Prostatic Inflammation in Prostate Cancer: Protective Effect or Risk Factor?

Round 1

Reviewer 1 Report

Some corrections are required and additional comments are desirable:

Some minor grammar issues must be resolved (eg: pag 1 line 36 “Ho+wever”)

To improve the quality of your “Viewpoint”, a new paragraph shoudl be created (number 5). In particular, I suggest to focus on causes of prostate inflammation (bacteria triggering prostatitis and sexually-transmitted diseases, estrogen hormone imbalance, physical trauma, urine reflux to the prostate gland, and environmental factors such as diet) and to give to the reader some clinical details and therapeutic perspectives.

Author Response

We thank the reviewer for the comment. We carefully reviewed the entire manuscript and many typos were corrected. Like you suggested in your comment we added a paragraph about epidemiology and aetiologies of prostate inflammation:

Prostatitis (Type I to III) and prostatitis-like symptoms can seriously impact men's health and quality of life and represent a common cause of medical con-sultations accounting for around 8% of urologist visits although the real preva-lence of this condition remains uncertain [3, 4].

Prostatitis might result from different mechanisms. Frequently, it is caused by specific gram-positive or negative bacterial subspecies according to prostatitis type, but uropathogenic organisms can be detected in less than 10% of symp-tomatic men, and they remain hidden in most of cases [5]. If a specific treatment is not properly adopted, 10% of the acute bacterial prostatitis will hesitate into chronic bacterial prostatitis/chronic pelvic pain syndrome [6]. The prostatic reflux of contaminated urine through prostatic ducts can prompt and perpetuate acute and chronic prostatitis when bladder outlet obstruction (BOO) secondary to benign prostatic hyperplasia (BPH) is present. Additionally, sexually transmitted pathogens can be involved in prostatitis pathogenesis due to their ability to an-terogradely reach the prostate [5].  Moreover, transrectal biopsy or urethral in-strumentation are frequent causes of prostate infection due to a direct intro-duction of bacteria while performing the maneuvers [5]. Uncommonly the source of the infection harbors in distant organs and microorganisms reach the prostate gland through hematogenous seeding [5]. Animal model studies report that sex hormone levels are involved in the regulation of prostate inflammation, and different levels of estrogen and androgen hormones have different levels of in-flammatory response influencing specific interleukins expression in the prostatic microenvironment [7].  It is also known that dietetic costumes result in different metabolic phenotypes and differentially impact prostate size, epithelial volume, inflammation, and gene expression [8]

Reviewer 2 Report

The topic of this manuscript, inflammation, is highly significant in all prostatic diseases, which includes prostate cancer.  The volume of literature on this topic is voluminous and I applaud the authors for tackling such an endeavor. There is much merit in the author's manuscript that makes it worthy of publication.  But there are some significant criticisms that in my opinion need to be resolved before this submission is acceptable for publication.  I will enumerate these below; they can be shared with all of the authors. My goal, as I see it, is to contribute to the readability of the Tafuri et al. article and the impact it will make on the reader. 

1. The English grammar needs a great deal of improvement to enhance readability and comprehension. I have taken the time to share my edits with the authors (Word document).  Given the time for these edits, I hope the authors read the edited manuscript & see if they agree with most or all changes and also address any comments. In essence, the "content" was very good but the "form" needs many changes.
2. I was not convinced about the protective role of inflammation as it relates to PCa.  But I would agree to revisit this issue once the "form" issues are resolved. What I will do in the short term is accept the editing, re-read the paper and see if this impression of a protective role of inflammation has changed. If not, then the title of the manuscript must be changed. For sure, the adverse effects of inflammation on the development and prognosis of prostate cancer outweigh the benefits (protective role). 
3. I think this paper becomes more powerful in impact if the authors were to create a table. Such a graphic would show the major mechanisms of action of inflammation they have cited with author, reference number and other pertinent columns. 
4. The presentation of the references needs to follow the conventions used by Uro. In a publication with multiple authors the citation should not be only the senior author et al. See references 5-7 in the manuscript as examples. In my review of other articles already published in Uro, this issue of a uniform citation format needs to be addressed as well. 

To summarize: this is an important paper and should be published. The manuscript needs some fine-tuning that can be rapidly resolved by the authors and would not involve a great deal of labor. If there is a need to re-review this work, I would be glad to do so in order to expedite publication in Uro. 

