James Nagarajah

Glucose Transporter 1 Expression, Tumor Proliferation, and Iodine/Glucose Uptake in Thyroid Cancer With Emphasis on Poorly Differentiated Thyroid Carcinoma

Purpose: Glucose transporters 1 (GLUT1) facilitates glucose uptake in cancer. An inverse relationship between I-131 and F-18 fluorodeoxyglucose (FDG) uptake in PET/CT (“flip-flop phenomenon”) was described for thyroid cancers (TCs) during dedifferentiation. We investigated the relationship among GLUT1 expression, proliferation, iodine concentration, and glucose uptake in different TC types, with emphasis on “poorly differentiated thyroid carcinoma” (PDTC). Methods: For immunohistochemistry, 95 thyroid tumors (follicular adenoma, papillary TC, follicular TC, PDTC, and anaplastic TC [ATC]) were investigated for GLUT1 expression and proliferation (Ki-67 index). For PET/CT study, 47 F-18 FDG PET/CT of patients with TC (22 PDTC), 39 corresponding I-124 PET/CT, and glucose and iodine uptake were evaluated. PTC and FTC were summarized under differentiated TC (DTC). Results: Immunohistochemistry: 65% of TC expressed GLUT1. The number of GLUT1-positive TC and GLUT1 expression increased with escalating dedifferentiation/aggressiveness of TC types (P < 0.001). A correlation between proliferation and GLUT1 expression was noted (P < 0.001). PET/CT study: F-18 FDG uptake was measured in 81% of cases. Occurrence of F-18 FDG-avid cases as well as median F-18 FDG maximum standardized uptake values were lowest in DTC, intermediate in PDTC, and highest in ATC. Accordingly, numbers of iodine-avid cases and median I-124 maximum standardized uptake value featured an inverse pattern. Conclusions: Dedifferentiation in TC is accompanied by GLUT1 upregulation and increased proliferation. PDTC was found to be intermediate between DTC and ATC in terms of GLUT1 expression and F-18 FDG or I-124 uptake, suggesting that the flip-flop phenomenon occurs at a dedifferentiation stage in between. Furthermore, the results suggest that F-18 FDG PET/CT is an important imaging modality for ATC and PDTC.

Evaluation of the PET component of simultaneous [ 18 F]choline PET/MRI in prostate cancer: comparison with [ 18 F]choline PET/CT

PurposeThe aim of this study was to evaluate the positron emission tomography (PET) component of [18F]choline PET/MRI and compare it with the PET component of [18F]choline PET/CT in patients with histologically proven prostate cancer and suspected recurrent prostate cancer.MethodsThirty-six patients were examined with simultaneous [18F]choline PET/MRI following combined [18F]choline PET/CT. Fifty-eight PET-positive lesions in PET/CT and PET/MRI were evaluated by measuring the maximum and mean standardized uptake values (SUVmax and SUVmean) using volume of interest (VOI) analysis. A scoring system was applied to determine the quality of the PET images of both PET/CT and PET/MRI. Agreement between PET/CT and PET/MRI regarding SUVmax and SUVmean was tested using Pearson’s product-moment correlation and Bland-Altman analysis.ResultsAll PET-positive lesions that were visible on PET/CT were also detectable on PET/MRI. The quality of the PET images was comparable in both groups. Median SUVmax and SUVmean of all lesions were significantly lower in PET/MRI than in PET/CT (5.2 vs 6.1, p < 0.05 and 2.0 vs 2.6, p < 0.001, respectively). Pearson’s product-moment correlation indicated highly significant correlations between SUVmax of PET/CT and PET/MRI (R = 0.86, p < 0.001) as well as between SUVmean of PET/CT and PET/MRI (R = 0.81, p < 0.001). Bland-Altman analysis revealed lower and upper limits of agreement of −2.77 to 3.64 between SUVmax of PET/CT vs PET/MRI and −1.12 to +2.23 between SUVmean of PET/CT vs PET/MRI.ConclusionPET image quality of PET/MRI was comparable to that of PET/CT. A highly significant correlation between SUVmax and SUVmean was found. Both SUVmax and SUVmean were significantly lower in [18F]choline PET/MRI than in [18F]choline PET/CT. Differences of SUVmax and SUVmean might be caused by different techniques of attenuation correction. Furthermore, differences in biodistribution and biokinetics of [18F]choline between the subsequent examinations and in the respective organ systems have to be taken into account.

