Heikki Minn

Florodeoxyglucose imaging: A method to assess the proliferative activity of human cancer in vivo. Comparison with DNA flow cytometry in head and neck tumors

Thirteen patients with malignant head and neck tumors were studied before they were treated with (18F) fluorodeoxyglucose (FDG) imaging and DNA flow cytometry (FCM). The nuclear DNA content and the percentage of proliferative cells (S+G2/M) were compared with the FDG uptake; FDG was retained in the primary tumor and/or neck metastasis in all patients. The accumulation of FDG did not correlate with histologic grade of the tumors, but there was a clear correlation (r = 0.86, P > 0.001) between the proportion of the cells in S+G2/M phases of the cell cycle and the intensity of FDG accumulation. The uptake of FDG by the tumor also correlated with the percentage of S‐phase cells (r = 0.82, P > 0.001). The result suggests that enhanced glucose metabolism, measured by FDG uptake, is associated with the proliferative activity of the tumor. Thus, imaging with FDG may offer a new method to assess the aggressiveness of human cancer growth in vivo.

A prospective diagnostic accuracy study of 18F-fluorodeoxyglucose positron emission tomography/computed tomography, multidetector row computed tomography, and magnetic resonance imaging in primary diagnosis and staging of pancreatic cancer.

Objective:To prospectively compare the accuracy of combined positron emission tomography/computed tomography using 18F-fluorodeoxyglucose (FDG-PET/CT), multidetector row computed tomography (MDCT), and magnetic resonance imaging (MRI) in the evaluation of patients with suspected pancreatic malignancy. Summary Background Data:FDG-PET/CT imaging is increasingly used for staging of pancreatic cancer. Preliminary data suggest a significant influence of FDG-PET/CT on treatment planning, although its role is still evolving. Methods:Thirty-eight consecutive patients with suspicion of pancreatic malignancy were enrolled. Patients underwent a protocol including FDG-PET/CT, MDCT, and MRI combined with magnetic resonance cholangiopancreatography, all of which were blindly evaluated. The findings were confirmed macroscopically at operation and/or by histopathologic analysis (n = 29) or follow-up (n = 9). Results of TNM classification of different imaging methods were compared with clinical TNM classification. Results:Pancreatic adenocarcinoma was diagnosed in 17 patients, neuroendocrine tumor in 3, mass-forming pancreatitis in 4, cystic lesion in 6, and fibrosis in 2. Six patients had a finding of a normal pancreas. The diagnostic accuracy of FDG-PET/CT for pancreatic malignancy was 89%, compared with 76% and 79% for MDCT and MRI, respectively. In the differential diagnosis of suspected malignant biliary stricture at endoscopic retrograde cholangiopancreaticography (n = 21), FDG-PET/CT had a positive predictive value of 92%. In 17 patients with advanced pancreatic adenocarcinoma, FDG-PET/CT had a sensitivity of 30% for N- and 88% for M-staging. Both MDCT and MRI had sensitivities of 30% for N- and 38% for M-staging. Furthermore, the clinical management of 10 patients (26%) was altered after FDG-PET/CT. Conclusion:FDG-PET/CT was more sensitive than conventional imaging in the diagnosis of both primary pancreatic adenocarcinoma and associated distant metastases. In contrast, the sensitivity of FDG-PET/CT was poor in detecting local lymph node metastasis, which would have been important for an assessment of resectability. We recommend the use of FDG-PET/CT in the evaluation of diagnostically challenging cases, especially in patients with biliary strictures without evidence of malignancy in conventional imaging.

