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01 juli 2023, Contains fulltext : 294539.pdf (Publisher’s version ) (Open Access), Prostate-specific membrane antigen (PSMA) is expressed by the majority of clinically significant prostate adenocarcinomas, and patients with target-positive disease can easily be identified by PSMA PET imaging. Promising results with PSMA-targeted radiopharmaceutical therapy have already been obtained in early-phase studies using various combinations of targeting molecules and radiolabels. Definitive evidence of the safety and efficacy of [(177)Lu]Lu-PSMA-617 in combination with standard-of-care has been demonstrated in patients with metastatic castration-resistant prostate cancer, whose disease had progressed after or during at least one taxane regimen and at least one novel androgen-axis drug. Preliminary data suggest that (177)Lu-PSMA-radioligand therapy (RLT) also has high potential in additional clinical situations. Hence, the radiopharmaceuticals [(177)Lu]Lu-PSMA-617 and [(177)Lu]Lu-PSMA-I&T are currently being evaluated in ongoing phase 3 trials. The purpose of this guideline is to assist nuclear medicine personnel, to select patients with highest potential to benefit from (177)Lu-PSMA-RLT, to perform the procedure in accordance with current best practice, and to prepare for possible side effects and their clinical management. We also provide expert advice, to identify those clinical situations which may justify the off-label use of [(177)Lu]Lu-PSMA-617 or other emerging ligands on an individual patient basis.

Item does not contain fulltext, For localization of biochemical recurrence of prostate cancer, 68Ga-PSMA-11 PET/CT imaging was performed in a 66-year-old man with no suspicious findings at 1 hour p.i. Additional 89Zr-PSMA-617 PET/CT revealed a small local recurrence in the prostate bed, facilitating consecutive local therapy. This interesting image points to the potential of PET/CT with 89Zr-labeled PSMA ligands, for example, 89Zr-PSMA-617, for identifying the source of biochemical recurrence despite otherwise negative imaging including conventional PSMA PET/CT.

Item does not contain fulltext, RATIONALE: Prolonged in vivo evaluation of PSMA tracers could improve tumor imaging and patient selection for (177)Lu-PSMA-617 and (177)Lu-PSMA-I&T. In this study, we present the radiolabeling method of PSMA-617 and PSMA-I&T with the long-lived positron emitter (89)Zr to enable PET imaging up to 7 days post-injection. We compared the biodistribution of (89)Zr-PSMA-617 and (89)Zr-PSMA-I&T to those of (177)Lu-PSMA-617 and (177)Lu-PSMA-I&T, respectively, in a PSMA(+) xenograft model. Moreover, we provide the first human (89)Zr-PSMA-617 images. MATERIALS AND METHODS: PSMA ligands were labeled with 50-55 MBq [(89)Zr]ZrCl4 using a two-step labeling protocol. For biodistribution, BALB/c nude mice bearing PSMA(+) and PSMA(-) xenografts received 0.6 microg (0.6-1 MBq) of (89)Zr-PSMA-617, (89)Zr-PSMA-I&T, (177)Lu-PSMA-617, or (177)Lu-PSMA-I&T intravenously. Ex vivo biodistribution and PET/SPECT imaging were performed up to 168 h post-injection. Dosimetry was performed from the biodistribution data. The patient received 90.5 MBq (89)Zr-PSMA-617 followed by PET/CT imaging. RESULTS: (89)Zr-labeled PSMA ligands showed a comparable ex vivo biodistribution to its respective (177)Lu-labeled counterparts with high tumor accumulation in the PSMA(+) xenografts. However, using a dose estimation model for (177)Lu, absorbed radiation dose in bone and kidneys differed among the (177)Lu-PSMA and (89)Zr-PSMA tracers. (89)Zr-PSMA-617 PET in the first human patient showed high contrast of PSMA expressing tissues up to 48 h post-injection. CONCLUSION: PSMA-617 and PSMA-I&T were successfully labeled with (89)Zr and demonstrated high uptake in PSMA(+) xenografts, which enabled PET up to 168 h post-injection. The biodistribution of (89)Zr-PSMA-I&T and (89)Zr-PSMA-617 resembled that of (177)Lu-PSMA-I&T and (177)Lu-PSMA-617, respectively. The first patient (89)Zr-PSMA-617 PET images were of high quality warranting further clinical investigation.

