|Year : 2018 | Volume
| Issue : 3 | Page : 280-286
Clinical and biochemical markers of visceral adipose tissue activity: Body mass index, visceral adiposity index, leptin, adiponectin, and matrix metalloproteinase-3. Correlation with Gleason patterns 4 and 5 at prostate biopsy
Vincenzo Serretta1, Alberto Abrate1, Simone Siracusano1, Cristina Scalici Gesolfo1, Marco Vella1, Fabrizio Di Maida1, Antonina Cangemi1, Giuseppe Cicero1, Elisabetta Barresi2, Chiara Sanfilippo3
1 Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Palermo, Italy
2 Department of Human Pathology, University of Palermo, Palermo, Italy
3 Stastistics, GSTU Foundation, Palermo, Italy
|Date of Submission||04-Dec-2017|
|Date of Acceptance||18-May-2018|
|Date of Web Publication||12-Jul-2018|
Prof. Vincenzo Serretta
Department of Surgical, Oncological and Stomatological Sciences of Urology, University of Palermo, Via Del Vespro 129, Palermo 90127
| Abstract|| |
Context: The correlation between aggressive prostate cancer and obesity mainly based on body mass index (BMI) and pathology after surgery remains controversial.
Aims: The aim of the study was to correlate BMI, visceral adiposity index (VAI), and the plasmatic levels of leptin, adiponectin, and matrix metalloproteinase-3 (MMP-3), and biomarkers of adipose tissue function, with the detection of Gleason patterns 4 and 5 at biopsy.
Subjects and Methods: Consecutive patients with prostate cancer at 12-core transrectal biopsy were enrolled. BMI, waist circumference (WC), blood samples to evaluate the plasmatic levels of triglycerides (TG) and high-density lipoproteins (HDL), adiponectin, leptin, and MMP-3 were obtained immediately before biopsy. The VAI was calculated according to the formula: WC/(39.68 + [1.88 × BMI]) × TG/1.03 × 1.31/HDL.
Results: One hundred and forty-nine patients were entered. The median PSA, BMI, and VAI were 10.0 ng/ml, 27.6 kg/m2, and 4.6, respectively. Gleason patterns 4 or 5 were detected in 68 (45.6%) patients; in 15 (41.7%), 31 (44.9%), and 22 (50.0%) among normal weight, overweight, and obese patients, respectively (P = 0.55). The statistical analysis did not show any significant correlation between BMI, VAI, the plasmatic levels of leptin, adiponectin, MMP-3, and the detection of Gleason patterns 4 and 5 at biopsy. A statistically significant association emerged with older age (P = 0.017) and higher PSA values (P = 0.02).
Conclusion: We did not find any association between BMI, VAI, the plasmatic levels of adiponectin, leptin, and MMP-3 and the detection of Gleason patterns 4 and 5 at prostate biopsy.
Keywords: Adiponectin, body mass index, Gleason pattern, leptin, matrix metalloproteinase-3, obesity, prostate cancer, visceral adiposity index
|How to cite this article:|
Serretta V, Abrate A, Siracusano S, Gesolfo CS, Vella M, Di Maida F, Cangemi A, Cicero G, Barresi E, Sanfilippo C. Clinical and biochemical markers of visceral adipose tissue activity: Body mass index, visceral adiposity index, leptin, adiponectin, and matrix metalloproteinase-3. Correlation with Gleason patterns 4 and 5 at prostate biopsy. Urol Ann 2018;10:280-6
|How to cite this URL:|
Serretta V, Abrate A, Siracusano S, Gesolfo CS, Vella M, Di Maida F, Cangemi A, Cicero G, Barresi E, Sanfilippo C. Clinical and biochemical markers of visceral adipose tissue activity: Body mass index, visceral adiposity index, leptin, adiponectin, and matrix metalloproteinase-3. Correlation with Gleason patterns 4 and 5 at prostate biopsy. Urol Ann [serial online] 2018 [cited 2020 Oct 27];10:280-6. Available from: https://www.urologyannals.com/text.asp?2018/10/3/280/234081
| Introduction|| |
