Ratio of periprostatic to subcutaneous fat thickness on MRI is an independent survival predictor in hormone-naïve men with advanced PCa

[pjoshea13]

New study from Japan [1].

Visceral fat is associated with a poorer prognosis. Visceral fat is hormonally active (& not in a good way.) Many researchers who have reported on obesity & PCa mortality, acknowledge that BMI (body mass index) is a surrogate for visceral fat. However, one can be thin outside (low BMI) yet fat inside.

If visceral fat is such a danger, perhaps the fat around the prostate (periprostatic fat) is particularly dangerous. The new study is just another of a long line of periprostatic fat studies.

They looked at the ratio of periprostatic to subcutaneous fat thickness [PPF/SCF].

"The 5-year OS {overall survival} in the patients with higher PPF/SCF ratio (≥ 1) and lower PPF/SCF ratio (< 1) was 49.5% and 66.5%, respectively".

***

Also recently, a study from China [2]:

"The aim of this study was to evaluate the association between periprostatic fat thickness (PPFT) and time to castration-resistant prostate cancer (CRPC) in newly diagnosed patients with prostate cancer (PCa) treated with androgen deprivation therapy (ADT)."

"Patients with high PPFT (measured on MRI) showed a significantly shorter PFS than patients with low PPFT."

"PPFT measured on MRI is a readily available and significant predictor of time to CRPC in patients with PCa receiving ADT as the primary treatment."

***

And from Australia (Apr/May):

"Here for the first time, based on a unique cohort of patients with 6-month profound androgen suppression and receptor blockade, we performed an integrative study of the molecular and cellular changes in periprostatic fat associated with androgen deprivation. In this study, we show that ADT is associated with a pro-inflammatory and obesity-like adipose tissue microenvironment."

A case for destroying the "mother ship" has been made elsewhere, but the Australian study suggests that ADT might turn an intact prostate into an even bigger threat.

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/316...

Int J Clin Oncol. 2019 Oct 15. doi: 10.1007/s10147-019-01559-y. [Epub ahead of print]

Pre-treatment ratio of periprostatic to subcutaneous fat thickness on MRI is an independent survival predictor in hormone-naïve men with advanced prostate cancer.

Sasaki T1, Sugino Y2, Kato M2, Nishikawa K2, Kanda H2.

Author information

1

Department of Nephro-Urologic Surgery and Andrology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan. [e-mail].

2

Department of Nephro-Urologic Surgery and Andrology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.

Abstract

BACKGROUND:

Epidemiological studies have shown an association between obesity and prostate cancer (PCa) aggressiveness. However, little is known about periprostatic fat (PPF) and its relationship with overall fat deposition in PCa. PPF is thought to contribute to PCa growth and migration via secreted factors and induction of chronic inflammation. We investigated if pre-treatment PPF thickness correlates with overall survival (OS).

METHODS:

We reviewed 85 hormone-naïve men with advanced PCa who had received androgen deprivation therapy (ADT). PPF thickness was measured by magnetic resonance imaging (MRI) and compared with subcutaneous fat (SCF) thickness as an internal control. Visceral fat (VF) area measured by computed tomography served as an additional control. We evaluated the relationship between laboratory data, pathology results, and obesity parameters and OS.

RESULTS:

Median follow-up was 50.6 months. Thirty-six patients died during follow-up. Univariate analysis revealed that nadir PSA titer, Gleason score, N stage, M stage, extent of disease by bone scan grade, hemoglobin, lactate dehydrogenase, alkaline phosphatase, and PPF/SCF ratio were associated with OS. Multivariate analysis revealed that nadir PSA titer, N stage, and PPF/SCF ratio were independent prognostic factors for survival. The 5-year OS in the patients with higher PPF/SCF ratio (≥ 1) and lower PPF/SCF ratio (< 1) was 49.5% and 66.5%, respectively (P = 0.039).

CONCLUSIONS:

Pre-treatment ratio of PPF-to-SCF thickness on MRI is an independent predictor of survival in hormone-naïve men with advanced PCa. This could be useful for predicting which patients are more likely to develop castration-resistant PCa.

KEYWORDS:

Overall survival; Periprostatic fat; Prostate cancer; Subcutaneous fat

PMID: 31617025 DOI: 10.1007/s10147-019-01559-y

***

[2] ncbi.nlm.nih.gov/pubmed/312...

Clin Genitourin Cancer. 2019 Oct;17(5):e1036-e1047. doi: 10.1016/j.clgc.2019.06.001. Epub 2019 Jun 13.

