Early response monitoring during [177Lu]Lu-PSMA I&T therapy with quantitated SPECT/CT predicts overall survival of mCRPC patients: subgroup analysis of a Swiss-wide prospective registry study.

PURPOSE: To assess early tumor response with quantitated SPECT/CT and to correlate it with clinical outcome in metastatic castration-resistant prostate cancer (mCRPC) patients treated with 177Lutetium-PSMA I&T therapy. METHODS: Single-center, observational study, part of the prospective Swiss national cancer registry study investigating the safety and efficacy of [177Lu]Lu-PSMA I&T (EKNZ: 2021-01271) in mCRPC patients treated with at least two cycles of [177Lu]Lu-PSMA I&T 6-weekly. After the first and second cycle quantitated SPECT/CT (Symbia Intevo, Siemens) was acquired 48 h after injection (three fields of view from head to thigh, 5 s/frame) and reconstructed using xQuant® (48i, 1 s, 10-mm Gauss). Image analysis: The PSMA-positive total tumor volumes (TTV) were semi-automatically delineated using a SUV threshold of 3 with MIMencore® (version 7.1.3, Medical Image Merge Software Inc.). Changes in TTV, highest tumor SUVmax, and total tumor SUVmean between cycles 1 and 2 were calculated and grouped into a) stable or decrease and b) increase. Serum PSA levels were assessed at each therapy cycle and at follow-up until progression or death. Changes in TTV, PSA, SUVmax, and SUVmean were correlated with PSA-progression-free survival (PSA-PFS) and the overall survival (OS) using the Kaplan-Meier methodology (log-rank test). RESULTS: Between 07/2020 and 04/2022, 111 patients were screened and 73 finally included in the data analysis. The median follow-up was 8.9 months (range 1.4-26.6 months). Stable or decreased TTV at cycle 2 was associated with longer OS (hazard ratio (HR) 0.28, 95% confidence interval (CI) 0.09-0.86, p < 0.01). Similar, stable, or decreased PSA was associated with longer OS (HR 0.21; CI 0.07-0.62, p < 0.01) and PSA-PFS (HR 0.34; 95% CI 0.16-0.72, p < 0.01). Combining TTV and PSA will result in an augmented prognostic value for OS (HR 0.09; CI 0.01-0.63; p < 0.01) and for PSA-PFS (HR 0.11; CI 0.02-0.68; p < 0.01). A reduction of SUVmax or SUVmean was not prognostically relevant, neither for OS (p 0.88 and 0.7) nor for PSA-PFS (p 0.73 and 0.62, respectively). CONCLUSION: Six weeks after initiating [177Lu]Lu-PSMA I&T, TTV and serum PSA appear to be good prognosticators for OS. Combined together, TTV + PSA change demonstrates augmented prognostic value and can better predict PSA-PFS. Larger studies using TTV change prospectively as an early-response biomarker are warranted for implementing management change towards a more personalized clinical practice.

Joint EANM/SNMMI procedure guideline for the use of 177Lu-labeled PSMA-targeted radioligand-therapy (177Lu-PSMA-RLT).

Prostate-specific membrane antigen (PSMA) is expressed by the majority of clinically significant prostate adenocarcinomas, and patients with target-positive disease can easily be identified by PSMA PET imaging. Promising results with PSMA-targeted radiopharmaceutical therapy have already been obtained in early-phase studies using various combinations of targeting molecules and radiolabels. Definitive evidence of the safety and efficacy of [177Lu]Lu-PSMA-617 in combination with standard-of-care has been demonstrated in patients with metastatic castration-resistant prostate cancer, whose disease had progressed after or during at least one taxane regimen and at least one novel androgen-axis drug. Preliminary data suggest that 177Lu-PSMA-radioligand therapy (RLT) also has high potential in additional clinical situations. Hence, the radiopharmaceuticals [177Lu]Lu-PSMA-617 and [177Lu]Lu-PSMA-I&T are currently being evaluated in ongoing phase 3 trials. The purpose of this guideline is to assist nuclear medicine personnel, to select patients with highest potential to benefit from 177Lu-PSMA-RLT, to perform the procedure in accordance with current best practice, and to prepare for possible side effects and their clinical management. We also provide expert advice, to identify those clinical situations which may justify the off-label use of [177Lu]Lu-PSMA-617 or other emerging ligands on an individual patient basis.

