Surgical navigation for challenging recurrent or pretreated intra-abdominal and pelvic soft tissue sarcomas.

BACKGROUND: This study assessed whether electromagnetic navigation can be of added value during resection of recurrent or post-therapy intra-abdominal/pelvic soft tissue sarcomas (STS) in challenging locations. MATERIALS AND METHODS: Patients were included in a prospective navigation study. A pre-operatively 3D roadmap was made and tracked using electromagnetic reference markers. During the operation, an electromagnetic pointer was used for the localization of the tumor/critical anatomical structures. The primary endpoint was feasibility, secondary outcomes were safety and usability. RESULTS: Nine patients with a total of 12 tumors were included, 7 patients with locally recurrent sarcoma. Three patients received neoadjuvant radiotherapy and three other patients received neoadjuvant systemic treatment. The median tumor size was 4.6 cm (2.4-10.4). The majority of distances from tumor to critical anatomical structures was <0.5 cm. The tumors were localized using the navigation system without technical or safety issues. Despite the challenging nature of these resections, 89% were R0 resections, with a median blood loss of 100 ml (20-1050) and one incident of vascular damage. Based on the survey, surgeons stated navigation resulted in shorter surgery time and made the resections easier. CONCLUSION: Electromagnetic navigation facilitates resections of challenging lower intra-abdominal/pelvic STS and might be of added value.

CBCT-based navigation system for open liver surgery: Accurate guidance toward mobile and deformable targets with a semi-rigid organ approximation and electromagnetic tracking of the liver.

PURPOSE: The surgical navigation system that provides guidance throughout the surgery can facilitate safer and more radical liver resections, but such a system should also be able to handle organ motion. This work investigates the accuracy of intraoperative surgical guidance during open liver resection, with a semi-rigid organ approximation and electromagnetic tracking of the target area. METHODS: The suggested navigation technique incorporates a preoperative 3D liver model based on diagnostic 4D MRI scan, intraoperative contrast-enhanced CBCT imaging and electromagnetic (EM) tracking of the liver surface, as well as surgical instruments, by means of six degrees-of-freedom micro-EM sensors. RESULTS: The system was evaluated during surgeries with 35 patients and resulted in an accurate and intuitive real-time visualization of liver anatomy and tumor's location, confirmed by intraoperative checks on visible anatomical landmarks. Based on accuracy measurements verified by intraoperative CBCT, the system's average accuracy was 4.0 ± 3.0 mm, while the total surgical delay due to navigation stayed below 20 min. CONCLUSIONS: The electromagnetic navigation system for open liver surgery developed in this work allows for accurate localization of liver lesions and critical anatomical structures surrounding the resection area, even when the liver was manipulated. However, further clinically integrating the method requires shortening the guidance-related surgical delay, which can be achieved by shifting to faster intraoperative imaging like ultrasound. Our approach is adaptable to navigation on other mobile and deformable organs, and therefore may benefit various clinical applications.

Association of Image-Guided Navigation With Complete Resection Rate in Patients With Locally Advanced Primary and Recurrent Rectal Cancer: A Nonrandomized Controlled Trial.

