Bile Flow Dynamics in Patients with Cholelithiasis: An Evaluation with Cine-Dynamic Magnetic Resonance Cholangiopancreatography Using a Spatially Selective Inversion-Recovery Pulse

Round 1

Reviewer 1 Report

The work is interesting and well written. Gallstones are a very frequent pathology, and MRI-cholangiopancreatography is an exam usually performed in every hospital, so the topic is very useful. I have the following comment:

Line 163-164: the Authors wrote that “the diameter of the common bile duct was significantly larger in the gallstone group (7 [range, 6-8] mm) than in the non-gallstone group (6 [range, 5-7.5] mm) “ but it doesn’t seems to be significantly larger, based on the numbers in the parenthesis; Authors don’t calculate the p for those numbers.

More detailed comments：

1. Do you consider the topic original or relevant in the field, and if so, why?

The topic is not too original because other Authors have investigate the role of this technique (see references 9 and 10), but not in relation to gallstones. This work could be relevant because gallstones are a very frequent pathology, and radiologists usually performed MRCP to better characterize them and the changes that they determined in the biliary sistems. The present work studies in particular the anterograde flow of the bile in patients with and without gallstones.

2. To improve the manuscript, what does it should add on the subject area?

The manuscript add to the subject area the role of cine-dynamic MRCP with a spatially selective inversion-recovery (IR) pulse in the diagnostic pathway of patients with gallstones. Maybe they can increase their study population, and the measures (the maximal diameter of the common bile duct and the SIs of the gallbladder and of the paraspinal muscles in the T1 GE in-phase and opposite-phase images) could be done by all of the 3 radiologist instead by only by 2 of them.

3. To improve the manuscript, what does it should add on the subject area?

The manuscript add to the subject area the role of cine-dynamic MRCP with a spatially selective inversion-recovery (IR) pulse in the diagnostic pathway of patients with gallstones. Maybe they can increase their study population, and the measures (the maximal diameter of the common bile duct and the SIs of the gallbladder and of the paraspinal muscles in the T1 GE in-phase and opposite-phase images) could be done by all of the 3 radiologist instead by only by 2 of them.

4. What specific improvements could the authors consider regarding the methodology?

They have to increase the number of patients in the gallstone group, because they are only 1/3 if compared with the non-gallstone group. The measures could be done by all of the 3 radiologist instead by only by 2 of them.

5. Are the references appropriate?

Yes. They can add: Higashi M, Tanabe M, Inhara K, et al.  “Pancreatobiliary Flow Dynamics: Association Between Bile and Pancreatic Juice Evaluated With Cine-Dynamic Magnetic Resonance Cholangiopancreatography Using Spatially Selective Inversion Recovery Pulse” J Magn Reson Imaging 2021 Dec;54(6):1902-1911.doi: 10.1002/jmri.27775

6. Please include any additional comments on the tables and figures.

Figures and Tables are clear and consistent with Authors results.

Maybe Authors can add other figures, because they submitted only one figure related to the calculation of SIR and SRR and another related to the an example of their grading score (grade 1 and 2); maybe they can add other examples of other grading scores.

Fig. 3 legend has to be in the same page with fig.3; the short arrow in fig.3b has to be shorter, because it’s too similar to the first cited arrow in the same image.

In tab.1 they reported the p-value of the common bile duct diameter: they have to cite it also in the text.

Author Response

Response to Reviewer 1 Comments

1. Line 163-164: the Authors wrote that “the diameter of the common bile duct was significantly larger in the gallstone group (7 [range, 6-8] mm) than in the non-gallstone group (6 [range, 5-7.5] mm), but it doesn’t seems to be significantly larger, based on the numbers in the parenthesis; Authors don’t calculate the p for those numbers.

Response 1;

In this study, the difference in the common duct diameter between the gallstone and non-gallstone group was “statistically” significant. However, as the reviewer pointed out, we are also not sure that this diameter difference would “clinically” significant. Therefore, the description in discussion on the difference in the common duct diameter between the two groups have been kept to a minimum.

Regarding the p value, we added the p value of the common duct diameter in the text.

