The Additional Role of F18-FDG PET/CT in Characterizing MRI-Diagnosed Tumor Deposits in Locally Advanced Rectal Cancer

Round 1

Reviewer 1 Report

The Authors have evaluated retrospectively SUVmax and SUVmean in nodular structures surrounding locally advanced rectal carcinoma, and found that there is a trend in higher SUVmax and SUVmean, although not significant, in vascular tumor deposit than in lymph nodes (metastatic or normal). The paper is overall well written and results are interesting, but some changes should be made to the text in order to clarify some methodological issues.

Particularly, since the Authors consider spill-in effect on SUVmax and SUVmean, it should be useful to know whether all patients had voided the bladder before the scan, and in case the bladder was full of radiourine at the whole-body scan patients repeated the PET acquisition of the pelvis after voiding; besides, which structure was considered for measuring distance from high-uptake organ? the most active or the nearest one to the considered nodule?   

Some information on MRI in LARC was reported in both introduction and discussion section: it should be better to shorten the description of available literature in the introduction, and to report more "in extenso" in the discussion.

Several studies cited in the discussion report on SUVmax or SUVmean cut-off for distinguishing vascular tumor deposits from lymph nodes: was a cut-off calculated in your study? If not, why? If yes, please explain how it was obtained, its value and sensitivity/specificity. 

In the limitations, it should be reported that when taking into account effects of partial volume and spill-in the number of remaining lymph nodes is very low, and much lower than vascular tumor deposit, therefore hampering the statistic significance of differences in SUVmax and SUVmean between these two entities. Also, suggest further studies on wider population to confirm these findings. 

Best regards 

Please correct some terms:

page 2 line 69 use "hypothesized" instead of "posited" and at line 71 use "size" instead of "dimensions"

page 8 line 276 please use "established" instead of "installed"

Author Response

Reviewer 1.

We thank this reviewer for his or her useful comments and have addressed them point by point:

The Authors have evaluated retrospectively SUVmax and SUVmean in nodular structures surrounding locally advanced rectal carcinoma, and found that there is a trend in higher SUVmax and SUVmean, although not significant, in vascular tumor deposit than in lymph nodes (metastatic or normal). The paper is overall well written and results are interesting, but some changes should be made to the text in order to clarify some methodological issues.

1. Particularly, since the Authors consider spill-in effect on SUVmax and SUVmean, it should be useful to know whether all patients had voided the bladder before the scan, and in case the bladder was full of radiourine at the whole-body scan patients repeated the PET acquisition of the pelvis after voiding; besides, which structure was considered for measuring distance from high-uptake organ? the most active or the nearest one to the considered nodule?

We agree with this reviewer about the relevance of voiding before scanning, which is common practice in our hospital. Thus, the bladder is the high-activity organ in only a small minority of the patients. Distance was measured to the nearest high-activity organ, usually the primary tumor. We will add all this information to the methods section.

2. Some information on MRI in LARC was reported in both introduction and discussion section: it should be better to shorten the description of available literature in the introduction, and to report more "in extenso" in the discussion.

We agree with this reviewer that there is some redundancy with respect to the MRI information. We have added some relevant PET/CT content to the introduction. We feel the introduction is more balanced this way.

3. Several studies cited in the discussion report on SUVmax or SUVmean cut-off for distinguishing vascular tumor deposits from lymph nodes: was a cut-off calculated in your study? If not, why? If yes, please explain how it was obtained, its value and sensitivity/specificity.

As mentioned in the introduction and discussed later on, we have chosen not to calculate a cut-off value because of the significant partial volume effects that are to be expected in the small nodular structures involved and the problems inherent to correcting for it. We feel that cut-off values are not reliable enough in this clinical situation.

4. In the limitations, it should be reported that when taking into account effects of partial volume and spill-in the number of remaining lymph nodes is very low, and much lower than vascular tumor deposit, therefore hampering the statistic significance of differences in SUVmax and SUVmean between these two entities. Also, suggest further studies on wider population to confirm these findings.

We agree with this reviewer that the remaining number of nodular structures after taking into account the effects of partial volume and spill-in is very low, hampering proper statistics. We will stress this notion in the discussion section.

Please correct some terms:

page 2 line 69 use "hypothesized" instead of "posited" and at line 71 use "size" instead of "dimensions"

This was changed accordingly.

page 8 line 276 please use "established" instead of "installed"

            This was changed as well.

Reviewer 2 Report

The study investigated the additional role of ¹⁸F-FDG PET/CT in tumor deposits in locally advanced rectal cancer, which showed that SUV measurements may help in separating TDs from lymph node metastases or normal lymph nodes in patients with high-risk LARC. However, the reviewer has the following concerns.

(1) In abstract section, what’s the aim or purpose of this study?

(2) Please use the standardized and unified format, for example, F-18 FDG PET/CT, F18-FDG-PET/CT, FDG-PET were used in the paper.

(3) Please avoid using first person pronouns in the writing.

(4)The introduction section mainly focuses on MRI. Please add more relevant PET/CT content.

(5) The biggest problem with this article is that it uses MRI as the gold standard, which could lead to biased or unreliable results. This is because MRI is not the gold standard for diagnosing or assessing many conditions.