Comparison of FDG-PET/CT and bone scintigraphy for detection of bone metastases in breast cancer

Background Bone scintigraphy is the standard procedure for the detection of bone metastases in breast cancer patients. FDG-PET/CT has been reported to be a sensitive tool for tumor staging in different malignant diseases. However, its accuracy for the detection of bone metastases has not been compared to bone scintigraphy. Purpose To compare whole-body FDG-PET/CT and bone scintigraphy for the detection of bone metastases on a lesion basis in breast cancer patients. Material and Methods Twenty-nine consecutive women (mean age 58 years, range 35-78 years) with histologically proven breast cancer were assessed with bone scintigraphy and whole-body FDG-PET/CT. Twenty-one patients (72%) were suffering from primary breast cancer and eight patients (28%) were in aftercare with a history of advanced breast cancer. Both imaging procedures were assessed for bone metastases by a radiologist and a nuclear medicine physician. Concordant readings between bone scintigraphy and FDG-PET/CT were taken as true. Discordant readings were verified with additional MRI imaging in all patients and follow-up studies in most patients. Results A total of 132 lesions were detected on bone scintigraphy, FDG-PET/CT or both. According to the reference standard, 70/132 lesions (53%) were bone metastases, 59/132 lesions (45%) were benign, and three lesions (2%) remained unclear. The sensitivity of bone scintigraphy was 76% (53/70) compared to 96% (67/70) for FDG-PET/CT. The specificity of bone scintigraphy and FDG-PET/CT was 95% (56/59) and 92% (54/59), respectively. According to the reference standard bone metastases were present in eight out of the 29 patients (28%), whereas 20 patients (69%) were free of bone metastases. One (3%) patient had inconclusive readings on both modalities as well as on MRI and follow-up studies. Bone scintigraphy and FDG-PET/CT correctly identified seven out of eight patients with bone metastases and 20 out of 20 patients free of metastases. Conclusion On a lesion-basis whole-body FDG-PET/CT is more sensitive and equally specific for the detection of bone metastases compared with bone scintigraphy.

Positron Emission Tomography/Magnetic Resonance Imaging for Local Tumor Staging in Patients With Primary Breast Cancer: A Comparison With Positron Emission Tomography/Computed Tomography and Magnetic Resonance Imaging.

