Search

Die diesjährige Frühjahrstagung der DGHO (Deutsche Gesellschaft für Hämatologie und Medizinische Onkologie e. V.) stand unter der Überschrift «Herausforderungen in der Onkologie – personalisierte Therapiesteuerung». Über drei Themenkomplexe hinweg wurden aktuelle Möglichkeiten und Perspektiven der Therapiesteuerung in der Onkologie hinsichtlich «Methoden», gelungenen «Beispielen» sowie der «Umsetzung in der Versorgung» diskutiert. [ABSTRACT FROM AUTHOR]

We show that longer exposure to 177Lu-PSMA-617 treatment for up to six cycles was not associated with greater toxicity risk. Safety analyses support a favourable benefit-risk profile for six cycles of 177Lu-PSMA-617 in patients with progressive, prostate-specific membrane antigen–positive, metastatic castration-resistant prostate cancer. [177Lu]Lu-PSMA-617 (177Lu-PSMA-617) plus the standard of care (SoC) significantly improved overall survival and radiographic progression-free survival versus SoC alone in patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer in the VISION trial. We evaluated the safety of additional cycles of 177Lu-PSMA-617 and the impact of longer observation time for patients receiving 177Lu-PSMA-617 plus SoC. VISION was an international, open-label study. Patients were randomised 2:1 to receive 177Lu-PSMA-617 plus SoC or SoC alone. The incidence of treatment-emergent adverse events (TEAEs) was assessed in prespecified subgroups of patients who received ≤4 cycles versus 5–6 cycles of treatment and during each cycle of treatment. The TEAE incidence was also adjusted for treatment exposure to calculate the incidence per 100 patient-treatment years of observation. This analysis was performed for the first occurrence of TEAEs. The any-grade TEAE incidence was similar in cycles 1–4 and cycles 5–6. TEAE frequency was similar across all cycles of 177Lu-PSMA-617 treatment. No additional safety concerns were reported for patients who received >4 cycles. The exposure-adjusted safety analysis revealed that the overall TEAE incidence was similar between arms, but distinct trends for different TEAE types were noted and the incidence of events associated with 177Lu-PSMA-617 remained higher in the 177Lu-PSMA-617 arm. Longer exposure to 177Lu-PSMA-617 plus SoC was not associated with a higher toxicity risk, and the extended time for safety observation could account for the higher TEAE incidence in comparison to SoC alone. The findings support a favourable benefit-risk profile for 6 cycles of 177Lu-PSMA-617 in this setting and the use of up to 6 cycles of 177Lu-PSMA-617 in patients who are clinically benefiting from and tolerating this therapy. For patients with metastatic prostate cancer no longer responding to hormone therapy, an increase in the number of cycles of treatment with a radioactive compound called 177Lu-PSMA-617 from four to six had no additional adverse side effects. [ABSTRACT FROM AUTHOR]

In VISION, the prostate-specific membrane antigen (PSMA)-targeted radioligand therapy lutetium-177 [177Lu]Lu-PSMA-617 (vipivotide tetraxetan) improved radiographic progression-free survival and overall survival when added to protocol-permitted standard of care in patients with metastatic castration-resistant prostate cancer. Here, we report additional health-related quality of life (HRQOL), pain, and symptomatic skeletal event results. This multicentre, open-label, randomised, phase 3 trial was conducted at 84 cancer centres in nine countries in North America and Europe. Eligible patients were aged 18 years or older; had progressive PSMA-positive metastatic castration-resistant prostate cancer; an Eastern Cooperative Oncology Group (ECOG) performance status score of 0–2; and had previously received of at least one androgen receptor pathway inhibitor and one or two taxane-containing regimens. Patients were randomly assigned (2:1) to receive either [177Lu]Lu-PSMA-617 plus protocol-permitted standard of care ([177Lu]Lu-PSMA-617 group) or standard of care alone (control group) using permuted blocks. Randomisation was stratified by baseline lactate dehydrogenase concentration, liver metastases, ECOG performance status, and androgen receptor pathway inhibitor inclusion in standard of care. Patients in the [177Lu]Lu-PSMA-617 group received intravenous infusions of 7·4 gigabecquerel (GBq; 200 millicurie [mCi]) [177Lu]Lu-PSMA-617 every 6 weeks for four cycles plus two optional additional cycles. Standard of care included approved hormonal treatments, bisphosphonates, and radiotherapy. The alternate primary endpoints were radiographic progression-free survival and overall survival, which have been reported. Here we report the key secondary endpoint of time to first symptomatic skeletal event, and other secondary endpoints of HRQOL assessed with the Functional Assessment of Cancer Therapy-Prostate (FACT-P) and EQ-5D-5L, and pain assessed with the Brief Pain Inventory-Short Form (BPI-SF). Patient-reported outcomes and symptomatic skeletal events were analysed in all patients who were randomly assigned after implementation of measures designed to reduce the dropout rate in the control group (on or after March 5, 2019), and safety was analysed according to treatment received in all patients who received at least one dose of treatment. This trial is registered with ClinicalTrials.gov , NCT03511664 , and is active but not recruiting. Between June 4, 2018, and Oct 23, 2019, 831 patients were enrolled, of whom 581 were randomly assigned to the [177Lu]Lu-PSMA-617 group (n=385) or control group (n=196) on or after March 5, 2019, and were included in analyses of HRQOL, pain, and time to first symptomatic skeletal event. The median age of patients was 71 years (IQR 65–75) in the [177Lu]Lu-PSMA-617 group and 72·0 years (66–76) in the control group. Median time to first symptomatic skeletal event or death was 11·5 months (95% CI 10·3–13·2) in the [177Lu]Lu-PSMA-617 group and 6·8 months (5·2–8·5) in the control group (hazard ratio [HR] 0·50, 95% CI 0·40–0·62). Time to worsening was delayed in the [177Lu]Lu-PSMA-617 group versus the control group for FACT-P score (HR 0·54, 0·45–0·66) and subdomains, BPI-SF pain intensity score (0·52, 0·42–0·63), and EQ-5D-5L utility score (0·65, 0·54–0·78). Grade 3 or 4 haematological adverse events included decreased haemoglobin (80 [15%] of 529 assessable patients who received [177Lu]Lu-PSMA-617 plus standard of care vs 13 [6%] of 205 who received standard of care only), lymphocyte concentrations (269 [51%] vs 39 [19%]), and platelet counts (49 [9%] vs five [2%]). Treatment-related adverse events leading to death occurred in five (1%) patients who received [177Lu]Lu-PSMA-617 plus standard of care (pancytopenia [n=2], bone marrow failure [n=1], subdural haematoma [n=1], and intracranial haemorrhage [n=1]) and no patients who received standard of care only. [177Lu]Lu-PSMA-617 plus standard of care delayed time to worsening in HRQOL and time to skeletal events compared with standard of care alone. These findings support the use of [177Lu]Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer who received previous androgen receptor pathway inhibitor and taxane treatment. Advanced Accelerator Applications (Novartis). [ABSTRACT FROM AUTHOR]

Abstract: Background and purpose: The present study evaluates the incidence of 11C-choline PET/CT positive findings in patients with recurrent prostate cancer referred for salvage radiotherapy (SRT) and the influence on the definition of the planning target volume (PTV). Material and methods: Thirty-seven patients treated with radical prostatectomy and referred to SRT to the prostatic fossa because of biochemical relapse, were analysed retrospectively. All patients underwent 11C-choline PET/CT before radiotherapy. The influence of PET/CT on the extent of the PTV was analysed. The median total follow up after SRT was 51.2months. Results: 11/37 (30%) patients had a positive finding in the 11C-choline PET/CT, 5 (13%) outside of the prostatic fossa (iliac lymph nodes), implicating an extension of the PTV. Patients with positive 11C-choline PET/CT had a significant higher PSA value than patients with no pathologic uptake (p =0.03). Overall, at the end of follow up 56% of the patients had a PSA⩽0.2ng/ml and 44% had a biochemical relapse of prostate cancer. Conclusions: 11C-choline PET/CT detects abnormalities outside of the prostatic fossa in 13% of patients referred for SRT because of biochemical relapse after radical prostatectomy, affecting the extent of the PTV. Prospective studies need to be implemented to evaluate the benefit of SRT with a PTV based on 11C-choline PET/CT. [Copyright &y& Elsevier]

Purpose: [C]Choline has been established as a PET tracer for imaging prostate cancer. The aim of this study was to determine whether [C]choline can be used for monitoring the effects of therapy in a prostate cancer mouse xenograft model. Methods: The androgen-independent human prostate cancer cell line PC-3 was implanted subcutaneously into the flanks of 13 NMRI (nu/nu) mice. All mice were injected 4–6 weeks after xenograft implantation with 37 MBq [C]choline via a tail vein. Dynamic imaging was performed for 60 min with a small-animal PET/CT scanner (Siemens Medical Solutions). Six mice were subsequently injected intravenously with docetaxel twice (days 1 and 5) at a dose of 3 mg/kg body weight. Seven mice were treated with PBS as a control. [C]Choline imaging was performed prior to and 1, 2 and 3 weeks after treatment. To determine choline uptake the images were analysed in terms of tumour-to-muscle (T/M) ratios. Every week the size of the implanted tumour was determined with a sliding calliper. Results: The PC-3 tumours could be visualized by [C]choline PET. Before treatment the T/M ratio was 1.6±0.5 in the control group and 1.8±0.4 in the docetaxel-treated group ( p=0.65). There was a reduction in the mean [C]choline uptake after docetaxel treatment as early as 1 week after initiation of therapy (T/M ratio 1.8±0.4 before treatment, 0.9±0.3 after 1 week, 1.1±0.3 after 2 weeks and 0.8±0.2 after 3 weeks). There were no decrease in [C]choline uptake in the control group following treatment (T/M ratio 1.6±0.5 before treatment, 1.7±0.4 after 1 week, 1.8±0.7 after 2 weeks and 1.7±0.4 after 3 weeks). For analysis of the dynamic data, a generalized estimation equation model revealed a significant decrease in the T/M ratios 1 week after docetaxel treatment, and the ratio remained at that level through week 3 (mean change −0.93±0.24, p<0.001, after 1 week; −0.78±0.21, p<0.001, after 2 weeks; −1.08±0.26, p<0.001, after 3 weeks). In the control group there was no significant decrease in the T/M ratios (mean change 0.085±0.39, p=0.83, after 1 week; 0.31±0.48, p=0.52, after 2 weeks; 0.11±0.30, p=0.72, after 3 weeks). Metabolic changes occurred 1 week after therapy and preceded morphological changes of tumour size during therapy. Conclusion: Our results demonstrate that [C]choline has the potential for use in the early monitoring of the therapeutic effect of docetaxel in a prostate cancer xenograft animal model. The results also indicate that PET with radioactively labelled choline derivatives might be a useful tool for monitoring responses to taxane-based chemotherapy in patients with advanced prostate cancer. [ABSTRACT FROM AUTHOR]

