68Ga-PSMA-11 Dynamic PET/CT Imaging in Primary Prostate Cancer.

PURPOSE The aim of our study is to assess the pharmacokinetics and biodistribution of Ga-PSMA-11 in patients suffering from primary prostate cancer (PC) by means of dynamic and whole-body PET/CT. MATERIALS AND METHODS Twenty-four patients with primary, previously untreated PC were enrolled in the study. All patients underwent dynamic PET/CT (dPET/CT) scanning of the pelvis and whole-body PET/CT studies with Ga-PSMA-11. The evaluation of dPET/CT studies was based on qualitative evaluation, SUV calculation, and quantitative analysis based on two-tissue compartment modeling and a noncompartmental approach leading to the extraction of fractal dimension (FD). RESULTS A total of 23/24 patients (95.8%) were Ga-PSMA-11 positive. In 9/24 patients (37.5%), metastatic lesions were detected. PC-associated lesions demonstrated the following mean values: SUVaverage = 14.3, SUVmax = 23.4, K1 = 0.24 (1/min), k3 = 0.34 (1/min), influx = 0.15 (1/min), and FD = 1.27. The parameters SUVaverage, SUVmax, k3, influx, and FD derived from PC-associated lesions were significantly higher than respective values derived from reference prostate tissue. Time-activity curves derived from PC-associated lesions revealed an increasing Ga-PSMA-11 accumulation during dynamic PET acquisition. Correlation analysis revealed a moderate but significant correlation between PSA levels and SUVaverage (r = 0.60) and SUVmax (r = 0.57), and a weak but significant correlation between Gleason score and SUVaverage (r = 0.33) and SUVmax (r = 0.28). CONCLUSION Ga-PSMA-11 PET/CT confirmed its capacity in detecting primary PC with a detection rate of 95.8%. Dynamic PET/CT studies of the pelvis revealed an increase in tracer uptake in PC-associated lesions during the 60 minutes of dynamic PET acquisition, a finding with potential applications in anti-PSMA approaches

Integration of CT urography improves diagnostic confidence of 68Ga-PSMA-11 PET/CT in prostate cancer patients

Background: To prove the feasibility of integrating CT urography (CTU) into 68Ga-PSMA-11 PET/CT and to analyze the impact of CTU on assigning focal tracer accumulation in the ureteric space to either ureteric excretion or metastatic disease concerning topographic attribution and diagnostic confidence. Methods: Ten prostate cancer patients who underwent 68Ga-PSMA-11 PET/CT including CTU because of biochemical relapse or known metastatic disease were retrospectively analyzed. CTU consisted of an excretory phase 10 min after injection of 80 mL iodinated contrast material. Ureter opacification at CTU was evaluated using the following score: 0, 0% opacification; 1, < 50%; 2, 50–99%; 3, 100%. Topographic attribution and confidence of topographic attribution of focal tracer accumulation in the ureteric space were separately assessed for 68Ga-PSMA-11 PET/CT without and with CTU. Diagnostic confidence was evaluated using the following score: 0, < 25% confidence; 1, 26–50%; 2, 51–75%; 3, 76–100%. Results: At CTU, mean ureter opacification score was 2.6 ± 0.7. At 68Ga-PSMA-11 PET/CT without CTU, mean confidence of topographic attribution of focal tracer accumulation was 2.5 ± 0.7 in total and 2.6 ± 0.7 for metastatic disease. At 68Ga-PSMA-11 PET/CT with CTU, mean confidence of topographic attribution of focal areas of tracer accumulation was significantly higher with 2.9 ± 0.2 in total and 2.7 ± 0.9 for metastatic disease (p < 0.001). In 4 of 34 findings (12%) attribution to either ureteric excretion or metastatic disease was discrepant between 68Ga-PSMA-11 PET/CT without and with CTU (n.s). Conclusions: Integration of CTU into 68Ga-PSMA-11 PET/CT is feasible and increases diagnostic confidence of assigning focal areas of tracer accumulation in the ureteric space to either metastatic disease or ureteric excretion

Static and dynamic 68Ga-FAPI PET/CT for the detection of malignant transformation of intraductal papillary mucinous neoplasia of the pancreas.

