLEAR MEDICINE Volume8Number2 December2013 pp1-69 Volume8Number2December2013 ISSN: EGYPTIANJOURNALOF NUCLEARMEDICINE EJNM EGYPTIANSOCIETYOFNUCLEARMEDICINESPECIALISTS

2 Egyptian Journal of Nuclear Medicine (EJNM) Journal of the Egyptian of Nuclear Medicine Specialists Editor in Chief: Prof. Dr. Hosna Moustafa Associate editors: 1- Consultant. Dr. Khaled Talaab 2-Dr. Yasser Gaber 3-Dr. Mai Amr Editorial Board - Abdel-Dayem H.M USA - Fawzy.A Egypt - Abozied, M. Saudi Arabia - Khairy A.T. Egypt - Alavi A. USA - Kamel I. Swizerland - Amin A. Egypt - kotb M. Egypt - Bayomy T. Bahrin - Osman M. USA - Ben Rais N. Marcco - Omar W. Egypt - Buscomb J. U.K - Sabry Sh. Egypt - El-Gazzar A. Kuwait - Senna H.A. Egypt - El-Maghraby T. A. Egypt - Van Eck-Smith B.L. Netherland - El-Nahas A. U.K - Wagieh Sh. Egypt - El-Rafiae Sh. Egypt - Zaher, A. Egypt - Elmann A. South Africa - Ziada G. Kuwait

3 ESNMS Contents Journal of the Egyptian Society of Nuclear Medicine Specialists (EJNMS) Volume 8, Number 2. December 2013 Editorial Radiation Exposure to Staff Using PET/CT Facility Taalab, Kh; and Mohsen, Z Original Article, Oncology Role of FDG-PET/CT in Assessment of Response to Therapy in Breast Cancer Patients Moustafa, H, 1. Younis, J 1. and Taalab, Kh 2. Original Article, Oncology Diagnostic Accuracy of 18F-FDG PET/CT in Detection of Local Recurrence in Rectal Cancer and the Added Value of Dual Time Point Scanning Farghaly H 1, Nasr H 2,and Nabulsi J 3 (1) (7) (15) Original Article, Oncology Patient And Lesion-Based Analysis Of 18F-FDG PET/CT Compared With Conventional CT During Follow Up of Patients With Colorectal Carcinoma Younis, J, 1 Taalab, Kh 2 and Kandeel, A. 1 Original Article, Cardiology Effect of Subclinical Thyroid Disease on Cardiac Function in Patients on Thyroid Replacement Therapy as Assessed by Radionuclide Ventriculography Elsayed, Y 1. Hasanin, E 2.Farouk, Sh 3. Zeiada, G 4. (45) (55) Original Article, Oncology A Comparison between FDG PET/CT, CT and MRI in Detection of Spinal Metastases and its Impact on Clinical Management Wafaie, A 1. El-Liethy, N 1. Kassem, H 2. and Kotb, M.H 3. (30) Original Article, Physics The Effect of Low Dose CT Matrix Size Variation on Qualitative and Semi-Quantitative Analysis of Positron Emission Tomography (PET) Images (63) Abdel Gawad, H 1. Elsayed Y 1. Abdelhafez, Y 2.

4 Egyptian J. Nucl. Med., Vol. 8, No. 2, December Editorial Radiation Exposure to Staff Using PET/CT Facility Taalab, Kh; and Mohsen, Z Department of Nuclear Medicine, International Medical Center; Cairo, Egypt ABSTRACT: Positron emission tomography (PET) combined with computed tomography (CT) has been playing key role in important clinical decision-making in many areas ever since its inception in the field of medical imaging. Most of the hospitals are enthusiastic for including PET/CT in their imaging services because of its increasing application particularly in oncology. However, the occupational workers are apprehensive about the risk of higher radiation exposure in a PET/CT facility even more than that in conventional nuclear medicine Gamma camera. There is a need therefore to make the staff aware of the radiation doses they may likely get while working using this facility. We have estimated the radiation exposure to the physicians & technologists working in our PET/CT facility based on the dose rate measurement with regularly calibrated pocket dosimeter and thermo-luminescent detector (TLD); for cumulative dose confirmation. The mean dose measured at the chest level per PET/CT procedure was 4 μsv and 4.75μSv for the physicians and technologists respectively. The mean dose to the physicians per MBq of 18F-FDG injected was 10 nsv/mbq and 35 nsv/mbq at the chest and wrist levels respectively; whereas it was 12 and 25 nsv/mbq for technicians respectively. Key words: Radiation dose, PET/CT, pocket dosimeter. Correspondence to: Kh. Taalab ktaalab@yahoo.com

5 Egyptian J. Nucl. Med., Vol. 8, No. 2, December INTRODUCTION: Functional disorders always predate anatomical abnormalities; hence availability of both physiological and anatomical images of the patient on the same system provides the early detection and precise location of the lesion that is helpful to the physicians in image interpretation to a great extent. Accordingly; multi-modality imaging technology like PET/CT has revolutionized and established the role of PET imaging as a diagnostic tool in many areas particularly in oncology (1). Due to newer developments in detector technology application of this imaging technology will continue to increase with higher patient throughput. The high patient throughput in PET/CT may also raise concern as it may increase the radiation exposure to staff members. The high specific gamma ray constant and penetrating 511-keV photons, result in a higher radiation exposure to staff if not adequately protected (2). The 140-keV photons from 99mTc have a half value layer of 0.28 mm of lead against 4.1 mm for 511-keV photons under narrow beam geometry (3). The amount of lead required to suitably shield these high-energy emissions is therefore proportionately increased. The specific gamma-ray constant for 18F is nearly six times greater than that for 99mTc (2, 3). Radiation safety issues with a PET/ CT facility have therefore to be addressed adequately. A large number of studies are available in the literature on the evaluation of radiation safety and dose received by staff performing imaging with conventional nuclear medicine tracers (4-8). Even though published data are available on exposure to staff working in a dedicated PET/CT facility, there is no consensus between them on the estimated dose to staff (9-11). In this study we have estimated the average dose received by the physicians and technologists at the chest and wrist level while performing 18F-FDG injections; dose dispensing and administration and patient positioning during acquisitions respectively. MATERIALS AND METHODS: A prospective pilot study was carried out to estimate the average dose to the physicians and technologists during 18F-FDG PET/CT imaging of 125 adult patients in International Medical Center (IMC) in May The center has a dedicated PET/CT scanner, (Philips; TF). For all PET/CT whole body imaging, first spiral CT is performed for the whole body by using a scout view with 30 ma and 130 kvp, followed by a spiral CT scan with 50 ma and 130 kvp. This is followed by 3D PET acquisition with 4 min bed positions depending upon the true count rate from the patient. For whole body PET/CT imaging of adult patients, around 370 MBq (10 mci) of 18F-FDG was injected. The total acquisition time per whole body scan varies from 20 to 25 min. On an average patients are imaged in this scanner a day; for two day per week. At any time two physicians and two technologists are posted in the facility for injections and PET/CT imaging of the patients respectively.

6 Egyptian J. Nucl. Med., Vol. 8, No. 2, December Dose measurements: Electronic pocket dosimeters (Siemens Medical Solutions Inc, USA), were used for dosimetry per PET/CT imaging procedure. The measurement range of the detector was from 0.1 μsv to 100 msv, with an in-built beeper. During the 1-month period of the study two TLD dosimeters were given to each physician and technologist to wear on the chest and wrist levels. These dosimeters have silicon semiconductor detectors with an accuracy of ±10%, linearity within ±10% and an energy response accuracy of ±20% between 50 KeV and 3 MeV. The constancy of the dosimeters was checked against a 137 Cs source before use. The dosimeters were worn at all times when the physicians and technologists are performing 18F-FDG injections and PET/CT imaging respectively. The radiation dose to physicians was recorded during the 18F-FDG injections whereas; the dose received by the technologists was measured while dose dispensing and performing PET/CT scans. The chest and wrist dose received by the staff were read directly from the dosimeters and recorded at the end of each working day, and the dosimeters were reset. The total activity administered by each of the physicians and the numbers of PET/CT scans performed by the technologists were recorded. Instantaneous dose rates measurements: The instantaneous dose rates were measured using a calibrated survey meter (Ludlum Measurements, Inc, USA) portable gamma ray survey meter. Prior to injection, patients were prepared with intravenous cannula in their vein for dose administration to minimize the time of injection. The syringe loaded with 18F- FDG was quickly removed from the lead container and dose was injected to the patients. The exposure rates to the chest and wrist levels of physicians were measured during 18F-FDG injections to the patients. The dose rates were also measured at 0, 0.5, 1.0 and 2.0 m distance from the anterior chest of each patient immediately after the administration of 18F-FDG and at the end of PET/CT imaging; i.e. about 90 minute after injection. RESULTS: The average dose received by the physicians and technologists per 18F-FDG PET/CT procedure is given in table 1. Table 1: Mean Average dose for Physician and Technologist Physician Technologist Average dose received per injection (μsv) Average dose received per MBq (nsv) Fractional Dose Received 46.5% 53.5% The average dose to the chest and wrist of the physicians per procedure were μsv and μsv respectively and similarly the average dose to the chest and wrist of the technologists per procedure were μsv and μsv respectively; table 2.

7 Egyptian J. Nucl. Med., Vol. 8, No. 2, December Table 2: Average Dose for Staff at Chest and Wrist. Worker Chest Level Wrist Level Chest Level Wrist Level Dose/procedure μsv Dose/ Procedure μsv Dose/1 mci μsv Dose/1 mci μsv Physician (n=68) Physician (n=57) Technologist (n=63) Technologist (n=62) The instantaneous dose rates were measured at different distances from the injected patients, immediately after 18F-FDG injections and at the end of PET/CT imaging. The exposure rates immediately technologists respectively. after 370 MBq (10 mci) 18F-FDG were very high at close contact and versus and at 200 cm for both physicians and So; each physician could inject up to 20 patients and each technologist could position up to 25 patients per day respectively; which are both out of the capacity of any department (Table 3) Table 3: Dose Rate at Different Distances for Physicians and Technologists: Dose Rate (msv/h) Physicians Technologists Average dose received at 0 cm Average dose received at 50 cm Average dose received at 100 cm Average dose received at 200 cm DISCUSSION: It is imperative to continually monitor the dose received by the staff to check whether they are within the prescribed annual dose limits and also to improve the work practice for containing the radiation exposure. The critical groups that get exposure from a radioactive patient in a PET facility are the physicians and technologists performing the injection and scanning respectively (12). In this pilot study we have estimated the dose to the physicians and technologists per PET/CT procedure. There are few studies available in the literature comparing the dose received by the staff in conventional nuclear medicine and PET imaging. The average whole body dose per procedure to the staff in conventional nuclear medicine has been reported to be lower than that in PET facility.this is understandable due to penetrating annihilation photons and higher exposure rate constant for positron emitting radiopharmaceuticals (4).

8 Egyptian J. Nucl. Med., Vol. 8, No. 2, December Our estimated values of exposure to the staff are comparable with those published in the literature (13-15). The average dose received by the physicians administering the activity at the chest level was 4 μsv per procedure which is nearly two times higher than any conventional nuclear medicine procedure. The radiation dose as estimated to the chest (whole body dose) and wrist; for the two physicians and two technologists are in agreement with that measured by Egyptian Authority of Atomic Energy (EAAE). Although; our study showed higher wrist dose for the two physicians; However if they continue to work the whole year with the same workload their wrist dose would be less than 15 msv against the annual limit of 500 msv. Whereas the whole body dose of all the staff was nearly same as in conventional nuclear medicine procedures. Similar and comparable results are seen in other PET facilities (16). The principles of time; distance and shielding (TDS) should be practiced for any procedure involving radioactive administration, So good work practice and use of shielding devices may further reduce exposure to staff. Particular care needs to be taken while working with the PET radiopharmaceuticals. Depending upon the workload physicians can be put on rotation to minimize their wrist dose. Alternatively, the wrist dose could be reduced by using a 511-KeV syringe shield (17). CONCLUSION: The staff should work without any anxiety and fear of radiation risk using a PET CT facility if safe working conditions are maintained as each physician could inject up to 20 patients and each technologist could position up to 25 patients per day respectively. REFRENCES: 1. Townsend DW, Carney JPJ, Yap JT, et al. PET/CT today and tomorrow. J Nucl Med.; 45:S Lundberg, T. M., Gray, P. J., Bartlett, M. L. Measuring and minimizing the radiation dose to nuclear medicine technologists. J Nucl Med Technol 30: 25-30, Dell MA. Radiation safety review for 511-keV emitters in nuclear medicine. J Nucl Med Technol.; 25:12 7. [PubMed] Roberts, F. O. Radiation dose to PET technologists and strategies to lower occupational exposure. J Nucl Med Technol 33: 44-47, Clarke EA, Thomson WH, Notghi A, Harding LK. Radiation doses from nuclear medicine patients to an imaging technologist: relation to ICRP recommendations for pregnant workers. Nucl Med Commun 13: , Harbottle, E. A., Parker, R. P., Davis, R. Radiation doses to staff in a department of nuclear medicine. Br J Radiol 49: , Smart, R. Task-specific monitoring of nuclear medicine technologists radiation exposure. Radiat Prot Dosimetry 109: , Lindner, O., Busch, F., Burchert, W. Performance of a device to minimise

9 Egyptian J. Nucl. Med., Vol. 8, No. 2, December radiation dose to the hands during radioactive syringe calibration. Eur J Nucl Med Mol Imaging 30: , Williams, E. D., Laird, E. E., Forster, E. Monitoring radiation dose to the hands in nuclear medicine: location of dosimeters. Nucl Med Commun 8: , Wu, T. H. Radiation exposure during transmission measurements: comparison between CT- and germanium-based techniques with a current PET scanner. Eur J Nucl Med Mol Imaging 31: 38-43, Chiesa C, De Sanctis V, Crippa F, et al. Radiation dose to technicians per nuclear medicine procedure: comparison between technetium- 99m, gallium-67, and iodine-131 radiotracers and fluorine-18 fluorodeoxyglucose. Eur J Nucl Med 24: , Mountford PJ, O Doherty MJ. Exposure of critical groups to nuclear medicine patients. Appl Radiat Isotop 50: , Brix G, Lechel U, Glatting G, et al. Radiation exposure of patients undergoing whole-body dual-modality 18F-FDG PET/CT examinations. J Nucl Med 46: , Robinson, C. N., Young, J. G., Wallace, A. B., Ibboton, V. J. A study of the personal radiation dose received by nuclear medicine technologists working in a dedicated PET center. Health Phys 88:S17-21, Benatar, N. A., Cronin, B. F., O Doherty, M. J. Radiatn dose rates from patients undergoing PET: implications for technologists and waiting areas. Eur J Nucl Med 27: , Pant GS, Senthamizhchelvan S. Radiation Exosure to the Staff in PET CT facility. IJNM 21: , Harding, L. K., Hesslewood, S., Ghose, S. K., ThomsonW. H. The value of syringe shields in a nuclear medicine department. Nucl Med Commun 6: , 1985.

10 Egyptian J. Nucl. Med., Vol. 8, No. 2, December Original Article, Oncology Role of FDG-PET/CT in Assessment of Response to Therapy in Breast Cancer Patients Moustafa, H, 1. Younis, J 1. and Taalab, Kh 2. 1 Department Of Oncology & Nuclear Medicine,(NEMROCK), Faculty of Medicine, Cairo University, Cairo, and, 2 Department Of Nuclear Medicine 2,Military Medical Academy, Egypt ABSTRACT: Objective: We aimed to assess the role of FDG PET/CT in evaluation of early response to chemotherapy after 2-3 cycles and late response after 6 cycles of chemotherapy to define responders from non-responders to treatment in breast cancer patients. Patients and Methods This prospective study included 52 female patients with locally advanced breast cancer, Group 1: Included 27 patients referred for PET/CT for assessment of primary lesion following 2-3 cycles of chemotherapy, twenty patients underwent a baseline study before initiation of therapy. Group 2: Included 25 patients with recurrent breast cancer referred for PET/CT following 6 cycles of chemotherapy for assessment of disease remission. They underwent a midline study after 2-3 cycles of chemotherapy. Results Only 4 patients out of 27 of group 1 showed significant early metabolic response with decrease of SUV value by (65.8%) following 2-3 cycles of treatment with significant reduction of mean SUV max implicating good response to therapy (p<0.005), while 23 patients showed partial metabolic response, with reduction of mean SUV max (36.2%). Nineteen out of 25 patients of group 2 (76%) showed significant metabolic response on completion of 6 cycles of chemotherapy with significant reduction of mean SUV max (69.6%) impressive of good therapy response (p<0.0001), while the other 6 patients (24%) showed poor metabolic response with mean reduction of SUV max of 30.8% and evidences of metastatic disease signifying poor therapy response. Conclusion: PET-CT seems to be useful for monitoring response to chemotherapy in locally advanced breast cancer differentiating responder from nonresponder in therapy evaluation. Key words: breast cancer, - 18 F -FDG-PET/CT, treatment monitoring Corresponding Author: Younis, J. jehan.nuc@hotyahoo.com.

11 Egyptian J. Nucl. Med., Vol. 8, No. 2, December INTRODUCTION: Neoadjuvant therapy is now commonly used in patients with locally advanced breast cancer, as it improves surgical options and provides prognostic information (1). Primary systemic chemotherapy was first introduced for managing inoperable locally advanced breast cancer (2). The availability of various new therapies for relapsing breast cancer as well as determination of the extent of disease and its precise localization of utmost importance (3).Combined PET/CT showed superior results in staging and impact on therapy response in advancing breast cancer (4). Imaging with PET/CT for tumor therapy monitoring has been introduced as it provides proper assessment of tumor response and improve the accuracy in the evaluation of treatment response by directly defining metabolic and morphological changes (5). Multiple studies have evaluated serial FDG PET imaging performed at different time points after initiation of neoadjuvant therapy and have demonstrated the following: (a) A serial decrease in tumor FDG uptake measured using SUV or the metabolic rate of FDG, is an indicator of response. (b) FDG PET performed early at mid therapy is predictive of complete microscopic response and may serve as a surrogate marker for response. (c) Changes in FDG metabolism often precede morphologic changes in tumor and therefore PET can demonstrate response sooner than conventional imaging techniques. (d) FDG PET is likely to be most helpful as an early marker for resistance to therapy. FDG PET imaging performed after completion of therapy allows confirmation of gross residual disease but does not allow exclusion of residual microscopic malignancy (6). The mean reduction in 18F- FDG uptake after the first 2 cycles of chemotherapy was significantly higher in responding than in non-responding tumor (6). We aimed to assess the role of FDG PET/CT in evaluation of early response to chemotherapy after 2-3 cycles and late response after 6 cycles of chemotherapy to define responders from non-responders to treatment in breast cancer patients. PATIENTS AND METHODS: Patient population this prospective study included 52 female patients with locally advanced breast cancer referred to PET/CT department of the International Medical Centre (IMC) between March 2009 and February 2012, their main age were years. Clinical and diagnostic methods including mammography, abdominal ultrasonography, bone scan, diagnostic CT and/or MRI were done for diagnostic work up. Patients were divided into two groups Group 1: 27 patients with locally advanced breast cancer referred for early PET/CT assessment of primary lesion before chemotherapy (20 patients) and following 2-3 cycles of chemotherapy, Group 2: 25 patients with recurrent breast cancer referred for PET/CT following 2-3 cycles and 6 cycles of chemotherapy for assessment of disease remission. The protocol of the study was approved by the ethical committee. Patient Preparation: The patient is asked to be fasting for 6 hours prior to scan. Remove metallic items from the patient. Insert an I.V. catheter in the patient s arm for administration of 18 F-FDG. They were instructed to avoid caffeinated drinks but can have water during this period. Patients