Variations in Radioiodine Therapy in Europe: Decision-Making after Total Thyroidectomy.

The role of radioiodine therapy (RIT) (used as ablation therapy or adjuvant therapy) following total thyroidectomy for differentiated thyroid cancer (DTC) changed. Major revisions of the American Thyroid Association (ATA) Guidelines in 2015 resulted in significant differences in treatment recommendations in comparison to the European Association of Nuclear Medicine (EANM) 2008 guidelines. Recently, we presented the effects on daily practice for RIT among Swiss Nuclear Medicine centres. We now performed a study at the European level and hypothesized that there is also considerable variability among European experts. We performed a decision-tree-based analysis of management strategies from all members of the EANM thyroid committee to map current practice among experts. We collected data on whether or not RIT is administered, on which criteria these decisions are based and collected details on treatment activities and patient preparation. Our study shows discrepancies for low-risk DTC, where "follow-up only" is recommended by some experts, while RIT with significant doses is used by other experts. E.g., for pT1b tumours without evidence of metastases, the level of agreement for the use of RIT is as low as 50%. If RIT is administered, activities of I-131 range from 1.1 GBq to 3.0 GBq. In other constellations (e.g., pT1a), experts diverge from current clinical guidelines as up to 75% administer RIT in certain cases. For intermediate and high-risk patients, RIT is generally recommended. However, dosing and treatment preparation (rhTSH vs. thyroid hormone withdrawal) vary distinctly. In comparison to the Swiss study, the general level of agreement is higher among the European experts. The recently proposed approach on the use of RIT, based on integrated post-surgery assessment (Martinique article) and results of ongoing prospective randomized studies are likely to reduce uncertainty in approaching RIT treatment. In certain constellations, consensus identified among European experts might be helpful in formulating future guidelines.

Early Prediction of Treatment Response of Neuroendocrine Hepatic Metastases after Peptide Receptor Radionuclide Therapy with 90Y-DOTATOC Using Diffusion Weighted and Dynamic Contrast-Enhanced MRI.

The purpose of this study was to determine if parameters derived from diffusion-weighted (DW-) and dynamic contrast-enhanced (DCE-) magnetic resonance imaging (MRI) can help to assess early response to peptide receptor radionuclide therapy (PRRT) with 90Y-DOTATOC in neuroendocrine hepatic metastases (NET-HM). Twenty patients (10 male; 10 female; mean age: 59.2 years) with NET-HM were prospectively enrolled in this single-center imaging study. DW-MRI and DCE-MRI studies were performed just before and 48 hours after therapy with 90Y-DOTATOC. Abdominal SPECT/CT was performed 24 hours after therapy. This MRI imaging and therapy session was repeated after a mean interval of 10 weeks. Up to four lesions per patient were evaluated. Response to therapy was evaluated using metastasis sizes at the first and second therapy session as standard for comparison (regressive, stable, and progressive). DW-MRI analysis included the apparent diffusion coefficient (ADC) and parameters related to intravoxel incoherent motion (IVIM), namely, diffusion (D), perfusion fraction (f) and pseudo-diffusion (D ∗ ). DCE-MRI analysis comprised Ktrans, v e and k ep. For statistical analysis of group differences, one-way analysis of variance (ANOVA) and appropriate post hoc testing was performed. A total of 51 lesions were evaluated. Seven of 51 lesions (14%) showed size progression, 18/51 (35%) regression, and 26/51 (51%) remained stable. The lesion-to-spleen uptake ratio in SPECT showed a decrease between the two treatment sessions that was significantly stronger in regressive lesions compared with stable (p = 0.013) and progressive lesions (p = 0.021). ANOVA showed significant differences in mean ADC after 48 h (p = 0.026), with higher ADC values for regressive lesions. Regarding IVIM, highest values for D at baseline were seen in regressive lesions (p = 0.023). In DCE-MRI, a statistically significant increase in v e after 10 weeks (p = 0.046) was found in regressive lesions. No differences were observed for the transfer constants Ktrans and k ep. Diffusion restriction quantified as ADC was able to differentiate regressive from progressive NET-HMs as early as 48 hours after PRRT. DW-MRI therefore may complement scintigraphy/SPECT for early assessment of response to PRRT. Assessment of perfusion parameters using IVIM and DCE-MRI did not show an additional benefit.