ObjectivesThis study aimed to assess the diagnostic performance of integrated positron emission tomography (PET)/magnetic resonance imaging (MRI) of the breast for lesion detection and local tumor staging of patients with primary breast cancer in comparison to PET/computed tomography (CT) and MRI. Materials and MethodsThe study was approved by the local institutional review board. Forty-nine patients with biopsy-proven invasive breast cancer were prospectively enrolled in our study. All patients underwent a PET/CT, and subsequently, a contrast-enhanced PET/MRI of the breast after written informed consent was obtained before each examination. Two radiologists independently evaluated the corresponding data sets (PET/CT, PET/MRI, and MRI) and were instructed to identify primary tumors lesions as well as multifocal/multicentric and bilateral disease. Furthermore, the occurrence of lymph node metastases was assessed, and the T-stage for each patient was determined. Histopathological verification of the local tumor extent and the axillary lymph node status was available for 30 of 49 and 48 of 49 patients, respectively. For the remaining patients, a consensus characterization was performed for the determination of the T-stage and nodal status, taking into account the results of clinical staging, PET/CT, and PET/MRI examinations. Statistical analysis was performed to test for differences in diagnostic performance between the different imaging procedures. P values less than 0.05 were considered to be statistically significant. ResultsPositron emission tomography/MRI and MRI correctly identified 47 (96%) of the 49 patients with primary breast cancer, whereas PET/CT enabled detection of 46 (94%) of 49 breast cancer patients and missed a synchronous carcinoma in the contralateral breast in 1 patient. In a lesion-by-lesion analysis, no significant differences could be obtained between the 3 imaging procedures for the identification of primary breast cancer lesions (P > 0.05). Positron emission tomography/MRI and MRI allowed for a correct identification of multifocal/multicentric disease in 3 additional patients if compared with PET/CT. For the definition of the correct T-stage, PET/MRI and MRI showed identical results and were correct in significantly more cases than PET/CT (PET/MRI and MRI, 82%; PET/CT, 68%; P < 0.05). Furthermore, the calculated sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy for the detection of nodal positive patients (n = 18) were 78%, 94%, 88%, 88%, and 88% for PET/CT; 67%, 87%, 75%, 82%, and 80% for MRI; and 78%, 90%, 82%, 88%, and 86% for PET/MRI, respectively. Differences between the imaging modalities were not statistically significant (P > 0.05). ConclusionsIntegrated PET/MRI does not provide diagnostic advantages for local tumor staging of breast cancer patients in comparison to MRI alone. Positron emission tomography/MRI and MRI enable an improved determination of the local tumor extent in comparison to PET/CT, whereas all 3 imaging modalities offer a comparable diagnostic performance for the identification of axillary disease.

Evaluation of ¹⁸F-FDG PET/MRI, ¹⁸F-FDG PET/CT, MRI, and CT in whole-body staging of recurrent breast cancer.

OBJECTIVES To compare the diagnostic performance of (18)F-fluordesoxyglucose positron emission tomography/magnetic resonance imaging ((18)F-FDG PET/MRI) with (18)F-FDG PET/computed tomography ((18)F-FDG PET/CT), MRI, and CT in whole-body staging of recurrent breast cancer. MATERIAL AND METHODS Twenty-one consecutive patients (age 59.4 ± 11.5 years, range 38.5-76.9 years; 20 female, 1 male) with suspected breast cancer recurrence underwent a clinically indicated (18)F-FDG PET/CT and subsequently a (18)F-FDG PET/MRI examination in a single injection protocol (mean injected activity: 257 ± 44 MBq (18)F-FDG). Each (18)F-FDG PET/MRI, (18)F-FDG PET/CT, as well as the CT component of PET/CT (CTPET/CT) and MR images of PET/MRI (MRIPET/MRI) were separately evaluated by two radiologists regarding lesion count, lesion localization, and lesion categorization (benign/malignant). The reference standard was based on histopathological results as well as prior and follow-up imaging. A Wilcoxon test assessed differences in SUVmax between (18)F-FDG PET/MRI and (18)F-FDG PET/CT. Correlation of SUVmax between (18)F-FDG PET/MRI and (18)F-FDG PET/CT was calculated using Pearsons correlation coefficient. Interobserver agreement on dignity ratings was evaluated using Cohens kappa. RESULTS According to the reference standard, 17 patients had breast cancer recurrence. (18)F-FDG PET/MRI, (18)F-FDG PET/CT, and MRIPET/MRI correctly identified each of the 17 patients, whereas CTPET/CT correctly identified 15 of the 17 patients. A total of 134 lesions were described (116 malignant, 18 benign). (18)F-FDG PET/MRI detected all 134 lesions, of which (18)F-FDG PET/CT, MRIPET/MRI, and CTPET/CT detected 97.0%, 96.2%, and 74.6%, respectively. (18)F-FDG PET/MRI yielded the highest proportion of correctly categorized lesions (98.5%) compared with (18)F-FDG PET/CT (94.8%), MRIPET/MRI (88.1%), and CTPET/CT (57.5%). SUVmax was strongly correlated (r=0.72) but measured significantly higher on (18)F-FDG PET/MRI than on (18)F-FDG PET/CT in corresponding PET-positive lesions (SUVmax: 5.6 ± 2.8 vs. 4.9 ± 1.8; p=0.001). Interobserver agreement on lesion dignity was substantial with (18)F-FDG PET/MRI (k=0.65; p<0.001) and (18)F-FDG PET/CT (k=0.65; p<0.001). With MRIPET/MRI interobserver analysis yielded a moderate agreement (k=0.56; p<0.001), whereas there was only fair agreement evaluating the CTPET/CT datasets (k=0.31; p=0.002). CONCLUSIONS (18)F-FDG PET/MRI offered the highest diagnostic performance compared with (18)F-FDG PET/CT, MRI and CT. Thus, (18)F-FDG PET/MRI should be regarded as a valuable alternative in whole-body staging of recurrent breast cancer.

