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PDF file - 45K, SUV in tumors normalized to body weight.

PDF file - 61K, SUV in tumors, average and maximum.

Purpose: This study sought to evaluate the reproducibility of [11C]choline-positron emission tomography and the effect of trastuzumab in breast cancer.Experimental Design: Twenty-one patients with newly diagnosed and recurrent breast cancer stage II-IV had a baseline dynamic [11C]choline-PET scan, 10 patients had a second [11C]choline-PET scan to examine reproducibility, and 6 patients had a second scan within a month after trastuzumab. Analysis of [11C]choline uptake was measured as the semiquantitative standardized uptake value at 30 and 60 minutes (SUV30 and SUV60), and quantitatively as the net irreversible retention of the radiotracer at steady-state (Ki) and plasma to tissue exchange at 60 minutes (IRF60min).Results: Breast tumor lesions in all patients were visualized by [11C]choline PET. The difference in tumor versus normal tissue uptake was significant for SUV30, SUV60, Ki, and IRF60 minutes (Wilcoxon P < 0.0001). At 60 minutes postinjection, 15.1 ± 2.16% of plasma radioactivity was due to unmetabolized [11C]choline radioactivity. [11C]Choline uptake was reproducible in breast tumor lesions (r2 = 0.9 for SUV, 0.9 for Ki, and 0.8 for IRF60). Early responses to trastuzumab measured by [11C]choline-PET were significant in three lesions occurring in two patients who responded clinically.Conclusions: [11C]Choline-PET uptake variables can be reproducibly assessed. Initial studies show that trastuzumab decreases [11C]choline uptake. Clin Cancer Res; 16(16); 4236–45. ©2010 AACR.

Supplementary Data from Altered Tissue 3′-Deoxy-3′-[18F]Fluorothymidine Pharmacokinetics in Human Breast Cancer following Capecitabine Treatment Detected by Positron Emission Tomography

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Purpose: To evaluate the accuracy and biological basis for [11C]choline-PET-CT in the nodal staging of high risk localized prostate cancer patients.Experimental Design: Twenty-eight patients underwent dynamic [11C]choline-PET-CT of the pelvis and lower abdomen prior to extended laparoscopic pelvic lymph node dissection (eLPL). The sensitivity and specificity of [11C]choline PET, [11C]choline PET-CT, and MRI for nodal detection were calculated. Average and maximal standardized uptake values (SUVave, SUVmax) were compared with choline kinase alpha (CHKα) and Ki67 immunohistochemistry scores.Results: Four hundred and six lymph nodes (LN), in 26 patients, were assessable. Twenty-seven (6.7%) involved pelvic nodes at eLPL were detected in 9 patients. Seventeen of the 27 involved nodes were subcentimeter. The sensitivity and specificity on a per nodal basis were 18.5% and 98.7%, 40.7% and 98.4%, and 51.9% and 98.4% for MRI, [11C]choline PET, and [11C]choline PET-CT, respectively. Sensitivity was higher for [11C]choline PET-CT compared with MRI (P = 0.007). A higher nodal detection rate, including subcentimeter nodes, was seen with [11C]choline PET-CT than MRI. Malignant lesions showed CHKα expression in both cytoplasm and nucleus. SUVave and SUVmax strongly correlated with CHKα staining intensity (r = 0.68, P < 0.0001 and r = 0.63, P = 0.0004, respectively). In contrast, Ki67 expression was generally low in all tumors.Conclusion: This study establishes the relationship between [11C]choline PET-CT uptake with choline kinase expression in prostate cancer and allows it to be used as a noninvasive means of staging pelvic LNs, being highly specific and more sensitive than MRI, including the detection of subcentimeter disease. Clin Cancer Res; 17(24); 7673–83. ©2011 AACR.

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Purpose: To establish biomarkers indicating clinical response to taxanes, we determined whether early changes in [18F]-3′deoxy-3′-fluorothymidine positron emission tomography (FLT-PET) can predict benefit from docetaxel therapy in breast cancer.Experimental Design: This was a prospective unblinded study in 20 patients with American Joint Committee on Cancer (AJCC) stage II–IV breast cancer unresponsive to first-line chemotherapy or progressing on previous therapy. Individuals underwent a baseline dynamic FLT-PET scan followed by a scan 2 weeks after initiating the first or second cycle of docetaxel. PET variables were compared with anatomic response midtherapy (after 3 cycles).Results: Average and maximum tumor standardized uptake values at 60 minutes (SUV60,av and SUV60,max) normalized to body surface area ranged between 1.7 and 17.0 and 5.6 and 26.9 × 10−5 m2/mL, respectively. Docetaxel treatment resulted in a significant decrease in FLT uptake (P = 0.0003 for SUV60,av and P = 0.0002 for SUV60,max). Reduction in tumor SUV60,av was associated with target lesion size changes midtherapy (Pearson R for SUV60,av = 0.64; P = 0.004) and predicted midtherapy target lesion response (0.85 sensitivity and 0.80 specificity). Decreases in SUV60,av in responders were due, at least in part, to reduced net intracellular trapping of FLT (rate constant, Ki). Docetaxel significantly reduced Ki by 51.1% (±28.4%, P = 0.0009).Conclusion: Changes in tumor proliferation assessed by FLT-PET early after initiating docetaxel chemotherapy can predict lesion response midtherapy with good sensitivity warranting prospective trials to assess the ability to stop therapy in the event of non–FLT-PET response. Clin Cancer Res; 17(24); 7664–72. ©2011 AACR.

PDF file - 46K, Changes in FLT SUV after 1 and 2 cycles of docetaxel.

