Comparison between <Superscript>68</Superscript>Ga-DOTA-NOC and <Superscript>18</Superscript>F-DOPA PET for the detection of gastro-entero-pancreatic and lung neuro-endocrine tumours

PURPOSE: (18)F-FDG positron emission tomography (PET) value for the assessment of neuro-endocrine tumours (NET) is limited. Preliminary studies indicate that (18)F-DOPA and (68)Ga-DOTA-NOC are more accurate for disease assessment and (68)Ga-DOTA peptides provide additional data on receptor status that are crucial for targeted radionuclide therapy. At present, there are no comparative studies investigating their role in NET. AIM: The aim of this study was to compare (68)Ga-DOTA-NOC and (18)F-DOPA for the evaluation of gastro-entero-pancreatic and lung neuro-endocrine tumours. MATERIALS AND METHODS: Thirteen patients with biopsy-proven NET (gastro-entero-pancreatic or pulmonary) were prospectively enrolled and scheduled for (18)F-DOPA and (68)Ga-DOTA-NOC PET. PET results obtained with both tracers were compared with each other, with other conventional diagnostic procedures (CT, ultrasound) and with follow-up (clinical, imaging). RESULTS: The most common primary tumour site was the pancreas (8/13) followed by the ileum (2/13), the lung (2/13) and the duodenum (1/13). The carcinoma was well differentiated in 10/13 and poorly differentiated in 3/13 cases. (68)Ga-DOTA-NOC PET was positive, showing at least one lesion, in 13/13 cases while (18)F-DOPA PET was positive in 9/13. On a lesions basis, (68)Ga-DOTA-NOC identified more lesions than (18)F-DOPA (71 vs 45), especially at liver, lung and lymph node level. (68)Ga-DOTA-NOC correctly identified the primary site in six of eight non-operated cases (in five cases, the primary was surgically removed before PET), while (18)F-DOPA identified the primary only in two of eight cases. CONCLUSIONS: Although the patients studied are few and heterogeneous, our data show that (68)Ga-DOTA-NOC is accurate for the detection of gastro-entero-pancreatic and lung neuro-endocrine tumours in either the primary or metastatic site and that it offers several advantages over (18)F-DOPA.     

Comparison of <Superscript>68</Superscript>Ga-DOTATOC PET and <Superscript>111</Superscript>In-DTPAOC (Octreoscan) SPECT in patients with neuroendocrine tumours

Purpose Neuroendocrine tumours (NETs) can be imaged with scintigraphy using radiolabelled somatostatin analogues. The aim of our study was to compare the value of ⁶⁸Ga-DOTATOC PET and ¹¹¹In-DTPAOC SPECT (Octreoscan) in the detection of NET manifestations. Methods Twenty-seven NET patients were prospectively examined. ⁶⁸Ga-DOTATOC PET and ¹¹¹In-DTPAOC SPECT were performed using standard techniques. Treatment was not applied in between. Mean and maximum standardised uptake values (SUVs) were calculated for PET findings. Tumour/non-tumour ratios were calculated for SPECT findings. Findings were compared by a region-by-region analysis and verified with histopathology, CT and MRI within 21 days. Results SUVs of positive lesions on ⁶⁸Ga-DOTATOC PET ranged from 0.7 to 29.3 (mean SUV) and from 0.9 to 34.4 (maximum SUV). Tumour/non-tumour ratios on ¹¹¹In-DTPAOC SPECT ranged from 1.8 to 7.3. In imaging lung and skeletal manifestations, ⁶⁸Ga-DOTATOC PET was more efficient than ¹¹¹In-DTPAOC SPECT. All discrepant lung findings and 77.8% of discrepant osseous findings were verified as true positive PET interpretations. In regional comparison of liver and brain, ⁶⁸Ga-DOTATOC PET and ¹¹¹In-DTPAOC SPECT were identical. In lymph nodes, the pancreas and the gastro-intestinal system, different values of the two techniques were not indicated in regional analyses. In a single patient, surgical interventions were changed on the basis of ⁶⁸Ga-DOTATOC PET findings. Conclusion ⁶⁸Ga-DOTATOC PET is superior to ¹¹¹In-DTPAOC SPECT in the detection of NET manifestations in the lung and skeleton and similar for the detection of NET manifestations in the liver and brain. ⁶⁸Ga-DOTATOC PET is advantageous in guiding the clinical management. M. Henze and S. Engelbrecht contributed equally to this paper.     