Importance: The percentage of tumor-positive surgical resection margin rates in patients treated for locally advanced primary or recurrent rectal cancer is high. Image-guided navigation may improve complete resection rates. Objective: To ascertain whether image-guided navigation during rectal cancer resection improves complete resection rates compared with surgical procedures without navigation. Design, Setting, and Participants: This prospective single-center nonrandomized controlled trial was conducted at the Netherlands Cancer Institute-Antoni van Leeuwenhoek in Amsterdam, the Netherlands. The prospective or navigation cohort included adult patients with locally advanced primary or recurrent rectal cancer who underwent resection with image-guided navigation between February 1, 2016, and September 30, 2019, at the tertiary referral hospital. Clinical results of this cohort were compared with results of the historical cohort, which was composed of adult patients who received rectal cancer resection without image-guided navigation between January 1, 2009, and December 31, 2015. Intervention: Rectal cancer resection with image-guided navigation. Main Outcomes and Measures: The primary end point was the complete resection rate, measured by the amount of tumor-negative resection margin rates. Secondary outcomes were safety and usability of the system. Safety was evaluated by the number of navigation system-associated surgical adverse events. Usability was assessed from responses to a questionnaire completed by the participating surgeons after each procedure. Results: In total, 33 patients with locally advanced or recurrent rectal cancer were included (23 men [69.7%]; median [interquartile range] age at start of treatment, 61 [55.0-69.0] years). With image-guided navigation, a radical resection (R0) was achieved in 13 of 14 patients (92.9%; 95% CI, 66.1%-99.8%) after primary resection of locally advanced tumors and in 15 of 19 patients (78.9%; 95% CI, 54.4%-94.0%) after resection of recurrent rectal cancer. No navigation system-associated complications occurred before or during surgical procedures. In the historical cohort, 142 patients who underwent resection without image-guided navigation were included (95 men [66.9%]; median [interquartile range] age at start of treatment, 64 [55.0-70.0] years). In these patients, an R0 resection was accomplished in 85 of 101 patients (84.2%) with locally advanced rectal cancer and in 20 of 41 patients (48.8%) with recurrent rectal cancer. A significant difference was found between the navigation and historical cohorts after recurrent rectal cancer resection (21.1% vs 51.2%; P = .047). For locally advanced primary tumor resection, the difference was not significant (7.1% vs 15.8%; P = .69). Surgeons stated in completed questionnaires that the navigation system improved decisiveness and helped with tumor localization. Conclusions and Relevance: Findings of this study suggest that image-guided navigation used during rectal cancer resection is safe and intuitive and may improve tumor-free resection margin rates in recurrent rectal cancer. Trial Registration: Netherlands Trial Register Identifier: NTR7184.

Accurate surgical navigation with real-time tumor tracking in cancer surgery.

In the past decades, image-guided surgery has evolved rapidly. In procedures with a relatively fixed target area, like neurosurgery and orthopedics, this has led to improved patient outcomes. In cancer surgery, intraoperative guidance could be of great benefit to secure radical resection margins since residual disease is associated with local recurrence and poor survival. However, most tumor lesions are mobile with a constantly changing position. Here, we present an innovative technique for real-time tumor tracking in cancer surgery. In this study, we evaluated the feasibility of real-time tumor tracking during rectal cancer surgery. The application of real-time tumor tracking using an intraoperative navigation system is feasible and safe with a high median target registration accuracy of 3 mm. This technique allows oncological surgeons to obtain real-time accurate information on tumor location, as well as critical anatomical information. This study demonstrates that real-time tumor tracking is feasible and could potentially decrease positive resection margins and improve patient outcome.

A workflow for automated segmentation of the liver surface, hepatic vasculature and biliary tree anatomy from multiphase MR images.

Accurate assessment of 3D models of patient-specific anatomy of the liver, including underlying hepatic and biliary tree, is critical for preparation and safe execution of complex liver resections, especially due to high variability of biliary and hepatic artery anatomies. Dynamic MRI with hepatospecific contrast agents is currently the only type of diagnostic imaging that provides all anatomical information required for generation of such a model, yet there is no information in the literature on how the complete 3D model can be generated automatically. In this work, a new automated segmentation workflow for extraction of patient-specific 3D model of the liver, hepatovascular and biliary anatomy from a single multiphase MRI acquisition is developed and quantitatively evaluated. The workflow incorporates course 4D k-means clustering estimation and geodesic active contour refinement of the liver boundary, based on organ's characteristic uptake of gadolinium contrast agents overtime. Subsequently, hepatic vasculature and biliary ducts segmentations are performed using multiscale vesselness filters. The algorithm was evaluated using 15 test datasets of patients with liver malignancies of various histopathological types. It showed good correlation with expert manual segmentation, resulting in an average of 1.76 ± 2.44 mm Hausdorff distance for the liver boundary, and 0.58 ± 0.72 and 1.16 ± 1.98 mm between centrelines of biliary ducts and liver veins, respectively. A workflow for automatic segmentation of the liver, hepatic vasculature and biliary anatomy from a single diagnostic MRI acquisition was developed. This enables automated extraction of 3D models of patient-specific liver anatomy, and may facilitating better perception of organ's anatomy during preparation and execution of liver surgeries. Additionally, it may help to reduce the incidence of intraoperative biliary duct damage due to an unanticipated variation in the anatomy.

