Annals of Nuclear Medicine (v.25, #2)

Yttrium-90 DOTATOC therapy in GEP-NET and other SST2 expressing tumors: a selected review by Lutfun Nisa; Giordano Savelli; Raffaele Giubbini (75-85).
Treatment of somatostatin receptor-positive tumors with radiolabeled somatostatin analog is a promising option. Several phase I and phase II studies done at a few centers around the world reported encouraging results with [90Y-DOTA-Tyr3]-octreotide (DOTATOC) and/or [177Lu-DOTA-Tyr3-Thr8]-octreotate (DOTATATE). The current article is a selective review of patients who were treated mainly with 90Y-DOTATOC after failure with conventional therapy. The aim is to provide an updated comprehensive evaluation of the overall effectiveness of 90Y-DOTATOC therapy in patients with somatostatin-positive tumors. Review of several studies revealed an objective response rate ranging from 20 to 28% for all neuroendocrine tumors (NET)s. For gastroenteropancreatic-NET (GEP-NET), the response rate was found to be consistently better in the range 28–38%. Overall, the cumulative response rate was found to be 24%. An important issue in peptide receptor radionuclide therapy (PRRT) is the dose–response relationship and finding the correct dose of 90Y-DOTATOC that will achieve an optimum tumor kill. Nephrotoxicity was common but could be minimized by taking adequate renal protective measures. In conclusion, PRRT remains a good option in patients with inoperable and/or metastatic NETs particularly of GEP origin. Over a decade of experience with 90Y-DOTATOC proves that it is still an effective tool for the treatment of large infiltrative NETs with achievement of objective radiological responses in nearly a quarter and disease stabilization in more than half the patients studied so far.
Keywords: 90Y-DOTATOC; Peptide receptor radionuclide therapy; Neuroendocrine tumors; Somatostatin analog; Gastroenteropancreatic-NET

Comparison of 99mTc-labeled PR81 and its F(ab′)2 fragments as radioimmunoscintigraphy agents for breast cancer imaging by Mojtaba Salouti; Mohammad Hossein Babaei; Hossein Rajabi; Haleh Foroutan; Mohammad Javad Rasaee; Ahmad Bitarafan Rajabi; Javad Mohammadnejad; Mohammad Shafiee; Mohammad Mazidi; Fariba Johari Daha (87-92).
We digested anti-MUC1 monoclonal antibody PR81 to produce F(ab′)2 fragments. A comparison was performed between the two radiolabeled PR81 and F(ab′)2 fragments for breast tumor imaging in a mouse model.The optimum conditions for pepsin digestion of PR81 were investigated in terms of enzymes: antibody ratio, digestion time duration and preserved immunoreactivity of the produced fragments. The F(ab′)2 fragments were labeled with Technetium-99m using HYNIC as a chelator and tricine as a co-ligand. The immunoreactivity of the complexes was assessed by radioimmunoassay using MCF7 cells. Biodistribution and imaging studies were performed in female BALB/c mice with breast tumor xenograft at 4, 8 and 24 h post-administration. The PR81 was labeled with technetium-99m in the same way for comparison.The optimum time duration for PR81 digestion was found to be 28 h at an enzyme:antibody weight ratio of 1:20 that resulted in 95.2 ± 4.7% purity. The labeling of intact PR81 and its F(ab′)2 fragments were 87.6 ± 4.2 and 76.1 ± 3.3% after 1 h, respectively (p value <0.05). The percentage of immunoreactivity of F(ab′)2 fragments and intact PR81 were 75.4 ± 2.1% and 85.7 ± 2.9%, respectively (p value <0.05). The biodistribution and imaging studies demonstrated localization of the fragments at 4 h post-administration with high sensitivity and specificity.The results showed that F(ab′)2 fragment of PR81 is more suitable than intact PR81 for safer and more rapid detection of human breast cancer.
Keywords: Breast cancer; Imaging; Monoclonal antibody PR81; F(ab′)2 fragment; 99mTc labeling

