Search

This study aimed to assess the role of a quantitative dynamic PET model in pancreatic cancer as a potential index of tumor aggressiveness and predictor of survival. Methods: Seventy-one patients with 18F-FDG–avid adenocarcinoma of the pancreas before treatment were recruited, including 27 with localized tumors (11 underwent pancreatectomy, and 16 had localized nonresectable tumors) and 44 with metastatic disease. Dynamic 18F-FDG PET images were acquired over a 60-min period, followed by a whole-body PET/CT study. Quantitative data measurements were based on a 2-compartment model, and the following variables were calculated: VB (fractional blood volume in target area), K1 and k2 (kinetic membrane transport parameters), k3 and k4 (intracellular 18F-FDG phosphorylation and dephosphorylation parameters, respectively), and 18F-FDG INF (global 18F-FDG influx). Results: The single significant variable for overall survival (OS) in patients with localized disease was 18F-FDG INF. Patients with a high 18F-FDG INF (>0.033 min−1) had a median OS of 6 and 5 mo for nonresectable and resected tumors, respectively, versus 15 and 19 mo for a low 18F-FDG INF in nonresectable and resected tumors, respectively (P

Dynamic PET (dPET) studies with 18F-FDG were performed in patients with unresectable aggressive fibromatosis before imatinib therapy. The goal of the study was to evaluate the impact of regression-based parametric imaging on tumor diagnostics. A comparison between the regression-based quantitative data (slope and intercept values) with the compartmental data of FDG was performed.The evaluation includes 24 patients with recurrent disease (n = 14), residual tissue (n = 2), or primary disease (n = 8), who were scheduled for palliative treatment with imatinib. Parametric images were calculated based on the dPET data by fitting a linear regression function to the time-activity data and for each voxel. Images of the slope and the intercept of the time-activity data were calculated using a dedicated software. A volume-of-interest-based analysis was also performed by applying a 2-tissue compartment model to the dPET data. The resulting parameters of the FDG kinetics [blood volume (VB), k1-k4] were compared with the volume-of-interest-based slope and intercept data. The evaluation of the parametric images was performed visually and quantitatively.Twenty of 24 tumors could be visualized in the SUV images with a moderate uptake, in locations that were already known from the MR images. Most (16/24) of the tumors demonstrated a clear enhancement in the intercept images, whereas 4 of them showed an intermediate enhancement and only 4 did not show any enhancement in the intercept images. In contrast, only 10 of 24 tumors demonstrated a clearly enhanced slope, 3 of them revealed a slightly enhanced slope, and 11 of the 24 patients did not demonstrate any slope enhancement within the area of the known desmoid tumors. The comparison of slope revealed the highest correlation to the SUV (r = 0.56, P0.05), whereas the intercept values demonstrated the highest correlation to k1 (r = 0.794, P0.05), followed by the fractional VB (r = 0.709, P0.05), followed by SUV (r = 0.630, P0.05). The results indicate that slope images are related to the transport/phosphorylation-dependent part of FDG, whereas intercept images are related to the transport/perfusion part of FDG.These data demonstrate that the use of regression-based parametric imaging helps to differentiate between transport/perfusion- and transport/phosphorylation-dependent FDG uptake and demonstrate that the transport/phosphorylation rate is low in most of these tumors.

The kinetics of Ga-68-BZH3, a Ga-68-bombesin analog, was compared to molecular biological data obtained from gene arrays in seven patients with a recurrent glioma. The primary aim of this study was the correlation of receptor expression and tracer kinetics.Dynamic positron emission tomography studies were performed and the data were analyzed by a volume-of-interest technique using a two-tissue compartment model as well as a non-compartment model. Gene array data were obtained from gene array analysis of tumor tissue samples.The correlation analysis revealed a significant nonlinear correlation of r = 0.89 (p 0.03) for k1 and BB(2) (gastrin-releasing peptide receptor). BB(1) and BB(3) were not significantly correlated with k1. vb and k3 were not significantly correlated with the expression data of the receptors on the p 0.05 level.The parameter k1 is correlated with the expression of BB(2) based on gene array data. The quantitative analysis of the Ga-68-BZH3 kinetics can be used to predict the receptor expression of BB(2) in gliomas based on k1 of the compartment analysis. However, this study is limited to the expression data on the mRNA level and further studies are needed to assess the correlation of gene expression on the protein level.

Purpose:Dynamic PET studies with a 68Ga-Bombesin analog, the 68Ga-BZH3, were performed in patients with highly suspected recurrent gliomas to investigate the effect of the receptor scintigraphy on tumor grading. Furthermore, dynamic F-18 Fluorodeoxyglucose (FDG) studies were performed for comparison

Background The degree of plasma cell (PC) infiltration in the bone marrow (BM) is an important diagnostic and prognostic marker in multiple myeloma. An infiltration of 60% or more has been included into the new criteria of the IMWG defining myeloma. PC infiltration can vary significantly within and among individual patients regarding growth patterns (focal, diffuse or mixed), bone destruction (best visible in CT), which may or may not be concomitantly present, and levels of PC metabolism (best detected by PET). Usually, BM examinations are performed by random biopsy and aspirate from the pelvis. It is up for debate whether the PC infiltration at this location is representative for the whole BM compartment or merely represents a local picture detail of the disease. In this prospective study we evaluated PC infiltration of osteolytic lesions (OL) and random BM biopsies and aspirates (RA) at the iliac crest with local parameters whole-body imaging with PET/CT. Patients and Methods 64 transplant-eligible patients with newly diagnosed multiple myeloma (NDMM) were enrolled in this ongoing prospective study to investigate the genetic heterogeneity of malignant cells from OL in different parts of the BM compared with a RA of the pelvis. Target OLs were identified by low-dose whole-body CT scan. Sample pairs (n=64) were obtained by CT-guided biopsies of OLs as well as simultaneous RAs of the iliac crest at diagnosis and before maintenance therapy (n=19). To analyze differences between PC infiltration of the BM in RA compared to OL, we performed immunohistochemistry (IHC) on trephines of the iliac crest and on samples from OL. Whole-body 18F-FDG PET/CT was performed at diagnosis (n=53) and before initiation of maintenance therapy (n=42) assessing PET/CT characteristics like uptake patterns, number of focal lesions, maximal Standardized Uptake Value (SUVmax) of the respective lesion, SUVmax of normal BM as reference and delta SUVmax (SUVmax lesion-SUVmax reference) at diagnosis and before maintenance therapy. Results and Discussion: At baseline, samples from OLs were obtained in the pelvis (47 patients), in the spine (18) or in the extremities (4). PET/CT at diagnosis showed 3 different infiltration patterns: focal lesions in 11 patients, diffuse infiltration in 11 patients, and a mixed pattern in 31 patients. The median number of focal lesions per patient was 7 (range, 0 to >20). PET/CT-detectable lesions were most frequent in patients with a mixed pattern (median, 8 OL, 14/31 patients had >10 lesions). Patients with a focal pattern had a median number of 3 focal lesions; only one patient had >10 OLs. Interestingly, the number of PET/CT-detectable focal lesions at diagnosis neither correlates with ISS stage of the patients nor with their response to therapy. At diagnosis, PC infiltration in OL was significantly higher in comparison to PC in random samples of the iliac crest (p=0.001). In 23 of 36 patients with a PC percentage in OL >=60%, the respective PC infiltration in RA of the iliac crest was In a preliminary follow-up analysis of 19 patients, neither PC infiltration, size, HU nor SUV of OL showed any significant association with the outcome seen at the time of imaging analysis. However, our analysis showed that after induction therapy and ASCT, 9 of 10 patients with remaining PET-CT-detectable, 18F-FDG avid OLs would progress within 12 months (90%, 4 patients with focal, 6 patients with mixed patterns at baseline). Conclusion Our data suggests that the routine assessment of PC infiltration in RA of the iliac crest might underestimate the degree of PC infiltration in the whole skeleton of NDMM. PC infiltration correlated significantly with the size of the lesion in CT but neither with HU nor SUVmax of OL in PET-CT. This raises the question whether the imaging techniques being used will pick up signatures of non-viable tumor, such as necrotic tissue or inflammation, instead of or in addition to malignant plasma cells. Interestingly, patients with PET-detectable, 18F-FDG avid residual lesions after therapy were at high risk of progression within 12 months. Disclosures Goldschmidt: Amgen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Adaptive Biotechnology: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Research Funding; Novartis: Honoraria, Research Funding; Mundipharma: Research Funding; Chugai: Honoraria, Research Funding; Takeda: Consultancy, Research Funding; ArtTempi: Honoraria. Hillengass:Celgene: Consultancy, Honoraria, Other: Advisory Board, Research Funding; Sanofi: Research Funding; BMS: Honoraria, Other: Advisory Board; Novartis: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; amgen: Consultancy, Honoraria, Other: Advisory Board.