<Superscript>68</Superscript>Ga-DOTANOC: biodistribution and dosimetry in patients affected by neuroendocrine tumors

Objectives The aim of this work was the evaluation of biodistribution and radiation dosimetry of ⁶⁸Ga-DOTANOC in patients affected by neuroendocrine tumors. Materials and methods We enrolled nine patients (six male and three female) affected by different types of neuroendocrine tumors (NETs). Each patient underwent four whole body positron emission tomography (PET) scans, respectively, at 5, 20, 60, and 120 min after the intravenous injection of about 185 MBq of ⁶⁸Ga-DOTANOC. Blood and urine samples were taken at different time points post injection: respectively, at about 5, 18, 40, 60, and 120 min for blood and every 40–50 min from injection time up to 4 h for urine. The organs involved in the dosimetric evaluations were liver, heart, spleen, kidneys, lungs, pituitary gland, and urinary bladder. Dosimetric evaluations were done using the OLINDA/EXM 1.0 software. Results A physiological uptake of ⁶⁸Ga-DOTANOC was seen in all patients in the pituitary gland, the spleen, the liver, and the urinary tract (kidneys and urinary bladder). Organs with the highest absorbed doses were kidneys . The mean effective dose equivalent (EDE) was . Discussion and conclusions The excretion of the compound was principally via urine, giving dose to the kidney and the urinary bladder wall. As SSTR2 is the most frequently expressed somatostatin receptor and ⁶⁸Ga-DOTANOC has high affinity to it, this compound might play an important role in PET oncology in the future. The dosimetric evaluation carried out by our team demonstrated that ⁶⁸Ga-DOTANOC delivers a dose to organs comparable to, and even lower than, analogous diagnostic compounds.     

Concordance between results of somatostatin receptor scintigraphy with <Superscript>111</Superscript>In-DOTA-DPhe<Superscript>1</Superscript>-Tyr<Superscript>3</Superscript>-octreotide and chromogranin A assay in patients with neuroendocrine tumours

Purpose  Somatostatin receptor scintigraphy (SRS) and chromogranin A (CgA) assay have successfully been implemented in the clinical work-up and management of neuroendocrine tumour (NET) patients. However, there is still a lack of studies comparing results in these patients. Our aim was to compare directly in NET patients SRS and CgA assay results with special regard to tumour features such as grade of malignancy, primary origin, disease extent and function. Methods  One hundred twenty consecutive patients with histological confirmed NETs were investigated with ¹¹¹In-DOTA-DPhe¹-Tyr³-octreotide (¹¹¹In-DOTA-TOC) SRS and CgA immunoradiometric assay. Tumours were classified by cell characteristics [well-differentiated NETs, well-differentiated neuroendocrine carcinomas, poorly differentiated neuroendocrine carcinomas (PDNECs)], primary origin (foregut, midgut, hindgut, undetermined), disease extent (limited disease, metastases, primary tumour and metastases) and functionality (secretory, nonsecretory). Results  SRS was positive in 107 (89%) patients; CgA levels were increased in 95 (79%) patients. Overall, concordance between SRS and CgA results was found in 84 patients. Positive SRS but normal CgA level were found in 24 patients, with higher prevalence (p < 0.05) in patients with nonsecretory tumours. Conversely, negative SRS but CgA level increased were seen in 12 patients, with higher proportion (p < 0.05) in patients with PDNECs and tumours of hindgut origin. Conclusions  Overall, ¹¹¹In-DOTA-TOC SRS proved to be more sensitive than CgA in NETs patients. Tumour differentiation, disease extent and presence of liver metastases impact both SRS and CgA results, whereas nonsecretory activity is a negative predictor of only CgA increase. PDNECs and hindgut origin of tumours predispose to discrepancies with negative SRS but increased CgA levels.     

Diagnostic impact of PET with <Superscript>18</Superscript>F-FDG, <Superscript>18</Superscript>F-DOPA and 3-<Emphasis Type="Italic">O</Emphasis>-methyl-6-[<Superscript>18</Superscript>F]fluoro-DOPA in recurrent or metastatic medullary thyroid carcinoma