Predictive value of interim positron emission tomography in diffuse large B-cell lymphoma: a systematic review and meta-analysis.

PURPOSE: Diffuse large B-cell lymphoma (DLBCL) represents the most common subtype of non-Hodgkin lymphoma. Most relapses occur in the first 2 years after diagnosis. Early response assessment with 18F-fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography (PET) may facilitate early change of treatment, thereby preventing ineffective treatment and unnecessary side effects. We aimed to assess the predictive value of visually-assessed interim 18F-FDG PET on progression-free survival (PFS) or event-free survival (EFS) in DLBCL patients treated with first-line immuno-chemotherapy regimens. METHODS: For this systematic review and meta-analysis Pubmed, Embase, and the Cochrane Library were searched until July 11, 2017. Prospective and retrospective studies investigating qualitative interim PET response assessment without treatment adaptation based on the interim PET result were eligible. The primary outcome was two-year PFS or EFS. Prognostic and diagnostic measures were extracted and analysed with pooled hazard ratios and Hierarchical Summary Receiver Operator Characteristic Curves, respectively. Meta-regression was used to study covariate effects. RESULTS: The pooled hazard ratio for 18 studies comprising 2,255 patients was 3.13 (95%CI 2.52-3.89) with a 95% prediction interval of 1.68-5.83. In 19 studies with 2,366 patients, the negative predictive value for progression generally exceeded 80% (64-95), but sensitivity (33-87), specificity (49-94), and positive predictive values (20-74) ranged widely. CONCLUSIONS: These findings showed that interim 18F-FDG PET has predictive value in DLBCL patients. However, (subgroup) analyses were limited by lack of information and small sample sizes. Some diagnostic test characteristics were not satisfactory, especially the positive predictive value should be improved, before a successful risk stratified treatment approach can be implemented in clinical practice.

Prospective study on image-guided navigation surgery for pelvic malignancies.

BACKGROUND AND OBJECTIVES: Surgery of advanced tumors and lymph nodes in the pelvis can be challenging due to the narrow pelvic space and vital surrounding structures. This study explores the application of a novel electromagnetic navigation system to guide pelvic surgery. METHODS: This was a prospective study on surgery for malignancies in the pelvis. Preoperatively obtained imaging was used to create a patient-specific three-dimensional (3D) roadmap. In the operating room, the 3D roadmap was registered to an intraoperative computed tomography scan. A tracked pointer was used during surgery for guidance. Primary endpoint was safety and feasibility, secondary endpoints were accuracy and usability. RESULTS: Twenty-eight colorectal, four liposarcomas, and one gynecological patient were included. There were no safety issues. Navigation was feasible in 31 patients. The mean target registration errors of 4.0 and 6.3 mm were achieved for straight and French position, respectively. In seven of seven patients with a locally advanced rectal tumor and in seven of eight patients with recurrences, negative margins were achieved. Thirty-three of 36 target lymph nodes were successfully removed. Surgeons using the system indicated faster localization of the tumor and improved decisiveness. CONCLUSION: This novel surgical navigation system was safe and feasible during pelvic surgery and can facilitate its users.

Repeatability of Quantitative Whole-Body 18F-FDG PET/CT Uptake Measures as Function of Uptake Interval and Lesion Selection in Non-Small Cell Lung Cancer Patients.

