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In patients with cancer, performance was assessed of a commercially available triple-head gamma camera fitted with ultra-high energy parallel-hole collimators performing single photon emission computed tomography (SPECT) with 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG). Results were compared with those of positron emission tomography (PET) with FDG.Performance characteristics were first determined in phantom studies for FDG PET and triple-head gamma camera SPECT systems. In 13 patients with malignancies, FDG PET was followed by SPECT of the same region, and imaging results were independently assessed.Sensitivity of the PET and SPECT systems was 58.3 counts/MBq/min and 4.5 counts/MBq/min, respectively. Reconstructed spatial resolution was approximately 7 mm for PET and 20 mm for SPECT. All known cancer foci were detected at PET. SPECT depicted 11 of the 22 lesions detected at PET, but only five of the 14 lesions less than 3 cm in diameter.FDG SPECT performed with a specially collimated triple-head gamma camera depicted some cancers but had an unacceptably low sensitivity compared with PET for lesions less than 3 cm in diameter. PET is preferable for detecting small cancers.

80 Background: Gastrin-releasing-peptide receptor (GRPr) is overexpressed in prostate carcinoma (PCa) and offer new means to detect prostate cancer. The bombesin derivative RM2 (DOTA-4-amino-1-carboxymethylpiperidine-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2) is a GRPr antagonist with high binding affinity (Kd 3 nM). A first-in-man study was performed to assess tumor targeting potential of [68Ga]RM2 in patients with local PCa using PET/CT. Based on promising results a Phase I/II study in local PCa was initiated. Methods: In the initial study eleven men with biopsy-proven PCa scheduled for radical prostatectomy were enrolled. The patients (pt) received an i.v. dose of 140 MBq of [68Ga]RM2 followed by dynamic imaging for at least 60 min p.i. The PET assessment included visual evaluation of [68Ga]RM2 intra-prostatic and nodal uptake as well as quantification. An ongoing Phase I/II study is designed to enroll 30+50 biopsy-positive PCa patients. The initial 30 pt have been enrolled, stratified into high, intermediate and low risk of prostate Ca recurrence as defined by NCCN criteria. Results: High uptake of [68Ga]RM2 is seen in pancreas and the urinary system with low background in the rest of the body. Despite of high bladder activity focal or multifocal intraprostatic uptake was detectable. In the first study 10 of 11 pt had positive scans. Subsector analysis of PET positivity vs. pathology yielded a sensitivity, specificity and accuracy of 89, 81, and 83%, respectively. SUVmax was measured in 14 lesions from 9 pts, classified in two groups according to postoperative Gleason score (GS). The higher GS group showed a trend toward higher SUV-values, 10.0 ± 6.7 vs. 6.2 ± 2.5 (t-test: t = -1.21, p-value = 0.28). Both of which were elevated compared to normal tissue 1.2 ± 0.8 The ongoing study is designed with a power of 95% to discriminate between the two GS groups with statistical significance (p = 0.05). Conclusions: [68Ga]RM2 is a promising new tracer with a high detection rate for PCa. Preliminary data indicates higher uptake in more aggressive cancers. The current study is assessing the diagnostic accuracy and impact of presurgical risk assessment on tumor detection in newly diagnosed PCa patients. Clinical trial information: NCT02483884.

Smoking is the major cause of lung, laryngeal and bladder cancer. The exact mechanisms of carcinogenic substances in tobacco smoke are not known, but signaling pathways mediated via cyclooxygenase and its derivatives are considered the most important mechanisms. Cessation of smoking lowers the risk of disease at all ages. Besides increasing the risk of developing cancer, smoking also worsens the prognosis of a cancer patient and increases adverse effects of cancer treatments. Cessation of smoking is an essential part of appropriate cancer therapy resulting in positive effect on the prognosis and quality of life of the patient.

Background and purpose Stereotactic lung radiotherapy (SLRT) has emerged as a curative treatment for medically inoperable patients with early-stage non-small cell lung cancer (NSCLC) and the use of intensity-modulated radiotherapy (IMRT) and volumetric modulated arc treatments (VMAT) have been proposed as the best practical approaches for the delivery of SLRT. However, a large number of narrow field shapes are needed in the dose delivery of intensity-modulated techniques and the probability of underdosing the tumour periphery increases as the effective field size is decreased. The purpose of this study was to evaluate small lung tumour doses irradiated by intensity-modulated techniques to understand the risk for dose calculation errors in precision radiotherapy such as SLRT. Materials and methods The study was executed with two heterogeneous phantoms with targets of Ø1.5 and Ø4.0 cm. Dose distributions in the simulated tumours delivered by small sliding window apertures (SWAs), IMRT and RapidArc treatment plans were measured with radiochromic film. Calculation algorithms of pencil beam convolution (PBC) and anisotropic analytic algorithm (AAA) were used to calculate the corresponding dose distributions. Results Peripheral doses of the tumours were decreased as SWA decreased, which was not modelled by the calculation algorithms. The smallest SWA studied was 2 mm, which reduced the 90% isodose line width by 4.2 mm with the Ø4.0 cm tumour as compared to open field irradiation. PBC was not able to predict the dose accurately as the gamma evaluation failed to meet the criteria of ±3%/±1 mm on average in 61% of the defined volume with the smaller tumour. With AAA the corresponding value was 16%. The dosimetric inaccuracy of AAA was within ±3% with the optimized treatment plans of IMRT and RapidArc. The exception was the clinical RapidArc plan with dose overestimation of 4%. Conclusions Overall, the peripheral doses of the simulated lung tumours were decreased by decreasing the SWA. To achieve adequate surface dose coverage to small lung tumours with a difference less than 1 mm in the isodose line radius between the open and modulated field, a larger than 6 mm SWA should be used in the dose delivery of SLRT.

