PET imaging of urokinase-type plasminogen activator receptor (uPAR) in prostate cancer:current status and future perspectives

Overexpression of urokinase-type plasminogen activator receptors (uPAR) represents an important biomarker for aggressiveness in most common malignant diseases, including prostate cancer (PC). Accordingly, uPAR expression either assessed directly in malignant PC tissue or assessed directly in plasma (intact/cleaved forms)—provides independent additional clinical information to that contributed by PSA, Gleason score, and other relevant pathological and clinical parameters. In this respect, non-invasive molecular imaging by positron emission tomography (PET) offers a very attractive technology platform, which can provide the required quantitative information on the uPAR expression profile, without the need for invasive procedures and the risk of missing the target due to tumor heterogeneity. These observations support non-invasive PET imaging of uPAR in PC as a clinically relevant diagnostic and prognostic imaging method. In this review, we will focus on the recent development of uPAR PET and the relevance within prostate cancer imaging. Novel antibody and small-molecule radiotracers-targeting uPAR, including a series of uPAR-targeting PET ligands, based on the high affinity peptide ligand AE105, have been synthesized and tested in vitro and in vivo in preclinical murine xenograft models and, recently, in a first-ever clinical uPAR PET study in cancer patients, including patients with PC. In this phase I study, a high and specific uptake of the tracer (64)Cu-DOTA-AE105 was found in both primary tumors and lymph node metastases. The results are encouraging and support large-scale clinical trials to determine the utility of uPAR PET in the management of patients with PC with the goal of improving outcome

Early-Onset Schizophrenia: Exploring the Contribution of the Thought Disorder Index to Clinical Assessment

Background: Differentiating diagnostically between schizophrenia and emotional and personality disorders with psychotic or psychotic-like symptoms is a challenging task. It is especially difficult when working with adolescent patients, because their symptoms tend to manifest at lower levels as compared with adult patients. Thought disorder is a core symptom of schizophrenia, and the Rorschach Inkblot Method is widely used for the assessment of formal thought disorder. Objective: In this study, which is situated within ongoing clinical practice, we investigated whether the Rorschach test is helpful for assessing early-onset schizophrenia due to its ability to detect thought disorder. We also wanted to examine whether the Thought Disorder Index (TDI) is superior to the Comprehensive System (CS) for differentiating between patients with early-onset schizophrenia and non-psychotic patients experiencing auditory and visual hallucinations. An additional aim was to examine whether the TDI correlated with the Positive and Negative Syndrome Scale (PANSS). Methods: Twenty-three subjects between the ages of 12 and 18 years were examined with the use of the Rorschach test, and the protocols were scored according to both the TDI and the CS. All subjects were also assessed with the Positive and Negative Syndrome Scale. The sample included 14 subjects who fulfilled the criteria for schizophrenia and 9 subjects who were experiencing hallucinations that emanated from severe emotional and relational problems but who had different non-psychotic disorders. Results: Although the two groups could not be distinguished with regard to their total scores for thought disorder, the identification of specific thought disorder types proved useful for differential diagnosis. Verbalizations that were categorized by the TDI as “absurd responses,” “fluidity,” “contamination,” “autistic logic,” and “word-finding difficulty” were only given by patients who had been diagnosed with schizophrenia. When patients’ responses were scored with the use of the CS, the “contamination” score was the only one found to be specific to schizophrenia. Conclusions: Although the sample size limits the conclusions that can be drawn, the results indicate that the TDI may be superior to the CS for the identification of thought disorder specific to—but not always present in—adolescents with schizophrenia. In other words, the absence of severe thought disorder is not synonymous with the absence of severe psychopathology, but the presence of the most severe thought disorder types (i.e., “absurd responses,” “fluidity,” “incoherence,” “contamination,” and “autistic logic”) seems to be a strong indicator of schizophrenic psychopathology

An advanced glycation endproduct (AGE)-rich diet promotes accumulation of AGEs in Achilles tendon

Advanced Glycation Endproducts (AGEs) accumulate in long‐lived tissue proteins like collagen in bone and tendon causing modification of the biomechanical properties. This has been hypothesized to raise the risk of orthopedic injury such as bone fractures and tendon ruptures. We evaluated the relationship between AGE content in the diet and accumulation of AGEs in weight‐bearing animal Achilles tendon. Two groups of mice (C57BL/6Ntac) were fed with either high‐fat diet low in AGEs high‐fat diet (HFD) (n = 14) or normal diet high in AGEs (ND) (n = 11). AGE content in ND was six to 50‐fold higher than HFD. The mice were sacrificed at week 40 and Achilles and tail tendons were carefully excised to compare weight and nonweight‐bearing tendons. The amount of the AGEs carboxymethyllysine (CML), methylglyoxal‐derived hydroimidazolone (MG‐H1) and carboxyethyllysine (CEL) in Achilles and tail tendon was measured using ultraperformance liquid chromatography tandem mass spectrometry (UPLC‐MS/MS) and pentosidine with high‐pressure liquid chromatography (HPLC) with fluorescent detection. AGEs in Achilles tendon were higher than in tail tendon for CML (P < 0.0001), CEL (P < 0.0001), MG‐H1 and pentosidine (for both ND and HFD) (P < 0.0001). The AGE‐rich diet (ND) resulted in an increase in CML (P < 0.0001), MG‐H1 (P < 0.001) and pentosidine (P < 0.0001) but not CEL, in Achilles and tail tendon. This is the first study to provide evidence for AGE accumulation in injury‐prone, weight‐bearing Achilles tendon associated with intake of an AGE‐rich diet. This indicates that food‐derived AGEs may alter tendon properties and the development of tendon injuries