Assessment of Lesion Response in the Initial Radioiodine Treatment of Differentiated Thyroid Cancer Using 124I PET Imaging

124I PET/CT images from differentiated thyroid cancer patients were retrospectively analyzed to assess the relationship between absorbed radiation dose (AD) to lesions and their response after radioiodine therapy. Methods: Patients received serial 124I PET/CT scans before and after their first radioiodine treatment. The pretherapy PET data were used to segment the lesion volumes and to predict the therapy-delivered ADs after administration of the therapeutic 131I activity. The segmentation method’s lower volume limit of determinability was a sphere of 0.80 mL, which classified the lesions into a known-volume group (>0.80 mL) or a small-volume group (≤0.80 mL) with their respective average and minimum ADs. The posttherapy PET data were used to assess the lesion-based therapy success. In the known-volume group, the response rate was calculated on the basis of lesions that received average ADs above the generally accepted threshold of 85 Gy for metastases and 300 Gy for thyroid remnants (TRs) and was expressed as the percentage of completely responding lesions. In the small-volume group, the metastasis and TR responses were evaluated for 3 minimum-AD groups: 5 to 10 Gy (TR, 5 to 30 Gy), >10 to 85 Gy (TR, >30 to 300 Gy), and >85 Gy (TR, >300 Gy). Their response rates were calculated in terms of the percentage of completely responding lesions in each minimum-AD group. Results: In total, 59 lesions in 17 patients were amenable to reliable volume estimation. The response rates were 63%, 88%, and 90% for lymph node metastases (LMs), pulmonary metastases, and TRs, respectively. The response rates of 168 small lesions in 34 patients were more than 82% for LMs and more than 91% for TRs in each of the 3 minimum-AD groups; all small pulmonary metastases responded completely. Conclusion: In the known-volume group, the response rate for TRs matched well with historical data derived using 131I scintigraphy imaging, whereas the response rate for LMs was not as high as expected, which may be explained by too short a follow-up time for a few LMs and a higher sensitivity of PET imaging. Small lesions were treated effectively, suggesting that they are considerably smaller than 0.80 mL.

Prognostic Stratification of Metastatic Gastroenteropancreatic Neuroendocrine Neoplasms by 18F-FDG PET: Feasibility of a Metabolic Grading System