12 Egyptian J. Nucl. Med., Vol. 8, No. 2, December are also instructed to avoid any kind of strenuous activity prior to the examination and following injection of the radioisotope to avoid physiologic muscle uptake of FDG. The patient is asked to void prior to scanning. Diabetic patients should be controlled prior to study with maximum glucose level of 160 mg/dl. Image acquisition: PET/CT is performed at International Medical Centre (IMC) on an integrated scanner (Philips; TOF; 64 slice CT) that combines both CT and PET capabilities in two sequential gantries, avoiding the need for patient motion between the CT and PET components of the study and thereby leading to accurate co-registration of the CT and PET data. PET images will be acquired during normal breathing in the three-dimensional mode for 2 minutes per bed position 60 minutes after intravenous administration of (0.1) mci FDG /Kg. PET images are reconstructed by using standard reconstruction algorithm (OSEM). Attenuation correction of PET images is performed by using attenuation data from the CT component of the examination. The CT component of the study comprises a multi-detector CT examination from the base of the skull to the upper thighs (120 mas, 140 kvp, table speed = 13.5 mm per rotation). PET/CT images are analyzed both qualitatively and semi quantitatively. The intensity of FDG uptake within specific lesions is calculated by using a volume of interest over the lesion, according to the following formula: SUV max = maximum measured activity in the volume of interest (millicuries per milliliter)/injected dose of FDG (millicuries) per gram of body weight. The standard SUV max of 2.5 was considered a cutoff point.suv max of 2.5 and above in PET/CT studies were considered positive for disease involvement, while SUV max below 2.5 were considered to be insignificant of disease involvement. Study interpretation: The PET, CT, and fused PET/CT Images were separately interpreted by 2 experienced nuclear medicine physicians and were compared to PET/CT images. Qualitative assessment for presence of hyper- metabolic lesions was evaluated on corrected PET images. Semi-quantitative evaluation was performed using the Standardized Uptake Value (SUV max), of all abnormal foci (Normal < 2.5). Data analysis: True-positive lesion was defined as a lesion seen on FDG PET/CT images with high SUV max >2.5 and found to be positive for tumor tissue at histological examination or clinical /radiological follow up. True-negative lesion was defined when no lesion was seen on FDG PET/CT images and the results on clinical /radiological follow up were negative. Assessment of response to therapy: (a) Good response to therapy was considered when there was significant metabolic response on PET/CT with reduction of SUV max 60% or more than the baseline study in the first group after 2-3 cycles or at end of 6 cycles of therapy in the second group. (b) Poor therapy response was considered when there was residual metabolic uptake by PET/CT with reduction of SUV max<60% than the baseline study or appearance of new metastatic lesions. Statistical Analysis: Standard statistical methods was applied including Chi-Square test and Receiver operating characteristics (ROC) curve analysis was performed to compare

13 Egyptian J. Nucl. Med., Vol. 8, No. 2, December sensitivity, specificity and accuracy between PET/CT and other conventional radiological modalities in follow up of breast cancer, determined on a lesion-based analysis. Statistical analysis was performed using SPSS (Version 20, 2011) (SPSS Inc., Chicago, llinois, USA) software. Results were considered statistically-significant if P-value <0.05. RESULTS: Fifty two female patients with previously diagnosed and treated breast cancer were included in the study with mean age of ± 5.76 years. Group1: Early Therapy Monitoring 27 patients with locally advanced breast cancer (21 patients with stage III B and 6 patient with stage III C) referred for PET/CT assessment of primary lesion before and following 2-3 cycles of chemotherapy. Only 4 out of 27 showed significant metabolic response on PET/CT with reduction of mean SUV max from 7.9 ±1.5 to 2.7±0.3 with (65.8%) degree of response (P<0.005). These 4 patients performed surgery in view of good response to therapy. The other 23 patients had mean SUV max of 8.3±1.2 with partial response and decrease of mean SUV max to 5.3±1.0 with response rate of (36.2%). These patients did not perform surgery and suggest to change line of chemotherapy. All results were confirmed by histopathological assessment following surgery or biopsy (Table1). (Table 1): Quantitative baseline PET/CT and following 2-3 cycles of chemotherapy in 27 patients of locally advanced breast cancer No of patients Degree of response to therapy with % reduction Mean SUV max in baseline PET'CT study Mean SUV max after2-3 cycles of on SUV value chemotherapy % 7.9± ± % 8.3± ±1.0 Group 2: Late Therapy Monitoring 25 patients with either recurrent or metastatic breast cancer referred for therapy monitoring after 2-3 cycles and repeated after 6 cycles of chemotherapy for assessment of disease remission. Nineteen out of 25 patients (78%) showed significant metabolic response on PET/CT with reduction of mean SUV max, from 6.5±1.1 to 2.1±0.6 (69.6%) (p<0.0001) denoting good responder (fig 1). While, the other 6 patients (24%) showed poor metabolic response with reduction of mean SUV max from 6.5±1.1 to 4.5±0.7 (30.8%) signifying non responders to therapy (Table 2). All 6 non responders showed also metastatic spread at 6-12 months follow up (bone in 2 patients, liver in one patient, lung in one patient and multiple organs in 2 patients. Metastatic spreads were confirmed by follow up PET/CT or other radiological imaging including chest and abdominal CT and bone scan.

14 Egyptian J. Nucl. Med., Vol. 8, No. 2, December (Table 2): Quantitative PET/CT after 2-3 and 6 cycles of chemotherapy in 25 patients with recurrent breast cancer No of patients Degree of Mean SUV max at Mean SUV max at response to therapy 2-3 cycles of chemotherapy 6 cycles of chemotherapy % 6.9± ± % 6.5± ±0.7 (Fig 1): 35 year-old female patient, (A) she has got right breast cancer, initial base line study showed right axillary LNs, (B) post therapy study showed complete disappearance of the axillary nodal lesions signifying good response to the given therapy.

15 Egyptian J. Nucl. Med., Vol. 8, No. 2, December DISCUSSION: Primary systemic chemotherapy was first introduced for managing advanced breast cancer (2).The availability of various new therapies for relapsing breast cancer as well as determination of the extent of disease and its precise localization of utmost importance (3).The main rationale for primary chemotherapy is to test for chemosensitivity, allowing for subsequent changes in the chemotherapy regimen, with the aim of designing a more individualized treatment plan (7, 8, 9). The use of 18F-FDG PET for predicting a therapeutic response is based on early changes in tumor glucose use and changes in 18F-FDG uptake indicating effectiveness of treatment (10, 11). The degree of change in FDG tumor uptake between baseline and after one or two courses of chemotherapy is correlated with histo-pathologic response after the completion of therapy. This approach appears to be of particular interest because it might offer an early opportunity to change therapeutic strategy in case of inadequate response (12, 13). The present study, confirms previous reports on the predictive value of early changes in glucose metabolism after initiation of chemotherapy. Four out of 27 patients with locally advanced breast lesions assessed after 2-3 cycles of chemotherapy, showed significant metabolic response in PET/CT in view of reduction of SUV max (65.8%) as compared to baseline study. while 23 patients (85%) defined as having poor therapy response in view of reduction of SUV max (36.2 %) than baseline study (Table 1). Andrade et al. suggested that the FDG- PET/CT after the second cycle of chemotherapy can predict pathological response in breast cancer, and potentially identify a subgroup of non-responding patients for whom ineffective chemotherapy should be avoided (14). Many studies determined a threshold value of decrease in FDG uptake to predict response to chemotherapy: This cutoff varies from 40% to 60% of baseline uptake after two courses of chemotherapy (15, 16, 17). Wahl et al. reported on changes in tumor metabolic activity in a series of 11 women who had locally advanced primary breast cancers and who had received a combination of primary chemotherapy and hormone therapy. Tumor 18F-FDG uptake promptly decreased in 8 patients, with subsequent partial or complete pathologic responses, whereas tumors in 3 non responding patients did not show a significant decrease in 18F-FDG uptake (18). Later studies confirmed a more pronounced decrease in 18F-FDG uptake SUV max after the first and second cycles of primary chemotherapy in patients showing a histo-pathologic response than in non-responders (19, 20). In another study, 30 breast cancer patients received 8 cycles of primary chemotherapy and the mean reduction in 18F-FDG uptake after the first cycle was significantly higher in lesions with a partial, complete macroscopic or complete microscopic response than in non-responding lesions (16). Furthermore, a multicenter trial in which

16 Egyptian J. Nucl. Med., Vol. 8, No. 2, December F-FDG PET scans were performed for 104 patients, confirmed that the greater the reduction in tumor metabolic activity early in the course of therapy, the more likely that patients would achieve a histopathologic response (17). Also, in another study with In patients who showed histo-pathologic response, the SUV decreased by 50.5%± 18.4% after the first cycle of primary chemotherapy; in comparison, the SUV decreased by 36.5%±6 20.9% in non-responders. Patients who did not show a histopathologic response were identified when the relative decrease in the SUV max of less than 45%was used as a cutoff (17). Emmering et al suggested that the residual tumor FDG uptake after completing neoadjuvant chemotherapy predicts residual disease and is highly predictive of relapse (21). In our study the second group of 25 patients referred for therapy monitoring after complete cessation of the therapy, 19 patients of them (76%) showed significant REFERENCES: 1. Mauri D, Pavlidis N, Ioannidis JP. Neoadjuvant versus adjuvant systemic treatment in breast cancer: a metaanalysis. J Natl Cancer Inst. 97 (3): , Bonadonna G, Valagussa P, Zucali R, et al. chemotherapy in surgically resectable breast cancer. CA Cancer J Clin. 45: , Fueger SR, Marven R, Erial MD. A meta-analysis of FDG-PET for the evaluation of breast cancer recurrence and metastases. Breast Cancer Res Treat. 55: , Antoch G, Saoudi N, Kuehl H, et al. FDG PET/CT for tumor staging in solid tumors: metabolic response in PET/CT in view of reduction of mean SUV max 69.6% as compared to mean value after 2-3 cycles suggestive of good responder (Table 2). Also, in monitoring disease response for metastatic cancer, a study involving 20 patients demonstrated that 75% of patients showing a metabolic response on visual analysis responded well to therapy (21). Dose Schwarz et al. confirmed previous observations on the predictive value of information about early changes in glucose metabolism for metastatic breast cancer, compared with the baseline PET/CT data, the18f-fdg uptake in responding metastatic lesions decreased to 54% ±16% after the second cycle of chemotherapy. In contrast, the 18F-FDG uptake in metastases not responding to chemotherapy declined only to 79% ± 6.9 % after the second cycle of chemotherapy (22) to conclude, FDG/PET can differentiate responder from nonresponder to chemotherapy after 2-3 cycle and end of 6 cycle of treatment. comparison with CT and PET. J Clinc Oncol. 22: , Dehdashti F, Flanagan FL, Mortimer JE, et al. Positron emission tomographic assessment of metabolic flare to predict response of metastatic breast cancer to antiestrogen therapy. Eur J Nucl Med.; 26:51 6., Eric L, William B, David A, et al. FDG PET, PET/CT, and Breast Cancer Imaging.Radio Graphics;27:S215-S229, Smith IC, Heys SD, Hutcheon AW, et al. Neoadjuvant chemotherapy in breast cancer: significantly enhanced response with docetaxel. J Clin Oncol.; 20: , 2002.

17 Egyptian J. Nucl. Med., Vol. 8, No. 2, December Hutcheon AW, Heys SD, Sarkar TK; Aberdeen Breast Group. Neoadjuvant docetaxel in locally advanced breast cancer. Breast Cancer Res Treat.; 79 (suppl 1):S19 S24, VonMinckwitz G, Blohmer JU, Raab G, et al. In vivo chemosensitivity-adapted preoperative chemotherapy in patients with early-stage breast cancer: the GEPARTRIO pilot study. Ann Oncol.; 16:56 63, Weber WA. Positron emission tomography as an imaging biomarker. J Clin Oncol.; 24: , Groheux D, Giacchetti S, Espied M, et al. Early monitoring of response to neoadjuvant chemotherapy in breast cancer with 18F-FDG PET/CT: defining a clinical aim. Eur J Nucl Med Mol Imaging.; 38 (3): , Gebhart G, Gámez C, Holmes E, et al.18f-fdg PET/CT for Early Prediction of Response, to Neoadjuvant Lapatinib, Trastuzumab, and Their Combination in HER2- Positive Breast Cancer: Results from Neo-ALTTO.J Nucl Med.; 54 (11): , Martoni AA, Zamagni C, Quercia S, et al. Early (18)F-2-fluoro-2-deoxy-dglucose positron emission tomography may identify a subset of patients with estrogen receptor-positive breast cancer who will not respond optimally to preoperative chemotherapy. Cancer.;116 (4): , Andrade WP, Lima EN, Osorio CA, et al. Can FDG-PET/CT predict early response to neoadjuvant chemotherapy in breast cancer? Eur J Surg Oncol.;39 (12) , Schelling M, Avril N, Nahrig J, et al. Positron emission tomography using [(18)F]Fluorodeoxyglucose for monitoring primary chemotherapy in breast cancer. J ClinOncol.; 18 (8): , McDermott GM, Welch A, Staff RT, et al. Monitoring primary breast cancer throughout chemotherapy using FDG- PET. Breast Cancer Res Treat.;102(1):75-84, Schwarz-Dose J, Untch M, Tiling R, et al. Monitoring primary systemic therapy of large and locally advanced breast cancer by using sequential positron emission tomography imaging with [18F] fluorodeoxyglucose. J Clin Oncol.;27: , Wahl RL, Zasadny K, Helvie M, et al. Metabolic monitoring of breast cancer chemohormonotherapy using positron emission tomography: initial evaluation. J Clin Oncol.;11: , Smith IC, Welch AE, Hutcheon AW, et al. Positron emission tomography using [18F]-fluorodeoxy-D-glucose to predict the pathologic response of breast cancer to primary chemotherapy. J Clin Oncol.; 18: , Rousseau C, Devillers A, Sagan C, et al. Monitoring of early response to neoadjuvant chemotherapy in stage II and III breast cancer by [18F] fluorodeoxyglucose positron emission tomography. J Clin Oncol.;24: , Emmering J, Krak NC, Van der Hoeven JJ, et al. Preoperative [18F] FDG- PET after chemotherapy in locally advanced breast cancer: prognostic value as compared with histopathology. Ann Oncol.;19 (9): , Dose Schwarz J, Bader M, Jenicke L, et al. Early prediction of response to chemotherapy in metastatic breast cancer using sequential 18F-FDG PET.J Nucl Med.; 46: , 2005.

18 Egyptian J. Nucl. Med., Vol. 8, No. 2, December Original Article, Oncology Diagnostic Accuracy of 18 F-FDG PET/CT in Detection of Local Recurrence in Rectal Cancer and the Added Value of Dual Time Point Scanning Farghaly H 1, Nasr H 2 and Nabulsi J 3 1 Nuclear Medicine Unit - Clinical Oncology department, Assiut University Hospital, Assiut, Egypt; 2 Nuclear Medicine Unit, Kasr Al-Aini - Cairo University Hospital, Cairo, Egypt and 3 Radiology department, Prince Sultan Military Medical City, Riyadh, Saudi Arabia ABSTRACT: Objectives: To assess diagnostic accuracy of FDG PET/CT and the added value of dual time point PET/CT (DTP) in detection of local recurrence (LR) in patients with rectal cancer (RC). Methods: Patients (n = 50, 41 males and 9 female, mean age 52 ± 11 years). All patients underwent resection ± chemotherapy and/or radiotherapy. 37 patients were suspicious for LR on contrast enhanced CT (ce CT). All patients underwent whole body FDG PET/CT scan. In 18 patients 2 hours delayed pelvic PET/CT images were done. SUVmax cut off of 3.0 was set to differentiate benign from malignant lesions based on ROC analysis. Suspicious pelvic lesions were correlated with biopsies in 28 patients (56%) and with clinical and/or imaging follow-up (FDG PET/CT, CT or MRI) in 22 patients (44%). Sensitivity, specificity, positive and negative predictive values, and accuracy in detection of LR using ce CT data and following PET/CT were calculated. Results: Nine patients had LR (18%). SUV max was higher in all patients with LR. Sensitivity specificity, PPV, NPV, and accuracy for detecting recurrent lesions were significantly higher for PET/CT and PET/CT with tumor markers versus ce CT (p<0.05). Delayed pelvic PET/CT revealed increase in delayed SUV max (ΔSUV max >0) in 4/18 patients with confirmed LR (true positive) and revealed increase in delayed SUV max (ΔSUV max >0) 4/18 with no evidences of LR (false positive) while 10/18 showed decrease in SUV max (ΔSUV max 0) in delayed images with confirmed no LR (true negative). The combined early SUVmax and delayed increase in SUVmax revealed improvement in overall accuracy compared to either parameter alone. Conclusions: PET/CT has an excellent sensitivity and a higher overall accuracy for detection of local rectal cancer recurrence when compared to ce CT. Delayed PET/CT when performed is capable of improving the specificity, PPV and accuracy of the PET/CT study. Key words: FDG PET/CT- rectal cancer- local recurrence. Corresponding Author: Hussein R. Farghaly hussen2h@yahoo.com

19 Egyptian J. Nucl. Med., Vol. 8, No. 2, December INTRODUCTION: Colorectal cancer (CRC) is the third most common cancer and the fourth most frequent cause of cancer deaths worldwide. Surgical resection is the mainstay of treatment for rectal cancer for curative intent. There are a variety of surgical options and combinations with preoperative therapies including preoperative radiotherapy or chemo-radiotherapy, all with various levels of morbidity and mortality risk (1). Local recurrence is defined as evidence of recurrent disease within the pelvis after a surgical resection, including recurrence at the site of anastomosis and perineal wound. Few studies are in the literature on loco-regional recurrence (LR) after a potentially curative resection of a rectal cancer because many authors mix colonic and rectal cancer and primary rectal cancer with recurrent disease (2). The overall recurrence rate of CRC was 27.9%, the anastomotic recurrence rate was 11.7%, and the distant metastasis rate was 14.4%.12. The average time for recurrence was 21.3 months (3). Locoregional recurrence is more common in rectal carcinoma than colonic cancer, typically in the pre-sacral region. Surgery is the main treatment with curative potential for recurrent and metastatic disease. Early diagnosis of local recurrence and small metastases is crucial, since surgery has a higher chance of success with 5 year survival rate of up to 30% in asymptomatic patients with limited disease (4-7). Confirmation of recurrence of CRC has been evaluated by physical examinations, colonoscopy and conventional diagnostic imaging (CDI) such as US, CT and MRI (8). However; there are several common features which limit the value of these CDI methods such as postoperative inflammatory scarring may persist for months and post irradiation changes frequently seen in the presacral space and in the muscles and may lead to an erroneous diagnosis of LR. Functional imaging using 18F-FDG PET/CT is a wellestablished method for the evaluation of patients with suspected CR. There are many studies in the literature compared FDG PET/CT with in carcino-embryonic antigen (CEA) measurement and contrastenhanced abdominal computed tomography (cect) in the detection of colorectal cancer (CRC) recurrence. Many of these studies showed higher sensitivity, specificity, and accuracy than ce CT and CEA (9-13). Our study is a retrospective comparative study in which we compared the diagnostic accuracy of FDG PET/CT, ce CT and tumor markers (CEA and/or CA19-9) in detection of rectal cancer recurrence and to evaluate the added value of DTP in detection of local rectal cancer recurrence. PATIENTS AND METHODS: Informed consent was not required for this retrospective analysis. Patient Population: 50 consecutive patients with rectal cancer, 41 males and 9 female, mean age 52 ± 11 years) were retrospectively reviewed. All patients treated by resection ± chemotherapy and/or radiotherapy. All patients underwent an abdominal ce CT and whole body FDG PET/CT scans. In 18