Purpose: We showed in preclinical models that thymidylate synthase (TS) inhibition leads to redistribution of the nucleoside transporter, ENT1, to the cell membrane and hence increases tissue uptake of [18F]fluorothymidine (FLT). In this study, we assessed for the first time the altered pharmacokinetics of FLT in patients following administration of capecitabine, a drug whose mode of action has been reported to include TS inhibition.Experimental Design: We analyzed 10 lesions from six patients with breast cancer by positron emission tomography before and after treatment with capecitabine. Although drug treatment did not alter tumor delivery pharmacokinetic variables (K1 and permeability product surface area) or blood flow, tumor FLT retention variables increased with drug treatment in all but one patient.Results: The baseline average standardized uptake value at 60 minutes, rate constant for the net irreversible transfer of radiotracer from plasma to tumor (Ki), and unit impulse response function at 60 minutes were 11.11 × 10−5 m2/mL, 4.38 × 10−2 mL plasma/min/mL tissue, and 4.93 × 10−2/min, respectively. One hour after capecitabine administration, the standardized uptake value was 13.55 × 10−5 m2/mL (P = 0.004), Ki 7.40 × 10−2 mL plasma/min/mL tissue (P = 0.004), and impulse response function was 7.40 × 10−2/min (P = 0.002). FLT pharmacokinetics did not change in normal tissues, suggesting that the effect was largely restricted to tumors (P = 0.55).Conclusions: We have identified FLT positron emission tomography retention parameters that could be used in future early clinical studies to measure the pharmacodynamics of TS inhibitors, as well as for identifying patients who are unlikely to benefit from TS inhibition. (Clin Cancer Res 2009;15(21):6649–57)

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Supplementary Figures S1-S2 and Supplementary Table S1.

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Rationale: Neuroendocrine neoplasia (NEN) of small bowel (SBNEN) frequently present with metastatic disease. Theranostics (molecular imaging followed by targeting therapy) allow for personalised medicine. Liquid biopsies enable precise identification of residual disease and real-time monitoring of therapeutic response. Our aim was to determine the clinical utility of a combination of surgery, theranostics, and a multigene blood measurement in metastasised SBNEN. Methods: Inclusion criteria were SBNEN, G1/G2 NEN, initial tumour diagnosis, stage IV NEN, positivity on 68Ga somatostatin analogue PET/CT, eligible for surgery, and 177Lu peptide receptor radionuclide therapy (PRRT). Blood samples for NETest were collected longitudinally. Progression-free survival (PFS) and overall survival (OS) were calculated. NETest results were assessed prior to surgery and during clinical follow-up. Results: A surgical cohort of 39 SBNEN patients met eligibility criteria. Thirty-two patients underwent ileal resection and 7 right hemicolectomy. The mean number of 177Lu PRRT cycles was 4. Mortality was nil. Surgical morbidity was 10.3%. Transient grade 1/2 toxicity occurred in 41% (PRRT). NETest scores (n=9 patients) decreased in 100% following treatment and correlated with diminished tumour volume and disease stabilization following surgery and PRRT. Median follow-up: 78 months. Median PFS and OS: 42.7 and 110 months, respectively. Progression-free survival at 1-, 3-, and 5-years was 79.4%, 57.1% and 40.5%, respectively. Overall survival at 1-, 3-, and 5-years was 97.4%, 97.4%, and 94.1%, respectively. Conclusions: Surgery combined with 177Lu PRRT is safe and provides favourable PFS and OS in selected patients with advanced SBNEN. Liquid biopsy (NETest) has the potential to accurately delineate disease status.

Purpose: The spatio-molecular distribution of choline and its metabolites in tumors is highly heterogeneous. Due to regulation of choline metabolism by hypoxic transcriptional signaling and other survival factors, we envisage that detection of such heterogeneity in patient tumors could provide the basis for advanced localized therapy. However, non-invasive methods to assess this phenomenon in patients are limited. We investigated such heterogeneity in Non-Small Cell Lung Cancer (NSCLC) with [18F]fluoromethyl-(1,2-2H4) choline ([18F]D4-FCH) and positron emission tomography/computed tomography (PET/CT). Experimental design: [18F]D4-FCH (300.5±72.9MBq [147.60-363.6MBq]) was administered intravenously to 17 newly diagnosed NSCLC patients. PET/CT scans were acquired concurrently with radioactive blood sampling to permit mathematical modelling of blood-tissue transcellular rate constants. Comparisons were made with biopsy-derived choline kinase-α (CHKα) expression and diagnostic [18F]fluorodeoxyglucose ([18F]FDG) scans. Results: Oxidation of [18F]D4-FCH to [18F]D4-fluorobetaine was suppressed (48.58±0.31% parent at 60 min) likely due to the deuterium isotope effect embodied within the design of the radiotracer. Early (5 min) and late (60 min) images showed specific uptake of tracer in all 51 lesions (tumors, lymph nodes and metastases) from 17 patients analyzed. [18F]D4-FCH-derived uptake (SUV60max) in index primary lesions (n=17) ranged between 2.87-10.13; lower than that of [18F]FDG PET [6.89-22.64]. Mathematical modelling demonstrated net irreversible uptake of [18F]D4-FCH at steady-state, and parametric mapping of the entire tumor showed large intratumorally heterogeneity in radiotracer retention, which is likely to have influenced correlations with biopsy-derived CHKα expression. Conclusions: [18F]D4-FCH is detectable in NSCLC with large intratumorally heterogeneity, which could be exploited in the future for targeting localized therapy.

Peptide receptor radionuclide therapy (PRRT) has been one of the most successful and exciting examples of theranostics in nuclear medicine in recent decades and is now firmly embedded in many treatment algorithms for unresectable or metastatic neuroendocrine neoplasms (NENs) worldwide. It is widely considered to be an effective treatment for well- or moderately differentiated neoplasms, which express high levels of somatostatin receptors that can be selectively targeted. This review article outlines the scientific basis of PRRT in treatment of NENs and describes its discovery dating back to the early 1990s. Early treatments utilizing Indium-111, a γ-emitter, showed promise in reduction in tumor size and improvement in biochemistry, but were also met with high radiation doses and myelotoxic and nephrotoxic effects. Subsequently, stable conjugation of DOTA-peptides with β-emitting radionuclides, such as Yttrium-90 and Lutetium-177, served as a breakthrough for PRRT and studies highlighted their potential in eliciting progression-free survival and quality of life benefits. This article will also elaborate on the key trials which paved the way for its approval and will discuss therapeutic considerations, such as patient selection and administration technique, to optimize its use.