Is contrast material needed after treatment of malignant lymphoma in positron emission tomography/computed tomography? by Yuji Nakamoto; Munenobu Nogami; Ryo Sugihara; Kazuro Sugimura; Michio Senda; Kaori Togashi (93-99).
Positron emission tomography (PET)/computed tomography (CT) with 18F-fluorodeoxyglucose is widely used for post-therapeutic surveillance of malignant lymphoma. Debate still exists as to whether intravenous contrast media during the CT stage of a PET/CT scan should be used. The purpose of this study was to investigate the clinical value of contrast agent in PET/CT in patients with lymphoma following treatment.One hundred and twenty-two consecutive patients with malignant lymphoma underwent 146 PET/CT scans to monitor therapeutic response (n = 57) or surveillance during follow-up (n = 89). All patients had a conventional PET/CT scan with low-dose CT without contrast (ldCT), and then a full-dose CT scan with contrast (ceCT). Two datasets were interpreted separately and prevalence of discrepant results between the two methods was evaluated. In addition, differences of diagnostic performance were investigated for restaging.Both PET + ldCT and PET + ceCT were positive in 22 cases and negative in 35 cases when monitoring response to therapy. There were no cases in which these techniques demonstrated inconsistent findings. For restaging, the patient-based sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of PET + ldCT were 70, 91, 76, 87, and 84%, respectively, and those of PET + ceCT were 74, 92, 81, 89, and 87%, respectively. Discrepant results between the two methods occurred in only 2 of 89 cases (2%).PET/ceCT yielded more accurate findings than PET/ldCT in a limited number of cases. PET/ldCT may, therefore, be sufficient for routine PET/CT scanning for post-therapeutic assessment or restaging of lymphoma patients.
Keywords: Malignant lymphoma; PET/CT; Restaging; Contrast material

The goals of this meta-analysis were to determine survival rates in patients with heart failure (HF) assessed by 123I-MIBG imaging results using recently published studies and to determine the prognostic value of 123I-MIBG imaging.We reviewed published cohort studies carried out in Japan that compared the prognosis of patients with their 123I-MIBG activity quantified as late heart-to-mediastinum ratio (H/M) or washout rate by performing a PubMed search for articles in English up to December 2006. Studies were selected if they analyzed a clearly defined lethal outcome (cardiovascular death) using life tables to estimate the odds ratio at 24 months after enrollment.Of 158 articles related to cardiac 123I-MIBG, seven referred to studies that met the inclusion criteria: 5 evaluated H/M via 123I-MIBG in a total of 866 patients and 4 calculated washout rate in a total of 491 patients. A low H/M indicated a high risk of cardiac death: pooled odds ratio, 5.2; 95% confidence interval (CI) of 3.1–5.7. A high washout was also associated with lethal events with a pooled odds ratio of 2.8 (CI: 1.6–5.0). The association between washout and cardiac death was heterogeneous (Chi-square = 11.0, P < 0.02), whereas that between late H/M and fatal events was homogeneous (Chi-square = 2.3, P = no significance).This meta-analysis of published studies of 123I-MIBG studies conducted in Japan indicated that both a decreased cardiac 123I-MIBG activity (H/M) and an increased washout rate are indicative of a poor prognosis in patients with chronic heart failure.
Keywords: Meta-analysis; 123I-MIBG imaging; Heart failure; Cardiac death

The objective of this study was to define the factors that correlate with differences in maximum standardized uptake value (SUVmax) in deep-inspiration breath-hold (DIBH) and free breathing (FB) PET/CT admixed with respiratory gating (RG) PET for reference.Patients (n = 95) with pulmonary lesions were evaluated at one facility over 33 months. After undergoing whole-body PET/CT, a RG PET and FB PET/CT scans were obtained, followed by a DIBH PET/CT scan. All scans were recorded using a list-mode dynamic collection method with respiratory gating. The RG PET was reconstructed using phase gating without attenuation correction; the FB PET was reconstructed from the RG PET sinogram datasets with attenuation correction. Respiratory motion distance, breathing cycle speed, and waveform of RG PET were recorded. The SUVmax of FB PET/CT and DIBH PET/CT were recorded: the percent difference in SUVmax between the FB and DIBH scans was defined as the %BH-index.The %BH-index was significantly higher for lesions in the lower lung area than in the upper lung area. Respiratory motion distance was significantly higher in the lower lung area than in the upper lung area. A significant relationship was observed between the %BH-index and respiratory motion distance. Waveforms without steady end-expiration tended to show a high %BH-index. Significant inverse relationships were observed between %BH-index and cycle speed, and between respiratory motion distance and cycle speed.Decrease in SUVmax of FB PET/CT was due to (1) tumor size, (2) distribution of lower lung, (3) long respiratory movement at slow breathing cycle speeds, and (4) respiratory waveforms without steady end-expiration.
Keywords: Deep-inspiration breath-hold; PET/CT; Maximum SUV; Respiratory gating; Lung cancer