20 Egyptian J. Nucl. Med., Vol. 8, No. 2, December patients 2 hours delayed (DTP: dual time point) pelvic PET/CT images were done. PET/CT scanning Patients fasted at least 4 hours before the tracer injection and received an intravenous injection (some patients were injected manually and the other by automatic injector) of approximately 5.18 MBq/Kg (0.14 mci/kg) of 18F-FDG, with a maximum of 444 MBq (12 mci). Blood glucose level was measured immediately prior to FDG injection and was < 165 mg in all studied cases. Patients were sitting calm in a quiet injection room without talking during the subsequent min of the FDG uptake phase. Patients were allowed to breathe normally during image acquisition without specific instructions. All scans were acquired using a Gemini TF PET/CT scanner (Philips Medical Systems). Emission data were acquired for bed positions (identical to the CT protocol). Emission scans were acquired at 1 minutes per bed position always in 3D which may increase up to 2 or 3 minutes per bed position in case of obese patients dependent on the body mass index (BMI). The FOV was from the base of the skull to mid thigh with the arms above the head unless the patient cannot tolerate positioning the arm above the head, arms down position was used and if there was a significant truncation artifact from the arms in the pelvic region a localized PET/CT scan was done with the arms over the chest. The CT scans were used for attenuation correction purposes and to help in anatomic localization of FDG. The 3-dimentional (3D) WB acquisition parameters consisted of a 128 x 128 matrix and an 18 cm FOV with a 50% overlap. CT scanning: The CT scan of the PET/CT scanner consisted of a 16 slice CT. Gantry allows for a patient port of 70 cm. CT Parameters: It is a single sweep: KV and mas (based on body mass index), 0.5 second per CT rotation, Pitch 1.675:1, Slice thickness is 5mm and matrix. CT acquisition was performed before emission acquisition. CT data were used for image fusion and the generation of the CT transmission map. All patients received gastrographin oral contrast in baseline PET/CT studies according the division protocol at that time for patients with gastrointestinal (GIT) cancer. In some patients who had follow-up PET/CT they received 1000 ml of water orally 30 minutes before imaging as negative contrast agent due the division protocol modification for GIT cancer patients. No IV contrast was used. Breathing technique is hold breath after normal expiration. If patient can t do it, then shallow breathing is acceptable. Image analysis: PET/CT scan or scans of each patient in our study population was reviewed by two nuclear medicine physician. Any suspicious lesion for local recurrence in CT or in FDG PET/CT (either FDG avid or not) were evaluated and either correlated by biopsy or follow-up FDG PET/CT or other imaging modalities (CT and/or MRI) and recorded and tabulated. Two hours delayed pelvic PET/CT was done in 18 patients out of 50 and interval changes in SUVmax (maximum standardized uptake value) were recorded. In the current study pelvic lesions were considered as local recurrence only if located at site of surgical anastomosis, perirectal or pre-secral and such lesions were analyzed as follows: True positive (TP) if initial SUVmax 3.0, increased SUV in delayed image (ΔSUV max >0) or both combined and confirmed to be malignant; False positive (FP) if

21 Egyptian J. Nucl. Med., Vol. 8, No. 2, December initial SUV max 3.0, ΔSUV max >0 or both combined and no evidence of malignancy on biopsy or follow up; True negative (TN) if initial SUV max <3.0 and/or ΔSUV max 0 and no evidence of malignancy on biopsy or follow up; False negative (FN) if initial SUV max <3.0 and/or ΔSUV max 0 and confirmed to be malignant. All the available non radionuclide imaging modalities such as CT and MRI were reviewed by consultant radiologist. Statistical analysis: Statistical analysis was performed using SPSS software (SSPS 13.0) and MedCalc ( ). Sensitivity, specificity, positive predictive value (PPV) negative predictive value (NPV), and accuracy were calculated for the diagnostic CT and for the PET/CT study. ROC analysis is used to define the best cut off value of SUVmax to differentiate benign from malignant lesions. McNemar test was used to test the difference between paired patient proportions using different methods of stratification, namely ce CT, PET/CT or combined PET/CT and tumor markers. Comparison of differences between area under the curve AUC of the different ROC curves for different ways of stratifying patients using ce CT, PET/CT or combined PET/CT and tumor markers had been performed. Non-paired student T-test was used to compare mean difference in SUV max or ΔSUV max between patients with confirmed positive and those with negative local recurrence (LR). For statistical significance a p value of <0.05 was required. RESULTS: The characteristics and clinical data of the study population are shown in Tables (1). Out of the 50 patients included in this study, 25 (50%) showed elevated blood levels of tumor markers (CEA 3.4 ug/l and/or CA U/ml). Nine of them were confirmed to have local recurrence, associated in 6 patients with distant metastases while 8 patients had isolated distant metastases. Metastatic sites included the liver in 8 patients, lungs in 12 patients, bone in 3 patients and abdominal lymph nodes in 1 patient. (Table1). Of the remaining 25 patients without elevated tumor markers none had local recurrence while only 1 patient had isolated distant metastases to the lung (Table2). The sensitivity, specificity, positive, negative predictive values and accuracy of tumor markers to detect local recurrence and/or metastases are 94% (17/18), 75% (24/32), 68% (17/25), 96% (24/25) and 82 (41/50) respectively (Table 2). Based on ce CT 37 patients were suspicious for having local recurrence and was able to identify 8 out of 9 patients with confirmed local recurrence with only 1 false negative, 12 true negative but with high number of false positives of 29 patients.(table 2).

22 Egyptian J. Nucl. Med., Vol. 8, No. 2, December Table (1): Demographic and clinical data of the study population Study group Study group (n=50) Mean age (years) 52.0 ± 11.0 Males 41 (82%) Previous surgery 50 (100%) Prior Chemotherapy 33 (66%) Prior Chemotherapy & Radiotherapy 20 (40%) Prior Radiotherapy 21 (42%) Elevated tumor markers (CEA &/or CA19-9) 25 (50%) Distant metastases 14 (28%) Liver Lungs Liver and Lungs Lungs and Bone Liver, Lungs and bone Lung and Abdominal LNs Follow up: Biopsy 28 (56%) CT, PET/CT or MRI 22 (44%) Follow up time if no biopsy (months) 8.8 ± 5.2 (2-21) Table (2): Comparison between patients with elevated tumor markers and those with non-elevated tumor markers as regards local recurrence and distant metastases. Non-Elevated Tumor (4%) 0 24 (96%) Markers N, number; LR, local recurrence; DM, distant metastases. Sensitivity, specificity, positive and negative predictive values and accuracy of cect to detect local recurrence were 88.9%, 29.3%, 21.6%, 92.3% and 40% respectively. The mean SUVmax in lesions with confirmed local recurrence was significantly higher than in those with no confirmed recurrence (5.40±2.84 vs. N LR DM LR & DM No LR or DM Elevated Tumor Markers 25 3 (12%) 8 (32%) 6 (24%) 8 (32%) 2.59±1.83; p<0.001). Using an SUVmax cut off value of 3 FDG PET/CT was able to detect all 9 patients with local recurrence in which 5 of them had the lesions located in the presacral region, 2 with the lesions in the surgical anastomotic site and 2 had lesions in perirectal regions. Twenty seven patients had no significant FDG uptake

23 Egyptian J. Nucl. Med., Vol. 8, No. 2, December (SUVmax <3) and were considered true negative while 14 patients had high FDG activity (SUVmax 3) and were considered false positive based on negative biopsy that revealed either inflammatory changes or granulation tissue in 8 patients while the other 6 patients showed no evidence of malignancy on imaging follow up. Sensitivity, specificity, PPV and NPV and accuracy of FDG PET/CT (SUVmax 3) to detect local recurrence were 100%, 65.9%, 39.1%, 100% and 72% respectively with highly significant improvement (p= ) compared to cect. After exclusion of 3 patients with SUVmax 3, high tumor markers and known distant metastases, addition of elevated tumor markers to further stratify patients together with early SUV max 3 resulted in again identification of all 9 patients with local recurrence though with significant reduction in the number of false positives from 11/47 to only 4/47 and significantly boosting the specificity, positive predictive value and accuracy from 71.1%, 45.0% and 76.6% to 89.5%, 69.2% and 91.5% respectively (p=0.0156) (Table 3). Comparison of ROC curves for detection of local recurrence using ce CT, FDG PET/CT as well as combined FDG PET/CT with tumor markers is show in figure 1. The area under the curve (AUC) of the ROC curve for PET/CT was significantly larger than that for ce CT (p=0.049) while the difference was highly significant when using combined PET/CT and markers versus ce CT (p=0.003) (Table 4). Table (3): Comparison between different stratification methods as regards sensitivity, N Sens. Spec. PPV NPV Acc. p-value Ce CT % 29.3% 21.6% 92.3% 40.0% Initial SUVmax % 65.9% 39.1% 100% 72.0% Ce CT* % 32.3% 32.3% 92.3% 51.1% Initial SUVmax 3 + TM* % 89.5% % 91.5% < Initial SUVmax 3* % 71.1% 45.0% 100% 76.6% specificity, PPV, NPV and accuracy for detection of local recurrence in the entire study population. * Three patients with isolated distant metastases and high tumor markers were excluded. Table (4): Pairwise comparisons between AUC of the different ROC curves for ce CT, PET/CT (SUVmax 3) and combined PET/CT (SUVmax 3) with tumor markers. AUC Difference P-value cect ~ PET/CT P = cect~ PET/CT & Markers P = PET/CT ~ PET/CT & Markers P = 0.302

24 Egyptian J. Nucl. Med., Vol. 8, No. 2, December Sensitivity AUC P-value cect PET/CT <0.01 PET/CT & <0.01 Markers cect PET/CT PET/CT & Markers Specificity Figure (1): Pairwise comparison of ROC curves for ce CT, PET/CT (SUVmax 3) and combined PET/CT (SUVmax 3) with tumor markers (47 patients). Among the subgroup of 18 patients who had delayed PET/CT images, 4 patients had confirmed local recurrence (early mean SUV max = 4.38±1.33 vs. delayed SUV max = 5.70±2.36; p=0.084) and were all identified by early images using SUV max of 3. Another 4 patients had increase in delayed SUV max but no evidence of local recurrence and were considered false positive (early mean SUV max = 3.98±1.02 vs. delayed SUV max=5.35±1.42; p=0.025). The remaining 10 patients had no increase in delayed SUV max with no evidence of local recurrence and all were considered as true negative (early mean SUV max = 3.64±2.13 vs. delayed SUV max = 3.16±1.84; p=0.009). Three of these 10 patients were converted from being false positive due to SUVmax of 3 in early images to being true negative after no increase but actually significant decrease in delayed SUV max (early mean SUV max = 4.65±2.13 vs. delayed SUV max= 4.23±1.84; p=0.032). The change in SUV max (ΔSUV max) was significantly higher in the 4 patients with proved local rectal recurrence compared to the 14 patients with no proven recurrence (1.33 ± 1.04 vs ± 0.99; p<0.04). On the other hand, p value did not reach statistically significant level between both groups as regards the stand alone early SUV max (4.38 ± 1.33 vs ± 1.84; p=0.53) or the stand alone delayed SUV max (5.70 ± 2.36 vs ± 1.97; p=0.12) respectively.

25 Egyptian J. Nucl. Med., Vol. 8, No. 2, December Table (5): Comparison between different stratification methods as regards sensitivity, specificity, PPV, NPV and accuracy for detection of local recurrence in patients with delayed PET/CT imaging. N Sens Spec PPV NPV Acc Initial SUV max % 42.9% 33.3% 100% 55.6% ΔSUV max > % 71.4% 50.0% 100% 77.8% Initial SUVmax 3 + ΔSUV max> % 78.6% % 83.3% N* Sens Spec PPV NPV Acc Initial SUV max % 46.2% 36.4% 100% 58.8% ΔSUV max> % 76.9% 57.1% 100% 82.4% Initial SUVmax 3 + TM % 76.9% 57.1% 100% 82.4% Initial SUVmax 3 + ΔSUV max> % 84.6% % 88.2% ΔSUV max> 0 + TM % 84.6% % 88.2% Initial SUVmax 3 + ΔSUV max > 0 + TM % 84.6% % 88.2% *1 patient with isolated liver metastases and elevated tumor markers was excluded. Sensitivity, specificity, positive and negative predictive values and accuracy of delayed PET/CT to detect local recurrence based on ΔSUV max > 0 were 100%, 71.4%, 50%, 100% and 77.8% respectively (Table 5). Stratifying the patients using both the early SUV max 3.0 and increase in delayed SUV max revealed further improvement in specificity, PPV and accuracy to 78.6%, 57.1% and 91.5% respectively. After exclusion of 1 patient with isolated hepatic metastases and elevated tumor markers, addition of tumor markers as a stratifying factor together with initial SUVmax 3.0 showed sensitivity, specificity, PPV, NPV and accuracy of 100%, 76.9%, 57.1%, 100% and 82.4% respectively. The same values were obtained by using the delayed increase in SUVmax alone. The sensitivity, PPV and accuracy were further improved to 84.6%, 66.7% and 88.2% by stratifying patients using combined early SUV 3.0 and delayed increase in SUV with no more improvement when adding tumor markers to the combined early and delayed imaging (Table 5). Illustrated examples from our patient population PET/CT images to detect local rectal cancer recurrence are shown in figures (2, 3 and 4).

26 Egyptian J. Nucl. Med., Vol. 8, No. 2, December A B Figure (2): 52 year old female with rectal cancer, post surgery with elevated tumor marker and CT showed enhancing lesion in the pelvis, FDG PET/CT to R/O recurrent or residual: (A) Early FDG PET/CT showed focal FDG avid soft tissue density in the right presacral region with SUVmax of 3.9 that increased to 4.4 in the 2 hours delayed pelvic FDG PET/CT images (B). The lesion confirmed to be malignant on biopsy. A B Figure (3): 51 year old male with rectal cancer, post surgery, chemotherapy and radiotherapy. (A) Early PET/CT showed FDG avid lesion in rectal anastomotic site with SUVmax of 7.6 decreased to 6.5 in the 2 hours delayed pelvic FDG PET/CT images (B). Biopsy revealed non-specific inflammatory changes.

27 Egyptian J. Nucl. Med., Vol. 8, No. 2, December Figure (4): 56 yrs male patient with cancer rectum, post surgery and chemotherapy, CT showed perirectal soft tissue density, FDG PET/CT done to rule out recurrence. (A) Early FDG PET/CT showed heterogeneous FDG uptake in the perirectal soft tissue density with SUVmax of 4.0. (B) 2 hours delayed pelvic FDG PET/CT showed decreased in SUV max to be 2.3 in the perirectal soft tissue density. Biopsy showed inflammatory changes with no evidence of malignancy. DISCUSSION: Unlike colonic cancer that tend to spread to intramural, peri-visceral and mesenteric nodes, that are easily resected, rectal cancer cells tend to invade perirectal and inferior mesenteric nodes as well as adjacent structures making surgery more complicated (14). While many previous studies had discussed the use of PET/CT in detection of colorectal cancer recurrence (9-10, 15-22), only few had emphasized its role in rectal cancer recurrence (12-14, 21, 23). O'Connor mentioned that local recurrence is more common in patients with rectal rather than colon cancer ranging from 7% to 33% and 1 19%, respectively. About 20% of recurrences are local and 43% are concurrent local and distant (24). In the current study, patients with local recurrence and/or distant metastases were 18/50 (36%) of the total population. Pure local recurrence was noted in 3 out of 18 patients (17%), while 6/18 patients (33%) had combined local and distant metastases and 9/18 (50%) patients had only distant metastases. This was close to what mentioned by Brethauer et al. reporting that 54% of recurrences had distant metastases alone at the time of recurrence and 67% had distant

28 Egyptian J. Nucl. Med., Vol. 8, No. 2, December metastases as a component of local failure (25). About 25% of patients with initially respectable colorectal cancer will have a recurrence within 2 years of resection (26). As a tumor marker CEA had been the most widely studied and used for preoperative staging and follow up, in patients with colorectal cancer (15). All patients with detected local or distant recurrence in our study had elevated CEA level except for one patient with isolated lung metastases. Moreover in 8/25 (32%) of patients who had elevated CEA, none had been confirmed to have local or distant recurrence using biopsy in 2 and on clinical and imaging follow up in the rest, despite that 5 patients of them showed enhanced FDG activity either in presacral space or around surgical bed, and such patients were treated as false positive. According to Even et al. (23), CEA levels may detect recurrent colorectal cancer months before it can be detected on a CT scan, though its benefit to patient survival or quality of life had not been well established, likely because the lack of lesion localization. Studies established the utility of PET in identifying a source of elevated CEA in a very high fraction of patients who had negative findings on CT (23). We believe that failure to confirm or even localize recurrent disease in some patients with elevated tumor markers could be related to inadequate follow up, histopathologic types of tumors that are less FDG avid or even inaccurate biopsy site in some patients. It had been also reported that the sensitivity of FDG-PET imaging for detection of mucinous carcinoma is significantly lower than in non-mucinous carcinoma (58% and 92%, respectively) (27), however in our study we did not perform an analysis for tumor histopathology in comparison to the FDG PET findings. Our analysis revealed a significantly higher SUVmax in patients with confirmed local recurrence versus those with no confirmed local recurrence. The local recurrence sites were presacral in 5 patients, perirectal in 2 patients and in surgical anastomotic site in 2 patients. Such locations following surgical resection are frequently difficult to assess by CT or even MRI due to post operative fibrotic or inflammatory changes. Delbeke and coworkers found that the greatest utility of 18F-FDG-PET in evaluating colorectal carcinoma was in differentiating tumor recurrence from scar as at the site of surgical resection, which could be difficult to assess by conventional imaging modalities (15). For detecting local rectal recurrence we found that the initial PET/CT imaging using SUVmax 3.0 is significantly better than ce CT with a sensitivity of 100% versus 92%, specificity of 71% versus 32% and accuracy of 77% versus 51% respectively. Several studies had reports that the FDG-PET accuracy in detecting CRC recurrence is higher than that of CT. A study by Chiwvit et al., showed that 18F- FDG-PET had an overall sensitivity of 94.4%, specificity of 66.7% and accuracy of 87.5% for recurrent colorectal cancer, with a lower values for ce CT, which had a sensitivity of 79% and a specificity of 73%.27 (9). Ozkan et al., in a study of 69 patients reported a sensitivity and specificity of 97% and 61% respectively for 18F-FDG PET/CT compared to 51% and 61% for ce CT in the detection of disease recurrence (10). In other study for 62 patients by Even-Sapir et al., PET/CT achieved an overall accuracy of 92% for detection of rectal recurrence (23). Selzner et al., reported that local recurrence at the

29 Egyptian J. Nucl. Med., Vol. 8, No. 2, December primary colorectal resection site were detected by ce CT and PET/CT with a sensitivity of 53% and 93%, respectively (P= 0.03) and PET/CT was superior to ce CT for the detection of recurrent intrahepatic tumors most other studies as regards the relatively low specificity and PPV of FDG PET/CT for detection of local rectal recurrence except for a meta-analysis by Huebner and coworkers (21) in which 5 studies (366 patients) were considered for assessment of local/pelvic recurrence and reported both high sensitivity and specificity of 94.5% and 97.7% respectively. We found that there is an additive value for both delayed PET/CT imaging (ΔSUV max>0) and elevated tumor markers when used to stratify patients combined with the initial SUVmax 3.0. The addition of tumor markers led to substantial improvement in specificity, PPV and accuracy from 71.1%, 45% and 76.6% to 81.5, 61.3 and 91.5%, respectively. Several previous studies had studied the accuracy of PET/CT imaging in comparison to tumor markers to detect colorectal cancer recurrence, however to the best of our knowledge there is no available studies addressing their combined accuracy specifically for rectal cancer recurrence. Our results revealed a significant improvement in specificity, PPV and accuracy from 71.1%, 45.0% and 76.6% to 89.5, 69.3 and 91.5%, respectively (p=0.0156) when tumor markers were used as an additional stratifying factor in addition to the initial SUV max 3.0. Ozkan et al. (10), reported an improvement in specificity of 18F-FDG PET/CT from 60% to 75% when measured in patients with elevation in CEA level less than two-fold compared to those with CEA elevation less than three-fold, however there was no further improvement in specificity when measured in patients with higher CEA level. In a recent study by Panagiotidis et al. (11) F-FDG PET/CT had higher accuracy (100%) in detecting recurrent colorectal cancer only in the group of patients with elevated tumor markers? We found that by the addition of ΔSUV max >0 to the initial SUVmax 3.0 as a stratifying factor, there was improvement in specificity, PPV and accuracy from 46.2%, 36.4% and 55.6% to 84.6, 66.7 and 88.4%, respectively, with no improvement when tumor marker results were used as an additional stratifying factor. Multiple previous studies (29-32) have shown that DTP imaging of FDG PET are potentially helpful in differentiating malignant from benign lesions. In a study by Lan et al. (31) to assess the value of DTP imaging in 96 patients with variable types of cancers, the author reported that 54 of 59 (92%) patients with malignant lesions including 17 of 18 patients with digestive system carcinoma had early SUVmax values 2.5 and all lesions showed an increase in SUVmax in delayed images. They also showed an improvement in sensitivity and specificity when using delayed imaging compared to early imaging (30). In another study to detect locoregional breast cancer recurrence, the best diagnostic accuracy was achieved by the combined use of delayed SUVmax > 2.5 and %ΔSUV max > 0%, with an overall accuracy better than that of delayed SUV max > 2.5 alone or %ΔSUV max > 0% alone (31). In a third study on 26 esophageal cancer patients specificity to detect metastatic lesions was improved when retention index (RI) 10% was used to supplement the early SUVmax of 2.5 (32). On the other hand there are other studies that reported no improvement in diagnostic

30 Egyptian J. Nucl. Med., Vol. 8, No. 2, December accuracy by the use of delayed imaging (33-36). In most of these studies the delayed SUVmax or RI were used separately versus the early SUVmax and not in conjunction with the early SUVmax. Furthermore some of these studies although showed no improvement in overall accuracy still demonstrated substantial improvement in specificity with the use of delayed SUVmax or RI as in the recent study by Choi et al. (36) that mentioned an improvement in specificity to detect extra hepatic cholangio-carcinoma lesions from 60% using the early SUVmax (cutoff 2.5) to 100% using the delayed SUVmax (cutoff 3.1) though with some corresponding deterioration in sensitivity from 97.6% to 88.2%. Study Limitations: A potential limitation point in our study are the relatively small sample size specially when it comes to the application of delayed imaging since it is only ordered by the nuclear medicine physician in selected patients when it is considered helpful in better clarifying equivocal findings or differentiating between pathologic and physiologic activity in the early images. The retrospective nature of the study is probably another potential limitation since the baseline clinical and laboratory data for some patients cannot be retrieved. A third potential limitation is the lack of histopathological gold standard in substantial portion of our patients (44%) and depending instead on follow up imaging with variable follow up imaging modalities and intervals, though the same methodology had been previously applied in multiple published studies and is probably accepted specially when the biopsy would not be clinically justified or would be questionable from the ethical or medicolegal aspects. CONCLUSIONS: The results of the current study suggest an excellent sensitivity and NPV of combined PET/low-dose non-enhanced CT in the detection of local recurrence in rectal cancer patients. On the other hand the FDG PET/CT specificity and PPV appear to be relatively less impressive, obviously due to the frequent false positive rate that is likely related to post-operative or inflammatory changes. The use of the combined PET/CT together with tumor markers to stratify patients, significantly improves the specificity and PPV of FDG PET/CT in detection of local recurrence. The addition of delayed imaging appears effective as well in improving the specificity and PPV regardless of tumor markers results. The correlations of PET/CT findings with tumor markers as CEA as well as the use of delayed imaging in some patients with equivocal findings in early images are both valid options whenever more confidence is needed in reporting PET/CT positive findings. We believe that the delayed PET/CT imaging to assess the change in SUV is helpful mainly in improving the specificity of the study and provides more data when compared to the interpretation of early or delayed images separately.

