Transplanted Mesenteric Lymph Node Metastasis After Free Jejunal Reconstruction in Head and Neck Cancer

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This manuscript is a retrospective cohort study that investigates mesenteric lymph node swelling in free jejunal grafts following TPL/TPLE for head and neck cancer. The authors describe the frequency of mesenteric lymph node swelling, temporal changes in lymph node size, and its relationship with cancer metastasis and prognosis. The study presents novel findings with clinical relevance and, in my opinion, is suitable for publication in this journal.

However, I believe the following revisions should be addressed prior to a final decision on acceptance:

 

Q1: Although the authors mention inconsistencies in the timing of CT evaluations for postoperative mesenteric lymph node swelling, they do not clearly define the postoperative period within which such swelling was detected and included in their analysis. I recommend that the authors clarify this in the Materials and Methods and Results sections.

 

Q2: In the TNM classification presented in Table 1 and the prognostic analysis shown in Figure 3, cases of head and neck cancer and esophageal cancer are presented and analyzed together. However, since these two distinct cancer types have different biological and clinical characteristics, it is inappropriate to combine them in the analysis. It would be more appropriate to either analyze them separately or exclude one of the two from the presentation and analysis.

 

Q3: Were the enlarged lymph nodes limited to one per patient, or were there cases with multiple swollen nodes? The authors should clarify this point in the Results section.

 

Q4: The manuscript does not mention the duration of the postoperative follow-up period. I recommend that the authors provide this information, including the mean (or median) follow-up duration.

 

Q5: In this manuscript, recurrence is included among the risk factors for mesenteric lymph node swelling in the multivariate analysis. However, in terms of causality, a risk factor should precede the outcome temporally, as it is considered a "cause" rather than a "consequence." If recurrence occurred after the lymph node swelling, it would be inappropriate to include it as a risk factor. The authors should provide a rationale for including recurrence as a risk factor in this context. This point is related to Q1.

 

Q6: Which came first: the CT-based evaluation of mesenteric lymph node swelling or the administration of PORT? The authors argue, based on previous studies, that PORT may suppress mesenteric lymph node swelling. However, if PORT was performed after the swelling had already occurred, this interpretation should be reconsidered. This point is also related to Q1.

 

Q7: In the Discussion section, the authors suggest that PET-CT should be considered in cases of lymph node swelling. Should PET-CT be performed in all cases with swelling greater than 5 mm, or only when additional findings are present? I would appreciate clarification from the authors on this point.

 

Q8: The sentence from page 6, line 146 to page 7, line 149 is unclear. I recommend that the authors revise this passage to improve clarity.

 

Q9: I would like the authors to explain why mesenteric lymph node swelling is more frequently observed following salvage surgery.

 

Q10: Please correct the following typographical errors found in the manuscript:

In Tables 3 and 5, "Rocal" should be corrected to "Local."

In Figure 2, "Recerrence" should be corrected to "Recurrence."

In the legend of Figure 3, "lympha" should be corrected to "lymph."

Author Response

Q1: Although the authors mention inconsistencies in the timing of CT evaluations for postoperative mesenteric lymph node swelling, they do not clearly define the postoperative period within which such swelling was detected and included in their analysis. I recommend that the authors clarify this in the Materials and Methods and Results sections.

 

Response:

To clearly define the postoperative period in our analysis, we added the following sentence: "All CT scans were evaluated from immediately after surgery until the completion of follow-up or until death." in the Materials and Methods section (Page 8, Lines 210-211), and "The median time at which the largest postoperative mesenteric lymph node was observed on CT was 8 months (range, 3 to 13 months) after surgery." in the Result section (Page 3, Lines 76-77).

 

 

Q2: In the TNM classification presented in Table 1 and the prognostic analysis shown in Figure 3, cases of head and neck cancer and esophageal cancer are presented and analyzed together. However, since these two distinct cancer types have different biological and clinical characteristics, it is inappropriate to combine them in the analysis. It would be more appropriate to either analyze them separately or exclude one of the two from the presentation and analysis.

 

Response:

We reanalyzed the data excluding esophageal cancer, and as a result, the values in Table 1-4 and Figure 1-3 have been changed.

 

 

Q3: Were the enlarged lymph nodes limited to one per patient, or were there cases with multiple swollen nodes? The authors should clarify this point in the Results section.