EANM procedure guidelines for radionuclide therapy with 177Lu-labelled PSMA-ligands (177Lu-PSMA-RLT).

Prostate-specific membrane antigen (PSMA) is expressed in most prostate cancers and can be identified by PSMA-ligand imaging, which has already become clinically accepted in several countries in- and outside Europe. PSMA-directed radioligand therapy (PSMA-RLT) with Lutetium-177 (177Lu-PSMA) is currently undergoing clinical validation. Retrospective observational data have documented favourable safety and striking clinical responses. Recent results from a prospective clinical trial (phase II) have been published confirming high response rates, low toxicity and reduction of pain in metastatic castration-resistant prostate cancer (mCRPC) patients who had progressed after conventional treatments. Such patients typically survive for periods less than 1.5 years. This has led some facilities to adopt compassionate or unproven use of this therapy, even in the absence of validation within a randomised-controlled trial. As a result, a consistent body of evidence exists to support efficacy and safety data of this treatment. The purpose of this guideline is to assist nuclear medicine specialists to deliver PSMA-RLT as an "unproven intervention in clinical practice", in accordance with the best currently available knowledge.

Myeloid neoplasms after chemotherapy and PRRT: myth and reality.

Peptide receptor radionuclide therapy (PRRT) with (90)Y-octreotide or (177)Lu-octreotate is an effective treatment for inoperable or metastatic neuroendocrine tumors (NETs), particularly well-differentiated gastroenteropancreatic or bronchopulmonary NETs. PRRT is generally extremely well tolerated, with modest toxicity to target organs, kidney and bone marrow. Nevertheless, a priori concerns regarding long-term effects lead clinicians such as Brieau and coworkers, in this ERC issue, to ascribe to the combination of alkylating agents and PRRT the apparently high occurrence (n=4) of myeloproliferative events (therapy-related myeloid neoplasms (t-MNs)) in a small cohort of 20 progressive, advanced digestive NETs treated with PRRT after chemotherapy. Anecdotal reports of myelotoxic events should be placed in the correct perspective of larger series, where the reported incidence of these events is ~2%, with the aim of promoting a balanced awareness of the issue and unbiased and reasonable overall conclusions. For a comprehensive definition of the issue, we provide an evaluation of the occurrence of t-MN in patients treated with various myelotoxic treatments.

Successful Medical Treatment of Adult Nesidioblastosis With Pasireotide over 3 Years: A Case Report.

Nesidioblastosis is a rare cause of endogenous hyperinsulinemic hypoglycemia in adults. Diagnosis is often challenging and therapeutic options are scarce.In 2009, a 46-year-old female patient presented with recurrent severe hypoglycemia and immediate recovery after glucose ingestion. Although 72-h-fasting test was positive, various imaging technologies (sonography, computed tomography, somatostatin receptor scintigraphy, dopamine receptor positron emission tomography [DOPA-PET]) were negative. Endoscopic ultrasound revealed a lesion in the pancreatic corpus, whereas selective arterial calcium stimulation test, portal venous sampling and GLP-1-receptor scintigraphy were indicative of a lesion in the pancreatic tail, which was surgically removed. The histopathologic examination revealed beta cell hyperplasia and microadenomas expressing glucagon. After surgery, the patient was free of symptoms for 6 months, after which hypoglycemic episodes recurred. After unsuccessful treatment with corticosteroids and somatostatin analogs, treatment with pasireotide, a novel somatostatin analog with high affinity to somatostatin receptor 5 and a possible side effect of hyperglycemia, was initiated (0.6 mg BID). To date, our patient has been free of severe hypoglycemic episodes ever since. Yearly repeated imaging procedures have shown no abnormities over the last 3 years.We report for the first time that pasireotide was successfully used in the treatment of adult nesidioblastosis.