Purpose In patients with medullary thyroid carcinoma (MTC), rising levels of the tumour markers calcitonin and CEA after primary surgery indicate tumour recurrence or metastases. The only chance of cure is the resection of localised tumour tissue. For positron emission tomography (PET) with ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) and ¹⁸F-dihydroxyphenylalanine (¹⁸F-DOPA), sensitivities of 78% and 63% have been reported, but in a considerable percentage of MTC patients the source of tumour marker elevation is not detected. The aim of this retrospective data evaluation was to compare the value of PET with ¹⁸F-FDG, ¹⁸F-DOPA and the amino acid tracer 3-O-methyl-6-[¹⁸F]fluoro-DOPA (¹⁸F-OMFD) in the detection of MTC recurrence. Methods Fifteen patients with elevated calcitonin were investigated with PET as part of their individual clinical work-up. All patients underwent ¹⁸F-FDG PET and ¹⁸F-DOPA PET, and ten patients underwent ¹⁸F-OMFD PET. Results With ¹⁸F-FDG, seven patients showed foci in the neck, mediastinum, upper abdomen or bone. In seven patients, ¹⁸F-DOPA revealed suspicious foci; five of these seven patients showed partially corresponding uptake of ¹⁸F-FDG in the neck and mediastinum. Two of these patients underwent surgery and metastases were verified. With ¹⁸F-OMFD, a small focus in the liver was suspected in one patient without a correlate on ¹⁸F-FDG PET, ¹⁸F-DOPA PET or conventional imaging. Conclusion ¹⁸F-FDG and ¹⁸F-DOPA showed foci that were highly suspicious for local recurrence or metastasis of MTC, although histological verification in these patients with numerous previous surgical interventions was performed in only two patients. The amino acid tracer ¹⁸F-OMFD had no diagnostic impact in these patients.     

Comparison of the pharmacokinetics of 68Ga-DOTATOC and [18F]FDG in patients with metastatic neuroendocrine tumours scheduled for 90Y-DOTATOC therapy

Purpose The purpose of this study was to evaluate and compare, by means of dynamic PET, the pharmacokinetics of ⁶⁸Ga-DOTATOC, a tracer which reflects the expression of somatostatin receptors (SSTRs), and of [¹⁸F]FDG, a marker of tumour viability, in patients with metastatic neuroendocrine tumours (NETs) in whom ⁹⁰Y-DOTATOC therapy was planned.Materials and methods Fifteen patients (63 lesions) with confirmed metastatic NETs were enrolled in this study. Dynamic [¹⁸F]FDG and ⁶⁸Ga-DOTATOC PET scans were performed on two different days in the same week. The data analysis was based on qualitative and quantitative analysis using a two-tissue compartment model with a blood compartment and a non-compartment model based on the fractal dimension (FD). Multivariate analysis was used for evaluation of the kinetic data.Results Enhanced [¹⁸F]FDG uptake was observed in 43/63 lesions. ⁶⁸Ga-DOTATOC showed pathologically enhanced uptake in all evaluated patients and in 57/63 lesions. Discordant scintigraphic results for [¹⁸F]FDG and ⁶⁸Ga-DOTATOC were observed in 6/15 patients. Global SUV was defined as the SUV measured in the last frame (55–60 min p.i.) of the dynamic series, for each tracer. The median global SUV uptake was 7.9 for ⁶⁸Ga-DOTATOC and 4.6 for [¹⁸F]FDG. The selection of patients for ⁹⁰Y-DOTATOC therapy was based on the uptake of ⁶⁸Ga-DOTATOC. Multiple linear regression analysis was applied to determine the effect of each kinetic parameter (K ₁–k ₄, V _B) on the global SUV of both tracers. The highest positive t-ratio was found for K ₁ (receptor binding), followed by k ₃ (cellular internalisation) and V _B (fractional blood volume), when using the global ⁶⁸Ga-DOTATOC uptake (SUV) as a target variable. Analysis of the [¹⁸F]FDG data revealed the highest positive t-ratio for V _B, followed by k ₃ (phosphorylation) and K ₁ (influx). The comparison of global SUV, K ₁–k ₄ and the FD for [¹⁸F]FDG and ⁶⁸Ga-DOTATOC did not show any statistically significant correlation. The only parameter that demonstrated a significant linear correlation between the tracers was V _B.Conclusion ⁶⁸Ga-DOTATOC is a promising tool for evaluation of the expression of SSTR2 in NETs. The combination of [¹⁸F]FDG and ⁶⁸Ga-DOTATOC dynamic PET studies provides different information regarding the biological properties of lesions in patients with metastatic NETs in whom ⁹⁰Y-DOTATOC therapy is planned. While the global ⁶⁸Ga-DOTATOC uptake is influenced mostly by K ₁, the global [¹⁸F]FDG uptake is mostly influenced by V _B. Only patients with enhanced ⁶⁸Ga-DOTATOC uptake (SUV >5.0) were referred to ⁹⁰Y-DOTATOC therapy.     