31 Egyptian J. Nucl. Med., Vol. 8, No. 2, December REFERENCES 1. J Brush, K Boyd, F Chappell, et al. The value of FDG positron emission tomography/computerized tomography (PET/CT) in pre-operative staging of colorectal cancer: a systematic review and economic evaluation. Health Technology Assessment. 15 (35):1-192, Johan N Wiig and Odd Søreide; Locoregional recurrence of rectal cancer. In: Holzheimer RG and Mannick JA, eds. Surgical Treatment: Evidence-Based and Problem-Oriented. Munich: Zuckschwerdt; Waldron R, Donovan I. Clinical follow up and treatment of locally recurrent colorectal cancer. Dis Colon Rectum; 30: , Titu LV, Nicholson AA, Hartley JE et al. Routine follow-up by magnetic resonance imaging does not improve detection of resectable local recurrences from colorectal cancer. Ann. Surg. 243, , Abir F, Alva S, Longo WE et al. The postoperative surveillance of patients with colon cancer and rectal cancer. Am. J. Surg. 192, , Huguier M, Houry S, Barrier A. Local recurrence of cancer of the rectum. Am. J. Surg. 182, , Arriola E, Navarro M, Pares D et al. Imaging techniques contribute to increased surgical rescue of relapse in the follow-up of colorectal cancer. Dis. Colon Rectum 49, , Kyoto Y, Momose M, Kondo C, Itabashi M, Kameoka S, Kusakabe K; Ability of 18F-FDG PET/CT to diagnose recurrent colorectal cancer in patients with elevated CEA concentrations. Ann Nucl Med. 24: , Chiewvit S, Jiranantanakorn T, Apisarnthanarak P et al. Detection of recurrent colorectal cancer by 18F-FDG PET/CT comparison with contrast enhanced CT scan. J Med Assoc Thai. 96(6):703-8, Ozkan E, Soydal C, Araz M, Aras G; Serum carcinoembryonic antigen measurement, abdominal contrastenhanced computed tomography, and fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography in the detection of colorectal cancer recurrence: a correlative study. Nucl Med Commun. 33 (9):990-4, Panagiotidis E, Datseris IE, Rondogianni P, Vlontzou E, et al. Does CEA and CA 19-9 combined increase the likelihood of 18F- FDG in detecting recurrence in colorectal patients with negative CeCT? Nucl Med Commun. 35(6): , Kau T, Reinprecht P, Eicher W, Lind P et al. FDG PET/CT in the detection of recurrent rectal cancer. Int Surg. 94(4):315-24, Schaefer O, Langer M; Detection of recurrent rectal cancer with CT, MRI and PET/CT. Eur Radiol. 17(8): , Bellomi M and Travaini LL; Imaging as a surveillance tool in rectal cancer. Expert Rev. Med. Devices 7(1), , Delbeke D, Vitola JV, Sandler MP et al. Staging recurrent metastatic colorectal carcinoma with PET. J. Nuc. Med. 38, , Flanagan FL, Dehdashti F, Ogunbiyi OA, Kodner U, Siegel BA; Utility of FOG-PET for investigating unexplained plasma CEA elevation in patients with colorectal cancer. Ann. Surg. 227, , Valk PE, Abella-Columna E, Hasemann MK et al. Whole body PET imaging with F-18 fluorodeoxyglucose in management of recurrent colorectal cancer. Arch. Surg. 134, , Ruhlmann J, Schomburg A, Bender H et al. Fluorodeoxyglucose whole-body positron emission tomography in colorectal cancer patients studied in routine daily practice. Dis. Colon Rectum 40, , Vitola JV, Delbeke D, Sandier MP et al. Positron emission tomography to stage suspected metastatic colorectal carcinoma to the liver. Am. J. Surg. 171, 21 26, 1996.

32 Egyptian J. Nucl. Med., Vol. 8, No. 2, December Kim JH, Crernin J, Allen-Auerbach MS et al. Comparison between 18F-FDG PET, inline PET/CT, and software fusion for restaging of recurrent colorectal cancer. J. Nucl. Med. 46, , Huebner RH, Park KC, Shepherd JE et al. A meta-analysis of the literature for wholebody FDG PET detection of recurrent colorectal cancer. J. Nuc. Med. 41, , Zamp MG, Labianca R, Beretta GD et al. Rectal cancer. Critical Reviews in Oncology/Hematology , Even-Sapir E, Parag Y, Lerman H et al. Detection of recurrence in patients with rectal cancer: PET/CT after abdominoperineal or anterior resection. Radiology 232, , O'Connor O J, McDermott S, Slattery J, Sahani D, et al. The use of PET-CT in the assessment of patients with colorectal carcinoma. International Journal of Surgical Oncology, Article ID , 14 pages, Brethauer SA, Magrino TJ, Riffenburgh RH, and Johnstone PAS; Management of recurrent colorectal carcinoma, Colorectal Disease, vol. 4, no. 4, pp , Fusai G, Davidson B: Management of colorectal liver metastases. Colorectal Dis, vol 5, no. 1, 2-23, Whiteford MH, Whiteford HM, Yee LF, Ogunbiyi OA, Dehdashti F, et al. Usefulness of FDG-PET scan in the assessment of suspected metastatic or recurrent adenocarcinoma of the colon and rectum. Dis Colon Rectum. 43: , Selzner M, Hany TF, Wildbrett P, et al. Does the novel PET/CT imaging modality impact on the treatment of patients with metastatic colorectal cancer of the liver? Ann Surg. 240: , Suga K, Kawakami Y, Hiyama A, Sugi K, Okabe K et al. Dual-time point 18F-FDG PET/CT scan for differentiation between 18F-FDG-avid non-small cell lung cancer and benign lesions. Ann Nucl Med. 23(5):427-35, Lan XL, Zhang YX, Wu ZJ, Jia Q, et al. The value of dual time point (18)F-FDG PET imaging for the differentiation between malignant and benign lesions. Clin Radiol. 63(7):756-64, Suga K, Kawakami Y, Hiyama A, Matsunaga N. Differentiation of FDG-avid loco-regional recurrent and compromised benign lesions after surgery for breast cancer with dual-time point F-18- fluorodeoxy-glucose PET/CT scan. Ann Nucl Med. 23(4): , Shum WY, Hsieh TC, Yeh JJ, Chen JH, Su CC, et al. Clinical usefulness of dualtime FDG PET-CT in assessment of esophageal squamous cell carcinoma. Eur J Radiol. 81(5):1024-8, Hahn S, Hecktor J, Grabellus F, Hartung V, Pöppel T, et al. Diagnostic accuracy of dual-time-point 18F-FDG PET/CT for the detection of axillary lymph node metastases in breast cancer patients. Acta Radiol. 53 (5):518-23, (2012). 34. Choi WH, Yoo IR, Hyun J, et al. The value of dual-time-point 18F-FDG PET/CT for identifying axillary lymph node metastasis in breast cancer patients. Br J Radiol. 84:593 9, Toriihara A, Nakamura S, Kubota K, Makino T, Okochi K, Shibuya H; Can dual-time-point 18F-FDG PET/CT differentiate malignant salivary gland tumors from benign tumors? AJR Am J Roentgenol. 201(3):639-44, Choi EK, Yoo IeR, Kim SH, O JH, et al. The clinical value of dual-time point 18F- FDG PET/CT for differentiating extrahepatic cholangiocarcinoma from benign disease. Clin Nucl Med. 38 (3):e106-11, 2013.

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34 Egyptian J. Nucl. Med., Vol. 8, No. 2, December Original Article, Oncology A Comparison between FDG PET/CT, CT and MRI in Detection of Spinal Metastases and its Impact on Clinical Management Wafaie, A 1. El-Liethy, N 1. Kassem, H 2. and Kotb, M.H 3. 1 Department of Radiology, Cairo University. 2 Department of Radiology, Benha University. 3 Department of Nuclear Medicine, National Cancer Institute, Egypt. ABSTRACT: The aim of this study was to compare the diagnostic value of combined F-18-FDG PET/CT, CT and MRI indetection of spinal metastatic lesionsand their impact on management of these patients. Patients and methods: A total of 22 patients with biopsy-proven malignancy were enrolled. All patients underwent spinal MRI and whole body F-18-FDG PET/CT examinations using standard techniques. The diagnostic capabilities of the imaging modalities were compared in the same spinal field of view. F-18-FDG PET/CT and MRI findings were compared with the results of biopsy or clinical / radiological follow up for at least 12 months as the reference standards. Results: A total of 214 vertebral lesions were detected in 22 cancer patients based on combined clinical and radiological follow up (FU), these lesions were divided into: 129 metastatic & 85 benign lesions. Moreover these 22 patients were divided into: 12 with spinal metastases and 10 free from spinal metastases. Both lesions & patients based data analysis showed a significant higher diagnostic accuracy for the combined F-18- FDG PET/CT (98.5% and 94.5%) compared to MRI (86% and 68%) and CT (79.5% & 54.5%) respectively (P<0.05).The significant difference between F-18 FDG PET/CT and morphological techniques were more obvious on specificity indices rather than sensitivity indices in both lesion and patient based analysis. On the other hand, MRI results were superior to those of CT on both lesions and patients data analysis. On lesion-based analysis, the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for F- 18 FDG PET/CT were 99%, 98%, 98% & 99%, For MRI were 88.4%, 82.4%,88.4% and 82.3%, and for CT were 83.7%, 73%, 82.4 and 74.5% respectively. On patientbased analysis the sensitivity and specificity for F-18 FDG PET/CT were 100% & 90% compared to 75% &60% in MRI and 66.6% &40% in CT (P<0.05). The relative superiority of the F-18 FDG based technique compared to the morphological techniques in respect to sensitivity and specificity provide significant changes in patient management in 27.2 % & 41% of cases compared to MRI & CT respectively. Conclusion: Combined F-18 FDG PET/CT scan showed the highest utmost sensitivity, specificity and accuracy followed by MRI and lastly CT in the

35 Egyptian J. Nucl. Med., Vol. 8, No. 2, December detection of spinal metastatic lesions. Consequently18F-FDG PET/CT has a better impact on clinical management compared to MRI&CT. Keywords: FDGPET/CT MRI Spine Cancer. Corresponding Author: Kotb, M.H. mag_kotb@yahoo.com INTRODUCTION: The skeletal system, especially the spine, is a frequent target of metastatic spread from various primary tumors like carcinoma of the breast, lung and prostate. Moreover, primary malignancies may also originate from the bone marrow, such as lymphoma and multiple myeloma. Beside its poor prognostic aspect, spinal bone metastases cause serious significant cumulative morbidity including bone pain fractures, spinal cord compression and other nerve compression syndrome (1). Proper evaluation of bone metastases and early detection of occult bone metastases is essential for correct treatment decision (1).Overlapping benign vertebral lesions such as spinal degenerative changes, osteoporosis & collapse which are not uncommon in old age group of cancer patients may provide an additional challenging issue for detection of vertebral metastases (2,3).Variable imaging tools are available for exploration of vertebral metastases including bone scan (BS), computed tomography (CT) and magnetic resonance imaging (MRI) with variable merits, advantages and limitations. The sensitivity of bone scan is unsatisfactory in detection of spinal lesions due to limited spatial resolution. CT enjoyed high spatial resolution that provide high yield in anatomical details, better detection of cortical based lesions as well as detection of soft tissue components of tumor involving the vertebral column (4,5). On the other hand unsatisfactory CT results are seen in detection of metastases associated with severe osteoporosis and marked degenerative changes as well as bone marrow based metastases, (5, 6).The high spatial and soft tissue contrast resolution of MRI escalate its sensitivity in early detection of bone marrow based and intramedullary lesions and provide better differentiation between benign & malignant causes of cord and vertebral fracture compression. However MRI has a limited ability in detection of cortical based lesion & differentiation of osteomyelitis from vertebral metastases (6,7). Finally morphological modalities suffer from limited ability in proper monitoring of response of vertebral metastases to variable therapeutic tools (4,5,6,7,8). F-18 FDG has been established as a PET imaging tracer for the detection and monitoring of numerous malignancies owing to the increased glycolysis of most of tumor cells. However the results obtained investigating F-18-FDG PET in detection of bone metastases is conflicting with sensitivity varying widely from 56.5% to 100%. F-18- FDG PET is more sensitive in detecting lytic rather than sclerotic metastases due to its higher glycolytic activity and cellularity (9, 10, 11). F-18 FDG provides early detection and better monitoring response to therapy for bone marrow based metastases compared to other diagnostic tools. False positive F-18 FDG results may occurs with

36 Egyptian J. Nucl. Med., Vol. 8, No. 2, December benign metabolically active lesions e.g. histiocytic or giant cell-containing lesions, inflammatory & infection as well as nonspecific para-spinal muscle uptake. Moreover variable FDG uptake was noticed in degenerative spinal process. The availability of hybrid PET/CT enables us to correlate directly the F-18 FDG uptake features with CT morphology and this would ideally investigated by sequential F- 18 FDG-PET/CT studies performed on the same patients treated during a certain time period. These significantly escalate the diagnostic accuracy & limit the causes of false positive results for F-18 FDG PET (12, 13, 14).The fore mentioned consideration encouraging us to perform the current prospective study aiming to compare the diagnostic value of F-18 FDG PET, CT, combined F-18 FDG PET/CT and MRI in detection of spinal metastatic lesions and the impact of F-18 FDG PET-CT on patient management. PATIENTS AND METHODS: The study population comprised 22 patients with biopsy-proven malignancy. All patients underwent MRI of the spine and whole-body F-18 FDG PET/CT. The maximum elapsed time interval between both techniques did not exceed two weeks during which no therapy was given to the patients. MRI Scanning: MRI studies were performed at 1 and 1.5 T (Intera and Achieva; Philips) along sagittal and axial planes. MRI sequences included T1, T2weighted turbo-spin-echo images and post contrast T1-weighted images (5 mins after intravenous administration of 0.1 mmol/g gadopentetatedimeglumine [Magnevist]; Schering). FDG PET/CT Scanning: Combined PET/CT scan was performed using Siemens Biograph true V with a 64 multi-slice CT scanner. F-18 FDG-PET/CT was performed following intravenous administration of 5.5 MBq/Kg F-18 FDG with patient fasting for 6 hours. Serum glucose levels were lower than 150 mg/dl & images were acquired 90 minutes after tracer injection, while patient in supine position from the base of the skull to the mid-thigh region. A PET emission scan was performed over several bed positions (5to7) for 2 minutes per bed position with an axial field of view of approximately 21.6 cm per bed position & in-plane spatial resolution of 2 mm covering the same field of view as with CT. Diagnostic CT with contrast was performed using the following parameters; (350 ma, 120 KV, 0.5 second tube rotation time, slice thickness 5 mm, 8- mm table feed & 3 mm incremental reconstruction). Non-contrast CT was done in patient with impaired renal function (creatinine level >2 mg/dl) and/or has history of hypersensitivity for contrast media. To calculate maximal standardized uptake values (SUVmax), manually defined regions of interest (ROI) were drawn on the attenuation corrected emission image throughout the axial planes. Image analysis: The PET/CT data were separated into PET and CT image sets. Two specialists, a radiologist and a nuclear medicine physician, performed an independent

37 Egyptian J. Nucl. Med., Vol. 8, No. 2, December interpretation of the CT and PET images. In a separate session afterward, the readers interpreted the combined PET/CT images in consensus. The MRI images of the patients were interpreted separately by two experienced radiologists working in consensus and were blind to the PET/CT findings. The whole FDG PET/CT and MRI findings were compared to the results of biopsy or clinical / radiological follow up for at least 12 months as the reference standards. F-18 FDG PET images: F-18 FDG PET images were assessed for presence or absence of osseous tumor deposits by using a five-point grading system in which the lesion uptake was compared to liver uptake (or blood pool in patients with liver disease) as follow:- score 0 (no uptake): the lesion was definitely negative ; score 1 (lesion uptake < liver uptake): the lesion was probably negative ; score 2 (lesion uptake = liver uptake): the lesion was equivocal; score 3 (lesion uptake slightly higher than liver): the lesion was probably positive; score 4 (intense lesion uptake that significantly higher than liver): the lesion was definitely positive. CT images: On CT, bone lesions were classified into benign & malignant according to their morphological appearance. Malignant lesions were suggested by the presence of lytic, sclerotic or mixed lytic sclerotic intramedullary changes. Cortical disruption with or without extra osseous soft tissue component was considered sign of malignancy. Sclerotic changes close to end plates and lytic lesions with regular sclerotic margin close to facets and vertebral end plates were considered benign. Well defined osteolytic lesions with vertical sclerotic striations (Polka dot sign of hemangioma) were also considered benign. Para-vertebral soft tissue masses, including epidural masses, or masses involving neural foramina were recorded. In case of vertebral collapse, associated medullary lytic lesions, para vertebral mass and abnormal contrast enhancement were considered signs of metastasis. Combined F-18 FDG PET/CT images: Combined F-18 FDG PET/CT images were assessed for presence or absence of spinal metastases by matching the level of FDG uptake using the fore mentioned five-point grading system with CT changes as follow: Concordant PET/CT changes: 1-Malignant spinal lesion: - Grade 3,4 F-18 FDG uptake with malignant CT changes. 2-Benign spinal lesion: - Grade0,1, 2F-18 FDG uptake corresponding to definite CT benign changes. Discordant PET/CT: 1-Malignant lesion:-grade 3,4 spinal lesion without CT changes for malignancy. 2-Benign lesions:- Grade 0,1,2 corresponding to a suspicious CT changes for metastases. MRI Images: On MRI, marrow infiltrative lesions of abnormal signal intensity in T1 and T2 weighted images (especially in vertebral body and pedicles) and showing post contrast enhancement were considered positive for metastasis. Cortical disruption with or without extra-osseous soft tissue component was considered sign of malignancy. In case of vertebral collapse, associated medullary marrow signal infiltration, para vertebral mass and abnormal contrast enhancement were considered signs of metastasis. Marrow changes close to vertebral end plates and