90Y-DOTATOC as a Therapeutic Option for Complex Recurrent or Progressive Meningiomas.

UNLABELLED: The standard treatment of meningiomas is surgery or radiotherapy. Complex, especially recurrent or progressive cases, may exhibit tumor growth involving critical neurovascular structures or diffuse growth, resulting in limited efficacy and higher risk of standard treatment. We evaluated whether somatostatin receptor-targeted radionuclide therapy with (90)Y-DOTATOC may be a therapeutic option. METHODS: Fifteen patients with recurrent or progressive meningiomas after multimodal pretreatment or unfavorable medical risk profile were treated with systemic (90)Y-DOTATOC. Endpoints were progression-free survival and toxicity. RESULTS: Usually applied doses were 7,400 MBq/m(2) of (90)Y-DOTATOC in 2 fractions. Mean observation time was 49.7 mo (range, 12-137 mo). Overall median progression-free survival was at least 24 mo. Toxicity was moderate, mostly hematologic (n = 8) and transient. CONCLUSION: (90)Y-DOTATOC therapy is feasible and may represent a promising second- or third-line option for complex meningiomas, which are progressive or otherwise not treatable with a reasonable risk-benefit ratio.

4D-SPECT/CT in orthopaedics: a new method of combined quantitative volumetric 3D analysis of SPECT/CT tracer uptake and component position measurements in patients after total knee arthroplasty.

OBJECTIVE: The purpose was to evaluate the intra- and inter-observer reliability of combined quantitative 3D-volumetric single-photon emission computed tomography (SPECT)/CT analysis including size, intensity and localisation of tracer uptake regions and total knee arthroplasty (TKA) position. MATERIALS AND METHODS: Tc-99m-HDP-SPECT/CT of 100 knees after TKA were prospectively analysed. The anatomical areas represented by a previously validated localisation scheme were 3D-volumetrically analysed. The maximum intensity was recorded for each anatomical area. Ratios between the respective value and the mid-shaft of the femur as the reference were calculated. Femoral and tibial TKA position (varus-valgus, flexion-extension, internal rotation- external rotation) were determined on 3D-CT. Two consultant radiologists/nuclear medicine physicians interpreted the SPECT/CTs twice with a 2-week interval. The inter- and intra-observer reliability was determined (ICCs). Kappa values were calculated for the area with the highest tracer uptake between the observers. RESULTS: The measurements of tracer uptake intensity showed excellent inter- and intra-observer reliabilities for all regions (tibia, femur and patella). Only the tibial shaft area showed ICCs <0.89. The kappa values were almost perfect (0.856, p < 0.001; 95 % CI 0.778, 0.922). For measurements of the TKA position, there was strong agreement within and between the readings of the two observers; the ICCs for the orientation of TKA components for inter- and intra-observer reliability were nearly perfect (ICCs >0.84). CONCLUSION: This combined 3D-volumetric standardised method of analysing the location, size and the intensity of SPECT/CT tracer uptake regions ("hotspots") and the determination of the TKA position was highly reliable and represents a novel promising approach to biomechanics.

Radioimmunotherapy with 177Lu-DOTA-rituximab: final results of a phase I/II Study in 31 patients with relapsing follicular, mantle cell, and other indolent B-cell lymphomas.

UNLABELLED: The aim of this study was to determine the maximum tolerated dose (MTD) and to explore the clinical response to (177)Lu-DOTA-rituximab in the treatment of patients with relapsed follicular, mantle cell, or other indolent lymphomas such as marginal zone lymphoma. METHODS: To evaluate the MTD, we adjusted the dosage of the radiopharmaceutical according to body surface area (BSA). RESULTS: The MTD using (177)Lu-DOTA-rituximab was 1,665 MBq/m(2) of BSA. Thrombocytopenia and leukopenia were the dose-limiting toxicities. Significant anemia occurred only at dose level 7 (1,850 MBq/m(2) of BSA). We observed the nadir of platelets after a median of 36 d from treatment and the nadir of granulocytes after a median of 50 d. Median time to recovery to the next lower grade of toxicity was 7 d. Nonhematologic toxicity was negligible. We observed clinical responses at all dose levels and for all lymphoma entities. Some of the responses were durable; the longest follow-up is currently over 8 y. At present, 11 patients are alive and 8 patients are disease-free. CONCLUSION: Our results demonstrate the safety and feasibility of (177)Lu-DOTA-rituximab treatment for the lymphoma entities tested in this study.