Prostate cancer is the most frequent tumor and the second leading cause of cancer deaths in men from Western countries., To select for prostatic biopsy patients at risk for aggressive tumors avoiding diagnosis of indolent, low-risk prostatic cancer is a major challenge for the urologic and scientific community. Several studies indicate that prostate cancer in obese patients might show higher Gleason score and worse prognosis., Obesity and metabolic syndrome (MetS) are highly prevalent all around the world. Mets is a complex disorder, strictly related to obesity, defined by a cluster of interconnected factors that increase the risk of cardiovascular and atherosclerotic diseases and diabetes mellitus type 2., Epidemiological studies associate obesity and Mets with a multitude of cancer types., The correlation between prostate cancer and obesity remains controversial ,,,,, mainly based on the relation between body mass index (BMI) and pathology after surgery. A detection bias in obese patients due to lower plasmatic levels of prostate-specific antigen (PSA), diffcult digital rectal examination, and higher prostate volumes, could be responsible for later diagnosis, higher stage, and Gleason score. Moreover, the lower serum testosterone levels in obese patients could promote the growth of high grade (HG), androgen-independent prostate cancer.,
The “Diet, Cancer and Health” prospective cohort study that accrued 26,944 men considering BMI, waist circumference (WC), and body fat percentage found a slightly lower incidence rate but more advanced stage of prostate cancer in obese men compared with nonobese men. There is some evidence that obese patients might be at higher risk for Gleason patterns 4 or 5 prostate cancer at biopsy., Both BMI and WC are predictors of HG prostate cancer, however, obesity with central adiposity is the strongest predictor of HG prostate cancer.
Boehm et al. on 1933 incident prostate cancers concluded that abdominal fat is a predictor of prostate cancer risk, whereas BMI alone is not. Nonetheless, BMI is the most commonly used anthropometric method to evaluate obesity even though it does not consider body mass composition and fat distribution  and is not related to the endocrine activity of the visceral adipose tissue. Visceral adiposity index (VAI) is a sex-specific obesity index, based on WC, BMI, plasmatic triglycerides (TG), and high-density lipoproteins (HDL), evaluating more accurately the dysfunction of visceral adipose tissue. The endocrine activity of visceral fat might play a carcinogenetic role increasing circulating adipokines and pro-inflammatory factors and favoring the growth of more aggressive tumor clusters. It is plausible that abnormal levels of adipokines interacting with androgens and other factors might select cells with a higher aggressiveness in an early phase when obesity is not yet clinically relevant.
Abnormal serum levels of biomarkers related to obesity and MetS, as adiponectin, leptin, and pro-inflammatory factors such as matrix metalloproteinase (MMP)-3 could indicate an higher risk of Gleason patterns 4 and 5 at biopsy. The plasmatic levels of leptin are proportional to fat mass and body weight. It enhances the growth of prostate cancer cell lines stimulating cell survival pathways, proliferation, angiogenesis, and cell migration. Adiponectin has been reported to have a prohibitory effect on prostate cancer showing an inverse correlation with stage and grade., MMPs are essential for proper extracellular matrix remodeling, a process that takes place during obesity-mediated adipose tissue formation. They act as pro-inflammatory agents  and can mediate the release and/or activation of sequestered growth factors and the cleavage of cell surface adhesion receptors. MMP-3 participates in many physiological and pathological processes such as angiogenesis, reproductive cycling, and metastasis.,
The aim of the present study was to correlate the abovementioned anthropometric and biological markers of obesity with the detection of Gleason patterns 4 and 5 at prostate biopsy.
| Subjects and Methods|| |
Consecutive patients undergoing 12-core transrectal biopsy for elevated PSA levels and/or positive digital rectal examination were prospectively enrolled in an institutional research evaluating the correlation between MetS and the risk of prostate cancer at biopsy in everyday common clinical practice.
In the present study, only the subset of patients with histological diagnosis of adenocarcinoma of the prostate are included. The main end-point of the study was to investigate the association of anthropometric (BMI and VAI) and biological (plasmatic adiponectin, leptin, and MMP-3) markers of obesity and MetS with the detection of Gleason patterns 4 and 5 at prostate biopsy. Written informed consent was obtained in all patients. Patient with one previous negative biopsy were also included.
