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Background: The prostate-specific membrane antigen (PSMA) is a relevant target in prostate cancer, and immunohistochemistry studies showed associations with outcome. PSMA-ligand positron emission tomography (PET) is increasingly used for primary prostate cancer staging, and the molecular imaging TNM classification (miTNM) standardizes its reporting. We aimed to investigate the potential of PET-imaging to serve as a noninvasive imaging biomarker to predict disease outcome in primary prostate cancer after radical prostatectomy (RP). Methods: In this retrospective analysis, 186 primary prostate cancer patients treated with RP who had undergone a 68Ga-PSMA-11 PET up to three months prior to the surgery were included. Maximum standardized uptake value (SUVmax), SUVmean, tumor volume (TV) and total lesion (TL) were collected from PET-imaging. Moreover, clinicopathological information, including age, serum prostate-specific antigen (PSA) level, and pathological characteristics, was assessed for disease outcome prediction. A stage group system for PET-imaging findings based on the miTNM framework was developed. Results: At a median follow-up after RP of 38 months (interquartile range (IQR) 22–53), biochemical recurrence (BCR) was observed in 58 patients during the follow-up period. A significant association between a positive surgical margin and miN status (miN1 vs. miN0, odds ratio (OR): 5.428, p = 0.004) was detected. miT status (miT ≥ 3a vs. miT < 3, OR: 2.696, p = 0.003) was identified as an independent predictor for Gleason score (GS) ≥ 8. Multivariate Cox regression analysis indicated that PSA level (hazard ratio (HR): 1.024, p = 0.014), advanced GS (GS ≥ 8 vs. GS < 8, HR: 3.253, p < 0.001) and miT status (miT ≥ 3a vs. miT < 3, HR: 1.941, p = 0.035) were independent predictors for BCR. For stage I disease as determined by PET-imaging, a shorter BCR-free survival was observed in the patients with higher SUVmax (IA vs. IB stage, log-rank, p = 0.022). Conclusion: Preoperative miTNM classification from 68Ga-PSMA-11 PET correlates with postoperative GS, surgical margin status and time to BCR. The association between miTNM staging and outcome proposes 68Ga-PSMA-11 PET as a novel non-invasive imaging biomarker and potentially serves for ancillary pre-treatment stratification. [ABSTRACT FROM AUTHOR]

Background: The prostate-specific membrane antigen (PSMA) is a relevant target in prostate cancer, and immunohistochemistry studies showed associations with outcome. PSMA-ligand positron emission tomography (PET) is increasingly used for primary prostate cancer staging, and the molecular imaging TNM classification (miTNM) standardizes its reporting. We aimed to investigate the potential of PET-imaging to serve as a noninvasive imaging biomarker to predict disease outcome in primary prostate cancer after radical prostatectomy (RP). Methods: In this retrospective analysis, 186 primary prostate cancer patients treated with RP who had undergone a 68Ga-PSMA-11 PET up to three months prior to the surgery were included. Maximum standardized uptake value (SUVmax), SUVmean, tumor volume (TV) and total lesion (TL) were collected from PET-imaging. Moreover, clinicopathological information, including age, serum prostate-specific antigen (PSA) level, and pathological characteristics, was assessed for disease outcome prediction. A stage group system for PET-imaging findings based on the miTNM framework was developed. Results: At a median follow-up after RP of 38 months (interquartile range (IQR) 22–53), biochemical recurrence (BCR) was observed in 58 patients during the follow-up period. A significant association between a positive surgical margin and miN status (miN1 vs. miN0, odds ratio (OR): 5.428, p = 0.004) was detected. miT status (miT ≥ 3a vs. miT < 3, OR: 2.696, p = 0.003) was identified as an independent predictor for Gleason score (GS) ≥ 8. Multivariate Cox regression analysis indicated that PSA level (hazard ratio (HR): 1.024, p = 0.014), advanced GS (GS ≥ 8 vs. GS < 8, HR: 3.253, p < 0.001) and miT status (miT ≥ 3a vs. miT < 3, HR: 1.941, p = 0.035) were independent predictors for BCR. For stage I disease as determined by PET-imaging, a shorter BCR-free survival was observed in the patients with higher SUVmax (IA vs. IB stage, log-rank, p = 0.022). Conclusion: Preoperative miTNM classification from 68Ga-PSMA-11 PET correlates with postoperative GS, surgical margin status and time to BCR. The association between miTNM staging and outcome proposes 68Ga-PSMA-11 PET as a novel non-invasive imaging biomarker and potentially serves for ancillary pre-treatment stratification. [ABSTRACT FROM AUTHOR]