Evaluation of radioiodinated quinazoline derivative as a new ligand for EGF receptor tyrosine kinase activity using SPECT by Masahiko Hirata; Yasukazu Kanai; Sadahiro Naka; Keiji Matsumuro; Shinya Kagawa; Mitsuyoshi Yoshimoto; Yoshiro Ohmomo (117-124).
A radioiodinated analog of PD153035 (m-IPQ) was evaluated as a potential epidermal growth factor receptor tyrosine kinase (EGFR-TK) activity imaging ligand for SPECT.The 50% inhibition concentration (IC50) value of m-IPQ for EGFR-TK phosphorylation inhibition was evaluated and compared to various EGFR-TK inhibitors. [125I]m-IPQ was synthesized by iododestannylation reaction. Biodistribution study of [125I]m-IPQ was conducted in normal mice and tumor-bearing mice. The selectivity and binding characteristics (B max and K d) were analyzed.The quinazoline derivative m-IPQ was found to have high inhibitory potency (IC50: 50.5 ± 3.5 nM) and selectivity toward EGFR-TK. In vivo biodistribution studies of [125I]m-IPQ demonstrated its rapid clearance and low retention in normal tissue. On the other hand, high tumor uptake was observed. However, the increase in [125I]m-IPQ uptake in the stomach as a deiodination parameter was found. Thus, [125I]m-IPQ showed low in vivo stability. The selectivity toward EGFR-TK of m-IPQ was confirmed by the pretreatment experiment with EGFR-TK specific inhibitors, PD153035, Genistein. [125I]m-IPQ bound to single population of binding sites with high affinity and kinetic parameter. In addition, [125I]m-IPQ was bound to EGFR-TK according to the amount of EGFR-TK expression in the tumor.[125I]m-IPQ showed a relatively high tumor accumulation with selective EGFR-TK binding. Moreover, the tumor uptake of [125I]m-IPQ might be reflected in the amount of EGFR-TK expression in the tumor. These good characteristics of [125I]m-IPQ suggested that a 123I-labeled counterpart, [123I]m-IPQ, would have great potential for EGFR-TK imaging with SPECT. However, the in vivo stability of this compound needs to improve.
Keywords: EGF; Radiopharmaceutical; SPECT; Tyrosine kinase; PD153035

Comparison of left ventricular functional parameters obtained from three different commercial automated software cardiac quantification program packages and their intraobserver reproducibility by Zeki Dostbil; Zuhal Arıtürk; Habib Çil; Mehmet Ali Elbey; Ebru Tekbaş; Mehmet Yazıcı; İsmail Yıldız; Bekir Taşdemir (125-131).
ECG-gated myocardial perfusion scintigraphy (MPS) can be used to determine several cardiac functional parameters (e.g., left ventricular ejection fraction (LVEF), end-diastolic volume (EDV), and end-systolic volume (ESV)). In this study, we aimed to compare these cardiac functional parameters calculated by the following cardiac quantification programs: Emory Cardiac Toolbox (ECTb), Quantitative Gated SPECT (QGS), and Myometrix. We also evaluated reproducibility of the cardiac programs.Fifty-seven patients (27 male, 30 female) at Elazig Research and Training Hospital from 2008 to 2009 were included in this study. In all patients, 99mTc-MIBI ECG-Gated (8-bin frame mode) myocardial perfusion scintigraphies were performed. By using 3 different cardiac quantification programs (ECTb, QGS, and Myometrix); LVEF, EDV, and ESV were calculated. The same raw data of MPS images were reprocessed at different time periods, and these 3 parameters were recalculated. LVEF, EDV, and ESV yielded by 3 different programs were compared for interprogram variability assessment, and parameters calculated at two different time periods were compared to evaluate intraprogram reproducibility.There were statistically significant differences between ECTb, QGS, and Myometrix programs for LVEF, EDV, and ESV (p < 0.001). There was also a statistically significant correlation between LVEF and EDV (p < 0.001, r = 0.546; p < 0.001, r = 0.45, respectively), but no statistically significant correlation was present between the ESV values (p > 0.05, r = 0.09). Statistically significant differences were not found between the values of LVEF, EDV, and ESV obtained from the first and second reconstruction analysis of 3 cardiac quantification programs.Different MPS cardiac software programs give variable (but correlated) LVEF and left ventricular volumetric measures. Those obtained from different cardiac softwares cannot be used interchangeably. Our findings have shown that ECTb, QGS, and Myometrix programs are reproducible, with respect to LVEF, EDV, and ESV.
Keywords: Cardiac gated SPECT; ECTb; QGS; Myometrix