Main exclusion criteria were as follows: negative prostate biopsy, HG intraepithelial neoplasia or atypical small acinar proliferation (ASAP), more than one previous negative prostate biopsy, recurring urinary tract infection, tumor in another site excluding basalioma, <12 evaluable cores at biopsy, PSA <4 ng/ml, and negative digital rectal examination.
The number of cores was increased to 24 in case of rebiopsy. All specimens were reviewed by the same expert pathologist.
BMI (Kg/m 2) and WC were obtained at the time of biopsy. Blood samples were collected immediately before biopsy to evaluate the plasmatic levels of TG and HDL. The VAI was obtained according to the following formula: WC/(39.68 + [1.88 × BMI]) × TG/1.03 × 1.31/HDL as described by Amato et al. A blood sample was also collected immediately before biopsy, centrifuged for 10 min at 3000 rpm and stored at –80°C. Plasmatic adiponectin, leptin, and MMP-3 were measured using “Human Leptin Instant ELISA,” “Human Adiponectin ELISA,” and “Human MMP-3 ELISA” kits (Life Technologies ®), respectively.
The end-point of the study was to investigate the association between BMI, VAI, the plasmatic levels of adiponectin, leptin, and MMP-3 and the detection of Gleason patterns 4 and 5 at prostate biopsy.
A database including clinical, biochemical, and pathological data was built.
The ANOVA one-way analysis was performed to compare each variable between the groups. The Pearson correlation coefficient (ρ) was calculated to investigate the correlation between the variables and to correlate the plasmatic levels of the serum biomarkers with the detection of Gleason patterns 4 and 5 at biopsy. Receiver operating characteristic (ROC) curve analysis was performed through the DeLong method to assess the ability of the BMI and VAI, compared to PSA, to predict the presence of Gleason patterns 4 and 5 at biopsy. Considering 350–400 biopsies/year and the presence of patterns 4 or 5 in 40%–50% of positive cases, a sample size of 147 evaluable patients with prostate carcinoma was required to achieve 85% confidence level and 5% confidence interval. P ≤ 0.05 was considered statistically significant.
| Results|| |
Out of 355 consecutive patients undergoing biopsy between 2014 and 2015, 38 (11.9%) were not evaluable, 168 had a negative biopsy, and 149 showed a prostate adenocarcinoma and fulfilled the admission criteria of the study. Of the 38 not evaluable patients, 8 showed HG prostatic intraepithelial neoplasia, 4 had ASAP, 9 patients with negative biopsy had less than 12 cores available at histological review. Moreover, in 11 patients, VAI was not calculated and in 6 biological markers were missing.
Patients' characteristics according to BMI class are given in [Table 1]. The median age was 70.5 years. The median BMI was 27.6 kg/m 2; 69 (46.3%) patients were overweight and 44 (29.5%) obese, with a median BMI of 27.3 and 32.7 kg/m 2, respectively. Median PSA was 10.0 ng/ml. The median VAI value was 4.4 (range: 1–27) with no significant variation among BMI classes (P = 0.33). Seventeen patients (11.4%) had a previous negative biopsy. At digital examination, prostate cancer was suspected in 78 (52.3%) patients. The median prostatic volume calculated by transrectal ultrasound was 38.1 cc (range: 14–187 cc). A Gleason pattern 4 or 5 was detected in 68 (45.6%) patients; in 15 (41.7%), 31 (44.9%), and 22 (50.0%) among normal weight, overweight, and obese patients, respectively (P = 0.55) [Table 1] and [Figure 1].
|Figure 1: Distribution of Gleason patterns according to body mass index classes (P = 0.55)|
Click here to view
Patients' characteristics according to the Gleason pattern at biopsy are given in [Table 2]. No correlation was found with BMI (P = 0.56), VAI (P = 0.35), and prostate volume (P = 0.93). A statistically significant association emerged only between older age (P = 0.017), higher PSA values (P = 0.02), and Gleason patterns 4 and 5 at biopsy.
|Table 2: Patients' characteristics according to Gleason pattern at biopsy|
Click here to view
The distribution of the median values of BMI and VAI according to Gleason patterns are showed in [Figure 2]. The ability of BMI and VAI to predict the presence of Gleason pattern 4 and 5 was also investigated through ROC curve analysis [Figure 3]. The area under the curve of BMI and VAI (0.534 and 0.548, respectively) were lower than that of tPSA (0.74).