UNLABELLED: Change in (18)F-FDG uptake may predict response to anticancer treatment. The PERCIST suggest a threshold of 30% change in SUV to define partial response and progressive disease. Evidence underlying these thresholds consists of mixed stand-alone PET and PET/CT data with variable uptake intervals and no consensus on the number of lesions to be assessed. Additionally, there is increasing interest in alternative (18)F-FDG uptake measures such as metabolically active tumor volume and total lesion glycolysis (TLG). The aim of this study was to comprehensively investigate the repeatability of various quantitative whole-body (18)F-FDG metrics in non-small cell lung cancer (NSCLC) patients as a function of tracer uptake interval and lesion selection strategies. METHODS: Eleven NSCLC patients, with at least 1 intrathoracic lesion 3 cm or greater, underwent double baseline whole-body (18)F-FDG PET/CT scans at 60 and 90 min after injection within 3 d. All (18)F-FDG-avid tumors were delineated with an 50% threshold of SUVpeak adapted for local background. SUVmax, SUVmean, SUVpeak, TLG, metabolically active tumor volume, and tumor-to-blood and -liver ratios were evaluated, as well as the influence of lesion selection and 2 methods for correction of uptake time differences. RESULTS: The best repeatability was found using the SUV metrics of the averaged PERCIST target lesions (repeatability coefficients < 10%). The correlation between test and retest scans was strong for all uptake measures at either uptake interval (intraclass correlation coefficient > 0.97 and R(2) > 0.98). There were no significant differences in repeatability between data obtained 60 and 90 min after injection. When only PERCIST-defined target lesions were included (n = 34), repeatability improved for all uptake values. Normalization to liver or blood uptake or glucose correction did not improve repeatability. However, after correction for uptake time the correlation of SUV measures and TLG between the 60- and 90-min data significantly improved without affecting test-retest performance. CONCLUSION: This study suggests that a 15% change of SUVmean/SUVpeak at 60 min after injection can be used to assess response in advanced NSCLC patients if up to 5 PERCIST target lesions are assessed. Lower thresholds could be used in averaged PERCIST target lesions (<10%).

18F-FDG or 3'-deoxy-3'-18F-fluorothymidine to detect transformation of follicular lymphoma.

UNLABELLED: Considering the different treatment strategy for transformed follicular lymphoma (TF) as opposed to follicular lymphoma (FL), diagnosing transformation early in the disease course is important. There is evidence that (18)F-FDG has utility as a biomarker of transformation. However, quantitative thresholds may require inclusion of homogeneous non-Hodgkin lymphoma subtypes to account for differences in tracer uptake per subtype. Moreover, because proliferation is a hallmark of transformation, 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) might be superior to (18)F-FDG in this setting. To define the best tracer for detection of TF, we performed a prospective a head-to-head comparison of (18)F-FDG and (18)F-FLT in patients with FL and TF. METHODS: (18)F-FDG and (18)F-FLT PET scans were obtained in 17 patients with FL and 9 patients with TF. We measured the highest maximum standardized uptake value (SUVmax), defined as the lymph node with the highest uptake per patient, and SUVrange, defined as the difference between the SUVmax of the lymph node with the highest and lowest uptake per patient. To reduce partial-volume effects, only lymph nodes larger than 3 cm(3) (A50 isocontour) were analyzed. Scans were acquired 1 h after injection of 185 MBq of (18)F-FDG or (18)F-FLT. To determine the discriminative ability of SUVmax and SUVrange of both tracers for TF, receiver-operating-characteristic curve analysis was performed. RESULTS: The highest SUVmax was significantly higher for TF than FL for both (18)F-FDG and (18)F-FLT (P < 0.001). SUVrange was significantly higher for TF than FL for (18)F-FDG (P = 0.029) but not for (18)F-FLT (P = 0.075). The ability of (18)F-FDG to discriminate between FL and TF was superior to that of (18)F-FLT for both the highest SUVmax (P = 0.039) and the SUVrange (P = 0.012). The cutoff value for the highest SUVmax of (18)F-FDG aiming at 100% sensitivity with a maximum specificity was found to be 14.5 (corresponding specificity, 82%). For (18)F-FLT, these values were 5.1 and 18%, respectively. When the same method was applied to SUVrange, the cutoff values were 5.8 for (18)F-FDG (specificity, 71%) and 1.5 for (18)F-FLT (specificity, 36%). CONCLUSION: Our data suggest that (18)F-FDG PET is a better biomarker for TF than (18)F-FLT PET. The proposed thresholds of highest SUVmax and SUVrange should be prospectively validated.

The dopamine stabilizer (-)-OSU6162 occupies a subpopulation of striatal dopamine D2/D3 receptors: an [(11)C]raclopride PET study in healthy human subjects.