 

Response:

In the Result section, we added the following sentence: “Although there were cases in which multiple lymph nodes were enlarged, this study evaluated the largest lymph node regardless of the number.” (Page 3, Lines 79-80)

 

Q4: The manuscript does not mention the duration of the postoperative follow-up period. I recommend that the authors provide this information, including the mean (or median) follow-up duration.

 

Response:

In the Result section, we added the following sentence: “The median postoperative follow-up duration was 25.6 months (range: 1-88.6 months).” (Page 2, Lines 65-66)

 

 

Q5: In this manuscript, recurrence is included among the risk factors for mesenteric lymph node swelling in the multivariate analysis. However, in terms of causality, a risk factor should precede the outcome temporally, as it is considered a "cause" rather than a "consequence." If recurrence occurred after the lymph node swelling, it would be inappropriate to include it as a risk factor. The authors should provide a rationale for including recurrence as a risk factor in this context. This point is related to Q1.

 

Response:

We excluded "recurrence" from the risk factors and reanalyzed the data (Figure 2, Table 4).

 

 

Q6: Which came first: the CT-based evaluation of mesenteric lymph node swelling or the administration of PORT? The authors argue, based on previous studies, that PORT may suppress mesenteric lymph node swelling. However, if PORT was performed after the swelling had already occurred, this interpretation should be reconsidered. This point is also related to Q1.

 

Response:

Because the CT evaluation included the period immediately after surgery, it also evaluated the short period before PORT. However, we think this mechanism was due to the inhibition of lymphangiogenesis rather than a direct effect on the lymph nodes. In other words, we believe that PORT suppressed the growth of lymph nodes that may have originally shown a tendency to grow, resulting in fewer cases of lymph node swelling in the PORT group.

 

 

Q7: In the Discussion section, the authors suggest that PET-CT should be considered in cases of lymph node swelling. Should PET-CT be performed in all cases with swelling greater than 5 mm, or only when additional findings are present? I would appreciate clarification from the authors on this point.

 

Response:

As the reviewer pointed out, the timing of PET is difficult. Based on the results of this study, we recommend it for cases of enlargement of 5 mm or more, rather than just simple swelling. In the Disccusion section, we added the following sentence: “In the group with postoperative mesenteric lymph node swelling, close attention should be paid to any increase in lymph node size, and in cases with an increase in size of 5 mm or more, further evaluation such as PET-CT may be helpful in making a diagnosis.” (Page 7, Lines 171-174)

 

 

Q8: The sentence from page 6, line 146 to page 7, line 149 is unclear. I recommend that the authors revise this passage to improve clarity.

 

Response:

We fixed it as follows: “The reason why postoperative mesenteric lymph node swellingwas more common in cases without PORT is that the cases without ECE and the cases without PORT were almost the same patient group, in short, the presence of ECE is one of the criteria for PORT [12].” (Page 7, Lines 152-155)

 

 

Q9: I would like the authors to explain why mesenteric lymph node swelling is more frequently observed following salvage surgery.

 

Response:

In the Disccusion section, we added the following sentence: “In cases of salvage surgery, the resected edges of the pharynx and esophagus are post-RT and have strong inflammatory changes, which leads to a stronger reaction of the transplanted tissue (FJ) to the surrounding environment. Furthermore, since the FJ itself has not received RT and lymphangiogenesis was not suppressed, it is thought that there were more cases of postoperative mesenteric lymph node swelling in the salvage surgery group.” (Page 7, Lines 158-163)

 

 

Q10: Please correct the following typographical errors found in the manuscript:

 

In Tables 3 and 5, "Rocal" should be corrected to "Local."

→We fixed it.

 

In Figure 2, "Recerrence" should be corrected to "Recurrence."

→We removed the "recurrence" section.

 

In the legend of Figure 3, "lympha" should be corrected to "lymph."

→We fixed it.

 

 

 

 

Reviewer 2 Report

Comments and Suggestions for Authors

The authors present a retrospective cohort analysis on mesenteric lymph node (LN) swelling and metastasis following free jejunal reconstruction. The study includes 55 cases, among which LN swelling was observed in 18 cases (32.7%) and LN metastasis in 2 cases (3.6%). These rates appear consistent with previously reported frequencies in the literature.