Periprostatic Fat Thickness on MRI is an Independent Predictor of Time to Castration-resistant Prostate Cancer in Chinese Patients With Newly Diagnosed Prostate Cancer Treated With Androgen Deprivation Therapy.

Huang H1, Chen S2, Li W1, Bai P1, Wu X2, Xing J3.

Author information

1

Department of Urology, The First Affiliated Hospital of Xiamen University, Siming District, Xiamen, Fujian, China.

2

Department of Radiology, The First Affiliated Hospital of Xiamen University, Siming District, Xiamen, Fujian, China.

3

Department of Urology, The First Affiliated Hospital of Xiamen University, Siming District, Xiamen, Fujian, China. Electronic address: [e-mail].

Abstract

BACKGROUND:

The aim of this study was to evaluate the association between periprostatic fat thickness (PPFT) and time to castration-resistant prostate cancer (CRPC) in newly diagnosed patients with prostate cancer (PCa) treated with androgen deprivation therapy (ADT).

PATIENTS AND METHODS:

We retrospectively reviewed the medical records of 150 patients with PCa treated with ADT at our hospital between June 2011 and June 2017. PPFT measured on magnetic resonance imaging (MRI) and PPFT/periprostatic fat volume (PPFV) measured on computed tomography (CT) were evaluated. Kaplan-Meier curves and log-rank tests were used to assess significant differences in time to CRPC between the 2 groups (high PPFT vs. low PPFT, determined by PPFT > or < the median value, respectively). Univariable and multivariable Cox regression analyses were employed to identify the potential prognostic factors for survival.

RESULTS:

The median value of PPFT measured on MRI was 0.555 cm. PPFT was significantly associated with PPFV measured on CT images (with a correlation coefficient of 0.825; P < .001). A total of 66 patients (44%) progressed to CRPC during the follow-up period. Patients with high PPFT (measured on MRI) showed a significantly shorter PFS than patients with low PPFT. Multivariable Cox analysis demonstrated that T stage, presence of distant metastasis, shorter time to prostate-specific antigen nadir, higher prostate-specific antigen nadir, Gleason score (greater than 4 + 4), and high PPFT were significantly associated with shorter PFS.

CONCLUSIONS:

PPFT is significantly associated with PPFV measured on CT images. PPFT measured on MRI is a readily available and significant predictor of time to CRPC in patients with PCa receiving ADT as the primary treatment.

Copyright © 2019 Elsevier Inc. All rights reserved.

KEYWORDS:

Androgen-deprivation therapy; Body fat patterning; Castration-resistant prostatic cancer; Magnetic resonance imaging; Prostate cancer

PMID: 31281063 DOI: 10.1016/j.clgc.2019.06.001

***

[3] ncbi.nlm.nih.gov/pmc/articl...

Abstract

Prostate cancer is a leading cause of morbidity and cancer-related death worldwide. Androgen deprivation therapy (ADT) is the cornerstone of management for advanced disease. The use of these therapies is associated with multiple side effects, including metabolic syndrome and truncal obesity. At the same time, obesity has been associated with both prostate cancer development and disease progression, linked to its effects on chronic inflammation at a tissue level. The connection between ADT, obesity, inflammation and prostate cancer progression is well established in clinical settings; however, an understanding of the changes in adipose tissue at the molecular level induced by castration therapies is missing. Here, we investigated the transcriptional changes in periprostatic fat tissue induced by profound ADT in a group of patients with high-risk tumours compared to a matching untreated cohort. We find that the deprivation of androgen is associated with a pro-inflammatory and obesity-like adipose tissue microenvironment. This study suggests that the beneficial effect of therapies based on androgen deprivation may be partially counteracted by metabolic and inflammatory side effects in the adipose tissue surrounding the prostate.

Introduction

For over 80 years, androgen deprivation by surgical or medical castration has been the cornerstone of treatment for advanced prostate cancer (1). As new cytotoxic and androgen receptor-targeted therapies have been developed, demonstrating survival benefit in combination with androgen deprivation in a number of clinical settings, the duration a patient can expect to be in a castrated state prior to death has been extended significantly (2). Given that androgen signalling is important for homeostasis in a number of different organ systems, it is not surprising that both short- and long-term use is associated with a number of deleterious effects (3).