(-)-OSU6162 is a dopamine stabilizer that can counteract both hyperdopaminergic and hypodopaminergic states. In this study, D2/D3 receptor occupancy of (-)-OSU6162 in the human brain was investigated using positron emission tomography (PET). Twelve male healthy volunteers underwent [(11)C]raclopride PET scanning before and 1 h after a single oral dose of (-)-OSU6162 (15-90 mg). Blood samples for determination of (-)-OSU6162 and prolactin plasma levels were collected at Tmax. Parametric images of [(11)C]raclopride binding potential relative to nondisplaceable tissue (cerebellar grey matter) uptake (BPND) at baseline and after (-)-OSU6162 administration were generated using the simplified reference tissue model. MRI-based regions of interest were defined for the striatum, composed of caudate nucleus and putamen, and projected onto the co-registered parametric [(11)C]raclopride BPND image. Furthermore, three striatal subregions, ie, anterior dorsal caudate, anterior dorsal putamen, and ventral striatum, were defined manually and additionally analyzed. Plasma concentrations of (-)-OSU6162, ranging from 0.01 to 0.9 µM, showed a linear relationship with prolactin levels, reflecting blockade of pituitary D2 receptors. A concentration-dependent increase in striatal D2/D3 receptor occupancy was observed, reaching a value of about 20% at an (-)-OSU6162 plasma level of 0.2 µM, and which for higher concentrations leveled off to a maximal occupancy of about 40%. Findings were similar in the striatal subregions. The present data corroborate the notion that (-)-OSU6162 binds preferentially to a subpopulation of D2/D3 receptors, possibly predominantly extrasynaptic, and this may form the basis for the dopamine-stabilizing properties of (-)-OSU6162.

Detection of subclinical synovitis with macrophage targeting and positron emission tomography in patients with rheumatoid arthritis without clinical arthritis.

OBJECTIVE: To determine whether macrophage targeting by (R)-11C-PK11195 positron emission tomography (PET) can visualize subclinical joint inflammation in patients with rheumatoid arthritis (RA) without clinical arthritis during or after treatment, with flare as clinical outcome measure. METHODS: (R)-11C-PK11195 PET and contrast-enhanced magnetic resonance imaging (MRI) of hands/wrists were performed in 29 patients with RA without clinical arthritis. (R)-11C-PK11195 PET uptake (semiquantitative score 0-3) in metacarpophalangeal, proximal interphalangeal, and wrist joints (i.e., 22 joints per patient) was scored and summed to obtain a cumulative PET score (range 0-66). Rheumatoid Arthritis Magnetic Resonance Imaging Scoring (RAMRIS) was performed on similar joints. Synovitis and bone marrow edema scores (>1) were summed to obtain a cumulative MRI score (range 0-288). Occurrence of flare was determined during 3-year followup. RESULTS: Flare was observed in 17/29 patients (59%). (R)-11C-PK11195 PET showed enhanced tracer uptake in 16/29 patients (55%), of which 11 (69%) developed a flare. Highest cumulative PET scores (>6, n=3) corresponded with highest cumulative MRI scores (>39) and were related to development of flare in hands/wrists within 6 months. Cumulative PET scores of patients developing a flare were higher than those of patients without a flare [median (interquartile range) 2 (0-4.5) vs 0 (0-1), p<0.05]. In contrast, no significant differences were found between cumulative MRI scores of patients with and without a flare. CONCLUSION: (R)-11C-PK11195 PET showed enhanced uptake, pointing to presence of subclinical synovitis in over half of patients without clinical arthritis. (R)-11C-PK11195 PET may be of value for prediction of exacerbation of RA, since cumulative PET scores > 1 were associated with development of flare within 3 years.