Detection of gastric cancer using <Superscript>18</Superscript>F-FLT PET: comparison with <Superscript>18</Superscript>F-FDG PET

Purpose  We prospectively investigated the feasibility of 3′-deoxy-3′-¹⁸F-fluorothymidine (FLT) positron emission tomography (PET) for the detection of gastric cancer, in comparison with 2-deoxy-2-¹⁸F-fluoro-d-glucose (FDG) PET, and determined the degree of correlation between the two radiotracers and proliferative activity as indicated by Ki-67 index. Methods  A total of 21 patients with newly diagnosed advanced gastric cancer were examined with FLT PET and FDG PET. Tumour lesions were identified as areas of focally increased uptake, exceeding that of surrounding normal tissue. For semiquantitative analysis, the maximal standardized uptake value (SUV) was calculated. Results  For detection of advanced gastric cancer, the sensitivities of FLT PET and FDG PET were 95.2% and 95.0%, respectively. The mean (±SD) SUV for FLT (7.0 ± 3.3) was significantly lower than that for FDG (9.4 ± 6.3 p < 0.05). The mean FLT SUV and FDG SUV in nonintestinal tumours were higher than in intestinal tumours, although the difference was not statistically significant. The mean (±SD) FLT SUV in poorly differentiated tumours (8.5 ± 3.5) was significantly higher than that in well and moderately differentiated tumours (5.3 ± 2.1; p < 0.04). The mean FDG SUV in poorly differentiated tumours was higher than in well and moderately differentiated tumours, although the difference was not statistically significant. There was no significant correlation between Ki-67 index and either FLT SUV or FDG SUV. Conclusion  FLT PET showed as high a sensitivity as FDG PET for the detection of gastric cancer, although uptake of FLT in gastric cancer was significantly lower than that of FDG.     

Evaluation of the pharmacokinetics of 68Ga-DOTATOC in patients with metastatic neuroendocrine tumours scheduled for 90Y-DOTATOC therapy

Purpose The purpose of the study was to evaluate the pharmacokinetics of ⁶⁸Ga-DOTATOC in order to ascertain which parameters have the greatest impact on the global DOTATOC standardised uptake value (SUV), defined as the mean SUV of the last frame of the dynamic study 55–60 min p.i. Methods Twenty-two patients with 74 metastatic lesions were examined with dynamic ⁶⁸Ga-DOTATOC PET studies. Standardised uptake values (SUVs) were calculated for all frames following the injection of the tracer. We defined global SUV as the mean SUV of the last frame (frame duration 5 min) of the dynamic study 55–60 min p.i. A two-tissue compartment model with a blood compartment was used for the evaluation of the rate constants k ₁ (receptor binding), k ₂ (displacement from the receptor), k ₃ (cellular internalisation), k ₄ (cellular externalisation) and fractional blood volume (V_b). Furthermore, a non-compartmental model was applied for calculation of the fractal dimension (FD) of the time-activity curves based on the box counting procedure. Results Qualitative analysis revealed increased uptake of ⁶⁸Ga-DOTATOC in 21/22 patients and in 72/74 lesions. The SUV for ⁶⁸Ga-DOTATOC was highly variable, with a range from 0.877 to 28.07 (mean 8.73). The highest uptake was measured in a patient with a NET of the pancreas and the lowest in a patient with a medullary thyroid carcinoma (MEN II). The quantitative evaluation based on the compartmental analysis revealed high receptor binding (k ₁) and internalisation (k ₃) for ⁶⁸Ga-DOTATOC, and low cellular externalisation (k ₄) as well as a relatively low fractional blood volume (V_b). The FD values varied from 1.10 to 1.45, with a mean of 1.33. No significant linear correlation was found for k ₁ and k ₃. A low, linear correlation was noted for k ₁ and V_b (r=0.25,p=0.03), and there was a significant non-linear correlation between SUV and FD (r=0.74, p<0.001). Best subset analysis demonstrated that k ₁ had the greatest impact on the global SUV, followed by V_b and k ₃. Conclusion DOTATOC uptake in NETs is mainly dependent on k ₁ (receptor binding) and V_b (fractional blood volume). Pharmacokinetic data analysis can help to separate blood background activity (V_b) from the receptor binding (k ₁), which may help to optimise planning of ⁹⁰Y-DOTATOC therapy.     

Report on short-term side effects of treatments with <Superscript>177</Superscript>Lu-octreotate in combination with capecitabine in seven patients with gastroenteropancreatic neuroendocrine tumours

Purpose Treatment with the radiolabelled somatostatin analogue ¹⁷⁷Lu-octreotate results in tumour remission in 47% of patients with gastroenteropancreatic neuroendocrine tumours. Adding capecitabine to ¹⁷⁷Lu-octreotate, as a radio-sensitiser, may enhance these anti-tumour effects. We now present the short-term toxicity profile of this novel combination. Methods Seven patients were treated with 7.4 GBq ¹⁷⁷Lu-octreotate and capecitabine (1650 mg/m² per day) for 2 weeks with an intended number of four cycles. Toxicity, and especially haematological and renal parameters, were monitored on a weekly basis for the first two cycles and 4 and 6 weeks after subsequent cycles. Results None of the patients had hand-foot syndrome. One patient had grade 1 stomatitis occurring after one of four cycles. Grade 3 or 4 leukopenia or neutropenia did not occur. One patient had grade 3 anaemia, but none had grade 4 anaemia. One patient had grade 2 thrombocytopenia after the fourth cycle, and one had grade 3 thrombocytopenia. Grade 4 thrombocytopenia did not occur. No significant changes in serum creatinine levels were observed. None of the patients had symptoms of cardiac ischaemia. Conclusions Treatment with the combination of ¹⁷⁷Lu-octreotate and capecitabine was feasible and safe considering acute and subacute side effects. We therefore started a randomised, controlled clinical trial to compare this combination with ¹⁷⁷Lu-octreotate as single agent with regard to anti-tumour effects and side effects.     