Introduction: The radiohybrid (rh) prostate-specific membrane antigen (PSMA)-targeted ligand [18F]Ga-rhPSMA-7 has previously been clinically assessed and demonstrated promising results for PET-imaging of prostate cancer. The ligand is present as a mixture of four stereoisomers ([18F]Ga-rhPSMA-7.1, − 7.2, − 7.3 and − 7.4) and after a preclinical isomer selection process, [18F]Ga-rhPSMA-7.3 has entered formal clinical trials. Here we report on the establishment of a fully automated production process for large-scale production of [18F]Ga-rhPSMA-7/ -7.3 under GMP conditions (EudraLex). Methods: [18F]Fluoride in highly enriched [18O]H2O was retained on a strong anion exchange cartridge, rinsed with anhydrous acetonitrile and subsequently eluted with a solution of [K+ ⊂ 2.2.2]OH− in anhydrous acetonitrile into a reactor containing Ga-rhPSMA ligand and oxalic acid in DMSO. 18F-for-19F isotopic exchange at the Silicon-Fluoride Acceptor (SiFA) was performed at room temperature, followed by dilution with buffer and cartridge-based purification. Optimum process parameters were determined on the laboratory scale and thereafter implemented into an automated synthesis. Data for radiochemical yield (RCY), purity and quality control were analyzed for 243 clinical productions (160 for [18F]Ga-rhPSMA-7; 83 for [18F]Ga-rhPSMA-7.3). Results: The automated production of [18F]Ga-rhPSMA-7 and the single isomer [18F]Ga-rhPSMA-7.3 is completed in approx. 16 min with an average RCY of 49.2 ± 8.6% and an excellent reliability of 98.8%. Based on the different starting activities (range: 31–130 GBq, 89 ± 14 GBq) an average molar activity of 291 ± 62 GBq/μmol (range: 50–450 GBq/μmol) was reached for labeling of 150 nmol (231 μg) precursor. Radiochemical purity, as measured by radio-high performance liquid chromatography and radio-thin layer chromatography, was 99.9 ± 0.2% and 97.8 ± 1.0%, respectively. Conclusion: This investigation demonstrates that 18F-for-19F isotopic exchange is well suited for the fast, efficient and reliable automated routine production of 18F-labeled PSMA-targeted ligands. Due to its simplicity, speed and robustness the development of further SiFA-based radiopharmaceuticals is highly promising and can be of far-reaching importance for future theranostic concepts. [ABSTRACT FROM AUTHOR]

Aims  Balance between inflammatory and reparative leucocytes allows optimal healing after myocardial infarction (MI). Interindividual heterogeneity evokes variable functional outcome complicating targeted therapy. We aimed to characterize infarct chemokine CXC-motif receptor 4 (CXCR4) expression using positron emission tomography (PET) and establish its relationship to cardiac outcome. We tested whether image-guided early CXCR4 directed therapy attenuates chronic dysfunction. Methods and results  Mice (n  = 180) underwent coronary ligation or sham surgery and serial PET imaging over 7 days. Infarct CXCR4 content was elevated over 3 days after MI compared with sham (%ID/g, Day 1:1.1 ± 0.2; Day 3:0.9 ± 0.2 vs. 0.6 ± 0.1, P  < 0.001), confirmed by flow cytometry and histopathology. Mice that died of left ventricle (LV) rupture exhibited persistent inflammation at 3 days compared with survivors (1.2 ± 0.3 vs. 0.9 ± 0.2% ID/g, P  < 0.001). Cardiac magnetic resonance measured cardiac function. Higher CXCR4 signal at 1 and 3 days independently predicted worse functional outcome at 6 weeks (r partial = −0.4, P  = 0.04). Mice were treated with CXCR4 blocker AMD3100 following the imaging timecourse. On-peak CXCR4 blockade at 3 days lowered LV rupture incidence vs. untreated MI (8% vs. 25%), and improved contractile function at 6 weeks (+24%, P  = 0.01). Off-peak CXCR4 blockade at 7 days did not improve outcome. Flow cytometry analysis revealed lower LV neutrophil and Ly6Chigh monocyte content after on-peak treatment. Patients (n  = 50) early after MI underwent CXCR4 PET imaging and functional assessment. Infarct CXCR4 expression in acute MI patients correlated with contractile function at time of PET and on follow-up. Conclusion  Positron emission tomography imaging identifies early CXCR4 up-regulation which predicts acute rupture and chronic contractile dysfunction. Imaging-guided CXCR4 inhibition accelerates inflammatory resolution and improves outcome. This supports a molecular imaging-based theranostic approach to guide therapy after MI. Open in new tab Download slide Open in new tab Download slide [ABSTRACT FROM AUTHOR]