Purpose: Pancreatic ductal adenocarcinoma (PDAC) may arise from intraductal papillary-mucinous neoplasms (IPMN) with malignant transformation, but a significant portion of IPMN remains to show benign behavior. Therefore, it is important to differentiate between benign IPMN and IPMN lesions undergoing malignant transformation. However, non-operative differentiation by ultrasound, CT, MRI and carbohydrate antigen 19-9 (CA19-9) is still unsatisfactory. Here, we assessed the clinical feasibility of additional assessment of malignancy by positron emission tomography using 68Gallium-labeled Fibroblast Activation Protein Inhibitors (68Ga-FAPI-PET) in 25 patients with magnetic resonance imaging (MRI) - or computed tomography (CT) - proven cystic pancreatic lesions. Methods: 25 patients with cystic pancreatic lesions who were followed up in the European Pancreas Center of Heidelberg University hospital and who were led to surgical resection or fine needle aspiration (FNA) due to suspicious clinical, laboratory chemistry or radiological findings were examined by static (all patients) and dynamic (20 patients) 68Ga-FAPI-PET. Cystic pancreatic lesions were delineated and maximum and mean standardized uptake values (SUVmax / SUVmean) were determined. Time activity curves and dynamic parameters (time to peak, K1, k2, K3, k4) were extracted from dynamic PET data. Receiver operating curves (ROC) of static and dynamic PET parameters were calculated. Results: 11 of the patients suffered from menacing IPMN (high grade IPMN with (6 cases) or without (5 cases) progression into PDAC) and 11 from low grade IPMN, 3 patients from other benign entities. Menacing IMPN showed significantly elevated 68Ga-FAPI uptake compared to low grade IPMN and other benign cystic lesions. In dynamic imaging, menacing IPMN showed increasing time activity curves (TAC) followed by slow decrease afterwards, TAC of low grade IPMN showed an immediate peak followed by rapid decrease for about 10 minutes and slower decrease for the rest of the time. ROC curves showed high sensitivity and specificity (area under the curve (AUC) greater than 80%) of static and dynamic PET parameters for the differentiation of IPMN subtypes. Conclusion: 68Ga-FAPI-PET is a helpful new tool for the differentiation of menacing and low grade IPMN and shows the potential to avoid unnecessary surgery for non-malignant pancreatic IPMN

Optimization of a Novel Peptide Ligand Targeting Human Carbonic Anhydrase IX

BACKGROUND: Carbonic anhydrase IX (CA IX) is a hypoxia-regulated transmembrane protein over-expressed in various types of human cancer. Recently, a new peptide with affinity for human carbonic anhydrase IX (CaIX-P1) was identified using the phage display technology. Aim of the present study is to characterize the binding site in the sequence of CaIX-P1, in order to optimize the binding and metabolic properties and use it for targeting purposes. METHODOLOGY/PRINCIPAL FINDINGS: Various fragments of CaIX-P1 were synthesized on solid support using Fmoc chemistry. Alanine scanning was performed for identification of the amino acids crucial for target binding. Derivatives with increased binding affinity were radiolabeled and in vitro studies were carried out on the CA IX positive human renal cell carcinoma cell line SKRC 52 and the CA IX negative human pancreatic carcinoma cell line BxPC3. Metabolic stability was investigated in cell culture medium and human serum. Organ distribution and planar scintigraphy studies were performed in Balb/c nu/nu mice carrying subcutaneously transplanted SKRC 52 tumors. The results of our studies clearly identified amino acids that are important for target binding. Among various fragments and derivatives the ligand CaIX-P1-4-10 (NHVPLSPy) was found to possess increased binding potential in SKRC 52 cells, whereas no binding capacity for BxPC3 cells was observed. Binding of radiolabeled CaIX-P1-4-10 on CA IX positive cells could be inhibited by both the unlabeled and the native CaIX-P1 peptide but not by control peptides. Stability experiments indicated the degradation site in the sequence of CaIX-P1-4-10. Biodistribution studies showed a higher in vivo accumulation in the tumor than in most healthy tissues. CONCLUSIONS: Our data reveal modifications in the sequence of the CA IX affine ligand CaIX-P1 that might be favorable for improvement of target affinity and metabolic stability, which are necessary prior to the use of the ligand in clinical approaches

Investigation of tumor hypoxia using a two-enzyme system for in vitro generation of oxygen deficiency