<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.     

The value of 18F-DOPA PET-CT in patients with medullary thyroid carcinoma: comparison with 18F-FDG PET-CT

The purpose of this prospective study was to compare the value of DOPA PET-CT with FDG PET-CT in the detection of malignant lesions in patients with medullary thyroid carcinoma (MTC). Twenty-six consecutive patients (10 men, 16 women, mean age 59 ± 14 years) with elevated calcitonin levels were evaluated in this prospective study. DOPA and FDG PET-CT modalities were performed within a maximum of 4 weeks (median 7 days) in all patients. The data were evaluated on a patient- and lesion-based analysis. The final diagnosis of positive PET lesions was based on histopathological findings and/or imaging follow-up studies (i.e., DOPA and/or FDG PET-CT) for at least 6 months (range 6–24 months). In 21 (21/26) patients at least one malignant lesion was detected by DOPA PET, while only 15 (15/26) patients showed abnormal FDG uptake. DOPA PET provided important additional information in the follow-up assessment in seven (27%) patients which changed the therapeutic management. The patient-based analysis of our data demonstrated a sensitivity of 81% for DOPA PET versus 58% for FDG PET, respectively. In four (4/26) postoperative patients DOPA and FDG PET-CT studies were negative in spite of elevated serum calcitonin and CEA levels as well as abnormal pentagastrin tests. Overall 59 pathological lesions with abnormal tracer uptake were seen on DOPA and/or FDG PET studies. In the final diagnosis 53 lesions proved to be malignant. DOPA PET correctly detected 94% (50/53) of malignant lesions, whereas only 62% (33/53) of malignant lesions were detected with FDG PET. DOPA PET-CT showed superior results to FDG PET-CT in the preoperative and follow-up assessment of MTC patients. Therefore, we recommend DOPA PET-CT as a one-stop diagnostic procedure to provide both functional and morphological data in order to select those patients who may benefit from (re-)operation with curative intent as well as guiding further surgical procedures.     

<Superscript>68</Superscript>Ga-labelled DOTA-derivatised peptide ligands

⁶⁸Ge/⁶⁸Ga generators provide cyclotron-independent access to positron emission tomography (PET) radiopharmaceuticals. We describe a system which allows the safe and efficient handling of ⁶⁸Ge/⁶⁸Ga generator eluates for labelling of DOTA-derivatised peptide ligands. The system comprises concentration and purification of the ⁶⁸Ga eluate as well as labelling and purification steps for peptides, and can be used with different ⁶⁸Ge/⁶⁸Ga generator types. The suitability and efficiency were tested with two different DOTA-derivatised somatostatin derivatives and a DOTA-derivatised bombesin derivative. Amounts of 10–20 nmol of the peptides were sufficient and resulted in labelling yields of 50% for all peptides. The built-in safety precautions have proven to be appropriate in allowing use of the method for routine clinical applications. The system was set up and operated in a hot lab by personnel with no previous experience in the preparation of PET radiopharmaceuticals.     

Correlation of <Superscript>18</Superscript>F-FLT and <Superscript>18</Superscript>F-FDG uptake on PET with Ki-67 immunohistochemistry in non-small cell lung cancer

Purpose The nucleoside analogue 3′-deoxy-3′-¹⁸F-fluorothymidine (FLT) has recently been introduced for imaging cell proliferation with positron emission tomography (PET). We prospectively evaluated whether FLT uptake reflects proliferative activity as indicated by the Ki-67 index in non-small cell lung cancer (NSCLC), in comparison with 2-deoxy-2-¹⁸F-fluoro-D-glucose (FDG). Methods A total of 18 patients with newly diagnosed NSCLC were examined with both FLT PET and FDG PET. PET imaging was performed at 60 min after each radiotracer injection. Tumour lesions were identified as areas of focally increased uptake, exceeding background uptake in the lungs. For semi-quantitative analysis, the maximum standardised uptake value (SUV) was calculated. Proliferative activity as indicated by the Ki-67 index was estimated in tissue specimens. Immunohistochemical findings were correlated with SUVs. Results The sensitivity of FLT and FDG PET for the detection of lung cancer was 72% and 89%, respectively. Four of the five false-negative FLT PET findings occurred in bronchiolo-alveolar carcinoma. The mean FLT SUV was significantly lower than the mean FDG SUV. A significant correlation was observed between FLT SUV and Ki-67 index (r = 0.77; p < 0.0002) and for FDG SUV (r = 0.81; p < 0.0001). Conclusion The results of this preliminary study suggest that, compared with FDG, FLT may be less sensitive for primary staging in patients with NSCLC. Although FLT uptake correlated significantly with proliferative activity in NSCLC, the correlation was not better than that for FDG uptake.     

