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  • The initial submission of this article was received on December 10th, 2018 and was peer-reviewed by 2 reviewers and the Academic Editor.
  • The Academic Editor made their initial decision on January 28th, 2019.
  • The first revision was submitted on February 26th, 2019 and was reviewed by 2 reviewers and the Academic Editor.
  • A further revision was submitted on March 21st, 2019 and was reviewed by the Academic Editor.
  • The article was Accepted by the Academic Editor on March 21st, 2019.

Version 0.3 (accepted)

· Mar 21, 2019 · Academic Editor


I attached a pdf file with more corrections to perform (marked in yellow), I think you can fix them without a new revision round, just while in production.

Version 0.2

· Mar 11, 2019 · Academic Editor

Minor Revisions

Please consider further minor revisions to the manuscript and rephrase sentences as suggested by the reviewers.

Reviewer 1 ·

Basic reporting

please see minor comments below

Experimental design

meets standards of publishing

Validity of the findings

meets standards of publishing

Additional comments

Please rephrase sentences below to improve clarity and avoid grammatical errors:
• The aim of this study was better characterize the clinicopathological features and prognosis of pulmonary LCNEC in patients aged ≥ 65 years.
• In the following 1999 and 2004, the World Health Organization (WHO) admitted that LCNEC was a variant of large cell carcinoma, belonging to neuroendocrine tumors and one of the non-small cell lung cancer (NSCLC).
• Meanwhile, the older group in nearly all the subgroups had the significantly lower OS, except the patients with primary site at main bronchus, bilateral tumor, AJCC stage II , stage III and patients received segmentectomy, pneumonectomy and radiotherapy (Figures 4).
• What is more, tumor size, AJCC stage, surgery, chemotherapy, radiotherapy were independent risk factors for prognosis in older patients.
• But now the mainstream view was that primary surgery still should be the first option in operable patients
• But we still did not know how to choose chemotherapy and chemotherapeutic regimen
• This study is the largest retrospective analysis on the prognosis effect of age in pulmonary LCNEC. The current research was based on a large population, but there were remain certain limitations that should be noted.
• However, any retrospective study could not include all possible factors, and our results are still of great clinical value

Reviewer 2 ·

Basic reporting

Manuscript have been improved in this revision.

Experimental design

All the methodological issues have been addressed.

Validity of the findings

The discussion is now clearer.

Additional comments

The manuscript have been improved in this revision. However, the manuscript still needs some language improvements, in particular in the new parts of the discussion section. Please, consider revision of the whole manuscript by a native English speaker.

Version 0.1 (original submission)

· Jan 28, 2019 · Academic Editor

Major Revisions

This is an interesting paper with important information on pulmonary LCNEC aged patients prognosis. In my opinion the paper is well organized but can be improved following reviewers suggestions.

Reviewer 1 ·

Basic reporting

Manuscript is overall well written and meets professional standards in terms of language, context of study,article structure, data . Minor comments are mentioned in note to author below which require correction/revision.

Experimental design

Yes this manuscript has a very good data resource for LCNEC patients which is very valuable to the scientific community. Sufficient background is provided and research aim is outlined clearly. Sufficient statistical parameters have been applied (see below in author comments for additional suggestions). Methods have been clearly explained and raw data has been provided.

Validity of the findings

Since this is the first time such a large dataset has been used for LCNEC patients it is very useful. While it is known that age correlates with prognosis in LCNEC patients, the fact that it is validated in the larger dataset is useful. Further the observation that older patients handle surgery of therapy better (whenever administered) requires further investigation but is still an important advance in the field.
Cohort size is good and standard statistical procedures appear to have been applied
Conclusions are well stated and summarize the study appropriately.

Additional comments

Abstract :
• Clear, concise and comprehensive.
Introduction :
• Overall Good description of lung cancers. Importance of study stated but can be improved (see below)
Rephrase of line 65-66 required : “However, research of older patients with pulmonary LCNEC has, to the best of knowledge, never been undertaken.” This statement is a bit contradictory since median age of LCNEC in several cohorts is 60+!! This paper adds value because it is explicitly comparing patients in two age groups.
• Connection between LCNEC and NSCLC not explained.
• No full form for “NSCLC” in line 58
Materials and Methods :
• Ethics statement is present
• Inclusion/ Exclusion is clearly stated
• Raw data is present in supplemental folder
• Covariates clearly explained. LCNEC strongly correlates with smoking habit. This should be included in paper if data is available.
• Citation for “AJCC TNM staging system 6th edition”
• Statistical analysis details were clearly mentioned.
• It would be interesting to see results of the correlations between the different survival rates and factors being assessed using other tests (besides Cox) such as parametric models (eg. as in PMID: 29582630)