Abstract: Functional neuroimaging techniques using positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) have provided new insights in our understanding of brain function from the molecular to the systems level. While subtraction strategy based data analyses have revealed the involvement of distributed brain regions in memory processes, covariance analysis based data analysis strategies allow functional interactions between brain regions of a neuronal network to be assessed. The focus of this chapter is to (1) establish the functional topography of episodic and working memory processes in young and old normal volunteers, (2) to assess functional interactions between modules of networks of brain regions by means of covariance based analyses and systems level modelling and (3) to relate neuroimaging data to the underpinning neural networks. Male normal young and old volunteers without neurological or psychiatric illness participated in neuroimaging studies (PET, fMRI) on working and episodic memory. Distributed brain areas are involved in memory processes (episodic and working memory) in young volunteers and show much of an overlap with respect to the network components. Systems level modelling analyses support the hypothesis of bihemispheric, asymmetric networks subserving memory processes and revealed both similarities in general and differences in the interactions between brain regions during episodic encoding and retrieval as well as working memory. Changes in memory function with ageing are evident from studies in old volunteers activating more brain regions compared to young volunteers and revealing more and stronger influences of prefrontal regions. We finally discuss the way in which the systems level models based on PET and fMRI results have implications for the understanding of the underlying neural network functioning of the brain. [Copyright &y& Elsevier]

Background: [177Lu]Lu–PSMA‐617 (177Lu‐PSMA‐617) plus protocol‐permitted standard of care (SOC) prolonged overall survival (OS) and radiographic progression‐free survival (rPFS) versus SOC in patients with prostate‐specific membrane antigen (PSMA)–positive metastatic castration‐resistant prostate cancer (mCRPC) in the phase 3 VISION study, in addition to beneficial effects on symptomatic skeletal events (SSEs) and health‐related quality of life (HRQOL). Methods: Post hoc analyses used the full analysis set from the VISION study (N = 831) overall and by randomized treatment arm (177Lu‐PSMA‐617 plus SOC, n = 551; SOC, n = 280). Correlations were determined between OS and rPFS and between rPFS or OS and time to SSE or to worsening HRQOL (Functional Assessment of Cancer Therapy–Prostate [FACT‐P] and 5‐level EQ‐5D [EQ‐5D‐5L]). Correlation analyses used an iterative multiple imputation copula‐based approach (correlation coefficients [rho] of <0.3 were defined as weak, ≥0.3 and <0.5 as mild, ≥0.5 and <0.7 as moderate, and ≥0.7 as strong). Results: In the overall population, rPFS correlated strongly with OS (rho, ≥0.7). Correlations between rPFS or OS and time to SSE without death were weak or mild. Time to worsening in the FACT‐P total score and emotional and physical well‐being domains correlated mildly or moderately with rPFS and moderately with OS. Correlation coefficients for time‐to‐worsening EQ‐5D‐5L scores were mild to moderate for both rPFS and OS. Correlation coefficients were similar between treatment arms. Conclusions: In this analysis of the VISION study, rPFS correlated strongly with OS but not with time to SSE or worsening HRQOL. These findings require further investigation. In patients with metastatic castration‐resistant prostate cancer participating in the VISION randomized phase 3 trial, radiographic progression‐free survival correlated strongly with overall survival but not with time to a first symptomatic skeletal event or worsening health‐related quality of life or pain. There were no clear or consistent differences in the strengths of correlation between the two treatment groups ([177Lu]Lu‐PSMA‐617 plus protocol‐permitted standard of care vs. standard of care alone). [ABSTRACT FROM AUTHOR]

Purpose: The present study aims at evaluating the preclinical and the clinical performance of [68Ga]Ga-DATA5m.SA.FAPi, which has the advantage to be labeled with gallium-68 at room temperature. Methods: [68Ga]Ga-DATA5m.SA.FAPi was assessed in vitro on FAP-expressing stromal cells, followed by biodistribution and in vivo imaging on prostate and glioblastoma xenografts. Moreover, the clinical assessment of [68Ga]Ga-DATA5m.SA.FAPi was conducted on six patients with prostate cancer, aiming on investigating, biodistribution, biokinetics, and determining tumor uptake. Results: [68Ga]Ga-DATA5m.SA.FAPi is quantitatively prepared in an instant kit-type version at room temperature. It demonstrated high stability in human serum, affinity for FAP in the low nanomolar range, and high internalization rate when associated with CAFs. Biodistribution and PET studies in prostate and glioblastoma xenografts revealed high and specific tumor uptake. Elimination of the radiotracer mainly occurred through the urinary tract. The clinical data are in accordance with the preclinical data concerning the organ receiving the highest absorbed dose (urinary bladder wall, heart wall, spleen, and kidneys). Different to the small-animal data, uptake of [68Ga]Ga-DATA5m.SA.FAPi in tumor lesions is rapid and stable and tumor-to-organ and tumor-to-blood uptake ratios are high. Conclusion: The radiochemical, preclinical, and clinical data obtained in this study strongly support further development of [68Ga]Ga-DATA5m.SA.FAPi as a diagnostic tool for FAP imaging. [ABSTRACT FROM AUTHOR]

Here we aim to provide updated guidance and standards for the indication, acquisition, and interpretation of PSMA PET/CT for prostate cancer imaging. Procedures and characteristics are reported for a variety of available PSMA small radioligands. Different scenarios for the clinical use of PSMA-ligand PET/CT are discussed. This document provides clinicians and technicians with the best available evidence, to support the implementation of PSMA PET/CT imaging in research and routine practice. [ABSTRACT FROM AUTHOR]

In this paper, a model-based tracking control is proposed for a mechanism dedicated to accurately reproduce the breathing-induced motion of a human lung tumour. In former work, a 3-dimensional mechanism equipped with three pneumatically driven axes has been developed and constructed for this purpose. The overall control structure consists of decentralised axis controller for each pneumatic cylinder with a cascaded structure: A fast inner control loop governs the pressure induced drive force using backstepping techniques, whereas the outer control loop is related to an optimal, robust position control of the cylinder. Additionally, discrete-time iterative learning controllers are utilised to compensate lumped disturbance forces and model uncertainties. The suggested overall control structure has been implemented on the innovative test rig and successfully validated in a clinical framework. The given work represents the basis for future improvements of algorithms regarding PET/CT-imaging as well as radiotherapy. • Clinical investigation of precisely gated PET/CT and the influence on identified target volumes. • Modelling of a pneumatically actuated lung tumour mimic model. • Nonlinear control design using Lyapunov methods for the mechanical and pneumatic subsystems. • LMI approach for stability proof for a polytopic system description. • Norm-optimal ILC for tracking improvement and disturbance rejection. [ABSTRACT FROM AUTHOR]

Purpose: The mammalian brain glucose metabolism is tightly and sensitively regulated. An ischemic brain injury caused by cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) affects cerebral function and presumably also glucose metabolism. The majority of patients who survive CA suffer from cognitive deficits and physical disabilities. Toll-like receptor 2 (TLR2) plays a crucial role in inflammatory response in ischemia and reperfusion (I/R). Since deficiency of TLR2 was associated with increased survival after CA-CPR, in this study, glucose metabolism was measured using non-invasive [18F]F-FDG PET-CT imaging before and early after CA-CPR in a mouse model comparing wild-type (WT) and TLR2-deficient (TLR2−/−) mice. The investigation will evaluate whether FDG-PET could be useful as an additional methodology in assessing prognosis. Procedures: Two PET-CT scans using 2-deoxy-2-[18F]fluoro-D-glucose ([18F]F-FDG) tracer were carried out to measure dynamic glucose metabolism before and early after CPR. To achieve this, anesthetized and ventilated adult female WT and TLR2−/− mice were scanned in PET-CT. After recovery from the baseline scan, the same animals underwent 10-min KCL-induced CA followed by CPR. Approximately 90 min after CA, measurements of [18F]F-FDG uptake for 60 min were started. The [18F]F-FDG standardized uptake values (SUVs) were calculated using PMOD-Software on fused FDG-PET-CT images with the included 3D Mirrione-Mouse-Brain-Atlas. Results: The absolute SUVmean of glucose in the whole brain of WT mice was increased about 25.6% after CA-CPR. In contrast, the absolute glucose SUV in the whole brain of TLR2−/− mice was not significantly different between baseline and measurements post CA-CPR. In comparison, baseline measurements of both mouse strains show a highly significant difference with regard to the absolute glucose SUV in the whole brain. Values of TLR2−/− mice revealed a 34.6% higher glucose uptake. Conclusions: The altered mouse strains presented a different pattern in glucose uptake under normal and ischemic conditions, whereby the post-ischemic differences in glucose metabolism were associated with the function of key immune factor TLR2. There is evidence for using early FDG-PET-CT as an additional diagnostic tool after resuscitation. Further studies are needed to use PET-CT in predicting neurological outcomes. [ABSTRACT FROM AUTHOR]