<Superscript>11</Superscript>C-methionine uptake in cerebrovascular disease: A comparison with<Superscript>18</Superscript>F-FDG PET and<Superscript>99m</Superscript>Tc-HMPAO SPECT

OBJECTIVES: Carbon-11-L-methyl-methionine (11C-methionine) has been reported to be useful for evaluating brain tumors, but several other brain disorders have also shown signs of high methionine uptake. We retrospectively evaluated the significance of 11C-methionine uptake in cerebrovascular diseases, and also compared our results with those for 18F-FDG PET and 99mTc-HMPAO SPECT. METHODS: Seven patients, including 3 patients with a cerebral hematoma and 4 patients with a cerebral infarction, were examined. All 7 patients underwent both 11C-methionine PET and 99mTc-HMPAO SPECT, and 6 of them underwent 18F-FDG PET. RESULTS: A high 11C-methionine uptake was observed in all 3 patients with cerebral hematoma. Increased 99mTc-HMPAO uptake was observed in 2 out of 3 patients, and all 3 patients had decreased 18F-FDG uptake. Of 4 patients with a cerebral infarction, high 11C-methionine uptake was observed in 3. Increased 99mTc-HMPAO uptake was also observed in one patient, whereas 3 patients had decreased 18F-FDG uptake. CONCLUSIONS: We should keep in mind that high 11C-methionine uptake is frequently observed in cerebrovascular diseases. CVD should therefore be included in the differential diagnosis when encounting patients with a high 11C-methionine uptake.     

<Superscript>18</Superscript>F-choline in experimental soft tissue infection assessed with autoradiography and high-resolution PET

For each oncological tracer it is important to know the uptake in non-tumorous lesions. The purpose of this study was to measure the accumulation of fluorine-18 choline (FCH), a promising agent for the evaluation of certain tumour types, in infectious tissue. Unilateral thigh muscle abscesses were induced in five rats by intramuscular injection of 0.1 ml of a bacterial suspension (Staphylococcus aureus, 1.2×10⁹ CFU/ml). In all animals, FCH accumulation was measured with high-resolution positron emission tomography (PET) on day 6. Autoradiography of the abscess and ipsilateral healthy muscle was performed on day 7 (three animals) and day 11 (two animals) and correlated with histology. In addition, ¹⁸F-fluorodeoxyglucose (FDG) PET was performed on day 5. Increased FCH uptake was noted in specific layers of the abscess wall which contained an infiltrate of mainly granulocytes on day 7 and mainly macrophages on day 11. The autoradiographic standardised uptake values in the most active part of the abscess wall were 2.99 on day 7 (n=3) and 4.05 on day 11 (n=2). In healthy muscle the corresponding values were 0.99 and 0.64. The abscesses were clearly visualised on the FCH and FDG PET images. In conclusion, this study demonstrated avid FCH accumulation in inflammatory tissue, which limits the specificity of FCH for tumour detection. Future studies are now needed to determine the degree of this limitation in human cancer patients.     

<Superscript>11</Superscript>C-methionine (MET) and <Superscript>18</Superscript>F-fluorothymidine (FLT) PET in patients with newly diagnosed glioma