Hypoxia is one of the key features conferring resistance to oncologic treatment. Modern radiotherapy aims at overcoming hypoxia-induced resistance by escalating or redistributing dose or by modulating the sensitivity of poorly oxygenated but viable tumour cells. To accomplish this, it is necessary to detect hypoxia both spatially and temporally and to recognise limitations in sensitivity to differentiate oxic and hypoxic tumour subvolumes. Currently, PET/CT-based imaging using radiolabelled nitroimidazole or thiosemicarbazone compounds is the preferred technique for biological dose planning targeting hypoxia. Hypoxic tumour cells identified on PET/CT may be treated by giving a graded higher dose in a limited number of hypoxic compartments or by individually prescribing a dose to each volume unit based on 3D mapping of tumour oxygenation status. The latter technique is commonly called dose painting by numbers (DPN) to illustrate the heterogeneous dose received by the hypoxic target. Dose planning requires sophisticated computer algorithms where intensity-modulated radiotherapy (IMRT) is used to deliver irradiation. It is not yet known which strategy for planning and delivering hypoxia-targeted radiotherapy is the most appropriate in the clinical setting and what role chemical and biological modifiers of oxygenation will play given the lack of outcome data. Furthermore, adaptive strategies accounting for the effect of reoxygenation and cyclic hypoxia should be studied as well. This chapter outlines biological, methodological and technical issues associated with hypoxia-directed radiation therapy planning with emphasis on their potential application in clinical practice.

The expression of glucose transporter genes (GLUTI-4) was studied in 20 head-and-neck tumors of 18 patients. All tumors--16 of which were squamous-cell carcinomas (SCC)--expressed GLUT1 and/or GLUT3 mRNA, while detectable levels of GLUT2 or GLUT4 mRNA were not observed. The signals for GLUT1 and GLUT3 mRNAs varied markedly throughout the SCC tumor population but no clear relationship with the grade of differentiation was found. The high GLUT expression observed in some tumors was not associated with amplification or rearrangement of the corresponding genes. Immunohistochemistry of 5 SCCs showed that GLUT1 protein was located in tumor-cell membranes in relation to the level of mRNA expression. We conclude that both GLUT1 and GLUT3 are involved in basal glucose uptake of extracranial head-and-neck tumors. The increased expression of these high-affinity GLUT isoforms may be related to the growth maintenance of cancer tissue in cases of limited supply of substrate e.g., in poorly vascularized tumor areas.

Precise staging and knowledge of the aggressiveness and manner of growth of the tumor provide the cornerstone for a treatment plan for head and neck cancer. Although the basic methods of imaging have remained relatively unchanged for some decades, the information about the properties of the tumor provided by molecular imaging and gene research is changing the status of diagnostics. The aim is more personalized treatment. Appropriately conducted imaging reduces total treatment costs, despite the fact that novel methods may seem expensive at the time of therapeutic decision.

Securin is an oncogene with functions in cell proliferation, tumour initiation and progression. Its prognostic value in rectal cancer is somewhat unknown. Accordingly, we studied securin expression together with Ki-67 in rectal cancer in relation to preoperative (chemo)radiotherapy (RT) and disease outcome.Biopsies (n = 65 for securin; n = 57 for Ki-67) and operative specimens (n = 207) from 211 patients treated with short-course RT (n = 87), long-course RT (n = 54) or surgery only (n = 70) were studied with immunohistochemistry (IHC) for securin and Ki-67 expression. In the long-course RT group, 45 patients received chemotherapy (5-fluorouracil or capecitabine) concomitantly with RT. The results of IHC were related to clinicopathological variables, disease outcome and tumour regression grade (TRG) after long-course RT.Both markers showed significant reduction after RT (p0.001). No differences in expression was seen in the long-course RT group between the patients with or without concomitant chemotherapy (p = 0.23 for securin; p = 0.31 for Ki-67). Low Ki-67 expression, but not that of securin, in operative specimens was significantly related to excellent TRG (p = 0.02 for Ki-67; p = 0.21 for securin). In univariate survival analysis, excellent TRG predicted longer disease-specific survival (DSS; p = 0.03). In multivariate Cox analysis, high securin expression after long-course (chemo)RT was an independent predictor of shorter DSS (p = 0.036) together with patient age (p = 0.043) and disease recurrence (local or distant; p = 0.009), whereas no similar appearance was seen in other treatment groups.Securin expression in rectal cancer is significantly reduced after RT. High securin expression and poor TRG after long-course (chemo)RT are indicators of unfavourable disease outcome.

A positron-sensitive, large-window single-wire proportional counter was used for measurements of [11C]CO 2 in exhaled air after i.v. injection of [11C]acetate. The performance of the proportional counter was studied using Geant4 and Garfield simulation tools as well as experimentally by injections of known amounts of radioactive gas into the measuring volume. The proportional counter was found to be sensitive enough for measuring the low concentrations of [11C]CO 2 in the air exhaled by patients after i.v. injection of an 11C-labelled radiopharmaceutical. The limit of detection was 200 Bq/L for [11C]CO 2 .

Combination of positron emission tomography (PET) and computed tomography (CT) has revolutionized imaging of cancer. The most often used PET tracer is fluorodeoxyglucose (FDG). FDG-PET/CT shows the extent of the disease more accurately than either CT or MRI alone. With FDG-PET/CT imaging, up to 30% more patients are presented with unexpected distant metastases. This helps to guide patient management.

This study suggests that although oxygen partial pressure in tissue (p(ti)O(2)) measurement is a feasible method for continuous postoperative monitoring of free flaps, low correlation between blood pressure (BP) and p(ti)O(2) might predict compromised overall outcome. Thus, it is of utmost importance to keep the BP optimal for adequate perfusion of re-anastomosed tissue transfers.Optimal BP is an important factor in assuring adequate blood flow in a free flap. Tissue oxygenation in free flaps as a postoperative monitoring target is in routine clinical use in some clinics. Correlation between p(ti)O(2) and systemic BP was investigated.Ten consecutive patients underwent resection of head and neck squamous cell carcinoma followed by microvascular reconstruction with a free microvascular flap. P(ti)O(2) of each flap was continuously monitored for 3 postoperative days with a polarographic measurement system. BP was measured invasively and continuously during the operation and during the first postoperative day at the intensive care unit. The correlation coefficient between p(ti)O(2) and BP was analysed.The correlation coefficient between p(ti)O(2) and BP was relatively high in all patients with uneventful flap survival (r (mean) = 0.63, n = 5). In flaps with haemodynamic problems or compromised flap vitality the correlation appeared low (r(mean) = -0.02, n = 5).

