11C-choline PET/CT predicts prostate cancer-specific survival in patients with biochemical failure during androgen-deprivation therapy.

UNLABELLED: Several studies have shown that (11)C-choline PET/CT may be useful for restaging prostate cancer (PCa) patients with biochemical failure after radical prostatectomy. However, validation of (11)C-choline PET/CT findings scarcely relied on histologic findings, and prognostic implications of (11)C-choline PET/CT are currently unknown. The aim of this study was to assess whether (11)C-choline PET/CT predicts survival in PCa patients. METHODS: This retrospective study included 195 PCa patients treated with radical prostatectomy who underwent (11)C-choline PET/CT from December 1, 2004, to July 31, 2007, due to biochemical failure (prostate-specific antigen > 0.2 mg/mL) during androgen-deprivation therapy. PCa-specific survival was computed as the interval from radical prostatectomy to PCa-specific death. RESULTS: The median interval after radical prostatectomy was 8.9 y (95% confidence interval [CI], 1.7-18.9 y). The median follow-up after (11)C-choline PET/CT was 4.5 y (95% CI, 0.4-8.5 y). (11)C-choline PET/CT results were positive in 57% of patients. The median PCa-specific survival was 16.4 y (95% CI, 14.0-18.8 y) in patients with negative (11)C-choline PET/CT results and 11.2 y (95% CI, 9.8-12.6 y) in patients with positive (11)C-choline PET/CT results (log-rank: χ(2) = 19.3, P < 0001). At multivariate analysis, statistical significance was obtained for (11)C-choline PET/CT (hazard ratio, 2.53; 95% CI, 1.41-4.53; P = 0.002), prostate-specific antigen (hazard ratio, 1.03; 95% CI, 1.00-1.05; P = 0.037), and Gleason score (>7: hazard ratio, 2.49; 95% CI, 1.25-4.95; P = 0.009). Patients with pathologic (11)C-choline uptake in the prostatic bed or in pelvic or retroperitoneal lymph nodes had longer PCa-specific survival (median, 12.1 y; 95% CI, 10.5-13.7 y) in comparison to patients with pathologic tracer uptake in the skeleton (median, 9.9 y; 95% CI, 6.8-13.1 y) (log-rank: χ(2) = 6.5, P = 0.010). Two internally validated nomograms predicted 10- and 15-y PCa-specific survival probability with an accuracy of 76% and 74%, respectively. In an ancillary analysis, we also showed that (11)C-choline PET/CT predicts PCa-specific survival after PET/CT, with similar statistical power. CONCLUSION: (11)C-choline PET/CT predicts PCa-specific survival in PCa patients treated with radical prostatectomy who develop biochemical failure during androgen-deprivation therapy. If independent or multicenter confirmation of these findings is obtained, (11)C-choline PET/CT might be more widely used in the follow-up of PCa patients for tailoring salvage therapy.

Characterization of biological features of a rat F98 GBM model: a PET-MRI study with [18F]FAZA and [18F]FDG.

INTRODUCTION: The prognosis of malignant gliomas remains largely unsatisfactory for the intrinsic characteristics of the pathology and for the delayed diagnosis. Multimodal imaging based on PET and MRI may assess the dynamics of disease onset and progression allowing the validation of preclinical models of glioblastoma multiforme (GBM). The aim of this study was the characterization of a syngeneic rat model of GBM using combined in vivo imaging and immunohistochemistry. METHODS: Four groups of Fischer rats were implanted in a subcortical region with increasing concentration of rat glioma F98 cells and weekly monitored with Gd-MR, [(18)F]FDG- and [(18)F]FAZA-PET starting one week after surgery. Different targets were evaluated on post mortem brain specimens using immunohistochemistry: VEGF, GFAP, HIF-1α, Ki-67 and nestin. RESULTS: Imaging results indicated that tumor onset but not progression was related to the number of F98 cells. Hypoxic regions identified with [(18)F]FAZA and high-glucose metabolism regions recognized with [(18)F]FDG were located respectively in the core and in external areas of the tumor, with partial overlap and remodeling during disease progression. Histological and immunohistochemical analysis confirmed PET/MRI results and revealed that our model resumes biological characteristics of human GBM. IHC and PET studies showed that necrotic regions, defined on the basis of [(18)F]FDG uptake reduction, may include hypoxic clusters of vital tumor tissue identified with [(18)F]FAZA. This last information is particularly relevant for the identification of the target volume during image-guided radiotherapy. CONCLUSIONS: In conclusion, the combined use of PET and MRI allows in vivo monitoring of the biological modification of F98 lesions during tumor progression.

