Title: Characterization of Primary Small Intestinal Lymphoma: A Retrospective Study Based
on Double Balloon Endoscopy
Version: 5 Date: 09 Jan 2024
Reviewer's report:
1. In the Methods section, the authors stated "All cases were admitted in the First Affiliated
Hospital of Zhejiang University. The pathology findings were reviewed by an expert pathologist
(Jun Li), and the endoscopies were performed by experienced endoscopists (Lin Li and Hong
Zhang). CT findings were confirmed by expert radiologists (Baishu Zhong and Lingxiang
Ruan)." However, the methodology requires more rigor. Specifically:
1.1) It is essential that all 255 small intestinal biopsy samples be reviewed by the expert
pathologist to ensure consistency and accuracy.
1.2) The qualifications of Jun Li, the designated expert pathologist, should be clearly specified,
particularly his or her expertise in small intestinal lymphoma.
1.3) The process by which the two radiologists reviewed CT images needs clarification. Were
the images read independently? How were discrepancies between their findings resolved?
1.4) The qualifications of both the pathologists and radiologists are crucial for ensuring the
validity and reproducibility of the study's results.
2. In the Results section, the authors stated "Pairwise comparisons were conducted to compare
the DLBCL group with the T cell lymphoma and B cell lymphoma group respectively. The
P-values reported for pairwise comparisons between two groups are nominal and were not
adjusted for multiplr comparisons or multiple outcomes." This appears to represent an incorrect
application of inferential statistics.
2.1) The details of statistical methods should be described in the Methods section, not the
Results.
2.2) Given the multiple comparisons made, it's important to adjust for potential increases in type
I error. The Bonferroni correction is one such method that could be applied to Tables 1, 2, 3,
4, and 5.
3. The Introduction's rationale for using DLBCL as a universal reference is flawed. DLBCL,
being a type of B-cell lymphoma, does not justify its selection as a baseline for comparison
with other lymphomas. A more traditional approach would classify lymphomas into Hodgkin's
and non-Hodgkin's, with further subdivision of non-Hodgkin's lymphoma into B-cell and T-
cell origins. The author should categorize cases into Hodgkin's lymphoma (if any), B-cell
lymphoma, and T-cell lymphoma for comparison, unless justified otherwise. Should the primary
classification be revised, the entire manuscript must be appropriately updated.
4. The second paragraph of the Discussion section requires careful review.  Mix the information
with the discussion about "prognosis" (as stated by the authors, mortality) is improper. Especially
in the paragraphs removed from previous version of manuscript, the these 30 cases, the
"prognosis" (survival) was not different between DLBCL and T-cell lymphoma or T-cell
lymphoma.
4.1) Sentences like "CRP has been used as a diagnostic and prognostic marker for a number
of neoplasms, particularly colon, ovarian and breast cancer as well as hepatocellular carcinoma
and other malignant diseases. As literature reports, elevated CRP levels reflect the increase in
inflammatory cytokines, particularly IL-6, which are associated with malignant processes in
lymphomas. The production of CRP was induced by IL-6, which is produced by the lymphoma
cells. LDH level was generally considered as a prognostic factor, and its higher level implied
poor prognosis27,28. LDH is an active enzyme in the pathway of anaerobic metabolism, which
facilitate the reversible conversion of lactate to pyruvate with simultaneous reduction of NAD
+ to NADH and vice versa.hus, it promotes the proliferation and progression of lymphoma27.
" The detailed information on CRP and LDH as diagnostic and prognostic markers, while
informative, does not contribute new insights relevant to this study's results.
4.2) "In our study, LDH elevated significantly in patients with DLBCL rather than indolent BCL,
which may suggest a worse prognosis in these patients. " The assertion that elevated LDH in
DLBCL patients suggests a worse prognosis is not substantiated by the study's findings.
4.3) "CEA is not specific only for tumors of endodermal origin, but also may be elevated in
tumors of mesodermal origin including malignant lymphomas1. However, a previous study
point to the fact that neither HL or NHL are associated with elevated CEA serum levels." The
discussion on CEA's elevation in various tumor types, including lymphomas, is irrelevant to
this study.
4.4) "Elevated levels of serum ferritin have been reported to be associated with worse outcomes
in malignant lymphoma" Claims regarding serum ferritin levels and lymphoma outcomes are
not backed by the presented data.
Overall, the discussion section needs a focused revision to align with the study's results and
avoid incorporating unsupported or irrelevant information.
5. In the last paragraph of "DBE findings" in the Results section, the analysis of risk factors for
mortality needs further detail:
5.1) Clarification is required on how mortality status was ascertained.
