Review for 10.1186/s12876-023-03076-9 (2023)

Title: The association between jaundice and poorly differentiated pancreatic neuroendocrine
neoplasms (Ki67 index > 55.0%)
Version: 0 Date: 04 Sep 2023
Reviewer's report:
This paper attempts to explore the association between jaundice and poorly differentiated
pancreatic neuroendocrine neoplasms (PNENs) with a ki67 index greater than 55.0%. While the
study addresses an intriguing aspect of PanNENs, the methodology and analysis raise several
concerns.
Indeed, on one hand, investigating the connection between jaundice and poorly differentiated
PNENs is a noteworthy endeavor, as it could potentially enhance our understanding of the
clinical presentation and prognosis of these neoplasms. Moreover, the study acknowledges the
clinical relevance of poorly differentiated PNENs and their impact on therapeutic strategies
and prognosis (see also PMID: 31557757) and provides a practical model incorporating age,
tumor size, and jaundice as predictors for poorly differentiated PNENs. Such a model could
have clinical utility if validated properly.
However, these are possible Weaknesses:
1. Sample Size and Scope: The study's retrospective, single-center design and limited sample
size (93 patients) could potentially compromise the generalizability of its findings. The study
only considers tumors located in the head-neck region of the pancreas, limiting the scope of the
conclusions.
2. External Validation: The lack of external validation for the developed nomogram model is
a significant drawback. Without validation in an independent population, the reliability and
generalizability of the model remain uncertain.
3. Moreover, there are further aspects the authors could have addressed to enhance the
comprehensiveness and impact of their study: Thrombosis as a Prognostic Factor: Given that
thrombosis is a recognized negative prognostic factor for both pancreatic ductal adenocarcinoma
(PDAC) and pancreatic neuroendocrine neoplasms (PanNEN) (see also PMID 34276200), the
authors missed an opportunity to include this variable in their analysis. It's recommended that
the authors explore whether the presence of thrombosis could influence the risk of poorly
differentiated PNENs and its potential interaction with jaundice. Even if data are not available,
please a a comment.
1. Clinical and Genetic Syndromes: To comprehensively evaluate the factors influencing
PNENs, the authors should have considered the presence of clinical syndromes (e.g., multiple
endocrine neoplasia syndromes) or genetic syndromes (e.g., mutations in MEN1, VHL, or other
relevant genes). The presence of such syndromes could have a significant impact on PNEN grade
and prognosis, and their absence from the analysis is a notable limitation. The authors could
refer to a study like PMID 36436191 for insights into the significance of genetic syndromes in
PNENs.
2. Additionally, the rationale for selecting specific cutoff values, such as 55% for the ki67 index,
should be explicated (see also PMID: 36417840 and PMID: 32365350)
3. Discussion of Limitations: While some limitations are mentioned in the "Discussion" section,
they should be more thoroughly addressed throughout the paper. Additionally, the paper does
not address potential biases or confounders adequately as well as the limitations of the findings.
4. Language and Structure: The writing style and structure of the paper could be improved for
clarity. Certain sentences are convoluted, and the organization of ideas can be confusing. A
clearer presentation would enhance the reader's comprehension.
5. Discussion of Potential Mechanisms: The authors missed an opportunity to discuss potential
mechanisms underlying the association between jaundice and poorly differentiated PNENs.
Exploring whether jaundice is a mere consequence of tumor size or if there are other biological
factors at play could provide deeper insights.
6. Enhanced Bibliography: The current bibliography is notably limited and lacks references
to key studies that could provide a broader context for the findings. Including relevant
literature, such as studies on the molecular basis of PanNENs, clinical guidelines for PanNEN
management, and other related research, would enrich the discussion and demonstrate the
authors' familiarity with the existing body of knowledge. Only as examples see also PMID:
32224077, PMID: 37174986,PMID: 31557757
In conclusion, the authors could have further strengthened their study by considering
the presence of thrombosis, evaluating clinical and genetic syndromes, enhancing the
bibliography with relevant references, providing clearer explanations of statistical methods, and
discussing potential underlying mechanisms. Addressing these aspects would result in a more
comprehensive and impactful research contribution in the field of pancreatic neuroendocrine
neoplasms.