Item does not contain fulltext, PURPOSE: Prostate-specific membrane antigen (PSMA)-targeted PET/CT has become increasingly important in the management of prostate cancer, especially in localization of biochemical recurrence (BCR). PSMA-targeted PET/CT imaging with long-lived radionuclides as 89Zr (T1/2 = 78.4 h) may improve diagnostics by allowing data acquisition on later time points. In this study, we present our first clinical experience including preliminary biodistribution and dosimetry data of [89Zr]Zr-PSMA-617 PET/CT in patients with BCR of prostate cancer. METHODS: Seven patients with BCR of prostate cancer who revealed no (n = 4) or undetermined (n = 3) findings on [68Ga]Ga-PSMA-11 PET/CT imaging were referred to [89Zr]Zr-PSMA-617 PET/CT. PET/CT imaging was performed 1 h, 24 h, 48 h, and 72 h post injection (p.i.) of 111 +/- 11 MBq [89Zr]Zr-PSMA-617 (mean +/- standard deviation). Normal organ distribution and dosimetry were determined. Lesions visually considered as suggestive of prostate cancer were quantitatively analyzed. RESULTS: Intense physiological uptake was observed in the salivary and lacrimal glands, liver, spleen, kidneys, intestine and urinary tract. The parotid gland received the highest absorbed dose (0.601 +/- 0.185 mGy/MBq), followed by the kidneys (0.517 +/- 0.125 mGy/MBq). The estimated overall effective dose for the administration of 111 MBq was 10.1 mSv (0.0913 +/- 0.0118 mSv/MBq). In 6 patients, and in particular in 3 of 4 patients with negative [68Ga]Ga-PSMA-11 PET/CT, at least one prostate cancer lesion was detected in [89Zr]Zr-PSMA-617 PET/CT imaging at later time points. The majority of tumor lesions were first visible at 24 h p.i. with continuously increasing tumor-to-background ratio over time. All tumor lesions were detectable at 48 h and 72 h p.i. CONCLUSION: [89Zr]Zr-PSMA-617 PET/CT imaging is a promising new diagnostic tool with acceptable radiation exposure f

Item does not contain fulltext, PURPOSE: Prostate-specific membrane antigen radioligand therapy (PSMA-RLT) is a novel treatment for castration-resistant prostate cancer (mCRPC). While the majority of patients responds to PSMA-RLT, with 10-15% having an exceptional response, approximately 30% of patients is unresponsive to PSMA-RLT. The molecular underpinning may in part explain these varying responses. This study investigated alterations in DNA damage repair (DDR) genes in tumour biopsies and their association with response to PSMA-RLT. METHODS: A predefined retrospective cohort study was performed in mCRPC patients of whom the tumours had undergone next-generation sequencing of 40 DDR genes and received Lu-177-PSMA and/or Ac-225-PSMA-RLT. The primary outcome of this study was to compare the progression free survival (PFS) after PSMA-RLT for patients with and without pathogenic DDR aberrations in their tumour. Secondary outcomes were prostate-specific antigen (PSA) response and overall survival (OS). RESULTS: A total of 40 patients were included of which seventeen had a tumour with a pathogenic DDR aberration (DDR+), of which eight had defects in BRCA1/2. DDR+ patients had an equal varying response to PSMA-RLT compared to those without pathological DDR anomalies (DDR-) in terms of PFS (5.9 vs. 6.4 months, respectively; HR 1.14; 95% CI 0.58-2.25; p = 0.71), ≥50% PSA response (59% vs. 65%, respectively; p = 0.75) or OS (11.1 vs. 10.7 months, respectively; HR 1.40; 95% CI: 0.68-2.91; p = 0.36). CONCLUSION: In this study of a selected cohort, pathogenic DDR aberrations were not associated with exceptional responsiveness to PSMA-RLT. Translational studies in larger prospective cohorts are warranted to associate DDR gene defects with differential responses to PSMA-RLT.

Neuroendocrine neoplasms (NEN) of the distal jejunum and ileum derive from serotonin-producing enterochromaffin (EC) cells. Due to their low proliferation rate and their infiltrative growth, they are often discovered at an advanced disease stage when metastasis has already occurred. The biology of these tumours is different from other NEN of the digestive tract. In order to standardise and improve diagnosis and therapy, the guidelines for the diagnosis and clinical management of jejuno-ileal NEN as well as for the management of patients with liver and other distant metastases from NEN were revised by the European Neuroendocrine Tumour Society (ENETS) in 2012. This review focuses on aspects relevant for surgical pathology.