Comparison of 18F-fluoroazomycin-arabinofuranoside and 64Cu-diacetyl-bis(N4-methylthiosemicarbazone) in preclinical models of cancer.

UNLABELLED: Hypoxic regions are present in different types of cancer and are a negative prognostic factor for disease progression and response to therapy. (18)F-fluoroazomycin-arabinofuranoside ((18)F-FAZA) and (64)Cu-diacetyl-bis(N4-methylthiosemicarbazone) ((64)Cu-ATSM) have been widely used to visualize hypoxic regions in preclinical and clinical studies. Although both these radioligands have high signal-to-noise ratios, (64)Cu-ATSM may be suitable for use in in vivo imaging and as a radiotherapeutic agent. Despite encouraging results suggesting that it may have a role as a prognostic tracer, (64)Cu-ATSM was recently shown to display cell line-dependent kinetics of oxygen-dependent uptake. We set out to evaluate the kinetics of (64)Cu-ATSM distribution in different cancer models, using (18)F-FAZA as the gold standard. METHODS: (18)F-FAZA and (64)Cu-ATSM uptake were compared ex vivo using dual-tracer autoradiography and in vivo using PET in different xenograft mouse models (FaDu, EMT-6, and PC-3). (18)F-FAZA uptake was compared with (64)Cu-ATSM uptake in PET studies acquired at early (2 h after injection) and delayed time points (24 h after injection). To evaluate the presence of hypoxia and copper pumps, the tumors from animals submitted to PET were harvested and analyzed by an immunohistochemical technique, using antibodies against carbonic anhydrase IX (CAIX) and copper pumps (Ctr1 and ATP7B). RESULTS: (64)Cu-ATSM showed a higher tumor-to-muscle ratio than did (18)F-FAZA. In the FaDu mouse model, radioactivity distribution profiles were overlapping irrespective of the hypoxic agent injected or the time of (64)Cu acquisition. Conversely, in the EMT-6 and PC-3 models there was little similarity between the early and delayed (64)Cu-ATSM images, and both the radiotracers showed a heterogeneous distribution. The microscopic analysis revealed that (18)F-FAZA-positive areas were also positive for CAIX immunostaining whereas immunolocalization for copper pumps in the 3 models was not related to radioactivity distribution. CONCLUSION: The results of this study confirm the cell-dependent distribution and retention kinetics of (64)Cu-ATSM and underline the need for proper validation of animal models and PET acquisition protocols before exploration of any new clinical applications.

The p53-p66Shc apoptotic pathway is dispensable for tumor suppression whereas the p66Shc-generated oxidative stress initiates tumorigenesis.

Reactive oxygen species (ROS) are regarded as hazardous by-products of mitochondrial respiration. In addition to the respiratory chain, specific ROS-generating systems have evolved. In particular, p66Shc is a mitochondrial redox protein that oxidizes cytochrome c to generate H2O2. Consistently, the deletion of p66Shc in cells and tissue results in reduced levels of ROS and oxidative stress. Taking advantage of the p66Shc knock out (p66KO) mouse model of decreased ROS production, we assessed the role of endogenously-produced ROS in tumorigenesis. Spontaneous tumor incidence was investigated and found unaltered in two different strains, 129Sv and C57Bl/6J, p66KO mice. In addition, papilloma formation upon exposure to ultraviolet radiation (UV) or 7,12-Dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol- 13-acetate (DMBA/TPA) was found to be slightly lower in the absence of p66Shc. The role of p66Shc in tumorigenesis was also investigated in the absence of the tumor suppressor gene p53 (p53KO) by generating p53-p66Shc double knock out (DKO) mice. Notably, DKO mice displayed a significantly increased lifespan compared to p53KO mice. In addition, 2-deoxy-2-(18F)fluoro-D-glucose Positron Emission Tomography ([18F]FDG PET) analysis allowed to determine that disease onset occurred later in life in DKO mice compared to p53KO and that a low percentage of these mice did not develop tumors. Overall, these results indicate that although tumor incidence is not decreased in p66KO mice, p66Shc contributes to tumor initiation, in particular upon activation by carcinogens as well as when p53- mediated tumor suppression mechanisms defect.