Background: Thymic carcinoma (TC) is a rare aggressive tumour. Median survival with current treatments is only 2 years. Sunitinib is a multi-targeted tyrosine kinase inhibitor that has shown benefit in various other cancers. Methods: Laboratory analyses of snap-frozen tumour tissues were performed to detect activation and genetic mutations of receptor tyrosine kinases (RTKs) in TC samples. On the basis of molecular analyses showing activation of multiple RTKs in their tumour, four patients with metastatic TCs refractory to conventional therapies were treated with sunitinib according to standard protocols. Results: RTK analysis in three of the patients showed activation of multiple RTKs, including platelet-derived growth factor-β and vascular endothelial growth factor 3. Mutations of EGFR, c-KIT, KRAS, and BRAF genes were not found. Administration of sunitinib yielded a partial remission (lasting 2 to 18+ months) according to the RECIST criteria in three patients and stable disease with excellent metabolic response in 18F-FDG-PET in another one. The overall survival with sunitinib treatment ranges from 4 to 40+ months. Withdrawal of the drug in one patient prompted rapid tumour progression that could be controlled by re-administration of sunitinib. Conclusions: Sunitinib is an active treatment for metastatic TC. A panel of molecular analyses may be warranted for optimal patient selection.

We used (18)F-FDG PET to evaluate the FDG uptake in patients with aggressive fibromatosis (AF, also known as desmoid tumours) undergoing therapy with imatinib (imatinib mesylate, Glivec).The pilot study included nine patients with progressive AF receiving oral treatment with imatinib at a daily dose of 800 mg. Patients were examined using PET prior to the start of therapy and during imatinib treatment. Restaging according to the Response Evaluation Criteria in Solid Tumors (RECIST) was performed in parallel using CT and/or MRI and served as reference.The clinical outcomes in nine evaluable patients were as follows: seven patients with stable disease, and two patients with progressive disease. A 27% decrease in the median average standardized uptake value (SUV) of the sequential PET examinations was demonstrated in all evaluable patients with three patients (33%) showing a decrease in SUV of more than 40% (48%, 52% and 54%, respectively); no patient showed a substantial increase in SUV.To our knowledge, this is the first series of AF patients undergoing treatment with imatinib and monitored using sequential PET imaging, that allows detection of SUV changes after imatinib induction, thus helping to decide whether treatment should be continued or not.

Dynamic PET studies with 18F-FDG were performed in patients with metastatic soft tissue sarcomas who received conventional chemotherapy with doxorubicin hydrochloride (Adriamycin) and ifosfamide (AI-G). The goal of the study was to evaluate the impact of full kinetic analysis and assess its value with regard to the therapy outcome based on survival data. The evaluation included 17 patients with 29 metastatic lesions of soft tissue sarcomas, who were treated with chemotherapy consisting of an AI-G regimen prior to high-dose chemotherapy and peripheral blood stem cell transplantation where applicable. Patients were examined prior to onset of therapy and after completion of the first cycle of AI-G. Restaging data (n = 17) based on Response Evaluation Criteria in Solid Tumors were available. Survival data (n = 14) served for reference. The following parameters were retrieved from the dynamic PET studies: standardized uptake value (SUV), fractal dimension, two-compartment model with computation of k1, k2, k3, k4 (unit: 1/min), the fractional blood volume and the FDG influx calculated according to Patlak. The mean SUV was 6.9 prior to therapy and 4.7 after one cycle. The mean influx was 0.066 prior to therapy in comparison to 0.058 after one cycle. We dichotomized the patients according to the median survival time of 320 days into response (n = 6) and non-response (n = 8). The mean SUV was 7.6 in the group of responders and 5.4 in the group of non-responders prior to therapy. Responders revealed a mean SUV of 3.8 after therapy as compared to 5.0 SUV for non-responders. We used discriminant analysis to classify the patients into the two response groups. The classification of the non-responders was generally higher (negative predictive value > 61%) than for the responders. Finally, the combined use of the four predictor variables, namely mean SUV and k1 of both studies led to the highest accuracy of 90% for both groups. The data demonstrate that only a multiparameter analysis based on a combination of the absolute values of mean SUV and k1 of a baseline study and a follow-up study after completion of one cycle was the best combination for a group-based analysis, into response or non-response. The quantitative assessment of the FDG kinetics in tumours should be used to quantify the “inhibitory effect” of chemotherapy and to individualize treatment. The main effect of the AI-G therapy may be on angiogenesis (k1 effect) rather than on proliferation.

Methods:Dynamic positron emission tomography (PET) studies with F-18deoxyglucose were performed in patients with multiple myeloma who received anthracycline-based chemotherapy to evaluate the impact of full kinetic analysis and assess its value with regard to progression-free survival (PFS). The evaluation included 19 patients (56 metastatic lesions) with multiple myelomas. All patients received combined anthracycline-based chemotherapy. PFS served as a reference for the PET data. All patients were examined prior to the onset of chemotherapy and on days 23 to 28 after the onset of the first cycle (prior to the second cycle). The following parameters were retrieved from the dynamic PET studies: Standardized Uptake Value (SUV), fractal dimension (FD), 2 compartment model with computation of K1, k2, k3, k4 (unit: 1/min), the fractional blood volume (vB), and the FDG-influx according to Patlak were calculated. Results:The observed PFS varied from!1 month to 64.1 months with a median PFS of 26 months. Most kinetic parameters demonstrated only small changes, primarily declining after 1 cycle. We compared the kinetic data of each study using a Wilcoxon matched-pairs signed rank test. The results were considered significant forP!0.05. The test revealed a significant change for the SUV (z"4.954,P!0.0000), the FD (z"5.036,P! 0.0000), the fractional blood volume vB (z"4.116,P!0.0000) and influx (z"2.614,P!0.0090) when the absolute values of the first and the second study were compared. We dichotomized the patients according to the PFS of 18 months and defined 2 survival groups. The data demonstrate that the correct classification rate (CCR) of group 2 (survival:#18 months) was generally higher (exceeding 94%) than for group 1. The use of the baseline SUV led to a CCR of 82% for the group 2 with the longer survival. The CCR of group 1 with the short survival varied between 55% and 70% depending on the parameter and the study used for prediction. Furthermore, the CCR for both groups based only on the data of the second study was somewhat lower (74%‐75%) as compared with the baseline FDG study (75%‐82%). Finally, the combined use of the 6 predictor variables, namely SUV, k3, and FD (selected by the Wilcoxon rank sum test) of each study led to the highest CCR of 85% for both groups. This combination was in particular useful for the prediction of group 2 with the longer survival with a CCR of 94%. Best cutoff-values for the differentiation between short and long PFS were SUV of 4.0 and a k3 of 0.07 of the baseline study. Conclusions:The results demonstrate, that a full kinetic analysis of the FDG studies prior and after 1 chemotherapeutic cycle in patients with multiple myeloma is helpful for the prediction of PFS and may be used to identify those patients who benefit from this chemotherapeutic protocol. A high SUV (#4.0 SUV) as well as a high k3 (#0.07) of the baseline study were bad prognostic parameters and related to a short PFS.

The very early chemotherapeutic effects of the FOLFOX (fluorouracil, folinic acid, oxaliplatin) protocol were assessed in mice implanted with a human colorectal cell line. The aim of this study was to identify changes in gene expression patterns and to detect combinations of PET parameters that may be helpful in identifying treated tumours early after chemotherapy using dynamic PET studies.A human colorectal cell line (HCT 116) was used in nude mice. Dynamic PET studies were performed in untreated (n = 13) and treated (n = 12) animals. The data were assessed using compartmental and noncompartmental analysis. The removed tumour specimens were assessed by gene array analysis to obtain quantitative information on gene expression.One chemotherapeutic treatment using the FOLFOX protocol resulted in an upregulation of 2,078 gene probes by more than 25%, while 2,254 probes were downregulated following treatment. The gene array data demonstrated primarily an enhancement of genes related to apoptosis. In particular, the apoptosis antigen 1 (APO-1), p21 and the G protein-coupled receptor 87 (G-87) were 2.6- to 3.3-fold upregulated as compared to the expression in untreated animals. There was a 100% separation of untreated and treated animals on the basis of these three genes. The SUV and the FDG kinetic parameters obtained by compartmental and noncompartmental fitting were not significantly different when individual parameters were compared between groups. However, classification analysis of the combination of the PET parameters VB, K1, k3, and influx revealed an overall accuracy of 84%. We were able to identify 91.7% (11/12) of the treated animals and 76.9% (10/13) of the untreated animals correctly using the classification analysis of PET data.Even one chemotherapeutic treatment using FOLFOX has an impact on gene expression and significantly modulates FDG kinetics. Quantitative assessment of the tracer kinetics and the application of classification analysis to the data are promising tools to identify those tumours that demonstrate a chemotherapeutic effect very early following treatment.

