Background: Prostate-specific membrane antigen (PSMA)-targeted positron emission tomography (PET) can visualize metastatic lesions in recurrent prostate cancer (PC). However, reliable... Show moreBackground: Prostate-specific membrane antigen (PSMA)-targeted positron emission tomography (PET) can visualize metastatic lesions in recurrent prostate cancer (PC). However, reliable identification of small and/or atypically localized lesions during salvage surgery procedures is challenging.Objective: To describe the technique, feasibility, and short-term outcomes of (99m)Technetium (Tc-99m)-based PSMA-radioguided surgery (Tc-99m-PSMA-RGS) for removal of recurrent PC lesions.Design, setting, and participants: Thirty-one consecutive patients with evidence of recurrent PC on Ga-68-PSMA N,N'-bis[2-hydroxy-5-(carboxyethyl)benzyl] ethylenediamine-N,N'-diacetic acid (Ga-68-PSMA-11) PET after radical prostatectomy undergoing Tc-99m-PSMA-RGS were retrospectively analyzed.Surgical procedure: Salvage surgery with intraoperative radioguidance using a gamma probe was performed after intravenous application of Tc-99m-PSMA investigation and surgery (mean activity 571 MBq, mean time to surgery 19.7 h).Measurements: Radioactive rating (positive vs negative) of resected tissue was compared with the findings of postoperative histopathological analysis. Best prostate-specific antigen (PSA) response without additional treatment was determined after 8-16 wk postoperatively. Biochemical recurrence- and treatment-free survival was evaluated.Results and limitations: In total,132 tissue specimens were removed, of which 58 showed metastatic involvement on histological analysis. On a specimen basis, radioactive rating yielded a sensitivity of 83.6% (confidence interval [CI]: 70.9-91.5%), a specificity of 100%, and an accuracy of 93.0% (CI: 85.5-96.7%). With Tc-99m-PSMA-RGS, all lesions visualized on preoperative Ga-68-PSMA-11 PET could be removed. Moreover, Tc-99m-PSMA-RGS detected additional metastases as small as 3 mm in two patients. Thirteen patients suffered from complications related to surgery (Clavien-Dindo grade 1: 12 patients; grade 3a: one patient). A PSA reduction below 0.2 ng/ml was observed in 20 patients. Thirteen patients remained biochemical recurrence free after a median follow-up of 13.8 (range: 4.6-18.3) mo. Twenty patients continued to be treatment free after a median follow-up of 12.2 (range: 5.5-18.3) mo.Conclusions: As a new technique for surgical guidance, Tc-99m-PSMA-RGS is feasible, and has been proved to be of high value for successful intraoperative detection and removal of metastatic lesions in PC patients scheduled for salvage surgery. Its long-term impact on outcome has to be evaluated.Patient summary: In this report, we evaluated a novel technique to identify metastatic lesions intraoperatively in patients with recurrent prostate cancer to facilitate surgical removal. After intravenous injection of radioactive molecules that specifically bind to prostate cancer cells that show increased expression of the prostate-specific membrane antigen, we were able to detect and remove these metastatic lesions during surgery. Following salvage surgery, 41.9% of patients remained biochemical recurrence free (median follow-up of 13.8 mo) and 64.5% continued to be treatment free (median follow-up of 12.2 mo). (C) 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved. Show less
In the past decade it became increasingly clear that tumor heterogeneity represents one of the major problems for cancer treatment, also in prostate cancer. The identification of the molecular... Show moreIn the past decade it became increasingly clear that tumor heterogeneity represents one of the major problems for cancer treatment, also in prostate cancer. The identification of the molecular properties of highly aggressive cells (Cancer Stem Cells, CSCs) dispersed within the tumor represents a challenge for the identification of new efficient therapies. In most of the cases, current treatments are indeed successful in eradicating the primary tumor. However, the clinical evidence of relapse and the occurrence of therapy resistance, suggest the presence of subpopulation of cells within the tumor, that can survive such treatments and can perpetuate the cancer. In this thesis we investigated the molecular properties of selected highly aggressive CSCs and indentified novel modulators responsible for the maintenance of their aggressive behavior. Collectively, the studies described in this thesis have increased our insights into the molecular properties of highly metastatic and tumorigenic prostate cancer stem-like cells and provided new targets for possible diagnostic and therapeutic applications. Show less
Cancer and fibrosis are devastating diseases of high mortality rate and with limited curative therapies available. A better understanding of the biological drivers of these diseases is fundamental... Show moreCancer and fibrosis are devastating diseases of high mortality rate and with limited curative therapies available. A better understanding of the biological drivers of these diseases is fundamental in order to develop effective therapeutics. At the molecular level, signaling pathways control cell growth, differentiation or apoptosis during development and adult life of the organism ensuring homeostasis. Paradoxically, the same signals are often implicated or even drive disease progression. One of the signaling pathways with key regulatory functions in homeostasis, tissue fibrosis and cancer in many organs is the TGFβ/BMP pathway. In this thesis we addressed the role and therapeutic potential of TGFβ/BMP pathway inhibition using different drug compounds that are currently towards the clinic or being tested in clinical trials. Three distinct types of inhibitors were used; small molecule inhibitors of the ALK4, 5 and 7 TGFβ receptor kinases, an antisense oligonucleotide interfering with ALK5 mRNA splicing and an ALK1 ligand trap; a peptide that contains the extracellular domain of ALK1 fused to Fc and sequesters BMP9 and BMP10. These inhibitors were used in an ex vivo human fibrosis model and in vivo mouse models of various human diseases (acute liver failure/ liver regeneration, Dupuytren's fibrosis) and cancer (prostate, liver). Show less