The tumor proliferation marker, Ki-67 index, is a well-established prognostic marker in gastroenteropancreatic neuroendocrine neoplasms (NENs). Noninvasive molecular imaging allows whole-body metabolic characterization of metastatic disease. We investigated the prognostic impact of 18F-FDG PET in inoperable multifocal disease. Methods: Retrospective, dual-center analysis was performed on 89 patients with histologically confirmed, inoperable metastatic gastroenteropancreatic NENs undergoing 18F-FDG PET/CT within the staging routine. Metabolic (PET-based) grading was in accordance with the most prominent 18F-FDG uptake (reference tumor lesion): mG1, tumor-to-liver ratio of maximum standardized uptake value ≤ 1.0; mG2, 1.0–2.3; mG3, >2.3. Other potential variables influencing overall survival, including age, tumor origin, performance status, tumor burden, plasma chromogranin A (≥600 μg/L), neuron-specific enolase (≥25 μg/L), and classic grading (Ki-67–based) underwent univariate (log-rank test) and multivariate analysis (Cox proportional hazards model), with a P value of less than 0.05 considered significant. Results: The median follow-up period was 38 mo (95% confidence interval [CI], 27–49 mo); median overall survival of the 89 patients left for multivariate analysis was 29 mo (95% CI, 21–37 mo). According to metabolic grading, 9 patients (10.2%) had mG1 tumors, 22 (25.0%) mG2, and 57 (64.8%) mG3. On multivariate analysis, markedly elevated plasma neuron-specific enolase (P = 0.016; hazard ratio, 2.9; 95% CI, 1.2–7.0) and high metabolic grade (P = 0.015; hazard ratio, 4.7; 95% CI, 1.2–7.0) were independent predictors of survival. Conclusion: This study demonstrated the feasibility of prognostic 3-grade stratification of metastatic gastroenteropancreatic NENs by whole-body molecular imaging using 18F-FDG PET.

Combined PET Imaging and Diffusion-Weighted Imaging of Intermediate and High-Risk Primary Prostate Carcinomas with Simultaneous [18F] Choline PET/MRI

Purpose To characterize intermediate and high-risk prostate carcinomas with measurements of standardized uptake values (SUVs) and apparent diffusion coefficient (ADC) values by means of simultaneous [18F] choline PET/MRI. Materials and Methods 35 patients with primary prostate cancer underwent simultaneous [18F] choline PET/MRI. From these, 21 patients with an intermediate and high risk constellation who were not under ongoing hormonal therapy were included. Altogether 32 tumor lesions with a focal uptake of [18F] choline could be identified. Average ADC values (ADCaver) minimum ADC values (ADCmin) as well as maximum and mean SUVs (SUVmax, SUVmean) of tumor lesions were assessed with volume-of-interest (VOI) and Region-of-interest (ROI) measurements. As a reference, also ADCaver, ADCmin and SUVmax and SUVmean of non-tumorous prostate tissue were measured. Statistical analysis comprised calculation of descriptive parameters and calculation of Pearson’s product moment correlations between ADC values and SUVs of tumor lesions. Results Mean ADCaver and ADCmin of tumor lesions were 0.94±0.22×10−3 mm2/s and 0.65±0.21×10−3 mm2/s, respectively. Mean SUVmax and SUVmean of tumor lesions were 6.3±2.3 and 2.6±0.8, respectively. These values were in each case significantly different from the reference values (p<0.001). There was no significant correlation between the measured SUVs and ADC values (SUVmax vs. ADCaver: R = −0.24, p = 0.179; SUVmax vs. ADCmin: R = −0.03, p = 0.877; SUVmean vs. ADCaver: R = −0.27, p = 0.136; SUVmean vs. ADCmin: R = −0.08, p = 0.679). Conclusion Both SUVs and ADC values differ significantly between tumor lesions and healthy tissue. However, there is no significant correlation between these two parameters. This might be explained by the fact that SUVs and ADC values characterize different parts of tumor biology.

Does PRRT with standard activities of 177Lu-octreotate really achieve relevant somatostatin receptor saturation in target tumor lesions?: insights from intra-therapeutic receptor imaging in patients with metastatic gastroenteropancreatic neuroendocrine tumors