Background: Salvage radiotherapy (SRT) is clinically established in prostate cancer (PC) patients with PSA persistence or biochemical relapse (BCR) after prior radical surgery. PET/CT imaging prior to SRT may be performed to localize disease recurrence. The recently introduced Ga-PSMA outperforms other PET tracers for detection of recurrence and is therefore expected also to impact radiation planning. Forty-five patients with PSA persistence (16 pts) or BCR (29 pts) after prior prostatectomy, scheduled to undergo SRT of the prostate bed, underwent Ga-PSMA PET/CT. The median PSA level was 0.67 ng/ml. The impact of Ga-PSMA PET/CT on the treatment decision was assessed. Patients with oligometastatic (≤5 lesions) PC underwent radiotherapy (RT), with the extent of the RT area and dose escalation being based on PET positivity. Results: Suspicious lesions were detected in 24/45 (53.3 %) patients. In 62.5 % of patients, lesions were only detected by Ga-PSMA PET. Treatment was changed in 19/45 (42.2 %) patients, e.g., extending SRT to metastases (9/19), administering dose escalation in patients with morphological local recurrence (6/19), or replacing SRT by systemic therapy (2/19). 38/45 (84.4 %) followed the treatment recommendation, with data on clinical follow-up being available in 21 patients treated with SRT. All but one showed biochemical response (mean PSA decline 78 ± 19 %) within a mean follow-up of 8.12 ± 5.23 months. Conclusions: Ga-PSMA PET/CT impacts treatment planning in more than 40 % of patients scheduled to undergo SRT. Future prospective studies are needed to confirm this significant therapeutic impact on patients prior to SRT. [ABSTRACT FROM AUTHOR]

Due to favourable in vivo characteristics, its high specificity and the longer half-life of F (109.8 min) allowing for remote-site delivery, O-(2-[F]fluoroethyl)- l-tyrosine ([F]FET) has gained increased importance for molecular imaging of cerebral tumors. Consequently, the development of simple and efficient production strategies for [F]FET could be an important step to further improve the cost-effective availability of [F]FET in the clinical environment. In the present study [F]FET was synthesized via direct nucleophilic synthesis using an earlier developed chiral precursor, the Ni complex of an alkylated ( S)-tyrosine Schiff base, Ni-( S)- BPB-( S)-Tyr-OCHCHOTs. The purification method has been developed via solid phase extraction thereby omitting cumbersome HPLC purification. The suggested SPE purification using combination of reverse phase and strong cation exchange cartridges provided [F]FET in high chemical, radiochemical and enantiomeric purity and 35 % radiochemical yield (decay-corrected, 45 min synthesis time). The method was successfully automated using a commercially available synthesis module, Scintomics Hotbox. Based on the current results, the proposed production route appears to be well suited for transfer into an automated cassette-type radiosynthesizers without using HPLC. [ABSTRACT FROM AUTHOR]