Clinical and immunologic responses in melanoma patients vaccinated with MAGE-A3-genetically modified lymphocytes.

Cancer vaccines have recently been shown to induce some clinical benefits. The relationship between clinical activity and anti-vaccine T cell responses is somewhat controversial. Indeed, in many trials it has been documented that the induction of vaccine-specific T cells exceeds the clinical responses observed. Here, we evaluate immunological and clinical responses in 23 MAGE-A3(+) melanoma patients treated with autologous lymphocytes genetically engineered to express the tumor antigen MAGE-A3 and the viral gene product thymidine kinase of the herpes simplex virus (HSV-TK). HSV-TK was used as safety system in case of adverse events and as tracer antigen to monitor the immune competence of treated patients. The increase of anti-TK and anti-MAGE-A3 T-cells after vaccination was observed in 90 and 27% of patients, respectively. Among 19 patients with measurable disease, we observed a disease control rate of 26.3%, with one objective clinical response, and four durable, stable diseases. Three patients out of five with no evidence of disease (NED) at the time of vaccination remained NED after 73+, 70+ and 50+ months. Notably, we report that only patients experiencing MAGE-A3-specific immune responses showed a clinical benefit. Additionally, we report that responder and non-responder patients activate and expand T cells against the tracer antigen TK in a similar way, suggesting that local rather than systemic immune suppression might be involved in limiting clinically relevant antitumor immune responses.

Time course of metabolic activity and cellular infiltration in a murine model of acid-induced lung injury.

PURPOSE: This study investigates whether positron emission tomography (PET) can be used to monitor the inflammatory response and its correlation with the later fibroproliferative phase in an experimental model of acute lung injury. METHODS: Hydrochloric acid (0.1 N, pH 1, 1.5 ml/kg) was instilled into the right bronchus of mice. A group of mice underwent a micro-computed tomography (CT) scan 1 h after lung injury and a series of 2-[(18)F]fluorine-2-deoxy-D: -glucose (FDG)-PET scans (6, 24 and 48 h and 7 days after surgery). After 21 days respiratory static compliance was assessed and lung tissue was collected in order to measure the hydroxy (OH)-proline content. Other groups of mice underwent micro-CT and micro-PET scans at the same time points, and then were immediately killed to assess arterial blood gases and histology. RESULTS: Histological analysis showed the recruitment of neutrophils and macrophages into the damaged lung, reaching the peak at 24 and 48 h, respectively. The time course of the [(18)F]FDG signal, used as a marker of inflammation, correlated with that of recruited inflammatory cells. In mice killed 21 days after the surgery, a correlation was found between reduced respiratory static compliance and high PET signal 7 days after lung injury. The PET signal also correlated with the OH-proline content. CONCLUSIONS: This study demonstrated that PET imaging is a valid means of tracking the inflammatory response, also in longitudinal studies. Moreover, a correlation was found between persistence of the inflammatory response and fibrotic evolution of the injury.

Evaluation of the role of tumor-associated macrophages in an experimental model of peritoneal carcinomatosis using (18)F-FDG PET.

UNLABELLED: PET is widely used at the clinical and preclinical levels for tumor assessment and evaluation of treatment efficacy. Here, we established and took advantage of a preclinical model of peritoneal carcinomatosis to evaluate the contribution of inflammatory infiltrating macrophages in tumor progression that was followed using (18)F-FDG PET. METHODS: Groups of mice with peritoneal carcinomatosis were longitudinally evaluated with (18)F-FDG PET. Intraperitoneal depletion of macrophages was achieved by an approach (i.e., administration of clodronate encapsulated into liposomes) that proved to be safe and effective. Sham liposomes were used in control animal cohorts. RESULTS: (18)F-FDG PET allowed us to detect and monitor peritoneal lesion growth and diffusion. Macrophage-depleted animals showed a substantial reduction in tumor burden paralleled by a decrement in the extent of radioactivity distribution. A significant correlation between lesion dimension and metabolic volume was observed not only in macrophage-depleted but also in sham-treated mice. CONCLUSION: (18)F-FDG PET allowed a noninvasive detection of peritoneal carcinomatosis lesions. Although macrophages play a key role in the early growth and spreading of lesions in the peritoneal cavity, neoplastic cells apparently represent the major player in this system in the uptake of (18)F-FDG.