|Figure 2: Body mass index (a) and visceral adiposity index (b) according to Gleason patterns|
Click here to view
|Figure 3: Receiver operating characteristic curve analysis of body mass index, visceral adiposity index and tPSA predicting Gleason patterns >3 at biopsy|
Click here to view
Median serum levels of leptin, adiponectin, and MMP-3 were 0.82, 1.72, and 1.77 ng/mL, respectively. The plasmatic levels of leptin and MMP-3 were significantly higher in obese (P = 0.02) and in normal-weight patients (P = 0.02), respectively. No statistically significant association was evident between the serum levels of leptin (P = 0.18), adiponectin (P = 0.68), and MMP-3 (P = 0.49) and the detection of Gleason patterns 4 or 5 at biopsy [Table 3].
|Table 3: Leptin, adiponectin, and matrix metalloproteinase-3 plasmatic values (ng/ml)|
Click here to view
| Discussion|| |
A large meta-analysis of prospective cohort studies including more than 2,000,000 men confirmed an association between obesity and increased risk of advanced prostate cancer at diagnosis. The REDUCE study investigated dutasteride for PC risk reduction and included 6729 men who underwent at least one biopsy with a PSA of 2.5–10.0 ng/mL. A recent analysis of this study found that obesity, while generally unrelated to prostate cancer risk, was associated with reduced risk of low-grade and increased risk of HG tumor at biopsy, independently from PSA levels. In the prostate cancer prevention trial, a randomized trial evaluating finasteride for prostate cancer prevention, 10,258 men undergoing biopsy at the end of the study period were included. Obese men showed 18% reduced risk of low grade, but 29% increased risk of HG tumor at biopsy. Both studies were limited by several biases because were not designed to investigate the correlation between obesity and prostate cancer. Moreover, both use of dutasteride and finasteride has been associated with higher grade tumors.
Liang et al. recently reported a correlation between BMI and diagnosis of high-risk prostate cancer at biopsy on 1902 men identified from the Selenium and Vitamin E Cancer Prevention Trial, especially among men without a known family history of prostate cancer.
While most of the studies on obesity and prostate cancer either have an epidemiological design dealing with screening populations or are extrapolated from randomized trials with different end-points, our study includes a patient population with biopsy-proven prostate cancer in common clinical practice. In our cohort, according to other Authors,, we failed in demonstrating an association between BMI and high-risk tumors at biopsy. Chamie et al. in 573 patients with biopsy-proven prostate cancer discovered statistically significant differences among BMI categories. After adjusting for age, race, language, education, T-stage, and other clinical parameters, they found no statistically significant association between BMI and Gleason score. Bhindi et al. reported that no individual MetS component was independently associated with prostate cancer, although an increasing number of MetS components was related to higher Gleason grade at biopsy.
We investigated in this setting the use of VAI index that is considered a marker of visceral fat activity more accurate than BMI taking into account several components of METS. In our experience, VAI resulted statistically independent from BMI nevertheless it was not related to the detection of aggressive prostate cancer at biopsy.
Recently, de Cobelli et al. showed that elevated BMI in patients potentially candidates to active surveillance was significantly associated with upgrading and upstaging at radical prostatectomy, suggesting that the diagnostic approach adopted in common clinical practice might be not able to detect at biopsy high-risk prostatic carcinoma in obese or overweight patients.
It would be beneficial to identify a biological marker linking obesity, overweight, and Mets to the presence of high-risk prostate cancer indicating the need for a specific and more accurate diagnostic procedure.
Adipose tissue physiology has been revised in the last two decades based on its ability to act as an extremely active endocrine organ. More than fifty adipokines produced by the “white adipose tissue,” mainly present in the visceral fat, have been identified. The endocrine activity of visceral fat stimulating the insulin/insulin-like growth factor-1 axis could increase the risk of HG prostate cancer.,, The adipokines could promote the progression of latent microscopic low-grade prostate cancer , in an early phase of MetS when obesity is not yet clinically relevant. Although up today, the molecular changes remain unclear, the distinct behavior between Gleason pattern 3 and pattern 4 or 5 could be the result of different developmental pathways , that could be influenced by adipokines.