[18F]Fluorodeoxyglucose (FDG) uptake in noncerebral tumors is commonly reported as tissue radioactivity concentration normalized to injected dose and body weight. We studied the feasibility of this approach by imaging 68 tumors in 46 oncologic patients with dynamic FDG-PET and compared kinetic and static methods of quantitation of FDG uptake. Further, the effect of plasma glucose and insulin concentration on the obtained quantitative indexes was analyzed in all patients. The metabolic rate for FDG was strongly associated with normalized uptake value adjusted for injected dose (r = 0.92, p < 0.0001), dose and patient weight (r = 0.91, p < 0.0001), and dose and body surface area (r = 0.94, p < 0.0001). The FDG uptake was not related to plasma glucose concentration under euglycemic (< or = 6.5 mmol/L) conditions, but was low in two diabetic patients with overt hyperglycemia. Hyperinsulinemia was associated with a low to moderate FDG uptake, probably exerting its action through a metabolic shift of tracer influx to muscle and fat. Our results show that a single scan in the steady-state phase, e.g., 45-60 min from the injection, can be used for assessment of FDG uptake in tumors, making frequent blood sampling during imaging unnecessary. However, glucose concentration in blood must be monitored in patients with known or suspected abnormalities in glucose metabolism.

5 Objectives The novel PET tracer C-11 KR31173 (KR) binds specifically to the Angiotensin II type I receptor (AT1R), and has been successfully used in animals for imaging of healthy and post-infarction hearts. We aimed to study the global and regional myocardial retention, binding specificity and imaging feasibility of KR in the human heart, and to compare these characteristics with prior results from pig studies. Methods Four healthy volunteers (HV) were imaged at baseline using a 40-min dynamic PET acquisition after KR injection(740 MBq). To determine the specificity of myocardial uptake, 2 HV returned 24 hrs later and received a single 40mg dose of Olmesartan, 3 hrs prior to KR. Three healthy pigs from a previous protocol were used for comparison. Results Myocardial uptake of KR was stable over time both in the human and porcine heart. A global myocardial KR retention(KR-ret) index was obtained, which was 1.27±0.09 in HV, and decreased to 0.63±0.17%/min (51% blockage) after Olmesartan. In pigs, global KR-ret was significantly higher (2.64±0.81%/min,P=0.018) compared to HV. While regional retention was homogeneous in the porcine heart, KR-ret was significantly higher in the inferior wall than in the anterior wall in HV (1.54±0.25 vs. 1.04±0.07%/min). This difference was associated with intense liver activity in close proximity to the heart, resulting in scatter and spillover problems. Conclusions In this translational study, noninvasive imaging suggests higher global myocardial AT1R expression in pigs when compared to humans. There is regional heterogeneity in the human heart, associated with intense KR liver activity, which may impose a major limitation in humans. However, KR may still be feasible for evaluation of conditions where AT1R expression is expected to be globally abnormal. Functional and/or anatomical species differences are often overlooked in translational research, the presented data underscore the importance of such studies

The aim of this pilot study was to determine the postoperative blood perfusion (BFPET) and perfusion heterogeneity (BFPET HG) in free microvascular breast reconstruction flap zones with positron emission tomography (PET). Regional BFPET and BFPET HG of the adipose tissue in medial, central, and lateral parts of 13 free flaps were assessed on the first postoperative morning with PET using oxygen-15-labeled water ([15O]H2O) in 12 patients undergoing breast reconstruction with a deep inferior epigastric perforator (DIEP) or a transverse rectus abdominis muscle (TRAM) flap. The mean BFPET values did not differ between DIEP and TRAM flaps (P = 0.791). The mean BFPET values were higher in zone III compared with zone I (P = 0.024). During follow-up, fat necrosis was identified in three patients in the medial part (zone II) of the flap. However, the adipose tissue BFPET assessed on the first postoperative day from all zones of the flap using PET with radiowater was normal. The BFPET HG was higher in the control side (i.e., in the healthy breast tissue) compared with the flap (P = 0.042). The BFPET HG was lower in zone III than in zone I (P = 0.03) and in zone II (P < 0.001). In this pilot study, PET was used for the first time for studying the adipose tissue perfusion in different zones in free flaps in a clinical setup, finding that the mean BFPET values did not differ between DIEP and TRAM flaps, and that zone II was sometimes not as well perfused as zone III supporting revisited zone division. © 2010 Wiley-Liss, Inc. Microsurgery 30:430–436, 2010.

Although 6-(18)F-fluoro-L-dopa ((18)F-FDOPA) has been available to study the striatal dopaminergic system for more than 2 decades, the full potential of the tracer was not realized before the introduction of (18)F-FDOPA PET and PET/CT to image a variety of neuroendocrine tumors (NETs) and pancreatic beta-cell hyperplasia. Together with receptor-based imaging, (18)F-FDOPA offers a formerly unforeseen means to assist in the management of NETs and infants with persistent hyperinsulinemic hyperplasia. Institutions with special expertise in surgical, oncologic, and radiologic therapeutic modalities for NETs derive the highest benefit from (18)F-FDOPA PET/CT. (18)F-FDOPA-guided therapy may add to NET control by ensuring maximal cytoreduction.