Non-peptide NK1 receptor ligands based on the 4-phenylpyridine moiety.

The quinoline nucleus of the previously described 4-phenylquinoline-3-carboxamides NK(1) receptor ligands 7 has been transformed into either substituted or azole-(i.e., triazole or tetrazole) fused pyridine moieties of compounds 9 and 10, respectively, in order to obtain NK(1) receptor ligands showing lower molecular weight or higher hydrophilicity. The program of molecular manipulations produced NK(1) receptor ligands showing affinity in the nanomolar range. In particular, 4-methyl-1-piperazinyl derivative 9j showed an IC(50) value of 4.8 nM and was proved to behave as a NK(1) antagonist blocking Sar(9)-SP-sulfone induced proliferation and migration of microvascular endothelial cells. Therefore, compound 9j has been labeled with [(11)C]CH(3)I (t(1/2)=20.4 min, ß(+)=99.8%) starting from the corresponding des-methyl precursor 9i using with a radiochemical yield of about 10% (not decay corrected) and a specific radioactivity>1 Ci/µmol in order to be used as a radiotracer in next PET studies.

Hepatocellular carcinoma treated with transarterial chemoembolization: dynamic perfusion-CT in the assessment of residual tumor.

AIM: To asses the value of computed tomography (CT)-perfusion in the detection of residual hepatocellular carcinoma (HCC) vascularization after transarterial chemoembolization (TACE). METHODS: Thirty-two consecutive patients were prospectively included in this study. All patients had liver cirrhosis and a confirmed HCC lesion which was treated with TACE. One month after treatment, perfusion measurements of treated lesions were carried out. The CT-perfusion (CT-p) protocol was performed with 16 slice multidetector computed tomography which included the following parameters: 8 dynamic slices/scan per 40 scans after iv injection of 50 mL of iodinated contrast (350 mg/mL) at a flow rate of 6 mL/s. Treated lesions were evaluated using dedicated perfusion software, which generated a quantitative colour map of perfusion. The following parameters were considered: hepatic perfusion (HP), arterial perfusion (AP), blood volume (BV), hepatic perfusion index (HPI), and time to peak (TTP). Perfusion parameters were described with quartile values of their distribution and statistically analyzed. RESULTS: Perfusion parameters of the treated lesions could be quantitatively assessed using CT-p analysis. The presence of residual tumor tissue was observed in 13 of the 32 patients. The values of the perfusion parameters measured within the relapse tissue were: HP (mL/100 g per minute): median = 44.4 (1(st)qt = 31.3, 3(rd)qt = 55.8); BV (mL/100 g): median = 18.7 (1(st)qt = 11.5, 3(rd)qt = 22.5); AP (mL/min): median = 39.0 (1(st)qt = 36.5, 3(rd)qt = 61.3); HPI (%): median = 34.0 (1(st)qt = 30.4, 3(rd)qt = 38.9); TTP (s): median = 17.3 (1(st)qt = 15.8, 3(rd)qt = 26.5). With the use of the univariate paired Wilcoxon signed rank test, HP, AP and HPI were shown to be significantly higher (P < 0.001) in the relapse site than in the primary lesion. The BV and TTP parameters showed a tendency to be greater and lower, respectively, in the relapse site than in the primary lesion. CONCLUSION: In patients with HCC treated with TACE, CT-p provides measurement of flow parameters related to residual arterial structures in viable tumor, thus helping in the assessment of therapeutic response.

Perfusion CT in cirrhotic patients with early stage hepatocellular carcinoma: assessment of tumor-related vascularization.