18 F-fluorothymidine uptake in follicular lymphoma and error-prone DNA repair.

BACKGROUND: We observed a disproportional 18 F-fluorothymidine (F-FLT) uptake in follicular lymphoma (FL) relative to its low cell proliferation. We tested the hypothesis that the 'excess' uptake of 18 F-FLT in FL is related to error-prone DNA repair and investigated whether this also contributes to 18 F-FLT uptake in diffuse large B cell lymphoma (DLBCL). METHODS: We performed immunohistochemical stainings to assess the pure DNA replication marker MIB-1 as well as markers of both DNA replication and repair like PCNA, TK-1 and RPA1 on lymph node biopsies of 27 FLs and 35 DLBCLs. In 7 FL and 15 DLBCL patients, 18 F-FLT-PET had been performed. RESULTS: 18 F-FLT uptake was lower in FL than in DLBCL (median SUVmax 5.7 vs. 8.9, p = 0,004), but the ratio of 18 F-FLT-SUVmax to percentage of MIB-1 positive cells was significantly higher in FL compared with DLBCL (p = 0.001). The median percentage of MIB-1 positive cells was 10% (range, 10% to 20%) in FL and 70% (40% to 80%) in DLBCL. In contrast, the median percentages of PCNA, TK-1 and RPA1 positive cells were 90% (range, 80 to 100), 90% (80 to 100) and 100% (80 to 100) in FL versus 90% (60 to 100), 90% (60 to 100) and 100% (80 to 100) in DLBCL, respectively. CONCLUSIONS: This is the first demonstration of a striking discordance between 18 F-FLT uptake in FL and tumour cell proliferation. High expression of DNA replication and repair markers compared with the pure proliferation marker MIB-1 in FL suggests that this discordance might be due to error-prone DNA repair. While DNA repair-related 18 F-FLT uptake considerably contributes to 18 F-FLT uptake in FL, its contribution to 18 F-FLT uptake in highly proliferative DLBCL is small. This apparently high contribution of DNA repair to the 18 F-FLT signal in FL may hamper studies where 18 F-FLT is used to assess response to cytostatic therapy or to distinguish between FL and transformed lymphoma.

Cerebral blood flow and glucose metabolism measured with positron emission tomography are decreased in human type 1 diabetes.

Subclinical systemic microvascular dysfunction exists in asymptomatic patients with type 1 diabetes. We hypothesized that microangiopathy, resulting from long-standing systemic hyperglycemia and hyperinsulinemia, may be generalized to the brain, resulting in changes in cerebral blood flow (CBF) and metabolism in these patients. We performed dynamic [(15)O]H2O and [(18)F]-fluoro-2-deoxy-d-glucose brain positron emission tomography scans to measure CBF and cerebral glucose metabolism (CMRglu), respectively, in 30 type 1 diabetic patients and 12 age-matched healthy controls after an overnight fast. Regions of interest were automatically delineated on coregistered magnetic resonance images and full kinetic analysis was performed. Plasma glucose and insulin levels were higher in patients versus controls. Total gray matter CBF was 9%, whereas CMRglu was 21% lower in type 1 diabetic subjects versus control subjects. We conclude that at real-life fasting glucose and insulin levels, type 1 diabetes is associated with decreased resting cerebral glucose metabolism, which is only partially explained by the decreased CBF. These findings suggest that mechanisms other than generalized microangiopathy account for the altered CMRglu observed in well-controlled type 1 diabetes.

Cerebral blood flow and glucose metabolism in healthy volunteers measured using a high-resolution PET scanner.

BACKGROUND: Positron emission tomography (PET) allows for the measurement of cerebral blood flow (CBF; based on [15O]H2O) and cerebral metabolic rate of glucose utilization (CMRglu; based on [18 F]-2-fluoro-2-deoxy-d-glucose ([18 F]FDG)). By using kinetic modeling, quantitative CBF and CMRglu values can be obtained. However, hardware limitations led to the development of semiquantitive calculation schemes which are still widely used. In this paper, the analysis of CMRglu and CBF scans, acquired on a current state-of-the-art PET brain scanner, is presented. In particular, the correspondence between nonlinear as well as linearized methods for the determination of CBF and CMRglu is investigated. As a further step towards widespread clinical applicability, the use of an image-derived input function (IDIF) is investigated. METHODS: Thirteen healthy male volunteers were included in this study. Each subject had one scanning session in the fasting state, consisting of a dynamic [15O]H2O scan and a dynamic [18 F]FDG PET scan, acquired at a high-resolution research tomograph. Time-activity curves (TACs) were generated for automatically delineated and for manually drawn gray matter (GM) and white matter regions. Input functions were derived using on-line arterial blood sampling (blood sampler derived input function (BSIF)). Additionally, the possibility of using carotid artery IDIFs was investigated. Data were analyzed using nonlinear regression (NLR) of regional TACs and parametric methods. RESULTS: After quality control, 9 CMRglu and 11 CBF scans were available for analysis. Average GM CMRglu values were 0.33 ± 0.04 µmol/cm3 per minute, and average CBF values were 0.43 ± 0.09 mL/cm3 per minute. Good correlation between NLR and parametric CMRglu measurements was obtained as well as between NLR and parametric CBF values. For CMRglu Patlak linearization, BSIF and IDIF derived results were similar. The use of an IDIF, however, did not provide reliable CBF estimates. CONCLUSION: Nonlinear regression analysis, allowing for the derivation of regional CBF and CMRglu values, can be applied to data acquired with high-spatial resolution current state-of-the-art PET brain scanners. Linearized models, applied to the voxel level, resulted in comparable values. CMRglu measurements do not require invasive arterial sampling to define the input function. TRIAL REGISTRATION: ClinicalTrials.gov NCT00626080.