5.1.1) Was the patient followed every 1 month by telephone to ensure their survival? Or the
mortality status was checked by linking the patient ID to the national registry at the end of follow
up date (2022/12/31 maybe?)
5.1.2) What was the median or mean follow up period of the 30 cases?
5.1.3) Since the outcome was analyzed with logistic regression, the outcome was 30 days
cumulative mortality? Or 10 year cumulative mortality? Or?
5.2) Pathological type should be considered a key prognostic factor in the analysis of mortality
risk and included in the multivariable analysis
5.3) According to the methods section, "Clinical variables that were significant at p #0.05 in
univariate analysis along with clinically important factors were included in the multivariate
analysis and clinically meaningful interactions were also examined."
The authors should present the full model include all 12 variables (perhaps also the pathological
diagnosis, that makes 13 variables) and the interaction terms, in association with their beta
coefficients or odds ratio (with 95% confidence interval) into a table for readers to interpretate.
5.4) The authors should critically assess whether the identified risk factors merely reflect the
prognosis differences between DLBCL and B-cell lymphoma, since LDH and Deep ulcer was
only factors associated with mortality in the multivariable logistic regression model; and the
2 risk factors were significantly differently distributed between DLBCL and B-cell lymphoma
groups.
6. While acknowledging the challenges faced by the gastroenterology team, particularly in the
absence of collaboration with biostatisticians or epidemiologists, it is crucial that the authors
refer to relevant scientific literature to enhance the study's design and presentation. This is
particularly important for the accurate writing of the materials and methods section, including
statistical methods.
Title: Characterization of Primary Small Intestinal Lymphoma: A Retrospective Study Based
on Double Balloon Endoscopy
Version: 5 Date: 09 Jan 2024
Reviewer's report:
1. In the Methods section, the authors stated "All cases were admitted in the First Affiliated
Hospital of Zhejiang University. The pathology findings were reviewed by an expert pathologist
(Jun Li), and the endoscopies were performed by experienced endoscopists (Lin Li and Hong
Zhang). CT findings were confirmed by expert radiologists (Baishu Zhong and Lingxiang
Ruan)." However, the methodology requires more rigor. Specifically:
1.1) It is essential that all 255 small intestinal biopsy samples be reviewed by the expert
pathologist to ensure consistency and accuracy.
1.2) The qualifications of Jun Li, the designated expert pathologist, should be clearly specified,
particularly his or her expertise in small intestinal lymphoma.
1.3) The process by which the two radiologists reviewed CT images needs clarification. Were
the images read independently? How were discrepancies between their findings resolved?
1.4) The qualifications of both the pathologists and radiologists are crucial for ensuring the
validity and reproducibility of the study's results.
2. In the Results section, the authors stated "Pairwise comparisons were conducted to compare
the DLBCL group with the T cell lymphoma and B cell lymphoma group respectively. The
P-values reported for pairwise comparisons between two groups are nominal and were not
adjusted for multiplr comparisons or multiple outcomes." This appears to represent an incorrect
application of inferential statistics.
2.1) The details of statistical methods should be described in the Methods section, not the
Results.
2.2) Given the multiple comparisons made, it's important to adjust for potential increases in type
I error. The Bonferroni correction is one such method that could be applied to Tables 1, 2, 3,
4, and 5.
3. The Introduction's rationale for using DLBCL as a universal reference is flawed. DLBCL,
being a type of B-cell lymphoma, does not justify its selection as a baseline for comparison
with other lymphomas. A more traditional approach would classify lymphomas into Hodgkin's
and non-Hodgkin's, with further subdivision of non-Hodgkin's lymphoma into B-cell and T-
cell origins. The author should categorize cases into Hodgkin's lymphoma (if any), B-cell
lymphoma, and T-cell lymphoma for comparison, unless justified otherwise. Should the primary
classification be revised, the entire manuscript must be appropriately updated.
4. The second paragraph of the Discussion section requires careful review.  Mix the information
with the discussion about "prognosis" (as stated by the authors, mortality) is improper. Especially
in the paragraphs removed from previous version of manuscript, the these 30 cases, the
"prognosis" (survival) was not different between DLBCL and T-cell lymphoma or T-cell
lymphoma.
4.1) Sentences like "CRP has been used as a diagnostic and prognostic marker for a number
of neoplasms, particularly colon, ovarian and breast cancer as well as hepatocellular carcinoma
and other malignant diseases. As literature reports, elevated CRP levels reflect the increase in
inflammatory cytokines, particularly IL-6, which are associated with malignant processes in
lymphomas. The production of CRP was induced by IL-6, which is produced by the lymphoma
cells. LDH level was generally considered as a prognostic factor, and its higher level implied
poor prognosis27,28. LDH is an active enzyme in the pathway of anaerobic metabolism, which
facilitate the reversible conversion of lactate to pyruvate with simultaneous reduction of NAD
+ to NADH and vice versa.hus, it promotes the proliferation and progression of lymphoma27.