PURPOSE: To assess the value of CT-perfusion in determining the quantitative vascularization features of early hepatocellular carcinoma (HCC) in cirrhotic patients. MATERIALS AND METHODS: A total of 35 cirrhotic patients with single histologically proven HCC not exceeding 3cm in diameter underwent conventional triple-phase multidetector computed tomography (MDCT) examination. All patients were also examined with CT-perfusion (CTp) technique after i.v. injection of 50mL of iodinated contrast. Data were analyzed using a dedicated software which generated a quantitative map of liver parenchyma perfusion. The following parameters were assessed: hepatic perfusion (HP); blood volume (BV); arterial perfusion (AP); time to peak (TTP) and hepatic perfusion index (HPI). Univariate Wilcoxon signed rank test was used for statistical analysis. RESULTS: In the 35 HCCs evaluated, the following quantitative data were obtained: HP (mL/s/100g): median=47.0 (1(st)qt=35.5; 3(st)qt=61.2); BV (mL/100mg): median=22.5 (1(st)qt=18.4; 3(st)qt=27.7); AP (mL/min): median=42.9 (1(st)qt=35.8; 3(st)qt=55.6); HPI(%): median=75.3 (1(st)qt=63.1; 3(st)qt=100); TTP(s): median=18.7 (1(st)qt=16.8; 3(st)qt=24.5). Perfusion values calculated in cirrhotic liver parenchyma were HP: median=10.3 (1(st)qt=9.1; 3(st)qt=13.2); BV: median=11.7 (1(st)qt=9.6; 3(st)qt=15.5); AP: median=10.4 (1(st)qt=8.6; 3(st)qt=11.3); HPI: median=17.5 (1(st)qt=14.3; 3(st)qt=19.7); TTP: median=44.6 (1(st)qt=40.3; 3(st)qt=50.1). HP, BV, HPI and AP were found to be significantly higher in HCC lesion than in liver parenchyma (p<0.001), while TTP was significantly lower (p<0.001). CONCLUSION: CT-perfusion technique allows obtaining quantitative information about tumor-related vascularization of early HCC, in patients with liver cirrhosis.

A modified damped Richardson-Lucy algorithm to reduce isotropic background effects in spherical deconvolution.

Spherical deconvolution methods have been applied to diffusion MRI to improve diffusion tensor tractography results in brain regions with multiple fibre crossing. Recent developments, such as the introduction of non-negative constraints on the solution, allow a more accurate estimation of fibre orientations by reducing instability effects due to noise robustness. Standard convolution methods do not, however, adequately model the effects of partial volume from isotropic tissue, such as gray matter, or cerebrospinal fluid, which may degrade spherical deconvolution results. Here we use a newly developed spherical deconvolution algorithm based on an adaptive regularization (damped version of the Richardson-Lucy algorithm) to reduce isotropic partial volume effects. Results from both simulated and in vivo datasets show that, compared to a standard non-negative constrained algorithm, the damped Richardson-Lucy algorithm reduces spurious fibre orientations and preserves angular resolution of the main fibre orientations. These findings suggest that, in some brain regions, non-negative constraints alone may not be sufficient to reduce spurious fibre orientations. Considering both the speed of processing and the scan time required, this new method has the potential for better characterizing white matter anatomy and the integrity of pathological tissue.

Automated production of copper radioisotopes and preparation of high specific activity [(64)Cu]Cu-ATSM for PET studies.

(60)Cu and (64)Cu are useful radioisotopes for positron emission tomography (PET) radiopharmaceuticals and may be used for the preparation of promising agents for diagnosis and radiotherapy. In this study, the production and purification of (60/64)Cu starting from (60/64)Ni using a new automated system, namely Alceo, is described. A dynamic process for electrodeposition and dissolution of (60/64)Ni/(60/64)Cu was developed. Preliminary production yields of (60)Cu and (64)Cu were 400 and 300mCi, respectively. (64)Cu was used to radiolabel the hypoxia detection tracer ATSM with a specific activity of 2.2+/-1.3Ci/micromol.

Predictive factors of [(11)C]choline PET/CT in patients with biochemical failure after radical prostatectomy.