The human epithelial cell adhesion molecule (EpCAM) is highly expressed in a variety of clinical tumour entities. Although an antibody against EpCAM has successfully been used as an adjuvant therapy in colon cancer, this therapy has never gained wide-spread use. We have therefore investigated the possibilities and limitations for EpCAM as possible molecular imaging target using a panel of preclinical cancer models. Twelve human cancer cell lines representing six tumour entities were tested for their EpCAM expression by qPCR, flow cytometry analysis and immunocytochemistry. In addition, EpCAM expression was analyzed in vivo in xenograft models for tumours derived from these cells. Except for melanoma, all cell lines expressed EpCAM mRNA and protein when grown in vitro. Although they exhibited different mRNA levels, all cell lines showed similar EpCAM protein levels upon detection with monoclonal antibodies. When grown in vivo, the EpCAM expression was unaffected compared to in vitro except for the pancreatic carcinoma cell line 5072 which lost its EpCAM expression in vivo. Intravenously applied radio-labelled anti EpCAM MOC31 antibody was enriched in HT29 primary tumour xenografts indicating that EpCAM binding sites are accessible in vivo. However, bound antibody could only be immunohistochemically detected in the vicinity of perfused blood vessels. Investigation of the fine structure of the HT29 tumour blood vessels showed that they were immature and prone for higher fluid flux into the interstitial space. Consistent with this hypothesis, a higher interstitial fluid pressure of about 12 mbar was measured in the HT29 primary tumour via ''wick-in-needle'' technique which could explain the limited diffusion of the antibody into the tumour observed by immunohistochemistry. [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]

Somatostatin receptor (sstr) positive tumours vary widely in uptake of radiolabelled somatostatin (sst) analogues. This study determinates variability in lesion uptake of the glycosylated sst analogon Nα-(1-deoxy- d-fructosyl)-Nɛ-(2-[18F]fluoropropionyl)-Lys0-Tyr3-octreotate (Gluc-Lys([18F]FP)-TOCA) and correlates it with lesion size and arterial perfusion as measured on computed tomography (CT). Ten patients with metastasized neuroendocrine carcinomas were investigated with positron emission tomography PET/CT (Biograph 16, Siemens, Germany). Lesion standardized uptake values (SUVs) were determined at ∼50 min post tracer injection according to a 60% isocontour volume of interest around each lesion. Lesion size and enhancement in the arterial phase (hounsfield units, HUs) were derived from CT. 114 lesions in the upper abdomen had a correlate on both, PET and CT. Variability in lesion SUVs was high (SUVmean 22 ± 13). Intraindividually, there was a sigmoid positive correlation between lesion SUV and lesion diameter indicating partial volume effects. Residual variability in lesions ≥3 cm (≥2.5 cm) ranged down to about half (third) of the maximum lesion uptake and remained unexplained by partial volume effects. No correlation with measured HU in the arterial phase was found, neither intraindividually nor interindividually. Partial volume effects were a major source of intraindividual variability in tumour tracer uptake. Lesions below 2.5 to 3 cm should thus be used with caution when performing dose calculations. In larger lesions residual variability in uptake must be considered; it may be due to variable sstr2 expression on the tumours’ cell surfaces. [ABSTRACT FROM AUTHOR]

Background: Glucose regulated proteins (GRPs) are main regulators of cellular homeostasis due to their role as molecular chaperones. Moreover, the functions of GRPs suggest that they also may play important roles in cancer biology. In this study we investigated the glucose regulated proteins GRP78 (BiP) and GRP94 (GP96) in a series of human esophageal adenocarcinomas to determine their implications in cancer progression and prognosis. Methods: Formalin-fixed, paraffin-embedded tissues of primary resected esophageal (Barrett) adenocarcinomas (n = 137) and corresponding normal tissue were investigated. mRNA-gene expression levels of GRP78 and GRP94 were determined by quantitative real-time RT-PCR after mRNA extraction. Protein expression analysis was performed with immunohistochemical staining of the cases, assembled on a tissue micorarray. The results were correlated with pathologic features (pT, pN, G) and overall survival. Results: GRP78 and GRP94 mRNA were expressed in all tumors. The relative gene expression of GRP78 was significantly higher in early cancers (pT1m and pT1sm) as compared to more advanced stages (pT2 and pT3) and normal tissue (p = 0.031). Highly differentiated tumors showed also higher GRP78 mRNA levels compared to moderate and low differentiated tumors (p = 0.035). In addition, patients with higher GRP78 levels tended to show a survival benefit (p = 0.07). GRP94 mRNA-levels showed no association to pathological features or clinical outcome. GRP78 and GRP94 protein expression was detectable by immunohistochemistry in all tumors. There was a significant correlation between a strong GRP78 protein expression and early tumor stages (pT1m and pT1sm, p = 0.038). For GRP94 low to moderate protein expression was significantly associated with earlier tumor stage (p = 0.001) and less lymph node involvement (p = 0.036). Interestingly, the patients with combined strong GRP78 and GRP94 protein expression exclusively showed either early (pT1m or pT1sm) or advanced (pT3) tumor stages and no pT2 stage (p = 0.031). Conclusion: We could demonstrate an association of GRP78 and GRP94 mRNA and protein expression with tumor stage and behaviour in esophageal adenocarcinomas. Increased expression of GRP78 may be responsible for controlling local tumor growth in early tumor stages, while high expression of GRP78 and GRP94 in advanced stages may be dependent from other factors like cellular stress reactions due to glucose deprivation, hypoxia or the hosts' immune response. [ABSTRACT FROM AUTHOR]

