99m Tc-MIP-1404-SPECT/CT for the detection of PSMA-positive lesions in 225 patients with biochemical recurrence of prostate cancer.

BACKGROUND: 99m Tc-MIP-1404 (Progenics Pharmaceuticals, Inc., New York, NY) is a novel, SPECT-compatible 99m Tc-labeled PSMA inhibitor for the detection of prostate cancer. We present results of its clinical use in a cohort of 225 men with histologically confirmed prostate cancer referred for workup of biochemical relapse. METHODS: From April 2013 to April 2017, 99m Tc-MIP1404-scintigraphy was performed in 225 patients for workup of PSA biochemical relapse of prostate cancer. Whole-body planar and SPECT/CT images of the lower abdomen and thorax were obtained 3-4 h p.i. of 710 ± 64 MBq 99m Tc-MIP-1404. Images were visually analyzed for presence and location of abnormal uptake. In addition, quantitative analysis of the SPECT/CT data was carried out on a subset of 125 patients. Follow-up reports of subsequent therapeutic interventions were available for 59% (139) of all patients. RESULTS: Tracer-positive lesions were detected in 77% (174/225) of all patients. Detections occurred at the area of local recurrence in the prostate in 25% of patients (or a total of 56), with metastases in lymph nodes in 47% (105), bone in 27% (60), lung in 5% (12), and other locations in 2% (4) of patients. Detection rates were 90% at PSA levels ≥2 ng/mL and 54% below that threshold. Lesional SUVmax values were, on average, 32.2 ± 29.6 (0.8-142.2), and tumor-to-normal ratios 146.6 ± 160.5 (1.9-1482.4). The PSA level correlated significantly with total uptake of MIP-1404 in tumors (P < 0.001). Furthermore, total tumor uptake was significantly higher in patients with Gleason scores ≥8 compared to those with Gleason scores ≤7 (P < 0.05). In patients with androgen deprivation therapy, the detection rate was significantly higher compared to patients without androgen deprivation therapy (86% vs 71%, P < 0.001). Based on 99m Tc-MIP-1404-imaging and other information, an interdisciplinary tumor board review recommended changes to treatment plans in 74% (104/139) of those patients for whom the necessary documentation was available. CONCLUSION: SPECT/CT with 99m Tc-labeled MIP-1404 has a high probability in detecting PSMA-positive lesions in patients with elevated PSA. Statistical analysis disclosed significant relationship between quantitative 99m Tc-MIP-1404 uptake, PSA level, and Gleason score.

Quantitative Analysis of Multimodal Skeletal SPECT/CT Reconstructions in Diagnosing Medication-related Osteonecrosis of the Jaw.

AIM: Our goal was to assess visual and quantitative aspects of multimodal skeletal SPECT/CT reconstructions (recon) in differentiating necrotic and healthy bone of patients with suspected MRONJ. METHODS: Prior to surgery, 20 patients with suspected MRONJ underwent SPECT/CT of the jaw 3-4 hours after injection of Tc-99m-DPD (622±112.4 MBq). SPECT/CT data were reconstructed using the multimodal xSPECT Bone and xSPECT Quant algorithms as well as the OSEM-algorithm FLASH 3D. For analysis, we divided the jaw into 12 separate regions. Both xSPECT Bone and FLASH 3D datasets were scored on a four-point scale (VIS xSPECT; VIS F3D), based on the intensity of localized tracer uptake. In F3D and xSPECT Quant datasets, local tracer uptake of each region was recorded as semi-quantitative uptake ratio (SQR F3D) or SUVs, respectively. ROC analysis was performed. Postoperative histologic results served as gold standard. RESULTS: VIS F3D, VIS xSPECT and SQR F3D did not differ significantly in diagnostic accuracy (VIS xSPECT sensitivity=0.64; specificity=0.89). Of the quantitative parameters, SUVpeak yielded the best interobserver reproducibility. SUVpeak was 9.9±7.1 (95%CI: 7.84-11.95) in MRONJ regions, as opposed 3.6±1.8 (95% CI:3.36-3.88) elsewhere, with a cutpoint of 4.5 (sensitivity=0.83; specificity=0.80). Absolute quantitation significantly surpassed VIS and SQR (p<0.05) in accuracy and interobserver agreement (SUVpeak: κ=0.92; VIS xSPECT: κ=0.61; SQR F3D κ=0.66). CONCLUSION: Absolute quantitation proved significantly more accurate than visual and semi-quantitative assessment in diagnosing MRONJ, with higher interobserver agreement.

Regulation of uptake of 18F-FDG by a follicular human thyroid cancer cell line with mutation-activated K-ras.

