Long-term toxicity of [<Superscript>177</Superscript>Lu-DOTA<Superscript>0</Superscript>,Tyr<Superscript>3</Superscript>]octreotate in rats

Purpose and methods Studies on peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues have shown promising results with regard to tumour control. The efficacy of PRRT is limited by uptake and retention in the proximal tubules of the kidney, which might lead to radiation nephropathy. We investigated the long-term renal toxicity after different doses of [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate and the effects of dose fractionation and lysine co-injection in two tumour-bearing rat models. Results Significant renal toxicity was detected beyond 100 days after start of treatment as shown by elevated serum creatinine and proteinuria. Microscopically, tubules were strongly dilated with flat epithelium, containing protein cylinders. Creatinine levels rose significantly after 555 MBq [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate, but were significantly lower after 278 MBq (single injection) or two weekly doses of 278 MBq. Renal damage scores were maximal after 555 MBq and significantly lower in the 278 and 2×278 MBq groups. Three doses of 185 MBq [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate with intervals of a day, a week or a month significantly influenced serum creatinine (469±18, 134±70 and 65±15 μmol/l, respectively; p<0.001). Renal histological damage scores were not significantly influenced by dose fractionation. Lysine co-administration with three weekly treatments of 185 MBq significantly lowered serum creatinine and proteinuria. Conclusion Injection of high doses of [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate resulted in severe renal damage in rats as indicated by proteinuria, elevated serum creatinine and histological damage. This damage was dose dependent and became overt between 100 and 200 days after treatment. Dose fractionation had significant beneficial effects on kidney function. Also, lysine co-injection successfully prevented functional damage.     

Effects of therapy with [<Superscript>177</Superscript>Lu-DOTA<Superscript>0</Superscript>,Tyr<Superscript>3</Superscript>]octreotate on endocrine function

Purpose  

Peptide receptor radionuclide therapy (PRRT) with radiolabelled somatostatin analogues is a novel therapy for patients with somatostatin receptor-positive tumours. We determined the effects of PRRT with [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate (¹⁷⁷Lu-octreotate) on glucose homeostasis and the pituitary-gonadal, pituitary-thyroid and pituitary-adrenal axes.     

Amifostine protects rat kidneys during peptide receptor radionuclide therapy with [<Superscript>177</Superscript>Lu-DOTA<Superscript>0</Superscript>,Tyr<Superscript>3</Superscript>]octreotate

Purpose In peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues, the kidneys are the major dose-limiting organs, because of tubular reabsorption and retention of radioactivity. Preventing renal uptake or toxicity will allow for higher tumour radiation doses. We tested the cytoprotective drug amifostine, which selectively protects healthy tissue during chemo- and radiotherapy, for its renoprotective capacities after PRRT with high-dose [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate. Methods Male Lewis rats were injected with 278 or 555 MBq [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate to create renal damage and were followed up for 130 days. For renoprotection, rats received either amifostine or co-injection with lysine. Kidneys, blood and urine were collected for toxicity measurements. At 130 days after PRRT, a single-photon emission computed tomography (SPECT) scan was performed to quantify tubular uptake of ^99mTc-dimercaptosuccinic acid (DMSA), a measure of tubular function. Results Treatment with 555 MBq [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate resulted in body weight loss, elevated creatinine and proteinuria. Amifostine and lysine treatment significantly prevented this rise in creatinine and the level of proteinuria, but did not improve the histological damage. In contrast, after 278 MBq [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate, creatinine values were slightly, but not significantly, elevated compared with the control rats. Proteinuria and histological damage were different from controls and were significantly improved by amifostine treatment. Quantification of ^99mTc-DMSA SPECT scintigrams at 130 days after [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate therapy correlated well with 1/creatinine (r ² = 0.772, p < 0.001). Conclusion Amifostine and lysine effectively decreased functional renal damage caused by high-dose [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate. Besides lysine, amifostine might be used in clinical PRRT as well as to maximise anti-tumour efficacy.     