In vivo quantification of striatal dopamine D2 receptor occupancy by JNJ-37822681 using [11C]raclopride and positron emission tomography.

JNJ-37822681 is a novel, fast-dissociating dopamine D(2) receptor antagonist, currently in development as an antipsychotic drug candidate. A previous first-in-human study demonstrated mild central nervous system effects of JNJ-37822681 in healthy male volunteers. Significant but transient serum prolactin elevations were demonstrated, whereas other neurophysiological effects were relatively small. To investigate striatal dopamine D(2) receptor occupancy by variable single doses of JNJ-37822681, an open-label [(11)C]raclopride positron emission tomography study was performed in 12 healthy male volunteers, using the simplified reference tissue model with cerebellum as reference tissue. Oral administration of JNJ-37822681 resulted in dose-dependent dopamine D(2) receptor occupancy. Receptor occupancy increased from 9-19% at 2 mg doses to 60-74% at 20 mg doses of JNJ-37822681. Therefore, single oral doses of JNJ-37822681 can produce occupancy levels that are generally associated with clinical efficacy for registered antipsychotic drugs.

Blood-brain barrier P-glycoprotein function in Alzheimer's disease.

A major pathological hallmark of Alzheimer's disease is accumulation of amyloid-ß in senile plaques in the brain. Evidence is accumulating that decreased clearance of amyloid-ß from the brain may lead to these elevated amyloid-ß levels. One of the clearance pathways of amyloid-ß is transport across the blood-brain barrier via efflux transporters. P-glycoprotein, an efflux pump highly expressed at the endothelial cells of the blood-brain barrier, has been shown to transport amyloid-ß. P-glycoprotein function can be assessed in vivo using (R)-[(11)C]verapamil and positron emission tomography. The aim of this study was to assess blood-brain barrier P-glycoprotein function in patients with Alzheimer's disease compared with age-matched healthy controls using (R)-[(11)C]verapamil and positron emission tomography. In 13 patients with Alzheimer's disease (age 65 ± 7 years, Mini-Mental State Examination 23 ± 3), global (R)-[(11)C]verapamil binding potential values were increased significantly (P = 0.001) compared with 14 healthy controls (aged 62 ± 4 years, Mini-Mental State Examination 30 ± 1). Global (R)-[(11)C]verapamil binding potential values were 2.18 ± 0.25 for patients with Alzheimer's disease and 1.77 ± 0.41 for healthy controls. In patients with Alzheimer's disease, higher (R)-[(11)C]verapamil binding potential values were found for frontal, parietal, temporal and occipital cortices, and posterior and anterior cingulate. No significant differences between groups were found for medial temporal lobe and cerebellum. These data show altered kinetics of (R)-[(11)C]verapamil in Alzheimer's disease, similar to alterations seen in studies where P-glycoprotein is blocked by a pharmacological agent. As such, these data indicate that P-glycoprotein function is decreased in patients with Alzheimer's disease. This is the first direct evidence that the P-glycoprotein transporter at the blood-brain barrier is compromised in sporadic Alzheimer's disease and suggests that decreased P-glycoprotein function may be involved in the pathogenesis of Alzheimer's disease.

Measuring response to therapy using FDG PET: semi-quantitative and full kinetic analysis.