Since the 1980s major advances in surgery, radiotherapy and chemotherapy have established multimodal approaches as curative treatment options for oesophageal cancer. In addition the introduction of functional imaging modalities such as PET-CT created new opportunities for a more adequate patient selection and therapy response assessment. The majority of oesophageal carcinomas are represented by two histologies: squamous cell carcinoma and adenocarcinoma. In recent years an epidemiological shift towards the latter was observed. From a surgical point of view, adenocarcinomas, which are usually located in the distal third of the oesophagus, may be treated with a transhiatal resection, whereas squamous cell carcinomas, which are typically found in the middle and the upper third, require a transthoracic approach. Since overall survival after surgery alone is poor, multimodality approaches have been developed. At least for patients with locally advanced tumors, surgery alone can no longer be advocated as routine treatment. Nowadays, scientific interest is focused on tumor response to induction radiochemotherapy. A neoadjuvant approach includes the early and accurate assessment of clinical response, optimally performed by repeated PET-CT imaging and endoscopic ultrasound, which may permit early adaption of the therapeutic concept. Patients with SCC that show clinical response by PET CT are considered to have a better prognosis, regardless of whether surgery will be performed or not. In non-responding patients salvage surgery improves survival, especially if complete resection is achieved. [ABSTRACT FROM AUTHOR]

Describes a fully-automatic three-dimensional (3-D)-segmentation technique for brain magnetic resonance (MR) images, with focus on Markov random fields (MRF's). Methodology used to develop the technique; Indepth look at MRF's; Classification of MR images; Presentation of a simulated annealing and iterated conditional mode.

Background: To date, there are no effective treatments for Alzheimer's disease (AD). Thus, a significant need for research of therapies remains.Objective: One promising pharmacological target is the hormone fibroblast growth factor 21 (FGF21), which is thought to be neuroprotective. A clinical candidate for medical use could be the FGF21 analogue LY2405319 (LY), which has a specificity and potency comparable to FGF21.Methods: The present study investigated the potential neuroprotective effect of LY via PPARγ/apoE/abca1 pathway, which is known to degrade amyloid-β (Aβ) plaques by using primary glial cells and hippocampal organotypic brain slice cultures (OBSCs) from 30- and 50-week-old transgenic APPswe/PS1dE9 (tg) mice. By LY treatment of 52-week-old tg mice with advanced Aβ deposition, we further aimed to elaborate the effect of LY on AD pathology in vivo.Results: LY application to primary glial cells caused an upregulation of pparγ, apoE, and abca1 mRNA expression and significantly decreased number and area of Aβ plaques in OBSCs. LY treatment in tg mice increased cerebral [18F] FDG uptake and N-acetylaspartate/creatine ratio indicating enhanced neuronal activity and integrity. Although LY did not reduce the number of Aβ plaques in tg mice, the number of iba1-positive cells was significantly decreased indicating reduced microgliosis.Conclusion: These data identified LY in vitro as an activator of Aβ degrading genes leading to cerebral Aβ load amelioration in early and late AD pathology. Although Aβ plaque reduction by LY failed in vivo, LY may be used as therapeutic agent to treat AD-related neuroinflammation and impaired neuronal integrity. [ABSTRACT FROM AUTHOR]

Background: Amyloid-β accumulation was found to alter precuneus-based functional connectivity (FC) in mild cognitive impairment (MCI) and Alzheimer's disease (AD) dementia, but its impact is less clear in subjective cognitive decline (SCD), which in combination with AD pathologic change is theorized to correspond to stage 2 of the Alzheimer's continuum in the 2018 NIA-AA research framework.Objective: This study addresses how amyloid pathology relates to resting-state fMRI FC in SCD, especially focusing on the precuneus.Methods: From the DELCODE cohort, two groups of 24 age- and gender-matched amyloid-positive (SCDAβ+) and amyloidnegative SCD (SCDβ-) patients were selected according to visual [18F]-Florbetaben (FBB) PET readings, and studied with resting-state fMRI. Local (regional homogeneity [ReHo], fractional amplitude of low-frequency fluctuations [fALFF]) and global (degree centrality [DC], precuneus seed-based FC) measures were compared between groups. Follow-up correlation analyses probed relationships of group differences with global and precuneal amyloid load, as measured by FBB standard uptake value ratios (SUVR=⫖FBB).Results: ReHo was significantly higher (voxel-wise p < 0.01, cluster-level p < 0.05) in the bilateral precuneus for SCDAβ+patients, whereas fALFF was not altered between groups. Relatively higher precuneus-based FC with occipital areas (but no altered DC) was observed in SCDAβ+ patients. In this latter cluster, precuneus-occipital FC correlated positively with global (SCDAβ+) and precuneus SUVRFBB (both groups).Conclusion: While partial confounding influences due to a higher APOE ε4 carrier ratio among SCDAβ+ patients cannot be excluded, exploratory results indicate functional alterations in the precuneus hub region that were related to amyloid-β load, highlighting incipient pathology in stage 2 of the AD continuum. [ABSTRACT FROM AUTHOR]

Radium Ra-223 dichloride (radium-223, Xofigo®) is a targeted alpha therapy approved for the treatment of castration-resistant prostate cancer (CRPC) with symptomatic bone metastases and no known visceral metastatic disease. Radium-223 is the first targeted alpha therapy in this indication providing a new treatment option, with evidence of a significant survival benefit, both in overall survival and in the time to the first symptomatic skeletal-related event. The skeleton is the most common metastatic site in patients with advanced prostate cancer. Bone metastases are a clinically significant cause of morbidity and mortality, often resulting in bone pain, pathologic fracture, or spinal cord compression necessitating treatment. Radium-223 is selectively accumulated in the bone, specifically in areas of high bone turnover, by forming complexes with the mineral hydroxyapatite (the inorganic matrix of the bone). The alpha radiation generated during the radioactive decay of radium-223 produces a palliative anti-tumour effect on the bone metastases. The purpose of this guideline is to assist nuclear medicine specialists in evaluating patients who might be candidates for treatment using radium-223, planning and performing this treatment, understanding and evaluating its consequences, and improving patient management during therapy and follow-up. [ABSTRACT FROM AUTHOR]

Intrastriatal injection of botulinum neurotoxin A (BoNT-A) results in improved motor behavior of hemiparkinsonian (hemi-PD) rats, an animal model for Parkinson’s disease. The caudate–putamen (CPu), as the main input nucleus of the basal ganglia loop, is fundamentally involved in motor function and directly interacts with the dopaminergic system. To determine receptor-mediated explanations for the BoNT-A effect, we analyzed the dopamine D2/D3 receptor (D2/D3R) in the CPu of 6-hydroxydopamine (6-OHDA)-induced hemi-PD rats by [18F]fallypride-PET/CT scans one, three, and six months post-BoNT-A or -sham-BoNT-A injection. Male Wistar rats were assigned to three different groups: controls, sham-injected hemi-PD rats, and BoNT-A-injected hemi-PD rats. Disease-specific motor impairment was verified by apomorphine and amphetamine rotation testing. Animal-specific magnetic resonance imaging was performed for co-registration and anatomical reference. PET quantification was achieved using PMOD software with the simplified reference tissue model 2. Hemi-PD rats exhibited a constant increase of 23% in D2/D3R availability in the CPu, which was almost normalized by intrastriatal application of BoNT-A. Importantly, the BoNT-A effect on striatal D2/D3R significantly correlated with behavioral results in the apomorphine rotation test. Our results suggest a therapeutic effect of BoNT-A on the impaired motor behavior of hemi-PD rats by reducing interhemispheric changes of striatal D2/D3R. [ABSTRACT FROM AUTHOR]

Purpose: From 2010 until July 2016, the EANM Research Ltd. (EARL) FDG-PET/CT accreditation program has collected over 2500 phantom datasets from approximately 200 systems and 150 imaging sites worldwide. The objective of this study is to report the findings and impact of the accreditation program on the participating PET/CT systems. Methods: To obtain and maintain EARL accredited status, sites were required to complete and submit two phantom scans - calibration quality control (CalQC), using a uniform cylindrical phantom and image quality control (IQQC), using a NEMA NU2-2007 body phantom. Average volumetric SUV bias and SUV recovery coefficients (RC) were calculated and the data evaluated on the basis of quality control (QC) type, approval status, PET/CT system manufacturer and submission order. Results: SUV bias in 5% ( n = 96) of all CalQC submissions ( n = 1816) exceeded 10%. After corrective actions following EARL feedback, sites achieved 100% compliance within EARL specifications. 30% ( n = 1381) of SUVmean and 23% ( n = 1095) of SUVmax sphere recoveries from IQQC submissions failed to meet EARL accreditation criteria while after accreditation, failure rate decreased to 12% ( n = 360) and 9% ( n = 254), respectively. Most systems demonstrated longitudinal SUV bias reproducibility within ±5%, while RC values remained stable and generally within ±10% for the four largest and ±20% for the two smallest spheres. Conclusions: Regardless of manufacturer or model, all investigated systems are able to comply with the EARL specifications. Within the EARL accreditation program, gross PET/CT calibration errors are successfully identified and longitudinal variability in PET/CT performances reduced. The program demonstrates that a harmonising accreditation procedure is feasible and achievable. [ABSTRACT FROM AUTHOR]

