Comparison between PSMA PET/CT and MRI for Characterizing Hepatocellular carcinoma: A Real-World Study

Round 1

Reviewer 1 Report

Dear authors,

Thank you for the manuscrip you submitted, which is quite interesting. However a few points need to be furyher clarified.

My first question would concern wether sensitivities, specificities etc refer to per lesion or per patient basis. If they refer to per lesion, were they individually evaluated during follow up? In the table you describe the pd per patient to my understanding. Could you provide more information regarding your methodology?

Was the median AFP at the time of the study normal? (see table 1,2 and 3)

Was the heterogeinity in PSMA uptake considered pos, neg or undetermined? (ie table 3 15RC).

A few acronyms or symbols in table 3 need explanation (ie does Y mean positive?)

Three months between  PSMA-PET and MRI may be a long interval for HCC patients, please comment in the discussion part.

Also please comment on the false negative results and the drawbacks of the study.

Could you provide more information about the interval between treatment and PSMA-PET examination?

Finally, perhaps it would be interesting to also seperate the two groups of patients (primary and reccurent) and provide more details about sens and spec for each group.

Once again thank you for sharing your study

Author Response

Please see the attachment.

Author Response File: Author Response.docx

Reviewer 2 Report

In the retrospective study under evaluation the diagnostic performance of PET/CT with 68Ga-PSMA-11 has been compared with that of MRI for HCC detection in a specific clinical setting of high-risk patient. The paper is clear and focused on a very interesting and cutting-edge topic.

The main limitations of the study are represented by the low number of patient and the lack of histological confirmation.

Some considerations:

- Introduction:  page 2, line 51, the authors state: “the addition of PSMA PET may provide an additional metabolic assessment for a suspected tumor”. I would change the sentence into “additional assessment of a suspected tumor with a molecular probe”, according to the specific mechanism by which the tracer is incorporated into lesions.

- Materials and methods: the authors write: “PET images were acquired 30 minutes after tracer injection over ~ 1 hour. “. Actually there is no consensus on the most adequate timing to carry out a PET/CT scan with PSMA tracer for HCC. How did the authors chose this timing instead of, as an example, the standard timing employed for PCa (60 min)?

- Page 3, lines 82-84. As the same authors state, histology is not commonly performed in HCC, therefore the standard-of-truth is often composite and based on clinical evidences. However, since it is of utmost importance as a reference in this paper, it should be better detailed.

- Results: it is not clear for me if the authors calculated a per-patient or per-lesion sensitivity, specificity, etc.. From Table 2 and 3, I presume that we deal with a per-lesion analysis but it would be worthy of specification.

- Figure 2: it’s nice. However, I suggest to describe this case in details: patient’s age, sex, risk factors, previous loco-regional therapy (there is a gross hypodense area, it should be described), explanation of each image section; please add lettering for making the image clearer; please add a correlative ce-CT image if it is available.

- Discussion: I warmly suggest to add a paragraph describing the different PET-based approaches for the imaging of HCC, also mentioning tracers other than PSMA, such as choline and FDG, citing relevant references in the field (ref. DOI: 10.1080/17434440.2019.1608817, doi: 10.23736/S1824-4785.17.02994-6).

The authors write: “tumour vascularity, supporting this as one of the mechanisms of action for PSMA in malignancies including renal cell carcinoma, prostate cancer, and hepatocellular carcinoma”. Indeed, neovascularization is not the main mechanism of incorporation into PCa, since in such a case PSMA is expressed on tumor cells. Please amend.

Among study limitations, I suggest to include that not all the patients who performed PSMA PET were also submitted to MRI.

I would at least mention that PSMA-positivity paves the ground for theranostic approaches (doi. org/ 10. 1007/ s00259- 022- 05884-9).

Conclusions: taking into account the aforementioned study limitations (and, in general, the relatively low strength of real-world studies), I would change the sentence: “This exploratory study suggests that PSMA PET/CT may be equivalent to MRI” into “In our exploratory study, PSMA PET/CT resulted as sensitive as MRI” . Consider also to change the title accordingly, as an example “Comparison between PSMA PET/CT and MRI for characterizing hepatocellular carcinoma: a real-world study”. Or something similar.

Author Response

Please see the attachment.

Author Response File: Author Response.docx

Round 2

Reviewer 2 Report

The authors have properly addressed Reviewers' criticisms.