 

The presence of mesenteric LN metastasis, although rare, holds significant clinical value. The two cases identified in this study warrant detailed documentation. While the Methods section notes that the diagnosis of metastasis was confirmed pathologically, the specific histopathological findings and clinical course (including imaging such as PET-CT) are not described. Given the rarity of mesenteric LN metastasis—as noted by the authors themselves referencing 6 previous reports involving 8 cases—these two cases alone would be worth reporting individually. I strongly recommend adding a dedicated figure/table or section describing the clinical course, PET-CT findings (e.g., FDG uptake and SUVmax), and histological features of these two patients.

 

Figure 1, which illustrates the time course of LN size changes, is highly informative. It clearly demonstrates that simple LN swelling may regress or remain stable over time, while metastatic nodes enlarge beyond 5 mm and do not regress. This contrast between the clinical trajectories of swollen versus metastatic LNs is an important and visually compelling finding that enhances the value of the paper.

 

The risk factor analysis is also compelling. The authors identify the absence of pathological extranodal extension (ENE) and the absence of postoperative radiotherapy (PORT) as risk factors for mesenteric LN swelling. At first glance, this may appear paradoxical—one would expect ENE-positive cases to have a higher risk of metastasis. However, the authors provide a plausible explanation: patients with ENE generally receive PORT, which may suppress lymphangiogenesis and thereby reduce the risk of mesenteric LN swelling. While this is an interesting and logical interpretation, the underlying mechanism may be difficult for some readers to grasp. I suggest creating a schematic diagram to visually explain the proposed pathway. This would improve clarity and make the discussion more accessible to a broader readership.

 

Finally, the take-home message for clinicians should be emphasized more clearly. The authors propose PET-CT as a method to distinguish between mesenteric LN metastasis and benign swelling, based on the presence or absence of FDG uptake. While this is a reasonable and intuitive recommendation, further scientific evidence is needed to support this conclusion. Specifically, PET-CT images from the two metastatic cases should be presented, including SUVmax values and comparative findings in swelling-only cases. Without such data, the recommendation to use PET-CT as a diagnostic discriminator remains speculative.

 

Moreover, it may be worthwhile to consider and discuss alternative or adjunctive approaches. For instance:

1. If the aim is to monitor LN size over time, could ultrasound be a simpler, more cost-effective, and less invasive option?
2. Do mesenteric LN metastases show classic ultrasound features such as increased vascularity, or do they behave differently?
3. Would a size-based cutoff (e.g., >5 mm) followed by fine-needle aspiration (FNA) biopsy be feasible?
4. If the authors are reluctant to perform FNA, what are the concerns—risk to flap vasculature, technical difficulty, or lack of supporting evidence for safety? How could those safety concerns be addressed?

 

By expanding the discussion to include these practical clinical questions, the paper will become more robust and appealing to both surgeons and oncologists managing postoperative surveillance in head and neck cancer patients.

Author Response

The presence of mesenteric LN metastasis, although rare, holds significant clinical value. The two cases identified in this study warrant detailed documentation. While the Methods section notes that the diagnosis of metastasis was confirmed pathologically, the specific histopathological findings and clinical course (including imaging such as PET-CT) are not described. Given the rarity of mesenteric LN metastasis—as noted by the authors themselves referencing 6 previous reports involving 8 cases—these two cases alone would be worth reporting individually. I strongly recommend adding a dedicated figure/table or section describing the clinical course, PET-CT findings (e.g., FDG uptake and SUVmax), and histological features of these two patients.

 

Response:

One of the two cases has been previously reported as a case report, so we did not include the individual images to avoid the possibility of duplicate submission. Instead, we added the SUV values for the PET scans. We added the following sentence to the Results section 2.2:” and the Standardized Uptake Value (SUV) max was 6.08 in Case 8 and 12.25 in Case 12 (Table 3)” (Page 3, Lines 85-86)

 

 

Figure 1, which illustrates the time course of LN size changes, is highly informative. It clearly demonstrates that simple LN swelling may regress or remain stable over time, while metastatic nodes enlarge beyond 5 mm and do not regress. This contrast between the clinical trajectories of swollen versus metastatic LNs is an important and visually compelling finding that enhances the value of the paper.