Results :
• Study has a very good sample size of patients in both age groups specially since this is not a very common cancer subtype
• All figures/figure legends, tables/table legends look fine
• Older patients had bigger or smaller tumors? From the table it seems that older patients had higher percentage of smaller tumors (<5%) compared to younger patients? However statement in Results says “In the older group, more patients were white (P=0.004), married (P<0.001), stage I (P=0.022), had a larger tumor size ˂5 cm (P=0.013); and the proportion of surgery (P<0.001), radiotherapy (P<0.001), chemotherapy (P<0.001) was significantly lower.”
• Do older patients have lower surgery rates because of the smaller tumor sizes?
• It would be very valuable to see what chemotherapy treatment regimen was administered to patients and if different regimens would have different effects based on age (considering chemotherapy regimens could be so different for LCNEC patients)
• It would be interesting to see how metastasis and location of metastasis correlate with age and prognosis in LCNEC patients
• It would be intriguing to test how genomic LCNEC subtypes (as classified in the field for eg PMID: 29066508 etc) correlate with age and survival in this study if tissue is available for such analysis
• Status of expression of neuro endocrine markers such as CD56,CGA,SYN etc (PMID:25596870) or immune checkpoint molecules in tumors across age could be interesting given current developments and trials.

Discussion :
Well written. Results highlighted clearly and good inferences. Strengths and limitations of study acknowledged well.

Minor typos/ Grammatical errors in following lines :
• Tumor size was a continuous variable was transformed into a categorical variable on the basis of recognized cut-off values.
• The 5-year OS rate for LCNEC after resection has been reported to be between 13and 57%
• However, there are only 23 patients (5.7%) large cell neuroendocrine carcinoma, and the sample size is too small.
• Only a multidisciplinary medical assessment of the patient should be able to evaluate the risks and benefits of a treatment

Reviewer 2 ·

Basic reporting

The paper from Ling Cao and colleagues retrospectively evaluates public data on LCNEC patients from a public registry in order to find differences in clinicopathological features and prognostic factors according to age.

Even if the results are novel and interesting, the authors need to make consistent changes to paper to introduce the problem and adequately support their data.

-Introduction "Therefore, elderly patients often go without proper representation during clinical trials". Please rephrase this sentence

-What is the link between "LCNEC is thought to be an aggressive malignancy with a worse prognosis and more risks of reoccurrence in comparison with other types of NSCLC" and the need to evaluate LCNEC in elderly people?

- References are quite recent, but in insufficient number

- update the legends with the number of subjects in each curve/group and how the p-value was determined (cox regression)
- label "follow time" on the x axis is not appropriate

Experimental design

- The authors should be more clear on the aim of their study, besides the lack of previous literature.

- The study is well designed, however the authors should present proper comparison of potential prognostic factors between the two groups and not only between general population (Table 2) and elderly patients (Table 4)

- Methods section is sufficiently detailed and provided supplementary material allows the replication of the analysis.

Validity of the findings

- The author should comment on the differences they found in the CSS/OS rates between stages I/IV and II/III

In my opinion, discussion needs thorough and significant improvements. In detail:

- The author should include and discuss more literature, also on similar studies on other subtypes of NSCLC

- Remove p-values from discussion

- "However, it was discovered by Kujtan and colleagues, that patients over the age of 70, who were comorbid white patients that had sublobar resection of tumors over 20 mm had the worst survival outcomes" This sentence should be rephrased.

- English need some improvements, e.g. avoid the term "discovered"

- "Our findings could be used by clinical workers to better understand..." This sentence should be moved in the conclusions.

- When describing the study limitations, the authors should better clarify what they mean with selection bias. Moreover, they should explain why they think their results are still strong despite these limitations.

- "In conclusion, older age (>65years) IS an independent prognostic factor for..." -> survival in LCNEC patients.

- The authors state that their results "showed that the elderly can obviously benefit significantly from these treatments" (i.e. surgery, chemo- and radiotherapy). The author should discuss the different findings for chemoterapy in terms of CSS/OS between entire population (n.s.) and older subjects (p<0.0001)

- Please include some comment on the limited use of surgery, chemotherapy, radioterapy in the older group.

- The concept that the treatment of pulmonary LCNEC is still based on age alone (see conclusions) has been not satisfactorily explained.

- Conclusions are somehow hasty and does not fit to the real aim of the study

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