2. They have to increase the number of patients in the gallstone group, because they are only 1/3 if compared with the non-gallstone group.

Response 2;

As the reviewer said, it will be desirable to increase the number of patients with gallstones, but the research proposal of this study does not allow for an increase of the subject number. We think that further evaluation using a large patient population with gallstones will be needed to confirm our results.

We described as follows in the Discussion.

Further prospective clinical studies considering these factors with a large sample size of gallstones will thus be needed to validate our results.

3. The measures (the maximal diameter of the common bile duct and the SIs of the gallbladder and of the paraspinal muscles in the T1 GE in-phase and opposite-phase images)　could be done by all of the 3 radiologist instead by only by 2 of them.

Response 3;

MRI measurements (the common bile duct diameter and the SIs of the gallbladder and of the paraspinal muscles in the T1 GE in-phase and opposite-phase images) were performed by three radiologists (M.H., M.T., K.I., with 6, 19, and 33 years of clinical experience, respectively) including one additional radiologist instead by 2 according to the reviewers’ comment.

4. They can add: Higashi M, Tanabe M, Inhara K, et al.  “Pancreatobiliary Flow Dynamics: Association Between Bile and Pancreatic Juice Evaluated With Cine-Dynamic Magnetic Resonance Cholangiopancreatography Using Spatially Selective Inversion Recovery Pulse” J Magn Reson Imaging 2021 Dec;54(6):1902-1911.doi: 10.1002/jmri.27775

Response 4;

We added the reference (the reference #10) in the Introduction according to the reviewers’ comment.

5. Maybe Authors can add other figures, because they submitted only one figure related to the calculation of SIR and SRR and another related to the an example of their grading score (grade 1 and 2); maybe they can add other examples of other grading scores.

Response 5;

We added another figure of other grading scores (Figure 4) according to the reviewers’ comment.

6. 3 legend has to be in the same page with fig.3; the short arrow in fig.3b has to be shorter, because it’s too similar to the first cited arrow in the same image.

Response 6;

We moved Figure 3 legend to the same page as Figure 3. In addition, we changed the length of the arrows in Figure 3b according to the reviewers’ comment.

7. In tab.1 they reported the p-value of the common bile duct diameter: they have to cite it also in the text.

Response 7;

We added the p value of the common duct diameter in the text according to the reviewers’ comment.

Reviewer 2 Report

Regarding Kappa according to Fleiss (Results, page 4): Are the two Kappa values really identical (0.922). Because of the ordinal scaled parameters (frequencies observed and secretion grade) a weighted Kappa seems to be appropriate.

The difference between common bile duct diameter between th gallstone and the non-gallstone group is statistically significant (p = 0.015). However, is it also clinically relevant? The difference between the medians is only 1. 

The first sentence on page 6 (In the gallstone group, ...) is cumbersomely worded.

Table 2: The non-signficant correlations in the non-gallstone group should be commented in the text.

A multiple logistic regression analysis for the binary outcome "gallstone" (yes / no) is recommended. This analysis may elucidate the importance and the relevance of each significant parameter in table 2. 

The retrospective study design is mentioned at the very end of the discussion. This very important information should be given already in the abstract and in section 2 "Materials and methods".

Discussion, last sentence: PROSPECTIVE studies are needed.

Author Response

Response to Reviewer 2 Comments

1. Regarding Kappa according to Fleiss (Results, page 4): Are the two Kappa values really identical (0.922). Because of the ordinal scaled parameters (frequencies observed and secretion grade) a weighted Kappa seems to be appropriate.

Response 1;

We evaluated interobserver agreement by using weighted kappa coefficient according to the reviewers’ comment.

We described as follows in the first paragraph of the Results;

The interobserver agreement among the 3 reviewers for the frequency of antegrade and reverse bile flow observed (reviewer 1 vs. reviewer 2, κ = 0.892; reviewer 1 vs. reviewer 3, κ = 0.886; reviewer 2 vs. reviewer 3, κ = 0.986) and the moving distance (secretion grade) of antegrade and reverse bile flow (reviewer 1 vs. reviewer 2, κ = 0.914; reviewer 1 vs. reviewer 3, κ = 0.907; reviewer 2 vs. reviewer 3, κ = 0.988) was excellent.