Hormonal crises following receptor radionuclide therapy with the radiolabeled somatostatin analogue [<Superscript>177</Superscript>Lu-DOTA<Superscript>0</Superscript>,Tyr<Superscript>3</Superscript>]octreotate

Introduction Receptor radionuclide therapy is a promising treatment modality for patients with neuroendocrine tumors for whom alternative treatments are limited. The aim of this study was to investigate the incidence of hormonal crises after therapy with the radiolabeled somatostatin analogue [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate (¹⁷⁷Lu-octreotate). Materials and methods All ¹⁷⁷Lu-octreotate treatments between January 2000 and January 2007 were investigated. Four hundred seventy-six patients with gastroenteropancreatic neuroendocrine tumors and three patients with metastatic pheochromocytoma were included for analysis. Results Four hundred seventy-nine patients received a total of 1,693 administrations of ¹⁷⁷Lu-octreotate. Six of 479 patients (1%) developed severe symptoms because of massive release of bioactive substances after the first cycle of ¹⁷⁷Lu-octreotate. One patient had a metastatic hormone-producing small intestinal carcinoid; two patients had metastatic, hormone-producing bronchial carcinoids; two patients had vasoactive intestinal polypeptide-producing pancreatic endocrine tumors (VIPomas); and one patient had a metastatic pheochromocytoma. With adequate treatment, all patients eventually recovered. Conclusion Hormonal crises after ¹⁷⁷Lu-octreotate therapy occur in 1% of patients. Generally, ¹⁷⁷Lu-octreotate therapy is well tolerated.     

[<Superscript>99m</Superscript>Tc]Demotate,a new <Superscript>99m</Superscript>Tc-based [Tyr<Superscript>3</Superscript>]octreotate analogue for the detection of somatostatin receptor-positive tumours: synthesis and preclinical results

Demotate is a new tetraamine-functionalised [Tyr3]octreotate derivative that binds technetium-99m with a high efficiency under mild conditions. The resulting radioligand, [99mTc]Demotate, forms in a high purity and is stable for at least 6 h after labelling. The affinity of the unlabelled peptide for somatostatin receptors is high (IC(50)=0.13 n M) and comparable to that of [Tyr3]octreotate or [Tyr3]octreotide, as demonstrated by competition binding experiments in rat brain cortex or AR42J cell membrane preparations. An equally very high affinity ( K(d)=0.07 n M) was exhibited by [99mTc/99gTc]Demotate during saturation binding experiments using rat brain cortex membrane homogenates. The radioligand resisted hydrolytic degradation in mouse plasma and was excreted intact in mouse urine. In vivo, [99mTc]Demotate cleared very rapidly from non-target tissues into the bladder via the kidneys, while radioactivity uptake in target organs was very high. In mice bearing the experimental AR42J tumour, [99mTc]Demotate demonstrated a very high tumour uptake at 1 h p.i. (25%ID/g) that remained high (20%ID/g) at 4 h p.i. This uptake could be effectively blocked by co-injection of a high dose of [Tyr3]octreotate together with the radioligand. High-quality planar and single-photon emission tomographic images were acquired 1 h after injection of [99mTc]Demotate in tumour-bearing mice, illustrating the excellent properties of this agent for somatostatin receptor tumour imaging.     

Improved synthesis of [<Superscript>11</Superscript>C]SA4503, [<Superscript>11</Superscript>C]MPDX and [<Superscript>11</Superscript>C]TMSX by use of [<Superscript>11</Superscript>C]methyl triflate

Recently we have clinically used three new radioligands, [11C]SA4503, [11C]MPDX, and [11C]TMSX, for mapping sigma1, adenosine A1, and adenosine A2A receptors, respectively, in the human brain by positron emission tomography. These radioligands are synthesized by methylation of the respective demethyl precursor with [11C]methyl iodide. Here we demonstrate the improved syntheses of these compounds by use of [11C]methyl triflate, a highly reactive alternative to [11C]methyl iodide.     