Forefront of these is the association of androgen deprivation with metabolic syndromes such as diabetes mellitus (4) and obesity (5), as androgens play a key role in the regulation of intermediate metabolism and tissue composition (6). Increased fat tissue mass (known in conjunction with loss of muscle mass as sarcopenic obesity) is one of the main metabolic side effects of androgen deprivation therapy (ADT) (7), even for short-term treatment (8, 9, 10). At the molecular level, lack of androgen-related hormones leads to changes in tissue lipid composition and decreased insulin sensitivity (4). For example, gonadotropin-releasing hormone agonists have been shown to alter tissue lipid profiles with cholesterol levels, triglycerides and high-density lipoproteins shown to increase up to 10.6, 25 and 8–20%, respectively (8, 10).

The promotion of an obese-like phenotype by androgen deprivation is highly clinically relevant, as obesity (expressed as BMI) is itself associated with the development of prostate cancer, post-prostatectomy biochemical failure and risk of death from prostate cancer. Although the link between elevated BMI and increased risk of prostate cancer is still controversial (11, 12, 13), several studies have found a positive association between BMI and cancer grade and/or stage at the time of radical prostatectomy (14, 15, 16). Two recent studies identified an association between BMI and biochemical failure rates following radical prostatectomy, based on a large-scale, multi-ethnic cohort (13, 17). The relationship between BMI and prostate cancer-specific mortality is also widely supported (18, 19, 20, 21).

Although the connection between ADT, obesity and prostate cancer progression is well established in clinical settings, a molecular understanding of the changes in adipose tissue associated with castrating therapies is still missing, in part due to a paucity of appropriate clinical specimens. This is especially important for periprostatic adipose tissue due to its proximity to the cancer site and its potential to influence prostate hormonal and immune homeostasis (22). Here for the first time, based on a unique cohort of patients with 6-month profound androgen suppression and receptor blockade, we performed an integrative study of the molecular and cellular changes in periprostatic fat associated with androgen deprivation. In this study, we show that ADT is associated with a pro-inflammatory and obesity-like adipose tissue microenvironment.

Conclusions.

The prostate gland is enveloped in adipose tissue, and over the last decade a number of lines of evidence suggest that paracrine interactions between this fat depot and prostate epithelium play a role in prostate cancer development and/or progression. For instance, tumour cell invasion into the periprostatic fat compartment where direct cell-to-cell interaction can occur has been reported to be a stronger determinant of cancer recurrence than acquisition of the ability to invade across tissue boundaries (50). Periprostatic adipose tissue has been shown to elaborate a number of cytokines including IL6, osteopontin, and TNF-alpha, that promote prostate tumour cell migration and invasion (51, 52), and at least for IL6 correlates with downstream pathway activation in high-grade tumours (53). In addition, there is evidence of a positive feedback loop, with conditioned media from prostate cancer cells significantly increasing the secretion of these cytokines from adipose tissue explants (52).

The role of adipose tissue in prostate cancer progression is perhaps best understood in the context of obesity, where numerous clinical studies report positive associations between BMI and high-risk pathological findings at prostatectomy as well as adverse clinical outcomes post treatment (54). Obesity induces a persistent inflammatory and hormone-rich tissue microenvironment that contributes to high-risk disease (55, 56). ADT is a known cause of increased fat body mass (14, 15, 16); yet, the cellular and molecular processes that are altered in association with ADT, especially in the periprostatic adipose tissue microenvironment, have not been completely resolved. In this study, we showed that profound ADT is associated with a pro-inflammatory adipose tissue microenvironment, as well as with altered obesity-related gene transcription linked with cholesterol and hormonal homeostasis. Both differential tissue composition and gene enrichment analyses pointed to an enrichment of infiltrating immune cell types within the tissue as the predominant cause of this difference. Monocytes and macrophages had the greatest presence within the periprostatic adipose tissue, compared with other immune cells. The abundance of these immune cell types was positively associated with androgen deprivation, suggesting their infiltration of the tissue, which is consistent with in vivo studies (57). Macrophages have been shown to interact with adipose tissue in a paracrine manner, where TNF-α secretion from macrophages interferes with adipocyte insulin signalling and induces fatty acid lipolysis, which commences a vicious inflammatory cycle and contributes to insulin resistance (58). Furthermore, an elevated blood monocyte count is an independent prognostic predictor for poor prostate cancer outcome in cancer-specific and overall survival studies (59, 60). These finding are perhaps not surprising, given numerous reports describing the anti-inflammatory properties of androgen receptor signalling. How this is mediated is not clear, although testosterone has been reported to attenuate both Th2 and Th17 inflammatory responses (61, 62), as well as directly suppressing the section of monocyte chemoattractant protein-1 in adipocytes, a key cytokine that promotes monocyte infiltration (63).