Purpose  The purpose of this prospective study was to clarify the individual and combined role of l-methyl-¹¹C-methionine-positron emission tomography (MET-PET) and 3′-deoxy-3′-[¹⁸F]fluorothymidine (FLT)-PET in tumor detection, noninvasive grading, and assessment of the cellular proliferation rate in newly diagnosed histologically verified gliomas of different grades. Materials and methods  Forty-one patients with newly diagnosed gliomas were investigated with MET-PET before surgery. Eighteen patients were also examined with FLT-PET. MET and FLT uptakes were assessed by standardized uptake value of the tumor showing the maximum uptake (SUV_max), and the ratio to uptake in the normal brain parenchyma (T/N ratio). All tumors were graded by the WHO grading system using surgical specimens, and the proliferation activity of the tumors were determined by measuring the Ki-67 index obtained by immunohistochemical staining. Results  On semiquantitative analysis, MET exhibited a slightly higher sensitivity (87.8%) in tumor detection than FLT (83.3%), and both tracers were 100% sensitive for malignant gliomas. Low-grade gliomas that were false negative on MET-PET also were false negative on FLT-PET. Although the difference of MET SUV_max and T/N ratio between grades II and IV gliomas was statistically significant (P < 0.001), there was a significant overlap of MET uptake in the tumors. The difference of MET SUV_max and T/N ratio between grades II and III gliomas was not statistically significant. Low-grade gliomas with oligodendroglial components had relatively high MET uptake. The difference of FLT SUV_max and T/N ratio between grades III and IV gliomas was statistically significant (P < 0.01). Again, the difference of FLT SUV_max and T/N ratio between grades II and III gliomas was not statistically significant. Grade III gliomas with non-contrast enhancement on MR images had very low FLT uptake. In 18 patients who underwent PET examination with both tracers, a significant but relatively weak correlation was observed between the individual SUV_max of MET and FLT (r = 0.54, P < 0.05) and T/N ratio of MET and FLT (r = 0.56, P < 0.05). Total FLT uptake in the tumor had a higher correlation (r = 0.89, P < 0.001) with Ki-67 proliferation index than MET uptake (r = 0.49, P < 0.01). Conclusions  PET studies using MET and FLT are useful for tumor detection in newly diagnosed gliomas. However, there is no complimentary information in tumor detection with simultaneous measurements of MET- and FLT-PET in low grade gliomas. FLT-PET seems to be superior than MET-PET in noninvasive tumor grading and assessment of proliferation activity in gliomas of different grades.     

Correlation of immunohistopathological expression of somatostatin receptor 2 with standardised uptake values in <Superscript>68</Superscript>Ga-DOTATOC PET/CT

Purpose  In clinical routine somatostatin analogue positron emission tomography/computed tomography (PET/CT) such as ⁶⁸Ga-DOTA-Tyr-octreotide (DOTATOC)-PET/CT could substitute conventional ¹¹¹In-Octreotide scintigraphy. Immunohistochemistry (IHC) for somatostatin receptor 2 (SSTR2) might be a tool to predict positivity of ⁶⁸Ga-DOTATOC in patients where initial staging was not performed, e.g., in incidental findings. We therefore compared a score of SSTR2-IHC with the in vivo standard uptake value (SUV) of preoperative or prebiopsy ⁶⁸Ga-DOTATOC PET/CT. Materials and methods  In 18 patients, ⁶⁸Ga-DOTATOC PET/CT scans were quantified with SUV calculations and correlated to a cell membrane-based SSTR2-IHC score (ranging from 0 to 3). Results  Negative IHC scores were consistent with SUV values below 10. Furthermore, all score 2 and 3 specimens corresponded with high SUV values (above 15). Conclusion  SSTR2-IHC scores correlated well with SUV values and we propose to use SSTR2 immunohistochemistry in patients missing a preoperative PET scan to indicate ⁶⁸Ga-DOTATOC-PET/CT as method for restaging and follow-up in individual patients.     

Radio-guided surgery with the use of [<Superscript>99m</Superscript>Tc-EDDA/HYNIC]octreotate in intra-operative detection of neuroendocrine tumours of the gastrointestinal tract

Purpose Radio-guided surgery (RGS) is an intra-operative localising technique which enables identification of tissue “marked” by a specific radiotracer injected before surgery. It is mainly used for sentinel node mapping and for detection of parathyroid adenomas and other tumours, including neuroendocrine tumours of the gastrointestinal tract (GEP-NET). The aim of this study was to determine whether intra-operative radio-detection with the use of [^99mTc-EDDA/HYNIC]octreotate, a new somatostatin analogue, is able to reveal an unknown primary and secondary sites, thereby improving surgical treatment and the final outcome of GEP-NET. Methods The study group included nine patients with suspected GEP-NET (four carcinoids, five pancreatic NET) localised with somatostatin receptor scintigraphy (with [^99mTc-EDDA/HYNIC]octreotate), who had negative results on other pre-operative imaging tests. At surgery, suspected tumours were measured in situ and ex vivo and precise exploration of the abdominal cavity was performed with the intra-operative scintillation detector (Navigator). Results Intra-operative gamma counting localised three carcinoids. In one patient SRS was false positive (owing to inflammatory infiltration). Compared with SRS, RGS revealed additional lymph node metastases in one case. RGS resulted in successful localisation of all pancreatic NET (the smallest lesion was 8 mm in diameter). Conclusion [^99mTc-EDDA/HYNIC]octreotate SRS followed by RGS is a promising technique to improve the rate of detection and efficacy of treatment of GEP-NET, especially in the presence of occult endocrine tumours. The imaging properties of [^99mTc-EDDA/HYNIC]octreotate and the 1-day imaging protocol offer opportunities for more widespread application of this tracer followed by RGS in oncology.     