In the past decade, there have been major improvements in our understanding of angiogenesis at the genetic, molecular and cellular levels. Concentrated efforts in this area have led to new therapeutic approaches to ischaemic heart disease using angiogenic factors, gene therapy and progenitor cells. Despite very promising experimental results in animal studies, large clinical trials have failed to confirm the results in patients with coronary artery disease. Important questions such as selection of growth factors and donor cells, as well as the timing, dose and route of administration, have been raised and need to be answered. Molecular imaging approaches which may provide specific markers of the angiogenic process (e.g. integrin expression in endothelial cells) have been introduced and are expected to address some of these questions. Although few clinical imaging results are currently available, animal studies suggest the potential role of molecular imaging for characterisation of the angiogenetic process in vivo and for the monitoring of therapeutic effects. [ABSTRACT FROM AUTHOR]

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Background: Glucose regulated proteins (GRPs) are main regulators of cellular homeostasis due to their role as molecular chaperones. Moreover, the functions of GRPs suggest that they also may play important roles in cancer biology. In this study we investigated the glucose regulated proteins GRP78 (BiP) and GRP94 (GP96) in a series of human esophageal adenocarcinomas to determine their implications in cancer progression and prognosis.Methods: Formalin-fixed, paraffin-embedded tissues of primary resected esophageal (Barrett) adenocarcinomas (n = 137) and corresponding normal tissue were investigated. mRNA-gene expression levels of GRP78 and GRP94 were determined by quantitative real-time RT-PCR after mRNA extraction. Protein expression analysis was performed with immunohistochemical staining of the cases, assembled on a tissue micorarray. The results were correlated with pathologic features (pT, pN, G) and overall survival.Results: GRP78 and GRP94 mRNA were expressed in all tumors. The relative gene expression of GRP78 was significantly higher in early cancers (pT1m and pT1sm) as compared to more advanced stages (pT2 and pT3) and normal tissue (p = 0.031). Highly differentiated tumors showed also higher GRP78 mRNA levels compared to moderate and low differentiated tumors (p = 0.035). In addition, patients with higher GRP78 levels tended to show a survival benefit (p = 0.07). GRP94 mRNA-levels showed no association to pathological features or clinical outcome.GRP78 and GRP94 protein expression was detectable by immunohistochemistry in all tumors. There was a significant correlation between a strong GRP78 protein expression and early tumor stages (pT1m and pT1sm, p = 0.038). For GRP94 low to moderate protein expression was significantly associated with earlier tumor stage (p = 0.001) and less lymph node involvement (p = 0.036). Interestingly, the patients with combined strong GRP78 and GRP94 protein expression exclusively showed either early (pT1m or pT1sm) or advanced (pT3) tumor stages and no pT2 stage (p = 0.031).Conclusion: We could demonstrate an association of GRP78 and GRP94 mRNA and protein expression with tumor stage and behaviour in esophageal adenocarcinomas. Increased expression of GRP78 may be responsible for controlling local tumor growth in early tumor stages, while high expression of GRP78 and GRP94 in advanced stages may be dependent from other factors like cellular stress reactions due to glucose deprivation, hypoxia or the hosts' immune response. [ABSTRACT FROM AUTHOR]