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.     

Radiation exposure after <Superscript>177</Superscript>Lu-DOTATATE and <Superscript>177</Superscript>Lu-PSMA-617 therapy

Purpose

As radionuclide therapy is gaining importance in palliative treatment of patients suffering from neuroendocrine tumour (NET) as well as castration resistant prostate cancer (CRPC), the radiation protection of patients, staff, family members and the general public is of increasing interest. Here, we determine patient discharge dates according to European guidelines.

Methods

In 40 patients with NET and 25 patients with CRPC organ and tumour doses based on the MIRD concept were calculated from data obtained during the first therapy cycle. Planar whole body images were recorded at 0.5, 4, 20, 68 und 92 h postinjection. Residence times were calculated from the respective time-activity-curves based on the conjugated view method. Residence times for critical organs were fitted into the commercially available OLINDA software to calculate the organ doses. The doses of tumours and salivary glands were calculated via their self-irradiation by approximation with spheres of equivalent volume. Kidney volumes were gained by organ segmentation, volumes of all other organs were estimated by means of OLINDA and hence were lean body mass corrected. Out of the whole body curves reference points for patient discharge were estimated.

Results

In patients with NET discharge dates could be properly estimated from dosimetric data, which is not only crucial for radiation protection, but also makes therapy planning easier. For ¹⁷⁷Lu-PSMA-617 ligand therapy it is difficult to seriously estimate a generalized discharge date due to large interpatient variation resulting from different tumor loads and heavy pre-treatment.

Conclusion

Patient release is predictable for ¹⁷⁷Lu-DOTATATE therapy but not for ¹⁷⁷Lu-PSMA ligand therapy.

     

Optimising conditions for radiolabelling of DOTA-peptides with <Superscript>90</Superscript>Y, <Superscript>111</Superscript>In and <Superscript>177</Superscript>Lu at high specific activities

DOTA-conjugated peptides, such as [DOTA(0),Tyr(3)]octreotide (DOTATOC) and [DOTA(0),Tyr(3)]octreotate (DOTA-tate), can be labelled with radionuclides such as (90)Y, (111)In and (177)Lu. These radiolabelled somatostatin analogues are used for peptide receptor radionuclide therapy (PRRT). Radioligands for PRRT require high specific activities. However, although these radionuclides are produced without addition of carrier, contaminants are introduced during production and as decay products. In this study, parameters influencing the kinetics of labelling of DOTA-peptides were investigated and conditions were optimised to obtain the highest achievable specific activity. The effects of contaminants were systematically investigated, concentration dependently, in a test model mimicking conditions for labelling with minimal molar excess of DOTA-peptides over radionuclide. Kinetics of labelling of DOTA-peptides were optimal at pH 4-4.5; pH <4 strongly slowed down the kinetics. Above pH 5, reaction kinetics varied owing to the formation of radionuclide hydroxides. Labelling with (90)Y and (177)Lu was completed after 20 min at 80 degrees C, while labelling with (111)In was completed after 30 min at 100 degrees C. The effects of contaminants were systematically categorised, e.g. Cd(2+) is the target and decay product of (111)In, and it was found to be a strong competitor with (111)In for incorporation in DOTA. In contrast, Zr(4+) and Hf(4+), decay products of (90)Y and (177)Lu, respectively, did not interfere with the incorporation of these radionuclides. The following conclusions are drawn: (a) DOTA-peptides can be radiolabelled at high specific activity; (b) reaction kinetics differ for each radionuclide; and (c) reactions can be hampered by contaminants, such as target material and decay products.     

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.     