Prospective Analysis of Accuracy of Positron Emission Tomography, Computed Tomography, and Endoscopic Ultrasonography in Staging of Adenocarcinoma of the Esophagus and the Esophagogastric Junction

AbstractBackground: Exact preoperative staging of esophageal cancer is essential for accurate prognosis and selection of appropriate treatment modalities. Methods: Forty-two patients with adenocarcinoma of the esophagus or the esophagogastric junction suitable for radical esophageal resection were staged with positron emission tomography (PET), spiral computed tomography (CT), and endoscopic ultrasonography (EUS). Results: Diagnostic sensitivity for the primary tumor was 83% for PET and 67% for CT; for local peritumoral lymph node metastasis, it was 37% for PET and 89% for EUS; and for distant metastasis, it was 47% for PET and 33% for CT. Diagnostic specificity for local lymph node metastasis was 100% with PET and 54% with EUS, and for distant metastasis, it was 89% for PET and 96% for CT. Accuracy for locoregional lymph node metastasis was 63% for PET, 66% for CT, and 75% for EUS, and for distant metastasis, it was 74% with PET and 74% with CT. Of the 10 patients who were considered inoperable during surgery, PET identified 7 and CT 4. The false-negative diagnoses of stage IV disease in PET were peritoneal carcinomatosis in two patients, abdominal para-aortic cancer growth in one, metastatic lymph nodes by the celiac artery in four, and metastases in the pancreas in one. PET showed false-positive lymph nodes at the jugulum in three patients. Conclusions: The diagnostic value of PET in the staging of adenocarcinoma of the esophagus and the esophagogastric junction is limited because of low accuracy in staging of paratumoral and distant lymph nodes. PET does, however, seem to detect organ metastases better than CT.

18F-EF5: A New PET Tracer for Imaging Hypoxia in Head and Neck Cancer

The aim of this study was to evaluate 2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)-acetamide (EF5) labeled with 18F-fluorine to image hypoxia in patients with squamous cell carcinoma of the head and neck (HNSCC). Methods: Fifteen patients with HNSCC were studied. Measurement of tumor blood flow was followed by an 18F-EF5 PET/CT scan. On a separate day, 18F-FDG PET/CT was performed to determine the metabolically active tumor volume. In 6 patients, dynamic 18F-EF5 images of the head and neck area were acquired, followed by static images acquired at 1, 2, and 3 h after injection. In the remaining 9 patients, only static images were obtained. 18F-EF5 uptake in tumors was compared with that in neck muscle, and the 18F-EF5 findings were correlated with the 18F-FDG PET/CT studies. Results: A total of 13 primary tumors and 5 lymph node metastases were evaluated for their uptake of 18F-EF5. The median tumor-to-muscle 18F-EF5 uptake ratio (T/M) increased over time and was 1.38 (range, 1.1–3.2) 3 h after tracer injection. The median blood flow in tumors was 36.7 mL/100 g/min (range, 23.3–78.6 mL/100 g/min). Voxel-by-voxel analysis of coregistered blood flow and 18F-EF5 images revealed a distinct pattern, resulting in a T/M of 1.5 at 3 h to be chosen as a cutoff for clinically significant hypoxia. Fourteen of 18 tumors (78%) had subvolumes within the metabolically active tumor volumes with T/M greater than or equal to 1.5. Conclusion: On the basis of these data, the potential of 18F-EF5 to detect hypoxia in HNSCC is encouraging. Further development of 18F-EF5 for eventual targeting of antihypoxia therapies is warranted.

Radiotherapy treatment planning and long-term follow-up with [11C]methionine PET in patients with low-grade astrocytoma

PURPOSE To evaluate the feasibility of [(11)C]-methionine positron emission tomography (MET PET) in radiotherapy (RT) treatment planning and long-term follow-up in patients with low-grade glioma. PATIENTS Thirteen patients with low-grade astrocytoma and 1 with anaplastic astrocytoma underwent sequential MET PET and magnetic resonance imaging (MRI) before and 3, 6, 12, and 21-39 months after RT, respectively. Ten patients were studied after initial debulking surgery or biopsy and 4 in the recurrence phase. METHODS A total of 58 PET scans were performed. After transmission scanning, a median dose of 425 MBq of MET was injected intravenously and emission data was acquired 20 min after injection for 20 min. The uptake of MET in tumor area was measured as standardized uptake value (SUV) and tumor-to-contralateral brain SUV ratios were generated to assess irradiation effects on tumor metabolism. Functional imaging with PET was compared with concurrent MRI in designing the RT planning volumes and in assessment of response to RT during a median follow-up time of 33 months. RESULTS In 12 patients (86%), tumor area was clearly discernible in the baseline PET study. In the remaining 2 patients with a suspected residual tumor in MRI, PET showed only a diffuse uptake of MET interpreted as negative in the original tumor area. In the dose planning of RT, MET PET was helpful in outlining the gross tumor volume in 3 of 11 cases (27%), whereas PET findings either coincided with MRI (46%) or were less distinctive (27%) in other cases. In quantitative evaluation, patients with a low tumor SUV initially had significantly better prognosis than those with a high SUV. Tumor-to-contralateral brain uptake ratios of MET discriminated well patients remaining clinically stable from those who have since relapsed or died of disease. CONCLUSION Quantitative MET PET has prognostic value at the time of initial treatment planning of low-grade glioma. Some patients may benefit of RT volume definition with MET PET, which seems to disclose residual tumor better than MRI in selected cases. Stable or decreasing uptake of MET in tumor area after RT during follow-up seems to be a favorable sign.