[<Superscript>18</Superscript>F]EF3 is not superior to [<Superscript>18</Superscript>F]FMISO for PET-based hypoxia evaluation as measured in a rat rhabdomyosarcoma tumour model

Purpose  The aim of this investigation was to quantitatively compare the novel positron emission tomography (PET) hypoxia marker 2-(2-nitroimidazol-1-yl)-N-(3[¹⁸F],3,3-trifluoropropyl)acetamide ([¹⁸F]EF3) with the reference hypoxia tracer [¹⁸F]fluoromisonidazole ([¹⁸F]FMISO). Methods  [¹⁸F]EF3 or [¹⁸F]FMISO was injected every 2 days into two separate groups of rats bearing syngeneic rhabdomyosarcoma tumours. In vivo PET analysis was done by drawing regions of interest on the images of selected tissues. The resulting activity data were quantified by the percentage of injected radioactivity per gram tissue (%ID/g) and tumour to blood (T/B) ratio. The spatial distribution of radioactivity was defined by autoradiography on frozen tumour sections. Results  The blood clearance of [¹⁸F]EF3 was faster than that of [¹⁸F]FMISO. The clearance of both tracers was slower in tumour tissue compared with other tissues. This results in increasing T/B ratios as a function of time post tracer injection (p.i.). The maximal [¹⁸F]EF3 tumour uptake, compared to the maximum [¹⁸F]FMISO uptake, was significantly lower at 2 h p.i. but reached similar levels at 4 h p.i. The tumour uptake for both tracers was independent of the tumour volume for all investigated time points. Both tracers showed heterogeneous intra-tumoural distribution. Conclusions  [¹⁸F]EF3 tumour uptake reached similar levels at 4 h p.i. compared with tumour retention observed after injection of [¹⁸F]FMISO at 2 h p.i. Although [¹⁸F]EF3 is a promising non-invasive tracer, it is not superior over [¹⁸F]FMISO for the visualisation of tumour hypoxia. No significant differences between [¹⁸F]EF3 and [¹⁸F]FMISO were observed with regard to the intra-tumoural distribution and the extra-tumoural tissue retention.     

[<Superscript>18</Superscript>F]Fluoroacetate is not a functional analogue of [<Superscript>11</Superscript>C]acetate in normal physiology

Purpose  [¹¹C]Acetate (C-AC) is a general PET tracer of cellular carbon flux and useful for clinical imaging in heart disease as well as prostate cancer and other tumours. C-AC has a high (70%) whole-body extraction fraction, proportional to blood flow in many organs. Trapping is related to organ-specific enzymatic activation and formation of [¹¹C]-acetyl-CoA, the fate of which has been well characterized. Due to the logistic challenges with C-AC, 2-[¹⁸F]fluoroacetate (F-AC) has been proposed as a marker for prostate cancer imaging. Method  We evaluated the potential of F-AC as a tracer for imaging blood flow and early enzymatic steps in the intermediary metabolism. C-AC and F-AC were injected serially in three cynomolgus monkeys and one domestic pig and scanned using PET/CT. A dynamic scan covering heart and liver was followed by repeated whole-body imaging. Kinetic patterns were compared for the myocardium, liver, blood and other organs. Results  C-AC kinetics and organ distribution in both species were similar to those previously established in man. In contrast, F-AC showed prolonged blood retention, no detectable trapping in myocardium or salivary glands, rapid clearance from liver and extensive excretion to bile and urine. Massive defluorination was seen in the pig, resulting in intense skeletal activity. Conclusion  2-[¹⁸F]Fluoroacetate cannot be regarded as a functional analogue of 1-[¹¹C]acetate in normal physiology and appears to be of little use for studies of organ blood flow, intermediary metabolism or lipid synthesis. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Kinetics of [<Superscript>11</Superscript>C]choline uptake in prostate cancer: a PET stydy

