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PEER REVIEW HISTORY
BMJ Open publishes all reviews undertaken for accepted manuscripts. Reviewers are asked to
complete a checklist review form (see an example) and are provided with free text boxes to elaborate
on their assessment. These free text comments are reproduced below.
This paper was submitted to the THORAX but declined for publication following peer review. The
authors addressed the reviewers‟ comments and submitted the revised paper to BMJ Open where it
was re-reviewed and accepted.
ARTICLE DETAILS
TITLE (PROVISIONAL)
AUTHORS
Diagnostic values of soluble mesothelin-related peptides for
malignant pleural mesothelioma: updated meta-analyses
Cui, Ai; Jin, Xiao-Guang; Zhai, Kan; Tong, Zhao-Hui; Shi, HuanZhong
VERSION 1 - REVIEW
REVIEWER
REVIEW RETURNED
GENERAL COMMENTS
Pantazopoulos, Ioannis
Sotiria General Hospital, 12th Dept of Respiratory Medicine
15-Sep-2013
Thank you very much for giving me the opportunity to review this
manuscript. Recently, mesothelin family proteins (mesothelin &
megakaryocyte potentiating factor) have attracted attention as
potential candidates as malignant mesothelioma tumor markers. The
authors of the present meta-analysis have investigated the
diagnostic accuracy of mesothelin family proteins for the diagnosis
of malignant pleural mesothelioma.
Regarding the manuscript itself:
Major remarks
• The manuscript is generally written in acceptable English, but there
are several sentences that could be polished to make the meaning
sharper and more to the point. I strongly advice some editing by a
native speaker.
• The term “soluble mesothelin-related peptide” or “SMRP” is
referred to the three isoforms of “serum mesothelin” which can enter
the blood circulation, either by shedding of the membrane-bound
portion (variants 1 and 2), or by a frameshift mutation (variant 3).
Although serum mesothelin refers to all isoforms that are present in
the circulation, research shows that variant 1 is predominantly
expressed and released from the membrane (refer to
http://www.ncbi.nlm.nih.gov/pubmed/16702385). For this reason,
most experienced research groups now prefer the term “serum
mesothelin” or “mesothelin”. The term SMRP is an outmoded term,
which unfortunately is still used by some. I strongly advice the
authors to omit the term „SMRP‟. A short letter by Hellstrom in 2008
(!) (http://www.ncbi.nlm.nih.gov/pubmed/18789894) clearly explains
why it‟s better not to use the term „SMRP‟. To refer to both
mesothelin and MPF you can use the term “mesothelin family
proteins”.
• In the conclusion section the authors state that “…positive test
results indicate that further invasive diagnostic steps might be
necessary for the diagnosis of MPM”. I agree that a positive
mesothelin test would provide a strong incentive to urge ensuing
Downloaded from http://bmjopen.bmj.com/ on June 18, 2017 - Published by group.bmj.com
diagnostic steps. However, this is a suggestion and not a conclusion
so it would be better to include this comment only in the discussion
section. Furthermore, in the discussion section you report that
patients with MPM have a near 6-fold higher chance of being SMRPpositive compared with patients without MPM, and that this is not
high enough for the clinical purpose as it might lead to an inordinate
number of individuals undergoing unnecessary diagnostic work-ups
or biopsies. This is a contradictory statement.
• The title of the current paper is almost the same with the previous
paper that you have published entitled “Diagnostic value of soluble
mesothelin-related peptides for malignant mesothelioma: A metaanalysis”. Change it or at least say that this is an update.
Minor remarks
• Discussion section: Explanations regarding SROC and DOR have
been previously described in your paper entitled “Diagnostic value of
soluble mesothelin-related peptides for malignant mesothelioma: A
meta-analysis” (Respir Med 2010; 104:149-56). Do not repeat them.
Just say “…as previously described”
• Multiple assays are available today for the measurement of
mesothelin. However, only Mesomark TM (Fujirebio Diagnostics
Inc., Malvern, PA, USA) kit has been approved by the US Food and
Drug Administration. If different assays were used in the studies that
you included, please mention this in the limitations section?
• Diagnostic accuracy section, line 16: “25 serum SMRP assays”.