We investigated the correlation between the detection of Gleason patterns 4 and 5 at biopsy and the plasmatic levels of adipose tissue biological markers as leptin, adiponectin, and MMP-3. Among patients with prostate cancer at biopsy, we found significantly higher levels of leptin in obese patients and significantly higher levels of MMP-3 in normal-weight patients compared to individuals with negative biopsy. These observations, although preliminary and obtained in a small number of patients, could be the start point of further research. However, no statistically significant association emerged in relation with the Gleason pattern at biopsy.
A limitation of our study is that including a small number of unselected consecutive patients in which more than 70% of them were overweight or obese. Thus, our negative findings could be simply due to a relatively homogeneous population underpowering the study for a relatively small number of normal weight patients. Another critical point is that 12-core biopsy might not reflect the whole histology of the prostate and considering radical prostatectomy specimen could have been more appropriate. On the other hand, our study had the setting of unselected patients submitted to prostate biopsy in common clinic practice.
Moreover, since our study was brought out in South Italy, we cannot exclude a protective action of the Mediterranean diet, lifestyle, and other environmental factor against the negative effect of obesity and MetS.,,,, We could hypothesize that not every obese or overweight patient is at higher risk for aggressive prostate cancer since the diet and lifestyle factors inducing obesity might vary from country to country. For instance, a case–control study among US males showed an increased risk of prostate cancer associated with high consumption of well-done meat  that was not confirmed in two studies conducted in Italy.,
To investigate the endocrine fat activity in relation to race, diet, and other environmental and genetic factors playing a promoting or protective role in prostate cancer should be the aim of future research in this field.
| Conclusion|| |
Most of the patients undergoing prostate biopsy in our clinical practice are overweight or obese. Although prostate cancer showing Gleason patterns 4 and 5 at biopsy has been reported to be more frequent in patients with elevated BMI, we did not detect their association with clinical markers of obesity as BMI or VAI. Moreover, we find no association between the plasmatic levels of leptin, adiponectin, and MMP-3, biomarkers of visceral fat activity, and the presence of Gleason pattern 4 and 5.
The authors would like to thank GSTU Foundation for laboratory kits supply and for statistical analysis.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016;66:7-30.
Dy GW, Gore JL, Forouzanfar MH, Naghavi M, Fitzmaurice C. Global burden of urologic cancers, 1990-2013. Eur Urol 2017;71:437-46.
Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of childhood and adult obesity in the united states, 2011-2012. JAMA 2014;311:806-14.
Bandini M, Gandaglia G, Briganti A. Obesity and prostate cancer. Curr Opin Urol 2017;27:415-21.
De Nunzio C, Truscelli G, Trucchi A, Petta S, Tubaro M, Gacci M, et al.
Metabolic abnormalities linked to an increased cardiovascular risk are associated with high-grade prostate cancer: A single biopsy cohort analysis. Prostate Cancer Prostatic Dis 2016;19:35-9.
Kassi E, Pervanidou P, Kaltsas G, Chrousos G. Metabolic syndrome: Definitions and controversies. BMC Med 2011;9:48.
Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. Adults. N
Engl J Med 2003;348:1625-38.
Byers T, Sedjo RL. Body fatness as a cause of cancer: Epidemiologic clues to biologic mechanisms. Endocr Relat Cancer 2015;22:R125-34.
Allott EH, Masko EM, Freedland SJ. Obesity and prostate cancer: Weighing the evidence. Eur Urol 2013;63:800-9.
De Nunzio C, Freedland SJ, Miano R, Trucchi A, Cantiani A, Carluccini A, et al.
Metabolic syndrome is associated with high grade Gleason score when prostate cancer is diagnosed on biopsy. Prostate 2011;71:1492-8.
Jentzmik F, Schnoeller TJ, Cronauer MV, Steinestel J, Steffens S, Zengerling F, et al.
Corpulence is the crucial factor: Association of testosterone and/or obesity with prostate cancer stage. Int J Urol 2014;21:980-6.
Divella R, De Luca R, Abbate I, Naglieri E, Daniele A. Obesity and cancer: The role of adipose tissue and adipo-cytokines-induced chronic inflammation. J Cancer 2016;7:2346-59.