 

The risk factor analysis is also compelling. The authors identify the absence of pathological extranodal extension (ENE) and the absence of postoperative radiotherapy (PORT) as risk factors for mesenteric LN swelling. At first glance, this may appear paradoxical—one would expect ENE-positive cases to have a higher risk of metastasis. However, the authors provide a plausible explanation: patients with ENE generally receive PORT, which may suppress lymphangiogenesis and thereby reduce the risk of mesenteric LN swelling. While this is an interesting and logical interpretation, the underlying mechanism may be difficult for some readers to grasp. I suggest creating a schematic diagram to visually explain the proposed pathway. This would improve clarity and make the discussion more accessible to a broader readership.

 

Response:

Because these mechanisms have no scientific basis and are merely our speculation based on a literature review. In consideration of possible critical opinions, we have not created a schematic diagram. Instead, to aid in understanding these mechanisms, we have revised the text as follows to include the mechanism of salvage surgery: “The reason why postoperative mesenteric lymph node swelling was more common in cases without PORT is that the cases without ECE and the cases without PORT were almost the same patient group, in short, the presence of ECE is one of the criteria for PORT [12]. PORT may cause inhibition of lymphangiogenesis, leading to impaired lymphatic flow into the mesentery [13]. As a result, cases with PORT, which were also those with ECE, might have shown fewer cases of postoperative mesenteric lymph node swelling. In cases of salvage surgery, the resected edges of the pharynx and esophagus are post-RT and have strong inflammatory changes, which leads to a stronger reaction of the transplanted tissue (FJ) to the surrounding environment. Furthermore, since the FJ itself has not re-ceived RT and lymphangiogenesis was not suppressed, it is thought that there were more cases of postoperative mesenteric lymph node swelling in the salvage surgery group.” (Page 7, Lines 152-163)

 

Finally, the take-home message for clinicians should be emphasized more clearly. The authors propose PET-CT as a method to distinguish between mesenteric LN metastasis and benign swelling, based on the presence or absence of FDG uptake. While this is a reasonable and intuitive recommendation, further scientific evidence is needed to support this conclusion. Specifically, PET-CT images from the two metastatic cases should be presented, including SUVmax values and comparative findings in swelling-only cases. Without such data, the recommendation to use PET-CT as a diagnostic discriminator remains speculative.

 

Response:

In cases where there is swelling but no metastasis, PET-CT scans were not performed in many cases, so comparative data cannot be presented. As the reviewer pointed out, there is little scientific evidence to support the use of PET-CT as a diagnostic indicator, and it is merely speculation. Therefore, the text in the Discussion section has been changed to the following:” In the group with postoperative mesenteric lymph node swelling, close attention should be paid to any increase in lymph node size, and in cases with an increase in size of 5 mm or more, further evaluation such as PET-CT may be helpful in making a diagnosis” (Page 7, Lines 171-174)

 

 

Moreover, it may be worthwhile to consider and discuss alternative or adjunctive approaches. For instance:

1. If the aim is to monitor LN size over time, could ultrasound be a simpler, more cost-effective, and less invasive option?
2. Do mesenteric LN metastases show classic ultrasound features such as increased vascularity, or do they behave differently?
3. Would a size-based cutoff (e.g., >5 mm) followed by fine-needle aspiration (FNA) biopsy be feasible?
4. If the authors are reluctant to perform FNA, what are the concerns—risk to flap vasculature, technical difficulty, or lack of supporting evidence for safety? How could those safety concerns be addressed?

By expanding the discussion to include these practical clinical questions, the paper will become more robust and appealing to both surgeons and oncologists managing postoperative surveillance in head and neck cancer patients.

 

Response:

As the reviewer pointed out, US and FNA could be alternative approaches. This study did not include data on US. Also, as the reviewer commented, FNA of mesenteric lymph nodes is not actively performed due to the risk to the flap vessels. The following sentence was added to the discussion section:” An alternative or adjunctive approach to PET-CT is ultrasound (US). It is considered a more cost-effective and less invasive option than PET-CT, but US data were not included in this study. Another method is fine-needle aspiration (FNA), but its availability is limited due to the risk of puncturing flap vessels.” (Page 7, Lines 174-177)

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The "RocaL" in Table 5, which was pointed out in Q10, has not been corrected. It should ben"Local".

On page8, lane210, there is an unnecessary Japanese character "い". 

Author Response

The "RocaL" in Table 5, which was pointed out in Q10, has not been corrected. It should ben"Local".

 →We fixed it.

 On page8, lane210, there is an unnecessary Japanese character "い".

 →We deleted it.