Estimating and reporting treatment effects in clinical trials for weight management: using estimands to interpret effects of intercurrent events and missing data

In the approval process for new weight management therapies, regulators typically require estimates of effect size. Usually, as with other drug evaluations, the placebo-adjusted treatment effect (i.e., the difference between weight losses with pharmacotherapy and placebo, when given as an adjunct to lifestyle intervention) is provided from data in randomized clinical trials (RCTs). At first glance, this may seem appropriate and straightforward. However, weight loss is not a simple direct drug effect, but is also mediated by other factors such as changes in diet and physical activity. Interpreting observed differences between treatment arms in weight management RCTs can be challenging; intercurrent events that occur after treatment initiation may affect the interpretation of results at the end of treatment. Utilizing estimands helps to address these uncertainties and improve transparency in clinical trial reporting by better matching the treatment-effect estimates to the scientific and/or clinical questions of interest. Estimands aim to provide an indication of trial outcomes that might be expected in the same patients under different conditions. This article reviews how intercurrent events during weight management trials can influence placebo-adjusted treatment effects, depending on how they are accounted for and how missing data are handled. The most appropriate method for statistical analysis is also discussed, including assessment of the last observation carried forward approach, and more recent methods, such as multiple imputation and mixed models for repeated measures. The use of each of these approaches, and that of estimands, is discussed in the context of the SCALE phase 3a and 3b RCTs evaluating the effect of liraglutide 3.0 mg for the treatment of obesity

Use of Cis-[18F]Fluoro-Proline for Assessment of Exercise-Related Collagen Synthesis in Musculoskeletal Connective Tissue

Protein turnover in collagen rich tissue is influenced by exercise, but can only with difficulty be studied in vivo due to use of invasive procedure. The present study was done to investigate the possibility of applying the PET-tracer, cis-[18F]fluoro-proline (cis-Fpro), for non-invasive assessment of collagen synthesis in rat musculoskeletal tissues at rest and following short-term (3 days) treadmill running. Musculoskeletal collagen synthesis was studied in rats at rest and 24 h post-exercise. At each session, rats were PET scanned at two time points following injection of cis-FPro: (60 and 240 min p.i). SUV were calculated for Achilles tendon, calf muscle and tibial bone. The PET-derived results were compared to mRNA expression of collagen type I and III. Tibial bone had the highest SUV that increased significantly (p<0.001) from the early (60 min) to the late (240 min) PET scan, while SUV in tendon and muscle decreased (p<0.001). Exercise had no influence on SUV, which was contradicted by an increased gene expression of collagen type I and III in muscle and tendon. The clearly, visible uptake of cis-Fpro in the collagen-rich musculoskeletal tissues is promising for multi-tissue studies in vivo. The tissue-specific differences with the highest basal uptake in bone are in accordance with earlier studies relying on tissue incorporation of isotopic-labelled proline. A possible explanation of the failure to demonstrate enhanced collagen synthesis following exercise, despite augmented collagen type I and III transcription, is that SUV calculations are not sensitive enough to detect minor changes in collagen synthesis. Further studies including kinetic compartment modeling must be performed to establish whether cis-Fpro can be used for non-invasive in-vivo assessment of exercise-induced changes in musculoskeletal collagen synthesis

BNP predicts chemotherapy-related cardiotoxicity and death:comparison with gated equilibrium radionuclide ventriculography

UNLABELLED:Cardiotoxicity is a dose-limiting side-effect of cancer chemotherapeutics such as anthracyclines. The drug-induced cardiac toxicity is currently monitored with repeated assessments of the left ventricular ejection fraction (LVEF) using multigated equilibrium radionuclide ventriculography (MUGA) or echocardiography. However, the plasma cardiac biomarker B-type natriuretic peptide (BNP) has been suggested for early identification of cardiac dysfunction. The aim of the study was to compare LVEF obtained by MUGA and plasma BNP as predictors of developing congestive heart failure (CHF) or death in a population of anthracycline-treated cancer patients. METHODS:We prospectively followed 333 cancer patients referred to our department for routine monitoring of LVEF with MUGA and measurement of BNP, January-December 2004. Study end points were hospitalization for CHF and death during follow-up 2004-2010. Data were obtained from the Danish National Patient Registry. RESULTS:During follow-up (mean 1,360 days), 21 of the patients were admitted to hospital with a diagnosis of CHF and 194 of the patients died. BNP levels were significantly higher and LVEF lower in the group of patients that developed CHF. Using cut-off points of BNP>100 pg/ml (HR 5.5; CI 1.8-17.2; p = 0.003) and LVEF <50% (HR 7.9; CI 3.0-21.4; p<0.001) both significantly predicted CHF. Using the same cut-off points only BNP (HR 1.9; CI 1.3-2.9; p = 0.002) and not LVEF (HR 1.1; CI 0.7-1.8; p = 0.58) was predictive of overall death. In multivariate Cox analysis both BNP and LVEF were independent predictors of CHF while age remained the only independent predictor of overall death. CONCLUSION:In cancer patients treated with cardiotoxic chemotherapy both BNP and LVEF can significantly predict subsequent hospitalization with CHF. In addition, BNP and not LVEF has a prognostic value in detecting overall death. This prospective study based on the hitherto largest study population supports BNP as a clinical relevant method for monitoring chemotherapy-related cardiac failure and death