18F-FDG kinetics are primarily dependent on the expression of genes associated with glucose transporters and hexokinases but may be modulated by other genes. The dependency of 18F-FDG kinetics on angiogenesis-related gene expression was evaluated in this study. Methods: Patients with primary colorectal tumors (n = 25) were examined with PET and 18F-FDG within 2 days before surgery. Tissue specimens were obtained from the tumor and the normal colon during surgery, and gene expression was assessed using gene arrays. Results: Overall, 23 angiogenesis-related genes were identified with a tumor-to-normal ratio exceeding 1.50. Analysis revealed a significant correlation between k1 and vascular endothelial growth factor (VEGF-A, r = 0.51) and between fractal dimension and angiopoietin-2 (r = 0.48). k3 was negatively correlated with VEGF-B (r = −0.46), and a positive correlation was noted for angiopoietin-like 4 gene (r = 0.42). A multiple linear regression analysis was used for the PET parameters to predict the gene expression, and a correlation coefficient of r = 0.75 was obtained for VEGF-A and of r = 0.76 for the angiopoietin-2 expression. Thus, on the basis of these multiple correlation coefficients, angiogenesis-related gene expression contributes to about 50% of the variance of the 18F-FDG kinetic data. The global 18F-FDG uptake, as measured by the standardized uptake value and influx, was not significantly correlated with angiogenesis-associated genes. Conclusion:18F-FDG kinetics are modulated by angiogenesis-related genes. The transport rate for 18F-FDG (k1) is higher in tumors with a higher expression of VEGF-A and angiopoietin-2. The regression functions for the PET parameters provide the possibility to predict the gene expression of VEGF-A and angiopoietin-2.

The combination of the short physical half-life of C-11, thenumber of different metabolites and the complexity of dataanalysis, which requires compartment modeling and me-tabolite measurements in blood, has limited the use of C-11-thymidine, like in the case of C-11-glucose. A thymidineanalogue, which is more stable against metabolic degrada-tion, is F-18-fluoro-3′-deoxy-3′

Human troponin I (TROP), the soluble receptor for vascular endothelial growth factor (sFLT) and angiostatin (ASTAT) are potent inhibitors of endothelial cell proliferation, angiogenesis and tumour growth in vivo. Transfer of these genes into tumours may induce changes not only in perfusion, but also more general ones such as changes in metabolism. The aim of this study was to assess these reactions using FDG-PET and high-throughput methods such as gene profiling. We established Morris hepatoma (MH3924A) cell lines expressing TROP, sFLT or ASTAT and quantified 18F-fluorodeoxyglucose (18FDG) uptake by dynamic positron emission tomography (PET) after tumour inoculation in ACI rats. Furthermore, expression of glucose transporter-1 and -3 (GLUT-1 and GLUT-3) as well as hexokinase-1 and -2 were investigated by RT-PCR and immunohistomorphometry. In addition, gene array analyses were performed. 18FDG uptake, vascular fraction and distribution volume were significantly higher in all genetically modified tumours. Immunohistomorphometry showed an increased percentage of hexokinase-1 and -2 as well as GLUT-1 and -3 immunoreactive (ir) cells. Using gene arrays and comparing all three groups of genetically modified tumours, we found upregulated expression of 36 genes related to apoptosis, signal transduction, stress or metabolism. TROP-, sFLT- or ASTAT-expressing MH3924A tumours show enhanced influx of 18FDG, which seems to be caused by several factors: enhanced exchange of nutrients between blood and tumour, increased amounts of glucose transporters and hexokinases, and increased expression of genes related to apoptosis, matrix and stress, which induce an increased demand for glucose.

Dynamic PET studies with a 68Ga-bombesin analog, DOTA-PEG2-[d-Tyr6, β-Ala11,Thi13,Nle14] BN(6-14) amide (68Ga-BZH3; DOTA is 1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid, and PEG is ethylene glycol [2-aminoethyl-carboxymethyl ether]), were performed on patients with gastrointestinal stromal tumors (GIST) to investigate the impact of complementary receptor scintigraphy on diagnosis and the potential of a radionuclide treatment. Furthermore, dynamic 18F-FDG studies were performed on the same patients. Methods: This study comprised 17 patients with GIST. All patients were scheduled for therapy with imatinib because of unresectable primary or recurrent GIST or because of metastatic disease. Dynamic PET scans using 68Ga-BZH3 and 18F-FDG were obtained on 2 consecutive days. Multivariate analysis was used to evaluate the kinetic data. Standardized uptake values (SUVs) were calculated, and a compartmental model (2-tissue) and noncompartmental model were used for data evaluation of both tracers. Results: Fourteen of 17 patients (25/30 lesions) were positive for uptake on 18F-FDG imaging, whereas 68Ga-BZH3 demonstrated an enhanced accumulation in 7 of 17 patients (8/30 lesions). Thirteen lesions were confirmed by histologic examination, and the remaining 17 were confirmed by follow-up. One recurrent tumor in the stomach could not be delineated on 18F-FDG imaging but showed enhanced 68Ga-BZH3 uptake. The median SUV for 68Ga-BZH3 was 3.3, in comparison with 7.9 for 18F-FDG. Best-subset analysis demonstrated that the global SUV (55–60 min after injection) for 18F-FDG was primarily dependent on k3, followed by k1. Multivariate analysis did not show a significant correlation between the kinetic parameters (k1–k4, fractional blood volume, and SUV) for 18F-FDG and bombesin. Conclusion:68Ga-BZH3 may be helpful for diagnostic reasons in a subgroup of patients with GIST, as in the case of negative 18F-FDG findings and suspicion of viable tumor tissue. The meaning of the enhanced 68Ga-BZH3 uptake is open at the moment.

The development of several biomedical ontologies and databases for structuring and categorizing knowledge in life sciences, and particularly the ones which refer to the functions and interactions of biomolecules, have contributed to the rapid inflation of the semantic information universe that describes cellular complexity, at different scales. Together with the ever-growing number of high-throughput molecular data, generated by DNA microarray or NGS experiments, they stress the need for powerful, intuitive data representation methods, which manage to make sense out of the myriads of interactions and pinpoint those with a causal contribution to the phenotypes studied. In this paper, we present a web application, which overall combines computational methodologies and data visualization techniques, in order to deliver comprehensible illustrations of cellular complexity, for voluminous, molecular datasets, linking the individual genes, with the relevant biological processes, in which they participate, while it manages to prioritize those processes according to their involvement in the cellular phenotype studied. The application highlights molecular information (functions, processes, cellular compartments) according several criteria (enrichment score, expression, etc) sorts out regulatory hub genes, with a pivotal role in the phenotype studied, while, most importantly, novel visualization modules provide an efficient, intuitive illustration that aids easy systems' level interpretation. The pipeline is showcased here using a colon cancer dataset.

We aim to investigate the pharmacokinetics and distribution of the recently clinically introduced radioligand (68)Ga-PSMA-11 in men with recurrent prostate cancer (PC) by means of dynamic and whole-body PET/CT. The correlation between PSA levels and (68)Ga-PSMA-11 PET parameters is also investigated.31 patients with biochemical failure after primary PC treatment with curative intent (median age 71.0 years) were enrolled in the analysis. The median PSA value was 2.0 ng/mL (range = 0.1 - 130.0 ng/mL) and the median Gleason score was 7 (range = 5 - 9). 8/31 (25.8 %) of the included patients had a PSA value 0.5 ng/ml. All patients underwent dynamic PET/CT (dPET/CT) scanning (60 min) of the pelvis and lower abdomen as well as whole-body PET/CT with (68)Ga-PSMA-11. dPET/CT assessment was based on qualitative evaluation, SUV calculation, and quantitative analysis based on a two-tissue compartment model and a non-compartmental approach leading to the extraction of fractal dimension (FD).22/31 patients (71.0 %) were (68)Ga-PSMA-11-positive, while 9/31 (29.0 %) patients were (68)Ga-PSMA-11-negative. The median PSA value in the (68)Ga-PSMA-11-positive group was significantly higher (median = 2.35 ng/mL; range = 0.19 - 130.0 ng/mL) than in the (68)Ga-PSMA-11-negative group (median value: 0.34 ng/mL; range = 0.10 - 4.20 ng/mL). A total of 76 lesions were semi-quantitatively evaluated. PC recurrence-associated lesions demonstrated a mean SUVaverage = 12.4 (median = 9.0; range = 2.2 - 84.5) and mean SUVmax = 18.8 (median = 14.1; range = 3.1 - 120.3). Dynamic PET/CT studies of the pelvis revealed the following mean values for the PC recurrence-suspicious lesions: K1 = 0.26, k3 = 0.30, influx = 0.14 and FD = 1.24. Time-activity curves derived from PC-recurrence indicative lesions revealed an increasing (68)Ga-PSMA-11 accumulation during dynamic PET acquisition. Correlation analysis revealed a moderate, but significant, correlation between PSA levels and the number of lesions detected on (68)Ga-PSMA-11 PET/CT (r = 0.54) and between PSA levels and SUVaverage (r = 0.48) or SUVmax (r = 0.44).Ga-PSMA-11 PET/CT demonstrated an overall detection rate of 71.0 % 60 min p.i. of the radiotracer in a mixed patient population with respect to PSA levels and including patients with very low PSA values. Higher PSA values were associated with a higher detection rate. The tracer uptake in PC-recurrence-indicative lesions is increasing during the 60 minutes of dynamic PET acquisition.