<p>Abstract</p> <p>Background</p> <p>Oxygen deficiency in tumor tissue is associated with a malign phenotype, characterized by high invasiveness, increased metastatic potential and poor prognosis. Hypoxia chambers are the established standard model for <it>in vitro </it>studies on tumor hypoxia. An enzymatic hypoxia system (GOX/CAT) based on the use of glucose oxidase (GOX) and catalase (CAT) that allows induction of stable hypoxia for <it>in vitro </it>approaches more rapidly and with less operating expense has been introduced recently. Aim of this work is to compare the enzymatic system with the established technique of hypoxia chamber in respect of gene expression, glucose metabolism and radioresistance, prior to its application for <it>in vitro </it>investigation of oxygen deficiency.</p> <p>Methods</p> <p>Human head and neck squamous cell carcinoma HNO97 cells were incubated under normoxic and hypoxic conditions using both hypoxia chamber and the enzymatic model. Gene expression was investigated using Agilent microarray chips and real time PCR analysis. ¹⁴C-fluoro-deoxy-glucose uptake experiments were performed in order to evaluate cellular metabolism. Cell proliferation after photon irradiation was investigated for evaluation of radioresistance under normoxia and hypoxia using both a hypoxia chamber and the enzymatic system.</p> <p>Results</p> <p>The microarray analysis revealed a similar trend in the expression of known HIF-1 target genes between the two hypoxia systems for HNO97 cells. Quantitative RT-PCR demonstrated different kinetic patterns in the expression of carbonic anhydrase IX and lysyl oxidase, which might be due to the faster induction of hypoxia by the enzymatic system. ¹⁴C-fluoro-deoxy-glucose uptake assays showed a higher glucose metabolism under hypoxic conditions, especially for the enzymatic system. Proliferation experiments after photon irradiation revealed increased survival rates for the enzymatic model compared to hypoxia chamber and normoxia, indicating enhanced resistance to irradiation. While the GOX/CAT system allows independent investigation of hypoxia and oxidative stress, care must be taken to prevent acidification during longer incubation.</p> <p>Conclusion</p> <p>The results of our study indicate that the enzymatic model can find application for <it>in vitro </it>investigation of tumor hypoxia, despite limitations that need to be considered in the experimental design.</p

Sequential FDG-PET and induction chemotherapy in locally advanced adenocarcinoma of the Oesophago-gastric junction (AEG): The Heidelberg Imaging program in Cancer of the oesophago-gastric junction during Neoadjuvant treatment: HICON trial

<p>Abstract</p> <p>Background</p> <p>18-Fluorodeoxyglucose-PET (¹⁸F-FDG-PET) can be used for early response assessment in patients with locally advanced adenocarcinomas of the oesophagogastric junction (AEG) undergoing neoadjuvant chemotherapy. It has been recently shown in the MUNICON trials that response-guided treatment algorithms based on early changes of the FDG tumor uptake detected by PET are feasible and that they can be implemented into clinical practice.</p> <p>Only 40%-50% of the patients respond metabolically to therapy. As metabolic non-response is known to be associated with a dismal prognosis, metabolic non-responders are increasingly treated with alternative neoadjuvant chemotherapies or chemoradiation in order to improve their clinical outcome. We plan to investigate whether PET can be used as response assessment during radiochemotherapy given as salvage treatment in early metabolic non-responders to standard chemotherapy.</p> <p>Methods/Design</p> <p>The HICON trial is a prospective, non-randomized, explorative imaging study evaluating the value of PET as a predictor of histopathological response in metabolic non-responders. Patients with resectable AEG type I and II according to Siewerts classification, staged cT3/4 and/or cN+ and cM0 by endoscopic ultrasound, spiral CT or MRI and FDG-PET are eligible. Tumors must be potentially R0 resectable and must have a sufficient FDG-baseline uptake. Only metabolic non-responders, showing a < 35% decrease of SUV two weeks after the start of neoadjuvant chemotherapy are eligible for the study and are taken to intensified taxane-based RCT (chemoradiotherapy (45 Gy) before surgery. ¹⁸FDG-PET scans will be performed before ( = Baseline) and after 14 days of standard neoadjuvant therapy as well as after the first cycle of salvage docetaxel/cisplatin chemotherapy (PET 1) and at the end of radiochemotherapy (PET2). Tracer uptake will be assessed semiquantitatively using standardized uptake values (SUV). The percentage difference ΔSUV = 100 (SUV_Baseline- SUV _PET1)/SUV_Baselinewill be calculated and assessed as an early predictor of histopathological response. In a secondary analysis, the association between the difference SUV_PET1- SUV_PET2and histopathological response will be evaluated.</p> <p>Discussion</p> <p>The aim of this study is to investigate the potential of sequential ¹⁸FDG-PET in predicting histopathological response in AEG tumors to salvage neoadjuvant radiochemotherapy in patients who do not show metabolic response to standard neoadjuvant chemotherapy.</p> <p>Trial Registration</p> <p>Clinical trial identifier <a href="http://www.clinicaltrials.gov/ct2/show/NCT01271322">NCT01271322</a></p

A New Peptide Ligand for Targeting Human Carbonic Anhydrase IX, Identified through the Phage Display Technology

Carbonic anhydrase IX (CAIX) is a transmembrane enzyme found to be overexpressed in various tumors and associated with tumor hypoxia. Ligands binding this target may be used to visualize hypoxia, tumor manifestation or treat tumors by endoradiotherapy