Prostate-Specific Membrane Antigen Expression in Patients with Primary Prostate Cancer: Diagnostic and Prognostic Value in Positron Emission Tomography-Prostate-Specific Membrane Antigen

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This review manuscript by Omar Tayara and coworkers provided a comprehensive and insightful overview of recent development in PSMA-targeted PET imaging technologies and methodologies. The authors introduced the biological mechanism and highlighted the advancement of PSMA-targeted PET imaging in diagnostic and therapeutic applications across different stages of Prostate Cancer. However, some minor issues need to be addressed.

 

1.      While PSMA is a protein and enzyme, it's somehow commonly misused to refer to an imaging tracer. Tracers are molecules specifically designed to target PSMA for diagnostic or therapeutic purposes. Therefore, the sentence on page 4, line 144, requires correction. Instead of "Radiolabeled PSMA is considered a more suitable tracer...", a more accurate term could be "A radiolabeled PSMA-targeted agent," "radiolabeled PSMA ligand," or "PSMA radioligand." These terms accurately reflect that PSMA itself isn't the tracer, but rather the target for the tracer molecule.

 

2.      All the PET tracers discussed in this manuscript are urea-based ligands. While they contain amino acids as building blocks, they are not peptides. Therefore, the phrase "PSMA peptides" used on page 5, line 165, is not an accurate description.

 

3.      Figure 3 appears to contain a typo. It should read "No PSMA," not "No PMSA." While PSMA is highly upregulated in many prostate cancer cells, making it a valuable target for PET tracers, it's important to acknowledge that PSMA is weakly expressed in healthy prostate tissue. Therefore, “No PSMA” is not scientifically accurate.

 

4.      To enhance clarity for new readers unfamiliar with this field, the authors should consider adopting a consistent naming convention for the PET tracer referred to throughout the manuscript. Currently, several abbreviations are used to refer to the same tracer, including 68Ga-PSMA-11, Ga-68 PSMA-11, 68GaPSMA11, 68Ga-PSMA, and 68Ga-PSMA HBED-CC. Using a single, unambiguous term would improve readability and avoid potential confusion, especially for new readers unfamiliar with this field.

 

5.      The development of PSMA-targeted radiotracers is a rapidly advancing field, with numerous promising candidates currently undergoing clinical trials or already receiving FDA approval. The authors have mentioned several such tracers throughout the manuscript, including 68Ga-PSMA-11, 18F-PSMA-1007, 18F-DCFPyL, and 177Lu-PSMA-617. Including a dedicated paragraph to summarizing these tracers, their potential applications, and their current stage of development could benefit new readers.

Author Response

This review manuscript by Omar Tayara and coworkers provided a comprehensive and insightful overview of recent development in PSMA-targeted PET imaging technologies and methodologies. The authors introduced the biological mechanism and highlighted the advancement of PSMA-targeted PET imaging in diagnostic and therapeutic applications across different stages of Prostate Cancer. However, some minor issues need to be addressed.

Thank you for opinion, we addressed suggestions below.

1. While PSMA is a protein and enzyme, it's somehow commonly misused to refer to an imaging tracer. Tracers are molecules specifically designed to target PSMA for diagnostic or therapeutic purposes. Therefore, the sentence on page 4, line 144, requires correction. Instead of "Radiolabeled PSMA is considered a more suitable tracer...", a more accurate term could be "A radiolabeled PSMA-targeted agent," "radiolabeled PSMA ligand," or "PSMA radioligand." These terms accurately reflect that PSMA itself isn't the tracer, but rather the target for the tracer molecule.

Thank you for suggestion, we corrected it as proposed.

2. All the PET tracers discussed in this manuscript are urea-based ligands. While they contain amino acids as building blocks, they are not peptides. Therefore, the phrase "PSMA peptides" used on page 5, line 165, is not an accurate description.

Thank you for suggestion, we corrected it.

3. Figure 3 appears to contain a typo. It should read "No PSMA," not "No PMSA." While PSMA is highly upregulated in many prostate cancer cells, making it a valuable target for PET tracers, it's important to acknowledge that PSMA is weakly expressed in healthy prostate tissue. Therefore, “No PSMA” is not scientifically accurate.

 Thank you for suggestion, we corrected it.

4. To enhance clarity for new readers unfamiliar with this field, the authors should consider adopting a consistent naming convention for the PET tracer referred to throughout the manuscript. Currently, several abbreviations are used to refer to the same tracer, including 68Ga-PSMA-11, Ga-68 PSMA-11, 68GaPSMA11, 68Ga-PSMA, and 68Ga-PSMA HBED-CC. Using a single, unambiguous term would improve readability and avoid potential confusion, especially for new readers unfamiliar with this field.

Thank you for suggestion, we corrected it.

5. The development of PSMA-targeted radiotracers is a rapidly advancing field, with numerous promising candidates currently undergoing clinical trials or already receiving FDA approval. The authors have mentioned several such tracers throughout the manuscript, including 68Ga-PSMA-11, 18F-PSMA-1007, 18F-DCFPyL, and 177Lu-PSMA-617. Including a dedicated paragraph to summarizing these tracers, their potential applications, and their current stage of development could benefit new readers.

Thank you for suggestion, we added that paragraph.

Reviewer 2 Report

Comments and Suggestions for Authors

The topic highlighted in this paper is of current interest. PET-PSMA imaging has now become a standard procedure in clinical practice for the management of prostate cancer in various settings. The review presented by the authors it is interesting to read, underlining interesting insights for the clinician involved in the evaluation of patients with prostate cancer, and highlights the advantages and possible pitfalls in using this method.For primary staging, the well-known superiority of PSMA PET over conventional imaging (especially for high and intermediate risk patients) is emphasized. I suggest giving more space to the mpMRI and the divergent data regarding the possible method of choice for the evaluation of primary pelvic disease. Certainly, PET-MRI imaging, as underlined by the authors, could be the best solution for primary staging even if it is not a method used worldwide. The heterogeneity of prostatic disease in terms of PSMA expression and the possible implications in the response to therapy and in the selection of patients for different therapeutic options are well expressed and described. Two more sections could be added describing the issue of different tracers (consequently different pattern, detection rate, sensitivity and specificity) and homogeneity in reporting.

Comments on the Quality of English Language

The paper could be accepted after minor revision of text and addition of clinical data specified in the comment to the authors

Author Response

The topic highlighted in this paper is of current interest. PET-PSMA imaging has now become a standard procedure in clinical practice for the management of prostate cancer in various settings. The review presented by the authors it is interesting to read, underlining interesting insights for the clinician involved in the evaluation of patients with prostate cancer, and highlights the advantages and possible pitfalls in using this method.For primary staging, the well-known superiority of PSMA PET over conventional imaging (especially for high and intermediate risk patients) is emphasized. I suggest giving more space to the mpMRI and the divergent data regarding the possible method of choice for the evaluation of primary pelvic disease. Certainly, PET-MRI imaging, as underlined by the authors, could be the best solution for primary staging even if it is not a method used worldwide. The heterogeneity of prostatic disease in terms of PSMA expression and the possible implications in the response to therapy and in the selection of patients for different therapeutic options are well expressed and described. Two more sections could be added describing the issue of different tracers (consequently different pattern, detection rate, sensitivity and specificity) and homogeneity in reporting.

Thank you for opinion, we added them to the text.