PURPOSE: Detection of recurrence in prostate cancer patients with biochemical failure after radical prostatectomy by [(11)C]choline PET/CT depends on the prostate-specific antigen (PSA) level. The role of other clinical and pathological variables has not been explored. METHODS: A total of 2,124 prostate cancer patients referred to our Institution for [(11)C]choline PET/CT from December 2004 to January 2007 for restaging of disease were retrospectively considered for this study. Inclusion criteria were: previous treatment by radical prostatectomy, and biochemical failure, defined as at least two consecutive PSA measurements of >0.2 ng/ml. These criteria were met for 358 patients. Binary logistic analysis was used to investigate the predictive factors of [(11)C]choline PET/CT. PET/CT findings were validated using criteria based on histological analysis, and follow-up clinical and imaging data. Receiver operating characteristic (ROC) analysis was used to assess the performance of [(11)C]choline PET/CT in relation to PSA levels. RESULTS: The mean PSA level was 3.77 +/- 6.94 ng/ml (range 0.23-45 ng/ml; median 1.27 ng/ml). PET/CT was positive for recurrence in 161 of 358 patients (45%). On an anatomical region basis, [(11)C]choline pathological uptake was observed in lymph nodes (107/161 patients, 66%), prostatectomy bed (55/161 patients, 34%), and in the skeleton (46/161 patients, 29%). PET/CT findings were validated using histological criteria (46/358, 13%), and follow-up clinical and imaging criteria (312/358, 87%). Sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy were, respectively, 85%, 93%, 91%, 87%, and 89%. In multivariate analysis, high PSA levels, advanced pathological stage, previous biochemical failure and older age were significantly (P < 0.05) associated with an increased risk of positive PET/CT findings. The percentage of positive scans was 19% in those with a PSA level between 0.2 and 1 ng/ml, 46% in those with a PSA level between 1 and 3 ng/ml, and 82% in those with a PSA level higher than 3 ng/ml. ROC analysis showed that PET/CT-positive and PET/CT-negative patients could be best distinguished using a PSA cut-off value of 1.4 ng/ml. CONCLUSIONS: In addition to PSA levels, pathological stage, previous biochemical failure and age should be considered by physicians when referring prostate cancer patients with biochemical failure after radical prostatectomy to [(11)C]choline PET/CT.

4D-PET data sorting into different number of phases: a NEMA IQ phantom study.

This study aims at evaluating the dependence of 4D-PET data sorting on the number of phases in which the respiratory cycle can be divided. The issue is to find the best compromise to reduce the conflicting effects induced by increasing the number of phases: lesion motion on each set of images decreases, but on the other hand image noise increases. The IQ NEMA 2001 IEC body phantom was used to simulate the movement of neoplastic lesions in the thorax and abdomen, investigating the effect of target size (10-37 mm), lesion to background activity concentrations ratio (4-to-1 and 8-to-1), total acquisition time (3, 6, 12, 20 min) and number of phase partition (1, 2, 4, 6, 8, 10, 13). The phantom was moved in a cranial-caudal direction with an excursion of 25 mm and with a period of 4.0 s. Five parameters associated to lesion volume and activity concentration were considered to assess the capability of the 4D-PET technique to "freeze" the phantom motion. The results for all the parameters showed the capability of the 4D-PET acquisition technique to "freeze" the lesion motion. The division into 6 phases was found to be the best compromise between temporal resolution and image noise for the phase where the "lesions" move faster, whereas the partition into 4 phases could be used if a stable breathing phase is considered.

Fluorodeoxyglucose uptake measured by positron emission tomography and standardized uptake value predicts long-term survival of CT screening detected lung cancer in heavy smokers.

BACKGROUND: Fluorodeoxyglucose-positron emission tomography (FDG-PET) has proven its value in the diagnosis of undetermined pulmonary lesions, lung cancer staging, and assessment of prognosis. Purpose of this study is to clarify whether standardized uptake value (SUV) can predict clinical outcome of computed tomography (CT) screening detected lung cancer. METHODS: We tested the predictive value of FDG-PET using SUV on long-term survival of 34 lung cancer patients, detected from 1035 heavy smokers > or = 50 years monitored by annual low-dose CT for 5 years, with a median follow-up of 75 months from diagnosis. FINDINGS: PET scan was performed in 34 (89%) of 38 lung cancer patients diagnosed during the 5 years of screening and was positive in 32 (94%). Complete resection was achieved in 30 cases (88%), 20 (59%) were pathologic stage I and 23 (68%) were adenocarcinoma. Median SUV was 5.0 overall, being significantly lower in stage I (2.5 vs. 10.1, p = 0.001) and in adenocarcinoma (2.5 vs. 13.0, p = 0.001). The 5-year survival of lung cancer patients was 100% for SUV levels < or = 2.5, 60% for SUV more than 2.5 and less than 8, and only 20% for SUV > or = 8 (p = 0.001). CONCLUSIONS: FDG-PET using SUV can predict long-term survival of screening detected lung cancer, in a noninvasive manner. Metabolic assessment of biologic behavior might improve the clinical management of CT-detected lung cancer and reduce the risk of unnecessary treatments for indolent disease.