Purpose [177Lu]DOTATATE prolongs progression free survival (PFS) in metastatic neuroendocrine tumours (NETs). However, objective response rate is low. This, coupled with long duration of therapy and expense suggest need for better selection. We aim to assess whether baseline [68Ga]DOTATATE-PET/CT parameters, and whether response assessment by PET accurately predicts clinical outcome to [177Lu]DOTATATE. Experimental design Retrospective study of patients receiving [177Lu]DOTATATE was conducted. Patients were followed 3-monthly until disease progression. Four [68Ga]DOTATATE-PET parameters (single lesion SUVmax, tumour to spleen and liver SUV ratios, and SUVmax-av using up to five target lesions in multiple organ sites) were determined at baseline and follow-up. The association between these PET parameters either at baseline, or any changes following treatment, and PET response criteria (PERCIST and modified PERCIST) to predict PFS were determined. Patients were followed 3-monthly until disease progression. Response was determined using RECIST 1.1. Baseline SSTR2 expression was assessed and compared with PET parameters. Results 55 patients with metastatic NETs were identified predominantly small bowel (N = 18) and pancreatic (N = 8) in origin. 16 were low grade, 15 intermediate and 3 high grade. Response to PRRT (N = 47): partial response (PR) 28%, stable disease (SD) 60% progressive disease (PD) 13%. Response to PRRT predicted PFS: PR 71.8 months (95%CI: not achieved), SD 29.1 months (95%CI: 15.2–43.1), and PD 9.7 months (95%CI: 0–21.02). Baseline, single lesion SUVmax predicted both response and PFS with SUV cut-off of 13.0 giving high sensitivity and specificity. Tumoural SUVmax correlated with SSTR2 expression, Spearman’s rho – 0.69, p Conclusions Baseline single lesion SUVmax and SUVmax-av predicts response to [177Lu]DOTATATE. Objective response following PRRT defines a subset of patients with markedly improved PFSBaseline SUVmax 13.0 defines a threshold below which patients have poor response to PRRT and worse PFS. SUV threshold analysis should be taken forward into prospective studies.

Background: The incidence of pancreatic Neuroendocrine Tumours (pNETs) has increased considerably in the last few decades. The characteristic features of this tumour and the development of new investigative and therapeutic methods had a great impact on its management. Objective: The aim of this review is to investigate the outcome of Peptide Receptor Radionuclide Therapy (PRRT) in the treatment of pancreatic neuroendocrine tumours. Methods: A comprehensive literature search strategy was used based on two databases (SCOPUS, and PubMed). We considered all studies published in English, evaluating the use of PRRT (177Luteciuim- DOTA-conjugated peptides and 90Yetrium- DOTA- conjugated peptides) in the treatment of pancreatic neuroendocrine tumours as a standalone entity or as a subgroup within the wider category of Gastroenteropancreatic Neuroendocrine Tumours (GEP NETs). Results: PRRT was found to be an effective treatment modality as a monotherapy or in combination with other therapies in the treatment of non-operable and metastatic pNETs where other options are limited. Complete response was reported to be between 2-6% while partial response was achieved in up to 60% of cases. Survival analysis was also impressive. Progression Free Survival (PFS) reached a mean of 34 months and Overall Survival (OS) of 53 months. PRRT also proved to improve patients’ Quality of Life (QoL). Acute and sub-acute side effects like nephrotoxicity and haematotoxicity are usually mild and reversible. Conclusion: PRRT is well tolerated and effective treatment option for non-operable and/or metastatic pNETs. Side effects are usually mild and reversible. Larger randomized controlled trails need to be done to compare PRRT with other treatment modalities and to provide more detailed guidelines regarding patient selections, the choice of PRRT, follow up and response assessment to maximum potential benefit.

Purpose: The spatio-molecular distribution of choline and its metabolites in tumors is highly heterogeneous. Due to regulation of choline metabolism by hypoxic transcriptional signaling and other survival factors, we envisage that detection of such heterogeneity in patient tumors could provide the basis for advanced localized therapy. However, non-invasive methods to assess this phenomenon in patients are limited. We investigated such heterogeneity in Non-Small Cell Lung Cancer (NSCLC) with [18F]fluoromethyl-(1,2-2H4) choline ([18F]D4-FCH) and positron emission tomography/computed tomography (PET/CT). Experimental design: [18F]D4-FCH (300.5±72.9MBq [147.60-363.6MBq]) was administered intravenously to 17 newly diagnosed NSCLC patients. PET/CT scans were acquired concurrently with radioactive blood sampling to permit mathematical modelling of blood-tissue transcellular rate constants. Comparisons were made with biopsy-derived choline kinase-α (CHKα) expression and diagnostic [18F]fluorodeoxyglucose ([18F]FDG) scans. Results: Oxidation of [18F]D4-FCH to [18F]D4-fluorobetaine was suppressed (48.58±0.31% parent at 60 min) likely due to the deuterium isotope effect embodied within the design of the radiotracer. Early (5 min) and late (60 min) images showed specific uptake of tracer in all 51 lesions (tumors, lymph nodes and metastases) from 17 patients analyzed. [18F]D4-FCH-derived uptake (SUV60max) in index primary lesions (n=17) ranged between 2.87-10.13; lower than that of [18F]FDG PET [6.89-22.64]. Mathematical modelling demonstrated net irreversible uptake of [18F]D4-FCH at steady-state, and parametric mapping of the entire tumor showed large intratumorally heterogeneity in radiotracer retention, which is likely to have influenced correlations with biopsy-derived CHKα expression. Conclusions: [18F]D4-FCH is detectable in NSCLC with large intratumorally heterogeneity, which could be exploited in the future for targeting localized therapy.