Bhindi B, Locke J, Alibhai SM, Kulkarni GS, Margel DS, Hamilton RJ, et al.
Dissecting the association between metabolic syndrome and prostate cancer risk: Analysis of a large clinical cohort. Eur Urol 2015;67:64-70.
Barqawi AB, Golden BK, O'Donnell C, Brawer MK, Crawford ED. Observed effect of age and body mass index on total and complexed PSA: Analysis from a national screening program. Urology 2005;65:708-12.
Hoffman MA, DeWolf WC, Morgentaler A. Is low serum free testosterone a marker for high grade prostate cancer? J Urol 2000;163:824-7.
Schatzl G, Madersbacher S, Thurridl T, Waldmüller J, Kramer G, Haitel A, et al.
High-grade prostate cancer is associated with low serum testosterone levels. Prostate 2001;47:52-8.
Møller H, Roswall N, Van Hemelrijck M, Larsen SB, Cuzick J, Holmberg L, et al.
Prostate cancer incidence, clinical stage and survival in relation to obesity: A prospective cohort study in Denmark. Int J Cancer 2015;136:1940-7.
De Nunzio C, Albisinni S, Freedland SJ, Miano L, Cindolo L, Finazzi Agrò E, et al.
Abdominal obesity as risk factor for prostate cancer diagnosis and high grade disease: A prospective multicenter Italian cohort study. Urol Oncol 2013;31:997-1002.
Boehm K, Sun M, Larcher A, Blanc-Lapierre A, Schiffmann J, Graefen M, et al.
Waist circumference, waist-hip ratio, body mass index, and prostate cancer risk: Results from the North-American case-control study prostate cancer & environment study. Urol Oncol 2015;33:494.e1-7.
Okorodudu DO, Jumean MF, Montori VM, Romero-Corral A, Somers VK, Erwin PJ, et al.
Diagnostic performance of body mass index to identify obesity as defined by body adiposity: A systematic review and meta-analysis. Int J Obes (Lond) 2010;34:791-9.
Amato MC, Giordano C, Galia M, Criscimanna A, Vitabile S, Midiri M, et al.
Visceral adiposity index: A reliable indicator of visceral fat function associated with cardiometabolic risk. Diabetes Care 2010;33:920-2.
Roberts DL, Dive C, Renehan AG. Biological mechanisms linking obesity and cancer risk: New perspectives. Annu Rev Med 2010;61:301-16.
Alshaker H, Sacco K, Alfraidi A, Muhammad A, Winkler M, Pchejetski D, et al.
Leptin signalling, obesity and prostate cancer: Molecular and clinical perspective on the old dilemma. Oncotarget 2015;6:35556-63.
Burton A, Martin RM, Holly J, Lane JA, Donovan JL, Hamdy FC, et al.
Associations of adiponectin and leptin with stage and grade of PSA-detected prostate cancer: The ProtecT study. Cancer Causes Control 2013;24:323-34.
Medina EA, Shi X, Grayson MH, Ankerst DP, Livi CB, Medina MV, et al.
The diagnostic value of adiponectin multimers in healthy men undergoing screening for prostate cancer. Cancer Epidemiol Biomarkers Prev 2014;23:309-15.
Muppala S, Konduru SK, Merchant N, Ramsoondar J, Rampersad CK, Rajitha B, et al.
Adiponectin: Its role in obesity-associated colon and prostate cancers. Crit Rev Oncol Hematol 2017;116:125-33.
Chavey C, Mari B, Monthouel MN, Bonnafous S, Anglard P, Van Obberghen E, et al.
Matrix metalloproteinases are differentially expressed in adipose tissue during obesity and modulate adipocyte differentiation. J Biol Chem 2003;278:11888-96.
Gao D, Bing C. Macrophage-induced expression and release of matrix metalloproteinase 1 and 3 by human preadipocytes is mediated by IL-1β via activation of MAPK signaling. J Cell Physiol 2011;226:2869-80.
Sternlicht MD, Werb Z. How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol 2001;17:463-516.
Discacciati A, Orsini N, Wolk A. Body mass index and incidence of localized and advanced prostate cancer – A dose-response meta-analysis of prospective studies. Ann Oncol 2012;23:1665-71.