Carbon-11 choline has recently been introduced as a potential tracer for tumour imaging with positron emission tomography (PET). We evaluated the kinetics of the uptake of [¹¹C]choline in prostate cancer and benign prostatic hyperplasia. We also evaluated the association between the uptake of [¹¹C]choline and the histological grade of malignancy, Gleason score, volume of the prostate and prostate-specific antigen (PSA). Fourteen patients with histologically confirmed prostate cancer and five patients with benign prostatic hyperplasia were studied with [¹¹C]choline PET. A mean dose of 430±31 MBq of [¹¹C]choline was injected intravenously and a dynamic emission acquisition of prostate was performed for 30 min. The uptake of [¹¹C]choline was measured as a standardised uptake value (SUV) and as a kinetic influx constant (K _i) obtained from graphical analysis. Both cancerous and hyperplastic prostate were well visualised with [¹¹C]choline against low or moderate tracer accumulation in the bladder and rectal wall. The measured radioactivity in urine was invariably low. In the graphical analysis, linear plots were achieved. The mean K _i of the untreated tumour was 0.205±0.089 min^–1 (range 0.128–0.351; n=7) and the mean SUV was 5.6±3.2 (range 1.9–15.5; n=15). K _i values and SUVs correlated closely (r=0.964, P=0.0005), whereas no correlation could be demonstrated between the tumour uptake of [¹¹C]choline and the histological grade, Gleason score, volume of the prostate or PSA . The mean SUV and the mean K _i of benign hyperplastic prostate were 3.5±1.0 (range 2.0–4.5; n=4) and 0.119±0.076 min^–1 (range 0.065–0.173; n=2). In conclusion, a high uptake of [¹¹C]choline characterises not only carcinomatous but also hyperplastic prostatic tissue. Dynamic imaging of the uptake of [¹¹C]choline in the prostate shows a good applicability of the graphical analysis model with an irreversible compartment. A close correlation between the K _i values and semiquantitative SUVs of tumours supports the use of the simpler SUV in the clinical setting.     

Age-related changes of the binding of [<Superscript>3</Superscript>H]SA4503 to sigma<Subscript>1</Subscript> receptors in the rat brain

We have recently developed 1-([3-O-methyl-11C]3,4-dimethoxyphenethyl)-4-(3-phenylpropyl) piperazine ([11C]SA4503) as a selective radioligand for mapping sigma1 receptors in the brain by positron emission tomography (PET). In the present short communication we evaluated the age-related changes of the binding of this ligand to sigma1 receptors in Fisher-344 rats (1.5-, 6-, 12-, and 24-month-old) by the in vitro binding assay. We also measured the binding of [3H](+)-pentazocine to sigma1 receptors and the binding of [3H]1,3-di-O-tolylguanidine to sigma2 receptors, which are current standard methods. The specific binding of the three radioligands increased age-dependently. Both Kd and Bmax values of the 24-month-old rats for each radioligand were significantly higher than those of the young rats (1.5- and 6-month-old). The increased numbers of both sigma1 and sigma2 receptor subtypes in the aged rats compensate for the lowered affinity, and rather enhanced the radioligand-receptor binding. The results contrast strikingly with the age-dependent decrease in the dopaminergic, cholinergic and glutamatergic receptors that are reported to be correlated with the sigma receptors, and indicate that a PET study with [11C]SA4503 to evaluate the aging process in humans would be of great interest.     

Comparison of [<Superscript>68</Superscript>Ga]Ga-PSMA-11 PET/CT with [<Superscript>18</Superscript>F]NaF PET/CT in the evaluation of bone metastases in metastatic prostate cancer patients prior to radionuclide therapy

Aim

The purpose of this study was to investigate the diagnostic performance of ⁶⁸Ga-PSMA-11 PET/CT in the evaluation of bone metastases in metastatic prostate cancer (PC) patients scheduled for radionuclide therapy in comparison to [¹⁸F]sodium fluoride (¹⁸F-NaF) PET/CT.