<Superscript>11</Superscript>C-acetate PET imaging of lung cancer: comparison with <Superscript>18</Superscript>F-FDG PET and <Superscript>99m</Superscript>Tc-MIBI SPET

Recently carbon-11 acetate (AC) positron emission tomography (PET) has been reported to be of clinical value for the diagnosis of cancer that is negative on fluorine-18 fluorodeoxyglucoce (FDG) PET. We investigated the uptake of AC in lung cancer to determine whether this tracer is of potential value for tumour detection and characterisation, and to compare AC PET imaging with FDG PET and technetium-99m sestamibi (MIBI) single-photon emission tomography (SPET). Twenty-three patients with 25 lung cancers underwent AC and FDG PET. Twenty of 23 patients were also investigated with MIBI SPET. Dynamic images were acquired for 26 min after the injection of 555 MBq of AC. Standardised uptake values (SUVs) and/or tumour to non-tumour activity ratios (T/N) for each tumour were investigated at 10–20 min after AC administration, 40–60 min after administration of 185 MBq FDG and 15–45 min after administration of 555 MBq MIBI. Twenty lung cancers were resected surgically, and the degree of tracer uptake in the primary lesion was correlated with histopathological features (cell dedifferentiation and aggressiveness) and prognosis. Rapid uptake of AC followed by extremely slow clearance was observed. For the purpose of tumour identification, AC PET was inferior to FDG PET in 8 of 25 (32%) lung cancers, and the T/N of AC was lower than that of FDG. However, AC PET was superior to FDG PET in the identification of a slow-growing tumour (bronchiolo-alveolar carcinoma). There was a positive correlation between AC uptake (T/N) and MIBI uptake (T/N) (r=0.799, P<0.0001). A positive correlation was not observed between either AC or MIBI uptake and the degree of cell dedifferentiation in lung adenocarcinomas, whereas FDG uptake did correlate with the degree of cell dedifferentiation. In lung adenocarcinoma, there was a weak correlation between aggressiveness and FDG uptake, but no correlation was evident for AC and MIBI. In addition, a positive correlation was not observed between AC or MIBI uptake and postoperative recurrence in lung adenocarcinoma, whereas FDG uptake did correlate with postoperative recurrence. Thus, the greater the FDG uptake, the higher the malignant grade. In conclusion, for the purpose of tumour identification, AC PET was inferior to FDG PET but superior to MIBI SPET. Neither AC nor MIBI uptake reflects the malignant grade in lung adenocarcinoma, whereas FDG uptake does. AC PET is less diagnostically informative than FDG PET in patients with lung cancer. However, AC PET may play a complementary role in the identification of low-grade malignancies that are not FDG avid.     

<Superscript>99m</Superscript>Tc-EDDA/HYNIC-TOC and <Superscript>18</Superscript>F-FDG in thyroid cancer patients with negative <Superscript>131</Superscript>I whole-body scans

Several studies have reported on the expression of somatostatin receptors in patients with differentiated thyroid cancer (DTC). The aim of this study was to evaluate the imaging abilities of a recently developed technetium-99m labelled somatostatin analogue, ^99mTc-EDDA/HYNIC-TOC (^99mTc-TOC), in terms of precise localisation of disease. The study population comprised 54 patients (24 men, 30 women; age range 22–90 years) with histologically confirmed DTC who presented with recurrent or persistent disease as indicated by elevated Tg levels after initial treatment. All patients were negative on the iodine-131 post-therapy whole-body scans. Fluorine-18 fluorodeoxyglucose positron emission tomography (¹⁸F-FDG PET) was performed in a subgroup of 36 patients. The study population consisted of two groups: Group A (n=22) comprised patients with disease recurrence as shown by elevated Tg levels but without detectable pathology. In group B (n=32), pre-existing lesions were known. Among the 54 cases, SSTR scintigraphy was true positive in 33 (61.1%), true negative in 4 (7.4%) and false negative in 17 (31.5%) cases, which resulted in a sensitivity of 66%. A total of 138 tumour foci were localised in 33 patients. The fraction of true positive ^99mTc-TOC findings was positively correlated (P<0.01) with elevated Tg levels (higher than 30 ng/ml). Despite two false positive findings, analysis on a lesion basis demonstrated better diagnostic efficacy with ¹⁸F-FDG PET (P<0.001); however, it also revealed substantial agreement between the imaging techniques [Cohens kappa of 0.62 (0.47–0.78)]. In conclusion, scintigraphy with ^99mTc-TOC might be a promising tool for treatment planning; it is easy to perform and showed sufficient accuracy for localisation diagnostics in thyroid cancer patients with recurrent or metastatic disease.     