Background: Circulating tumor cell (CTCs) counts might serve as early surrogate marker for treatment efficacy in metastatic castration-resistant prostate cancer (mCRPC) patients. We prospectively assessed categorical and continuous CTC-counts for their utility in early prediction of radiographic response, progression-free (PFS) and overall survival (OS) in mCRPC patients treated with docetaxel. Methods: CTC-counts were assessed in 122 serial samples, as continuous or categorical (<5 vs. =5 CTCs) variables, at baseline (q0) and after 1 (q1), 4 (q4) and 10 (q10) cycles of docetaxel (3-weekly, 75 mg/m2) in 33 mCRPC patients. Treatment response (TR) was defined as non-progressive (non-PD) and progressive disease (PD), by morphologic RECIST or clinical criteria at q4 and q10. Binary logistic and Cox proportional hazards regression analyses were used as statistical methods. Results: Categorical CTC-count status predicted PD at q4 already after one cycle (q1) and after 4 cycles (q4) of chemotherapy with an odds ratio (OR) of 14.9 (p = 0.02) and 18.0 (p = 0.01). Continuous CTC-values predicted PD only at q4 (OR 1.04, p = 0.048). Regarding PFS, categorical CTC-counts at q1 were independent prognostic markers with a hazard ratio (HR) of 3.85 (95 % CI 1.1-13.8, p = 0.04) whereas early continuous CTC-values at q1 failed significance (HR 1.02, 95 % CI 0.99-1.05, p = 0.14). For OS early categorical and continuous CTC-counts were independent prognostic markers at q1 with a HR of 3.0 (95 % CI 1.6-15.7, p = 0.007) and 1.02 (95 % CI 1.0-1.040, p = 0.04). Conclusions: Categorical CTC-count status is an early independent predictor for TR, PFS and OS only 3 weeks following treatment initiation with docetaxel whereas continuous CTC-counts were an inconsistent surrogate marker in mCRPC patients. For clinical practice, categorical CTC-counts may provide complementary information towards individualized treatment strategies with early prediction of treatment efficacy and optimized sequential treatment. [ABSTRACT FROM AUTHOR]

Background: In patients with bladder cancer (BCa) preoperative staging with 11C-choline positron emission tomography-computed tomography (PET/CT) could be used to derive prognostic information and hence stratify patients preoperatively with respect to disease management. Methods: From June 2004 to May 2007, 44 patients with localized BCa were staged with 11C-choline PET/CT before radical cystectomy. The results of imaging were correlated to overall survival (OS) and cumulative incidence of cancer-specific death (CSD). Results: There was no statistically significant difference in OS and CSD between the patient groups when stratified for organ-confined versus non-organ-confined disease or lymph node involvement defined by either 11C-choline PET/CT (OS: p = 0.262, hazard ratio [HR] = 1.60; p = 0.527, HR = 0.76; CSD: p = 0.144, HR = 2.25; p = 0.976, HR = 0.98) or CT (OS: p = 0.518, HR = 1.34; p = 0.228, HR = 1.67; CSD: p = 0.323, HR = 1.90; p = 0.136, HR = 2.38). The limitation of this study is the small number of included patients. Conclusion: In our prospective trial neither CT nor 11C-choline PET/CT were able to sufficiently predict OS or CSD in BCa patients treated with radical cystectomy albeit trends and moderately increased HRs could be demonstrated without significant differences between CT or 11C-choline PET/CT. However, these trends might prove statistically significant in bigger patient cohorts. Therefore initial transsectional imaging might be of clinical relevance in respect to prognosis and could play a role in the counseling of BCa patients. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Purpose: Attenuation correction (AC) based on low-dose computed tomography (CT) could be more accurate in brain single-photon emission computed tomography (SPECT) than the widely used Chang method, and, therefore, has the potential to improve both semi-quantitative analysis and visual image interpretation. The present study evaluated CT-based AC for dopamine transporter SPECT with I-123-ioflupane. Materials and methods: Sixty-two consecutive patients in whom I-123-ioflupane SPECT including low-dose CT had been performed were recruited retrospectively at 3 centres. For each patient, 3 different SPECT images were reconstructed: without AC, with Chang AC and with CT-based AC. Distribution volume ratio (DVR) images were obtained by scaling voxel intensities using the whole brain without striata as reference. For assessing the impact of AC on semi-quantitative analysis, specific-to-background ratios (SBR) in caudate and putamen were obtained by fully automated SPM8-based region of interest (ROI) analysis and tested for their diagnostic power using receiver-operator-characteristic (ROC) analysis. For assessing the impact of AC on visual image reading, screenshots of stereotactically normalized DVR images presented in randomized order were interpreted independently by two raters at each centre. Results: CT-based AC resulted in intermediate SBRs about half way between no AC and Chang. Maximum area under the ROC curve was achieved by the putamen SBR, with negligible impact of AC (0.924, 0.935 and 0.938 for no, CT-based and Chang AC). Diagnostic accuracy of visual interpretation also did not depend on AC. Conclusions: The impact of CT-based versus Chang AC on the interpretation of I-123-ioflupane SPECT is negligible. Therefore, CT-based AC cannot be recommended for routine use in clinical patient care, not least because of the additional radiation exposure. [ABSTRACT FROM AUTHOR]

Background Patients with locally advanced and high-risk prostate cancer (LAPC) are prone to experience biochemical recurrence despite radical prostatectomy (RP). We evaluated feasibility, safety and activity of a neoadjuvant chemohormonal therapy (NCHT) with 3-weekly full dose docetaxel and complete androgen blockade (CAB) in locally advanced and high-risk prostate cancer patients (LAPC) undergoing RP. Methods Patients (n = 30) were selected by Kattans' preoperative score and received trimestral buserelin 9,45 mg, bicalutamide 50 mg/day and 3 cycles docetaxel (75 mg/m2) followed by RP. Primary endpoints were biochemical (PSA) and local downstaging. Secondary endpoints included toxicity and operability assessments, pathological complete response (pCR), time to PSA progression, 5-year biochemical recurrence free survival (bRFS) and overall survival (OS). Results Median baseline PSA was 25.8 ng/ml (2.1-293), and the predicted probability of 5-year bRFS was 10% (0-55). NCHT induced PSA-reduction was 97.3% (81.3-99.9%; p < 0.001) and post-RP 96.7% of patients were therapy responders, with undetectable PSA-values. Postvs. pretreatment MRI indicated a median tumor volume reduction of 46.4% (-31.3-82.8; p < 0.001). A pathological downstaging was observed in 48.3%. Severe hematologic toxicities (≥CTC3) were frequent with 53.8% leucopenia, 90% neutropenia and 13.3% febrile neutropenia. RP was performed in all patients. While resectability was hindered in 26.7%, continence was achieved in 96.7%. Pathologic analyses revealed no pCR. Lymph node- and extracapsular involvement was observed in 36.7% and 56.7% with 33.3% positive surgical margins. After a median of 48.6 (19.9-87.8) months, 55.2% of therapy responders experienced PSA-recurrence. The estimated median time to PSA-progression was 38.6 months (95%CI 30.9-46.4) and 85.3 months (95%CI 39.3-131.3) for OS. The 5-year bRFS was improved to 40%, but limiting for interpretation adjuvant treatment was individualized. Conclusions NCHT is feasible despite high hematotoxicity, with excellent functional results. Significant downstaging was observed without pCR. NCHT seems to improve the cohort adjusted 5-year bRFS, but clinical value needs further investigation in randomized trials. [ABSTRACT FROM AUTHOR]

Since the 1980s major advances in surgery, radiotherapy and chemotherapy have established multimodal approaches as curative treatment options for oesophageal cancer. In addition the introduction of functional imaging modalities such as PET-CT created new opportunities for a more adequate patient selection and therapy response assessment.The majority of oesophageal carcinomas are represented by two histologies: squamous cell carcinoma and adenocarcinoma. In recent years an epidemiological shift towards the latter was observed. From a surgical point of view, adenocarcinomas, which are usually located in the distal third of the oesophagus, may be treated with a transhiatal resection, whereas squamous cell carcinomas, which are typically found in the middle and the upper third, require a transthoracic approach. Since overall survival after surgery alone is poor, multimodality approaches have been developed. At least for patients with locally advanced tumors, surgery alone can no longer be advocated as routine treatment. Nowadays, scientific interest is focused on tumor response to induction radiochemotherapy. A neoadjuvant approach includes the early and accurate assessment of clinical response, optimally performed by repeated PET-CT imaging and endoscopic ultrasound, which may permit early adaption of the therapeutic concept. Patients with SCC that show clinical response by PET CT are considered to have a better prognosis, regardless of whether surgery will be performed or not. In non-responding patients salvage surgery improves survival, especially if complete resection is achieved. [ABSTRACT FROM AUTHOR]

Purpose: To determine the clinical value of two novel molecular imaging techniques: 11C-choline positron emission tomography (PET)/computed tomography (CT) and ferumoxtran-10 enhanced magnetic resonance imaging (magnetic resonance lymphography [MRL]) for lymph node (LN) treatment in prostate cancer (PCa) patients. Therefore, we evaluated the ability of PET/CT and MRL to assess the number, size, and location of LN metastases in patients with primary or recurrent PCa. Methods and Materials: A total of 29 patients underwent MRL and PET/CT for LN evaluation. The MRL and PET/CT data were analyzed independently. The number, size, and location of the LN metastases were determined. The location was described as within or outside the standard clinical target volume for elective pelvic irradiation as defined by the Radiation Therapy Oncology Group. Subsequently, the results from MRL and PET/CT were compared. Results: Of the 738 LNs visible on MRL, 151 were positive in 23 of 29 patients. Of the 132 LNs visible on PET/CT, 34 were positive in 13 of 29 patients. MRL detected significantly more positive LNs (p < 0.001) in more patients than PET/CT (p = 0.002). The mean diameter of the detected suspicious LNs on MRL was significantly smaller than those detected by PET/CT, 4.9 mm and 8.4 mm, respectively (p < 0.0001). In 14 (61%) of 23 patients, suspicious LNs were found outside the clinical target volume with MRL and in 4 (31%) of 13 patients with PET/CT. Conclusion: In patients with PCa, both molecular imaging techniques, MRL and 11C-choline PET/CT, can detect LNs suspicious for metastasis, irrespective of the existing size and shape criteria for CT and conventional magnetic resonance imaging. On MRL and PET/CT, 61% and 31% of the suspicious LNs were located outside the conventional clinical target volume. Therefore, these techniques could help to individualize treatment selection and enable image-guided radiotherapy for patients with PCa LN metastases. [Copyright &y& Elsevier]