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)

Purpose To demonstrate the theoretical feasibility of [ 11 C]acetate PET/CT in delineating the malignant intraprostatic lesions (IPL's) in prostate cancer and to use the data in external beam radiotherapy to boost the biologically defined target volume (BTV). Methods and materials Twelve men with intracapsular prostate carcinoma were imaged with [ 11 C]acetate PET/CT and the data were used to delineate the BTV. Six dynamic IMRT plans were generated to each patient: a standard IMRT (sIMRT) plan with a 77.9Gy dose to PTV (prostate gland with a 6-mm margin) and a simultaneous integrated boost IMRT (SIB IMRT ) plan to deliver 77.9Gy, 81Gy, 84Gy, 87Gy and 90Gy to the BTV and 72Gy to the rest of PTV. To study the theoretical dose escalation based on the delineation of BTV, tumor control probabilities (TCPs) and normal tissue complication probabilities (NTCPs) of bladder and rectum were calculated and compared between the treatment plans. Results [ 11 C]Acetate was used to delineate the IPL's of all 12 patients. With every patient the TCP was increased with SIB IMRT without increasing the NTCP of the bladder or rectum. The probability of uncomplicated control (PUC) was increased on average by 28% with the SIB IMRT treatment plans. The highest PUC was achieved with an average dose of 82.1Gy to the BTV. Conclusions Our study indicates that [ 11 C]acetate can be used to define the IPL's and in combination with SIB IMRT the defined areas can theoretically be treated to ultra high doses without increasing the treatment toxicity. These results motivate the formal validation of [ 11 C]acetate PET for biological dose planning in prostate cancer.

The aim of the study is to assess the value of carbonic anhydrase isozyme IX (CA IX) expression as a predictor of disease-free survival (DFS) and disease-specific survival (DSS) in rectal cancer treated by preoperative radio- or chemoradiotherapy or surgery only. Archival tumour samples from 166 patients were analysed for CA IX expression by three different evaluations: positive/negative, proportion of positivity and staining intensity. The results of immunohistochemical analysis were confirmed by demonstrating CA IX protein in western blotting analysis. Forty-four percent of the operative samples were CA IX positive, of these 34% had weak and 66% moderate/strong staining intensity. In univariate survival analysis, intensity of CA IX expression was a predictor of DFS (P=0.003) and DSS (P=0.034), both being markedly longer in tumours with negative or weakly positive staining. In multivariate Cox model, number of metastatic lymph nodes and CA IX intensity were the only independent predictors of DFS. Carbonic anhydrase isozyme IX intensity was the only independent predictor of DSS, with HR=9.2 for dying of disease with moderate-intense CA IX expression as compared with CA IX-negative/weak cases. Negative/weak CA IX staining intensity is an independent predictor of longer DFS and DSS in rectal cancer.

The glucose analogue 2-fluoro-2-deoxy-D-glucose (FDG) was used to study chemosensitivity of two human ovarian cancer cell lines and of murine L1210 cells. Cell viability was determined by measuring intracellular adenosine triphosphate (ATP) with a bioluminescence method, which has been shown to correlate closely with trypan blue, stem cell, and [3H]TdR assays. All three cell lines were sensitive to cytostatic drugs, which exerted a parallel decrease in the intracellular FDG and ATP levels. The two measures correlated positively (r = 0.66, P less than 0.001), indicating that FDG uptake is closely linked with ATP production. Relatively low hexokinase (HK)-to-glucose 6-phosphatase (HK/G6-Pase) ratios were measured, which suggests that the metabolic trapping of FDG 6-phosphate within the cytosol is incomplete. Apparently, these cell lines may not depend exclusively on glycolysis for their energy requirement. We conclude that cell killing caused by cytostatic drugs is associated with a decreased ATP content and FDG uptake. This indicates that not only ATP but also FDG may be used to study drug effects in vitro.

Twenty patients with malignant head and neck tumours were imaged with 99Tcm-labelled hexamethylpropylene amine oxime (HMPAO), a radiopharmaceutical generally used for blood flow studies. Before radiotherapy (RT), 93% of the tumours could be detected with single photon emission computed tomography (SPECT) and 45% with planar imaging. Whole tumour-to-background 99TcmHMPAO uptake ratios ranged from 3.6 to 1.0 (mean 1.7 +/- 0.6) in untreated tumours. There was a good correlation between tumour volume and uptake (r = 0.69, P = 0.002). Sixteen patients were reimaged during or shortly after radical RT. 99TcmHMPAO uptake was significantly lower after treatment (mean uptake ratio 1.2 +/- 0.3, P less than 0.001). However, RT associated changes in 99TcmHMPAO uptake were in agreement with the clinical response in only 63% of the studies. This study indicates that 99TcmHMPAO SPECT imaging can be used for pretherapeutic localisation of head and neck tumours. Although most tumours show a decrease in uptake after irradiation the poor association with tumour regression does not allow for reliable assessment of treatment response. Images Figure 1 Figure 4

The study was set up to determine the clinical value of dihydroxyphenylalanine positron emission tomography-computed tomography ([18F]DOPA PET-CT) in patients with neuroendocrine tumors (NETs). Eighty-two patients with suspected/known NET were imaged with PET(-CT) using [18F]DOPA. Patients were divided into two groups: primary diagnosis/staging and restaging of disease. All patients without previous diagnosis of NET had biochemical proof of disease. The diagnostic accuracy of PET was assessed by comparing the histopathology and clinical follow-up. The overall accuracy of [18F]DOPA PET was 90%. In patients having PET for primary diagnosis/staging (n=32), the accuracy of PET was 88%, and for restaging 92% (n=61). The mean s.d. sizes of primary and metastatic lesions detected by PET were 26±11 and 16±9 mm respectively. In organ-region-specific analysis, the sensitivity and specificity were 100% in the primary diagnosis of pheochromocytoma (n=16) and metastases were found in all cases with recurrent disease (n=5). The accuracy for NET of gastrointestinal tract was 92% in restaging (n=24). For the NETs located in the head–neck–thoracic region (n=19), the overall accuracy of PET was 89% including 12 cases of recurrent medullary thyroid cancer with a sensitivity of 90%. In analysis of patients with biochemical proof of disease combined with negative conventional imaging methods, PET had positive and negative predictive value of 92% and 95% respectively. [18F]DOPA PET-CT provided important additional information in the diagnosis of pheochromocytoma and restaging of known NET. Both in primary diagnosis and in patients with formerly known NET and increasing tumor markers, [18F]DOPA PET-CT is a sensitive first-line imaging method.