Aim of this prospective study was to assess the sensitivity of positron emission tomography (PET) and diffusion-weighted imaging (DWI) in detecting multiple myeloma (MM) lesions, using the well-established morphologic modalities magnetic resonance imaging (MRI) and computed tomography (CT) as the standard of reference (RS). The study included 24 MM patients (15 newly diagnosed, 9 pre-treated). All underwent (18)F-FDG PET/CT and wholebody DWI. The findings in PET and DWI were compared to matching imaging findings in combined non-enhanced T1w, fat-saturated T2w (TIRM)- MRI, and low-dose CT. Patient-based analysis revealed that 15/24 patients (10 primary MM, 5 pre-treated) had myeloma lesions according to our RS. PET was positive in 13/24 patients (11 primary MM, 2 pre-treated) and DWI in 18/24 patients (12 primary MM, 6 pre-treated). Lesion-based analysis demonstrated 128 MM lesions, of which PET depicted 60/128 lesions (sensitivity 47%), while DWI depicted 99/128 lesions (sensitivity 77%). Further analysis including only the 15 untreated MM patients revealed a sensitivity of 90% for both PET and DWI and an overall concordance of PET and DWI of 72%. In conclusion, DWI was more sensitive than (18)F-FDG PET in detecting myeloma lesions in a mixed population of primary and pre-treated MM patients. However, (18)F-FDG PET and DWI demonstrated equivalent sensitivities in the sub-population of primary, untreated MM patients. This higher sensitivity of DWI in pre-treated patients may be due to the fact that (18)F-FDG PET becomes negative earlier in the course of treatment in contrary to MRI, in which already treated lesions can remain visible.

PET/MRI represents a promising hybrid imaging modality with several potential clinical applications. Although PET/MRI seems highly attractive in the diagnostic approach of multiple myeloma (MM), its role has not yet been evaluated. The aims of this prospective study are to evaluate the feasibility of (18)F-FDG PET/MRI in detection of MM lesions, and to investigate the reproducibility of bone marrow lesions detection and quantitative data of (18)F-FDG uptake between the functional (PET) component of PET/CT and PET/MRI in MM patients. The study includes 30 MM patients. All patients initially underwent (18)F-FDG PET/CT (60 min p.i.), followed by PET/MRI (120 min p.i.). PET/CT and PET/MRI data were assessed and compared based on qualitative (lesion detection) and quantitative (SUV) evaluation. The hybrid PET/MRI system provided good image quality in all cases without artefacts. PET/MRI identified 65 of the 69 lesions, which were detectable with PET/CT (94.2%). Quantitative PET evaluations showed the following mean values in MM lesions: SUVaverage=5.5 and SUVmax=7.9 for PET/CT; SUVaverage=3.9 and SUVmax=5.8 for PET/MRI. Both SUVaverage and SUVmax were significantly higher on PET/CT than on PET/MRI. Spearman correlation analysis demonstrated a strong correlation between both lesional SUVaverage (r=0.744) and lesional SUVmax (r=0.855) values derived from PET/CT and PET/MRI. Regarding detection of myeloma skeletal lesions, PET/MRI exhibited equivalent performance to PET/CT. In terms of tracer uptake quantitation, a significant correlation between the two techniques was demonstrated, despite the statistically significant differences in lesional SUVs between PET/CT and PET/MRI.

Hypoxia is an important resistance factor in radiotherapy and measuring its spatial distribution in tumors non-invasively is therefore of major importance. This study characterizes the hypoxic conditions of three tumor sublines (AT1, HI and H) of the Dunning R3327 prostate tumor model, which differ in histology, differentiation degree, volume doubling time and androgenic sensitivity, using dynamic Fluoromisonidazole ((18)F-FMISO)-Positron Emission Tomography/Computed Tomography (PET-CT) and histology. Measurements were performed for two tumor volumes (average 0.8±0.5 cm(3) vs 4.4±2.8 cm(3)). Data were analyzed according to tumor subline as well as to the shape of the time activity curves (TACs), based on standardized uptake values (SUVs) and a two-tissue compartment model. Quantitative immunohistochemical studies of the hypoxic fraction, vessel density and vessel size were performed using pimonidazole, Hoechst 33342 and CD31 dyes. No significant FMISO uptake was found in small tumors, which had a mean SUV of 0.64±0.36, 0.55±0.10 and 0.45±0.08, for AT1, HI and H sublines respectively. In large tumors, the SUVs were 1.33±0.52, 1.12±0.83 and 0.63±0.16 for AT1, HI and H sublines and the corresponding hypoxic fractions obtained with pimonidazole staining were 0.62±0.23, 0.54±0.24 and 0.07±0.10, respectively. The AT1- was the most and H-tumor was the least hypoxic for both methods (P0.05). All measurements were able to discriminate different hypoxic conditions, however despite SUV and kinetic parameters correlated with the three identified TAC shapes, most of the histological results did not. These results demonstrate impact and limitations of static and dynamic PET-CT measurements to assess hypoxia non-invasively.

PURPOSE: The value of F-FDG PET in the diagnostic approach of multiple myeloma (MM) remains incompletely elicited. Little is known about the kinetics of F-FDG in the bone marrow and extramedullary sites in MM. This study aimed to evaluate quantitative data on kinetics and distribution patterns of F-FDG in MM patients with regard to pelvic bone marrow plasma cell infiltration. PROCEDURES: The study included 40 patients with primary MM. Dynamic PET/CT scanning of the lower lumbar spine and pelvis was performed after the administration of F-FDG. Whole-body PET/CT studies were performed. Sites of focal increased tracer uptake were considered as highly suggestive of myelomatous involvement after taking into account the patient history and CT findings. Bone marrow of the os ilium without pathologic tracer accumulation served as reference. The evaluation of dynamic PET/CT studies was based in addition to the conventional visual (qualitative) assessment, on semiquantitative (SUV) calculations, as well as on absolutequantitative estimations after application of a 2-tissue compartment model and a noncompartmental approach. F-FDG quantitative information and corresponding distribution patterns were correlated with pelvic bone marrow plasma cell infiltration. RESULTS: Fifty-two myelomatous lesions were detected in the pelvis. All parameters in suspected MM lesions ranged in significantly higher levels than in reference tissue (P < 0.01). Correlative analyses revealed that bone marrow plasma cell infiltration rate correlated significantly with SUVaverage, SUVmax, and the parameters K1, influx, and fractal dimension of F-FDG in reference bone marrow (P < 0.01). In addition, whole-body static PET/CT imaging demonstrated 4 patterns of tracer uptake; these are as follows: negative, focal, diffuse, and mixed (focal/diffuse) tracer uptake. Patients with a mixed pattern of radiotracer uptake had the highest mean plasma cell infiltration rate in their bone marrow, whereas those with negative PET/CT scans demonstrated the lowest bone marrow plasma cell infiltration. In total, 265 focal myeloma-indicative F-FDG-avid lesions were detected, 129 of which correlated with low-dose CT osteolytic findings. No significant correlation between the number of focal lesions detected in PET/CT and bone marrow infiltration was detected. CONCLUSIONS: The F-FDG kinetic parameters K1, influx, and fractal dimension as well as SUVaverage from reference tissue correlated significantly with bone marrow malignant plasma cell infiltration rate. Patients with negative PET/CT demonstrated the lowest bone marrow infiltration by malignant plasma cells, whereas those with a mixed pattern of tracer uptake had the highest infiltration.