Comparison of the biodistribution of two hypoxia markers [<Superscript>18</Superscript>F]FETNIM and [<Superscript>18</Superscript>F]FMISO in an experimental mammary carcinoma

The first aim of this study was to compare the hypoxia imaging ability of fluorine-18 fluoroerythronitroimidazole ([¹⁸F]FETNIM) with that of fluorine-18 fluoromisonimidazole ([¹⁸F]FMISO) in murine tumours of different sizes under two different oxygenation conditions. Secondly, we wanted to assess the biodistribution of the markers in normal tissues under similar conditions. Female CDF1 mice with a C3H mammary carcinoma grown on their backs were used. Tumours were size matched and animals breathed either normal air (21% O₂) or carbogen gas (95% O₂ + 5% CO₂). The gassing procedure was begun 5 min before the intravenous injection of either [¹⁸F]FETNIM or [¹⁸F]FMISO and continued until the mice were sacrificed at 120 min. Blood, tumour, muscle, heart, lung, liver, kidney and fat were removed, counted for radioactivity and weighed. The tumour and muscle were frozen and cut with a cryomicrotome into sections. The spatial distribution of radioactivity from the tissue sections was determined with digital autoradiography. Estimation of the necrotic fraction was made on sections from formalin-fixed tumours. Digital autoradiography showed that the whole tumour-to-muscle radioactivity uptake ratios were significantly higher in normal air-breathing mice than in carbogen-treated mice for both [¹⁸F]FETNIM (4.9±2.6 vs 1.8±0.5; P<0.01) and [¹⁸F]FMISO (4.4±1.0 vs 1.5±0.4; P<0.01). The carbogen treatment had only slight effects on the biodistribution of either marker in normal tissues. The necrotic fraction determined in tumours did not correlate with the tumour volume or with the tumour-to-muscle radioactivity uptake ratio. This study shows that the uptake of both [¹⁸F]FETNIM and [¹⁸F]FMISO correlates with the oxygenation status in tumours. In addition, our data show no significant difference in the intratumoral uptake between the two markers. However, significantly higher radioactivity uptake values were measured for [¹⁸F]FMISO than for [¹⁸F]FETNIM in normal tissues.     

Optimal dose of <Superscript>18</Superscript>F-FDG required for whole-body PET using an LSO PET camera

Reducing the acquisition time of whole-body fluorine-18 fluorodeoxyglucose positron emission tomography (¹⁸F-FDG PET) (corrected for attenuation) is of major importance in clinical practice. With the introduction of lutetium oxyorthosilicate (LSO), the acquisition time can be dramatically reduced, provided that patients are injected with larger amounts of tracer and/or the system is operated in 3D mode. The aim of this study was to determine the optimal dose of ¹⁸F-FDG required in order to achieve good-to-excellent image quality when a "3-min emission, 2-min transmission/bed position" protocol is used for an LSO PET camera. A total of 218 consecutive whole-body ¹⁸F-FDG PET studies were evaluated retrospectively. After excluding patients with liver metastases, hyperglycaemia and paravenous injections, the final study population consisted of 186 subjects (112 men, 74 women, age 59±15 years). Patients were injected with an activity of ¹⁸F-FDG ranging from 2.23 to 15.21 MBq/kg. Whole-body images corrected for attenuation (3 min emission, 2 min transmission/bed position) were acquired with an LSO PET camera (Ecat Accel,Siemens) 60 min after tracer administration. Patients were positioned with their arms along the body. Image reconstruction was done iteratively and a post-reconstruction filter was applied. Image quality was scored visually by two independent observers using a five-point scoring scale (poor, reasonable, good, very good, excellent). In addition, the coefficient of variability (COV) was measured in a region of interest over the liver in order to quantify noise. Of the images obtained in 118 patients injected with 8 MBq/kg ¹⁸F-FDG, 92% and 90% were classified as good, very good or excellent by observer 1 and observer 2, respectively. The COV averaged 10.63%±3.19% for doses 8 MBq/kg and 16.46%±5.14% for doses <8 MBq/kg. Administration of an ¹⁸F-FDG dose of 8 MBq/kg results in images of good to excellent quality in the vast majority of patients when using an LSO PET camera and applying a 3-min emission, 2-min transmission/bed position acquisition protocol. At lower doses, a rapid decline in image quality and increasing noise are observed. Alternative protocols should be adopted in order to compensate for the loss in image quality when doses <8 MBq/kg are used.