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.

Methods for predicting the outcome of radiation treatment are discussed. The correlation of tumour decrease during irradiation with recurrence-free survival is poor. A reliable method for predicting the long-term result of radiation therapy is urgently needed. Methods using flow cytometry, electron microscopy and positron emission tomography with short-lived radiopharmaceuticals are under investigation.

Tissue oxygen measurement and positron emission tomography (PET) were evaluated as methods for predicting ischemia in microvascular free flaps of the head and neck. Ten patients with head and neck squamous cell cancer underwent resection of the tumour followed by microvascular reconstruction with a free flap. Tissue oxygenation of the flap (P(ti)O(2)) was continuously monitored for three postoperative (POP) days and the blood flow of the flap was assessed using oxygen-15 labelled water and PET. In three free flaps a perfusion problem was suspected due to a remarkable drop in P(ti)O(2)-values, due to two anastomosis problems and due to POP turgor. No flap losses occurred. During the blood flow measurements with PET [mean 8.5 mL 100 g(-1) min(-1 )(SD 2.5)], the mean P(ti)O(2) of the flaps [46.8 mmHg (SD 17.0)] appeared to correlate with each other in each patient (p0.05, n=10). Tissue oxygenation measurement is a feasible monitoring system of free flaps. The perfusion-study with PET correlates with P(ti)O(2)-measurement.

The aim of this study was to determine the clinical impact of whole body positron emission tomography (FDG PET) to detect clinically silent metastases in the follow-up of patients with high risk melanoma. FDG PET was performed to 30 asymptomatic melanoma patients (AJCC stage IIB-IIIC) 7-24 months after the primary surgery and sentinel node biopsy. FDG PET was able to detect six of seven recurrences, constituting 20% of all study patients. One patient presented with a negative FDG PET finding at the very first scanning, but was positive later in a repeated scan after manifestation of palpable mass in the axilla. The positive PET finding had an impact on treatment decisions in every case: three patients underwent surgical resection and four patients received chemotherapy or interferon. The mean follow-up time was 27 months (range, 12-48 months) and during that time the other 23 patients with true negative FDG PET were disease-free. One of the seven recurrences was in remission after surgical metastasectomy. In conclusion, whole body FDG PET is a valuable follow-up tool in high risk melanoma to diagnose recurrences and to select the patients, who are suitable for surgical metastasectomy.

Background: Congenital hyperinsulinism (CHI) is a cause of severe hypoglycemia in the neonatal and infancy period. Histologically, there are two subtypes with diffuse and focal disease. The preoperative differentiation of these two forms is very important because the surgical management is radically different. The focal form of the disease can be cured if the focal lesion can be localized accurately and completely resected with surgery. Aim: We report the case of a child who underwent three pancreatectomies with a choledochoduodenostomy and a cholecystectomy but continued to have severe hyperinsulinemic hypoglycemia. Methods/Results: Radiological investigations including imaging with 18fluoro-l-Dopa positron emission tomography scan showed a clear focus of increased 18F-fluoro-l-Dopa uptake in the vicinity of the former head of the pancreas. On the magnetic resonance imaging scan, this focal uptake appeared to localize adjacent or next to duodenum (in the wall or cavity of the duodenum). Conclusions: This unique case highlights the importance of correctly localizing and completely resecting the focal lesion in patients with CHI. 18Fluoro-l-Dopa positron emission tomography scan can identify ectopic focal lesions in patients with CHI.

Low-grade gliomas (LGG) account for 30-40% of all gliomas and are primarily treated with surgery. Since both timing and use of other oncological treatments in LGG are a matter of controversy, there has been a constantly increasing demand to characterize these often slowly growing neoplasms with functional imaging methods, such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT). PET and SPECT yield information on growth rate and heterogeneity of LGG and are especially useful in follow-up since metabolic changes tend to precede structural changes detected with structure-based imaging methods. Furthermore, for planning of LGG surgery or radiotherapy coregistration of functional images with CT and MRI is invaluable. This is increasingly performed with a new generation of hybrid scanners with integrated PET or SPECT and CT.

In adenocarcinoma of the esophagus and esophagogastric junction for prognostication and treatment allocation, one prerequisite is accurate pretreatment staging. This staging, we hypothesized, would be improved by the use of positron emission tomography (PET). After 55 patients suitable for radical esophageal resection were staged with PET, spiral computed tomography (CT), and endoscopic ultrasonography (EUS), results were compared with histopathology and with survival. Accuracy in detecting locoregional lymph node metastasis did not differ significantly between EUS (72%), PET (60%), and CT (58%). Adding PET to standard staging failed to improve the accuracy of N staging (P = 0.250). In M staging, accuracy between CT (75%) and PET (76%) did not differ. The accuracy of combined studies of CT and PET and of EUS, CT, and PET were 87% (P = 0.016 versus CT) and 91% (P = 0.031 versus EUS and CT), respectively. Of the 55 patients, 19 (35%) had metastatic lesions. By combined use of CT and EUS and by combined use of CT, EUS, and PET, 8 and 14 (P = 0.031), respectively, could be detected. In nodal disease without distant metastases, PET did not improve the prediction of survival. However, positive PET for distant metastasis by either positive EUS or CT predicts well the poor survival of these patients. The staging value of PET by itself in adenocarcinoma of the esophagus is limited because of low accuracy for nodal and the lack of specificity for distant disease prognosis. Adding PET to standard staging does, however, improve detection of stage IV disease and its associated poor survival.