38 Egyptian J. Nucl. Med., Vol. 8, No. 2, December facet joints (as part of spondylotic process) were considered negative. Well defined lesions of high signal in both T1 and T2 (characteristic for hemangioma) were also considered negative for malignancy. Determination of true or false positive and/or negative lesions were based on biopsy (histopathological examination) as well as clinical and radiological follow for at least 12 months as follow: - True-positive: Score 3 4 with or without radiological finding for metastases,histopathologically was positive or progressed during follow. True-negative: Score 0 2concordant with negative radiological features for metastases. Histology was negative or examinations did not show progression during follow up. False-positive: Score 3 4 discordant with negative radiological findings for RESULTS: The current study included 22 histopathologically proven cancer patients. There were 9 male and 13 female patients with mean age of 44 year ± 22. Histopathologically, the study included 7 breast cancers, 4 Hodgkin lymphoma, 3 Non- Hodgkin lymphoma, 2 rectal carcinoma, 2 bronchogenic carcinoma, 1 hepatocellular carcinoma and 1 patient had malignant neuro-endocrinal tumor. The remaining two patients had metastases of unknown primary. Comparing the results of all modalities, within the same field of view, revealed the following: Metastatic lesion detection: Lesion-based data analysis: A total of 214 vertebral lesions were detected in the current study. According to follow up period of at least 12 months, combined metastases, and histopathology were negative or it showed no progression at follow-up sessions. False-negative: Score 0 2 discordant with positive radiological finding of metastases and histology was positive or follow-up examinations showed growth of the lesion(s). Statistical analysis: Predictive values for different imaging tools were calculated using Wilson score which was generated by the open Epiprogram.the significant of correlation was assessed with the Fisher Z test. The multiple comparisons were adjusted by using the Benferroni-Holm method. P values of less than 0.05 were considered to indicate significant difference. radiological & histo-pathologically proven data, these lesions were divided into 129 metastatic lesions and 85 were of benign nature. All the bone lesions were separately analyzed on F-18 FDG PET/CT, CT as well as MRI and compared to clinicoradiological follow up data for at least 12 months &/or biopsy proven pathological data as a reference standard. In attempt to explore the additive value of combined F-18 FDG PET/CT compared to F-18 FDG PET results without CT combination, the detection capability of both techniques were estimated and compared to FU clinic-radiological results (Tables 1 and 2). Based on the 5 point visual grading score, F-18 FDG PET divided the documented 214 lesions into 128 malignant & 86 benign lesions. According to follow up data, the F-18 FDG

39 Egyptian J. Nucl. Med., Vol. 8, No. 2, December PET detected 128 malignant lesions are divided into 120 true positive and 8 false positive lesions. On the other hand, the F- 18-FDG PET detected 86 benign lesions were divided into 77 true negative and 9 false negative lesions. The 8 false positive F-18 FDG PET uptakes include (2 nonspecific para-spinal muscular uptake, 2 nodal lesions, 1 spondylodiscitis and 3 severe degenerative changes) (Figure1). Nine false negative irregularly sclerotic lesions with score 2 were missed by FDG PET that progressed during follow up. Therefore, F-18 FDG PET/CT had significantly additive value to F-18 FDG PET in respect to reducing false positive & false negative results. (Figures 2, 3). Figure 1: A 66 year-old male presented with soft tissue metastatic deposits of unknown primary malignancy. MRI of lumbar spine (in sagittal and axial T1, T2 and T1 postcontrast, A, B, C, G, H, I respectively) showed spondylodiscitis of T12, L1 and the intervening disc with abnormally enhanced paravertebral and intraspinal epidural soft tissue component compromising the conus medullaris. CT (D and J) showed vertebral endplate erosions and reduced height of discs at T9-10, T12-L1, L4-5 and L5-S1 levels (multilevel spondylodiscitis) with no evidence of osteolytic lesion. FDG PET (E and K) showed focally increased uptake in upper lumbar region suspicious of active metastatic lesion. FDG PET/CT (F and L) showed increased FDG uptake of T12-L1 disc and adjacent vertebral endplates as well as accompanied paravertebral and intraspinal epidural soft tissue component denoting active spondylodiscitis. Diagnosis: active spondylodiscitis at T12-L1 with no metastatic deposits.

40 Egyptian J. Nucl. Med., Vol. 8, No. 2, December Figure2: A 30 yrs-old female, with a history of left breast cancer, underwent left mastectomy followed by radiation and chemotherapy. MRI of dorsal and lumbar spine (T1, T2 and T1 post contrast, A to F) showed diffuse bone marrow infiltrative neoplastic lesions showing low signal in T1, intermediate to low signal in T2 with patchy contrast enhancement involving most of thoracic and lumbar vertebrae with associated pathological fracture of T11 vertebra. CT (G) showed multiple sclerotic deposits with pathological fracture of T11 vertebra. FDG PET (H) revealed multilevel metabolically active metastatic lesions of dorso-lumbar spine. FDG PET/CT (I) showed multiple disseminated metabolically active FDG avid sclerotic osseous lesions involving most of the vertebral column. Diagnosis: disseminated active sclerotic metastases of the spine. Figure 3: A 26 yrs.-old male, with relapsed HD, received chemotherapy and underwent bone marrow transplantation. MRI (sagittal A, B and C) showed diffuse L5 vertebral marrow infiltration of low T1 and T2 signal intensity with post contrast enhancement. Anterior wedging of L2 with no underlying infiltrative marrow lesion. CT (D) showed patchy sclerosis of L5 and upper sacral segments. FDG PET and combined FDG PET/CT(E and F) were negative for abnormal FDG uptake. Diagnosis: complete disease remission.

41 Egyptian J. Nucl. Med., Vol. 8, No. 2, December Table1: Correlation between F-18 FDG PET and clinical /radiological follow up results in 22 cancer patients: n= 214 FU True positive Spinal lesions(n) FU True Negative Spinal lesions (n) Total (n) PET Positive lesions (n) PET Negative lesions (n) *FU : Follow up F-18-FDG PET/CT results: F-18 FDG PET/CT divided the documented 214 lesions into: 130 malignant and 84 benign lesions. Out of the F-18 FDG PET/CT detected 130 malignant lesions, there were two false positive lesions that showed severe degenerative changes with marked sclerosis and high grade FDG uptake (score> 2) that remained stationary during follow up. On the other hand, out of the (84) F-18 FDG PET/CT suggested benign lesions there were single false negative lesion with low grade F-18 FDG uptake (less than 2) and limited sclerotic changes that progressed during follow up (Table 2). Table2: Correlation between F-18 FDG PET/CT and clinical /radiological follow up results in 22 cancer patients: n= 214. FU True positive Spinal lesions(n) FU True Negative Spinal lesions (n) Total (n) F-18 FDG PET/CT Positive lesions (n) F-18 FDG PET/CT Negative lesions (n) *FU: Follow up CT Results: Based on CT criteria, CT divided the 214 documented lesions into: 131 malignant and 83 benign lesions. According to the clinico-radiological follow up data, the CT depicted 131 malignant spinal lesions were classified into 108true positive and 23 false positive lesions. On the other hand, the remaining 83 benign spinal lesions on CT were divided to 62 true negative and 21 false negative (Table 3). The 62 benign lesions compromised 5 haemangiomas, 34 degenerative end plates changes and 17 degenerated facet joints, 2 pars interarticularis breaks and 4 spondylodiscitis (one of them was associated with soft tissue component) (Figure1). Pathological

42 Egyptian J. Nucl. Med., Vol. 8, No. 2, December compression of the vertebral body was identified 9 out of the 108 (8.3%) CT detected malignant lesions. On the other hand, 17 compression fractures were detected in seven patients, secondary to osteoporotic changes of the vertebral column (benign fractures) (Figure 3). Table3: Correlation between CT and combined clinical /radiological follow up results in 22 cancer patients: n= 214. FU True positive FU True Negative Total (n) Spinal lesions (n) Spinal lesions (n) CT Positivelesions(n) CT Negative lesions (n) Total (n) *n= number **FU : Follow up MRI Results: MRI divided the 214 documented clinical and follow up lesions into 129 malignant and 85 benign lesions. In comparison to clinical and radiological follow up data, the MRI depicted 129 malignant spinal lesions were classified as 114 true positive (Figure 2) and 15 false positive lesions (Figure 3) while the remaining 85 benign spinal lesions were divided into70 true negative and 15 false negative (Table 4). Table 4: Correlation between MRI and combined clinical /radiological follow up results in 22 cancer patients: n= 214. FU True positive Spinal lesions (n) FU True Negative Spinal lesions (n) Total (n) MRI Positive spinal lesions (n) MRI Negative spinal lesions(n) Total (n) *n= number **FU: Follow Overall results of F-18, FDG PET/CT, CTand MRI: Table 5 shows a comparison between the overall results of F-18 FDG PET/CT, CT and MRI based on biopsy results and/or combined clinical and radiological follow up. Based on the net results of false & true lesions in each technique the sensitivity, specificity, accuracy, PPV & NPV were estimated for each technique. F-18 FDG PET/CT results exhibit the utmost high figures in the fore mentioned parameters that was clearly superior to MRI & CT results (P<0.05). CT had the lowest yield among the three assessed techniques.

43 Egyptian J. Nucl. Med., Vol. 8, No. 2, December Table 5: Lesion- based comparison between F-18 FDG PET/CT, CT and MRI in detection of spinal metastases in 22 cancer: n=214. True Positive (n) False Positive (n) True Negative (n) False Negative (n) Sensitivity (%) Specificity (%) PPV (%) NPV (%) Overall Accuracy(%) F-18 FDG PET/CT (n) CT (n) MRI (n) % % 98% 73% 82.3% 98% 82.4% 88.4% 99% 74.5% 82.3% 98.5% 79.5% 86% *n= number **PPV= positive predictive value ***NPV = Negative predictive value. Patient-Based Analysis: According to clinico-radiological FU & histo-pathological biopsies, the 22 studied patients were divided into: 12 patients with spinal metastases and 10 patients free of spinal deposits. Patient based data analysis (Table 6) showed the utmost high F-18 FDG PET/CT results are remained. F-18 FDG PET/CT had better accuracy compared to MRI & CT as it eliminates their false positive more than false negative results. Therefore higher significant differences for specificity indices rather than sensitivity indices were demonstrated when comparing F-18 FDG PET/CT with MRI. The lowest yield among the three assessed techniques was still noticed in the CT results. Accordingly, F-18 FDG PET/CT avoided further therapy in 3 & 6 patients compared to MRI and CT respectively. On the other hand, F-18 FDG PET/CT recommended further therapy for 3 & 4 patients compared to MRI & CT respectively. Therefore, F-18 FDG PET/CT changed management in 27.2% & 41% of cases compared to MRI & CT respectively. Table 6:- Patient- based comparison between F-18 FDG PET/CT, CT and MRI in correlation with FU data in detection of spinal metastases in 22 cancers. F-18 FDG CT MRI PET/CT True Positive (n) False Positive (n) True Negative (n) False Negative (n) Sensitivity (%) 100 % 66.6% 75% Specificity (%) 90% 40% 60% PPV (%) 92.3% 57% 69% NPV (%) 100% 50% 89% Overall Accuracy (%) 95.4% 54.5% 68% *PPV= positive predictive value **NPV = Negative predictive value.

44 Egyptian J. Nucl. Med., Vol. 8, No. 2, December Soft Tissue Abnormalities at the Vertebral Region: Six of the 129 malignant lesions, detected in two of the 22 study patients, had associated para-spinal soft tissue masses. These lesions displayed epidural extension of tumor with neural foramen involvement. Subsequently, they were seen indenting the spinal cord/ thecal sac. Only one benign lesion showed soft tissue abnormality accompanying vertebral involvement in one patient with multilevel spondylodiscitis (Figure1). It also elicited combination of intraspinal epidural and neural foramen involvement causing compression of the spinal cord and exiting nerve roots. DISCUSSION: Bone metastases have important implications in terms of worsening morbidity and mortality of patients, as more than 2 out of 3 patients who die from cancer have bone metastases. Cancer cells are lodged in the bone marrow as the initial site for skeletal metastasis by means of hematogenous spread. Being richin red marrow in adults, spine represents common targeted sites for metastases. The more frequent metastatic events, the weight bearing and protective function of spine for spinal cord, the associated spondylodegenerative and osteoporotic changes as well as serious related morbidity events create a strong need for a highly sensitive and accurate diagnostic tool for early detection and accurate assessment of spinal metastases (8, 15, 16, and 17). Different diagnostic imaging tools are used to assess spinal metastases including F-18 FDG PET/CT, CT and MRI with variable success rate. The current study shows the superiority of F-18 FDG PET/CT compared to morphological imaging in detection of spinal lesions.ct is widely accepted in assessment of cancer patients because of its high spatial resolution that provide satisfactory anatomical details, better detection of cortical based lesions and associated soft tissue component. However many investigators show unsatisfactory CT results in assessment of spinal metastases (17, 18, 19, 20). This low CT yield was attributed to many factors including: delayed diagnosis as considerable level of cortical destruction is required for visualization of metastases by CT, limited sensitivity in detection of metastases within a vanity of osteoporotic &spondylo-degenerative changes and CT is not able to early detect bone marrow lesions. Moreover poor CT results were obtained in assessment of response of spinal metastases to therapy. In agreement with the fore mentioned data, the current study showed that CT had the lowest diagnostic efficiency compared to MRI and F-18 FDG PET/CT with statistically significant difference. Associated osteoporosis, old poroticfracture and inactive post therapy sclerosis for completely remitted lesions were the main reasons for such low CT diagnostic yield in the current study.in clinical practice MRI is widely used for assessment of spinal lesions with higher diagnostic yield compared to CT. This isattributed to its higher soft tissue contrast & better spatial resolution compared to CT. coinciding with that the current study showed superior MRI diagnostic efficiency compared to CT in the current study. On the other hand MRI results were significantly lower than F-18

45 Egyptian J. Nucl. Med., Vol. 8, No. 2, December FDG PET/CT (P<0.05). This isattributed to false positive results of MRI in cases of inactive completely remitted vertebral lesions and recent porotic collapse on top of degenerative changes. Moreover false negative MRI results were noticed in early developing cortical based lesions. These MRI limitations were successfully solved by F-18 FDG PET/CT in the current study (27, 28, and 29).F-18 FDG PET/CT has gained wide acceptance in clinical use in imaging algorithm of oncological patients with a special interest for exploration of spinal metastases. In this work F-18 FDG PET/CT provided the utmost diagnostic efficiency with variable significant higher difference in term of sensitivity, specificity, accuracy, PPV and NPV compared to MRI and CT. It should be noted that the significant difference between F-18 FDG PET/CT and the morphological techniques was more obvious on specificity indices rather than sensitivity indices in both lesion and patient based analysis. Early detection of bone marrow based lesions, less affected by osteoporotic and/orspondylo-degenerative changes and its more appropriate monitoring of lesion metabolic activity and response to therapy are attributed to the fore mentioned results regarding assessment of spinal lesions (21, 22, 23, 24, and 25). Moreover, this work showed the additive value of F-18 FDG PET/CT compared to F-18 FDG PET. The observed complementary effect of CT and F-18 FDG PET in assessment of spinal vertebral lesions limited the false positive and false negative results for either technique separately. In F-18 FDGPET/CT, the CT component provided better anatomical details with some specific structural changes that limited false positive F-18 FDG uptake (with specific benign structural changes e.g. spondylodiscitis& improper uptake localization i.epara-spinal uptake) and reduced false negative low grade FDG uptake in irregular sclerotic malignant lesions. On the other hand, the better sensitivity & specificity of F-18 FDG PET component reduce false negative CT results in detection of bone marrow based lesions, lesions associated with osteoporosis & severe degenerative changes as well as with post therapy sclerosis (26). Our data coincided with other authors who reported the higher diagnostic efficiency of complementary F-18 FDG PET/CT than isolated F-18 FDG PET &CT (23, 24, and 25).A major contribution of CT in F-18 FDG PET/CT studies is its complementary role in detection of soft tissue component of tumor involving the vertebral component. It has additional diagnostic impact, dire prognostic impact & serious morbidity (4, 8). Our study described soft tissue component in 6 malignant spinal lesions (4.7% of all malignant F-18 FDG PET/CT lesions) depicted in 2 of the study subjects compromising the spinal cord or thecal sac. On the other hand, only one benign soft tissue lesion was detected related to spondylodiscitis also compromising the spinal cord (Figure1). These soft tissue components were detected by both CT and MRI.Detection of pathological fracture and differentiation of benign from malignant compression fracture is crucial clinically desired information. In this work CT was able to detect 26 pathological vertebral fractures but cannot differentiate benign porotic fracture from metastatic compression fractures in all cases (6). This issue was solved through monitoring of FDG uptake that was high in 9 malignant compression fractures, while no uptake was seen in 17 porotic fractures. Post therapy osteoblastic bone reaction is accompanied

46 Egyptian J. Nucl. Med., Vol. 8, No. 2, December by increasing sclerosis from periphery of the lesions inward on CT images (Figure3) that may falsely suggesting disease progression 4. Similarly appearance of post therapy marrow necrosis in MRI may suggest presence of progressive metastatic lesions 19. The current results are partially affected by the effect of therapy on the detected spinal lesions with false positive sclerotic CT changes & marrow necrosis in MRI. Fortunately, these false positive CT & MRI lesions were clarified by lacking of FDG uptake in F-18 FDG PET/CT in the current study. Changes in patient management: F-18 FDG PET/CT avoided unnecessary overtreatment in 3& 6 patients with false positive MRI & CT vertebral lesions. Moreover F-18 FDG PET/CT recommended further therapy in three and four patients with false negative MRI & CT vertebral lesions. Similar results were obtained by other authors (27, 28, 29).The strength of the current study includes its prospective nature for addressing a REFRENCES: 1. Schmidt G.P, Reiser M.F and Melnyk A.B.: Whole-body imaging of the musculoskeletal system: the value of MR imaging. Skeletal Radiol,; 36 (12): , Bohdiewicz P.J, Wong C.Y, Kondas D, Gaskill M and Dworkin H.J.: High predictive value of F-18 FDG PET patterns of the spine for metastases or benign lesions with good agreement between readers. ClinNucl Med,; 28: , Grankvista J, Fiskera R, Iyer V, Fründc E.T, Simonsena C, Christensena T, Stenbygaardd L, Ewertze M and Larsson E.M.: MRI and PET/CT of patients with bone metastases comparison between F-18 FDG PET/CT, CT and MRI in detection of vertebral metastases as well as assessment of their impact on patients management. The limitations of the study lie in its running on a short term basis on a limited number of heterogeneous groups of patients with different age groups, pathology of primary malignancy, therapy & duration of disease. CONCLUSIONS: F-18 FDG PET/CT showed the higher sensitivity, specificity and accuracy in detection of spinal metastatic lesions, followed by MRI and lastly CT. Combined FDG PET/CT had a better clinical impact in respect to changing patient management compared to MRI & CT however it was more obvious on the latter. The complementary effect of F-18 FDG and CT in the co-registered combined F-18 FDG PET/CT seems to play a major role in such high diagnostic yield in detection & assessment of spinal metastases. from breast carcinoma. European Journal of Radiology,; 81:13-18, Metser U, Lerman H, Blank A, Lievshitz G, Bokstein F and Even- Sapir E.: 18F-FDG PET/CT in soinal metastases. Journal of Nuclear Medicine,; 45: , Even-Sapir E.: Imaging of Malignant Bone Involvement by Morphologic, Scintigraphic, and Hybrid Modalities. Journal of Nuclear Medicine,; 46: , Yang H.L, Liu T, Wang X.M, Xu Y and Deng S.M.: Diagnosis of bone metastases: a meta-analysis comparing 18FDG PET, CT, MRI and bone scintigraphy. Eur Radio,; 21(12): , 2011.