Methods

Sixteen metastatic PC patients with known skeletal metastases, who underwent both ⁶⁸Ga-PSMA-11 PET/CT and ¹⁸F-NaF PET/CT for assessment of metastatic burden prior to radionuclide therapy, were analysed retrospectively. The performance of both tracers was calculated on a lesion-based comparison. Intensity of tracer accumulation of pathologic bone lesions on ¹⁸F-NaF PET and ⁶⁸Ga-PSMA-11 PET was measured with maximum standardized uptake values (SUV_max) and compared to background activity of normal bone. In addition, SUV_max values of PET-positive bone lesions were analysed with respect to morphologic characteristics on CT. Bone metastases were either confirmed by CT or follow-up PET scan.

Results

In contrast to 468 PET-positive lesions suggestive of bone metastases on ¹⁸F-NaF PET, only 351 of the lesions were also judged positive on ⁶⁸Ga-PSMA-11 PET (75.0%). Intensity of tracer accumulation of pathologic skeletal lesions was significantly higher on ¹⁸F-NaF PET compared to ⁶⁸Ga-PSMA-11 PET, showing a median SUV_max of 27.0 and 6.0, respectively (p?<?0.001). Background activity of normal bone was lower on ⁶⁸Ga-PSMA-11 PET, with a median SUV_max of 1.0 in comparison to 2.7 on ¹⁸F-NaF PET; however, tumour to background ratio was significantly higher on ¹⁸F-NaF PET (9.8 versus 5.9 on ⁶⁸Ga-PSMA-11 PET; p?=?0.042). Based on morphologic lesion characterisation on CT, ¹⁸F-NaF PET revealed median SUV_max values of 23.6 for osteosclerotic, 35.0 for osteolytic, and 19.0 for lesions not visible on CT, whereas on ⁶⁸Ga-PSMA-11 PET median SUV_max values of 5.0 in osteosclerotic, 29.5 in osteolytic, and 7.5 in lesions not seen on CT were measured. Intensity of tracer accumulation between¹⁸F-NaF PET and ⁶⁸Ga-PSMA-11 PET was significantly higher in osteosclerotic (p?<?0.001) and lesions not visible on CT (p?=?0.012).

Conclusion

In comparison to ⁶⁸Ga-PSMA-11 PET/CT, ¹⁸F-NaF PET/CT detects a higher number of pathologic bone lesions in advanced stage PC patients scheduled for radionuclide therapy. Our data suggest that ⁶⁸Ga-PSMA-11 PET should be combined with ¹⁸F-NaF PET in PC patients with skeletal metastases for restaging prior to initiation or modification of therapy.

     

<Superscript>177</Superscript>Lu-immunotherapy of experimental peritoneal carcinomatosis shows comparable effectiveness to <Superscript>213</Superscript>Bi-immunotherapy,but causes toxicity not observed with <Superscript>213</Superscript>Bi

Purpose  

²¹³Bi-d9MAb-immunoconjugates targeting gastric cancer cells have effectively cured peritoneal carcinomatosis in a nude mouse model following intraperitoneal injection. Because the β-emitter ¹⁷⁷Lu has proven to be beneficial in targeted therapy, ¹⁷⁷Lu-d9MAb was investigated in this study in order to compare its therapeutic efficacy and toxicity with those of ²¹³Bi-d9MAb.     

The prognostic value of [<Superscript>123</Superscript>I]-vascular endothelial growth factor ([<Superscript>123</Superscript>I]-VEGF) in glioma

Purpose

Recent studies have shown that tumor vascular endothelial cells and various tumor cells overexpress receptors for vascular endothelial growth factor (VEGF). The aim of this study was to investigate the prognostic value of [¹²³I]-VEGF scintigraphy in patients with histologically verified brain tumors.