You mean 25 studies that measured SMRP for the diagnosis of
MM? Same for line 34.
• Page 10, line 57: Delete the word “that”.
• Page 11, line 50: “…compared with from healthy controls or
asbestos exposed people.” Delete the word from
• Page 14, line 31: “It a value is greater than 10…” has to be “If a
value is…”.
-
The manuscript receives two reviews at THORAX but the other referee had declined to make
the comments public.
VERSION 1 – AUTHOR RESPONSE
Comment 1: The manuscript is generally written in acceptable English, but there are several
sentences that could be polished to make the meaning sharper and more to the point. I strongly
advice some editing by a native speaker.
Response 1: We have tried our best to use correct English.
Comment 2: The term “soluble mesothelin-related peptide” or “SMRP” is referred to the three
isoforms of “serum mesothelin” which can enter the blood circulation, either by shedding of the
membrane-bound portion (variants 1 and 2), or by a frameshift mutation (variant 3). Although serum
mesothelin refers to all isoforms that are present in the circulation, research shows that variant 1 is
predominantly expressed and released from the membrane (refer to
http://www.ncbi.nlm.nih.gov/pubmed/16702385). For this reason, most experienced research groups
now prefer the term “serum mesothelin” or “mesothelin”. The term SMRP is an outmoded term, which
unfortunately is still used by some. I strongly advice the authors to omit the term „SMRP‟. A short
Downloaded from http://bmjopen.bmj.com/ on June 18, 2017 - Published by group.bmj.com
letter by Hellstrom in 2008 (!) (http://www.ncbi.nlm.nih.gov/pubmed/18789894) clearly explains why
it‟s better not to use the term „SMRP‟. To refer to both mesothelin and MPF you can use the term
“mesothelin family proteins”.
Response 2: We agree that this is a very valid point. Throughout, “soluble mesothelin-related
peptides/SMRPs” have been replaced by “mesothelin family proteins/SMFPs”.
Comment 3: In the conclusion section the authors state that “…positive test results indicate that
further invasive diagnostic steps might be necessary for the diagnosis of MPM”. I agree that a positive
mesothelin test would provide a strong incentive to urge ensuing diagnostic steps. However, this is a
suggestion and not a conclusion so it would be better to include this comment only in the discussion
section. Furthermore, in the discussion section you report that patients with MPM have a near 6-fold
higher chance of being SMRP-positive compared with patients without MPM, and that this is not high
enough for the clinical purpose as it might lead to an inordinate number of individuals undergoing
unnecessary diagnostic work-ups or biopsies. This is a contradictory statement.
Response 3: The sentence “the positive test results would indicate that further invasive diagnostic
steps might be necessary and could possibly lead to an earlier diagnosis.” has been removed from
the conclusion section. The sentence “This might lead to an inordinate number of individuals
undergoing unnecessary diagnostic work-ups or biopsies.” has been deleted from the revision.
Comment 4: The title of the current paper is almost the same with the previous paper that you have
published entitled “Diagnostic value of soluble mesothelin-related peptides for malignant
mesothelioma: A meta-analysis”. Change it or at least say that this is an update.
Response 4: We have revised the title.
Comment 5: Discussion section: Explanations regarding SROC and DOR have been previously
described in your paper entitled “Diagnostic value of soluble mesothelin-related peptides for malignant
mesothelioma: A meta-analysis” (Respir Med 2010; 104:149-56). Do not repeat them. Just say “…as
previously described”
Response 5: We have revised the manuscript according to the above comments.
Comment 6: Multiple assays are available today for the measurement of mesothelin. However, only
Mesomark TM (Fujirebio Diagnostics Inc., Malvern, PA, USA) kit has been approved by the US Food
Downloaded from http://bmjopen.bmj.com/ on June 18, 2017 - Published by group.bmj.com
and Drug Administration. If different assays were used in the studies that you included, please
mention this in the limitations section?
Response 6: The following statement “Fourth, multiple assays were available for determining
mesothelin concentrations, and Mesomark, which has been approved by the US Food and Drug
Administration, was used in most studies. The other mesothelin ELISA kits were used in 4 studies.
21,
30, 31, 35
” has been added into the revision.