47 Egyptian J. Nucl. Med., Vol. 8, No. 2, December Raya J.G, Dietrich O, Reiser M.F and Baur-Melnyk A.: Methods and applications of diffusion imaging of vertebral bone marrow. J MagnReson Imaging,; 24 (6): , Masala S, Schillaci O, Massari F, Danieli R, Ursone A, Fiori R and Simonetti G.: MRI and bone scan imaging in the preoperative evaluation of painful vertebral fractures treated with vertebroplasty and kyphoplasty. In Vivo,; 19(6): , Even-Sapir E, Flusser G and Blachar A.: Malignancy of the Bone: Primary Tumors, Lymphoma and Skeletal Metastases InDelbeke D, Israel O. (eds.): Hybrid PET/CT and SPECT/CT Imaging,: , Scott J.A and Palmer E.L.: PET-CT of Bone Metastases In Shreve P. and Townsend D.W. (eds.): Clinical PET-CT in Radiology: Integrated Imaging in Oncology. Springer Science:Business Media,: , Du Y, Cullum I, Illidge T.M and Ell P.J.: Fusion of metabolic function and morphology: Sequential [18F] Fluorodeoxyglucose positron-emission tomography /computed tomography studies yield new insights into the natural history of bone metastases in breast cancer. J ClinOncol,; 25: , Rosen R.S, Fayad L and Wahl R.L.: Increased 18F-FDG Uptake in Degenerative Disease of the Spine: Characterization with 18F-FDG PET/CT. J Nucl Med,; 47: , Fayad L.M, Kamel I.R, Kawamoto S,Bluemke D.A, Frassica F.J and Fishman E.K.: Distinguishing stress fractures from pathologic fractures: a multimodality approach. Skeletal Radiol,; 34 (5): , Bredella M.A, Essary B, Torriani M, Ouellette H.A and Palmer W.E.: Use of FDG-PET in differentiating benign from malignant compression fractures. Skeletal Radiol,; 37: , Walsh P.C, De Weese T.L and Eisenberger M.A.: Clinical practice. Localized prostate cancer. N Engl J Med,; 357: , Kwee T.C, de Klerk J.M.H and Nievelstein R.A.J.: Imaging of Bone Marrow Involvement in Lymphoma: State of the Art and Future Directions. The Scientific World Journal,; 11: , Liu T, Cheng T, Xu W, Yan W.L, Liu J and Yang H.L.: A meta-analysis of 18F- FDG PET, MRI and bone scintigraphy for diagnosis of bone metastases in patients with breast cancer. Skeletal Radiology,; 40: , Evangelista L, Panunzio A, Polverosi R, Ferretti A, Chondrogiannis S, Pomerri F, Rubello D, Muzzio P.C.: Early bone marrow metastasis detection: The additional value of FDG-PET/CT vs. CT imaging. Biomedicine & Pharmacotherapy; 66: , Tateishi U, Gamez C, Dawood S, Yeung H.W.D, Cristofanilli M and Macapinlac H.A.: Bone Metastases in Patients with Metastatic Breast Cancer: Morphologic and Metabolic Monitoring of Response to Systemic Therapy with Integrated PET/CT. Radiology,; 247 (1): , Katayama T, Kubota K, Machida Y, Toriihara A and Shibuya H.: Evaluation of sequential FDG PET/CT for monitoring bone metastasis of breast cancer during therapy: correlation between morphological and metabolic changes with tumor markers. Ann Nucl Med,; 26: , Mawlawi O and Townsend D.W.: Multimodality imaging: an update on PET/CT technology. Eur. J. Nucl. Med. Mol. Imaging,; 36 (Suppl 1):15-29, Iagaru A, Mittra E, Dick D.W and Gambhir S.S.: Bone Scintigraphy and PET/CT for Detection of Skeletal Metastases. Molecular Imaging and Biology,; 14 (2): , Carkaci S, Macapinlac H.A, Cristofanilli M, Mawlawi O, Rohren E,

48 Egyptian J. Nucl. Med., Vol. 8, No. 2, December Gonzalez Angulo A.M, Dawood S, Resetkova E, Le-Petross H.T and Yang W.T.: Retrospective study of 18F-FDG PET/CT in the diagnosis of inflammatory breast cancer: Preliminary data. J Nucl Med,; 50: , Chang M.C, Chen J.H, Liang J.A, Lin C.C, Yang K.T, Cheng K.Y, Yeh J.J and Kao C.H.: Meta-analysis: comparison of F-18 fluorodeoxyglucosepositron emission tomography and bone scintigraphy in the detection of bone metastasis in patients with lung cancer. AcadRadiol,; 19: , Von Schulthess G.K.: Molecular anatomic imaging: PET-CT and SPECT- CT integrated modality imaging. Philadelphia: Lippincott Williams and Wilkins,: P 452., Costelloe C.M, Murphy W.A and Chasen B.A.: Musculoskeletal Pitfalls in 18F-FDG PET/CT. AJR,; 193:WS1- WS13, Fuster D, Duch J, Paredes P, Velasco M, Muñoz M, Santamaría G, Fontanillas M and Pons F.: Preoperative staging of large primary breast cancer with [18F] fluorodeoxyglucose positron emission tomography/computed tomography compared with conventional imaging procedures. J ClinOncol,; 26: , Alberini J.L, Lerebours F, Wartski M, Fourme E, Stanc E.L, Gontier E, Madar O, Cherel P and Pecking A.P.: 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) imaging in the staging and prognosis of inflammatory breast cancer. Cancer,; 115: , Heusner T.A, Kuemmel S, Koeninger A, Hamami M.E, Hahn S, Quinsten A, Bockisch A, Forsting M, Lauenstein T, Antoch G and Stahl A.: Diagnostic value of diffusion weighted magnetic resonance imaging (DWI) compared to FDG PET/CT for whole-body breast cancer staging. Eur J Nucl Med Mol Imaging,; 37: , 2010.

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50 Egyptian J. Nucl. Med., Vol. 8, No. 2, December Original Article, Oncology Patient And Lesion-Based Analysis Of 18F-FDG PET/CT Compared With Conventional CT During Follow Up of Patients With Colorectal Carcinoma Younis, J 1, Taalab, Kh 2 and Kandeel, A 1. 1 Nuclear Medicine units (NEMROCK), Faculty of Medicine, Cairo University & 2 Department Of Nuclear Medicine, Military Medical Academy, Egypt ABSTRACT: Objective: The aim of this study was to evaluate the potential significance of 18F- FDG PET/CT in detection of local or distant disease recurrence during routine follow up of patients with colorectal cancer (CRC) in comparison with conventional CT. Methods: Sixty seven patients (43 males and 24 females; age range years, mean 55.7±9.2 years) with histologically proven CRC previously treated by surgery and chemotherapy. 18F- FDG PET/CT and conventional CT were performed for all patients. Diagnostic ability was determined on a patient and on a lesion site basis (loco-regional recurrence, hepatic or extra-hepatic metastases that include LNs, bone and other sites). The final diagnosis was obtained from the results of histopathological examination after surgery or biopsy, or follow-up after at least 6-12 months on the basis of clinico-radiologic or follow up PET/CT. Results: On patientbasis analysis, PET/CT showed higher sensitivity, specificity and accuracy than CT in detection of local recurrence and metastatic lesions (94.6%, 100%, and 95.5% for PET/CT versus 83.9 %, 100% and 86.6% for diagnostic CT, respectively). On lesion-basis analysis, loco-regional recurrence was present in 23 patients, PET/CT detected all 25 lesions (100%) compared to 14/25 lesions (56%) detected by CT. Twenty-six Liver metastatic lesions were detected in 12 patients, PET/CT and CT accurately detected 22/26 (84.6%) and 21/26 (80.7%) hepatic lesions, respectively. PET/CT identified 32/42 LNs (76%) versus 23/42 LNs (55%) identified by CT in 19 patients. PET/CT had higher detectability of bone deposits than CT. PET/CT definitely changed the treatment modality in 28/67 patients (41.8%). PET/CT showed recurrent disease in 5/18 patients with elevated carcino-embryonic antigen who had negative CT. Conclusion: 18F-FDG PET/CT provides high accuracy for detection of recurrent and distant metastases than conventional CT in CRC patients during regular follow up. PET/CT changed the management strategy in a significant number of patients on lesion-based analysis. The use of 18F-FDG PET/CT in the regular follow up of CRC patients is worth considering. Key words: colorectal cancer; lesion-basis analysis; CT; 18F-FDG PET/CT. Corresponding Author: Younis, J. jehan.nuc@hotmail.com

51 Egyptian J. Nucl. Med., Vol. 8, No. 2, December INTRODUCTION: Colorectal cancer (CRC) is the third most common cancer diagnosed, and is associated with high rates of incidence and mortality for both men and women (1). In Egypt, CRC accounts for 6.53% of all cancers according to the National Cancer Institute, Cairo University (2). If colorectal cancer has already spread to distant organs, the long term survival is much lower (3). Furthermore, despite progress that has been made in the treatment of advanced cases of CRC, the clinical outcome of this disease still remains poor with recurrence and/or metastasis occur in 30-50% of the patients after surgery (4). Contrast-enhanced CT is currently the most established and important tool for restaging in patients with suspicion of CRC recurrence (5). MRI is often used for detecting pelvic recurrence of colorectal cancer due to its excellent soft tissue resolution (6). However, post therapy differentiated tumor recurrence or small intra-abdominal lymph node metastases may be missed in CT or MRI (7). FDG-PET provides functional information and has been found to be accurate in the detection of CRC and its distant metastasis. However, based on its limited spatial resolution, FDG-PET, often makes exact anatomical localization and demarcation of the lesion difficult, thus Fusion of functional PET with CT morphological data has provided benefit for tumor restaging and detection of metastatic spread in clinical practice using combined PET/CT imaging (8). There is no agreement as to whether FDG PET/CT screening for advanced colorectal neoplasms is meaningful (9). Aim of work: The aim of this study was to evaluate the potential significance of 18F- FDG PET/CT in detection of local or distant disease recurrence during routine follow up of patients with CRC in comparison with conventional CT. PATIENTS AND METHODS: Patient population: This prospective study included 67 patients with histologically diagnosed CRC previously treated surgically and with chemotherapy. Patients were referred to PET/CT department at the International Medical Center (IMC) during the period between December 2008 and January 2011 with presence of recently increased serum tumor marker carcino-embryonic antigen (CEA), equivocal conventional radiological findings or clinical symptoms suspecting either loco-regional recurrence or distant metastasis during follow up. PET/CT results were compared to the results of conventional CT. The study was approved by the local scientific and ethical committee. Patient preparation : Sixty seven patients (43 males and 24 females; age range 32 to 72 years, mean 55.7±9.2 years) with CRC underwent 18F-FDG PET/CT examination, the image data of diagnostic multi-slice CT scans of the abdomen/pelvis was acquired within 10 days prior to our study. Patients fasted for 6 hours before injection of MBq (10-15 mci) 18F-FDG via intravenous line. Diabetic patients were controlled prior to the study and blood glucose levels did not exceed 160 mg/dl. Patients were instructed to avoid any kind of strenuous activity prior to the examination and following injection of the radioisotope to avoid physiologic muscle

52 Egyptian J. Nucl. Med., Vol. 8, No. 2, December uptake of FDG and were asked to void prior to scanning. Image acquisition: Integrated 18F- FDG PET/CT Imaging: Whole body imaging was performed using a combined PET/CT scanner GEMINI TF; 64-slice PET/CT system; PHILIPS Medical Systems Nederland B.V.MDCT covered a region ranging from the meatus of the ear to the mid-thigh. The technical parameters of the 64-detector row helical CT scanner were a gantry rotation speed of 0.5 s and a table speed of 24 mm per gantry rotation. The PET component of the combined imaging system had an axial view of 16.2 cm per bed position) with an inter-slice spacing of 3.75 mm in one bed position and provided an image from the meatus of the ear to the mid-thigh. The trans-axial field of view & pixel size of the PET images reconstructed for fusion were 58.5 cm and 4.57 mm respectively, with a matrix size of Scanning started min after tracer injection (5 7 bed positions; acquisition time, 2-3 min/bed position adapted according to the patient s weight). Contrast agent was administered in the form of negative oral contrast (water with 5 % mannitol) 1 hour prior to study & Intravenous contrast (Non Ionic) injected at the time of imaging. Initially, patients were examined in the supine position with arms elevated, and CT scanning was started with the following parameters: 40 mas; 130 kv; slice thickness, 2.5 mm; pitch, 1.5. The CT scans were acquired during breath holding within the normal expiration position and reached caudally to the mid thighs. PET over the same region was performed immediately after acquisition of the CT images. Patients were instructed to take normal breathing during the PET and hold breath during the CT part of the study. Attenuation correction of PET images was performed by using attenuation data from the low dose CT component of the examination; emission data were corrected for scatter, random events and dead-time losses by using the manufacturer s software. Images were reconstructed as 5- mm slices applying a standard iterative algorithm (ordered-subset expectation maximization). Attenuation-corrected PET images, contrast-enhanced CT or non-contrast enhanced CT images and co-registered fused images were displayed together on the monitor. Non-attenuation corrected images are checked to avoid artifacts due to use of CT based attenuation correction. Conventional CT images: CT images were viewed in coronal, axial and sagittal sections. Peritoneal implantation was diagnosed when nodular, plaque-like or infiltrative soft tissue lesions with abnormal enhancement were seen in the peritoneal fat or on the peritoneal surface. Lymph nodes (LNs) with a short-axis diameter greater than 1 cm were defined as malignant. Furthermore, the presence of a central un-enhancing area suggesting central necrosis was considered a sign of malignancy, and the presence of peripheral low attenuation suggesting a fatty hilum within a LN was considered a benign sign, regardless of node size. Study interpretation: The PET, CT, and fused PET/CT Images were separately interpreted by 2 experienced nuclear medicine physicians and were compared to PET/CT images. Qualitative assessment for presence of hyper-metabolic lesions was evaluated on corrected PET images. Semiquantitative evaluation was performed using the Standardized Uptake Value (SUV max), of all abnormal foci (Normal < 2.5). Comparison with other clinical and diagnostic methods including laboratory,

53 Egyptian J. Nucl. Med., Vol. 8, No. 2, December bone scan, diagnostic CT or MRI were done. Criteria used for the evidence of recurrence were histopathological confirmation of suspicious lesions, further clinical follow-up 6-12 months suggestive of disease recurrence, tumor markers and other independent imaging studies (such as CT, MRI, PET/CT, bone scan and ultrasound). Focal hyper-metabolic activity within the liver greater than adjacent normal liver was considered abnormal. Diffuse mild activity in the bowel was considered normal physiologic uptake, while focal uptake equal or higher than liver uptake is considered abnormal, lymph nodes with increased glucose uptake were considered positive for metastatic spread even if they were smaller than 1 cm in short-axis diameter. Conversely, lymph nodes with no detectable tracer uptake less than mediastinum uptake were considered negative for metastatic spread, even if they were larger than 1 cm in short-axis diameter. Data analysis: True-positive lesion is defined as a focal active lesion seen on FDG PET/CT images and found to be positive for tumor tissue at histological examination or clinical/ radiological follow up. False-positive lesion is defined as a focal active lesion seen on FDG PET/CT images and found to be negative in tumor tissue at histological examination or clinical /radiological follow up. True-negative lesion is defined when no lesion was seen on FDG PET/CT images and the results at histological examination or clinical/radiological follow up were also negative. False-negative lesion is defined as a lesion that was missed in FDG PET/CT image analysis but was found to be positive for malignancy at histological examination or clinical/radiological follow up. Diagnostic ability was determined on a patient basis and on a lesion site basis (loco-regional recurrence, hepatic or extrahepatic metastases that include LNs, bone and other sites). The final diagnosis was obtained from the results of histopathological examination after surgery or biopsy, or follow-up after 6-12 months on the basis of clinical and imaging studies including ultrasound, CT, MRI, bone scan or PET/CT. Statistical analysis All data were collected, summarized, presented and analyzed by using appropriate statistical program SPSS version 20. The sensitivity and specificity of PET/CT and CT were calculated for the detection of loco-regional recurrence, metastatic nodal lesions, hepatic and extrahepatic metastases. Accuracy was represented with the terms sensitivity and specificity using standard statistical formulae to compare PET/CT with CT results during follow up of patients.

54 Egyptian J. Nucl. Med., Vol. 8, No. 2, December RESULTS: (Table 1): Patient characteristics in 67 patients with colorectal carcinoma. Parameter Age range (years) (mean±sd) Sex: Males female Primary site: Colon Rectum Sigmoid Colorectal Recto-segmoid Ano-rectal Carcino-embryonic (CEA) Positive Negative antigen All patients No= ± (64.2%) 24 (35.8%) (26.9%) 49 (73.1%) Patient-based analysis: In 56 out of 67 patients (83.5%), proved to have recurrence and/or distant metastasis was confirmed by histo-pathological examination after surgery or biopsy, or follow-up after at least 6-12 months. The remaining 11 patients (16.5%) were free of disease at the end of the study. 18F-FDG PET/CT was true positive in 53 out of 56 patients with sensitivity of (94.6%) with recurrence or metastases and while true negative in all 11 patients (100% specificity) without recurrence or metastases. was avidest the PPV, NPV and accuracy were. 95.5% and 86.6%. PET findings were false-negative in 3 patients with liver metastases detected by CT. CT findings showed true positive results in 47 out of 56 patients with sensitively of (83.9%) and showed true negative results in all 11 patients (100% specificity). proved to be free of disease recurrence or metastases. False negative results were seen in 9 patients (4 with loco-regional lesions, 3 with hepatic lesions, 1 with iliopsoas muscle lesion and 1 with bone metastases); all detected by PET/CT (Fig. 1). (Table 2) shows the Diagnostic performance of PET/CT and CT in detection of recurrent and metastatic CRC showed higher sensitivity, negative predictive value and accuracy for PET/CT as compared to CT (Table 2).

55 Egyptian J. Nucl. Med., Vol. 8, No. 2, December (Table 2): Patient based analysis for detection of recurrent and metastatic CRC using 18F-FDG PET/CT and diagnostic CT. Parameter PET/CT Diagnostic CT Sensitivity % Specificity % PPV % NPV % Accuracy % PPV = positive predictive value; NPV = negative predictive value. (Table 3) Lesions based analysis in detection of loco-regional recurrence or metastatic lesions. Site of recurrence No PET/CT Diagnostic CT Loco-regional (100%) 14 (56%) Liver (84.6%) 21 (80.7%) Lymph nodes (76%) 23 (55%) Extra-hepatic (100%) 8 (57%) Lesion-based analysis. On lesion based analysis, recurrent or metastatic lesions were classified into three major categories; loco-regional (local recurrence and LN lesions), hepatic and extra-hepatic lesions (Table 3). The last category is subdivided into pulmonary, peritoneal, abdominal wall, and bone metastases. 18F-FDG PET/CT was superior to CT in detection of local recurrence in all 25 local recurrent lesions (100%) compared to only 14 out of 25 lesions (56%) detected by CT. surgical decision was conducted in 15 patients. (Fig 1) represents a case with true positive PET/CT for local recurrence and para-aortic LNs metastases. Twenty six metastatic liver lesions proved to be positive at final diagnosis were present in 12 patients. PET/CT and CT accurately detected 22 lesion (84.6%) and 21 lesions (80.7%) respectively. PET-CT was able to detect additional 5 hepatic lesions not detected by CT, while CT detected 4 lesions that were missed by PET-CT. Final positive lesions were seen in 42 LNs in 19 patients. PET/CT detected 32 LNs (76%), While the missed 10 LNs were missed by PET/CT (two iliac LNs and one LN in each of the left axillary, pretracheal, omental, left para-aortic, retrocaval, pretracheal, subcarinal and inguinal regions). On the other hand, CT detected 23 positive LNs (55%), the missed 19 LNs were located in (hilar, paracaval, paratracheal, supraclavicular, obturator, mesentric, pelvic and iliac regions). All The 9 missed lesions by CT were detected by PET/CT. PET/CT detected 14 extrahepatic lesions including (3 peritoneal lesions, 2 pulmonary lesions, one uterine invasion, one abdominal wall nodule at site of operation scar, one Iliopsoas muscle metastasis and 6 osseous bone lesions). Diagnostic CT detected only 8 lesions of them. Fig. 2 shows extrahepatic lung metastases from rectal cancer.

56 Egyptian J. Nucl. Med., Vol. 8, No. 2, December Fig year old male with recurrent colonic adenocarcinoma in the splenic flexure. Transaxial, coronal and sagittal images show FDG PET/CT uptake in the operative bed denoting local recurrence (white arrows) and left para-aortic LNs metastases (black arrows). CT findings were false-negative for local recurrence lesion. Fig 2. A- Base-line 60 year old female with rectal carcinoma, 18F-FDG PET/CT scan A- Transaxial, sagittal and coronal (from LT to RT) images show FDG uptake in multiple bilateral lung metastases (black arrows). B- Contrast enhanced CT shows equivocal liver lesion as hyperdense nodule in segment VIII of liver in arterial phase (LT, red arrow), while venous phase (RT) is free. C- Follow-up PET/CT after 6 months confirmed lung metastases while hepatic lesion shows no FDG uptake and proved to be focal nodular hyperplasia.