Glucagon-like peptide-1 receptor imaging for the localisation of insulinomas: a prospective multicentre imaging study.

BACKGROUND: Small benign insulinomas are hard to localise, leading to difficulties in planning of surgical interventions. We aimed to prospectively assess the insulinoma detection rate of single-photon emission CT in combination with CT (SPECT/CT) with a glucagon-like peptide-1 receptor avid radiotracer, and compare detection rates with conventional CT/MRI techniques. METHODS: In our prospective imaging study, we enrolled adults aged 25-81 years at centres in Germany, Switzerland, and the UK. Eligible patients had proven clinical and biochemical endogenous hyperinsulinaemic hypoglycaemia and no evidence for metastatic disease on conventional imaging. CT/MRI imaging was done at referring centres according to standard protocols. At three tertiary nuclear medicine centres, we used whole body planar images and SPECT/CT of the abdomen up to 168 h after injection of (111)In-[Lys40(Ahx-DTPA-(111)In)NH2]-exendin-4 ((111)In-DTPA-exendin-4) to identify insulinomas. Consenting patients underwent surgery and imaging findings were confirmed histologically. FINDINGS: Between Oct 1, 2008, and Dec 31, 2011, we recruited 30 patients. All patients underwent (111)In-DTPA-exendin-4 imaging, 25 patients underwent surgery (with histological analysis), and 27 patients were assessed with CT/MRI. (111)In-DTPA-exendin-4 SPECT/CT correctly detected 19 insulinomas and four additional positive lesions (two islet-cell hyperplasia and two uncharacterised lesions) resulting in a positive predictive value of 83% (95% CI 62-94). One true negative (islet-cell hyperplasia) and one false negative (malignant insulinoma) result was identified in separate patients by (111)In-DTPA-exendin-4 SPECT/CT. Seven patients (23%) were referred to surgery on the basis of (111)In-DTPA-exendin-4 imaging alone. For 23 assessable patients, (111)In-DTPA-exendin-4 SPECT/CT had a higher sensitivity (95% [95% CI 74-100]) than did CT/MRI (47% [27-68]; p=0.011). INTERPRETATION: (111)In-DTPA-exendin-4 SPECT/CT could provide a good second-line imaging strategy for patients with negative results on initial imaging with CT/MRI. FUNDING: Oncosuisse, the Swiss National Science Foundation, and UK Department of Health.

Preoperative staging of non-small-cell lung cancer: comparison of whole-body diffusion-weighted magnetic resonance imaging and 18F-fluorodeoxyglucose-positron emission tomography/computed tomography.

OBJECTIVE: To investigate the diagnostic value of whole-body magnetic resonance imaging (MRI) including diffusion-weighted imaging with background signal suppression (DWIBS) for preoperative assessment of non-small-cell lung cancer (NSCLC) in comparison to (18)F-fluorodeoxyglucose (18)FDG) positron emission tomography/computed tomography (PET/CT). METHODS: Thirty-three patients with suspected NSCLC were enrolled. Patients were examined before surgery with PET/CT and whole-body MRI including T1-weighted turbo spin echo (TSE), T2-weighted short tau inversion recovery (STIR) and DWIBS sequences (b = 0/800). Histological or cytological specimens were taken as standard of reference. RESULTS: Whole-body MRI with DWIBS as well as PET/CT provided diagnostic image quality in all cases. Sensitivity for primary tumour detection: MRI 93%, PET/CT 98%. T-staging accuracy: MRI 63%, PET/CT 56%. N-staging accuracy: MRI 66%, PET/CT 71%. UICC staging accuracy: MRI 66%, PET/CT 74%. Sensitivity for metastatic involvement of individual lymph node groups: MRI 44%, PET/CT 47%. Specificity for individual non-metastatic lymph node groups: MRI 93%, PET/CT 96%. Assessment accuracy for individual lymph node groups: MRI 85%, PET/CT 88%. Observer agreement rate for UICC staging: MRI 74%, PET/CT 90%. CONCLUSION: Whole-body MRI with DWIBS provides comparable results to PET/CT in staging of NSCLC, but shows no superiority. Most relevant challenges for both techniques are T-staging accuracy and sensitivity for metastatic lymph node involvement. KEY POINTS: Numerous radiological methods are available for the crucial staging of lung cancer. Whole-body DWIBS MRI provides comparable results to PET/CT in NSCLC staging. No evident superiority of whole-body DWIBS over PET/CT in NSCLC staging. Challenges for both techniques are T-staging and detection of small metastases.