BackgroundPeptide receptor radionuclide therapy (PRRT) with 177Lu-[DOTA0,Tyr3]octreotate (177Lu-octreotate) is generally performed using a fixed activity of 7.4 GBq (200 mCi) per course bound to 180 to 300 μg of the peptide. While this single activity may lead to suboptimal radiation doses in neuroendocrine tumors (NET) with advanced or bulky disease, dose escalation has been withheld due to concerns on potential tumor somatostatin receptor saturation with reduced efficacy of the added activity. In vivo saturation effects during standard-dose PRRT based on quantification of pre- and intra-therapeutic 68Ga-DOTATOC positron emission tomography (PET) imaging might guide potential dose escalation.MethodsFive patients with metastatic NET of the pancreas underwent 68Ga-DOTATOC PET/CT before and directly after standard-dose PRRT with 177Lu-octreotate. In each patient, four target tumor lesions, normal liver parenchyma, and the spleen were evaluated and the ratios of SUVmax of the target lesions to liver (SUVT/L) and spleen (SUVT/S) were calculated; paired Students t test was performed with p < 0.05 for pre-/intra-PRRT comparisons.ResultsThe mean intra-therapeutic tumor SUVmax showed no significant change (per-lesion paired t test) compared to pretreatment values (-9.1%, p = 0.226). In contrast, the SUVmax of the normal liver parenchyma and spleen were significantly lower directly after infusion of 7.4 GBq 177Lu-octreotate. Consequently, SUVT/L and SUVT/S increased significantly from pretreatment to intra-therapeutic examination: SUVT/L (p < 0.001) from 2.8 ± 1.3 (1.3 to 5.8) to 4.7 ± 3.0 (2.1 to 12.7) and SUVT/S (p < 0.001) from 1.2 ± 0.7 (0.4 to 3.0) to 3.5 ± 1.5 (1.6 to 7.9).ConclusionsThis small retrospective study provides preliminary evidence for the absence of relevant in vivo saturation of somatostatin receptor subtype 2 (sst2) in tumor lesions during PRRT with standard activities of 177Lu-octreotate in contrast to normal tissue (liver, spleen) showing limited receptor capacity. After being confirmed by larger series, this observation will have significant implications for PRRT: (1) Higher activities of 177Lu-octreotate might be considered feasible in patients with high tumor disease burden or clinical need for remission, and (2) striving to reduce the amount of peptide used in standard preparations of 177Lu-octreotate appears futile.

Effects of rosiglitazone on radioiodine negative and progressive differentiated thyroid carcinoma as assessed by ¹²⁴I PET/CT imaging.

Aim: The aim of this study was to evaluate the redifferentiative and antiproliferative effects of rosiglitazone in patients with progressive differentiated thyroid cancer (DTC) without or with negligible overall radioiodine uptake. Materials and Methods: A total of 9 patients with progressive DTC with either no or only negligible radioiodine accumulation were enrolled in this study. Oral rosiglitazone treatment was applied for 6 months (4 mg per day for 2 weeks followed by 8 mg per day). The compatibility of the medication was initially checked twice weekly and then weekly by laboratory tests and clinical evaluation of side effects. The assessments of alterations in the doses absorbed by the tumor and in lesion sizes over the course of rosiglitazone treatment were performed using serial 124I positron emission tomography and computed tomography imaging. The assessment time points were before enrollment and 3 and 6 months posttreatment initiation. Results: Lesion dosimetry indicated that 5 of 9 patients had an improved lesion absorbed dose per administered activity (LDpA), yielding in radioiodine therapy treatment in 4 patients. One third of the patients (3/9) were unchanged with regard to LDpA, and 1 of 9 had deteriorated LDpA. Volumetric analyses revealed that lesion sizes were regredient in 3 of 9 patients, stable in 4 of 9, and was progressive in 1 of 9. The medication was well-tolerated, and no patient developed clinically important toxicity associated with rosiglitazone treatment. In 2 of 9 of the patients, the medication was terminated after 3 months as a precaution due to progressive heart disease in one patient and bone fracture within a known osteolytic bone lesion in another patient. It is not clear that these complications were caused by rosiglitazone. Conclusion: Rosiglitazone appears to be suitable as off-label therapy in radioiodine-negative and progressive DTC that lacks therapy alternatives. In Europe, rosiglitazone was removed for label use because of reported side effects during diabetes treatment. Further investigations of other available glitazone compounds are necessary.