Methods

23 consecutive patients (9 women and 14 men aged 30–83 years, mean age 56.6 ± 14.4 years) with histopathologically-verified primary brain tumors were included in the study. All patients had undergone [¹²³I]-VEGF scintigraphy. SPECT examinations of brain were performed 30 min and 18 h after injection. Additional [¹¹C]-methionine PET ([¹¹C]-MET PET) was performed in eight of the 23 patients. Both [¹²³I]-VEGF and [¹¹C]-MET PET were evaluated visually and semiquantitatively by tumor-to-normal brain uptake ratio (T/N ratio). Thresholds of the T/N ratio were evaluated by analysis of receiver operating characteristics (ROC). Overall survival (OS) was estimated using the Kaplan-Meier method.

Results

World Health Organization (WHO) grade IV glioma lesions showed [¹²³I]-VEGF uptake 18 h after the injection, whereas other brain tumors of grade II or III showed negative results. There was no significant difference in the tumor size between VEGF positive and VEGF negative tumors. Patients with [¹²³I]-VEGF T/N ratio threshold <1.32 showed significantly longer survival than patients with T/N ratio?≥?1.32 (2680 days vs 295 days; P?<?0.05). In the subgroup of 16 grade IV glioma patients, significant OS differences were found using a T/N ratio of 1.75 as threshold (T/N ratio?<?1.75: 720 days; T/N?≥?1.75: 183 days; P?<?0.05). Significant difference (P?<?0.05) was also found in [¹¹C]-MET PET T/N ratios between the grade IV glioma (mean T/N ratio: 3.71) and the grade II or III glioma (mean T/N ratio: 1.74).

Conclusion

Our results suggest that [¹²³I]-VEGF scintigraphy may be useful for visualization of tumor angiogenesis. In addition, [¹²³I]-VEGF may provide relevant prognostic information in patients with glioma.

     

Quantification of [<Superscript>18</Superscript>F]-FDG uptake in atherosclerotic plaque: impact of renal function

Objective  

Impaired renal function causes both increased and prolonged tracer availability in the blood-pool which might result in increased tracer accumulation in atherosclerotic lesions. Therefore, the aim of this study was to investigate a possible correlation between the intensity of tracer uptake in atherosclerotic lesions and renal function.     

Multimodal correlation of dynamic [<Superscript>18</Superscript>F]-AV-1451 perfusion PET and neuronal hypometabolism in [<Superscript>18</Superscript>F]-FDG PET

Purpose

Cerebral glucose metabolism measured with [18F]-FDG PET is a well established marker of neuronal dysfunction in neurodegeneration. The tau-protein tracer [18F]-AV-1451 PET is currently under evaluation and shows promising results. Here, we assess the feasibility of early perfusion imaging with AV-1451 as a substite for FDG PET in assessing neuronal injury.

Methods

Twenty patients with suspected neurodegeneration underwent FDG and early phase AV-1451 PET imaging. Ten one-minute timeframes were acquired after application of 200 MBq AV-1451. FDG images were acquired on a different date according to clinical protocol. Early AV-1451 timeframes were coregistered to individual FDG-scans and spatially normalized. Voxel-wise intermodal correlations were calculated on within-subject level for every possible time window. The window with highest pooled correlation was considered optimal. Z-transformed deviation maps (ZMs) were created from both FDG and early AV-1451 images, comparing against FDG images of healthy controls.

Results

Regional patterns and extent of perfusion deficits were highly comparable to metabolic deficits. Best results were observed in a time window from 60 to 360 s (r = 0.86). Correlation strength ranged from r = 0.96 (subcortical gray matter) to 0.83 (frontal lobe) in regional analysis. ZMs of early AV-1451 and FDG images were highly similar.