Thirty-two patients with relapsing glioma were treated with temozolomide in two university hospitals in Finland. One patient (3%) had complete response and 9 (28%) partial response, with 8 patients (25%) showing stable disease. Median progression-free survival for these 18 patients (56%) was 7 months (range 2-11+). The remaining either had progressive disease (25%) or only clinical evaluation (19%). Karnofsky score improved in 34% of patients and decreased in 3%. Symptoms were alleviated in 44% and deteriorated in 9%. Grade 3-4 toxicity was detected in 9% of the patients. Only 4% of the days in treatment were spent in hospital. An average 1.8 neuroradiological investigations, 6.9 laboratory visits, and 5.3 visits to the oncologist were made. This study confirms that temozolomide has positive effects on the outcome of often heavily pretreated glioma patients. High drug costs are compensated by prolonged home care and even the possibility to maintain working capacity.

Our patient developed Riedel's thyroiditis soon after having an exacerbation of multiple sclerosis (MS). MS has been associated with other autoimmune diseases, including thyroiditis, and both Hashimoto's thyroiditis and subacute thyroiditis have been described in connection with MS. Yet, we are not aware of any other patient reported to have concomitant MS and Riedel's thyroiditis. The association between MS and Riedel's thyroiditis remains obscure but may reflect an autoimmune disorder common to both diseases.

Our aim was to evaluate the use of PET with (11)C-metomidate and (18)F-FDG for the diagnosis of adrenal incidentalomas.Twenty-one patients underwent hormonal screening before dynamic imaging of the upper abdomen with (11)C-metomidate, and for 19 of these 21 patients, static (18)F-FDG imaging followed. Uptake of (11)C-metomidate and (18)F-FDG in incidentalomas was quantified and correlated with the hormonal work-up and the mass size on CT (median, 2.5 cm; range, 2-10 cm).The final diagnoses were hormonally active adenoma (n = 7), nonsecretory adenoma (n = 5), adrenocortical carcinoma (n = 1), pheochromocytoma (n = 2), benign noncortical tumor (n = 2), normal adrenal (n = 1), and malignant noncortical tumor (n = 3). Diagnosis was established at surgery (n = 9), percutaneous biopsy (n = 4), or follow-up (n = 8). The highest uptake of (11)C-metomidate, expressed as standardized uptake value (SUV), was found in adrenocortical carcinoma (SUV = 28.0), followed by active adenomas (median SUV = 12.7), nonsecretory adenomas (median SUV = 12.2), and noncortical tumors (median SUV = 5.7). Patients with adenomas had significantly higher tumor-to-normal-adrenal (11)C-metomidate SUV ratios than did patients with noncortical tumors. (18)F-FDG detected 2 of 3 noncortical malignancies but failed to detect adrenal metastases from renal cell carcinoma. All inactive and most active adenomas were difficult to detect with (18)F-FDG against background activity, whereas both pheochromocytomas and adrenocortical carcinoma showed slightly increased uptake of (18)F-FDG. There was no correlation between uptake of (11)C-metomidate or (18)F-FDG and mass size.(11)C-Metomidate is a promising PET tracer to identify incidentalomas of adrenocortical origin. (18)F-FDG should be reserved for patients with a moderate to high likelihood of neoplastic disease.

A large, rapidly progressing, unresectable undifferentiated sinonasal head and neck carcinoma regressed rapidly following single fraction boron neutron capture therapy (BNCT). The main toxicity consisted of mucositis lasting for a few days. The quality of life improved and was excellent until tumour recurrence 6 months after the date of BNCT.

The purpose of this study was to determine the efficacy and feasibility of full-dose preoperative radiation therapy (RT) in head and neck cancer presenting in the oral cavity, oro- and hypopharynx, within a single university hospital district. During a seven-year period, 1989 to 1995, 174 patients with squamous cell carcinoma (SCC) of the oral cavity (OC, 70% of all patients), oropharynx (OP, 15%) and hypopharynx (HP, 15%) were referred to Turku University Central Hospital. All patients were seen by a tumor board consisting of an ENT (ear-nose-throat) head and neck surgeon, a radiation oncologist and a dentist. Potentially curative treatment was given to 142 patients. Of these, 88 (62%) had preoperative RT, 6 (4%) postoperative RT, 34 (24%) definitive RT and 14 patients (10%) were treated with surgery only. The radiation dose wasor = 50 Gy. averagely 64 Gy. The major endpoints of the study were local control, overall survival and major complications of the combined treatment. The 5-year relative survival rate (RSR) was 40% for all, and 43% for patients treated with curative intent. For these, the local control at 5 years was 60%; the disease-specific 5-year survival rate was 65% for the patients with lingual SCC, 45% for those with other oral tumor localizations. 64% for the oropharynx patients and 47% for those with tumor in their hypopharynx, while it was 55% for all patients. The preoperative radiotherapy was fairly well tolerated. Ten (7%) of the patients treated with curative intent suffered major complications, and four patients had evidence of osteoradionecrosis. With the exception of patients with early SCC the outcome remains rather poor in this group of cancer patients who often have marked co-morbidity. In our opinion, preoperative radiotherapy to a dose of 62-64 Gy can safely be given, and remains a feasible means to treat patients with oral, oropharyngeal or hypopharyngeal cancer.