Changes in glucose metabolism during and after radiotherapy in non-small cell lung cancer.

AIMS AND BACKGROUND: Evaluation of the metabolic response to radiotherapy in nonsmall cell lung cancer patients is commonly performed about three months after the end of radiotherapy. The aim of the present study was to assess with positron emission tomography/computed tomography (PET/CT) and [18F]fluorodeoxyglucose changes in glucose metabolism during and after radiotherapy in non-small cell lung cancer patients. METHODS AND STUDY DESIGN: In 6 patients, PET/CT scans with [18F]fluorodeoxyglucose were performed before (PET0), during (PET1; at a median of 14 days before the end of radiotherapy) and after the end of radiotherapy (PET2 and PET3, at a median of 28 and 93 days, respectively). The metabolic response was scored according to visual and semiquantitative criteria. RESULTS: Standardize maximum uptake at PET1 (7.9 +/- 4.8), PET2 (5.1 +/- 4.1) and PET3 (2.7 +/- 3.1) were all significantly (P < 0.05; ANOVA repeated measures) lower than at PET0 (16.1 +/- 10.1). Standardized maximum uptake at PET1 was significantly higher than at both PET2 and PET3. There were no significant differences in SUV(max) between PET2 and PET3. PET3 identified 4 complete and 2 partial metabolic responses, whereas PET1 identified 6 partial metabolic responses. Radiotherapy-induced increased [l8F]fluorodeoxyglucose uptake could be visually distinguished from tumor uptake based on PET/CT integration and was less frequent at PET1 (n = 2) than at PET3 (n = 6). CONCLUSION: In non-small cell lung cancer, radiotherapy induces a progressive decrease in glucose metabolism that is greater 3 months after the end of treatment but can be detected during the treatment itself. Glucose avid, radiotherapy-induced inflammation is more evident after the end of radiotherapy than during radiotherapy and does not preclude the interpretation of [18F]fluorodeoxyglucose images, particularly when using PET/CT.

Lungs of patients with acute respiratory distress syndrome show diffuse inflammation in normally aerated regions: a [18F]-fluoro-2-deoxy-D-glucose PET/CT study.

OBJECTIVE: Neutrophilic inflammation plays a key role in the pathogenesis of acute respiratory distress syndrome (ARDS) and acute lung injury (ALI). Positron emission tomography (PET) with [F]-fluoro-2-deoxy-D-glucose (FDG) can be used to image cellular metabolism that, during lung inflammatory processes, likely reflects neutrophils activity. The aim of this study was to assess the magnitude and regional distribution of inflammatory metabolic activity in the lungs of patients with ALI/ARDS by PET with FDG. DESIGN: Prospective clinical investigation. PATIENTS: Ten patients with ALI/ARDS; four spontaneously breathing and two mechanically ventilated subjects, without known lung disease, served as controls. INTERVENTIONS: In each individual we performed an FDG PET/computed tomography of the thorax. MEASUREMENTS AND MAIN RESULTS: FDG cellular influx rate constant (Ki) was computed for the imaged lung field and for regions of interest, grouping voxels with similar density. In all patients with ALI/ARDS, Ki was higher than in controls, also after accounting for the increased lung density. Ki values differed greatly among patients, but in all patients Ki of the normally aerated regions was much higher (2- to 24-fold) than in controls. Whereas in some patients the highest Ki values corresponded to regions with the lowest aeration, in others these regions had lower Ki than normally and mildly hypoaerated regions. CONCLUSION: In patients with ALI/ARDS, undergoing mechanical ventilation since days, the metabolic activity of the lungs is markedly increased across the entire lung density spectrum. The intensity of this activation and its regional distribution, however, vary widely within and between patients.