PET imaging of hepatocellular carcinoma with <Superscript>18</Superscript>F-fluoroethylcholine and <Superscript>11</Superscript>C-choline

Purpose  

Choline-based radiotracers have been studied for PET imaging of hepatocellular carcinoma (HCC). Using an ¹⁸F-labeled choline analog, instead of the ¹¹C-labeled native choline, would facilitate its widespread use in the clinic. In this study, PET with ¹⁸F-fluoroethylcholine (FEC) and ¹¹C-choline (CHOL) were compared using an animal model of HCC. The effects of fasting on the performance of choline-based tracers were also investigated.     

<Superscript>18</Superscript>F-FDG and <Superscript>18</Superscript>F-FET uptake in experimental soft tissue infection

The aim of this study was to compare the uptake of (18)F-fluoroethyl- L-tyrosine ((18)F-FET) with that of (18)F-fluorodeoxyglucose ((18)F-FDG) in activated inflammatory white blood cells. Unilateral thigh muscle abscesses were induced in 11 rats by intramuscular inoculation of 0.1 ml of a bacterial suspension ( S. aureus, 1.2 x 10(9) CFU/ml). Four animals were intraperitoneally injected with 130-180 MBq (18)F-FDG, four with 140-170 MBq (18)F-FET and three with a mixture of 140-170 MBq (18)F-FET and 1.8 MBq (14)C-deoxyglucose. Autoradiography (10 microm slice thickness) of the abscess and the contralateral muscle was performed and detailed spatial correlation of autoradiography and histopathology (haematoxylin-eosin staining) was obtained. Regions of interest were placed on the abscess wall and the grey values (digitised image intensities) measured were converted to kBq/cc per kBq injected activity per gram (SUV). Areas with increased (18)F-FDG uptake corresponded to cellular inflammatory infiltrates mainly consisting of granulocytes. The SUV was calculated to be 4.08+/-0.65 (mean+/-SD). The uptake of (18)F-FET in activated white blood cells was not increased: the SUV of the abscess wall, at 0.74+/-0.14, was even below that of contralateral muscle. The low uptake of (18)F-FET in non-neoplastic inflammatory cells promises a higher specificity for the detection of tumour cells than is achieved with (18)F-FDG, since the immunological host response will not be labelled and inflammation can be excluded.     

EANM procedure guidelines for <Superscript>131</Superscript>I-meta-iodobenzylguanidine (<Superscript>131</Superscript>I-mIBG) therapy

Meta-iodobenzylguanidine, or Iobenguane, is an aralkylguanidine resulting from the combination of the benzyl group of bretylium and the guanidine group of guanethidine (an adrenergic neurone blocker). It is a noradrenaline (norepinephrine) analogue and so-called “false” neurotransmitter. This radiopharmaceutical, labeled with ¹³¹I, could be used as a radiotherapeutic metabolic agent in neuroectodermal tumours, that are derived from the primitive neural crest which develops to form the sympathetic nervous system. The neuroendocrine system is derived from a family of cells originating in the neural crest, characterized by an ability to incorporate amine precursors with subsequent decarboxylation. The purpose of this guideline is to assist nuclear medicine practitioners to evaluate patients who might be candidates for ¹³¹I-meta-iodobenzylguanidine to treat neuro-ectodermal tumours, to provide information for performing this treatment and to understand and evaluate the consequences 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.     

<Superscript>123</Superscript>I-MIBG scintigraphy/SPECT versus <Superscript>18</Superscript>F-FDG PET in paediatric neuroblastoma

Purpose  

To analyse different uptake patterns in ¹²³I-MIBG scintigraphy/SPECT imaging and ¹⁸F-FDG PET in paediatric neuroblastoma patients.     