Dynamic PET studies with(68)Ga-DOTATOC were performed in patients with non-small cell lung cancer (NSCLC) to assess the somatostatin receptor 2 (SSTR2) expression. Furthermore, dynamic(18)F-fluorodeoxyglucose (FDG) studies were performed in the same patients to compare the SSTR2 expression with the tumour viability.The study population comprised nine patients, examined with both tracers on two different days within 1 week. Standardised uptake values (SUVs) were calculated and a two-tissue compartment model was applied to the data. Furthermore, a non-compartment model based on the fractal dimension (FD) was applied to the data.The DOTATOC uptake was generally lower than the FDG uptake. Moderately enhanced DOTATOC uptake was noted in seven of the nine tumours. All kinetic parameters except k (4) were lower for DOTATOC than for FDG. The mean SUV was 2.018 for DOTATOC, in comparison to 5.683 for FDG. In particular, k (3) was highly variable for DOTATOC and showed an overlap with the normal lung tissue. The fractional blood volume V (B) was relatively low for both tracers, not exceeding 0.3. The highest significant logarithmic correlation was found for the FD of the two tracers (r=0.764, p=0.017). The logarithmic correlation for SUVs was also significant (r=0.646, p=0.060), as was that forV (B) (r=0.629, p=0.069). In contrast, none of the eight metastases which were positive on FDG PET showed any DOTATOC uptake.The results demonstrated moderate (68)Ga-DOTATOC uptake in primary NSCLC but did not provide any evidence for SSTR2 expression in metastases. This may be caused by loss of the gene expression in metastases as compared with the primary tumours.

Investigations into tumor angiogenesis and antiangiogenic treatment have renewed interest in tumor perfusion. To image tumor blood-pool by PET, suitable tracers are not generally available. In this experimental study, we characterized a 68 Ga-labeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) conjugate of rat serum albumin ( 68 Ga-DOTA-RSA) in vivo using a generator-produced isotope. Biodistribution was determined in ACI rats after intravenous administration of 3–6 MBq of 68 Ga-DOTA-RSA. Three ACI rats were imaged over 1 h by dynamic PET after intravenous administration of 15–25 MBq of 68 Ga-DOTA-RSA while the blood-pool activity was recorded simultaneously in a closed extracorporeal loop (ECL) between the carotid artery and the jugular vein. Time–activity curves (TACs) were obtained from volume of interest (VOI) analysis and from the ECL data. Stability and metabolites in plasma and urine were analyzed by size exclusion HPLC (SE-HPLC) 1 h after intravenous injection of 67 Ga-DOTA-RSA. Blood radioactivity decreased by 10% and 18% from 10 to 60 min p.i. by biodistribution and PET or ECL, respectively. Tissue sampling between 10 and 60 min p.i. showed slight increases in the uptake of spleen, myocardium, kidney and skeletal muscle while hepatic accretion remained unchanged. Total urinary excretion after 60 min amounted to 9% of the injected dose. HPLC demonstrated a single urinary metabolite corresponding in size to gallium-labeled DOTA. 68 Ga-DOTA-RSA is a blood-pool tracer whose physical and biological half-life is well suited for PET. Our findings support clinical imaging using 68 Ga-DOTA-labeled human serum albumin (HSA). The generator-produced label makes 68 Ga-DOTA-labeled albumin continuously available even to centers lacking an in-house cyclotron.

Purpose: Inhibition of tumor angiogenesis is emerging as a promising target in the treatment of malignancies. Therefore, monitoring of antiangiogenic approaches with functional imaging and histomorphometrical analyses are desirable to evaluate the biological effects caused by this treatment modality. Experimental Design: Using a bicistronic retroviral vector for transfer of the soluble receptor for the vascular endothelial growth factor (sFLT) hepatoma (MH3924A) cell lines with sFLT expression were generated. In human umbilical vein endothelial cells cultured with conditioned medium of sFLT-expressing hepatoma cells, the inhibitory action of secreted sFLT was determined using a Coulter counter and a thymidine incorporation assay. Furthermore, in vivo experiments were done to measure the effects on tumor growth and perfusion. Finally, the tumors were examined by immunohistochemistry (including computer-assisted morphometry) and DNA chip analysis. Results: Stable sFLT-expressing hepatoma cells inhibited endothelial cell proliferation in vitro. In vivo, growth and perfusion, as measured by H215O positron emission tomography, were reduced in genetically modified tumors. However, the immunohistochemically quantified microvascularization and macrovascularization, as indicated by CD31- and α-actin-positive area, revealed no significant changes, whereas the number of apoptotic cells was increased in sFLT-expressing tumors, although not significantly. DNA chip analysis of tumors with gene transfer showed an increase of genes related to apoptosis, signal transduction, and oxidative stress. Conclusion: Our results suggest that sFLT expression inhibits tumor growth and perfusion and enhances expression of apoptosis-related genes in this model. Enhanced expression of genes for signal transduction, stress, and metabolism indicates tumor defense reactions.

A preliminary study is presented on the potential role of similarity mapping (SM) in the evaluation of oncological dynamic 18F-fluorodeoxyglucose positron emission tomography studies, mainly in lesion localisation and detectability. Similarity maps were calculated using previously described (correlation coefficient (COR) and normalised correlation coefficient (NCOR)) and newly introduced similarity measures (sum of squares coefficient (SSQ), squared sum coefficient (SQS), sum of cubes coefficient (SC) and cubed sum coefficient (CS)). The results were evaluated using simulated and clinical data. The study revealed that the best-suited similarity measure for such applications was the CS similarity coefficient, which provided the best parametric images, delineating structures of interest and supporting the visual interpretation of data sets. It was shown that SM and standardised uptake value (SUV) images had comparable diagnostic performance, although SM was able to offer additional time-related information in a single image. For the case of colorectal recurrences (17 cases), the measured contrast values for the CS and SUV images were 2.36 +/- 0.47 and 4.12 +/- 0.42, respectively, whereas, for three cases of giant cell tumours, these values were 11.6 +/- 2.1 and 11.9 +/- 1.8, respectively.

Aims: Benign neurofibromas and malignant peripheral nerve sheath tumours (MPNST) commonly develop in patients with neurofibromatosis. Differentiation of benign from malignant tumours by conventional preoperative imaging is unreliable. FDG-PET is a non-invasive technique for biological tumour evaluation. The aim of this study was to assess the value of FDG-PET in patients with neurogenic tumours suspicious for MPNST. Methods: Benign and malignant neurogenic soft tissue tumours were prospectively evaluated by computed tomography or magnetic resonance imaging. Three-dimensional qualitative and quantitative FDG-PET was performed. Standard uptake value (SUV) was analyzed with respect to histological diagnosis and follow-up data. Results: Twenty-five neurogenic soft tissue tumours were included. FDG-PET identified all primary (n=6) and recurrent MPNST (n=7). Benign lesions (n=12) did not demonstrate high FDG uptake. The SUV was significantly higher in MPNST (median 2.9; range 1.8–12.3), than in benign tumours (median 1.1; range 0.5–1.8) (p

Purpose: The development, implementation and validation of simple, flexible and efficient iterative image reconstruction (IIR) methods for their take-up in routine clinical positron emission tomography (PET) static or dynamic studies. Procedures: The ordered subsets (OS) technique applied for the acceleration of the maximum likelihood expectation maximization (MLEM) IIR algorithm is here extended to include the weighted least-squares (WLS), image space reconstruction algorithm (ISRA) and the space alternating generalized EM (SAGE). The median root prior (MRP) has been successfully applied as a Bayesian regularization to control the noise level in the reconstructed images. All methods are implemented on distributed Pentium systems and tested using simulated PET data from a brain phantom. A Javascript is used for the initiation of the reconstruction. Results: Taking into consideration the image quality and the time required for the reconstruction, the MRP-OSEM (ordered subsets expectation maximization) seems to provide best results after four to eight iterations, with four subsets and a MRP coefficient of 0.2–0.4. Iterative reconstruction of the transmission images with OS-acceleration and MRP regularization with subsequent calculation of the attenuation correction factors (ACFs) is shown to effectively remove streak artifacts in the emission images, especially along paths of high attenuation. Conclusions: An efficient implementation using distributed processing principles and a web-based interface allows the reconstruction of one frame (with 63 cross-section slices) from a dynamic determination in few minutes. This work showed that regular PC systems can provide fast execution and produce results in clinically meaningful times. This eradicates the argument of the computational burden of the method that prevented the extensive use of IIR in today's modern PET systems. (Mol Imag Biol 2002;4:219–231)

The article “Imaging therapy response of gastrointestinal stromal tumors (GIST) with FDG PET, CT and MRI: a systematic review”, written by Antonia Dimitrakopoulou-Strauss, Ulrich Ronellenfitsch, Caixia Cheng, Leyun Pan, Christos Sachpekidis, Peter Hohenberger, and Thomas Henzler, was originally published Online First without open access. After publication in volume 5, issue 3, pages 183‒197, the author decided to opt for Open Choice and to make the article an open access publication. Therefore, the copyright of the article has been changed to © The Author(s) 2017 and the article is forthwith distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/ ), which permits use, duplication, adaptation, distribution and reproduction in any medium or format, as long as appropriate credit is given to the original author(s) and the source, a link is provided to the Creative Commons license, and any changes made are indicated.