Comment 7: Diagnostic accuracy section, line 16: “25 serum SMRP assays”. You mean 25 studies
that measured SMRP for the diagnosis of MM? Same for line 34.
Response 7: Yes, I do. Corrected.
Comment 8: Page 10, line 57: Delete the word “that”.
Response 8: Done.
Comment 9: Page 11, line 50: “…compared with from healthy controls or asbestos exposed people.”
Delete the word from
Response 9: Done.
Comment 10: Page 14, line 31: “It a value is greater than 10…” has to be “If a value is…”.
Response 10: Revised.
VERSION 2 – REVIEW
REVIEWER
REVIEW RETURNED
Kato, Bernet
Imperial College London, Respiratory Epidemiology and Public
Health
02-Nov-2013
GENERAL COMMENTS
GENERAL COMMENTS
This paper reports the results if a meta-analysis to evaluate the
effectiveness of soluble mesothelin-related peptides (SMRP) in
serum and pleural fluid to diagnose malignant pleural mesothelioma
(MPM). Current therapeutic options for MPM are limited and the
prognosis is poor. Therefore systematic reviews of the best available
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evidence for diagnostic accuracy of biomarkers for MPM can inform
decision making in clinical practice. The results are therefore of
considerable interest in clinical practice.
RESULTS AND CONCLUSIONS
Page 15: Under the “Discussion” section it is not clear what
message the authors are putting across in the sentence that begins
“The positive SMRPs….”. This should be clarified.
Furthermore, based on the results from the meta-analyses
conducted in the paper would the authors recommend or not
recommend the use of soluble mesothelin-related peptides (SMRP)
in serum and pleural fluid to diagnose malignant pleural
mesothelioma (MPM) in clinical practice?
Minor comments
Page 4: The second point under “Key messages” is not clear.
Page 11, the meaning of the sentence “Except for 2 studies, all
samples were collected from the consecutive patients in the
remaining 28 studies” is not clear.
Page 16, where limitations of the study are discussed: The sentence
that begins with “Second, pathological types of MPM ….” is not
clear.
Page 17: The sentence that begins “The negative results of SMRP
…” is not clear.
Edits
Page 4: Under “strengths and limitations of this study”, the first
sentence should read “The studies included in this meta-analysis
were methodologically satisfactory and their results were consistent.
Page 8: Second sentence in paragraph 2 should read “The studies
including at least 10 specimens were selected to be included in the
meta-analyses, since very small studies may be vulnerable to
selection bias”.
Page 10, line 3: spelling of the word “Appendix” should be corrected.
th
Page 12, 4 line from the bottom: replace the word “somehow” with
“some”.
Page 47: In the last column of the table for STARD checklist for
reporting of studies of diagnostic accuracy, what does A/N mean?
Did the authors intend to write N/A (not applicable)?
Downloaded from http://bmjopen.bmj.com/ on June 18, 2017 - Published by group.bmj.com
VERSION 2 – AUTHOR RESPONSE
DR. BERNET KATO
Comment 1: Page 15: Under the “Discussion” section it is not clear what message the authors are
putting across in the sentence that begins “The positive SMFPs….”. This should be clarified.
Furthermore, based on the results from the meta-analyses conducted in the paper would the authors
recommend or not recommend the use of soluble mesothelin-related peptides (SMFP) in serum and
pleural fluid to diagnose malignant pleural mesothelioma (MPM) in clinical practice?
Response 1: The sentence “The positive SMFPs results might be somehow helpful in confirming
(ruling in) MPM, suggesting that invasive diagnostic steps, such as medical thoracoscopy, might be
necessary.” has been revised to “SMFPs might be helpful in confirming (ruling in) MPM if the results
were higher than the cut-off values. Thus, positive SMFP test results suggested that invasive
diagnostic steps, such as medical thoracoscopy, might be necessary..”
Based on the results from the meta-analyses, I insisted that the following statement was reasonable
“In conclusion, current evidence supported that SMFPs in both serum and PF were helpful markers
for the diagnosis of MPM. The overall diagnostic performance of SMFPs in serum and PF was similar,
and serum MPF had superior diagnostic accuracy compared to serum mesothelin. The negative
results of SMFP determinations were not sufficiently to exclude non-MPM, whereas the positive test
results might be helpful in confirming MPM.”