PURPOSE: Imaging with positron emission tomography (PET) using (18)F-2-fluoro-2-deoxy-D: -glucose (FDG) plays an increasingly important role for response assessment in oncology. Several methods for quantifying FDG PET results exist. The goal of this study was to analyse and compare various semi-quantitative measures for response assessment with full kinetic analysis, specifically in assessment of novel therapies. METHODS: Baseline and response dynamic FDG studies from two different longitudinal studies (study A: seven subjects with lung cancer and study B: six subjects with gastrointestinal cancer) with targeted therapies were reviewed. Quantification of tumour uptake included full kinetic methods, i.e. nonlinear regression (NLR) and Patlak analyses, and simplified measures such as the simplified kinetic method (SKM) and standardized uptake value (SUV). An image-derived input function was used for NLR and Patlak analysis. RESULTS: There were 18 and 9 lesions defined for two response monitoring studies (A and B). In all cases there was excellent correlation between Patlak- and NLR-derived response (R (2) > 0.96). Percentage changes seen with SUV were significantly different from those seen with Patlak for both studies (p < 0.05). After correcting SUV for plasma glucose, SUV and Patlak responses became similar for study A, but large differences remained for study B. Further analysis revealed that differences in responses amongst methods in study B were primarily due to changes in the arterial input functions. CONCLUSION: Use of simplified methods for assessment of drug efficacy or treatment response may provide different results than those seen with full kinetic analysis.

Partial volume correction strategies for quantitative FDG PET in oncology.

PURPOSE: Quantitative accuracy of positron emission tomography (PET) is affected by partial volume effects resulting in increased underestimation of the standardized uptake value (SUV) with decreasing tumour volume. The purpose of the present study was to assess accuracy and precision of different partial volume correction (PVC) methods. METHODS: Three methods for PVC were evaluated: (1) inclusion of the point spread function (PSF) within the reconstruction, (2) iterative deconvolution of PET images and (3) calculation of spill-in and spill-out factors based on tumour masks. Simulations were based on a mathematical phantom with tumours of different sizes and shapes. Phantom experiments were performed in 2-D mode using the National Electrical Manufacturers Association (NEMA) NU2 image quality phantom containing six differently sized spheres. Clinical studies (2-D mode) included a test-retest study consisting of 10 patients with stage IIIB and IV non-small cell lung cancer and a response monitoring study consisting of 15 female breast cancer patients. In all studies tumour or sphere volumes of interest (VOI) were generated using VOI based on adaptive relative thresholds. RESULTS: Simulations and experiments provided similar results. All methods were able to accurately recover true SUV within 10% for spheres equal to and larger than 1 ml. Reconstruction-based recovery, however, provided up to twofold better precision than image-based methods. Clinical studies showed that PVC increased SUV by 5-80% depending on tumour size. Test-retest variability slightly worsened from 9.8 +/- 6.5 without to 10.8 +/- 7.9% with PVC. Finally, PVC resulted in slightly smaller SUV responses, i.e. from -30.5% without to -26.3% with PVC after the first cycle of treatment (p < 0.01). CONCLUSION: PVC improves accuracy of SUV without decreasing (clinical) test-retest variability significantly and it has a small, but significant effect on observed tumour responses. Reconstruction-based PVC outperforms image-based methods, but requires dedicated reconstruction software. Image-based methods are good alternatives because of their ease of implementation and their similar performance in clinical studies.

Downregulation of 18F-FDG uptake in PET as an early pharmacodynamic effect in treatment of non-small cell lung cancer with the mTOR inhibitor everolimus.

UNLABELLED: Everolimus downregulates glucose metabolism-associated genes in preclinical models. Inhibition of glucose metabolism measured by (18)F-FDG PET was postulated to serve as a pharmacodynamic marker in everolimus-treated non-small cell lung cancer (NSCLC) patients. METHODS: In 8 NSCLC patients treated with everolimus, the percentage change in (18)F-FDG PET uptake (days 8 and 28 relative to baseline) was determined using a variety of summed standardized uptake value (SUV) measures. Both maximum and mean SUVs were used, with normalizations to body surface area and body weight and with and without correcting for plasma glucose levels. RESULTS: In 5 patients, a reduction of (18)F-FDG PET uptake on day 8 was observed with all methods, ranging from -12.8% to -72.2%. CONCLUSION: These observations demonstrate that inhibition of glucose metabolism is an early effect of everolimus treatment in NSCLC patients and can be assessed using (18)F-FDG PET.