57 Egyptian J. Nucl. Med., Vol. 8, No. 2, December Follow up carcino-embryonic antigen level was elevated in only 18 patients (26.9%). PET/CT showed recurrent disease in the all 18 patients, 5 patients out of them were negative by CT. Collectively, 18F-FDG PET/CT changed the treatment modality in 28 out of our total 67 patients (41.7%) in which PET/CT was being able to detect recurrent and/or metastatic lesions during their regular follow up that were not detected by diagnostic CT. DISCUSSION: Local and distant recurrences of CRC occur in 30 50% of patients during follow-up after primary surgery (10). Accurate detection of recurrent CRC remains a clinical challenge. 18-Ffluorodeoxyglucose PET/CT -positron emission tomography allows direct evaluation of cellular metabolism (11). PET/CT is not routinely done for patients with CRC during their follow up unless there was an equivocal lesion seen on conventional imaging modalities. Thus the aim so, we aimed at this study is to reconsider the necessary introduction of PET/CT as a crucial part in routine follow up of these patients. The final diagnosis of recurrence and/or metastases based on patient analysis was evident in 83.5% in our patients with a sensitivity, specificity and accuracy of 94.6%, 100%, and 95.5% for FDG-PET/CT versus 83.9 %, 100% and 86.6% for CT scan, respectively. These findings match the results of several studies; Kalu et al. compared the results of PET/CT and CT scan in 69 patients for assessment of recurrence or metastatic lesions, they reported a sensitivity, specificity, and accuracy for malignant findings of 98%, 94% and 97% for FDG-PET/CT compared with 85%, 91% and 89% for CT scan, respectively (11). Also, Hirakawa et al. reported the sensitivity and specificity of PET/CT for detecting colorectal recurrent lesions were 96% and 98% respectively. They concluded that tumors 10 mm were significant factors for false-negative PET/CT (12). In the current study, FDG-PET/CT affect the clinical management in 28/67 patients (41.8%) by guiding further management. Surgical decision was conducted in 15 patients of them based on PET/CT results. Similary, Kalu et al. found that FDG- PET/CT influenced surgical decisions in 23.6% of their 69 patients with proven recurrent CRC (11). Detection of liver metastases in 12 patients in the present study showed nearly similar sensitivity results using, 18F-FDG PET/CT and diagnostic CT in detection of (84.6%) and (80.7%) of metastatic lesions. Based on lesion based analysis, similarly respectively. PET-CT was able to detect 5 hepatic lesions not seen by CT, while CT detected 4 lesions that were missed by PET/CT. This could be explained by whether CT was done with contrast or not, degree of differentiations and size of hepatic lesions. On the other hand, Kitajima et al, in their study of liver metastases of colorectal origin, found that the diagnostic sensitivity and specificity for both CT, PET/contrast-enhanced CT was 93.3% and 98.6 % respectively (13). For detection of lymph node involvement, PET/CT had relatively 76% sensitivity low which is (76%) but still higher than that of conventional CT (55%). The reasons for

58 Egyptian J. Nucl. Med., Vol. 8, No. 2, December low sensitivity might be due to small sized lesions that were difficult to distinguish and localize especially in the abdomen and pelvis, where physiologic uptake in the gut may mask them. Kitajima et al. mentioned that the sensitivity and specificity for detection of recurrent LNs lesions differ with the use of contrast enhancement material with PET/CT that improves sensitivity for abdominal and pelvic LNs (88.9% vs 94.4% for abdominal LNs and 85.7% vs 92.9% for Pelvic LNs). (13). In the current study, PET/CT detected further extra-hepatic lesions not identified by CT in 5 patients. Similar to our results, Israel and Kuten found that PET/CT had a superior rate of detection of extra-hepatic dissemination, with a sensitivity of 89%, compared with 64% sensitivity for CT (14). Ozkan et al. concluded that PET/CT is a safe imaging method that can be used in the determination of CRC recurrence in patients with elevated CEA levels, regardless of the CEA level (15). In this study, Follow up PET/CT showed additional recurrent disease in 18 patients with elevated CEA, 5 of them were negative by CT. Several studies support our findings, Metser et al performed a retrospective study on 50 patients with CRC and elevated CEA and they found that PET-CT was more sensitive than contrastenhanced 64-slice MDCT in identifying sites of recurrent and metastatic disease (was 97.3% versus 70.3%) with similar specificities for both modalities (94.4%) (16). Chen et al. also found that recurrence and/or metastasis was detected in 91.7% (22/24) of patients with elevated serum CEA levels by 18F-DG PET/CT imaging, but his study included all cases of elevated CEA not only those with negative CT and positive PET/CT (10). CONCLUSIONS: 18F-FDG PET/CT is superior to diagnostic conventional CT, in both lesion-by-lesion and patient based analysis in detection of recurrent and metastatic lesions in colorectal cancer patients. 18F-FDG PET/CT changed the treatment strategy in a significant number of patients which helped in providing the best management that will guarantee better survival for CRC patients. Consequently, the use of 18F- FDG PET/CT in the regular follow up of CRC patients is worth considering. REFERENCES: 1. Jemal A, Siegel R, Ward E, et al. Cancer statistics. CA J Clin;59:225-49, Mokhtar N, Gouda I, Adel I. Cancer pathology registry and time trend analysis. In: Malignant digestive system tumors. (Mokhtar N, Gouda I, and Adel I. editors) NCI, Elsheraa Press, Cairo;55 67, Davila RE, Rajan E, Baron TH, et al. ASGE guideline: colorectal cancer screening and surveillance. Gastrointest Endosc;63:546 57, Van der Pool AE, Damhuis RA, Ijzermans JN et al. Trends in incidence, treatment and survival of patients with stage IV colorectal cancer: a populationbased series. Colorectal Dis;14:56-61, Engstorm PF, Arnoletti JP, Benson AB 3rd, et al. NCCN clinical practice

59 Egyptian J. Nucl. Med., Vol. 8, No. 2, December guidelines in oncology: colon cancer. J Natl Compr Canc Netw. Sep;7(8): , Titu LV, Nicholson AA, Hartley JE, et al. Routine follow-up by magnetic resonance imaging does not improve detection of resectable local recurrences from colorectal cancer. Ann Surg;243(3):348 52, Kim JH, Czernin J, Allen-Auerbach MS, et al. Comparison Between 18F-FDG PET, In-Line PET/CT, and Software Fusion for Restaging of Recurrent Colorectal Cancer. J Nucl Med;46(4):587 95, Griffeth LK. Use of PET/CT scanning in cancer patients: technical and practical consideration. Proc;18 (4):321-30, Shu-Wei Huang, Chen-Ming Hsu, Wen- Juei Jeng, et al. A Comparison of Positron Emission Tomography and Colonoscopy for the Detection of Advanced Colorectal Neoplasms in Subjects Undergoing a Health Check-Up. PLOS ONE;8 (7):1-7, Chen LB, Tong JL, Song HZ, et al. (18)F- DG PET/CT in detection of recurrence and metastasis of colorectal cancer. World J Gastroenterol;13(37):5025 9, Kula Z, Szefer J, Zuchora Z, et al..evaluation of positron emission tomography by using F-18- fluorodeoxyglucose in diagnosis of recurrent colorectal cancer. Pol Merkur Lekarski;17 Suppl 1:63-6, Hirakawa T, Kato J, Okumura Y, et al. Detectability of colorectal neoplasia with fluorine-18-2-fluoro-2-deoxy-d-glucose positron emission tomography and computed tomography (FDG-PET/CT). J Gastroenterol;47(2):127-35, Kitajima K, Murakami K, Yamasaki E, et al. Performance of integrated FDG PET/contrast-enhanced CT in the diagnosis of recurrent colorectal cancer: Comparison with integrated FDG PET/non-contrastenhanced CT and enhanced CT. Eur J Nucl Med Mol Imaging; 36: , Israel O and Kuten A. Early Detection of Cancer Recurrence: 18F-FDG PET/CT Can Make a Difference in Diagnosis and Patient Care. J Nucl Med;48:28S 35S, Ozkan E, Soydal C, Araz M, et al. The role of 18F-FDG PET/CT in detecting colorectal cancer recurrence in patients with elevated CEA levels. Nucl Med Commun Apr; 33(4): , Metser U, You J, McSweeney S, et al. Assessment of Tumor Recurrence in Patients With Colorectal Cancer and Elevated Carcinoembryonic Antigen Level: FDG PET/CT Versus Contrast- Enhanced 64-MDCT of the Chest and Abdomen. Am J Roentgenol; 194 (3): , 2010.

60 Egyptian J. Nucl. Med., Vol. 8, No. 2, December Original Article, Cardiology Effect of Subclinical Thyroid Disease on Cardiac Function in Patients on Thyroid Replacement Therapy as Assessed by Radionuclide Ventriculography Elsayed, Y 1. Hasanin, E 2.Farouk, Sh 3. Zeiada, G 4. 1 Nuclear Medicine Unit, Faculty of Medicine, Cairo University. 2 Nuclear Medicine Unit, South Egypt Cancer Institute, Assuit University, 3 Nuclear Medicine Unit, Faculty of Medicine, Zagazig University, Egypt. 4 Nuclear Medicine Unit, Faculty of Science, Kuwait University. ABSTRACT: Objective: The evidence indicates that the cardiovascular system responds to the minimal but persistent changes in circulating thyroid hormone levels, which is typical of individuals with subclinical thyroid dysfunction. However, there is no study to compare between control or euthyroid and subclinical thyroid cases with tong-term L-thyroxine therapy regarding cardiac function of the heart using radionuclide ventriculography. The objective of our study is to assess and compare the left ventricular function through the evaluation of the radionuclide systolic parameters, diastolic parameters and heart rate for these conditions. Methods: Ten healthy controls and 32 patients with surgically treated differentiated thyroid carcinoma followed by radioactive iodine ablation and receiving suppressive L-thyroxine were evaluated by gated radionuclide ventriculography. The patients were divided into 3 groups according to their thyroid hormone profile. These groups were: euthyroid, subclinical hypothyroid, subclinical hyperthyroid groups. Results: Long-term L-thyroxine therapy significantly affected the left ventricular systolic function in patients with subclinical thyroid dysfunction. It prolonged TPER and TPFR in patients with subclinical hypothyroid dysfunction while it decreased TPER and TPFR in patients with subclinical hyperthyroid dysfunction. However, there was no effect on the euthyroid group. Conclusions: These abnormalities in cardiac function in subclinical hypo- or hyperthyroidism may lead to long-term effect on patient's lives. Early effective and accurate treatment for these patients is important to avoid the consequences of long term exposure of the cardiovascular system to small increases or decrease of thyroid hormone. Key Words: Heart, subclinical hypo or hyperthyroidism, thyroid hormones. Corresponding Author: Elsayed, Y 1. yassermohamednm@yahoo.com

61 Egyptian J. Nucl. Med., Vol. 8, No. 2, December INTRODUCTION: Subclinical hyper- or hypothyroidism is asymptomatic conditions with apparently normal serum free thyroxine (T4) and free triiodothyronine (T3) levels. Subclinical thyroid diseases diagnoses are based on laboratory evaluation. Subclinical hypothyroidism, defined by elevated serum levels of thyroid stimulating hormone (TSH) with normal serum levels of free thyroid hormones, (1).Among individuals with this condition, up to half of them may progress to overt thyroid failure. When lasting more than 6-12 months, it may be associated with abnormal lipid metabolism, a subtle cardiac defect with mainly diastolic dysfunction, impaired vascular function, elevated risk of atherosclerosis and ischemic heart disease (2). Restoration of euthyroidism by LT4 treatment may correct the cardiac abnormalities (3, 4). Subclinical hyperthyroidism is an increasingly recognized entity that is defined as a normal serum free thyroid hormones levels with suppressed TSH below the normal range (2). It has been reported that subclinical hyperthyroidism is not associated with coronary heart disease but induces arrhythmias including arterial fibrillation and arterial flutter (2). The more frequent causes of endogenous subclinical hyperthyroidism are toxic adenoma and Graves' disease; whereas the exogenous causes are induced by T4 therapy used to suppress TSH in patients with nontoxic goiter and differentiated thyroid cancer (DTC) (5).The evidence indicates that the cardiovascular system responds to the minimal but persistent changes in circulating thyroid hormone levels, which is typical of individuals with subclinical thyroid dysfunction (3). Although the effects of thyroid hormones, overt hyper-and hypothyroidism on the cardiovascular system have been diffusely studied (7-12) Only in the last years the effects of acute subclinical hyper- and hypothyroidism on the heart have been investigated (2, 6). Therefore subclinical thyroid dysfunction is currently the subject of many studies and remains controversial, particularly as it relates to cardiovascular effects and clinical applications. This study evaluates and compares the effects of subclinical thyroid disease on cardiac function in post I-131 ablation thyroid cancer patients on thyroid replacement therapy as assessed by radionuclide ventriculography. PATIENTS AND METHODS: The study population included 32 patients, male & females (mean age, 45±6.8 year) of differentiated thyroid carcinoma. All patients were receiving thyroid hormone replacement therapy (L-thyroxine) at the time of their enrolment in this study. In all patients, as per the routine practice, the treatment with L-thyroxine started with a dose 25 µg, and then increased gradually according to the medical need. The study population also consisted of ten healthy control, age matched (group 1). The patients were classified into 3 groups according to the level of T3, T4 and TSH as determined using radioimmunoassay with IMMUNOTECH kits. These groups were as follows: group 2 euthyroid cases (7 patients), group 3 subclinical hypothyroid cases (14 patients); group 4 subclinical hyperthyroid cases (18 patients). All patients entered the study only if they had shown stable subclinical hypo or hyper - thyroidism according to their group for at least 1 year before the study with TSH level >5 m U/L and < 0.2 m U/L respectively.

62 Egyptian J. Nucl. Med., Vol. 8, No. 2, December Cardiovascular and respiratory diseases or other systemic diseases were excluded in both patients and control subjects by a complete clinical work-up. Routine laboratory chemistry was normal in all, and none of the patients was being treated for any other clinical condition except for their primary cancer disease and only (4) patients were on beta blockers, The study protocol was reviewed approved by the institutional ethics committee; and all patients gave their informed written consent to this study. Radioimmunoassay: Serum T4, T3 and TSH were determined by a homogenous radio-immunoassay (IMMUNTECH kits). TSH is measured by radioimmunoassay in a third generation gamma counter. Gated Radionuclide Ventriculography: Standard protocol for in vivo labeling of RBCs with Tc-99m was followed. Stannous pyrophosphate (10 µg/kg) was injected intravenous to the patient. Tc-99m pertechnetate (20-25 mci) was injected minutes later. The patient was put in supine position under a gamma camera (ADAC) connected to ECG monitor and a computer. The camera head was adjusted in the left anterior oblique (LAO) view at 45 to the longitudinal axis of the body for the best septal separation of both ventricles. Gated acquisition of data was carried out and processed by analysis an area of interest (MX) around the left ventricle to get: Left ventricular end diastolic counts (LVEDC), left ventricular end systolic counts (LVESC), left ventricular ejection fraction (LVEF), differentiation of the left ventricular volume curve to obtain: Time to peak ejection rate (TPER), time to peak filling rate (TPFR), peak ejection rate (PER) & peak filling rate (PFR). Statistical analysis: Data were presented as mean ± S.E.M of (n) experiments. Where necessary, differences between two mean values were compared using Student's test paired or unpaired as appropriate. Where multiple comparisons were necessary, oneway analysis of variance (ANOVA) was used followed by Post Hoc Test (Benferroni). The difference was assumed to be significant at P<0.05. RESULTS: Thyroid hormones: A total of 32 patients were recruited for this study. The general characteristics of the study patients are summarized in (Table 1). The duration of thyroxine therapy was 3-14 yr. The mean L-thyroxine dosage was µg/ day (220±22/day). Mean serum T3 and T4 were increased in groups 4 (subclinical hyperthyroidism); while they decreased in groups 3 (subclinical hypothyroidism). The mean serum TSH concentration determined on the day of evaluation confirmed the chart review that TSH was suppressed to near the limits of assay detection (<0.01 µu/ml) for group 4 and significantly increase to 46.6±18 µu/ml for group 3. Mean serum T3, T4 & TSH levels in group 2 (euthyroidism); were similar to the control, therefore patients had minimal symptoms than the control (Table 2).

63 Egyptian J. Nucl. Med., Vol. 8, No. 2, December Table 1. Clinical characteristics of the study patients Patients Controls Number Age (Years) 45±6.8 47±4.9 L-T4 dose Duration of 3-14 years - Table 2. Hormonal patterns in patients during L-T4 suppressive therapy and in the control group Groups Classification Free T3 (µg/dl) Free T4 (µg/dl) TSH (µu/ml) Group 1 Control group 3 µg/dl ±1.39 Group 2 Euthyroid 3.81± ± ±1.58 Group 3 Subclinical hypothyroid 333± ±4.23* 46.6±18.8* Group 4 Subclinical hyperthyroidism * Significance between control and other groups <0.05 Hemodynamic changes 4.29± ±2.69* 0.01±0.003* There is no significant difference between the control and all the groups for heart rate (HR). Values of HR were detected for all groups with a tendency towards elevation in group 4 (Table 3). Although patients of group 4 are controlled by B- adrenal receptor antagonist. Table 3. Comparison of mean values of heart rate (HR) Groups Classification HR (bpm) Group 1 Control group 75.4±5.19 Group 2 Euthyroid 74.3±4.23 Group 3 Subclinical hypothyroid 76.6±13.8 Group 4 Subclinical hyperthyroidism 81.3±9.93 No significance between control and other groups > 0.05 Gated radionuclide ventriculography Systolic Function Systolic function parameters EF, PER & TPER were calculated (Table 4). There were no differences between the control and the euthyroid groups. However there were significant differences between these two groups, and groups 3 (subclinical hypothyroidism) and group 4 (subclinical hyperthyroidism) in TPER. In addition, there is also a difference between group 3 & group 4 in TPER.