Clinical usefulness of a collimator distance dependent resolution recovery in myocardial perfusion SPECT: a clinical report from a single institute by Kuniyuki Tashiro; Seiji Tomiguchi; Shinya Shiraishi; Morikatsu Yoshida; Fumi Sakaguchi; Yasuyuki Yamashita (133-137).
Imperfect image resolution because of finite-sized collimator channels often causes a decrease in diagnostic performance in myocardial perfusion single-photon emission computed tomography (SPECT). This prompted us to evaluate the clinical usefulness of collimator distance dependent resolution recovery (RR) in myocardial perfusion SPECT.We retrospectively reviewed myocardial SPECT images of 60 consecutive patients (26 men, 34 women; mean age 68 years). They consisted of 25 with coronary artery disease (CAD) and 35 without, as confirmed by the coronary angiography (CAG). The patients had undergone myocardial perfusion SPECT imaging with thallium-201 (111 MBq) under an exercise or pharmacological stress protocol. Two readers reviewed the myocardial SPECT images for the presence of CAD on a 4-point scale where 0 = normal, 1 = probably normal, 2 = probably abnormal, and 3 = abnormal. Three reading sessions were held: first, ordered subsets expectation maximization (OSEM) SPECT images, second, OSEM with RR images, and third, both OSEM and RR images. Diagnostic performance for accuracy of coronary arterial stenoses was compared for OSEM, RR and both the images.The sensitivity increased using RR images, but specificity decreased, and thus overall diagnostic accuracy was decreased, as compared with using OSEM images. The overall accuracy of using both the images showed the highest diagnostic performance among the three sets of image interpretations. The sensitivity, specificity and accuracy were 33, 92, 77% for OSEM, 53, 79, 72% for RR and 51, 90, 80% for both the images.These results suggest that RR for myocardial perfusion SPECT imaging has some potential to improve diagnostic accuracy, but both OSEM and RR image sets may have to be employed for the best diagnosis of CAD.
Keywords: Coronary artery disease; Myocardial perfusion SPECT; Tl-201; Collimator distance response compensation

Intestinal uptake of 99mTc-MDP: a case report of protein-losing enteropathy correlated with pathology findings from autopsy by Begoña Martinez-Sanchis; Virginia Cortés-Vizcaíno; Lorena Frontado-Morales; Pablo Sopena-Novales (139-141).
We present a case of a 60-year-old man with a history of severe hypoproteinemia and constitutional syndrome, suspected to have protein-losing enteropathy (PLE). Bone scintigraphy (99mTc-MDP) performed to rule out the presence of bone metastases incidentally showed abnormal uptake in abdominal soft tissue. The patient unexpectedly died of heart failure, and autopsy revealed microscopic alterations consistent with PLE exclusively in the right colon, corresponding to the area of abnormal uptake. Few similar cases have been published, but none of them reported correlative pathological findings affecting the area of abnormal tracer uptake. In this case of PLE, 99mTc-MDP scintigraphy was a useful imaging method for localizing the site of protein loss, showing a focal area of alteration in the right colon. This finding could also have been of great help in case that surgery had been finally performed to control the protein loss.
Keywords: Extraosseous uptake; Bone scan; Protein-losing enteropathy; 99mTc-MDP; Intestinal uptake

The aim of this work was to evaluate a pixelated semiconductor detector and non-pixelated scintillation detector in a pinhole SPECT system for small animal imaging.We assumed two pixelated CdTe semiconductor detectors (a monolithic type and a modular type) and two non-pixelated NaI(Tl) scintillation detectors (a conventional type and a large detector field type). For the monolithic semiconductor detector we assumed that the size of a pixel was 1.0 × 1.0 mm2, the thickness 1 mm, and an effective detector field 128 × 128 mm2. For the modular-type semiconductor detector we assumed that the size of a pixel was 2.5 × 2.5 mm2, the thickness 5 mm, and an effective detector field 320 × 320 mm2. For the two scintillation detectors we assumed that the size of a pixel was 1.4 × 1.4 mm2 and the intrinsic spatial resolution 4.0 mm FWHM, and the thickness 9 mm. For the conventional scintillation detector we assumed that the effective detector field was 179.2 × 179.2 mm2, and for the large field scintillation detector 358.2 × 358.2 mm2 and the magnification factor two. In the simulation we used a pinhole collimator with a pinhole size of 0.3 mm. We reconstructed SPECT images of hot-rod and cold-channel phantoms with projection data calculated with a Monte Carlo method assuming a fixed data acquisition time, and evaluated the image quality with respect to contrast and spatial resolution. In addition, we calculated the scatter fraction to compare the amount of scattered photons between the pixelated and non-pixelated detectors.The image quality of the modular-type pixelated detector was similar to that of the non-pixelated detector operated with a twofold magnified data acquisition. The scattered photons and the parallax effect in the pixelated detector were small and similar to those in the non-pixelated detector.The performance of a modular-type pixelated semiconductor detector was almost the same as that of a non-pixelated scintillation detector with a magnified data acquisition in a small animal pinhole SPECT system.
Keywords: Semiconductor detector; Scintillation detector; SPECT; Small animal imaging