Conclusion

Perfusion imaging with AV-1451 is a valid biomarker for assessment of neuronal dysfunction in neurodegenerative diseases. Radiation exposure and complexity of the diagnostic workup could be reduced significantly by routine acquisition of early AV-1451 images, sparing additional FDG PET.

     

[<Superscript>18</Superscript>F]DOPA PET/ceCT in diagnosis and staging of primary medullary thyroid carcinoma prior to surgery

Purpose

Medullary thyroid carcinoma (MTC) is characterized by a high rate of metastasis. In this study we evaluated the ability of [¹⁸F]DOPA PET/ceCT to stage MTC in patients with suspicious thyroid nodules and pathologically elevated serum calcitonin (Ctn) levels prior to total thyroidectomy and lymph node (LN) dissection.

Methods

A group of 32 patients with sonographically suspicious thyroid nodules and pathologically elevated basal Ctn (bCtn) and stimulated Ctn (sCtn) levels underwent DOPA PET/ceCT prior to surgery. Postoperative histology served as the standard of reference for ultrasonography and DOPA PET/ceCT region-based LN staging. Univariate and multivariate regression analyses as well as receiver operating characteristic analysis were used to evaluate the correlations between preoperative and histological parameters and postoperative tumour persistence or relapse.

Results

Primary MTC was histologically verified in all patients. Of the 32 patients, 28 showed increased DOPA decarboxylase activity in the primary tumour (sensitivity 88%, mean SUVmax 10.5). Undetected tumours were exclusively staged pT1a. The sensitivities of DOPA PET in the detection of central and lateral metastatic neck LN were 53% and 73%, in contrast to 20% and 39%, respectively, for neck ultrasonography. Preoperative bCtn and carcinoembryonic antigen levels as well as cN1b status and the number of involved neck regions on DOPA PET/ceCT were predictive of postoperative tumour persistence/relapse in the univariate regression analysis (P?<?0.05). Only DOPA PET/ceCT cN1b status remained significant in the multivariate analysis (P?=?0.016, relative risk 4.02).

Conclusion

This study revealed that DOPA PET/ceCT has high sensitivity in the detection of primary MTC and superior sensitivity in the detection of LN metastases compared to ultrasonography. DOPA PET/ceCT identification of N1b status predicts postoperative tumour persistence. Thus, implementation of a DOPA-guided LN dissection might improve surgical success.

     

Influence of TSH on uptake of [<Superscript>18</Superscript>F]fluorodeoxyglucose in human thyroid cells in vitro

Recent clinical evidence suggests that positron emission tomography with fluorine-18 fluorodeoxyglucose (FDG-PET) is more accurate in detecting thyroid carcinomatous tissue at high than at low TSH levels. The aim of this study was to determine the influence of TSH on FDG uptake in human thyroid cells in vitro. Monolayers of human thyroid tissue were cultured after mechanical disintegration and enzymatic digestion of samples from patients undergoing surgery for nodular goitre. The purity of thyroid cell preparations was ascertained by immunohistochemical staining for the epithelial antigen KL-1, and their viability by measuring the synthesis of thyroglobulin in vitro. The cells were incubated with 0.8–1.5 MBq FDG/ml uptake medium for 1 h. FDG uptake in thyroid cells was quantified as percent of whole FDG activity per well (% ID) or as % ID in relation to total protein mass. This experimental protocol was subsequently varied to study the effect of incubation time, glucose dependency and TSH. Furthermore, radio-thin layer chromatography was used to identify intracellular FDG metabolites. FDG accumulated in the thyroid cells linearly with time, doubling roughly every 20 min. Uptake was competitively inhibited by unlabelled glucose and decreased to approximately 70% at 100 mg/dl glucose compared to the value measured in glucose-free medium. FDG was intracellularly trapped as FDG-6 phosphate and FDG-1,6-diphosphate. TSH significantly increased FDG uptake in vitro in a time- and concentration-dependent manner: Cells cultured at a TSH concentration of 50 µU/ ml doubled FDG uptake compared to TSH-free conditions, and uptake after 72 h of TSH pre-incubation was approximately 300% of that without TSH pre-incubation. TSH stimulates FDG uptake by benign thyroid cells in a time- and concentration-dependent manner. This supports the clinical evidence that in well-differentiated thyroid carcinomas, most of which are still TSH-sensitive, FDG-PET is more accurate at high levels of TSH.     