2. The difference between common bile duct diameter between the gallstone and the non-gallstone group is statistically significant (p = 0.015). However, is it also clinically relevant? The difference between the medians is only 1. 

Response 2;

In this study, the difference in the common duct diameter between the gallstone and non-gallstone group was “statistically” significant. However, as the reviewer pointed out, we are also not sure that this diameter difference would “clinically” significant. Therefore, the description in discussion on the difference in the common duct diameter between the two groups have been kept to a minimum.

3. The first sentence on page 6 (In the gallstone group, ...) is cumbersomely worded.

Response 3;

We changed the first sentence on page 6 according to the reviewers’ comment as follows;

In the gallstone group, the frequency and mean secretion grade of the antegrade bile flow showed no significant correlations with the common bile duct diameter (frequency, r = -0.164, p = 0.433; mean secretion grade, r = -0.099, p = 0.638), SIR of the gallbladder on T1-weighted in-phase imaging (frequency, r = 0.194, p = 0.353; mean secretion grade, r = 0.192, p = 0.358) or SIR of the gallbladder on T1-weighted opposed-phase imaging (frequency, r = 0.209, p = 0.316; mean secretion grade, r = 0.135, p = 0.519).

4. Table 2: The non-significant correlations in the non-gallstone group should be commented in the text.

Response 4;

We added the non-significant correlations in the non-gallstone group in the Results as follows;

In the non-gallstone group, the frequency and mean secretion grade of the antegrade bile flow also showed no significant correlations with the common bile duct diameter (frequency, r = 0.065, p = 0.593; mean secretion grade, r = 0.061, p = 0.619), SIR of the gallbladder on T1-weighted in-phase imaging (frequency, r = -0.146, p = 0.232; mean secretion grade, r = -0.134, p = 0.273) or SIR of the gallbladder on T1-weighted opposed-phase imaging (frequency, r = -0.097, p = 0.428; mean secretion grade, r = -0.092, p = 0.450).

5. A multiple logistic regression analysis for the binary outcome "gallstone" (yes / no) is recommended. This analysis may elucidate the importance and the relevance of each significant parameter in table 2. 

Response 5;

According the reviewers’ comment, we conducted a multiple logistic regression analysis to examine the association of the presence or absence of gallstones with the MR measurements; analyzed MRI measurements included diameter of the common bile duct, SIR of the gallbladder on T1-weighted in-phase images, SIR of the gallbladder on T1-weighted opposed-phase images, frequency of the antegrade bile flow and mean secretion grade of the antegrade bile flow. In addition, we added the results of the analysis in the last paragraph of the Results as follows;

A multiple logistic regression analysis showed that the presence of gallstones was significantly associated with only mean secretion grade of the antegrade bile flow (p = 0.009, odds ratio = 3.972, 95% confidence interval = 1.409-11.198) and diameter of the common bile duct (p = 0.016, odds ratio = 1.424, 95% confidence interval = 1.067-1.899).

6. The retrospective study design is mentioned at the very end of the discussion. This very important information should be given already in the abstract and in section 2 "Materials and methods".

Response 6;

We added “retrospective study design” in the abstract according to the reviewers’ comment as follows ;

We retrospectively examined 25 patients with gallstones (gallstone group) and 69 patients without gallstones (non-gallstone group) who underwent abdominal MRI including in- and opposed-phase T1-weighted images and cine-dynamic MRCP with a spatially selective IR pulse.

In addition, we also added it in the Study population of the Materials and Methods as follows,

This retrospective study was approved by our institutional review board, and the need for informed consent from the patients was waived.

7. Discussion, last sentence: PROSPECTIVE studies are needed.

Response 7;

We added “prospective” in the last sentence of the Discussion as follows;

Further prospective clinical studies considering these factors with a large sample size of gallstones will thus be needed to validate our results.

Round 2

Reviewer 2 Report

Thank you fpr having considered and implemented my suggestions. I think the paper In my opinion, the paper is very good in the present form.