PSMA, EpCAM, VEGF and GRPR as Imaging Targets in Locally Recurrent Prostate Cancer after Radiotherapy

In this retrospective pilot study, the expression of the prostate-specific membrane antigen (PSMA), the epithelial cell adhesion molecule (EpCAM), the vascular endothelial growth factor (VEGF) and the gastrin-releasing peptide receptor (GRPR) in locally recurrent prostate cancer after brachytherapy or external beam radiotherapy (EBRT) was investigated, and their adequacy for targeted imaging was analyzed. Prostate cancer specimens were collected of 17 patients who underwent salvage prostatectomy because of locally recurrent prostate cancer after brachytherapy or EBRT. Immunohistochemistry was performed. A pathologist scored the immunoreactivity in prostate cancer and stroma. Staining for PSMA was seen in 100% (17/17), EpCAM in 82.3% (14/17), VEGF in 82.3% (14/17) and GRPR in 100% (17/17) of prostate cancer specimens. Staining for PSMA, EpCAM and VEGF was seen in 0% (0/17) and for GRPR in 100% (17/17) of the specimens’ stromal compartments. In 11.8% (2/17) of cases, the GRPR staining intensity of prostate cancer was higher than stroma, while in 88.2% (15/17), the staining was equal. Based on the absence of stromal staining, PSMA, EpCAM and VEGF show high tumor distinctiveness. Therefore, PSMA, EpCAM and VEGF can be used as targets for the bioimaging of recurrent prostate cancer after EBRT to exclude metastatic disease and/or to plan local salvage therapy

Expression of the Gastrin-Releasing Peptide Receptor, the Prostate Stem Cell Antigen and the Prostate-Specific Membrane Antigen in Lymph Node and Bone Metastases of Prostate Cancer

OBJECTIVE. Cell membrane antigens like the gastrin-releasing peptide receptor (GRPR), the prostate stem cell antigen (PSCA), and the prostate-specific membrane antigen (PSMA), expressed in prostate cancer, are attractive targets for new therapeutic and diagnostic applications. Therefore, we investigated in this study whether these antigens are expressed in metastasized prostate cancer. METHODS. Formalin-fixed, paraffin-embedded specimens of 15 patients with uni- or bilateral lymph node metastases of prostate cancer (totaling 21 cases) and 17 patient-cases of bone metastases were processed for immunohistochemistry with anti-GRPR, anti-PSCA, and anti-PSMA antibodies. A pathologist blinded to clinical and pathological data scored the immunoreactivity for these antibodies on a four-point scale (0=no staining; 1+=weak staining; 2+=moderate staining; 3+=strong staining) and documented the distribution pattern. RESULTS. GRPR staining in lymph node metastases was seen in 85.7% of cases (18 of 21 cases), PSCA in 95.2% (20/21), and PSMA in 100% (21/21). GRPR in bone metastases was seen in 52.9% of cases (9/17), PSCA in 94.1% (16/17), and PSMA in 100% (17/17). CONCLUSION. We have shown for the first time that GRPR is expressed in the vast majority of lymph node metastases and in 52.9% of bone metastases of prostate cancer. PSCA and PSMA are both highly expressed in lymph node and bone metastases. Although PSCA and PSMA are mostly expressed in prostate cancer metastases, GRPR offers an interesting alternative target as it can be targeted relatively easy with peptide-based (radio)pharmaceuticals. Prostate 69: 1101 1108, 2009. (C) 2009 Wiley-Liss, Inc

An Update of Radiolabeled Bombesin Analogs for Gastrin-Releasing Peptide Receptor Targeting

Prostate cancer is a critical public health problem in USA and Europe. New non-invasive imaging methods are urgently needed, due to the low accuracy and specificity of current screen methods and the desire of localizing primary prostate cancer and bone metastasis. Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) are the non-invasive and sensitive imaging methods which have been widely used for diagnosing diseases in the clinic. Lack of suitable radiotracers is the major issue for nuclear imaging of prostate cancer, although radiolabeled bombesin (BN) peptides targeting the Gastrin-Releasing Peptide Receptor (GRPR) on tumor cells are widely investigated. In this review we discuss the recent trends in the development of GRPR-targeted radiopharmaceuticals based on BN analogs with regard to their potential for imaging and therapy of GRPR-expressing malignancies. Following a brief introduction of GRPR and bombesin peptides, we summarize the properties of prostate cancer specific radiolabeled bombesins. New bombesin tracers published in the last five years are reviewed and compared according to their novelties in biomolecules, radionuclides, labeling methods, bifunctional chelators and linkers. Hot topics such as multimerization, application of agonists and antagonists are highlighted in the review. Lastly, a few clinical trials of cancer nuclear imaging with radiolabeled bombesin have been discussed

An Update of Radiolabeled Bombesin Analogs for Gastrin-Releasing Peptide Receptor Targeting

Prostate cancer is a critical public health problem in USA and Europe. New non-invasive imaging methods are urgently needed, due to the low accuracy and specificity of current screen methods and the desire of localizing primary prostate cancer and bone metastasis. Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) are the non-invasive and sensitive imaging methods which have been widely used for diagnosing diseases in the clinic. Lack of suitable radiotracers is the major issue for nuclear imaging of prostate cancer, although radiolabeled bombesin (BN) peptides targeting the Gastrin-Releasing Peptide Receptor (GRPR) on tumor cells are widely investigated. In this review we discuss the recent trends in the development of GRPR-targeted radiopharmaceuticals based on BN analogs with regard to their potential for imaging and therapy of GRPR-expressing malignancies. Following a brief introduction of GRPR and bombesin peptides, we summarize the properties of prostate cancer specific radiolabeled bombesins. New bombesin tracers published in the last five years are reviewed and compared according to their novelties in biomolecules, radionuclides, labeling methods, bifunctional chelators and linkers. Hot topics such as multimerization, application of agonists and antagonists are highlighted in the review. Lastly, a few clinical trials of cancer nuclear imaging with radiolabeled bombesin have been discussed.</p