" The detailed information on CRP and LDH as diagnostic and prognostic markers, while
informative, does not contribute new insights relevant to this study's results.
4.2) "In our study, LDH elevated significantly in patients with DLBCL rather than indolent BCL,
which may suggest a worse prognosis in these patients. " The assertion that elevated LDH in
DLBCL patients suggests a worse prognosis is not substantiated by the study's findings.
4.3) "CEA is not specific only for tumors of endodermal origin, but also may be elevated in
tumors of mesodermal origin including malignant lymphomas1. However, a previous study
point to the fact that neither HL or NHL are associated with elevated CEA serum levels." The
discussion on CEA's elevation in various tumor types, including lymphomas, is irrelevant to
this study.
4.4) "Elevated levels of serum ferritin have been reported to be associated with worse outcomes
in malignant lymphoma" Claims regarding serum ferritin levels and lymphoma outcomes are
not backed by the presented data.
Overall, the discussion section needs a focused revision to align with the study's results and
avoid incorporating unsupported or irrelevant information.
5. In the last paragraph of "DBE findings" in the Results section, the analysis of risk factors for
mortality needs further detail:
5.1) Clarification is required on how mortality status was ascertained.
5.1.1) Was the patient followed every 1 month by telephone to ensure their survival? Or the
mortality status was checked by linking the patient ID to the national registry at the end of follow
up date (2022/12/31 maybe?)
5.1.2) What was the median or mean follow up period of the 30 cases?
5.1.3) Since the outcome was analyzed with logistic regression, the outcome was 30 days
cumulative mortality? Or 10 year cumulative mortality? Or?
5.2) Pathological type should be considered a key prognostic factor in the analysis of mortality
risk and included in the multivariable analysis
5.3) According to the methods section, "Clinical variables that were significant at p #0.05 in
univariate analysis along with clinically important factors were included in the multivariate
analysis and clinically meaningful interactions were also examined."
The authors should present the full model include all 12 variables (perhaps also the pathological
diagnosis, that makes 13 variables) and the interaction terms, in association with their beta
coefficients or odds ratio (with 95% confidence interval) into a table for readers to interpretate.
5.4) The authors should critically assess whether the identified risk factors merely reflect the
prognosis differences between DLBCL and B-cell lymphoma, since LDH and Deep ulcer was
only factors associated with mortality in the multivariable logistic regression model; and the
2 risk factors were significantly differently distributed between DLBCL and B-cell lymphoma
groups.
6. While acknowledging the challenges faced by the gastroenterology team, particularly in the
absence of collaboration with biostatisticians or epidemiologists, it is crucial that the authors
refer to relevant scientific literature to enhance the study's design and presentation. This is
particularly important for the accurate writing of the materials and methods section, including
statistical methods.
Please review this paper.
user
Title: Characterization of Primary Small Intestinal Lymphoma: A Retrospective Study Based
on Double Balloon Endoscopy
Version: 5 Date: 09 Jan 2024
Reviewer's report:
1. In the Methods section, the authors stated "All cases were admitted in the First Affiliated
Hospital of Zhejiang University. The pathology findings were reviewed by an expert pathologist
(Jun Li), and the endoscopies were performed by experienced endoscopists (Lin Li and Hong
Zhang). CT findings were confirmed by expert radiologists (Baishu Zhong and Lingxiang
Ruan)." However, the methodology requires more rigor. Specifically:
1.1) It is essential that all 255 small intestinal biopsy samples be reviewed by the expert
pathologist to ensure consistency and accuracy.
1.2) The qualifications of Jun Li, the designated expert pathologist, should be clearly specified,
particularly his or her expertise in small intestinal lymphoma.
1.3) The process by which the two radiologists reviewed CT images needs clarification. Were
the images read independently? How were discrepancies between their findings resolved?
1.4) The qualifications of both the pathologists and radiologists are crucial for ensuring the
validity and reproducibility of the study's results.
2. In the Results section, the authors stated "Pairwise comparisons were conducted to compare
the DLBCL group with the T cell lymphoma and B cell lymphoma group respectively. The
P-values reported for pairwise comparisons between two groups are nominal and were not
adjusted for multiplr comparisons or multiple outcomes." This appears to represent an incorrect
application of inferential statistics.
2.1) The details of statistical methods should be described in the Methods section, not the
Results.