Abstract: Background: Current imaging techniques are of limited value for lymph node (LN) staging in bladder cancer (BCa) patients scheduled for radical cystectomy (RC). Objective: Evaluate the diagnostic efficacy of [11C]choline positron emission tomography in combination with computed tomography (PET/CT) for LN staging of patients with BCa scheduled for RC and compare that efficacy with the diagnostic efficacy of CT and the gold standard of histopathologic evaluation. Design, setting, and participants: From June 2004 to May 2007, 44 patients with localized BCa were staged with [11C]choline PET with low-dose CT for attenuation correction and simultaneous intravenous and rectal contrast-enhanced diagnostic CT before RC and pelvic lymph node dissection (PLND). LNs were dissected from the internal and external iliac arteries up to the origin of the inferior mesentery artery according to a template with 14 predefined anatomic fields. Intervention: Diagnostic [11C]choline PET/CT before RC and regional LN dissection. Measurements: Histopathologic findings of resected LN were correlated with the results of [11C]choline PET/CT and CT alone in a patient- and field-based manner. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of [11C]choline PET/CT and CT were assessed. Results and limitations: LN metastases were found in 12 of 44 patients (27%). On patient-based analysis, sensitivity, specificity, PPV, NPV, and accuracy for [11C]choline PET/CT were calculated as 58%, 66%, 39%, 81%, and 64%, respectively; and for CT the calculated percentages were 75%, 56%, 39%, 86%, and 61%, respectively. Twenty-five of 471 dissected LN fields (5%) showed metastases. On field-based analysis, sensitivity, specificity, PPV, NPV, and accuracy for [11C]choline PET/CT were 28%, 95%, 21%, 96%, and 91%, respectively; for CT, the calculated percentages were 39%, 92%, 20%, 96%, and 90%, respectively. Limitations of this study are small patient number and the fact that not all patients underwent extensive PLND. Conclusions: In patients with BCa who were scheduled for RC, preoperative LN staging with [11C]choline PET/CT was not able to improve diagnostic efficacy compared with conventional CT alone. [Copyright &y& Elsevier]

Aberrant activation and mutation status of proteins in the phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and the mitogen activated protein kinase (MAPK) signaling pathways have been linked to tumorigenesis in various tumors including urothelial carcinoma (UC). However, anti-tumor therapy with small molecule inhibitors against mTOR turned out to be less successful than expected. We characterized the molecular mechanism of this pathway in urothelial carcinoma by interfering with different molecular components using small chemical inhibitors and siRNA technology and analyzed effects on the molecular activation status, cell growth, proliferation and apoptosis. In a majority of tested cell lines constitutive activation of the PI3K was observed. Manipulation of mTOR or Akt expression or activity only regulated phosphorylation of S6K1 but not 4E-BP1. Instead, we provide evidence for an alternative mTOR independent but PI3K dependent regulation of 4E-BP1. Only the simultaneous inhibition of both S6K1 and 4E-BP1 suppressed cell growth efficiently. Crosstalk between PI3K and the MAPK signaling pathway is mediated via PI3K and indirect by S6K1 activity. Inhibition of MEK1/2 results in activation of Akt but not mTOR/S6K1 or 4E-BP1. Our data suggest that 4E-BP1 is a potential new target molecule and stratification marker for anti cancer therapy in UC and support the consideration of a multitargeting approach against PI3K, mTORC1/2 and MAPK. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to compare different analysis methods of 2-deoxy-2-[(18)F]fluoro-D-glucose positron emission tomography (FDG-PET) and magnetic resonance imaging (MRI) data for prediction of histopathological response (HPR) to neoadjuvant radiochemotherapy (RCTx) in patients with advanced rectal cancer.Procedures: Twenty-eight patients of a previously published clinical trial underwent serial FDG-PET/computed tomography scans at baseline, 14 days after initiation, and after completion of RCTx. In addition, MRI was performed at baseline and after the end of therapy. Response prediction was correlated with different image analysis algorithms comprising pure metabolic parameters taking into account the FDG uptake, volume-based parameters measuring the lesion volume in either MRI or PET data, and integrated parameters combining metabolic and volumetric information. The established two-dimensional (2D) regions of interest (ROI; diameter 1.5 cm) served as standard of reference. Changes between the parameters at the defined time points were calculated and analyzed for their potential to predict HPR to RCTx using receiver operating characteristic (ROC) analysis. Additionally, the interobserver reliability of fixed-size algorithms was analyzed.Results: Histopathology classified eight of 28 patients as non-responders and 20 patients as responders to RCTx. ROC analysis of the standard 2D ROI technique revealed areas under the curve (AUCs) of 0.64 and 0.71 for the early and late time points. Corresponding AUCs for three-dimensional (3D) volume of interest technique resulted in AUCs of 0.75 for both early and late time points, respectively. Volumetric parameters showed AUCs ranging from 0.52 to 0.57 (early time points) and 0.46 to 0.76 (later time points), respectively. Corresponding AUCs for the integrated parameters were ranging between 0.70 and 0.73 (early time points) and 0.66 and 0.76 (late time points). Analysis of intra-class correlation coefficients (ICC) for three different readers resulted in the best intra-class correlation values for the changes of 3D standard uptake value (SUV(3D)), for both early (ICC = 0.96) and late (ICC = 0.96) time points, respectively.Conclusions: Our study emphasizes that 3D-based approaches for assessing SUV values consistently belonged to the group of parameters with the highest AUC values for prediction of HPR to neoadjuvant RCTx in patients with rectal cancer. MRI was not a good predictor for therapy response; hence, the MRI information derived from combined anatomic and metabolic parameters showed unsatisfying results too. [ABSTRACT FROM AUTHOR]

Purpose: To assess the prognostic value of FDG PET/CT compared to the tumor markers S100B and melanoma inhibitory activity (MIA) in patients with high risk melanoma. Methods: Retrospective study in 125 consecutive patients with high risk melanoma that underwent FDG PET/CT for restaging. Diagnostic accuracy and prognostic value was determined for FDG PET/CT as well as for S100B and MIA. As standard of reference, cytological, histological, PET/CT or MRI follow-up findings as well as clinical follow-up were used Results: Of 125 patients, FDG PET/CT was positive in 62 patients. 37 (29.6%) patients had elevated S100B (>100 pg/ml) and 24 (20.2%) had elevated MIA (>10 pg/ml) values. Overall specificities for FDG PET/CT, S100B and MIA were 96.8% (95% CI, 89.1% to 99.1%), 85.7% (75.0% to 92.3%), and 95.2% (86.9% to 98.4%), corresponding sensitivities were 96.8% (89.0% to 99.1%), 45.2% (33.4% to 55.5%), and 36.1% (25.2% to 48.6%), respectively. The negative predictive values (NPV) for PET/CT, S100B, and MIA were 96.8% (89.1% to 99.1%), 61.4% (50.9% to 70.9%), and 60.6% (50.8% to 69.7%). The positive predictive values (PPV) were 96.7% (89.0% to 99.1%), 75.7% (59.9% to 86.6%), and 88.0% (70.0% to 95.8%). Patients with elevated S100B- or MIA values or PET/CT positive findings showed a significantly (p<0.001 each, univariate Cox regression models) higher risk of melanoma associated death which was increased 4.2-, 6.5- or 17.2-fold, respectively. [ABSTRACT FROM AUTHOR]

Purpose: (11)C-Choline-positron emission tomography (PET)/computed tomography (CT) is increasingly used in patients with prostate cancer. Another promising technique for assessment of tumor biology is diffusion-weighted MR imaging (DWI). The aim of the study was to compare the functional parameters standardized uptake value (SUV) in PET and apparent diffusion coefficient (ADC) value in DWI of lymph nodes in prostate cancer patients.Procedures: Fourteen patients with prostate cancer underwent DWI at 1.5T and (11)C-Choline-PET/CT. ADC values and SUVs of all lymph nodes larger than 5 mm (n = 55) were compared by using linear regression analysis. Performance of DWI and (11)C-Choline PET was assessed by receiver operator characteristic curve analysis using histopathology or clinical follow-up as standard of reference.Results: ADC values and SUV showed a moderate but highly significant inverse correlation (r = -0.5144, p < 0.0001). In lymph nodes with low ADC values, the dispersion of SUV was more pronounced. Moreover, a highly significant difference was observed for mean ADC values and SUV in lymph nodes considered as benign or malignant by follow-up/histopathology (ADC 1.60 ± 0.24 vs. 1.09 ± 0.23 × 10(-3) mm(2)/s; SUV 1.82 ± 0.57 vs. 4.68 ± 03.12; p < 0.0001, respectively).Conclusion: These pilot data propose the ADC value in DWI as a new potential imaging biomarker which might provide additional information on tumor pathophysiology compared to the SUV in (11)C-Choline PET/CT. [ABSTRACT FROM AUTHOR]