[18F]Fluorodeoxyglucose scintigraphy in diagnosis and follow up of treatment in advanced breast cancer

Seventeen patients with advanced breast cancer were imaged with a specially collimated gamma camera to study tumor uptake of 2-[18F]-fluoro-2-deoxy-D-glucose (FDG) before and during therapy. Fourteen patients (82%) showed increased FDG accumulation in metastatic tumors, 6/8 (75%) of axillary, supra or infraclavicular metastatic lymph nodes were detectable. In one of these cases, FDG imaging was the first method to identify axillary metastasis causing nerve compression. Also, pulmonary and liver metastases could be imaged with FDG; both in two patients. The intra individual variability in uptake was considerable in bone metastases, and some lesions remained FDG negative:99mTc-DPD was superior in detecting bone disease. Bone metastases of the osteolytic or mixed type were better visualized than sclerotic ones. Ten patients were reimaged later to assess the effect of therapy on FDG uptake. Increased uptake was associated with clinical progression, while unchanged or diminished uptake did not predict the course of disease as reliably. This study indicates that FDG can be used to image breast cancer metastases. FDG may be valuable in monitoring treatment response, but positron emission tomography (PET) would probably be more appropriate than planar imaging for this purpose.

Blood metabolism of [methyl-11C]choline; implications for in vivo imaging with positron emission tomography

Abstract.[methyl-11C]Choline (11C-choline) is a radioligand potentially useful for oncological positron emission tomography (PET). As a first step towards the development of a kinetic model for quantification of 11C-choline uptake, blood metabolism of 11C-choline during PET imaging was studied in humans. High-performance liquid chromatography (HPLC) and thin-layer chromatography (TLC) were used for the analysis of 11C-choline and its radioactive metabolites. Prior to human PET imaging we studied ex vivo the biodistribution and metabolism of intravenously administered 11C-choline in rats. Our results revealed that the radioactivity accumulated particularly in kidney, lung, adrenal gland and liver. Chromatographic analysis showed that the level of unmetabolized 11C-choline in rat plasma decreased from 42%±20% (mean±SD) at 5 min to 21%±10% at 15 min after injection. In accordance with these findings, in humans the unmetabolized 11C-choline represents 62%±19% of the total radioactivity in arterial plasma at 5 min after injection and 27%±12% at 15 min. In human venous plasma the corresponding values were 85%±12% and 48%±12% at 5 and 10 min, respectively. The major metabolite observed in both human and rat plasma was identified as 11C-betaine. In human arterial plasma this maximally represented 82%±9% of the total radioactivity at 25 min after radiotracer injection. By 20 min after injection, the 11C-choline and 11C-betaine in human arterial plasma reached a plateau, and their fractional activities remained nearly constant thereafter. Although most of the circulating 11C-choline in blood is transported to tissues, it does not disappear totally from blood within the first 40 min after tracer injection.