Comments for author File: Comments.docx

Author Response

We thank the reviewer for the comment. We really appreciated it.

1. The English grammar needs a great deal of improvement to enhance readability and comprehension. I have taken the time to share my edits with the authors (Word document).  Given the time for these edits, I hope the authors read the edited manuscript & see if they agree with most or all changes and also address any comments. In essence, the "content" was very good but the "form" needs many changes.

We thank the reviewer for the comment.

We included your preciouses edits in the manuscript and modified it according to them.

1. I was not convinced about the protective role of inflammation as it relates to PCa.  But I would agree to revisit this issue once the "form" issues are resolved. What I will do in the short term is accept the editing, re-read the paper and see if this impression of a protective role of inflammation has changed. If not, then the title of the manuscript must be changed. For sure, the adverse effects of inflammation on the development and prognosis of prostate cancer outweigh the benefits (protective role). 

We thank the reviewer for the comment. We agree the paragraph about PCI as protective factor was confusing.

We deleted the following paragraph:

“BPH is frequently associated with chronic inflammatory infiltrates mainly composed of T and B lymphoid cells and macrophages[17]. In its context they are chronically activated and evoke production of cytokines, mostly IL-2, IFN-γ and TGF-β, that may support fibromuscular growth in BPH. Certain TGF-β sub-types drive BPH stromal proliferation and differentiation. Macrophage activation relies on the secretion of IL-17, in patients with metabolic syndrome, with a possible hit to BPH initiation. Furthermore, inflammation can increase the expression of genes responsive to androgens in the stromal cells and macrophages. These cells are stimulated to secrete TGF-β and other immune-mediators, thus increasing the effects of androgen stimulation. This evidence, together with the abundance of androgen receptors in the transition zone of the prostate can explain the link between PCI and BPH[12]”.

We added the following paragraph where we reported important evidences about the inverse correlation between PCI and PCa.

“Vasavada et al performed a meta-analysis including 25 studies dealing with the topic for a total of 20,585 patients and 6,641 with prostate cancer. They found that the presence of any type of inflammation (acute and chronic) was signifi-cantly associated with a lower PCa risk. When subanalsis by inflammation type was performed, acute inflammation in 4 studies and chronic inflammation in 15 were each associated with a lower prostate cancer risk [12].

Recently, Moreira et al. found a protective role of inflammation against PCa, based on data coming from the REDUCE trial. They showed that men with baseline PCI had significantly fewer high-grade tumors compared to those without PCI at baseline chronic inflammation in a cohort of 889 men aged 50 to 75 years with negative baseline prostate biopsy and 2-year repeat biopsy positive for prostate cancer. Authors concluded that Chronic inflammation in a negative biopsy was associated with lower prostate cancer grade among men with cancer on follow-up 2-year biopsy [22].

1. I think this paper becomes more powerful in impact if the authors were to create a table. Such a graphic would show the major mechanisms of action of inflammation they have cited with author, reference number and other pertinent columns. 

We thank the reviewer for the comment.

We added Table 1 which summarizes cell types, cytokines and interleukins involved in prostate microenvironment during PCI and PCa induction.

1. The presentation of the references needs to follow the conventions used by Uro. In a publication with multiple authors the citation should not be only the senior author et al. See references 5-7 in the manuscript as examples. In my review of other articles already published in Uro, this issue of a uniform citation format needs to be addressed as well. 

We thank the reviewer for the comment. We modified reference format according to Uro rules.

To summarize: this is an important paper and should be published. The manuscript needs some fine-tuning that can be rapidly resolved by the authors and would not involve a great deal of labor. If there is a need to re-review this work, I would be glad to do so in order to expedite publication in Uro. 

We thank the reviewer for the comment.

Round 2

Reviewer 2 Report

In addition to the revisions by the authors, there has been new text and additional references provided by the authors. Perhaps this resulted from the other review of this manuscript.  I believe that the changes made have enhanced the quality and readability of this submission. The authors have published extensively on this topic. Please note the many comments I have made and need to double-check one of the references which does not seem to coordinate with the author's text.  

Comments for author File: Comments.docx

Author Response

Dear reviewer, 

We really appreciate your effort to help us improve the present study. 

We took in consideration your comments and modified the manuscript consequently. 

We think this managed to improve the quality of our work, and we hope you will agree to this. You can notice every change, with a reply to each one of your comments, in the "Track changes" section. 

On behalf of the Co-Authors,

Kindest regards,

The corresponding authors