Abstract: Context: Choline positron emission tomography (PET)/computed tomography (CT) is a currently used diagnostic tool in restaging prostate cancer (PCa) patients with increasing prostate-specific antigen (PSA) after either radical prostatectomy (RP) or external-beam radiation therapy (EBRT). However, no final recommendations have been made on the use of this modality for patient management. Objective: To critically analyse the current evidence for the use of choline PET/CT scanning in the management of patients with a progressive increase in PSA after radical treatment for PCa, evaluating its diagnostic accuracy in the detection of recurrences, the clinical predictors of positive PET/CT examinations, and the modalities’ role as a guide for tailored therapeutic strategies. Evidence acquisition: Data on recently published (2003–2010) original articles, review articles, and editorials concerning the role of choline PET/CT in this scenario were analysed. Evidence synthesis: The diagnostic accuracy of choline PET in detecting sites of PCa relapse has been investigated by several authors, and the overall reported sensitivity ranges between 38% and 98%. It has been demonstrated that choline PET technology''s positive detection rate improves with increasing PSA values. The routine use of choline PET/CT cannot be recommended for PSA values <1ng/ml. However, in addition to PSA serum value, PSA doubling time (PSA DT), and other clinical and pathologic features—including locally advanced tumour (pT3b–T4) or lymph node involvement at initial staging—should be considered to refer patients to choline PET/CT study. Choline PET/CT may be also proposed as a image guide either for experimental surgical or radiation therapy treatments. Conclusions: According to the current available data, choline PET/CT plays a role in the management of biochemical relapse. Its accuracy is correlated to PSA value, PSA DT, and other pathologic features. Choline PET/CT may be proposed as a guide for individualised treatment of recurrence. [Copyright &y& Elsevier]

Caffeine has been consumed since ancient times due to its beneficial effects on attention, psychomotor function, and memory. Caffeine exerts its action mainly through an antagonism of cerebral adenosine receptors, although there are important secondary effects on other neurotransmitter systems. Recently, functional MRI (fMRI) entered the field of neuropharmacology to explore the intracerebral sites and mechanisms of action of pharmacological agents. However, as caffeine possesses vasoconstrictive properties it may interfere with the mechanisms underlying the functional contrast in fMRI. Yet, only a limited number of studies dealt with the effect of caffeine on measures in fMRI. Even fewer neuroimaging studies examined the effects that caffeine exerts on cognition: Portas and colleagues used fMRI in an attentional task under different levels of arousal (sleep deprivation or caffeine administration), concluding that the thalamus is involved in mediating the interaction of attention and arousal. Bendlin and colleagues found caffeine to stabilize the extent of neuronal activation in repetitive word stem completion, counteracting the general task practice effect. Recently, Koppelstaetter and colleagues assessed the effect of caffeine on verbal working memory demonstrating a modulatory effect of caffeine on brain regions (medial frontopolar and anterior cingulate cortex) that have been associated with attentional and executive functions. This review surveys and discusses neuroimaging findings on 1) how caffeine affects the contrast underlying fMRI techniques, particularly the blood oxygen level dependent contrast (BOLD fMRI), and 2) how caffeine operates on neuronal activity underlying cognition, to understand the effect of caffeine on behavior and its neurobiological underpinnings. [ABSTRACT FROM AUTHOR]

Abstract: In working memory (WM), functional imaging studies demonstrate cerebellar involvement indicating a cognitive role of the cerebellum. These cognitive contributions were predominantly interpreted as part of the phonological loop within the Baddeley model of WM. However, those underlying investigations were performed in the context of visual verbal WM which could pose a bias when interpreting the results. The aim of this fMRI study was to address the question of whether the cerebellum supports additional aspects of WM in the context of higher cognitive functions. Furthermore, laterality effects were investigated to further disentangle the cerebellar role in the context of the phonological loop and the visuospatial sketchpad. A direct comparison of verbal and abstract visual WM was performed in 17 young volunteers by applying a 2-back paradigm and extracting the % change in BOLD signal from the fMRI data. To minimize potential verbal strategies, Attneave and Arnoult shapes of non-nameable objects were chosen for the abstract condition. The analyses revealed no significant differences in verbal vs. abstract WM. Moreover, no laterality effects were demonstrated in both verbal and abstract WM. These results provide further evidence of a broader cognitive involvement of the cerebellum in WM that is not only confined to the phonological loop but also supports central executive subfunctions. The fact that no lateralization effects are found might be attributed to the characteristics of the n-back paradigm which emphasizes central executive subfunctions over the subsidiary slave systems. [Copyright &y& Elsevier]

Abstract: Previous functional activation studies in patients with aphasia have mostly relied on standard group comparisons of aphasic patients with healthy controls, which are biased towards regions showing the most consistent effects and disregard variability within groups. Groups of aphasic patients, however, show considerable variability with respect to lesion localisation and extent. Here, we use a novel method, joint independent component analysis (jICA), which allowed us to investigate abnormal patterns of functional activation with O15-PET during lexical decision in aphasic patients after middle cerebral artery stroke and to directly relate them to lesion information from structural MRI. Our results demonstrate that with jICA we could detect a network of compensatory increases in activity within bilateral anterior inferior temporal areas (BA20), which was not revealed by standard group comparisons. In addition, both types of analyses, jICA and group comparison, showed increased activity in the right posterior superior temporal gyrus in aphasic patients. Further, whereas standard analyses revealed no decreases in activation, jICA identified that left perisylvian lesions were associated with decreased activation of left posterior inferior frontal cortex, damaged in most patients, and extralesional remote decreases of activity within polar parts of the inferior temporal gyrus (BA38/20) and the occipital cortex (BA19). Taken together, our results demonstrate that jICA may be superior in revealing complex patterns of functional reorganisation in aphasia. [Copyright &y& Elsevier]

Choline derivatives labelled with positron emitters are successfully used for PET imaging of prostate cancer patients. Since little is known about uptake mechanisms, the aim of this study was to characterize choline uptake in prostate cancer cells, also following anti-androgen treatment or chemotherapy. Choline uptake in prostate cancer cells (LNCaP, PC-3) and Michaelis-Menten kinetics were analysed using different concentrations of 3H-choline via liquid scintillation counting. Inhibition of 3H-choline uptake was assayed in the presence of hemicholinium-3 (HC-3), unlabelled choline, guanidine and tetraethylammonium (TEA), an inhibitor of the organic cation transporter (OCT). Changes in choline uptake triggered by bicalutamide and docetaxel were evaluated and choline transporters were detected via Western blotting. Michaelis-Menten kinetics yielded a saturable transport with Km values of 6.9 and 7.0 µmol/l choline for LNCaP and PC-3 cells, respectively. Treatment of cells with bicalutamide and docetaxel caused an increase in total choline uptake but had no significant effect on Km values. Uptake of 3H-choline was NaCl dependent and 4.5-fold higher in LNCaP cells than in PC-3 cells. 3H-Choline uptake was reduced by 92–96% using HC-3 and unlabelled choline, by 63–69% using guanidine and by 20% using TEA. The high-affinity choline transporter was detected via Western blotting. Choline uptake in prostate cancer cells is accomplished both by a transporter-mediated and a diffusion-like component. Results of inhibition experiments suggest that uptake is mediated by a selective choline transporter rather than by the OCT. Bicalutamide- and docetaxel-induced changes in total choline uptake could affect PET tumour imaging. [ABSTRACT FROM AUTHOR]

Purpose: To assess a threshold for Gluc-Lys[(18)F]-TOCA positron emission tomography (PET) in target volume delineation of glomus tumors in the skull base and to compare with MRI-based target volume delineation. Methods and Materials: The threshold for volume segmentation in the PET images was determined by a phantom study. Nine patients with a total of 11 glomus tumors underwent PET either with Gluc-Lys[(18)F]-TOCA or with (68)Ga-DOTATOC (in 1 case). All patients were additionally scanned by MRI. Positron emission tomography and MR images were transferred to a treatment-planning system; MR images were analyzed for lesion volume by two observers, and PET images were analyzed by a semiautomated thresholding algorithm. Results: Our phantom study revealed that 32% of the maximum standardized uptake value is an appropriate threshold for tumor segmentation in PET-based target volume delineation of gross tumors. Target volume delineation by MRI was characterized by high interobserver variability. In contrast, interobserver variability was minimal if fused PET/MRI images were used. The gross tumor volumes (GTVs) determined by PET (GTV-PET) showed a statistically significant correlation with the GTVs determined by MRI (GTV-MRI) in primary tumors; in recurrent tumors higher differences were found. The mean GTV-MRI was significantly higher than mean GTV-PET. The increase added by MRI to the common volume was due to scar tissue with strong signal enhancement on MRI. Conclusions: In patients with glomus tumors, Gluc-Lys[(18)F]-TOCA PET helps to reduce interobserver variability if an appropriate threshold for tumor segmentation has been determined for institutional conditions. Especially in patients with recurrent tumors after surgery, Gluc-Lys[(18)F]-TOCA PET improves the accuracy of GTV delineation. [ABSTRACT FROM AUTHOR]

Purpose: To assess a threshold for Gluc-Lys[18F]-TOCA positron emission tomography (PET) in target volume delineation of glomus tumors in the skull base and to compare with MRI-based target volume delineation. Methods and Materials: The threshold for volume segmentation in the PET images was determined by a phantom study. Nine patients with a total of 11 glomus tumors underwent PET either with Gluc-Lys[18F]-TOCA or with 68Ga-DOTATOC (in 1 case). All patients were additionally scanned by MRI. Positron emission tomography and MR images were transferred to a treatment-planning system; MR images were analyzed for lesion volume by two observers, and PET images were analyzed by a semiautomated thresholding algorithm. Results: Our phantom study revealed that 32% of the maximum standardized uptake value is an appropriate threshold for tumor segmentation in PET-based target volume delineation of gross tumors. Target volume delineation by MRI was characterized by high interobserver variability. In contrast, interobserver variability was minimal if fused PET/MRI images were used. The gross tumor volumes (GTVs) determined by PET (GTV-PET) showed a statistically significant correlation with the GTVs determined by MRI (GTV-MRI) in primary tumors; in recurrent tumors higher differences were found. The mean GTV-MRI was significantly higher than mean GTV-PET. The increase added by MRI to the common volume was due to scar tissue with strong signal enhancement on MRI. Conclusions: In patients with glomus tumors, Gluc-Lys[18F]-TOCA PET helps to reduce interobserver variability if an appropriate threshold for tumor segmentation has been determined for institutional conditions. Especially in patients with recurrent tumors after surgery, Gluc-Lys[18F]-TOCA PET improves the accuracy of GTV delineation. [Copyright &y& Elsevier]