Objective To compare positron emission tomography (PET) and magnetic resonance imaging (MRI) in the evaluation of inflammatory proliferation of synovium. Methods Ten patients (mean ± SD age 36 ± 13 years) with inflammatory joint disease and with clinical signs of inflammation of the joint were studied. A new tracer for cellular proliferation, methyl-11C-choline (11C-choline), and a widely used tracer for the detection of inflammation and cancer, 2-18F-fluoro-2-deoxy-D-glucose (18F-FDG), were applied for PET imaging, and the results were compared with the findings from gadolinium diethylenetriaminepentaacetic acid–enhanced MR images. The uptake of 11C-choline and 18F-FDG in the inflamed synovium was measured and expressed as the standardized uptake value (SUV) and the kinetic influx constant (Ki) obtained from graphic analysis, and these values were compared with quantitative values on MRI. Synovial volumes were measured on the coronal contrast-enhanced T1-weighted MR images using the standard software of the MR imager. Results All patients showed high accumulation of both 11C-choline and 18F-FDG at the site of arthritic changes, where quantification of the tracer uptake was performed. The SUV of 11C-choline was 1.5 ± 0.9 gm/ml (mean ± SD; n = 10) and the SUV of 18F-FDG was 1.9 ± 0.9 gm/ml (n = 10) (P = 0.017). The Ki of 11C-choline (mean ± SD 0.048 ± 0.042 minute−1) was 8-fold higher than the Ki of 18F-FDG (0.006 ± 0.003 minute−1) (P = 0.009). Both the uptake of 11C-choline and the uptake of 18F-FDG correlated highly with the volume of synovium; the highest correlation was observed with the Ki of 11C-choline (r = 0.954, P < 0.0001). Conclusion In the use of PET scans,11C-choline can be regarded as a promising tracer for quantitative imaging of proliferative arthritis changes. Nevertheless, subsequent prospective studies with larger numbers of patients are necessary to further characterize the relationship between the findings on PET imaging and the clinical and functional measures of inflammation.

Carbon-11 choline has recently been introduced as a potential tracer for tumour imaging with positron emission tomography (PET). We evaluated the kinetics of the uptake of [(11)C]choline in prostate cancer and benign prostatic hyperplasia. We also evaluated the association between the uptake of [(11)C]choline and the histological grade of malignancy, Gleason score, volume of the prostate and prostate-specific antigen (PSA). Fourteen patients with histologically confirmed prostate cancer and five patients with benign prostatic hyperplasia were studied with [(11)C]choline PET. A mean dose of 430+/-31 MBq of [(11)C]choline was injected intravenously and a dynamic emission acquisition of prostate was performed for 30 min. The uptake of [(11)C]choline was measured as a standardised uptake value (SUV) and as a kinetic influx constant ( K(i)) obtained from graphical analysis. Both cancerous and hyperplastic prostate were well visualised with [(11)C]choline against low or moderate tracer accumulation in the bladder and rectal wall. The measured radioactivity in urine was invariably low. In the graphical analysis, linear plots were achieved. The mean K(i) of the untreated tumour was 0.205+/-0.089 min(-1) (range 0.128-0.351; n=7) and the mean SUV was 5.6+/-3.2 (range 1.9-15.5; n=15). K(i) values and SUVs correlated closely ( r=0.964, P=0.0005), whereas no correlation could be demonstrated between the tumour uptake of [(11)C]choline and the histological grade, Gleason score, volume of the prostate or PSA. The mean SUV and the mean K(i) of benign hyperplastic prostate were 3.5+/-1.0 (range 2.0-4.5; n=4) and 0.119+/-0.076 min(-1) (range 0.065-0.173; n=2). In conclusion, a high uptake of [(11)C]choline characterises not only carcinomatous but also hyperplastic prostatic tissue. Dynamic imaging of the uptake of [(11)C]choline in the prostate shows a good applicability of the graphical analysis model with an irreversible compartment. A close correlation between the K(i) values and semiquantitative SUVs of tumours supports the use of the simpler SUV in the clinical setting.

We describe the usage of positron emission tomography (PET) as an aid in the initial diagnosis and follow-up of Riedel's thyroiditis. A 41-year-old patient was admitted for an enlarged and tender thyroid gland in association with severe systemic symptoms of inflammation. Imaging with fluorine-18 fluorodeoxyglucose (FDG) and PET demonstrated an intensive uptake of FDG in both lobes of the thyroid gland as an indication of severe inflammation. The diagnosis of Riedel's thyroiditis was confirmed by the histological findings of biopsy specimens taken during a palliative thyroid resection. The inflammatory symptoms and local pain dramatically disappeared after commencement of high-dose corticosteroid therapy. A follow-up PET scan after 2 weeks of corticosteroid treatment showed a 60% decrease in the uptake of FDG in the thyroid. This indicates that FDG metabolic activity can also be used to assess a patient's response to therapy in Riedel's thyroiditis.

Purpose The outcome of locally advanced head-and-neck cancer often is poor. An important determinant of treatment failure is tumor hypoxia arising from an inappropriate blood supply. Quantitation of the hypoxic fraction and blood flow in vivo may provide prognostic information and a means to target specifically tumor cells resistant to conventional treatment. Methods and materials Twenty-one patients with head-and-neck cancer underwent multitracer positron emission tomography (PET) before the start of preoperative or definitive radiotherapy (RT). Tumor blood flow was measured using the [ 15 O]H 2 O autoradiographic technique followed by evaluation of oxygenation status using [ 18 F]fluoroerythronitroimidazole ([ 18 F]FETNIM). [ 18 F]fluorodeoxyglucose PET was performed on a separate day to calculate the metabolically active tumor volume. The definition of the fractional hypoxic volume (FHV) in the tumor was determined by multiple voxel-wise measurements of the uptake of [ 18 F]FETNIM in well-oxygenated tissues and tumor. PET findings were then correlated with the RT outcome and survival. Results High blood flow was associated with poor local control after RT ( p = 0.021) and with poor survival ( p = 0.018). Patients with a FHV greater or equal to the median had significantly worse survival than those with a FHV less than the median ( p = 0.036). The relationship between tumor hypoxia and FHV was supported in 3 patients who underwent invasive measurement of the tissue O 2 partial pressure. Conclusion High tumor blood flow predicted for a poor response to RT in head-and-neck cancer. The use of [ 18 F]FETNIM for assessment of radiobiologic hypoxia requires a study with greater statistical power. PET with [ 15 O]H 2 O or [ 18 F]FETNIM may become useful in clinical trials in which novel therapeutic agents targeting tumor vasculature or hypoxia are evaluated.