There are a number of limitations to our study that merit enumeration, particularly the lack of orthogonal validation at the protein level for pathway and/or cell type tissue enrichment observed in our expression profiles. However, we note that previous studies have confirmed that alterations of inflammatory signalling identified expression data are accurately reflected by protein level changes in the abundance of key cytokines, including IL6 (64), and extensive validation studies have shown that the expression of key inflammatory cell markers are consistent with expression data from RNA-seq analysis (65) (proteinatlas.org). In addition, ideally we would use paired pre- and post-treatment samples from the same patients for analysis. However, this was not practical for clinical reasons, as collection of sufficient quantities of periprostatic adipose tissue for the type of exploratory analysis described is only possible at the time of prostatectomy. We have therefore tried to match patients as much as possible based on their pre-treatment clinical and pathological characteristics as described.

Taken together, our study demonstrates that androgen deprivation promotes an inflammatory and obesity-like microenvironment in periprostatic fat and suggests that the beneficial effect of ADT may be partially counteracted by metabolic and inflammatory side effects in the adipose tissue encompassing the prostate. This may be particular pertinent when the primary tumour is in situ, as tumour response within the prostate appears less profound compared to that observed for metastatic disease (66, 67). Further studies will need to investigate the immune infiltration profile associated with androgen deprivation, as well as the potential impact of anti-inflammatory therapies on local tumour response.

[6357axbz]

I wonder if a retrospective review of past MRI scans could determine PPF/SCF ratio????

[Graham49 in reply to 6357axbz]

Thanks for the post Patrick. Do you know of any reason why some people might put on more fat around the prostate than subcutaneously?

[pjoshea13 in reply to Graham49]

Hi Graham,

Please excuse lengthy response.

Although glucose is not the preferred energy source for PCa - at least not in earlier stages, glucose spikes are dangerous for two reasons: (a) excess glucose is converted to triglycerides & stored preferentially as visceral fat, & (b) glucose spikes cause a loss of insulin sensitivity & increased insulin production. Insulin is a PCa growth factor.

A major cause of glucose spikes are the carbohydrates in a low fat diet.

The Dean Ornish 10% fat high fiber vegan diet is excellent for control of most lipids, but triglycerides invariably increase.

The triglyceride:HDL-cholesterol ratio is a surrogate for insulin resistance.

Having a 3:1 triglyceride:HDL-cholesterol ratio is a clue that visceral fat may be high. A 40% fat Mediterranean diet might help control triglycerides & visceral fat:

"A Mediterranean Diet Reduces F2-Isoprostanes and Triglycerides among Older Australian Men and Women after 6 Months."

ncbi.nlm.nih.gov/pubmed/285...

(When my testosterone is high-normal my triglyceride:HDL-cholesterol ratio is about 1:1. As of last week it was 119:87 because I was 6 weeks into my 2 month BAT cycle. I hate for triglycerides to go above 100, but castrate-T messes up everything.)

Metformin is useful for glucose control.

-Patrick

[Graham49 in reply to pjoshea13]

Thanks Patrick

The Mediterranean diet is generally what is recommended by the UK NHS, but I don't think it is well defined. There seems to be considerable scope for consuming lots of bread and high fructose/sugar fruits eggs, dairy and chicken within the Mediterranean diet.

[PhilipSZacarias in reply to pjoshea13]

As usual, your breadth and depth of knowledge blows me away :). And thank you for posting. I have not paid much attention to the triglyceride/HDL ratio, which can be a surrogate for insulin resistance, but I will now. Cheers, Phil

[snoraste]

very interesting. Diet/exercise, and if possible, take out the mothership.

[PhilipSZacarias]

Hello Patrick, the Waist/Height and Waist/Hip Ratios may be better indicators of fatty liver and visceral fat (eg., around the intestines) instead of the BMI. I was borderline on BMI and significantly over with both ratios according WHO guidelines. After 3+ months following a time restricted feeding (TRF) regimen I lost ~15 lbs and the W/Ht and W/Hip ratios as well as BMI declined. I am close to normal with respect to the ratios now. My goal for following TRF was not weight loss per se, but as a means for reducing visceral fat and the associated inflammation. I strongly recommend TRF for members, especially those on ADT (like myself), who want to control their weight. Cheers, Phil