Aim of this study was to evaluate and compare, by means of dynamic and static PET/CT, the distribution patterns and pharmacokinetics of fluorine-18 fluorodeoxyglucose ((18)F-FDG) and of fluorine-18-fluoromisonidazole ((18)F-FMISO) in non-small cell lung cancer (NSCLC) patients scheduled for intensity modulated radiation therapy (IMRT). Thirteen patients suffering from inoperable stage III NSCLC underwent PET/CTs with (18)F-FDG and (18)F-FMISO for tumor metabolism and hypoxia assessment accordingly. Evaluation of PET/CT studies was based on visual analysis, semi-quantitative (SUV) calculations and absolute quantitative estimations, after application of a two-tissue compartment model and a non-compartmental approach. (18)F-FDG PET/CT revealed all thirteen primary lung tumors as sites of increased (18)F-FDG uptake. Six patients demonstrated also in total 43 (18)F-FDG avid metastases; these patients were excluded from radiotherapy. (18)F-MISO PET/CT demonstrated 12/13 primary lung tumors with faint tracer uptake. Only one tumor was clearly (18)F-FMISO avid, (SUVaverage = 3.4, SUVmax = 5.0). Mean values for (18)F-FDG, as derived from dPET/CT data, were SUVaverage = 8.9, SUVmax = 15.1, K1 = 0.23, k2 = 0.53, k3 = 0.17, k4 = 0.02, influx = 0.05 and fractal dimension (FD) = 1.25 for the primary tumors. The respective values for (18)F-FMISO were SUVaverage = 1.4, SUVmax = 2.2, K1 = 0.26, k2 = 0.56, k3 = 0.06, k4 = 0.06, influx = 0.02 and FD = 1.14. No statistically significant correlation was observed between the two tracers. (18)F-FDG PET/CT changed therapy management in six patients, by excluding them from planned IMRT. (18)F-FMISO PET/CT revealed absence of significant tracer uptake in the majority of the (18)F-FDG avid NSCLCs. Lack of correlation between the two tracers' kinetics indicates that they reflect different molecular mechanisms and implies the discordance between increased glycolysis and hypoxia in the malignancy.

BACKGROUND The aim of the current study was to measure and compare the effect of various biomaterials for the healing of osteoporotic bone defects in the rat femur using 18F-sodium fluoride dPET-CT. MATERIAL AND METHODS Osteoporosis was induced by ovariectomy and a calcium-restricted diet. After 3 months, rats were operated on to create a 4-mm wedge-shaped defect in the distal metaphyseal femur. Bone substitution materials of calcium phosphate cement (CPC), composites of collagen and silica, and iron foams with interconnecting pores were inserted. Strontium or bisphosphonate, which are well known for having positive effects in osteoporosis treatment, were added into the materials. Eighteen weeks after osteoporosis induction and 6 weeks following femoral surgery, dPET-CT studies scan were performed with 18F-Sodium Fluoride. Standardized uptake values (SUVs) and a 2-tissue compartmental learning-machine model (K1-k4, vessel density [VB], influx [ki]) were used for quantitative analysis. RESULTS k3, reflecting the formation of fluoroapatite, revealed a statistically significant increase at the biomaterial-bone interface due to the Sr release from strontium-modified calcium phosphate cement (SrCPC) compared to CPC, which demonstrated enhanced new bone formation. In addition, k3 as measured in the porous scaffold silica/collagen xerogel (Sc-B30), showed a significant increase based on Wilcoxon rank-sum test (p

Ipilimumab is a newly approved immunotherapeutic agent that has been shown to provide a survival benefit in patients with metastatic melanoma. (18)F-FDG PET/CT has demonstrated very satisfying results in detecting melanoma metastases in general. Using (18)F-FDG PET/CT we monitored patients with metastatic melanoma undergoing ipilimumab therapy during the course of treatment. The aim of our study was to evaluate the role of (18)F-FDG PET/CT performed after two cycles of ipilimumab in predicting the final response to therapy.In 22 patients suffering from unresectable metastatic melanoma, scheduled for ipilimumab treatment PET/CT scanning was performed before the start of treatment (baseline scan), after two cycles of treatment (early response) and at the end of treatment after four cycles (late response). Evaluation of the patient response to treatment on PET was based on the European Organization for Research and Treatment of Cancer 1999 criteria. Progression-free survival (PFS) and overall survival (OS) data are presented.After the end of treatment, 15 patients were characterized as having progressive metabolic disease (PMD) and five as having stable metabolic disease (SMD), and two patients showed a partial metabolic response (PMR). Early PET/CT performed after two ipilimumab cycles predicted treatment response in 13 of the 15 PMD patients, in five of the five SMD patients and in neither of the two PMR patients. Both patients with PMR showed pseudoprogression after the second cycle and were therefore wrongly classified. According to the patients' clinical outcome, patients with late PMD had a median PFS of 3.6 months (mean 5.6 months), while patients with late SMD had a median PFS of 9.8 months (mean 9.0 months). In comparison, patients with early PMD had a median PFS of 2.7 months (mean 5.5 months) and patients with early SMD had a median PFS of 6.3 months (mean 7.5 months). The difference in PFS between the two groups was statistically significant for both early and late responses (log-rank p0.001). Median OS among patients with late PMD was 9.1 months (mean 11.2 months) and among those with late SMD 9.8 months (mean 10.7 months). The difference in OS between the two groups was statistically significant (log-rank p = 0.013). The median OS among patients with early PMD was 8.8 months (mean 12.0 months) and among those with early SMD 9.8 months (mean 10.0 months). The difference in OS between the two groups was statistically significant (log-rank p0.001).(18)F-FDG PET/CT after two cycles of ipilimumab is highly predictive of the final treatment outcome in patients with PMD and SMD.

(68)Ga-DOTATOC-PET/CT is a well-established method for detecting and targeting the volume definition of meningiomas prior to radiotherapy. Moreover, there is evidence that this method is able to detect meningiomas with higher sensitivity than the goldstandard MRI. Since the hybrid PET/MRI scanner became available in the past few years, the next stage of development could consequently evolve by evaluating the feasibility of a hybrid PET/MRI scanner using (68)Ga-DOTATOC for detecting meningiomas.Fifteen patients received (68)Ga-DOTATOC-PET/CT (0.5 h post injection [p.i.]) followed by PET/MRI 2 hours p.i. Both investigations were analyzed separately and then compared with respect to image quality, detection of intracranial meningiomas, and radiotracer uptake values (RUVs). In addition, ratios between radiotracer uptake in meningiomas and pituitary glands were compared between both PET/CT and PET/MRI.Overall, 33 intracranial meningiomas were detected. All were visible with high contrast in both PET/CT and PET/MRI. (68)Ga-DOTATOC-PET/MRI provided flawless image quality without artefacts. Calculated RUV in meningiomas, as well as the ratios of RUVs in meningiomas to those of pituitary glands, were higher in PET/CT. As a result, meningiomas can be distinguished from pituitary glands better in early images.(68)Ga-DOTATOC-PET/MRI provided flawless image quality and presented an ideal combination of high sensitivity/specificity (PET) and the best possible morphological visualization of meningiomas (MRI). In addition, excellent detection of meningiomas is already possible at 0.5 hours p.i. Later images do not improve the distinction between pituitary gland and adjacent meningiomas. However, RUVs need to be carefully compared between both imaging modalities.

