Linking Cancer Pain Features and Biosignals for Automatic Pain Assessment

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Abstract, Author should clearly state the gap and novelity of study.

Introduction:

-state objective study clearly-

• can be improve by describing findings from similar studies.
• Introduce the method/technique for example, BITalino (r)evolution Board appear first time in method.
• Method: Describe the inclusion and exclusion criteria clearly.
• Results-
• Include findings on different type of cancer rather than general.
• Fig/table legend should in shrort able to describe method and statistics used.
• Quality of figure need to improve.
• Discusssion:
• Discussion is not clearly supported by findings and lack critical analysis.

Author Response

Reviewer 1:

 

Comment: Abstract, Author should clearly state the gap and novelity of study.

 

Response: We thank the Reviewer for this comment. We have revised the Abstract to explicitly highlight both the knowledge gap and the novelty of the present study.

 

Comment: Introduction: -state the objective study clearly-

 

Response: The study objective has now been clearly stated at the end of the Introduction.

 

Comment: It can be improved by describing findings from similar studies.

 

Response: We agree and have expanded the Introduction to better contextualize our work within existing literature on biosignal-based pain assessment in oncology. Different references were also added to underscore these crucial aspects.

 

Comment: Introduce the method/technique for example, BITalino (r)evolution Board appear first time in method.

 

Response: Thank you; please note that, according to your suggestion, the BITalino (r)evolution board is now briefly introduced in the Introduction to improve methodological clarity. “To address this issue, we employed a wearable biosignal acquisition system (BITalino (r)evolution board). The device enables high-resolution recording of electrodermal and cardiac signals in clinical oncology settings.”

 

Comment: Method: Describe the inclusion and exclusion criteria clearly.

 

Response: Inclusion and exclusion criteria have now been explicitly detailed in a dedicated paragraph.

 

Comment: Results. Include findings on different type of cancer rather than general.

 

Response: We acknowledge this point. Given the limited sample size and heterogeneity of cancer types, a stratified statistical analysis was not feasible. This limitation has now been explicitly stated.

 

Comment: Fig/table legend should in shrort able to describe method and statistics used.

 

Response: All figure legends have been revised to explicitly report the analysis method and statistical approach.

 

Comment: Quality of figure need to improve.

 

Response: we improved their quality as suggested.

 

Comment: Discussion is not clearly supported by findings and lack critical analysis.

 

Response: Thank you for this constructive comment. The Discussion has been revised to strengthen the link between results and interpretation and to include a more critical analysis of confounders and methodological constraints.

 

Reviewer 2 Report

Comments and Suggestions for Authors

This work addresses a very interesting and timely topic: the use of tools capable of recording biosignals, such as electrodermal activity (EDA), correlating them with pain assessment. A review of the results is deemed absolutely necessary, taking into account:

• pain duration
• concomitant opioids therapies
• concomitant oncological therapies

It's unclear when BTcP evaluation was conducted and how the conclusion were reached. This aspect should be clarified better as the data obtained are discordant with literature

The abstract' conclusions, to support the role of EDA as biomarker to detect intensity and type, are discordant with whose reported in the paper

 

 

Author Response

Reviewer 2:

This work addresses a very interesting and timely topic: the use of tools capable of recording biosignals, such as electrodermal activity (EDA), correlating them with pain assessment. A review of the results is deemed absolutely necessary, taking into account: pain duration, concomitant opioids therapies, concomitant oncological therapies.

 

Response: We agree that these variables are clinically relevant. While they were collected, the study was not powered for stratified analyses. This is now explicitly discussed as a limitation.

 

Comment: It's unclear when BTcP evaluation was conducted and how the conclusion were reached. This aspect should be clarified better as the data obtained are discordant with literature.

 

Response: In both Methods and Discussion, we clarified that BTCP was assessed at baseline and that biosignals likely reflect baseline autonomic tone rather than transient pain exacerbations.

 

Comment: The abstract' conclusions, to support the role of EDA as biomarker to detect intensity and type, are discordant with whose reported in the paper.

 

Response: The Abstract conclusions have been revised as suggested.

Reviewer 3 Report

Comments and Suggestions for Authors

This an interesting exploratory analysis trying to validate phsyiologic (objective) measures for pain. 

The study is interesting even if not very rich in significant results.

Some observations

1. How did you approached the stage of cancer in this analysis knowing that in more advanced stages the pain is different quantitatively and qualitatively from more localised stages
2. Can we use these methods to discriminate between nociceptive and neuropatic pain? because if so this would be a big step ahead in better treating each of the pathogenic types of pain

Please briefly elaborate on these two issues in the discussion

Author Response

Reviewer  3:

This an interesting exploratory analysis trying to validate phsyiologic (objective) measures for pain.

The study is interesting even if not very rich in significant results.

Some observations

Comment: How did you approached the stage of cancer in this analysis knowing that in more advanced stages the pain is different quantitatively and qualitatively from more localised stages

 

Response: Thank you for this comment. This point was highlighted by another reviewer. Unfortunately, cancer stage was not included as a stratification variable due to sample size. This has now been discussed explicitly.

 

Comment: Can we use these methods to discriminate between nociceptive and neuropatic pain? because if so this would be a big step ahead in better treating each of the pathogenic types of pain. Please briefly elaborate on these two issues in the discussion.

 

Response: We clarified in the Discussion that, in the present study, EDA parameters discriminated mixed pain from pure nociceptive or neuropathic phenotypes, but did not reliably distinguish nociceptive from neuropathic pain alone. We further expanded this point by explicitly stating that this represents a key objective of our ongoing research, which will adopt a multimethod framework integrating descriptive analyses and predictive machine-learning approaches to better characterize cancer pain phenotypes.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Revised manuscript looks satisfactory.

Author Response

Thank you

Reviewer 2 Report

Comments and Suggestions for Authors

Considering the patient population in which the study was conducted, the lack of the required data - even if underlined in the discussion - and the impossibility of analyzing their impact on the results, determines important limitation for the study's publication

Author Response

We thank the Reviewer for this important observation. In response to this comment, we have performed additional targeted sub-analyses to directly address the potential impact of key clinical variables relevant to the studied population. Specifically, we conducted subgroup analyses according to: (i) the presence of breakthrough cancer pain (BTCP), (ii) opioid intake, and (iii) the presence of bone metastases. These analyses were aimed at evaluating whether these clinically meaningful factors influenced the main study outcomes. The results of these additional analyses have now been included in the revised manuscript and are reported in two newly added tables (Tables 4 and 5). Importantly, the main findings of the study remained consistent across these subgroup, supporting the robustness of the results and partially mitigating the limitation originally highlighted. We have also updated the Methods and Discussion sections accordingly to clearly describe these additional analyses and to contextualize their implications within the clinical framework of cancer-related pain.