UNLABELLED: Dedifferentiation of thyroid carcinoma is accompanied by increased accumulation of the PET tracer (18)F-FDG. The molecular mechanisms responsible for this phenomenon are poorly understood. Therefore, we studied the regulation of (18)F-FDG uptake by the human follicular thyroid carcinoma cell line ML-1 and the as-yet-unknown oncogene expression of that cell line. The data obtained in ML-1 were compared with those of a well-differentiated thyroid cell line of rat origin (FRTL-5). METHODS: The expression of the thyroid-stimulating hormone (TSH) receptor was investigated by immunocytochemistry, and the expression of the glucose transporters (GLUTs) was determined by Western blotting. Mutation analysis of ML-1 was performed for K-ras codons 12 and 13. The effect of TSH on intracellular cAMP levels was determined by a competitive enzyme immunoassay. Cells were incubated with (18)F-FDG (0.5-1.0 MBq/mL) for 1 h, and tracer uptake was related to protein concentration. The effects of bovine TSH, the cAMP analog (Bu)(2)cAMP, and the phosphatidylinositol-3-kinase (PI3-kinase) inhibitor LY294002 on (18)F-FDG uptake were investigated. RESULTS: The TSH receptor was present in both cell lines. FRTL-5 clearly expressed GLUT-1 and also GLUT-4. In ML-1 only, the expression of GLUT-3 was detected. TSH and (Bu)(2)cAMP had a significant effect on (18)F-FDG uptake or GLUT-1 expression in FRTL-5, but not in ML-1 cells. PI3-kinase inhibition by LY294002 downregulated (18)F-FDG uptake in FRTL-5 by 58% +/- 9% (n = 6) and in ML-1 by 26% +/- 5% (n = 42, both P < 0.05). Mutation analysis of ML-1 cells revealed a Gly12Ser point mutation at codon 12 of the K-ras gene. CONCLUSION: (18)F-FDG uptake in the thyroid carcinoma cell line ML-1 is no longer regulated by TSH or cAMP or mediated by GLUT-1. However, in this cell line, this variable is still governed to some extent by PI3-kinase located downstream to the constitutively active K-ras in the Ras-PI3-kinase-Akt pathway. These data suggest that increases in (18)F-FDG uptake in thyroid carcinomas observed in vivo by PET may reflect activation of intracellular signal transduction cascades by oncogenes.

A case of severe acute necrotizing pancreatitis in a 38-year-old woman postpartum due to a parathyroid adenoma.

Lethal necrotizing pancreatitis postpartum due to primary hyperparathyroidism caused by a parathyroid adenoma can be considered as a rarity. Due to the unspecific clinical signs and uncommonness this disorder may be overseen very easily. The reported case illustrates the very importance of early diagnosis of this endocrine disorder in pregnancy in order to avoid a lethal course.

First Experience With SPECT/CT Using a 99mTc-Labeled Inhibitor for Prostate-Specific Membrane Antigen in Patients With Biochemical Recurrence of Prostate Cancer.

AIM: Prostate-specific membrane antigen (PSMA) is overexpressed in most prostate cancers (PCs). Here, we report our first experience using the Tc-labeled PSMA inhibitor MIP-1404 (Progenics Pharmaceuticals, Inc, Tarrytown, NY) in 60 patients with biochemically recurrent PC. METHODS: Whole-body planar scintigraphy and SPECT/CT of the lower abdominal pelvic region of 60 patients with biochemical relapse of PC were analyzed retrospectively. In these subjects, an average dose of 733.1 ± 49.5 MBq (19.8 ± 1.3 mCi) Tc-labeled MIP-1404 was injected 4 to 5 hours prior to imaging. In addition to visual evaluation, SUVmax were determined in the tumor lesions using a previously developed protocol for quantitative SPECT/CT. RESULTS: In 42 of 60 patients, Tc-MIP-1404-positive lesions could be detected (70%; 95% confidence interval [CI], 0.58-0.82). Twenty patients had Tc-MIP-1404-positive lymph nodes suggestive of metastasis, 14 patients had pathological uptake in the prostate region indicative of local recurrence, and for another 19 patients, there was tracer accumulation in the skeleton (n = 18) or lungs (n = 1). Detection rate was 91.4% (95% CI, 0.82-1) at prostate-specific antigen levels greater than 2 ng/mL and 40.0% (95% CI, 0.21-0.59) at lower prostate-specific antigen values (P < 0.01). Of the 60 patients, in total, 82 positive lesions were analyzed quantitatively. Average SUVmax of the lesions was 16.3 ± 21.6 with a range of 1.7 to 142.9. CONCLUSION: Tc-labeled PSMA inhibitor MIP-1404 is a promising SPECT tracer for detection of locally recurrent or metastatic prostate cancer.