Neuroendocrine tumours (NETs) are a heterogeneous group of tumours that arise in different tissues and organs and have an endocrine and neurological interface that differentiates them into a stand-alone entity. One of their interesting and unique criteria is the overexpression of somatostatin receptors (SSRs) on their cell membrane, which has allowed for specific diagnostic imaging techniques and targeted therapy like peptide receptor radionuclide therapy (PRRT). The aim of this study is to provide a literature review summarizing the latest available studies concerning the use of PRRT in treatment of neuroendocrine tumours including patient selection, the choice of PRPP, efficacy, side effects, and complications. A comprehensive search strategy was used based on SCOPUS and PubMed databases. We considered all studies published in English evaluating the use of PRRT (177Lu-Dotatate and 90Y-Dotatate) in treatment of NETs and its effectiveness and side effects and complications. PRRT was found to be effective as monotherapy or in combination with other therapies. 90Yttrium may be more appropriate for larger tumour lesions, while 177Lutetium is more appropriately used for smaller ones. A combination therapy with 90Yttrium and 177Lutetium has been suggested for variable sized lesions. Mild acute side effects were reported more in 177Lutetium, while sub-acute and long-term side effects are more with 90Yttrium. Heamatotoxicity is usually mild and reversible and only

Small intestinal neuroendocrine neoplasms (SI-NEN) frequently metastasise to regional lymph nodes, and surgery is the mainstay of therapy for such patients. However, despite the possible use of advanced surgical techniques, the resection of both primary and locoregional diseases is not always attainable. Intestinal and multivisceral transplantation has been performed in a small number of patients with conventionally nonresectable, slow-growing tumours threatening the mesenteric root but has remained controversial. The use of donor skin in “sentinel flaps” in transplantation theoretically offers advantages in tailoring immunosuppression and monitoring for rejection. We represent (with extended follow-up) the first case of a patient with inoperable extensive mesenteric metastases from SI-NEN, who underwent neoadjuvant peptide receptor radionuclide therapy before a modified multivisceral transplant with a concomitant vascularised sentinel forearm flap. At 48 months after transplantation, our patient remained at full physical activity with no evidence of disease recurrence on either tumour biochemistry or radiological imaging.

We conducted the first-in-human study of (18)F-fluoroethyl triazole [Tyr(3)] octreotate ((18)F-FET-βAG-TOCA) in patients with neuroendocrine tumors (NETs) to evaluate biodistribution, dosimetry, and safety. Despite advances in clinical imaging, detection and quantification of NET activity remains a challenge, with no universally accepted imaging standard.Nine patients were enrolled. Eight patients had sporadic NETs, and 1 had multiple endocrine neoplasia type 1 syndrome. Patients received 137-163 MBq (mean ± SD, 155.7 ± 8 MBq) of (18)F-FET-βAG-TOCA. Safety data were obtained during and 24 h after radioligand administration. Patients underwent detailed whole-body PET/CT multibed scanning over 4 h with sampling of venous bloods for radioactivity and radioactive metabolite quantification. Regions of interest were defined to derive individual and mean organ residence times; effective dose was calculated with OLINDA 1.1.All patients tolerated (18)F-FET-βAG-TOCA with no adverse events. Over 60% parent radioligand was present in plasma at 60 min. High tumor (primary and metastases)-to-background contrast images were observed. Physiologic distribution was seen in the pituitary, salivary glands, thyroid, and spleen, with low background distribution in the liver, an organ in which metastases commonly occur. The organs receiving highest absorbed dose were the gallbladder, spleen, stomach, liver, kidneys, and bladder. The calculated effective dose over all subjects (mean ± SD) was 0.029 ± 0.004 mSv/MBq.The favorable safety, imaging, and dosimetric profile makes (18)F-FET-βAG-TOCA a promising candidate radioligand for staging and management of NETs. Clinical studies in an expanded cohort are ongoing to clinically qualify this agent.

INTRODUCTION: Single-photon emission computed tomography (SPECT) myocardial perfusion imaging is an accepted method for reflecting the pathophysiological significance of lesions detected by coronary angiography. However, it has an inherent drawback in terms of false-positive perfusion defects for the inferior myocardial wall. To overcome this problem, different acquisition techniques have been proposed, including the computed tomographic-based attenuation correction method. In this respect, a new imaging technique, left supine lateral position SPECT myocardial perfusion imaging with technetium-99m methoxyisobutylisonitrile (Tc-99m MIBI), has been proposed to eliminate this problem and its value has been investigated in this report. MATERIALS AND METHODS: Sixty-two patients were prospectively and randomly enrolled in this study. They underwent Tc-99m MIBI SPECT in the supine, prone, left lateral, and sitting positions after an adequate stress test on the same day.The presence and extent of defects on stress images were noted in the supine image data set for the 11 myocardial segments, which were then labeled as 1 or 0 if a defect was present or absent, respectively. This evaluation sequence was repeated in all other image data sets. When defects persisted in other scan positions it was regarded as true positive, and when they were resolved they were regarded as false positive. By this means, the percentages of resolving perfusion defects by that imaging position were calculated for each observer per positional pair under comparison. RESULTS: From six interpretations carried out by the nuclear medicine physicians, 6×11×3=198 four-fold tables in 11 segments were analyzed for discrepancies between position pairs. In 31 of 33 discrepant interpretations, defects observed in any of the other positions were resolved in the lateral position. Only in two evaluations of one observer were the discrepancies against lateral positioning for the anterior wall. If the inferior wall was considered alone, it was clearly obvious that lateral positioning was more accurate than the other positions.Intraobserver evaluation showed the methodology to be highly reproducible.The SPECT findings were concordant with coronary angiography results in selected patients. CONCLUSION: Visual and quantitative evaluations of the variation in inferior wall activity lead us to suggest that SPECT imaging with Tc-99m MIBI be performed in the left lateral position to allow better visualization of the inferior and septal walls in those departments not able to utilize computed tomographic attenuation correction.