Overall survival and response pattern of castration-resistant metastatic prostate cancer to multiple cycles of radioligand therapy using [<Superscript>177</Superscript>Lu]Lu-PSMA-617

Purpose

Up to 30% of patients with castration-resistant prostate cancer (CRPC) do not show any response to the first cycle of radioligand therapy (RLT) with [¹⁷⁷Lu]Lu-PSMA-617 (Lu-PSMA). We evaluated patient response to the second and third cycles of RLT in patients that underwent at least three cycles. The second aim of this study was to calculate the median overall survival (OS) of responders and non-responders after the first cycle and after all three cycles of RLT.

Methods

CRPC patients were treated with Lu-PSMA, with a median interval of 8 weeks between each cycle. The tumour marker prostate-specific antigen (PSA) was used as the marker for response evaluation.

Results

Fifty-two patients underwent a total of 190 cycles of RLT (3–6 cycles per patient). Of these, 80.8% showed a decline in PSA 2 months after the first cycle, with 44.2% showing a PSA decline of ≥50%. When compared to baseline PSA, 73.1% showed a PSA decline after the third cycle. 50% of patients that did not show any response to the first cycle also did not respond to the second and third cycles. The median OS was 60 weeks in all patients. The median OS was significantly longer for patients that showed any PSA decline after the first cycle compared to patients without PSA decline (68 vs. 33 weeks). There was a significant difference in median OS between responders and non-responders for a change in PSA after the third cycle compared to baseline PSA.

Conclusion

Patients with a positive response to RLT, regardless of the rate of decline, had a significantly longer median OS. Of the patients that did not show any response to the first cycle, 50% responded to the second or third cycles.

     

Measuring [<Superscript>18</Superscript>F]FDG uptake in breast cancer during chemotherapy: comparison of analytical methods

Over the years several analytical methods have been proposed for the measurement of glucose metabolism using fluorine-18 fluorodeoxyglucose ([(18)F]FDG) and positron emission tomography (PET). The purpose of this study was to evaluate which of these (often simplified) methods could potentially be used for clinical response monitoring studies in breast cancer. Prior to chemotherapy, dynamic [(18)F]FDG scans were performed in 20 women with locally advanced ( n=10) or metastasised ( n=10) breast cancer. Additional PET scans were acquired after 8 days ( n=8), and after one, three and six courses of chemotherapy ( n=18, 10 and 6, respectively). Non-linear regression (NLR) with the standard two tissue compartment model was used as the gold standard for measurement of [(18)F]FDG uptake and was compared with the following methods: Patlak graphical analysis, simplified kinetic method (SKM), SUV-based net influx constant ("Sadato" method), standard uptake value [normalised for weight, lean body mass (LBM) and body surface area (BSA), with and without corrections for glucose (g)], tumour to non-tumour ratio (TNT), 6P model and total lesion evaluation (TLE). Correlation coefficients between each analytical method and NLR were calculated using multilevel analysis. In addition, for the most promising methods (Patlak, SKM, SUV(LBMg) and SUV(BSAg)) it was explored whether correlation with NLR changed with different time points after the start of therapy. Three methods showed excellent correlation ( r>0.95) with NLR for the baseline scan: Patlak10-60 and Patlak10-45 ( r=0.98 and 0.97, respectively), SKM40-60 ( r=0.96) and SUV(LBMg) ( r=0.96). Good correlation was found between NLR and SUV-based net influx constant, TLE and SUV(BSAg) (0.90< r<0.95). The 6P model and TNT had the lowest correlation ( r相似文献