We report on two cases of patients with fat-equivalent masses in computed tomography (CT), referred to our department for dynamic positron emission tomography/CT (dPET/CT) with 18F-fluorodeoxyglucose (18F-FDG) in order to investigate their dignity. Both qualitative and quantitative information, as derived from dPET/CTs, couldn’t exclude a high-grade liposarcoma: Visual evaluation, revealed a large hypermetabolic focus of intense 18F-FDG uptake in each patient (average SUVs 8.3 and 11.3). Regression-based parametric imaging demonstrated an enhanced distribution volume, which correlates to perfusion, and a high phosphorylation rate that correlates to cell viability. Kinetic analysis, based on a two-tissue compartment model demonstrated an enhanced FDG transport k1 and an enhanced phosphorylation rate k3. A non-compartmental approach based on fractal dimension revealed also enhanced values. However, final diagnosis was based on biopsy, which revealed hibernoma, a benign brown fat tumor. Brown adipose contains increased numbers of mitochondria and a high-rate of glucose metabolism. Therefore, they have increased FDG uptake. The evaluation of lipomatous lesions on CT, with high FDG uptake, should include the possibility of hibernoma as a differential diagnosis.

To evaluate the carbon 11 ethanol kinetics with positron emission tomography after intratumoral injection of the tracer and assess its redistribution and dilution in patients who have hepatocellular carcinomas and who were scheduled for treatment with percutaneous ethanol injection.The study included eight patients with hepatocellular carcinomas. 11C ethanol was administered via a puncture needle positioned with ultrasonographic guidance. Parametric images based on the Fourier transformation were created for further analysis of the local distribution patterns of the tracer. The ratio of the 45-minute postinjection standardized uptake value to the 5-minute postinjection standardized uptake value was used for the evaluation of ethanol dilution.Five of eight tumors demonstrated almost constant uptake values after the initial distribution phase. In contrast, a rapid elimination of the 11C ethanol from the tumor was documented in three of eight tumors. The 45 minute-to-5 minute ratio was 0.18-0.67 (median value, 0.56) in the tumors. The time-activity curves of the normal liver parenchyma increased slowly but steadily with time owing to a low ethanol elimination from the tumor. Fourier transformation demonstrated inhomogeneous parts on the amplitude images in seven of eight tumors and random redistribution on the phase images in six of eight tumors.Inhomogeneous drug distribution and drug dilution in the target area are likely to be the major limiting parameters for therapy response.

The management of patients who have malignant lymphomas requires functional methods to differentiate residual soft tissue masses. Positron emission tomography (PET) was performed in patients with histologically proven malignant lymphomas prior to the onset of second-line chemotherapy to examine tumor viability. Twenty patients (68 malignant lesions and 3 benign lesions) with Hodgkin lymphomas (HL) as well as 26 patients (46 malignant lesions and 1 benign lesion) with non-Hodgkin lymphomas (NHL) were studied with fluorine-18-deoxyglucose (FDG). Oxygen-15-labelled water was used in addition in 14 patients with 25 lesions to obtain information on the tissue perfusion. PET with FDG is highly sensitive for the detection of viable tumor tissue, all malignant lesions being correctly classified in this study. We noted no statistically significant difference in FDG metabolism for Hodgkin and non-Hodgkin lymphomas. Even normal-sized lymph-node metastases ( < 1 cm) were detected with PET and FDG. The possible limitations are inflammatory processes, which may obscure tumor detection because of the increased FDG uptake, as well as malignant lesions with low FDG uptake as a result of reduced perfusion. Comparison of tumor perfusion and FDG uptake showed a significant nonlinear correlation of r = 0.78 between the two parameters. Two patients with scar tissue and no evidence of malignancy were excluded from blood stem-cell support therapy as a result of the PET study. The data demonstrate that PET is a useful tool for making a diagnosis and deciding on therapy for malignant lymphomas.

We used 2-deoxy-2-[18F] fluoro-D-glucose (FDG) positron emission tomography (PET) to evaluate patients with desmoid tumors undergoing therapy with imatinib. The study included 22 patients with progressive disease (PD) of a biopsy proven desmoid tumor treated orally with imatinib 800 mg daily. Patients were examined using PET prior to onset of therapy and during treatment. Restaging was performed in parallel using computed tomography (CT) and/or magnetic resonance imaging (MRI). Outcome of 22 evaluable patients was as follows: five patients with partial response (PR); twelve patients with stable disease (SD) accounting for 77% with non-progressive disease; five patients showed PD. A 30% decrease of the mean average standardized uptake value (SUV) of sequential PET examinations could be demonstrated; no patient demonstrated a substantial increase in SUV. Patients with PR/SD were matched to a group of nonprogressive disease and tested versus PD. The initial average SUV and seem to be candidates for a response prediction with an approximate -value of0.06553and0.07785, respectively. This is the first larger series of desmoid patients monitored using PET showing that early SUV changes may help to discriminate responders from nonresponders and, thus, to decide whether imatinib therapy should be continued.

Background: Aim of the study was the biological characterization of melanoma metastases. Material and Methods: 27 patients with metastatic malignant melanoma (MM) were examined with PET and the radiot

The management of patients with treated malignant lymphomas requires functional methods to differentiate a residual soft tissue mass. Patients with treated Hodgkin's lymphoma (HL,n = 20, 68 malignant lesions, three benign lesions) or non-Hodgkin's lymphoma (NHL,n = 26, 46 malignant lesions, one benign lesion) were studied with positron emission tomography (PET) and fluorine-18 deoxyglucose (FDG). Oxygen-15 labelled water was used (n = 14, 25 lesions) in addition to FDG in order to obtain information on the tissue perfusion. Long-term follow-up studies with PET and FDG were performed in nine patients up to 511 days after the initiation of second-line therapy. Fourteen patients underwent single-photon emission tomography (SPET) with technetium-99m sestamibi immediately prior to the first PET examination. PET with FDG displays a high sensitivity for the detection of viable tumour tissue, all the malignant lesions being correctly classified in this study. The possible limitations are inflammatory processes, which may obscure tumour detection due to increased FDG uptake, and malignant lesions with low FDG uptake due to reduced perfusion. Difficulties exist in the prognosis of long-term response, since the change in FDG uptake may be variable. Long-term therapy outcome was correlated with the slope values obtained from the standardized integral uptake (SIU) data, which provides a new approach for the evaluation of PET follow-up studies.99mTc-sestamibi, which should reflect the multidrug resistance, was evaluated with respect to therapy outcome. A high uptake of99m-Tc-sestamibi was observed in patients with stable disease or better. The data support the hypothesis that sestamibi may reflect multidrug resistance. Due to technical limitations of the SPET technique, the use of a positron-labelled compound would be superior to SPET for clinical application.

Objective: Antineoplastic chemotherapy in cases of nonresectable advanced malignancies of the head and neck can be very debilitating for the patient. For individual treatment planning, it is important to evaluate the early clinical effect of therapy. Morphological parameters, such as the size of the tumor and its relationship to adjacent structures, which can be determined by a number of imaging procedures, hardly reflect early therapeutic effects. Therefore, the metabolic activity of the tumor should be studied during antineoplastic therapy. Design: Positron emission tomography was performed in 12 patients with metastasizing squamous cell carcinomas of the oropharynx, hypopharynx, and larynx before and after the first chemotherapeutic cycle. Results: The fludeoxyglucose F 18 uptake was increased in all tumors and lymph nodes. In most lesions, an obvious response to treatment was observed after the first cycle of chemotherapy. However, differences in metabolic activity and changes in metabolism occurred during therapy. The treatment response varied in different lymph nodes in the same patient. There was a linear relation between metabolic change and growth rate during therapy, with different regression functions for tumors and lymph node metastases. Conclusions: Positron emission tomography provides absolute and comparable quantitative data on tumor metabolism before and after chemotherapy. It is therefore a useful method for observation and possible improvement of therapeutic measures in patients undergoing systemic chemotherapy. (Arch Otolaryngol Head Neck Surg. 1995;121:272-276)

Rats with osteoporosis were involved by combining ovariectomy (OVX) either with calcium and Vitamin D deficiency diet (Group D), or with glucocorticoid (dexamethasone) treatment (Group C). In the period of 1-12 months, dynamic PET-CT studies were performed in three groups of rats including Group D, Group C and the control Group K (sham-operated). Standardized uptake values (SUVs) were calculated, and a 2-tissue compartmental learning-machine model (calculation of K1-k4, VB and the plasma clearance of tracer to bone mineral (Ki) as well as a non-compartmental model based on the fractal dimension (FD) was used for quantitative analysis of both groups. The evaluation of PET data was performed over the lumbar spine. The correlation analysis revealed a significant linear correlation for certain dPET quantitative parameters and time up to 12 months after induction of osteoporosis. Based on the (18)F-Fluoride data, we noted a significant negative correlation for K1 (the fluoride/hydroxyl exchange) in the Group C and a significant positive correlation for k3, SUV (bone metabolism) and FD in the Group K. The evaluation of the (18)F-FDG data revealed a significant positive correlation for SUV (glucose metabolism) only in Group C. The correlation between the two tracers revealed significant results between K1 of (18)F-Fluoride and SUV of FDG in Group K as well as between FD of (18)F-Fluoride and FDG in Group D and C and between k3 of (18)F-Fluoride and SUV of FDG in Group C.