Dose-volume relationships for acute bowel toxicity in patients treated with pelvic nodal irradiation for prostate cancer.

PURPOSE: To find correlation between dose-volume histograms (DVHs) of the intestinal cavity (IC) and moderate-severe acute bowel toxicity in men with prostate cancer treated with pelvic nodal irradiation. METHODS AND MATERIALS: The study group consisted of 191 patients with localized prostate cancer who underwent whole-pelvis radiotherapy with radical or adjuvant/salvage intent during January 2004 to November 2007. Complete planning/clinical data were available in 175 of these men, 91 of whom were treated with a conventional four-field technique (50.4 Gy, 1.8 Gy/fraction) and 84 of whom were treated with IMRT using conventional Linac (n = 26, 50.4 Gy, 1.8 Gy/fraction) or Helical TomoTherapy (n = 58, 50-54 Gy, 1.8-2 Gy/fraction). The IC outside the planning target volume (PTV) was contoured and the DVH for the first 6 weeks of treatment was recovered in all patients. The correlation between a number of clinical and DVH (V10-V55) variables and toxicity was investigated in univariate and multivariate analyses. The correlation between DVHs for the IC outside the PTV and DVHs for the whole IC was also assessed. RESULTS: Twenty-two patients experienced toxicity (3/22 in the IMRT/tomotherapy group). Univariate analyses showed a significant correlation between V20-V50 and toxicity (p = 0.0002-0.001), with a higher predictive value observed for V40-V50. Previous prostatectomy (p = 0.066) and abdominal/pelvic surgery (p = 0.12) also correlated with toxicity. Multivariate analysis that included V45, abdominal/pelvic surgery, and prostatectomy showed that the most predictive parameters were V45 (p = 0.002) and abdominal/pelvic surgery (p = 0.05, HR = 2.4) CONCLUSIONS: Our avoidance IMRT approach drastically reduces the incidence of acute bowel toxicity. V40-V50 of IC and, secondarily, previous abdominal/pelvic surgery were the main predictors of acute bowel toxicity.

Characterization of preclinical models of prostate cancer using PET-based molecular imaging.

PURPOSE: Transgenic adenocarcinoma of the mouse prostate (TRAMP) mice spontaneously develop hormone-dependent and hormone-independent prostate cancer (PC) that potentially resembles the human pathological condition. The aim of the study was to validate PET imaging as a reliable tool for in vivo assessment of disease biology and progression in TRAMP mice using radioligands routinely applied in clinical practice: [(18)F]FDG and [(11)C]choline. METHODS: Six TRAMP mice were longitudinally evaluated starting at week 11 of age to visualize PC development and progression. The time frame and imaging pattern of PC lesions were subsequently confirmed on an additional group of five mice. RESULTS: PET and [(18)F]FDG allowed detection of PC lesions starting from 23 weeks of age. [(11)C]Choline was clearly taken up only by TRAMP mice carrying neuroendocrine lesions, as revealed by post-mortem histological evaluation. CONCLUSION: PET-based molecular imaging represents a state-of-the-art tool for the in vivo monitoring and metabolic characterization of PC development, progression and differentiation in the TRAMP model.

Monitoring disease evolution and treatment response in lysosomal disorders by the peripheral benzodiazepine receptor ligand PK11195.

Microglia activation and neuroinflammation play a pivotal role in the pathogenesis of lysosomal storage disorders (LSD) affecting the central nervous system (CNS), which are amenable to treatment by hematopoietic stem cell transplantation (HSCT). HSCT efficacy relies on replacing the intra- and extra-vascular hematopoietic cell compartments, including CNS microglia, with a cell population expressing the functional enzyme. Non-invasive and quantitative assessment of microglia activation and of its reduction upon HSCT might allow for evaluation of disease evolution and response to treatment in LSD. We here demonstrate that microglia activation can be quantified ex vivo and in vivo by PET using the peripheral benzodiazepine receptor ligand PK11195 in two models of LSD. Furthermore, we show a differential PBR binding following microglia replacement by donor cells in mice undergoing HSCT. Our data indicates that PBR ligands constitute valuable tools for monitoring the evolution and the response to treatment of LSD with CNS involvement, and enable us to evaluate whether the turnover between endogenous and donor microglia following HSCT could be adequate enough to delay disease progression.