Endovascular Brachytherapy in the Femoropopliteal Segment Using <Superscript>192</Superscript>Ir and <Superscript>188</Superscript>Re

This report presents a review of the literature on endovascular brachytherapy (EVBT) after percutaneous transluminal angioplasty (PTA) in the femoropopliteal segment. We summarize the pathophysiological changes induced by PTA and EVBT within the vessel wall, technical considerations regarding various radiation sources and their application, the impact of stents on the radial dose profile, recommendations for dosimetry of beta and gamma sources, results of experimental and clinical trials, and the medication required before, during, and after EVBT. We aim to help to identify patients who are eligible for EVBT, to choose an appropriate technical approach, and to initiate adequate antiplatelet and anticoagulant therapy.     

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.     

Effect of the positron range of <Superscript>18</Superscript>F, <Superscript>68</Superscript>Ga and <Superscript>124</Superscript>I on PET/CT in lung-equivalent materials

Purpose  

The aim of this study was to investigate the effect of positron range on visualization and quantification in ¹⁸F, ⁶⁸Ga and ¹²⁴I positron emission tomography (PET)/CT of lung-like tissue.     

Impact of mediastinal,liver and lung <Superscript>123</Superscript>I-metaiodobenzylguanidine (<Superscript>123</Superscript>I-MIBG) washout on calculated <Superscript>123</Superscript>I-MIBG myocardial washout

Purpose  In planar ¹²³I-metaiodobenzylguanidine (¹²³I-MIBG) myocardial imaging mediastinum (M) activity is often used as a background correction in calculating “washout” (WO). However, the most likely sources for counts that might produce errors in estimating myocardial (Myo) activity are lung (Lu) and liver (Li), which typically have higher counts/pixel (cpp) than M. The present study investigated the relationship between changes in Lu, Li and Myo activity between early and late planar ¹²³I-MIBG images, with comparison to M as the best estimator of non-specific background activity. Methods  Studies on 98 subjects with both early (e) and late (l) planar ¹²³I-MIBG images were analysed. There were 68 subjects with chronic heart failure (CHF), 14 with hypertension (HTN) but no known heart disease and 16 controls (C). For each image, regions of interest (ROIs) were drawn: an irregular whole Myo, Lu, upper M and Li. For each ROI, WO was calculated as [(cpp(e)-cpp(l:decay corrected))/cpp(e)]×100%. Results   Multivariable forward stepwise regression analysis showed that overall a significant proportion of the variation in Myo WO could be explained by a model containing M WO and Lu WO (37%, p < 0.001). Only in controls was M WO the sole variable explaining a significant proportion of the variation in Myo WO (27%, p = 0.023). Conclusion  Although increased Myo WO in CHF subjects reflects disease severity, part of the count differences measured on planar ¹²³I-MIBG myocardial images likely reflects changes in the adjacent and surrounding Lu tissue. The results for the controls suggest that this is the only group where a mediastinum correction alone may be appropriate for cardiac WO calculations.     

Cholinergic PET imaging in infections and inflammation using <Superscript>11</Superscript>C-donepezil and <Superscript>18</Superscript>F-FEOBV

Introduction

Immune cells utilize acetylcholine as a paracrine-signaling molecule. Many white blood cells express components of the cholinergic signaling pathway, and these are up-regulated when immune cells are activated. However, in vivo molecular imaging of cholinergic signaling in the context of inflammation has not previously been investigated.

Methods

We performed positron emission tomography (PET) using the glucose analogue 18F-FDG, and 11C-donepezil and 18F-FEOBV, markers of acetylcholinesterase and the vesicular acetylcholine transporter, respectively. Mice were inoculated subcutaneously with Staphylococcus aureus, and PET scanned at 24, 72, 120, and 144 h post-inoculation. Four pigs with post-operative abscesses were also imaged. Finally, we present initial data from human patients with infections, inflammation, and renal and lung cancer.