64 Egyptian J. Nucl. Med., Vol. 8, No. 2, December Table 4. Comparison of the mean ± SD values for systolic function parameters Groups Classification EF (%) PER (EDV/s) TPER (Sec) Group 1 Control group 63.4± ± ± Group 2 Euthyroid 57.6± ± ± Group 3 Subclinical hypothyroid 54.9± ± ±0.001* + Group 4 Subclinical hyperthyroidism 59.0± ± ±0.003* + EF = Ejection Fraction; PER =Peak Ejection Rate; TPER =Time to Peak Ejection Rate * Significance between control and groups3,4 ( p<0.05) Diastolic Function Evaluation of PFR & TPFR parameters of diastolic function was done (Table 5). There were significant differences in TPFR between the control and groups 3 & 4. The mean values of TPFR and PFR were compared within the groups showing differences between the group 3 and group 4. Table 5. Comparison of the mean ± SD values for diastolic function parameters Groups Classification PFR (EDV/s) TPFR (sec) Group 1 Control group 3.24± ± Group 2 Euthyroid 2.89± ± Group 3 Subclinical hypothyroid 2.74± ±0.001 *+ Group 4 Subclinical hyperthyroidism 3.82± ±0.002 *+ PFR = Peak Filling Rate; TPFR = Time to Peak Filling Rate * Significance between control and other groups (P<0.05) +P < 0.05 between groups 3 & 4 for PER+P < 0.05 between groups 2, 3 & 4 fro TPFR DISCUSSION: The term subclinical thyroid disease is used to describe asymptomatic thyroid abnormalities found on imaging study or laboratory tests (13). Subclinical hypo- or hyper-thyroidism have been associated with cardiac dysfunction (6). Almost half of them may progress to overt thyroid failure (1). Previous studies have suggested that subclinical thyroid dysfunction, as manifested by abnormalities in TSH levels, are associated with detrimental effects on the cardiovascular system. Subclinical hypothyroidism is characterized by abnormal lipid metabolism, cardiac dysfunction, diastolic hypertension conferring an elevated risk of atherosclerosis, and ischemic heart disease. Similarly, patients with subclinical hyperthyroidism have 3 times the likelihood of arterial fibrillation (14). Our study showed that subclinical hypo- & hyper-thyroid groups had abnormality in diastolic and systolic parameters. It had higher or lower TPFR and TPER than the

65 Egyptian J. Nucl. Med., Vol. 8, No. 2, December control. There are few studies in the past have reported abnormal left ventricular systolic function (15-17) which were proven by the present study. Whereas impaired myocardial contractility in overt hypothyroidism has been documented clinically and experimentally, the presence of similar alterations in subclinical hypothyroidism is still under debate. An impairment of left ventricular systolic function has been reported in subclinical hypothyroid patients both at rest and during exercise, with a clear improvement after L- T4 replacement therapy (18). It was also reported an impairment of left ventricular diastolic function was reversed by 6 months of L-T4 replacement therapy (1). However other researchers did not find alterations of systolic time intervals or ejection fraction, as assessed by simultaneous recording of aortic and mitral flow velocities. It was reported that there is impairment of both left ventricular diastolic and systolic function in subclinical hypothyroidism (19). Subclinical hypothyroidism is associated with impaired left ventricular diastolic function at rest, systolic dysfunction on effort, and enhanced risk for atherosclerosis and myocardial infarction. Subclinical hyperthyroidism is associated with increased heart rate, arterial arrhythmias, increased left ventricular mass with marginal concentric remodeling, impaired ventricular relaxation, reduced exercise performance, and increased risk for cardiovascular death. All abnormalities were reversed by restoration of euthyroidism or were blunted by B- blockade and tailoring of the L-thyroxine dose. In this study there is no significant difference of HR between the control and all the groups. This is mainly because the HR of group 4 is treated by B-adrenal receptor antagonist. It regulates the heart rate and prevents the tachycardia. The significant increase in heart rate has many implications in patients. Enhanced heart rate has been shown to be associated with increased risk of cardiovascular and noncardiovascular mortality (20). Heart rate is an important mechanism for regulation of cardiac output. Apart from determining the rate of cardiac ejection, HR can affect both systolic and diastolic function (5).In our study, euthyroid group showed no difference than the control group in all the investigated parameters, starting with the level of the thyroid related hormones (T3, T4 & TSH) and the cardiac systolic (EF, PER & TPER) and diastolic (PFR & TPFR) or HR which was expected. These results verify that good and accurate treatment can prevent any abnormality in the heart. The long-term replacement thyroxin therapy in patients with differentiated thyroid carcinoma who underwent surgery followed by radioiodine ablation may significantly affects the left ventricular function. It impairs the diastolic and systolic function in patients with subclinical hyper- and hypo-thyroidism. It decreased TPER and TPFR in subclinical hyper-thyroid patients and prolonged them in hypothyroid patients. It was known that patients chronically treated with suppressive doses of L-T4 were usually free of symptoms and signs of thyrotoxicosis. However our results showed that they could suffer from left ventricular abnormality function if there is no continuous care. Therefore, early effective treatment of subclinical thyroid diseases is important for differentiated thyroid carcinoma patients to improve their quality of life and to avoid the consequences of long term exposure of the cardiovascular system to small increases or

66 Egyptian J. Nucl. Med., Vol. 8, No. 2, December decreases of thyroid hormone. Therefore we recommend deciding whether thyroxine therapy has a long-term benefit that outweighs the risks of cardiovascular before starting the treatment in each individual separately. We conclude that careful clinical evaluation, continuous cardiac laboratory studies, is sufficient to manage the patients with long-term thyroxine therapy. REFERENCES: 1. Palmieri EA, Fazio S, Lombardi G, Biondi B. Subclinical hypothyroidism and cardiovascular risik: a reason to treat?. Treat Endocrinol.; 3(4): , Dattilo G, Crosca S, Tavella S, Marte F, Patttane S. Pericardial effusion associated with subclinical hypothyroidism. Int J Cardiol.; ahead of print, Vanderpump MP, Tunbridge WM, French JM, Appleton D, Bates D, Clark F, Grimley Evans J, Hasan DM, Rodgers H, Tunbridge F, et al. The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey. Clin Endocrinol.;43(1):55-68, Vanderpump MP, Tunbridge WM. The effects of drugs on endocrine function. Clin Endocrinol (Oxf).;39 (4): , Biondi B, Fazio 5, Sacca L, et al. Effects of chronic subclinical hyperthyroidism from levothyroxine on cardiac morphology and function. Cardiologia.; 44 (5): 443-9, Rodondi N, Bauer DC, Cappola AR, Cornuz J, Robbins J, Fried LP, Ladenson PW, Vittinghoff E, Gottdiener JS, Newman AB. Subclinical thyroid dysfunction, cardiac function, and the risk of heart failure. The cardiovascular health study. J Am Coll Cardiol; 52(14): , Akincioglu C, Berman DS, Nishina H, Kavanagh P, Slomka P, Abidov A, Hayes S, Friedman JD, Germano G. Assessment of diastolic function using 16-frame 99mTcsestamibi gated myocardial perfusion SPECT: normal values. J Nucl Med.; 46 (7): , Fazio S, Palmieri EA, Lombardi G, Biondi B. Effects of thyroid hormone on the cardiovascular system. Recent Prog Horm Res.; 59:31-50, Biondi B, Palmieri EA, Lombardi G, Fasio S. Effects of thyroid hormone on cardiac function: the relative importance of heart rate, loading conditions and myocardial contractility in the regulation of cardiac performance in human hyperthyroidism. J Clin Endocrinol Metab; 87(3): , Cappola AR, Fried LP, Arnold AM, Danese MD, Kuller LH, Burke GL, Tracy RP, Ladenson PW. Thyroid status, cardiovascular risk, and mortality in older adults. JAMA.; 295 (9): , Tielens ET, Pillay M, Storm C, Berghout A. Cardiac function at rest in hypothyroidism evaluated by equilibrium radionuclide angiography. Clin Endocrinol (Oxf).; 50 (4): , Klein I, Ojamaa K. Thyrotoxicosis and the heart. Endocrinol Metab Clin North Am.; 27 (1): 51-62, Fatourechi V. Adverse effects of subclinical hyperthyroidism.lancet Oncology Journal ; 15; 856-7, Duggal J, Singh S, Barsano CP, Arora R. Cardiovascular risk with subclinical hyperthyroidism and hypothyroidism: pathophysiology and management.;2 (3): , 2007.

67 Egyptian J. Nucl. Med., Vol. 8, No. 2, December Biondi B, Fazio S, Carella C, Amato G, Cittadini A, Lupoli G, et al. Cardiac effects of long term thyrotropin-suppressive therapy levothyroxine. J Clin Endocrinol Metab.; 77 (2):332-3, Khanna CM, Dubey YS, Shankar R, Kaur G. Effects of long-term thyroid hormone suppressive treatment on the cardiac functions. Indian Heart J.; 49(3):289-92, Boutin JM, Matte R, D'Amour P, Gilbert F, Havrankova J, Belanger R, Chartrand R, Zakarija M. Characteristics of patients with normal T3 and T4 and a low TSH response to TRH. Clin Endocrinol. 1986;25(5): Vanderpump MP, Tunbridge WM. The effects of drugs on endocrine function. Clin Endocrinol :Oct;39(4):389-97, Biondi B, Palmieri EA, Lombardi G, Fazio S. Effect of thyroid hormone on cardiac function: the relative importance of heart rate, loading conditions and myocardial contractility in the regulation of cardiac performance in human hyperthyroidism. J Clin Endocrinol Metab.; 87(3): , Monzani F, Di Bello V, Caraccio N, Bertini A, Giorgi D, Giusti C, Ferrannini E. Effect of levothyroxine on cardiac function and structure in subclinical hypothyroidism: a double blind, placebocontrolled study. J Clin Endocrinol Metab.;86(3):1110-5,2001.

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69 Egyptian J. Nucl. Med., Vol. 8, No. 2, December Original Article, Physics The Effect of Low Dose CT Matrix Size Variation on Qualitative and Semi-Quantitative Analysis of Positron Emission Tomography (PET) Images Abdel Gawad, H 1. Elsayed Y 1. Abdelhafez, Y 2. 1 Nuclear Medicine Unit, Faculty of Medicine, Cairo University, Egypt 2 Nuclear Medicine Unit, South Egypt Cancer Institute, Assiut University, Egypt ABSTRACT: Objective: The purpose of the study was to evaluate the qualitative and semiquantitative effects of using different lowdose computed tomography (CT) matrix sizes for attenuation correction of PET images. Methods: Co-registered 2-[F18]- fluoro-2-deoxy-d-glucose (FDG)-PET and CT images were acquired using a combined PET/CT scanner according to a standardized protocol. PET/CT reconstruction was repeated using default reconstruction protocols with different matrix sizes for low dose CT (512,768 and 1024) in 25 patients. The resulting images were analyzed qualitatively image quality and semi-quantitatively using mean SUV & Signal to Noise Ratio (SNR). Results: No significant difference in the resulting attenuated corrected images reconstructed with the different matrix sizes either qualitatively or semiquantitatively. Conclusion: The matrix size of the low dose CT used in the attenuation correction of PET images does not affect the image quality or semi-quantitative parameters. Key Words: PET/CT, Attenuation Correction, Matrix Size, SUV, SNR. Corresponding Author: Abdel Gawad, H. hesham_ag@yahoo.com.

70 Egyptian J. Nucl. Med., Vol. 8, No. 2, December INTRODUCTION: Positron Emission Tomography (PET) is being increasingly used as an imaging tool for tumor diagnosis, staging and assessing treatment response in patients with various cancers. PET imaging is based on radiotracer compounds labeled with positron emitting radionuclides. This radiopharmaceutical can then be used to track biochemical and physiological processes in vivo. The largest area of clinical use of PET is in oncology and 2- [fluorine-18] fluoro-2-deoxy-d-glucose (18F-FDG), glucose analog, is the most widely used radiopharmaceutical because of their increased glucose metabolism in tumor cells. Although qualitative interpretation is the main stay for image interpretation, quantitative indices are used to measure tumor metabolic avidity and evaluate their responses to therapy (1). Standardized uptake value (SUV) is a semiquantitative measurement of radioactivity concentrations at a fixed time and it increases continuously in tumor cells as a function of time after 18 F-FDG intravenous administration. The SUV has been defined as tissue concentration (kbq/ml) divided by the activity injected per body weight (kbq/g) (1, 2). Despite the popularity of SUV, the reliability of SUV is still somewhat a debate. The primary problem with the SUV is that it is subjective to too many sources of variability which are not controlled such as glucose level, length of the uptake period, body weight, body composition, recovery coefficient and partial volume effect (PVE) (3,4). Biases in SUVs only slightly depend on the emission scan duration and on the presence of outof-the-field-of-view activity, but strongly depend on the attenuation coefficient (µ) map used for attenuation correction (6). Most of the factors affecting the SUV value have been thoroughly studied (5, 6) ; however, only few data discussed the effect of changing the matrix size of attenuation correction CT. The aim of this work is to evaluate the effects of changing PET reconstruction using different low-dose CT matrix sizes on the quality of PET images and semi-quantitative indices using SUV & SNR. PATIENTS AND METHODS: Patients: This prospective study was performed at a private radiology center and included a total of 25 patients referred for different oncological indications during November Patients with uncontrolled diabetes or known to have liver disease were excluded from the study. PET/CT study protocol: A standardized protocol was adopted. The patient was asked to fast for 6 hours prior to the study and have their blood glucose level checked on arrival. Blood glucose levels above 200 mg% were excluded from the study. FDG dose was calculated based on the patient s weight (about 5 MBq/Kg). Waiting time after injection varied from 45 to 90 minutes before the scan. PET/CT acquisition and reconstruction protocol: The study was performed on a combined PET/CT scanner Philips Gemini Time-of- Flight PET/CT machine equipped with LYSO crystals with 64 slice CT scanner; Philips, USA. First, a low-dose CT scan (5-mm contiguous axial cuts) was obtained in a 64 integrated multi-slice CT machine, from the skull base to the mid-thigh. The

71 Egyptian J. Nucl. Med., Vol. 8, No. 2, December acquisition was obtained in a helical mode, using 120 kv, 60 mas, and a 512 x 512 matrix size, acquiring a field of view (FOV) of 700 mm in 22.5 seconds. The first CT scan was used for attenuation correction. Immediately after the low-dose CT, an emission PET scan was acquired in a three-dimensional mode over the same anatomical regions starting from the base of the skull to the level of the mid-thigh. The acquisition time was 2 minutes per bed position in 9 bed positions, with a one-slice overlap at the borders of the FOV. Finally, a diagnostic CT was acquired using 120 kv, 300 mas, and a 512 x 512 matrix size. The acquired FOV was 500 mm using dose automatic modulation in the Z direction. The radiation exposure dose from low-dose CT was in average 3.37 mgray (mgy) while that for diagnostic CT was mgy. Reconstruction protocols: At the end of the study, additional offline reconstructions for the low dose CT were performed using two matrix sizes 768 x 768 & 1024 x 1024 in addition to the default reconstruction 512 x 512 matrix size. Hence, for each patient, 3 reconstructions were performed. Figure 1 : reconstruction 1: using matrix size 512 x 512, reconstruction 2: using matrix size 768 x 768, and reconstruction 3: using matrix size 1024 x Qualitative and semi-quantitative measurements: Each of the three produced reconstructions was evaluated visually by three independent readers with experience in reading PET/CT images taking into account contrast, resolution, sharpness and tissue details. The reader was asked if there is a difference between any of the three images or not, and if there is a difference, is it major affecting their diagnoses or minor not affecting their diagnoses. For semi quantitative analyses, three different ROIs, with the same pixel size, were drawn on non-lesion sites over the liver Figure 2. The ROIs were copied to ensure the exact size and location met among different reconstructed images. For each of the three ROIs, SUV mean & SNR were recorded: SUV was calculated according to the following equation: Where: C(T) is the radioactivity concentration in a given ROI (Bq/mL). D is the dose injected (Bq) & BW is the patient s body weight in (g) Since one gram of tissue can be approximated as having a volume of 1 ml, SUVBW is a unitless quantity. SNR was calculated as mean SUV within a ROI divided by the standard deviation (SD) recorded for the same ROI (mean SUV/SD). Statistical analysis: Inter-reader variability was assessed using weighted kappa test. The means of SUVs and SNRs within different ROIs were compared using repeated-measures ANOVA test. In all statistics, a P value of 0.05 was considered significant. The statistics were performed using SPSS version 18.0 SPSS Inc, Chicago, USA.

72 Egyptian J. Nucl. Med., Vol. 8, No. 2, December RESULTS: Qualitative assessment: There was excellent agreement between the three readers. All of them agreed in 24/25 images that there was no difference in the reconstructed images. Only one reader reported 1 image as being slightly sharper. That image was reconstructed using a matrix size of 1024 x 1024; however, it does not affect his clinical interpretation. Details are presented in Table 1. Table (1): Three reader's interpretation ratings for the different reconstructed images Readers No change Minor Change Major change Reader Reader Reader Fig. (1): Reconstructed attenuated corrected PET images using 3 different Methods; noncontrast low dose CT with matrix size 512 x 512 left, matrix size 768 x 768 middle, and matrix size 1024 x 1024 right. There is no significant difference in reader interpretation of all images evaluated. Fig (2): Three different regions of interests (ROIs) of the same pixel size drawn on the liver on non -lesion areas.

73 Egyptian J. Nucl. Med., Vol. 8, No. 2, December Semi-quantitative assessment: The measured SUV of the three ROIs R1, R2 & R3 according to different reconstruction matrices 512, 768 & 1024 and their mean values are illustrated in Tables 2 & 3 and Fig 1. There was no statistically-significant difference between the means of SUV generated from ROI 1, ROI 2 or ROI 3 using different reconstructions based on matrix 512, 768 & 1024 in Table 4 and Fig2. Table 2: Measured SUV mean at different ROIs R1, R2 & R3 using different reconstruction matrices 512, 768 & Table 3: Measured SNRs at different ROIs "R1, R2, &R3" using different reconstruction matrices 512, 768 & 1024.

74 Egyptian J. Nucl. Med., Vol. 8, No. 2, December Table 4: ANOVA testing for the mean differences in SUV and SNR between different ROIs Measurements P value ROI 1 ROI 2 ROI 3 SUV mean SNR DISCUSSION: Semi quantitative parameters from 18 F- FDG PET/CT are being increasingly incorporated in the guidelines of response evaluation for many Oncological diseases including lymphoma and other solid tumors (7-9). However, the reproducibility of SUV values among different centers is still a challenge. Many factors are reported to affect that measurement, starting from the patient s weight and blood sugar status, to the injected activity, timing of acquisition, and finally reconstruction procedures (2). In order to minimize these differences, procedure guidelines and standardized quantification protocols were issued (10, 11). It was reported that the attenuation correction, reconstruction method and number of iterations can significantly changes SUV values (6, 12). However, scarce reports evaluated the effect of different matrix sizes on the resulting attenuated corrected PET images. Adams et al. (2) tested three different image matrix sizes for their impact on SUV measurements for 1.0-cm spheres: , , and voxels. They reported that using a larger matrix for a given FOV increased SUVmax measurements for 1.0- cm spheres. However, that was likely because larger matrix sizes for a constant FOV make each voxel smaller. Smaller voxels may yield higher spatial resolution but also increase the probability of sampling the peak of the lesion. In this work, three different low-dose CT matrices were used for the attenuation correction of PET images. No significant difference in the resulting corrected PET images was observed either qualitatively or semi-quantitatively. This study has some points of weakness: first, it studied the impact of low-dose CT matrix on the attenuation-corrected images but did not actually change the PET matrix. size. Second, it includes relatively few patients. Third: it calculated the mean SUV over non-lesion sites using a fixed size ROI. Ongoing work is currently undertaken to test these results on lesion sites using different SUV metrics. Nevertheless, this was the first study to document that CT matrix size does not affect the resulting attenuation-corrected PET image. Its prospective design, and standardized acquisition and processing protocol are other points of strength.

75 Egyptian J. Nucl. Med., Vol. 8, No. 2, December CONCLUSION: The change of the low-dose CT matrix size used in attenuation correction of PET/CT studies does not affect the quality or semiquantitative measurements of the resulting attenuated-corrected PET images. REFERENCES: 1. Bar-Shalom R, Valdivia AY, Blaufox MD. PET imaging in oncology. Semin Nucl Med.; 30 (3): Adams MC, Turkington TG, Wilson JM, Wong TZ. A systematic review of the factors affecting accuracy of SUV measurements. AJR Am J Roentgenol.;195 (2): Keyes JW, Jr. SUV: standard uptake or silly useless value? J Nucl Med.; 36 (10): Sugawara Y, Zasadny KR, Neuhoff AW, Wahl RL. Reevaluation of the standardized uptake value for FDG: variations with body weight and methods for correction. Radiology.;213(2): Zasadny KR, Wahl RL. Standardized uptake values of normal tissues at PET with 2-[fluorine-18]-fluoro-2-deoxy-D-glucose: variations with body weight and a method for correction. Radiology.;189(3): Jaskowiak CJ, Bianco JA, Perlman SB, Fine JP. Influence of reconstruction iterations on 18F-FDG PET/CT standardized uptake values. J Nucl Med.;46 (3): Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol.; 25 (5): Wahl RL, Jacene H, Kasamon Y, Lodge MA. From RECIST to PERCIST: Evolving Considerations for PET response criteria in solid tumors. J Nucl Med.;50 Suppl 1:122S-50S Young H, Baum R, Cremerius U, et al. Measurement of clinical and subclinical tumour response using [18F]-fluorodeoxyglucose and positron emission tomography: review and 1999 EORTC recommendations. European Organization for Research and Treatment of Cancer (EORTC) PET Study Group. Eur J Cancer.; 35 (13): Boellaard R, O'Doherty MJ, Weber WA, et al. FDG PET and PET/CT: EANM procedure guidelines for tumour PET imaging: version 1.0. Eur J Nucl Med Mol Imaging.; 37 (1): Boellaard R, Oyen WJ, Hoekstra CJ, et al. The Netherlands protocol for standardisation and quantification of FDG whole body PET studies in multi-centre trials. Eur J Nucl Med Mol Imaging.;35(12): Westerterp M, Pruim J, Oyen W, et al. Quantification of FDG PET studies using standardised uptake values in multi-centre trials: effects of image reconstruction, resolution and ROI definition parameters. Eur J Nucl Med Mol Imaging.;34 (3):

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