Longitudinal analysis of bone metabolism using SPECT/CT and (99m)Tc-diphosphono-propanedicarboxylic acid: comparison of visual and quantitative analysis.

BACKGROUND: The therapy response of osseous metastases (OM) is commonly monitored by bone scintigraphies (BS). The aim of this study was to compare visual evaluation of changes in tracer uptake with quantitation in absolute units in OMs; 52 OMs from 19 patients who underwent BS with SPECT/CT at time points one and two (TP1/2) were analyzed retrospectively, with an average of 10.3 months between TP1 and 2. Tracer uptake in lesions was visually compared by two independent readers in both planar scintigraphies and SPECT/CT across both TPs and classified as regressive, stable, or progressive. Quantitative analysis was performed by measuring peak standardized uptake values (SUV). Based on quantitation, lesions were similarly classified as regressive (>30 % decrease), progressive (>30 % increase), or stable (rest). If available, uptake in reference regions in the lower thoracic or lumbar spine was used for normalization. RESULTS: In OMs at TP1 and TP2, mean SUVpeak (±SD) was found to be 20.4 (±20.8) and 16.4 (±11.5), respectively. For the reference region, mean SUVmean was 5.6 (±1.9) and 4.9 (±2.2). Agreement between quantitative and visual assessment was only moderate, with an average Cohen's kappa of 0.42 for planar scintigraphy and 0.62 for SPECT/CT. Discrepancies occurred in between 11 and 22 of the 52 lesions, depending on the reader and whether planar or SPECT imaging was considered. CONCLUSIONS: Compared to measuring uptake in absolute units, visual evaluation of skeletal scintigraphies for change in tumor metabolism yields inconsistent results in roughly one third of the cases.

Effects of recombinant human thyroid-stimulating hormone superagonists on thyroidal uptake of 18F-fluorodeoxyglucose and radioiodide.

BACKGROUND: Superagonist analogs of human thyroid-stimulating hormone (hTSH) may stimulate the uptake of (131)I-iodide and (18)F-fluorodeoxyglucose ((18)F-FDG) in thyroid carcinomas to a greater degree than hTSH. We herein report the potency and efficacy of two hTSH analogs, TR1401 and TR1402, to stimulate radioiodide and (18)F-FDG uptake in FRTL-5 cells and compared the effects of hTSH and TR1401 on radioiodide uptake in the thyroid in vivo in mice. METHODS: The effects of hTSH analogs on intracellular levels of cAMP, uptake of (131)I-iodide, and (18)F-FDG were studied in FRTL-5 cells to determine the stimulatory potency and efficacy of the compounds by calculating half-maximum effective concentration (EC(50)) values and maximal stimulatory effects (E(max)). Biodistribution studies (n = 96) and positron emission tomography/computed tomography imaging studies (single animals) on thyroid (125)I/(124)I-iodide uptake were performed with T3-suppressed CD-1 mice in a dose-dependent manner (3, 10, and 30 µg/animal). RESULTS: The EC(50) values of TR1401 and TR1402 demonstrated a 90-fold or 800-fold higher potency for their capacity to increase intracellular cAMP levels in comparison with hTSH (p < 0.05). Similar results were demonstrated for the stimulation of (18)F-FDG uptake. Bovine TSH, TR1401, and TR1402 were 85%-490% more potent to increase iodide uptake than hTSH (p < 0.05). TR1402 was 30% more efficacious to stimulate iodide uptake than hTSH. The agonist-induced increase in radiotracer uptake was paralleled by increases in NIS and GLUT-1 expression. Ex vivo biodistribution studies showed an increased iodide uptake in the thyroid of TR1401-treated mice at the low dose of 3 µg/animal in comparison with hTSH-treated mice (n = 16, p < 0.05). Positron emission tomography/computed tomography imaging studies confirmed the increased thyroidal iodide uptake in TR1401-treated mice in vivo. CONCLUSIONS: TR1401 and TR1402 have considerably higher potency than hTSH to stimulate thyroidal iodide and (18)F-FDG uptake in vitro. Moreover, in vivo studies indicated that at low but not higher doses, TR1401 induced an enhanced ability for the thyroid to concentrate iodide compared with hTSH. These properties makes TR1401 and TR1402 interesting candidates for use in humans to enhance uptake of radioiodine and (18)F-FDG by metastases and recurrences of thyroid carcinoma.