4093 Background: PRRT represents a step change in NET management, significantly improving survival. However, objective response to PRRT, approximately 20%, is poor. There are no predictive biomarkers of response. Uptake on 68Ga-DOTATATE PET/CT imaging is used to assess patient suitability for PRRT, highlighting the presence of somatostatin receptors (SSTR) to which PRRT selectively binds. We hypothesise that the density of SSTRs, as defined by a minimum SUV uptake, predicts for response to PRRT. Methods: 54 patients underwent PRRT. Modified PERCIST assessment was performed: up to 2 target lesions per organ were identified and volume of interest drawn. Maximum 5 targets were counted. Average SUV (SUVave) was calculated by dividing sum of SUVmax of target lesions by number of lesions. Response was determined by RECIST 1.1. Ki67 and SSTR2 expression were assessed on tumour samples and compared with SUVave. Results: Response to PRRT: partial response (PR) 26%, stable disease (SD) 40% progressive disease (PD) 12%. Response to PRRT predicted progression free survival (PFS) with patients experiencing PR having a PFS 2.5x that of those with SD, and almost 20x as long as PD. Using ROC curve analysis, SUVave of 21.6 predicted for tumour response with high sensitivity (0.74) and specificity (1.0), p = 0.15, 95% CI 0.71-3.96. No association between baseline SUVave and SSTR2 or Ki-67 was observed. SUVave > 21.6 was an independent predictor of clinical outcome. Conclusions: Objective response to PRRT defines a subset of patients with markedly improved PFS. SUVave 21.6 defines a threshold below which patients have a poor response to PRRT. This threshold should be taken forward into prospective study.

OBJECTIVES: This study investigated the incidence and clinical significance of arterial graft-associated uptake of fluorodeoxyglucose in large-vessel vasculitis (LVV). BACKGROUND: The role of (18)F-labeled fluorodeoxyglucose-positron emission tomography/computed tomography ([(18)F]FDG-PET/CT) in the management of LVV remains to be defined. Although [(18)F]FDG uptake at arterial graft sites raises concerns regarding active arteritis or infection, its clinical significance in LVV has never been formally studied. METHODS: An observational prospective study sought to identify patients with Takayasu arteritis (TA) undergoing [(18)F]FDG-PET/CT more than 6 months after graft surgery from a large cohort of patients from 2 tertiary referral centers. [(18)F]FDG uptake by the graft and native arteries was scored on a scale of 0 to 3 relative to hepatic uptake, and periprosthetic maximum standardized uptake value (SUVmax) was calculated. Periprosthetic [(18)F]FDG uptake in active disease was compared with that in inactive disease, and arterial progression was assessed by prospective magnetic resonance angiography (MRA). RESULTS: Twenty-six subjects with TA were enrolled. All were afebrile with negative blood culture. Periprosthetic uptake was significant in 23 of 26 patients, and the mean SUVmax was 4.21 ± 1.46. Median periprosthetic [(18)F]FDG uptake score (3; interquartile range [IQR]: 3 to 3) was higher than in native aorta (1; IQR: 0 to 1; p < 0.001). Graft-specific [(18)F]FDG uptake was unrelated to disease activity. Despite the high frequency of graft-associated [(18)F]FDG uptake, sequential MRAs did not reveal arterial progression in 25 of 26 patients; the 1 remaining case showed minor progression limited to native arteries. Nine patients underwent repeated PET/CT scanning without showing changes in graft-specific uptake, despite increased treatment. CONCLUSIONS: Significant [(18)F]FDG uptake that is confined to arterial graft sites in patients with LVV does not reflect clinically relevant disease activity or progression. To minimize exposure to immunosuppression and in the face of negative blood culture, clinically quiescent arteritis, normal or stably raised C-reactive protein levels, we elected not to escalate treatment and monitor progression with MRA.

The liver is a common site of malignant disease with hepatocellular carcinoma and liver metastases accounting for the majority of liver malignancies. Conventional treatment options are confined to chemotherapy, surgery and minimally invasive procedures such as radiofrequency ablation. External beam radiation therapy has a limited role in the treatment of liver malignancy, mainly due to the substantial risk of radiation-induced liver disease. Transarterial chemoembolisation is contraindicated in patients with portal vein thrombosis or advanced liver disease. Selective internal radiation therapy using yttrium-90 microspheres has emerged as a suitable treatment of liver tumours. In this review we discuss the principles behind this treatment, the process of patient selection, and the method of dose calculation and administration. We also highlight possible adverse effects and review the literature for data on response assessment and long-term outcome.

The aim of the study was to assess the effects of neoadjuvant androgen deprivation (NAD) and radical prostate radiotherapy with concurrent androgen deprivation (RT-CAD) on prostatic [C]choline kinetics and thus develop methodology for the use of [C]choline-PET/computed tomography (CT) as an early imaging biomarker.Ten patients with histologically confirmed prostate cancer underwent three sequential dynamic [C]choline-PET/CT pelvic scans: at baseline, after NAD and 4 months after RT-CAD. [C]Choline uptake was quantified using the average and maximum standardized uptake values at 60 min (SUV60,ave and SUV60,max), the tumour-to-muscle ratios (TMR60,max) and net irreversible retention of [C]choline at steady state (Kimod-pat).The combination of NAD and RT-CAD significantly decreased tumour [C]choline uptake (SUV60,ave, SUV60,max, TMR60,max or Kimod-pat) and prostate-specific antigen (PSA) levels (analysis of variance, P0.001 for all variables). Although the magnitude of reduction in the variables was larger after NAD, there was a smaller additional reduction after RT-CAD. A wide range of reduction in tumour SUV60,ave (38-83.7%) and SUV60,max (22.2-85.3%) was seen with combined NAD and RT-CAD despite patients universally achieving PSA suppression (narrow range of 93.5-99.7%). There was good association between baseline SUV60,max and initial PSA levels (Pearson's r=0.7, P=0.04). The reduction in tumour SUV60,ave after NAD was associated with PSA reduction (r=0.7, P=0.04). This association occurred despite the larger reduction in PSA (94%) compared with SUV60,ave (58%).This feasibility study shows that [C]choline-PET/CT detects metabolic changes within tumours following NAD and RT-CAD to the prostate. A differential reduction in [C]choline uptake despite a global reduction in PSA following NAD and RT-CAD could provide prognostic information and warrants further evaluation as an imaging biomarker in this setting.