Results

In mice, the FDG uptake in abscesses peaked at 24 h and remained stable. The 11C-donepezil and 18F-FEOBV uptake displayed progressive increase, and at 120–144 h was nearly at the FDG level. Moderate 11C-donepezil and slightly lower 18F-FEOBV uptake were seen in pig abscesses. PCR analyses suggested that the 11C-donepezil signal in inflammatory cells is derived from both acetylcholinesterase and sigma-1 receptors. In humans, very high 11C-donepezil uptake was seen in a lobar pneumonia and in peri-tumoral inflammation surrounding a non-small cell lung carcinoma, markedly superseding the 18F-FDG uptake in the inflammation. In a renal clear cell carcinoma no 11C-donepezil uptake was seen.

Discussion

The time course of cholinergic tracer accumulation in murine abscesses was considerably different from 18F-FDG, demonstrating in the 11C-donepezil and 18F-FEOBV image distinct aspects of immune modulation. Preliminary data in humans strongly suggest that 11C-donepezil can exhibit more intense accumulation than 18F-FDG at sites of chronic inflammation. Cholinergic PET imaging may therefore have potential applications for basic research into cholinergic mechanisms of immune modulation, but also clinical applications for diagnosing infections, inflammatory disorders, and cancer inflammation.

     

The potential of <Superscript>223</Superscript>Ra and <Superscript>18</Superscript>F-fluoride imaging to predict bone lesion response to treatment with <Superscript>223</Superscript>Ra-dichloride in castration-resistant prostate cancer

Purpose

The aims of this study were to calculate bone lesion absorbed doses resulting from a weight-based administration of ²²³Ra-dichloride, to assess the relationship between those doses and corresponding ¹⁸F-fluoride uptake and to assess the potential of quantitative ¹⁸F-fluoride imaging to predict response to treatment.

Methods

Five patients received two intravenous injections of ²²³Ra-dichloride, 6 weeks apart, at 110 kBq/kg whole-body weight. The biodistribution of ²²³Ra in metastatic lesions as a function of time after administration as well as associated lesion dosimetry were determined from serial ²²³Ra scans. PET/CT imaging using ¹⁸F-fluoride was performed prior to the first treatment (baseline), and at week 6 immediately before the second treatment and at week 12 after baseline.

Results

Absorbed doses to metastatic bone lesions ranged from 0.6 Gy to 44.1 Gy. For individual patients, there was an average factor difference of 5.3 (range 2.5–11.0) between the maximum and minimum lesion dose. A relationship between lesion-absorbed doses and serial changes in ¹⁸F-fluoride uptake was demonstrated (r² = 0.52). A log-linear relationship was demonstrated (r² = 0.77) between baseline measurements of ¹⁸F-fluoride uptake prior to ²²³Ra-dichloride therapy and changes in uptake 12 weeks after the first cycle of therapy. Correlations were also observed between both ²²³Ra and ¹⁸F-fluoride uptake in lesions (r = 0.75) as well as between ²²³Ra absorbed dose and ¹⁸F-fluoride uptake (r = 0.96).

Conclusions

There is both inter-patient and intra-patient heterogeneity of absorbed dose estimates to metastatic lesions. A relationship between ²²³Ra lesion absorbed dose and subsequent lesion response was observed. Analysis of this small group of patients suggests that baseline uptake of ¹⁸F-fluoride in bone metastases is significantly correlated with corresponding uptake of ²²³Ra, the associated ²²³Ra absorbed dose and subsequent lesion response to treatment.

     

Single-photon agents for tumor imaging:<Superscript>201</Superscript>TI,<Superscript>99m</Superscript>Tc-MIBI,and<Superscript>99m</Superscript>Tc-tetrofosmin

This review aims at fostering comprehension and knowledge not only for expert physicians who can skillfully handle various techniques for tumor imaging but also for young practitioners in the field of nuclear medicine. As image processing software and hardware become smaller, faster and better, SPECT will adapt and incorporate these advances. A principal advantage of SPECT over PET is the more widespread availability of the equipment and lower cost for the introduction of the system in community-based facilities. Moreover, SPECT has become less dependent on a limited number of acknowledged experts for its interpretation owing to a variety of handy computer tools for imaging analyses. The increasing use of PET in tumor imaging is not necessarily proportional to the decline of SPECT. General physicians' attention to SPECT technology would also increase more by evoking their interest in "tracer imaging."