Comment 2: Page 4: The second point under “Key messages” is not clear.
Response 2: The original sentence has been changed into “Determination of soluble mesothelinrelated peptides might be helpful in confirming pleural mesothelioma if the results were higher than
the cut-off values, while the negative results were not sufficiently to exclude non-mesothelioma.”
Comment 3: Page 11, the meaning of the sentence “Except for 2 studies, all samples were collected
from the consecutive patients in the remaining 28 studies” is not clear.
Response 3: The original sentence has been changed into “The samples were collected from the
consecutive patients in all studies but not 2 studies.”
Comment 4: Page 16, where limitations of the study are discussed: The sentence that begins with
“Second, pathological types of MPM ….” is not clear.
Response 4: The original sentence has been changed into “Second, pathological types of MPM were
not specified in 2 studies,34,41 epithelioid subtype of MPM was the most common pathological type
in all studies, excluding the one reported by Creaney et al.25”
Comment 5: Page 17: The sentence that begins “The negative results of SMFP …” is not clear.
Response 5: The original sentence has been changed into “The negative results of SMFP
determinations were not sufficiently to exclude non-MPM; on the other hand, the positive test results
might be helpful in confirming MPM, suggesting that further invasive diagnostic steps might be
necessary and could possibly lead to an earlier diagnosis.”
Comment 6: Page 4: Under “strengths and limitations of this study”, the first sentence should read
“The studies included in this meta-analysis were methodologically satisfactory and their results were
consistent.
Response 6: Revised.
Comment 7: Page 8: Second sentence in paragraph 2 should read “The studies including at least 10
specimens were selected to be included in the meta-analyses, since very small studies may be
vulnerable to selection bias”.
Downloaded from http://bmjopen.bmj.com/ on June 18, 2017 - Published by group.bmj.com
Response 7: Revised.
Comment 8: Page 10, line 3: spelling of the word “Appendix” should be corrected.
Response 8: “Appendix Table 1” has been changed into “Online supplementary appendix 2”.
Comment 9: Page 12, 4th line from the bottom: replace the word “somehow” with “some”.
Response 9: Replaced.
Comment 10: Page 47: In the last column of the table for STARD checklist for reporting of studies of
diagnostic accuracy, what does A/N mean? Did the authors intend to write N/A (not applicable)?
Response 10: Sorry, those were typos. Yes, the authors intended to write N/A (not applicable).
VERSION 3 - REVIEW
REVIEWER
REVIEW RETURNED
GENERAL COMMENTS
Ioannis Pantazopoulos
4th Department of Respiratory Medicine, Sotiria General Hospital,
Athens, Greece
06-Jan-2014
Thank you very much for giving me the opportunity to review this
manuscript. The authors have investigated the diagnostic accuracy
of mesothelin family proteins for the diagnosis of malignant pleural
mesothelioma.
Regarding the manuscript itself:
1. When referring to both mesothelin and MPF I would suggest using
the term “mesothelin family proteins” instead of SMRP (soluble
mesothelin related peptides). SMRP better defines the three
isoforms of “serum mesothelin” which can enter the blood
circulation, either by shedding of the membrane bound portion
(variants 1 and 2), or by a frameshift mutation (variant 3).
2. The manuscript is generally written in acceptable English but I
advice some editing by a native speaker.
3. Introduction section, page 7, third line “…our results showed that
serum SMRP determinations played a role in the diagnosis of MPM”.
Please change to…could play a role in the diagnosis of MPM if
interpreted in parallel with clinical findings and the results of
conventional tests.
4. Materials and methods, diagnostic accuracy section, page 12
second paragraph first line: “Figure 2B shows forest plot of
sensitivity and specificity 12 PF SMRP studies.” It should be
…specificity for 12 PF …
5. Discussion section, page 15, second paragraph, line 6: “However,
the relative low sensitivity, especially serum SMRPs, that was not
sufficiently low to exclude non-MPM when a patient‟s SMRP results
were lower than the cut-off values. Therefore, the associated poor
sensitivity of SMRPs clearly limits their added value to diagnosis of
MPM”. Something is wrong here. A positive mesothelin test at a
high-specificity threshold would provide a strong incentive to urge
ensuing diagnostic steps. On the other hand, the low sensitivity will
not allow exclusion of non-MM patients even if patients have
mesothelin concentrations lower than the cutoff value. Please
correct.