Prognosis of patients treated for intracranial metastases with whole-brain irradiation

Seventy-five patients with brain metastases from solid tumours were treated with whole-brain irradiation at our institution between 1990 and 1993. The primary cancers included 35 cases of lung cancer, 19 cases of breast cancer, nine cases of renal-cell cancer, six cases of melanoma and six cases of other primary sites. In each case the total dose to the whole brain was at least 25 gray (Gy). The primary site, age, performance status, number of brain metastases and the presence of extracranial disease were studied as prognostic factors for survival. The median survival for the whole population was 4 months (range 1-62 months). The patients with the brain as the only metastatic site had significantly better survival (P = 0.019) than those with both intracranial and extracranial metastatic sites. Poor performance status at the time of diagnosis of brain metastases was also related to short survival (P = 0.001). None of the other studied variables had prognostic significance. Four of the 75 patients with primary tumour sites in the breast (two patients) and the kidney (two patients) survived for more than 2 years. In general, patients with breast cancer had better survival than patients with other primary cancers. Our study confirms the generally poor prognosis of cancer with brain metastases, although individual patients may survive several years after whole-brain irradiation. Approximately two-thirds of the patients experienced a relief in symptoms allowing a reduction in the dose of corticosteroid medication, which clearly supports the use of whole-brain radiotherapy as a palliative treatment.

Experience in qualitative and quantitative FDG PET in follow-up of patients with suspected recurrence from head and neck cancer

We evaluated positron emission tomography (PET) with 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG) in the detection of recurrent head and neck cancer, and compared visual and quantitative interpretation of PET images for their accuracy in the identification of tumour recurrence. Sixty-two FDG PET studies were performed in 56 patients having a total of 81 lesions, which were clinically suspected for recurrent carcinoma of the head and neck. The PET images were interpreted visually, and tracer uptake was quantitated as the standardised uptake value adjusted to body weight (SUV). Sensitivity of visual interpretation of the PET images for the presence of malignancy ranged from 84 to 95%, and specificity from 84 to 93%, respectively, depending on the selected scheme for grading of the lesions. Malignant lesions accumulated significantly more FDG than the benign ones (the median SUVs were 6.8 and 3.3, respectively, P<0.001). However, there was a wide overlap of the FDG uptake values between these two groups. Hence, the highest accuracy of quantitative analysis in correct identification of tumour recurrence (75% at Receiver Operating Curve analysis) was inferior to that of visual analysis (89%). FDG PET is feasible for the detection of recurrent head and neck cancer. Although quantitation of FDG uptake using SUV shows significantly higher tracer concentrations for malignant than benign lesions, the wide overlap of individual SUVs between these two groups is a serious concern in diagnostic evaluation. Therefore, in clinical practice it may be preferable to identify the presence of tumour recurrence within this patient group by qualitative interpretation of the PET images.

Decreased Blood Flow with Increased Metabolic Activity: A Novel Sign of Pancreatic Tumor Aggressiveness

Purpose: To study blood flow (BF) and metabolism in normal pancreas and in different pancreatic lesions. We then determined the effect of these biomarkers on outcome in patients with pancreatic cancer. Experimental Design: Oxygen-15–labeled water and fluorodeoxyglucose positron emission tomography/computed tomography scans were used in 26 patients with a suspicion of pancreatic cancer to measure pancreatic BF and metabolism. In addition, the ratio of standardized uptake value to BF (SUV/BF) was calculated. Patients were divided into three groups: patients with a finding of normal pancreas (n = 7), benign lesions (n = 8), and malignant tumors (n = 11). Results: Patients with benign and malignant pancreatic tumors had decreased BF of the lesion by 48% and 60%, respectively, compared with patients with normal pancreatic tissue. SUVmax was 3-fold higher in malignant tumors compared with both benign lesions and normal pancreas (P < 0.05). In contrast, the SUVmax of patients with benign lesions and normal pancreas did not differ. The SUV/BF ratio was significantly higher in malignant lesions than in benign lesions or in patients with normal pancreas (P < 0.05). In patients with cancer, high SUV/BF ratio was a stronger predictor of poor survival compared with high metabolism or lower-than-normal pancreatic BF. Conclusions: BF in pancreatic cancer is significantly reduced compared with the normal pancreas, which may in part explain the poor success of both radiotherapy and chemotherapy. We suggest that the composite measurement of BF and metabolism in pancreatic cancer could serve as a novel tool in the planning of treatments targeting vasculature. (Clin Cancer Res 2009;15(17):5511–7)