18F-Fluoroerythronitromidazole (FETNIM) is a new promising PET tracer for imaging tumor hypoxia. Accurate radiation dosimetry is important for estimating absorbed radiation doses to patients and for calculating the allowable injected dose.Radiation absorbed doses were estimated from PET scans obtained on cancer patients on the basis of the MIRD procedure. Dynamic acquisition data was obtained from the thorax, abdomen, and head and neck regions. The tracer was injected intravenously and mean injected activity was 366 MBq (range, 288-385 MBq). Arterial blood was continuously assayed over dynamic PET imaging. The bladder wall dose was evaluated from the voided urine activity measurements.The effective dose to a 70-kg adult was 0.015 or 0.019 mSv/MBq, calculated on 2- or 4-h voiding intervals, respectively. The critical organ proved to be the urinary bladder wall, with a highest absorbed dose of 0.062 or 0.127 mGy/MBq depending on the voiding schedule as described above. Absorbed doses in all other organs were at least 5-fold smaller than the bladder wall doses.With an injected activity of 370 MBq (18)F-FETNIM, the radiation doses are generally comparable with those of other related radionuclide imaging procedures. Specifically, in comparison with (18)F-fluoromisonidazole, the absorbed doses of (18)F-FETNIM are equal. However, special attention should be given to adequate hydration and voiding to limit the relatively high exposure of the critical organ, bladder wall, to (18)F-FETNIM.

Abstract. The purpose of this study was to analyse the effects of irradiation and hyperbaric oxygenation (HBO) on mandibular osteodistraction (OD). Eighteen rabbits were divided into three groups: 1. Irradiation (R), 2. Irradiation+HBO (R-HO), and 3. Control group (C). Animals of groups R and R-HO received in the mandible irradiation 22.4Gy in four 5.6Gy fractions (equivalent to 50Gy/25 fractions). In addition, group R-HO was given HBO at 2.5ATA for 90min per day 18 times preoperatively. Unilateral osteotomy was made 1 month after completion of radiotherapy. After a 1 week latency period bone distraction was started at rate of 1mm per day, continued for 2 weeks, and left to consolidate for 4 weeks. Amount of new bone was measured histomorphometrically from midsagittal sections. Area of new bone was equal in all groups. Bone was more mature and bone spicules better organized in group C than in groups R and R-HO. Cartilaginous cells were found in distracted bone in all groups but larger chondroid islands were evident only in group R. It seems that despite delayed bone formation, OD can be performed after radiotherapy. HBO had a beneficial effect on bone quality of a previously irradiated mandible.

BACKGROUND Positron emission tomography (PET) scans of primary brain tumors were performed in pediatric patients to examine whether metabolic characteristics could be used as an index of clinical aggressiveness. METHODS Twenty-seven pediatric patients with untreated primary central nervous system neoplasms were studied with PET scans using 2-[18F] fluoro-2-deoxy-D-glucose (FDG) and/or L-[methyl-11C] methionine (MET). Metabolic characteristics as assessed with FDG and MET standardized uptake values (SUV) and SUV-to-normal brain ratios were compared with histopathology and selected histochemical features such as proliferation activity (Ki-67MIB-1) and apoptotic, vascular, and cell density indices. The median followup time was 43 months. RESULTS The accumulation of both FDG and MET was significantly higher in high-grade than in low-grade tumors, but a considerable overlap was found. The accumulation of both tracers was associated positively with age. High-grade tumors showed higher proliferative activity and vascularity than the low-grade tumors. In univariate analysis, FDG-PET, MET-PET, and apoptotic index were independent predictors of event-free survival. CONCLUSION We found that both FDG and MET uptake in pediatric brain tumors are associated with malignancy grade. However, no clear limits of SUVs and SUV-to-normal brain ratios can be set between low-grade and high-grade tumors, which makes the assessment of malignancy grade using metabolic imaging with PET scan difficult in individual cases. Although FDG-PET and MET-PET do not compensate for histopathologic evaluation, they may give valuable additional information especially if invasive procedures to obtain histopathologic samples are not feasible. Cancer 2002;95:1376–86. © 2002 American Cancer Society. DOI 10.1002/cncr.10798

Amino acid transport system A is expressed strongly in neoplastic cells. [ N-methyl-(11)C]alpha-Methylaminoisobutyric acid ((11)C-MeAIB) is a recently developed tracer for PET studies on system A amino acid transport. (11)C-MeAIB is a metabolically stable amino acid analogue which is transported from plasma into the tissue by system A. This study evaluated the kinetics of (11)C-MeAIB uptake from plasma into tumour tissue and normal tissues in 13 patients with untreated head and neck cancer. (11)C-MeAIB uptake in tumour was compared with histological grade and proliferative activity. Tracer uptake was quantitated by calculating the standardised uptake values (SUVs) and the kinetic influx constants ( K(i)) using graphical analysis. All tumours accumulated (11)C-MeAIB and were visualised clearly. In the graphical analysis, linear plots were achieved; the mean K(i) value of tumour was 0.056+/-0.026 min(-1), and the mean SUV was 6.1+/-2.7. A close correlation between graphically obtained K(i) and semi-quantitative SUV in tumours was found ( r=0.887, P=0.00005). We could not demonstrate a correlation between the uptake of (11)C-MeAIB and the grade of malignancy or the proliferative index, as assessed using Ki-67 immunohistochemical assay. Head and neck cancer can be effectively imaged with (11)C-MeAIB PET. (11)C-MeAIB showed active and rapid transport into tumour tissue and salivary glands. Further studies on the applicability of (11)C-MeAIB PET for radiation treatment planning in the head and neck region and the regulation of system A amino acid transport under different metabolic states are warranted.