Vidal AC, Howard LE, Moreira DM, Castro-Santamaria R, Andriole GL Jr., Freedland SJ, et al.
Obesity increases the risk for high-grade prostate cancer: Results from the REDUCE study. Cancer Epidemiol Biomarkers Prev 2014;23:2936-42.
Gong Z, Neuhouser ML, Goodman PJ, Albanes D, Chi C, Hsing AW, et al.
Obesity, diabetes, and risk of prostate cancer: Results from the prostate cancer prevention trial. Cancer Epidemiol Biomarkers Prev 2006;15:1977-83.
Andriole GL, Bostwick DG, Brawley OW, Gomella LG, Marberger M, Montorsi F, et al.
Effect of dutasteride on the risk of prostate cancer. N
Engl J Med 2010;362:1192-202.
Liang Y, Ketchum NS, Goodman PJ, Klein EA, Thompson IM Jr. Is there a role for body mass index in the assessment of prostate cancer risk on biopsy? J Urol 2014;192:1094-9.
Chamie K, Oberfoell S, Kwan L, Labo J, Wei JT, Litwin MS, et al.
Body mass index and prostate cancer severity: Do obese men harbor more aggressive disease on prostate biopsy? Urology 2013;81:949-55.
Tomaszewski JJ, Chen YF, Bertolet M, Ristau BT, Woldemichael E, Nelson JB, et al.
Obesity is not associated with aggressive pathologic features or biochemical recurrence after radical prostatectomy. Urology 2013;81:992-6.
de Cobelli O, Terracciano D, Tagliabue E, Raimondi S, Galasso G, Cioffi A, et al.
Body mass index was associated with upstaging and upgrading in patients with low-risk prostate cancer who met the inclusion criteria for active surveillance. Urol Oncol 2015;33:201.e1-8.
Ferro M, Terracciano D, Buonerba C, Lucarelli G, Bottero D, Perdonà S, et al.
The emerging role of obesity, diet and lipid metabolism in prostate cancer. Future Oncol 2017;13:285-93.
Rowlands MA, Gunnell D, Harris R, Vatten LJ, Holly JM, Martin RM, et al.
Circulating insulin-like growth factor peptides and prostate cancer risk: A systematic review and meta-analysis. Int J Cancer 2009;124:2416-29.
Li H, Stampfer MJ, Mucci L, Rifai N, Qiu W, Kurth T, et al.
A25-year prospective study of plasma adiponectin and leptin concentrations and prostate cancer risk and survival. Clin Chem 2010;56:34-43.
Lavery HJ, Droller MJ. Do Gleason patterns 3 and 4 prostate cancer represent separate disease states? J Urol 2012;188:1667-75.
Trock BJ, Guo CC, Gonzalgo ML, Magheli A, Loeb S, Epstein JI, et al.
Tertiary Gleason patterns and biochemical recurrence after prostatectomy: Proposal for a modified Gleason scoring system. J Urol 2009;182:1364-70.
Capurso C, Vendemiale G. The mediterranean diet reduces the risk and mortality of the prostate cancer: A narrative review. Front Nutr 2017;4:38.
Bosetti C, Micelotta S, Dal Maso L, Talamini R, Montella M, Negri E, et al.
Food groups and risk of prostate cancer in Italy. Int J Cancer 2004;110:424-8.
Eitan E, Tosti V, Suire CN, Cava E, Berkowitz S, Bertozzi B, et al.
In a randomized trial in prostate cancer patients, dietary protein restriction modifies markers of leptin and insulin signaling in plasma extracellular vesicles. Aging Cell 2017;16:1430-3.
Nowell S, Ratnasinghe DL, Ambrosone CB, Williams S, Teague-Ross T, Trimble L, et al.
Association of SULT1A1 phenotype and genotype with prostate cancer risk in African-Americans and Caucasians. Cancer Epidemiol Biomarkers Prev 2004;13:270-6.
Tavani A, La Vecchia C, Gallus S, Lagiou P, Trichopoulos D, Levi F, et al.
Red meat intake and cancer risk: A study in Italy. Int J Cancer 2000;86:425-8.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]