2.2) Given the multiple comparisons made, it's important to adjust for potential increases in type
I error. The Bonferroni correction is one such method that could be applied to Tables 1, 2, 3,
4, and 5.
3. The Introduction's rationale for using DLBCL as a universal reference is flawed. DLBCL,
being a type of B-cell lymphoma, does not justify its selection as a baseline for comparison
with other lymphomas. A more traditional approach would classify lymphomas into Hodgkin's
and non-Hodgkin's, with further subdivision of non-Hodgkin's lymphoma into B-cell and T-
cell origins. The author should categorize cases into Hodgkin's lymphoma (if any), B-cell
lymphoma, and T-cell lymphoma for comparison, unless justified otherwise. Should the primary
classification be revised, the entire manuscript must be appropriately updated.
4. The second paragraph of the Discussion section requires careful review.  Mix the information
with the discussion about "prognosis" (as stated by the authors, mortality) is improper. Especially
in the paragraphs removed from previous version of manuscript, the these 30 cases, the
"prognosis" (survival) was not different between DLBCL and T-cell lymphoma or T-cell
lymphoma.
4.1) Sentences like "CRP has been used as a diagnostic and prognostic marker for a number
of neoplasms, particularly colon, ovarian and breast cancer as well as hepatocellular carcinoma
and other malignant diseases. As literature reports, elevated CRP levels reflect the increase in
inflammatory cytokines, particularly IL-6, which are associated with malignant processes in
lymphomas. The production of CRP was induced by IL-6, which is produced by the lymphoma
cells. LDH level was generally considered as a prognostic factor, and its higher level implied
poor prognosis27,28. LDH is an active enzyme in the pathway of anaerobic metabolism, which
facilitate the reversible conversion of lactate to pyruvate with simultaneous reduction of NAD
+ to NADH and vice versa.hus, it promotes the proliferation and progression of lymphoma27.
" The detailed information on CRP and LDH as diagnostic and prognostic markers, while
informative, does not contribute new insights relevant to this study's results.
4.2) "In our study, LDH elevated significantly in patients with DLBCL rather than indolent BCL,
which may suggest a worse prognosis in these patients. " The assertion that elevated LDH in
DLBCL patients suggests a worse prognosis is not substantiated by the study's findings.
4.3) "CEA is not specific only for tumors of endodermal origin, but also may be elevated in
tumors of mesodermal origin including malignant lymphomas1. However, a previous study
point to the fact that neither HL or NHL are associated with elevated CEA serum levels." The
discussion on CEA's elevation in various tumor types, including lymphomas, is irrelevant to
this study.
4.4) "Elevated levels of serum ferritin have been reported to be associated with worse outcomes
in malignant lymphoma" Claims regarding serum ferritin levels and lymphoma outcomes are
not backed by the presented data.
Overall, the discussion section needs a focused revision to align with the study's results and
avoid incorporating unsupported or irrelevant information.
5. In the last paragraph of "DBE findings" in the Results section, the analysis of risk factors for
mortality needs further detail:
5.1) Clarification is required on how mortality status was ascertained.
5.1.1) Was the patient followed every 1 month by telephone to ensure their survival? Or the
mortality status was checked by linking the patient ID to the national registry at the end of follow
up date (2022/12/31 maybe?)
5.1.2) What was the median or mean follow up period of the 30 cases?
5.1.3) Since the outcome was analyzed with logistic regression, the outcome was 30 days
cumulative mortality? Or 10 year cumulative mortality? Or?
5.2) Pathological type should be considered a key prognostic factor in the analysis of mortality
risk and included in the multivariable analysis
5.3) According to the methods section, "Clinical variables that were significant at p #0.05 in
univariate analysis along with clinically important factors were included in the multivariate
analysis and clinically meaningful interactions were also examined."
The authors should present the full model include all 12 variables (perhaps also the pathological
diagnosis, that makes 13 variables) and the interaction terms, in association with their beta
coefficients or odds ratio (with 95% confidence interval) into a table for readers to interpretate.
5.4) The authors should critically assess whether the identified risk factors merely reflect the
prognosis differences between DLBCL and B-cell lymphoma, since LDH and Deep ulcer was
only factors associated with mortality in the multivariable logistic regression model; and the
2 risk factors were significantly differently distributed between DLBCL and B-cell lymphoma
groups.
6. While acknowledging the challenges faced by the gastroenterology team, particularly in the
absence of collaboration with biostatisticians or epidemiologists, it is crucial that the authors
refer to relevant scientific literature to enhance the study's design and presentation. This is
particularly important for the accurate writing of the materials and methods section, including
statistical methods.
assistant