Peptide receptor radionuclide therapy with somatostatin analogues in neuroendocrine tumors.

Neuroendocrine tumors (NETs) are rare tumors with variable malignant behavior. The majority of NETs express increased levels of somatostatin (SST) receptors, particularly SST2 receptors. Radiolabeled peptides specific for the SST2 receptors may be used for diagnosis of NETs and for peptide receptor radionuclide therapy (PRRT). [(111)In-DTPA(0)]-octreotide has been the first peptide used for PRRT. This radiolabeled peptide, emitting Auger electrons, often induced symptomatic relief, but objective morphological responses were rarely documented. After the introduction of the chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) other peptides, primarily [DOTA(0),Tyr(3)]octreotate (DOTATATE) and [DOTA(0),Tyr(3)]octreotide (DOTATOC) were labeled with (90)Y or (177)Lu and used for therapy applications. The rate of objective response obtained with these radiolabeled peptides ranges between 6% and 46%, owing to differences in inclusion criteria adopted in different studies, length and type of therapy, and criteria of evaluation of the response. The present data in the literature do not allow defining the most suitable peptide and radionuclide for the treatment of NETs. Instead emerging evidence indicates that a combination of nuclides with different physical characteristics might be more effective than the use of a single nuclide. Kidney and bone marrow toxicity are the limiting factors for PRRT. Mild toxicity is often encountered while severe toxicity is rarer. Toxicity could be reduced and therapeutic efficacy enhanced by patient-specific dosimetry. Future directions include different issues of PRRT, such as defining the most suitable treatment scheme, evaluation of new peptides with different affinity profiles to other SST receptor subtypes, and reduction of toxicity.

Radiopeptide imaging and therapy in Europe.

Receptor targeting with radiolabeled peptides has become an important topic, particularly in nuclear oncology. Strong research efforts are under way in radiopharmaceutical science laboratories and in nuclear medicine departments in Europe. The target receptors belong to the large family of G-protein-coupled receptors. The prototypes of these radiopeptides are based on analogs of somatostatin targeting somatostatin receptor-positive tumors, particularly well-differentiated neuroendocrine tumors. These radiopeptides have an important impact not only on diagnosis but also on targeted radionuclide therapy of these tumors. Besides the registered radiopeptide (111)In-pentetreotide, efficient SPECT tracers labeled with (99m)Tc and PET agents based on generator-produced (68)Ga have been developed and used in the clinic. In parallel to the development of diagnostic agents, radiopeptides labeled with the ß(-) emitters (90)Y and (177)Lu are also widely used. Because the same chelators and therefore the same conjugates can be used in diagnosis and therapy, they constitute ideal theranostic pairs. This progress is driven not only by scientists and clinicians but also by patient interest groups. New radiopeptides targeting other G-protein-coupled receptors are entering the clinic, among them glucagon-like peptide 1 receptor-targeting molecules. This receptor is overexpressed on literally all benign insulinomas. (111)In-labeled derivatives of the insulinotropic 39-mer peptide exendin-4 were beneficial in the pre- and perioperative localization of these benign lesions. In contrast, lack of localization may indicate malignant insulinoma. The bombesin- and gastrin-releasing peptide receptor family is potentially important because these receptors are overexpressed on major human tumors such as prostate tumors, breast tumors, gastrointestinal stromal tumors, and vessels of ovarian cancer. (99m)Tc-labeled peptides for SPECT and (68)Ga-, as well as (64)Cu-labeled agonists or antagonists, have been studied in breast tumors, prostate tumors, gastrointestinal stromal tumors, and gliomas with considerable success. A phase I therapeutic study with a (177)Lu-labeled agonist has been completed. There are not enough clinical data available to reveal the significance of these new modalities in patient care, but several phase I studies are under way in larger patient cohorts using PET agents. Another G-protein-coupled receptor with high overexpression on human tumors is the gastrin/cholecystokinin-2 receptor. It is overexpressed in more than 90% of cases of medullary thyroid cancer, in small cell lung cancer, and in a subgroup of neuroendocrine tumors. Correlating with in vitro receptor localization using autoradiography of 27 patients with metastasized medullary thyroid cancer, SPECT or planar imaging of these patients resulted in a 95% sensitivity of tumor localization. Finally, another G-protein-coupled receptor is found in brain tumors and peritumoral vessels. Literally all cases of glioblastoma multiforme overexpress the neurokinin type 1 receptor; the natural ligand is substance P, which was metabolically stabilized, labeled with (90)Y and (213)Bi, and injected into resection cavities or directly into tumors, which were critically located via a catheter system. The major advantage of this approach appeared to be the facilitated resectability of tumors, particularly in those patients who had been treated up front with the locoregional approach. It appears that neoadjuvant treatment before resection is a valid concept. Finally, another peptide family, the arginine-glycine-aspartate-based radiotracers, has made it to the clinic labeled with a variety of radioisotopes for monitoring the integrins α(v)ß(3) overexpressed during tumor angiogenesis.