4113 Background: Neuroendocrine neoplasia (NEN) of the pancreas (PanNEN) or small bowel (SBNEN) frequently present with metastases at initial diagnosis, undermining the efficacy of surgical treatment. Peptide receptor radionuclide therapy (PRRT) with radiolabelled somatostatin analogues, 90Y-DOTATOC and 177Lu-DOTATATE, has been shown to achieve prolonged progression-free survival (PFS) and overall survival (OS) in a substantial number of non-surgical patients with advanced NEN. Our aim was to prospectively determine the efficacy of a combination of radical loco-regional surgery and 177Lu PRRT in patients with metastasised NEN. Methods: A set of inclusion criteria was defined (e.g. PanNEN or SBNEN, G1/G2 NEN, initial tumour diagnosis, treatment naïve patient, stage IV NEN, positivity on 68Ga DOTATATE or DOTATOC PET/CT, eligibility for surgery and PRRT). Patients underwent PRRT within 3 months following surgery. Follow-up included biochemistry and imaging. Outcome measures included 1-, 3-, and 5-year OS and PFS from initial diagnosis. Results: Forty-one patients met eligibility criteria and were included. There were 26 males (63.4%) and median age at surgery was 58.8 years (range 32.1-78.3). All patients with SBNEN underwent right hemicolectomy, terminal ileal resection and mesenteric lympadenectomy. In PanNEN patients either Whipple procedure or distal pancreatectomy and peripancreatic lymphadenectomy were performed. The median number of PRRT cycles was 4 (range 2-6). Post-treatment mortality was 0%. Surgical morbidity was 12% (all grade 1 according Clavien-Dindo) and transient grade 1 toxicity occurred post PRRT in 40%. There was no grade 3 toxicity. Median follow-up was 5.48 years (range 0.53 – 11.98). Median PFS and OS were 3.33 years and 9.07 years, respectively. Progression-free survival (with 95% CI) was at 1-, 3-, and 5-years 80% (68.7-92.6), 60.9% (45.9-75.9) and 43.3% (27.4-59.3), respectively. Overall survival (with 95% CI) at 1-, 3-, and 5-years was 97.6% (93-100), 97.6% (93-100), and 95% (87-100), respectively. Conclusions: Radical loco-regional surgery for primary tumours combined with PRRT provides a novel, highly efficacious approach in metastasised NEN.

Dihydroxyphenylalanine (DOPA) is a neutral amino acid that resembles natural l-dopa (dopamine precursor). It enters the catecholamine metabolic pathway of endogenous l-DOPA in the brain and peripheral tissues. It is amenable to labeling with fluorine-18 (18F) for PET imaging and was originally used in patients with Parkinson’s disease to assess the integrity of the striatal dopaminergic system. The recent introduction and use of hybrid PET/CT scanners has contributed significantly to the management of a series of other pathologies including neuroendocrine tumors, brain tumors, and pancreatic cell hyperplasia. These pathologic entities present an increased activity of l-DOPA decarboxylase and therefore demonstrate high uptake of 18F-DOPA. Despite these potentially promising applications in several clinical fields, the role of 18F-DOPA has not been elucidated completely yet because of associated difficulties in synthesis and availability. Unfortunately, the available literature does not provide recommendations for procedures or administered activity, acquisition timing, and premedication with carbidopa. The aim of this paper is to outline the physiological biodistribution and normal variants, including possible pitfalls that may lead to misinterpretations of the scans in various clinical settings.

A 62-year-old female patient with suspected insulinoma underwent 68Ga DOTA-TATE PET/CT for characterization and staging. This demonstrated a focus of uptake in the pancreas and 3 foci of uptake in the spine. An MRI of the spine performed to further characterize the lesions revealed the presence of a meningioma and degenerative changes, both of which showed 68Ga DOTA-TATE uptake. A vertebral metastasis seen on PET was occult on CT and MRI. A vertebral hemangioma had no discrete tracer uptake. Awareness of sources of error in interpreting 68Ga DOTA-TATE scans is important in order to avoid pitfalls.

Effective anticancer therapy induces tumor cell death through apoptosis. Noninvasive monitoring of apoptosis during therapy may provide predictive outcome information and help tailor treatment. A caspase-3–specific imaging radiotracer, 18F-(S)-1-((1-(2-fluoroethyl)-1H-[1,2,3]-triazol-4-yl)methyl)-5-(2(2,4-difluorophenoxymethyl)-pyrrolidine-1-sulfonyl)isatin (18F-ICMT-11), has been developed for use in PET studies. We report the safety, biodistribution, and internal radiation dosimetry profiles of 18F-ICMT-11 in 8 healthy human volunteers. Methods:18F-ICMT-11 was intravenously administered as a bolus injection (mean ± SD, 159 ± 2.75 MBq; range, 154–161 MBq) to 8 healthy volunteers (4 men, 4 women). Whole-body (vertex to mid thigh) PET/CT scans were acquired at 6 time points, up to 4 h after tracer injection. Serial whole blood, plasma, and urine samples were collected for radioactivity measurement and radiotracer stability. In vivo 18F activities were determined from quantitative analysis of the images, and time–activity curves were generated. The total numbers of disintegrations in each organ normalized to injected activity (residence times) were calculated as the area under the curve of the time–activity curve, normalized to injected activities and standard values of organ volumes. Dosimetry calculations were then performed using OLINDA/EXM 1.1. Results: Injection of 18F-ICMT-11 was well tolerated in all subjects, with no serious tracer-related adverse events reported. The mean effective dose averaged over both men and women was estimated to be 0.025 ± 0.004 mSv/MBq (men, 0.022 ± 0.004 mSv/MBq; women, 0.027 ± 0.004 mSv/MBq). The 5 organs receiving the highest absorbed dose (mGy/MBq), averaged over both men and women, were the gallbladder wall (0.59 ± 0.44), small intestine (0.12 ± 0.05), upper large intestinal wall (0.08 ± 0.07), urinary bladder wall (0.08 ± 0.02), and liver (0.07 ± 0.01). Elimination was both renal and via the hepatobiliary system. Conclusion:18F-ICMT-11 is a safe PET tracer with a dosimetry profile comparable to other common 18F PET tracers. These data support the further development of 18F-ICMT-11 for clinical imaging of apoptosis.