Olfactory deficits occur as early non-motor symptoms of idiopathic Parkinson's disease (PD) in humans. The first central relay of the olfactory pathway, the olfactory bulb (OB), depends, among other things, on an intact, functional crosstalk between dopaminergic interneurons and dopamine receptors (D2/D3R). In rats, hemiparkinsonism (hemi-PD) can be induced by unilateral injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle (MFB), disrupting dopaminergic neurons of the substantia nigra pars compacta (SNpc). In a previous study, we showed that subsequent injection of botulinum neurotoxin-A (BoNT-A) into the striatum can reverse most of the pathological motor symptoms and normalize the D2/D3R availability. To determine whether this rat model is suitable to explain olfactory deficits that occur in humans with PD, we examined the availability of D2/D3R by longitudinal [18F]fallypride-PET/CT, the density of tyrosine hydroxylase immunoreactivity in the OB, olfactory performance by an orienting odor identification test adapted for rats, and a connectome analysis. PET/CT and immunohistochemical data remained largely unchanged after 6-OHDA lesion in experimental animals, suggesting that outcomes of the 6-OHDA hemi-PD rat model do not completely explain olfactory deficits in humans. However, after subsequent ipsilateral BoNT-A injection into the striatum, a significant 8.5% increase of the D2/D3R availability in the ipsilateral OB and concomitant improvement of olfactory performance were detectable. Based on tract-tracing meta-analysis, we speculate that this may be due to indirect connections between the striatum and the OB. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: To evaluate [11C]Choline positron emission tomography (PET)/computed tomography (CT) for staging and restaging of patients with advanced prostate cancer and to compare the diagnostic performance of PET, CT and PET/CT. Methods: Forty-five consecutive patients with advanced prostate cancer underwent [11C]Choline-PET/CT between 5/2004 and 2/2006. Results: Overall, 295 lesions were detected: PET alone, 178 lesions; diagnostic CT, 221 lesions; PET/CT (low-dose CT), 272 lesions; PET/CT (diagnostic CT), 295 lesions. Two thirds of the lesions were located in the bone; one third in the prostate, lymph nodes, periprostatic tissue and soft tissue (lung, liver). The use of diagnostic CT did not result in a statistically significant difference with respect to lesion localization certainty and lesion characterization (P=.063, P=.063). PET-negative but PET/CT-positive lesions were mostly localized in the bone (78%, 91/117) as were PET-positive and CT-negative lesions (72%, 53/74). Of the latter, 91% (48/53) represented bone marrow and 9% (5/53) cortical involvement. Conclusions: Staging and restaging with [11C]Choline PET/CT in patients with advanced prostate cancer improve the assessment of local and regional recurrent as well as metastatic disease including skeletal manifestations. [11C]Choline PET/CT (with a low-dose CT) results in improved localization and lesion characterization. [11C]Choline PET/CT provides an added value for skeletal manifestations. [11C]Choline PET/CT changed disease management in 11 (24%) of 45 patients with advanced prostate cancer. [Copyright &y& Elsevier]

Purpose: To evaluate the role of 11C-methionine positron emission tomography (MET-PET) in target volume delineation for meningiomas and to determine the interobserver variability. Methods and Materials: Two independent observers performed treatment planning in 10 patients according to a prospective written protocol. In the first step, they used coregistered computed tomography (CT) and magnetic resonance imaging (MRI). In the second step, MET-PET was added to CT/MRI (image fusion based on mutual information). Results: The correlation between gross tumor volume (GTVs) delineated by the two observers based on CT/MRI was r=0.855 (Spearman's correlation coefficient, p=0.002) and r=0.988 (p=0.000) when MET-PET/CT/MRI were used. The number of patients with agreement in more then 80% of the outlined volume increased with the availability of MET-PET from 1 in 10 to 5 in 10. The median volume of intersection between the regions delineated by two observers increased significantly from 69% (from the composite volume) to 79%, by the addition of MET-PET (p=0.005). The information of MET-PET was useful to delineate GTV in the area of cavernous sinus, orbit, and base of the skull. Conclusions: The hypothesis-generating findings of potential normal tissue sparing and reduced interobserver variability provide arguments for invasive studies of the correlation between MET-PET images and histologic tumor extension and for prospective trials of target volume delineation with CT/MRI/MET-PET image fusion. [ABSTRACT FROM AUTHOR]

Abstract: Cognitive control of alertness in unwarned situations (intrinsic alertness) relies on a predominantly right hemisphere cortical and subcortical network. In a previous functional activation study, we have demonstrated that this network comprises the anterior cingulate gyrus, the dorsolateral and polar frontal as well as the inferior parietal cortex, the thalamus and ponto-mesencephalic parts of the brain stem. The aim of this study was to study effective connectivity of this network by employing structural equation modeling. Fifteen right-handed male subjects participated in the PET study. The functional network showed stronger connectivity in the right hemisphere. Furthermore, there were strong effective connections between thalamus and brainstem on the one hand and between thalamus and anterior cingulate on the other. Our results suggest that the anterior cingulate functions as the central coordinating structure for the right hemispheric neural network of intrinsic alertness and that the anterior cingulate gyrus is modulated mainly by prefrontal and parietal cortex. [Copyright &y& Elsevier]

Abstract: Dissociations in the ability to produce words of different grammatical categories are well established in neuropsychology but have not been corroborated fully with evidence from brain imaging. Here we report on a PET study designed to reveal the anatomical correlates of grammatical processes involving nouns and verbs. German-speaking subjects were asked to produce either plural and singular nouns, or first-person plural and singular verbs. Verbs, relative to nouns, activated a left frontal cortical network, while the opposite contrast (nouns–verbs) showed greater activation in temporal regions bilaterally. Similar patterns emerged when subjects performed the task with pseudowords used as nouns or as verbs. These results converge with findings from lesion studies and suggest that grammatical category is an important dimension of organization for knowledge of language in the brain. [Copyright &y& Elsevier]

In this functional positron emission tomography study brain activations during an auditory lexical decision task with two experimental conditions were investigated. First, the subjects had to discriminate between real words and nonwords; second, real words varied with pseudowords. Comparing each of these tasks to an auditory control condition we found bilateral activation of the superior temporal and inferior frontal gyrus, lateralized to the left in the pseudoword condition. The comparison of the lexical decision tasks revealed higher rCBF during the pseudo-/real word decisions within BA 47, adjacent to Broca''s area, and the anterior cingulate. The data support the notion that the lexical decision during a nonword task is mainly based on a phonological discrimination process, whereas a pseudoword task more strongly requires lexical access resulting in activation of BA 47. [Copyright &y& Elsevier]

We investigated whether the brain–behavior relationship (BBR) between regional cerebral blood flow (rCBF) as measured by positron emission tomography (PET) and individual accuracy in verbal working memory (WM) can be modulated by repetitive transcranial magnetic stimulation (rTMS) of the left or right middle frontal gyrus (MFG). Fourteen right-handed male subjects received a 30-s rTMS train (4 Hz, 110% motor threshold) to the left or right MFG during a 2-back WM task using letters as stimuli. Simultaneously an rCBF PET tracer was injected and whole-brain functional images were acquired. A hypothesis-driven region-of-interest-analysis of the left and right MFG BBR as well as an explorative whole-brain analysis correlating the individual accuracy with rCBF was carried out. Without rTMS we found a negative BBR in the left but no significant BBR in the right MFG. This negative BBR is best explained by an increased effort of volunteers with an inferior task performance. Left-sided rTMS led to a shift of the BBR towards the superior frontal gyrus (SFG) and to a positive BBR in anterior parts of the left SFG. With rTMS of the right MFG the BBR was posterior and inferior in the left inferior frontal gyrus. Beyond the cognitive subtraction approach this correlation analysis provides information on how the prefrontal cortex is involved based on individual performance in working memory. The results are discussed along the idea of a short-term plasticity in an active neuronal network that reacts to an rTMS-induced temporary disruption of two different network modules. [Copyright &y& Elsevier]

Abstract Verbal working memory has been attributed to a left-dominant neuronal network, including parietal, temporal and prefrontal cortical areas. The current study was designed to evaluate the contribution of these brain regions to verbal working memory processes and to assess possible hemispheric asymmetry. The effect of repetitive transcranial stimulation (rTMS) on performance in a verbal working memory task both during, and after an rTMS train (110% of individual motor threshold, 4 Hz) over nine different scalp locations was studied [bilateral middle frontal gyrus (MFG), bilateral supramarginal gyrus (SMG), bilateral inferior parietal cortex (IP) and three different midline control sites]. Significant performance deterioration was observed during rTMS over the left and right MFG and left and right IP. There was no consistent interference effect across subjects over the left or right SMG and the three different midline control sites. The interference effect with the given stimulation parameters did not last beyond the rTMS train itself. The data provide evidence for a symmetrical, bilateral parieto-frontal verbal working memory network. The data are discussed with respect to the competing ideas of a parieto-frontal central executive network vs . a network that processes the inherent semantic and object features of the visually presented verbal stimuli in parallel. [ABSTRACT FROM AUTHOR]