An Update of Radiolabeled Bombesin Analogs for Gastrin-Releasing Peptide Receptor Targeting

Prostate cancer is a critical public health problem in USA and Europe. New non-invasive imaging methods are urgently needed, due to the low accuracy and specificity of current screen methods and the desire of localizing primary prostate cancer and bone metastasis. Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) are the non-invasive and sensitive imaging methods which have been widely used for diagnosing diseases in the clinic. Lack of suitable radiotracers is the major issue for nuclear imaging of prostate cancer, although radiolabeled bombesin (BN) peptides targeting the Gastrin-Releasing Peptide Receptor (GRPR) on tumor cells are widely investigated. In this review we discuss the recent trends in the development of GRPR-targeted radiopharmaceuticals based on BN analogs with regard to their potential for imaging and therapy of GRPR-expressing malignancies. Following a brief introduction of GRPR and bombesin peptides, we summarize the properties of prostate cancer specific radiolabeled bombesins. New bombesin tracers published in the last five years are reviewed and compared according to their novelties in biomolecules, radionuclides, labeling methods, bifunctional chelators and linkers. Hot topics such as multimerization, application of agonists and antagonists are highlighted in the review. Lastly, a few clinical trials of cancer nuclear imaging with radiolabeled bombesin have been discussed.http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000318156100015&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=8e1609b174ce4e31116a60747a720701Pharmacology &amp; PharmacySCI(E)26ARTICLE183329-33411

(99m)Technetium-HYNIC(tricine/TPPTS)-Aca-Bombesin(7-14) as a Targeted Imaging Agent with MicroSPECT in a PC-3 Prostate Cancer Xenograft Model

The peptide bombesin (BN) and derivates thereof show high binding affinity for the gastrin-releasing peptide receptor (GRPR), which is highly expressed in primary and metastasized prostate cancer. We have synthesized a new BN-based radiopharmaceutical (99m)technetium-HYNIC(tricine/TPPTS)-Aca-BN(7-14) (Tc-99m-HABN) and evaluated its GRPR targeting properties in vitro and in a xenograft tumor model for human prostate cancer in athymic mice. Tc-99m-HABN was synthesized, and its lipophilicity and stability were investigated. The IC50, internalization and efflux properties were determined in vitro using the GRPR expressing human prostate cancer cell line PC-3. Tc-99m-HABN biodistribution and microSPECT imaging were performed in PC-3 tumor-bearing athymic mice. Tc-99m-HABN was prepared with high labeling yield (>90%), hip radiochemical purity (>95%) and a specific activity of similar to 19.8 MBq/nmol. The partition coefficient log D value was -1.60 +/- 0.06. Tc-99m-HABN proved to be stable in human serum for 6 h. The IC50 of HYNIC-Aca-BN(7-14) was 12.81 +/- 0.14 nM. Incubation of PC-3 cells with Tc-99m-HABN demonstrated rapid cellular internalization and a long intracellular retention time. When mice were injected with Tc-99m-HABN, the activity was predominantly cleared via the kidneys. Uptake in the tumor was 2.24 +/- 0.64% ID/g after 30 min, with a steady decrease during the 4 h study period. In vivo experiments with a blocking agent showed GRPR mediated uptake. Tc-99m-HABN microSPECT imaging resulted in clear delineation of the tumor. Tc-99m-HABN is a novel BN-based radiopharmaceutical that proved to be suitable for targeted imaging of prostate cancer with microSPECT using the human prostate cancer cell line PC-3 in a xenograft mouse model

Transfer of cysto-urethroscopy skills from a virtual-reality simulator to the operating room:a randomized controlled trial

OBJECTIVE To assess whether real-time cysto-urethroscopy (CUS) performance improves by simulator-based training (criterion or predictive validity), addressing the research question 'Does practical skills training on the URO Mentor (UM, Simbionix USA Corp., Cleveland, OH, USA) virtual-reality simulator improve the performance of flexible CUS in patients'. SUBJECTS AND METHODS Participants (71 interns from Catharina Hospital Eindhoven, CHE, and 29 from University Medical Centre Groningen, UMCG) were randomized to carry out CUS in a patient after training on the UM (UM-trained, 50) or without training on UM (control, 50). The assessment of real-time performance consisted of scoring on a Global Rating Scale (GRS) by supervisors unaware of training status. Data were analysed using stepwise multiple linear regression. The effect size (ES) indication for correlations was used to interpret the magnitude of a standard regression coefficient (beta); an ES of 0.10, 0.30 and 0.50 were considered small, moderate and large, respectively. The study was approved by the Medical Review Ethics Committees of the participating hospitals. RESULTS Overall, the group that received training performed significantly better than the controls (P <0.003, beta range 0.30-0.47). There was no effect of training for participants with a specific preference for a surgical speciality in two of five GRS scores. Participants from CHE obtained higher GRS 3 scores than those from UMCG. Significantly more UMCG trainees indicated having had stress than those from CHE (P <0.001). CONCLUSIONS The results showed that interns who had trained on UM outperformed controls for a CUS procedure in a patient. Training for CUS on the UM is to be recommended for learning to respect tissue, procedural knowledge, flow of procedure and forward planning. Use of the UM to train interns with a specific interest in a surgical speciality in handling instruments, and time and motion, seems to be of limited value