Background 3’-Deoxy-3’-[18F]fluorothymidine ([18F]FLT) PET has limited utility in abdominal imaging due to high physiological hepatic uptake of a tracer. We evaluated [18F]FLT-PET/CT combined with a temporal-intensity information-based voxel-clustering approach termed kinetic spatial filtering (KSF) to improve tumour visualisation in patients with locally advanced and metastatic gastro-oesophageal cancer and as a marker of early response to chemotherapy. Dynamic [18F]FLT-PET/CT data were collected before and 3 weeks post first cycle of chemotherapy. Changes in tumour [18F]FLT-PET/CT variables were determined. Response was determined on contrast-enhanced CT after three cycles of therapy using RECIST 1.1. Results Ten patients were included. Following application of the KSF, visual distinction of all oesophageal and/or gastric tumours was observed in [18F]FLT-PET images. Among the nine patients available for response evaluation (RECIST 1.1), three patients had responded (partial response) and six patients were non-responders (stable disease). There was a significant association between Ki-67 and all baseline [18F]FLT-PET parameters. Area under the curve (AUC) from 0 to 1 min was associated with treatment response. Conclusions The results of this study indicate that application of the KSF allowed accurate visualisation of both primary and metastatic lesions following imaging with the proliferation marker, [18F]FLT-PET/CT. However, [18F]FLT-PET uptake parameters did not correlate with response. Instead, we observe significant changes in tracer delivery following chemotherapy suggesting that further [18F]FLT-PET/CT studies in this tumour type should be undertaken with caution.

Pheochromocytomas are tumors derived from chromaffin cells of the adrenal medulla that synthesize, store, metabolize, and usually, but not always, secrete catecholamines. Although pheochromocytomas are the cause of hypertension in only a small number of patients, they can precipitate life-threatening hypertension or cardiac arrhythmias caused by excessive and episodic catecholamine secretion. This article reviews the genetics, clinical presentation, and imaging of pheochromocytoma, with special emphasis on new positron emission tomographic radiopharmaceutical agents.

Small bowel neuroendocrine tumours are the commonest malignancy arising in the small intestine and have substantially increased in incidence in recent decades. Patients with small bowel neuroendocrine tumours commonly develop lymph node and/or distant metastases. Here, we examine the role of staging in 84 surgically treated patients with small bowel neuroendocrine tumours, comparing diagnostic information yielded from morphological, functional and endoscopic modalities. Furthermore, we correlate pre-operative staging with intra-operative findings in a sub-cohort of 20 patients. The vast majority of patients had been histologically confirmed to have low-grade (Ki-67

Key points Neuroendocrine tumours (NETs) are slow growing but potentially malignant, increasing in incidence due to advances in hormone and tumour markers assays improving detection Conventional imaging is routinely used for localisation but sensitivity is suboptimal due both to small size

Aim: To assess the potential role of 18F-Fluorodeoxiglucose (FDG) Positron Emission Tomography (PET)/Computed Tomography (CT) in characterizing indeterminate lung nodules detected at CT scan in patients previously treated for a breast cancer (BC). Materials and Methods: Twenty-nine consecutive BC patients (28 females, mean age 65 ± 12 years) with evidence of indeterminate lung nodules at contrast-enhanced CT (CECT) scan (lesions with axial diameter ≥8 mm) were retrospectively analysed: all patients underwent 18F-FDG PET/CT within a mean 2 ± 1 months from CECT imaging. PET/CT was considered positive in the presence of abnormal FDG uptake in the pulmonary nodules and/or in other organs. The nature of lung nodules was defined at histopathology and/or imaging follow-up. Results: Fourteen (48%) patients showed negative and 15 (52%) positive PET/CT scan in the lungs: of these 15 patients, 7 (47%) had pathologic FDG-uptake in lungs only, whereas 8 (53%) showed abnormal FDG-uptake also in sites different from lungs. At histology and/or imaging follow-up, five (17%) patients were considered positive for BC lung metastases while in seven (24%) a second cancer was diagnosed. In this subset of patients, the sensitivity and specificity for FDG PET/CT in revealing lung lesions were 17% and 100%, respectively, for nodules

This study evaluated the ability of 18F-FDG PET/CT imaging to predict early response to 90Y-radioembolization in comparison with contrast-enhanced CT (CECT) using RECIST and lesion density (Choi) criteria. Progression-free survival (PFS) in patients with liver metastases at 2 years and decline in tumour markers were the primary end-points of the study. A total of 121 liver lesions were evaluated in 25 patients (14 men, 11 women) with liver-dominant metastatic colorectal cancer who underwent 18F-FDG PET/CT and CECT before and 6–8 weeks after treatment. Changes in SUVmax, tumour density measured in terms of Hounsfield units and the sum of the longest diameters (LD) were calculated for the target liver lesions in each patient. The patient responses to treatment were categorized using EORTC PET criteria, tumour density criteria (Hounsfield units) and RECIST, and were correlated with the responses of tumour markers and 2-year PFS using Kaplan-Meier plots and the log-rank test for comparison. Multivariate proportional hazards (Cox) regression analysis was performed to assess the effect of relevant prognostic factors on PFS. Using 18F-FDG PET/CT response criteria, 15 patients had a partial response (PR) and 10 patients had stable disease (SD), while using RECIST only 2 patients had a PR and 23 had SD. Two patients had a PR, 21 SD and 2 progressive disease using tumour density criteria. The mean changes in SUVmax, sum of the LDs and tumour density after treatment were 2.9 ± 2.6, 7.3 ± 14.4 mm and 1.9 ± 13.18 HU, respectively. Patients who had a PR on 18F-FDG PET/CT had a mean decrease of 44.5 % in SUVmax compared to those with SD who had a decrease of only 10.3 %. The decreases in SUVmax and sum of the LDs were significant (p 0.1065). The responses on the 18F-FDG PET/CT studies were highly correlated with the responses of tumour markers (p