Aim of this study was to investigate the specific treatment effects of inhibiting αvβ3/αvβ5 integrins by cilengitide in an animal model of breast cancer bone metastases using dynamic (18)F-FDG PET and gene expression analysis.For this purpose, nude rats bearing bone metastases were treated with cilengitide, a small molecule inhibitor of αvβ3 and αvβ5 integrins, from day 30 to 55 after tumor cell inoculation of MDA-MB-231 breast cancer cells (25 mg/kg, 5 days per week; n = 8 rats) and compared to control rats (n = 8). Dynamic (18)F-FDG PET data were assessed at days 30, 35 and 55 after tumor cell inoculation determining the vascular fraction VB and the metabolic variables k1-k4. At day 55, genome-wide mRNA expression analysis was performed to assess the treatment-specific expression changes from cilengitide-treated and control rats.In a longitudinal (18)F-FDG PET study, the vascular fraction VB was significantly decreased in bone metastases between days 30/35, 30/55 and 35/55, whereas the kinetic parameters k1 and k4 were significantly decreased between days 30/55 in skeletal lesions of treated animals. Gene expression analysis from bone metastases at day 55 revealed that tumor-produced integrins (αvβ5) as well as factors relevant for angiogenesis (αvβ3, VEGF, PDGF), bone resorption (PTHrP and RANKL), extracellular matrix remodeling (collagen, CD44) and bone marrow microenvironment (CXCR4) were significantly reduced upon therapy with cilengitide.Here, we provide evidence that cilengitide inhibits pivotal factors of all compartments of bone metastases including tumor cells, vasculature and bone microenvironment in vivo and by whole-genome transcriptome analysis.

Objectives: The use of dynamic positron emission tomography/computed tomography (dPET/CT) studies with [18F]deoxyglucose (FDG) in oncological patients is limited and primarily confined to research protocols. A more widespread application is, however, desirable, and may help to assess small therapeutic effects early after therapy as well as to differentiate borderline differences between tumour and non-tumour lesions, e.g., lipomas versus low-grade liposarcomas. The aim is to present quantification approaches that can be used for the evaluation of dPET/CT series in combination with parametric imaging and to demonstrate the feasibility with regard to tumour diagnostics and therapy management. Methods: A 60-min data acquisition and short acquisition protocols (20-min dynamic series and a static image 60 min post injection) are discussed. A combination of a modified two-tissue compartment model and non-compartmental approaches from the chaos theory (fractal dimension of the time–activity curves) are presented. Fused PET/CT images as well as regression-based parametric images fused with CT or with PET/standardised uptake value images are demonstrated for the exact placement of volumes of interest. Results: The two-tissue compartmental method results in the calculation of 5 kinetic parameters, the fractional blood volume VB (known also as the distribution volume), and the transport rates k1 to k4. Furthermore, the influx according to Patlak can be calculated from the transport rates. The fractal dimension of the time–activity curves describes the heterogeneity of the tracer distribution. The use of the regression-based parametric images of FDG helps to visualise the transport/perfusion and the transport/phosphorylation-dependent FDG uptake, and adds a new dimension to the existing conventional PET or PET/CT images. Conclusions: More sophisticated quantification methods and dedicated software as well as high computational power and faster acquisition protocols can facilitate the assessment of dPET/CT, and may find use in clinical routine, in particular for the assessment of early therapeutic effects or new treatment protocols in combination with the new generation of PET/CT scanners.

The aim of the current study was to assess the formation of new bone in a 3-mm created defect in the femur and its adjacent bone tissue in osteoporotic and normal animals. The assessment is based on bone remodeling and glucose metabolism in a rat model with a 3-mm created defct in the femur using (18)F-fluoride and 2-deoxy-2-[(18)F]fluoro-D-glucose ((18)F-FDG) as tracers for dynamic PET-CT (dPET-CT). The (18)F-fluoride PET data were compared with those of (18)F-FDG.Osteoporosis was induced by ovariectomy and a calcium restricted diet in each rat (n = 7). Alternatively, a sham operation was performed in the control group (n = 8). After 3 months, all rats were operated to create a 3-mm defect using an oscillating saw in the distal metaphyseal femur, which was internally fixed with a metal plate. Eighteen weeks after osteoporosis induction and 6 weeks following femoral surgery, dPET-CT studies scan were performed with (18)F-FDG and (18)F-fluoride. Following PET data acquisition, standardized uptake values (SUVs) were calculated from the tracer concentration values. Then, a two-tissue compartmental learning-machine model was applied to the data for the calculation of the compartment parameters (K1-k4, VB, Ki). Furthermore, a non-compartmental model based on the fractal dimension was applied for quantitative analysis of both groups and both tracers. Finally, multivariate analysis was performed for the statistical analysis of the kinetic data.The values for K1 and Ki were higher in the osteoporotic rats than in the control group. Ki and K1 of (18)F-fluoride in the adjacent bone tissue differ significantly based on the Wilcoxon rank-sum test for the osteoporotic and control group (p 0.05). The sensitivity and the negative predictive value (NPV) based on linear discriminant analysis was high with a value of 100 % for both tracers and both evaluated regions (defect and adjacent bone tissue) when comparing control and osteoporotic rats. The overall accuracy with (18)F-FDG was generally higher than that with (18)F-fluoride for both evaluated regions for the control and osteoporotic rats based on a multiparameter evaluation.In this study, the changes in tracer kinetics accurately discriminated differences in the created defect in the femur and its adjacent bone tissue between osteoporotic and control rats.

Background Radiotherapy, preferably combined with chemotherapy, is the treatment standard for locally advanced, unresectable non-small cell lung cancer (NSCLC). The tumor response to different therapy protocols is variable, with hypoxia known to be a major factor that negatively influences treatment effectiveness. Visualisation of tumor hypoxia prior to the use of modern radiation therapy strategies, such as intensity modulated radiation therapy (IMRT), might allow optimized dose applications to the target volume, leading to improvement of therapy outcome. 18 F-fluoromisonidazole dynamic positron emission tomography and computed tomography (18 F-FMISO dPET-CT) and functional magnetic resonance imaging (functional MRI) are attractive options for imaging tumor hypoxia. Methods/design The HIL trial is a single centre study combining multimodal hypoxia imaging with 18 F-FMISO dPET-CT and functional MRI, with intensity modulated radiation therapy (IMRT) in patients with inoperable stage III NSCLC. 15 patients will be recruited in the study. All patients undergo initial FDG PET-CT and serial 18 F-FMISO dPET-CT and functional MRI before treatment, at week 5 of radiotherapy and 6 weeks post treatment. Radiation therapy is performed as inversely planned IMRT based on 4D-CT. Discussion Primary objectives of the trial are to characterize the correlation of 18 F-FMISO dPET-CT and functional MRI for tumor hypoxia imaging in NSCLC and evaluate possible effects of radiation therapy on tumor re-oxygenation. Further objectives include the generation of data regarding the prognostic value of 18 F-FMISO dPET-CT and functional MRI for locoregional control, progression free survival and overall survival of NSCLC treated with IMRT, which will form the basis for larger clinical trials focusing on possible interactions between tumor oxygenation and radiotherapy outcome. Trial registration The ClinicalTrials.gov protocol ID is NCT01617980

Purpose Cone beam computed tomography (CBCT) has the disadvantage of providing non-quantitative results for bone density determination. The aim of this study is to calibrate CBCT results by using an internal reference (such as muscle) for quantitatively assessing bone density. Methods We developed a new method using the relative attenuation ratio between two nearby materials (such as bone and muscle) for systemic error correction in CBCT that depends on the relative object position in the image volume. Phantom calibration was performed to calculate the acquired attenuation ratio in Hounsfield units (HU), comparable to the results from clinical multislice spiral computed tomography (MSCT). In addition, a small animal study with an osteoporotic rat model was evaluated to show the feasibility of this presented method to quantitatively assess bone density using a CBCT system. Results The phantom study results showed that the calibration process successfully corrected the systemic inaccuracy from CBCT, and the calibrated HU values agreed with the values measured from MSCT. In the small animal study, the quantitative bone densities assessed from the calibrated CBCT results were consistent with the results from MSCT data. Conclusion A practical method to quantitatively estimate attenuation (HU) values for bone tissues from CBCT scans that are comparable to MSCT scans is proposed. The method may improve the quantification ability of CBCT scanning without any additional hardware requirements.