6. I agree with the authors that the application of mesothelin family
proteins in the near future clinical practice will most probably be
situated in monitoring response to therapy, rather than in guiding
Downloaded from http://bmjopen.bmj.com/ on June 18, 2017 - Published by group.bmj.com
diagnostic decisions and risk assessment of asbestos-exposed
populations. Needless to say that the MESOMARK assay has not
been approved for diagnostic use, but as an aid in the monitoring of
epithelioid and biphasic MM. However, as the initial aim of this
systematic review was to investigate the “diagnostic accuracy” of
mesothelin family proteins for the diagnosis of malignant pleural
mesothelioma, the last paragraph should be removed from the
conclusion section and be placed in the discussion section.
VERSION 3 – AUTHOR RESPONSE
Comment 1: When referring to both mesothelin and MPF I would suggest using the term “mesothelin
family proteins” instead of SMRP (soluble mesothelin related peptides). SMRP better defines the
three isoforms of “serum mesothelin” which can enter the blood circulation, either by shedding of the
membrane bound portion (variants 1 and 2), or by a frameshift mutation (variant 3).
Response 1: I tried to use the term “mesothelin family proteins” instead of SMRP (soluble mesothelin
related peptides) when referring to both mesothelin and MPF in the new revision.
Comment 2: The manuscript is generally written in acceptable English but I advice some editing by a
native speaker.
Response 2: We have tried our best to use correct English.
Comment 3: Introduction section, page 7, third line “…our results showed that serum SMRP
determinations played a role in the diagnosis of MPM”. Please change to…could play a role in the
diagnosis of MPM if interpreted in parallel with clinical findings and the results of conventional tests.
Response 3: Changed.
Comment 4: Materials and methods, diagnostic accuracy section, page 12 second paragraph first
line: “Figure 2B shows forest plot of sensitivity and specificity 12 PF SMRP studies.” It should be
…specificity for 12 PF …
Response 4: Corrected.
Comment 5: Discussion section, page 15, second paragraph, line 6: “However, the relative low
sensitivity, especially serum SMRPs, that was not sufficiently low to exclude non-MPM when a
patient‟s SMRP results were lower than the cut-off values. Therefore, the associated poor sensitivity
of SMRPs clearly limits their added value to diagnosis of MPM”. Something is wrong here. A positive
mesothelin test at a high-specificity threshold would provide a strong incentive to urge ensuing
diagnostic steps. On the other hand, the low sensitivity will not allow exclusion of non-MM patients
even if patients have mesothelin concentrations lower than the cutoff value. Please correct.
Response 5: Corrected.
Comment 6: I agree with the authors that the application of mesothelin family proteins in the near
future clinical practice will most probably be situated in monitoring response to therapy, rather than in
guiding diagnostic decisions and risk assessment of asbestos-exposed populations. Needless to say
that the MESOMARK assay has not been approved for diagnostic use, but as an aid in the monitoring
of epithelioid and biphasic MM. However, as the initial aim of this systematic review was to investigate
the “diagnostic accuracy” of mesothelin family proteins for the diagnosis of malignant pleural
mesothelioma, the last paragraph should be removed from the conclusion section and be placed in
the discussion section.
Response 6: The last paragraph has been removed from the conclusion section and been placed in
the discussion section.
Downloaded from http://bmjopen.bmj.com/ on June 18, 2017 - Published by group.bmj.com
Diagnostic values of soluble
mesothelin-related peptides for malignant
pleural mesothelioma: updated meta-analysis
Ai Cui, Xiao-Guang Jin, Kan Zhai, Zhao-Hui Tong and Huan-Zhong Shi
BMJ Open 2014 4:
doi: 10.1136/bmjopen-2013-004145
Updated information and services can be found at:
http://bmjopen.bmj.com/content/4/2/e004145
These include:
Supplementary Supplementary material can be found at:
Material http://bmjopen.bmj.com/content/suppl/2014/02/24/bmjopen-2013-004
145.DC1
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