Neuroectodermal tumours arise from chromaffin cells and possess the ability to secrete catecholamines. They are generally rare and may occur in association with a variety of hereditary syndromes such as MEN-2A and 2B, neurofibromatosis type 1 and von Hippel-Lindau disease. The most common types are phaeochromocytoma arising from the adrenal medulla and paraganglioma of extra-adrenal origin. Phaeochromocytomas tend to be benign and are often associated with a gene mutation if the disease is bilateral, while paragangliomas are often malignant, have a more aggressive nature and tend to metastasize. There are no specific histological or immunohistochemical features that indicate the malignant potential and the diagnosis of malignancy can only be established by the presence of distant metastases. Therefore, imaging can play a vital role in the diagnosis, localization, staging and assessment of spread. Traditionally, this is achieved with a combination of cross-sectional (CT and MRI) and functional (123I-MIBG or 111In-octreotide) imaging. However, these modalities are not adequate and achieve moderate sensitivity. The introduction of 68Ga-DOTA peptide in PET/CT imaging has led to improved receptor targeting and superb PET resolution, as well as accurate localization of lesions. The use of this technique in neuroectodermal tumours has been shown to be superior to all available modalities, but the available data are limited and larger studies are awaited to establish its role in the management of these tumours.

Item does not contain fulltext The EANM Congress 2011 took place in Birmingham between the 15th and 19th October 2011 under the presidency of Professor Werner Langsteger. The attendance was reassuringly high, in line with other EANM congresses, despite the current 'Eurozone Crisis'. Participants from 87 countries came along, met old friends and made new ones. They were presented with a massive programme of 1,480 abstracts, symposia, and CME, scientific, plenary and featured sessions. The industry made a substantial contribution to the success of the congress with 109 hardware, software and radiopharmaceutical companies demonstrating the latest technology and innovations in the field. A feature in this year's congress was the emphasis on the role of the young generation. The highlight lecture was presented and this article was compiled by three young EANM members chosen from the young investigator project of the EANM. They review the most highly rated presentations in clinical and preclinical imaging in oncology, neuroendocrine tumours, cardiology, paediatrics and neurology, and provide an update on radionuclide therapy, physics, instrumentation, innovative tracers and techniques. 01 februari 2012

Item does not contain fulltext PURPOSE: Radionuclide imaging of phaeochromocytomas (PCCs) and paragangliomas (PGLs) involves various functional imaging techniques and approaches for accurate diagnosis, staging and tumour characterization. The purpose of the present guidelines is to assist nuclear medicine practitioners in performing, interpreting and reporting the results of the currently available SPECT and PET imaging approaches. These guidelines are intended to present information specifically adapted to European practice. METHODS: Guidelines from related fields, issued by the European Association of Nuclear Medicine and the Society of Nuclear Medicine, were taken into consideration and are partially integrated within this text. The same was applied to the relevant literature, and the final result was discussed with leading experts involved in the management of patients with PCC/PGL. The information provided should be viewed in the context of local conditions, laws and regulations. CONCLUSION: Although several radionuclide imaging modalities are considered herein, considerable focus is given to PET imaging which offers high sensitivity targeted molecular imaging approaches.

Objectives Breast cancer is the second cause of death in women in Europe and North America. The mortality of this disease can be reduced with effective therapy and regular follow up to detect early recurrence. Tumor markers are sensitive in detecting recurrent or residual disease but imaging is required to customize the therapeutic option. Rising tumor markers and negative conventional imaging (US, X-mammography, CT and MR) poses a management problem. Our aim is to assess the role of 18F-FDG-PET/CT in the management of post-therapy patients with rising markers but negative conventional imaging. Materials and methods In the period from January 2008 to September 2009, 89 female patients with breast cancer who developed post-therapy rising markers (serum Ca 15-3 levels = 64.8 ± 16.3 U/mL) but negative clinical examination and conventional imaging were investigated with 18F-FDG-PET/CT. Results Tumor deposits were detected in 40/89 patients in chest wall, internal mammary nodes, lungs, liver and skeleton. The mean SUVmax value calculated in these lesions was 6.6 ± 1.7 (range 3.1–12.8). In 23/40 patients solitary small lesion were amenable to radical therapy. In 7 out of these 23 patients a complete disease remission lasting more than 1 year was observed. Conclusions 18F-FDG-PET/CT may have a potential role in asymptomatic patients with rising markers and negative conventional imaging. Our findings agree with other studies in promoting regular investigations such as tumor markers and 18F-FDG-PET/CT rather than awaiting the developments of physical symptoms as suggested by current guidelines since the timely detection of early recurrence may have a major impact on therapy and survival.

OBJECTIVE The biological significance of [¹¹C]choline (CHO) uptake in human tumours is unclear and probably linked to choline kinase-α (CHKα) expression and cell proliferation. We directly compared CHO with [¹⁸F]fluorothymidine (FLT), an imaging biomarker of proliferation, by positron emission tomography (PET) in patients with breast cancer to investigate whether cell proliferation is an important determinant of CHO uptake. Furthermore, we evaluated CHKα and the Ki67-labelling index (LIKi67) in tumour biopsies. METHODS Sequential CHO-PET and FLT-PET within the same imaging session were performed in 21 patients with oestrogen receptor (ER)-positive breast cancer (28 lesions). Average and maximum CHO standardized uptake values (SUV) at 60 min: SUV60,av, and SUV60,max, and the rate constant of net irreversible uptake, Ki, were compared with FLT uptake at 60 min: SUV60,av and SUV60,max. Biopsies were stained for CHKα and LIKi67 in eight cases. RESULTS Tumours were equally visible on CHO-PET and FLT-PET imaging. Tumour CHO-PET strongly correlated with FLT imaging variables (Pearson's r=0.83; P

This short review aims at summarizing the available data pertaining to the usefulness of F-18 FDG PET/CT in rectal cancer. It is specifically focused on the emerging role of F-18 FDG PET/CT in assessing the response to neoadjuvant combined radiochemotherapy in locally advanced rectal cancer. It also probes the possibility of finding standardized PET/CT parameters that are capable of differentiating responders from nonresponders in whom therapeutic approach could be modified.