Simple Summary: In patients with progressive metastasized castration-resistance prostate cancer PSMA radioligand therapies have shown promising results regarding clinical safety and efficacy. Dosimetry is mandatory due to legal regulations and also required for the estimation of doses to organs at risk allowing for individual tailoring of treatment in PSMA-RLT. Due to those factors and the often poor health status of patients which restricts intense dosimetric imaging protocols, there is a clear need for simplified dosimetric approaches in mCRPC patients treated with [177Lu]Lu-PSMA-617. In this study, we evaluated different dosimetric methodologies and found that a streamlined dosimetric approach is feasible and valid. This approach is based on single time-point imaging at 48 h p.i. in cycle 2 to 6 taking into account kinetic results of a full dosimetric scheme performed only in cycle1. These results might have a relevant impact on patients handling regarding dosimetry during [177Lu]Lu-PSMA-617 radioligand therapy. (Background) Aim of this retrospective analysis was to investigate in mCRPC patients treated with [177Lu]Lu-PSMA-617 whether the absorbed dose (AD) in organs at risk (OAR, i.e., kidneys and parotid glands) can be calculated using simplified methodologies with sufficient accuracy. For this calculation, results and kinetics of the first therapy cycle were used. (Methods) 46 patients treated with 2 to 6 cycles of [177Lu]Lu-PSMA-617 were included. As reference (current clinical standard) full dosimetry of the OAR based on quantitative imaging (whole body scintigraphy and quantitative SPECT/CT at 2, 24, 48 and 72 h p.i.) for every cycle was used. Alternatively, two dosimetry schemes, simplified in terms of image acquisition and dose calculation, were established, both assuming nearly unchanged kinetics of the radiopharmaceutical for subsequent cycles. (Results) In general, for both OAR the simplified methods provided results that were consistent with the dosimetric reference method, both per cycle and in terms of cumulative AD. Best results were obtained when imaging was performed at 48 h p.i. in each of the subsequent cycles. However, both simplified methods tended to underestimate the cumulative AD. (Conclusion) Simplified dosimetry schemes are feasible to tailor multi-cycle [177Lu]Lu-PSMA-targeted therapies. [ABSTRACT FROM AUTHOR]

Simple Summary: Skin cancer still poses a great burden for patients. One of the most promising therapy approaches in recent years is cold atmospheric pressure plasma. The aim of the study was to assess in vivo the effect of cold atmospheric pressure plasma on human squamous cell carcinoma as well as malignant melanoma tumour cell lines in a longitudinal and non-invasive manner with multimodal imaging techniques such as MRI and [18F]FDG PET. By using these techniques and chemiluminescence imaging, we present in the current study that reactive species increase in vivo upon treatment with cold plasma and consequently decrease tumour growth. Therefore, we propose cold atmospheric pressure plasma may be a potential adjuvant therapy option to established standard therapies of skin cancer. Background: Skin cancer is the most frequent cancer worldwide and is divided into non-melanoma skin cancer, including basal cell carcinoma, as well as squamous cell carcinoma (SCC) and malignant melanoma (MM). Methods: This study evaluates the effects of cold atmospheric pressure plasma (CAP) on SCC and MM in vivo, employing a comprehensive approach using multimodal imaging techniques. Longitudinal MR and PET/CT imaging were performed to determine the anatomic and metabolic tumour volume over three-weeks in vivo. Additionally, the formation of reactive species after CAP treatment was assessed by non-invasive chemiluminescence imaging of L-012. Histological analysis and immunohistochemical staining for Ki-67, ApopTag®, F4/80, CAE, and CD31, as well as protein expression of PCNA, caspase-3 and cleaved-caspase-3, were performed to study proliferation, apoptosis, inflammation, and angiogenesis in CAP-treated tumours. Results: As the main result, multimodal in vivo imaging revealed a substantial reduction in tumour growth and an increase in reactive species after CAP treatment, in comparison to untreated tumours. In contrast, neither the markers for apoptosis, nor the metabolic activity of both tumour entities was affected by CAP. Conclusions: These findings propose CAP as a potential adjuvant therapy option to established standard therapies of skin cancer. [ABSTRACT FROM AUTHOR]

Schistosomiasis represents one of the most devastating worm parasitosis in the world. Current diagnostic methods are insufficient to determine the infection grade and the disease related organ damage. We herein investigated whether discrimination of infection grade and its correlation to liver damage could be accurately performed by multimodal imaging in a mouse model of Schistosoma mansoni infection. Therefore, groups of uninfected and infected mice underwent MRI and [18F]FDG PET/CT imaging. Anatomical MRI images were used for liver volumetry and for quantification of hepatic granulomas. For PET/CT images a volume of interest based analyses were employed to calculate the [18F]FDG uptake in liver, portal vein, spleen and abdomen. Herein, we demonstrate that the combined use of [18F]FDG-PET/CT and MRI represents an appropriate diagnostic tool for Schistosoma mansoni infection, but fails to discriminate the infection grade and the linked organ damage. Only the splenic [18F]FDG uptake in the 25 cercariae group (5.68 ± 0.90%ID/cc) and 50 cercariae group (4.98 ± 1.43%ID/cc) was significantly higher compared to the control group (2.13 ± 0.69%ID/cc). Nevertheless, future multimodal imaging studies with new radiopharmaceuticals could build a highly sensitive and specific basis for the diagnosis and evaluation of organ damage of schistosomiasis. [ABSTRACT FROM AUTHOR]

Background: Strong line of evidence suggests that the increased risk to develop AD may at least be partly mediated by cholesterol metabolism. A key regulator of cholesterol transport is the Apolipoprotein E4 (ApoE4), which plays a fundamental role in neuronal maintenance and repair. Impaired function of ApoE4 may contribute to altered cerebral metabolism leading to higher susceptibility to neurodegeneration. Methods: To determine a possible link between ApoE function and alterations in AD in the brain of Apolipoprotein E-deficient mice (ApoE−/−) in a longitudinal manner metabolic and neurochemical parameters were analyzed. Cortical metabolism was measured by 2-deoxy-2-[18F]fluoroglucose ([18F]FDG)-PET/CT and proton magnetic resonance spectroscopy (1H-MRS) served to record neurochemical status. Results: By using [18F]FDG-PET/CT, we showed that brain metabolism declined significantly stronger with age in ApoE−/− versus wild type (wt) mice. This difference was particularly evident at the age of 41 weeks in almost each analyzed brain region. In contrast, the 1H-MRS-measured N-acetylaspartate to creatine ratio, a marker of neuronal viability, did not decline with age and did not differ between ApoE−/− and wt mice. Conclusion: In summary, this longitudinal in vivo study shows for the first time that ApoE−/− mice depict cerebral hypometabolism without neurochemical alterations. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is a genetically heterogeneous cancer entity that causes challenges in pre-treatment clinical evaluation, such as the correct identification of the tumor stage. Conventional clinical tests based on digital rectal examination, Prostate-Specific Antigen (PSA) levels, and Gleason score still lack accuracy for stage prediction. We hypothesize that unraveling the molecular mechanisms underlying PCa staging via integrative analysis of multi-OMICs data could significantly improve the prediction accuracy for PCa pathological stages. We present a radiogenomic approach comprising clinical, imaging, and two genomic (gene and miRNA expression) datasets for 298 PCa patients. Comprehensive analysis of gene and miRNA expression profiles for two frequent PCa stages (T2c and T3b) unraveled the molecular characteristics for each stage and the corresponding gene regulatory interaction network that may drive tumor upstaging from T2c to T3b. Furthermore, four biomarkers (ANPEP, mir-217, mir-592, mir-6715b) were found to distinguish between the two PCa stages and were highly correlated (average r = ± 0.75) with corresponding aggressiveness-related imaging features in both tumor stages. When combined with related clinical features, these biomarkers markedly improved the prediction accuracy for the pathological stage. Our prediction model exhibits high potential to yield clinically relevant results for characterizing PCa aggressiveness. [ABSTRACT FROM AUTHOR]

Purpose: To analyze the contribution of Wnt signaling pathway to bladder cancer growth in order to identify suitable target molecules for therapy.Material and Methods: Expression of Wnt 2/4/7, LRP5/6, TCF1/2/4, LEF-1, and β-actin was detected by reverse transcription polymerase chain reaction in a panel of 9 and for Wntless (WLS) in 17 bladder cancer cell lines. Protein expression of WLS was detected in 6 cell lines. Wnt/β-catenin activity was analyzed using the TOPflash/FOPflash luciferase reporter assay. Expression level of β-catenin, WIF1, Dickkopf proteins (DKK), HSulf-2, sFRP4, and WLS was modulated by transfecting or infecting cells transiently or stably with respective shRNAs, siRNAs, or cDNAs. For protein detection, whole cell lysates were applied to sodium dodecyl sulfate polyacrylamide gel electrophoresis followed by immunoblots. Effects on cell growth were determined by cell viability assays and BrdU/APC incorporation/staining. For 3-dimensional tumor growth, the chicken chorioallantoic membrane model was used. Tumor growth was characterized by weight.Results: Expression of molecular components and activation of the Wnt signaling pathway could be detected in all cell lines. Expression level of β-catenin, WIF1, DKK, WLS, and HSulf-2 influenced Wnt activity. Expression of WLS was confirmed in 17 cell lines by reverse transcription polymerase chain reaction and in 6 cell lines by immunoblotting. WLS positively regulates Wnt signaling, cell proliferation, and tumor growth in vitro and in vivo. These effects could be reversed by the expression of the Wnt antagonist WIF1 and DKK. Synergistic activity of cisplatin and WLS inactivation by genetic silencing could be observed on cell viability.Conclusion: The Wnt signaling pathway is ubiquitously activated in bladder cancer and regulates tumor growth. WLS might be a target protein for novel therapies in combination with established chemotherapy regimens. [ABSTRACT FROM AUTHOR]