(6) In the Methods section, one radiologist and nuclear physician were in a consensus reading. This means that one radiologist and one nuclear physician were involved in the process of interpreting the medical images. They worked together to reach a consensus on the findings.However, what if they disagree?

(7) What’s the MRI diagnosis standard for TD and LN?

(8) What's the ¹⁸F-FDG PET imaging results? In table 1, it would be better if the ¹⁸F-FDG PET characteristics were added.

The writing of the paper is well organized, but there are some minor issues that need to be corrected. For example, the first person should not be used, and minor issues such as grammar and tense need to be corrected.

Author Response

Reviewer 2.

We thank this reviewer for his or her useful comments and have addressed them point by point:

The study investigated the additional role of ¹⁸F-FDG PET/CT in tumor deposits in locally advanced rectal cancer, which showed that SUV measurements may help in separating TDs from lymph node metastases or normal lymph nodes in patients with high-risk LARC. However, the reviewer has the following concerns.

1. In abstract section, what’s the aim or purpose of this study?

Please notice the rationale of the study in the first line of the abstract.

2. Please use the standardized and unified format, for example, F-18 FDG PET/CT, F18-FDG-PET/CT, FDG-PET were used in the paper.

This was changed accordingly, using F18-FDG PET/CT throughout the paper.

3. Please avoid using first person pronouns in the writing.

This was changed accordingly.

4. The introduction section mainly focuses on MRI. Please add more relevant PET/CT content.

More relevant PET/CT content was added. We feel the introduction is more balanced this way.

5. The biggest problem with this article is that it uses MRI as the gold standard, which could lead to biased or unreliable results. This is because MRI is not the gold standard for diagnosing or assessing many conditions.

We agree with this reviewer that MRI is not the gold standard. Actually, a gold standard is lacking for this clinical situation. Confirmation by pathology is lacking, because of the retrospective nature of the study. Besides, discrimination of TDs from LNs has prognostic significance, but no immediate consequences for initial patient management. Therefore no baseline biopsies of any of the nodular structures were performed. In addition, most of them respond well to these neoadjuvant therapies, leaving no histopathological substrate that can be examined. This is all mentioned in the discussion, limits of the study section.

6. In the Methods section, one radiologist and nuclear physician were in a consensus reading. This means that one radiologist and one nuclear physician were involved in the process of interpreting the medical images. They worked together to reach a consensus on the findings. However, what if they disagree?

When the radiologist and the nuclear physician disagreed, the radiologist was decisive with respect to the MRI determination of the nature of the nodule. The nuclear physician was decisive in correlating the nodular structures on the F18-FDG PET/CT images.

This was added to the methods section.

7. What’s the MRI diagnosis standard for TD and LN?

This is mentioned in the methods section. TDs were defined as irregular, nodule-like structures in line with a vessel without the typical characteristics of a lymph node, as described by Lord et al. [8].

8. What's the ¹⁸F-FDG PET imaging results? In table 1, it would be better if the ¹⁸F-FDG PET characteristics were added.

The patients that were retrospectively enrolled in this study, had their F18-FDG PET/CT scans for monitoring neoadjuvant therapies such as induction chemotherapy and chemoradiotherapy. The results are beyond the scope of this paper and only the baseline scans have been used. Based on these scans, only three patients were upstaged from N1 to N2, and three patients to a stage M1 because of distant lymph node metastases. This was added to the results section.

The writing of the paper is well organized, but there are some minor issues that need to be corrected. For example, the first person should not be used, and minor issues such as grammar and tense need to be corrected.

Round 2

Reviewer 2 Report

The revised version is better than the previous one. The reviewer has two concerns.

(1)In Table 1. "Pelvic MRI and F18-FDG PET/CT imaging details", the results of PET/CT only show the data of lymph nodes. It would be better if the data of TD could be added.

(2)In Figure 1 and 3, are the MRI sagittal images showing the tumor or the lymph nodes? Please label the lesions.

(3) In discussion part 4.1 and 4.2, most of the discussion is about the results of other people's research. It would be better if there could be more integration of the results of this study.

(4) As mentioned before, this study used MRI as a control, which may lead to some limitations in the conclusions of the study, which must be explained in the article.

Author Response

We thank reviewer 2 again for his or her useful comments.

The revised version is better than the previous one. The reviewer has two concerns.

• In Table 1. "Pelvic MRI and F18-FDG PET/CT imaging details", the results of PET/CT only show the data of lymph nodes. It would be better if the data of TD could be added.

We agree with this reviewer that obviously only lymph node data are shown. However, the TDs are incorporated in the N stage, i.e. N1c. F18-FDG PET/CT had only very limited impact on N staging, as stated in the results section and discussion.

(2) In Figure 1 and 3, are the MRI sagittal images showing the tumor or the lymph nodes? Please label the lesions.

Only the primary tumor is depicted in the sagittal images. This is added.

(3) In discussion part 4.1 and 4.2, most of the discussion is about the results of other people's research. It would be better if there could be more integration of the results of this study.

We agree with this reviewer that more integration is needed here. We have therefore added some relevant passages.  

(4) As mentioned before, this study used MRI as a control, which may lead to some limitations in the conclusions of the study, which must be explained in the article.

We agree with this reviewer that the lack of histopathological proof is a serious limitation and that MRI by no means can replace it. We have stressed this notion once more.