Bombesin antagonist-based radioligands for translational nuclear imaging of gastrin-releasing peptide receptor-positive tumors.

UNLABELLED: Bombesin receptors are overexpressed on a variety of human tumors. In particular, the gastrin-releasing peptide receptor (GRPr) has been identified on prostate and breast cancers and on gastrointestinal stromal tumors. The current study aims at developing clinically translatable bombesin antagonist-based radioligands for SPECT and PET of GRPr-positive tumors. METHODS: A potent bombesin antagonist (PEG(4)-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH(2) [AR]) was synthesized; conjugated to the chelators DOTA, 6-carboxy-1,4,7,11-tetraazaundecane (N4), 1,4,7-triazacyclononane, 1-glutaric acid-4,7 acetic acid (NODAGA), and 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (CB-TE2A); and radiolabeled with (111)In, (99m)Tc, (68)Ga, and (64)Cu, respectively. The radioconjugates were evaluated in vitro and in vivo in PC-3 tumor-bearing nude mice. Antagonist potency was determined by Ca(2+)-flux measurements and immunofluorescence. RESULTS: All the conjugates showed high binding affinity to GRPr (inhibitory concentration of 50% [IC(50)], 2.5-25 nmol/L). The immunofluorescence and Ca(2+)-flux assays confirmed the antagonist properties of the conjugates. Biodistribution revealed high and specific uptake in PC-3 tumor and in GRPr-positive tissues. Tumor uptake of (64)Cu-CB-TE2A-AR (31.02 ± 3.35 percentage injected activity per gram [%IA/g]) was higher than (99m)Tc-N4-AR (24.98 ± 5.22 %IA/g), (111)In-DOTA-AR (10.56 ± 0.70 %IA/g), and (68)Ga-NODAGA-AR (7.11 ± 3.26 %IA/g) at 1 h after injection. Biodistribution at later time points showed high tumor-to-background ratios because of the fast washout of the radioligand from normal organs, compared with tumor. High tumor-to-background ratios were further illustrated by PET and SPECT images of PC-3 tumor-bearing nude mice acquired at 12 h after injection showing high tumor uptake, clear background, and negligible or no radioactivity in the abdomen. CONCLUSION: The chelators do influence the affinity, antagonistic potency, and pharmacokinetics of the conjugates. The promising preclinical results warrant clinical translation of these probes for SPECT and PET.

Glucagon-like peptide-1 versus somatostatin receptor targeting reveals 2 distinct forms of malignant insulinomas.

UNLABELLED: Glucagon-like peptide-1 (GLP-1) receptor imaging is superior to somatostatin receptor subtype 2 (sst(2)) imaging in localizing benign insulinomas. Here, the role of GLP-1 and sst(2) receptor imaging in the management of malignant insulinoma patients was investigated. METHODS: Eleven patients with malignant insulinoma were prospectively included. (111)In-[Lys(40)(Ahx-diethylenetriaminepentaacetic acid [DTPA])NH(2)]-exendin-4 SPECT/CT, (68)Ga- DOTATATE PET/CT, and in vitro receptor autoradiography were performed to assess the receptor status and to evaluate the detection rate. RESULTS: GLP-1 receptor targeting was positive in 4 of 11 patients, and sst(2) receptor expression was positive in 8 of 11. In only 1 patient were both receptors expressed. In 1 patient, GLP-1 receptor imaging was the only method that successfully localized the primary tumor in the pancreas. In 3 patients with sst(2)-expressing tumors, DOTATATE radiotherapy was effectively applied. CONCLUSION: As opposed to benign insulinomas, malignant insulinomas often lack GLP-1 receptors. Conversely, malignant insulinomas often express sst(2), which can be targeted therapeutically.

Effect of amino acid infusion on potassium serum levels in neuroendocrine tumour patients treated with targeted radiopeptide therapy.

PURPOSE: Administration of positively charged amino acids has been introduced to reduce the nephrotoxicity of targeted radiopeptide therapy (TRT). However, the amino acid solution may have side effects, including hyperkalaemia. The aim of this study was to evaluate the frequency and the magnitude of hyperkalaemia in neuroendocrine tumour (NET) patients undergoing TRT. METHODS: Enrolled in the study were 31 patients with NET eligible for TRT with [(90)Y-DOTA(0),Tyr(3)]octreotide ((90)Y-DOTATOC). Their mean age was 54 ± 14 years. Of these 31 patients, 21 (67%) were referred for the first treatment cycle, while 10 (33%) were referred for a subsequent therapy cycle. Patients were treated with therapeutic doses of (90)Y-DOTATOC ranging from 7,030 to 35,520 MBq. To inhibit tubular reabsorption of (90)Y-DOTATOC, 1 l of physiological saline solution containing 25 g of arginine hydrochloride and 25 g of lysine hydrochloride was given over 4 h starting 1 h before (90)Y-DOTATOC injection. All patients underwent a standard biochemical blood analysis at baseline, and 4 h and 24 h after the beginning of the amino acid infusion. RESULTS: ANOVA repeated measures showed a significant overall effect on K(+) levels over time (F = 118.2, df = 2, P < 0.0001). Mean serum levels of K(+) were 4.00 ± 0.33 mmol/l at baseline, 5.47 ± 0.57 mmol/l at 4 h, and 4.38 ± 0.63 mmol/l at 24 h after the beginning of the infusion. Post-hoc analysis showed that K(+) levels at 4 h were significantly (P < 0.05) higher than at baseline. K(+) levels at 24 h were significantly (P < 0.05) lower than at 4 h but they were still significantly (P < 0.05) higher than K(+) levels at baseline. On a subject-by-subject basis, none of the 31 patients had increased K(+) levels at baseline. At 4 h, 24 of the 31 patients (77%) had K(+) levels above the normal range, and 6 patients (19%) experienced severe hyperkalaemia (K(+) ≥ 6 mmol/l). All patients with increased K(+) levels were clinically asymptomatic. At 24 h, only 4 patients (13%) had increased K(+) serum levels. The magnitude of the increase in K(+) levels between baseline and 4 h was relatively homogeneous over the whole group (1.41 ± 0.50 mmol/l) and it was not related (linear regression, P>0.05) to baseline K(+) levels. Intravenous administration of 40 mg furosemide 1 h after the beginning of the amino acid infusion did not have a significant effect on K(+) levels (P>0.05). No clinical characteristic was predictive for the increase in K(+) levels (chi-squared test, P > 0.05). CONCLUSION: Hyperkalaemia is a frequent, potentially life-threatening side effect of basic amino acid infusion during TRT. K(+) levels 4 h after the beginning of the infusion should be monitored in patients at risk of complications, such as those with heart disease and those with risk factors for nephrotoxicity.