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\begin{document}

\title{Possible Role of Advanced Glycation End Products (AGEs) In the Clinical
Course of Prostate Neoplasies Among Patients with and without Type 2
Diabetes Mellitus}



\author[1]{Gamze Akkus}%
\author[1]{Volkan Izol}%
\author[1]{Fesih OK}%
\author[1]{Mehtap Evran}%
\author[1]{Merve Inceman}%
\author[1]{Seyda Erdogan}%
\author[1]{Halil Mahir Kaplan}%
\author[1]{Murat Sert}%
\author[1]{Tamer Tetiker}%
\affil[1]{Cukurova University}%


\vspace{-1em}



  
  \date{May 05, 2024}


\begingroup
\let\center\flushleft
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\selectlanguage{english}
\begin{abstract}
Aim: The cognate receptor expression of AGE (RAGE; receptor for AGE) on
malignant tissues in diabetic patients has been suggested as a co-factor
in determining the clinical course and prognosis. We aimed to search
this relationship between RAGE expression and clinicopathological
features of prostate neoplasia. Methods: A total of 197 patients; 64
(diabetic n=24; non-diabetic n=40) with benign prostate hyperplasia, and
133 (diabetic n=71; non-diabetic n=62) with localized (LPCa)/metastatic
prostate cancer (MetPCa) were included the study. The expression of RAGE
was studied by immunohistochemically on prostate specimens. The RAGE
score was assessed in the specimens according to the extent of
immunoreactivity and staining intensity. Results: The RAGE scores of BPH
patients (diabetic and non-diabetic) were found as negative. Patients
with both LPCa and MetPCa showed significantly higher scores,
respectively (LPCa and MetPCa vs. BPH; p\textless{}0.01). RAGE scores of
diabetic patients with LPCa and MetPCa were found to be 4.71\selectlanguage{ngerman}±3.14 and
4.97±3.69, respectively. RAGE scores of the non-diabetic patients who
had LPCa and MetPCa were 1.52±1.87 and 1.69±1.58, respectively. When
compared both groups with LPCa, RAGE scores of the diabetic patients
were significantly higher than that of the non-diabetics (p=0.01).
Similar results were revealed as for the patients with MetPCa (4.97±3.69
vs. 1.69±1.58 (diabetic vs. non-diabetic), respectively
(p\textless{}0.01). Conclusion: We found a high rate of RAGE expression
in malign prostate neoplasias to the BPH. Furthermore, as expected,
higher scores were demonstrated in those with diabetes than
non-diabetics. Disease progression and survival parameters were worse in
the patients with high RAGE levels. RAGE may be useful in the diagnosis
of prostate cancer and in determining its prognosis.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\textbf{Possible Role of Advanced Glycation End Products (AGEs) In the
Clinical Course of Prostate Neoplasies Among Patients with and without
Type 2 Diabetes Mellitus~}

\textbf{Aim:} The cognate receptor expression of AGE (RAGE; receptor for
AGE) on malignant tissues in diabetic patients has been suggested as a
co-factor in determining the clinical course and prognosis. We aimed to
search this relationship between RAGE expression and clinicopathological
features of prostate neoplasia.

\textbf{Methods:} Atotal of 197 patients; 64 (diabetic n=24;
non-diabetic n=40) with benign prostate hyperplasia, and 133 (diabetic
n=71; non-diabetic n=62) with localized (LPCa)/metastatic prostate
cancer (MetPCa) were included the study. The expression of RAGE was
studied by immunohistochemically on prostate specimens. The RAGE score
was assessed in the specimens according to the extent of
immunoreactivity and staining intensity.

\textbf{Results:} The RAGE scores of BPH patients (diabetic and
non-diabetic) were found as negative. Patients with both LPCa and MetPCa
showed significantly higher scores, respectively (LPCa and MetPCa vs.
BPH; p\textless{}0.01). RAGE scores of diabetic patients with LPCa and
MetPCa were found to be 4.71\selectlanguage{ngerman}±3.14 and 4.97±3.69, respectively. RAGE
scores of the non-diabetic patients who had LPCa and MetPCa were
1.52±1.87 and 1.69±1.58, respectively. When compared both groups with
LPCa, RAGE scores of the diabetic patients were significantly higher
than that of the non-diabetics (p=0.01). Similar results were revealed
as for the patients with MetPCa (4.97±3.69 vs. 1.69±1.58 (diabetic vs.
non-diabetic), respectively (p\textless{}0.01).

\textbf{Conclusion:} We found a high rate of RAGE expression in malign
prostate neoplasias to the BPH. Furthermore, as expected, higher scores
were demonstrated in those with diabetes than non-diabetics. Disease
progression and survival parameters were worse in the patients with high
RAGE levels. RAGE may be useful in the diagnosis of prostate cancer and
in determining its prognosis.

\textbf{Keywords} : AGE, Type 2 Diabetes Mellitus, Prostate,
Carcinogenesis

\textbf{What's known}

\begin{itemize}
\tightlist
\item
  There is a complex relationship between type 2 diabetes and prostate
  cancer development and prognosis.
\item
  Advanced glycation end products have been shown to be associated with
  prostate cancer development in patients with diabetes.
\end{itemize}

\textbf{What's new}

\begin{itemize}
\tightlist
\item
  There is a higher rate of RAGE expression in diabetic patients
  compared to non-diabetics and patients with prostate cancer compared
  to BPH.
\item
  Prognosis is worse in patients with prostate cancer with high RAGE
  expression.
\end{itemize}

\textbf{INTRODUCTION}

Type 2 Diabetes mellitus (DM) is chronic, a metabolic disease that has
been associated with an increased risk of cancers including, pancreas,
breast, lung, kidney, liver\textsuperscript{1-5}. The association
between diabetes and prostate cancer risk has been studied in several
epidemiologic studies\textsuperscript{9-11}. Some
studies\textsuperscript{6-8} reported that prostate cancer had been
inversely correlated with type 2 DM due to suppressed
hypothalamic-pituitary-testicular axis. Otherwise, fewer
population-based cohort studies indicated that history of diabetes
mellitus was associated with an increased incidence of advanced prostate
cancer related to high circulating levels of insulin, insulin
resistance, or oxidative stress\textsuperscript{12-14}.

Glycation is the non-enzymatic reaction between reducing sugars, such as
glucose and proteins, lipids, or nucleic acids\textsuperscript{15}. The
formation of glycation products called AGE is a complicated process
involving simple and more complex multistep
reactions\textsuperscript{16}. Endogenous formation of AGE can occur
through three different pathways, including Maillard reactions, Polyol
pathways, and lipid peroxidation\textsuperscript{17}. Elevated levels of
glucose accelerate the formation of AGEs. AGEs via their cognate
receptor- the AGE specific receptor (RAGE)- can generate reactive oxygen
species, activate inflammation signaling cascades and consequently play
the role of development of diabetic complications\textsuperscript{18}.
AGE enhances several cancer cells by activating the cell cycle proteins
(e.g., cyclin D1), anti-apoptotic proteins (e.g., BCL2) and they can
contribute to development much cancer including gastric cancer, breast
cancer, melanoma, pancreatic cancer and prostate
cancer\textsuperscript{19-23}.

To represent the potentially complex relationship between type 2 DM and
prostate cancer, we aimed to examine RAGE expression in localize and
metastatic prostate cancer by using immunohistochemistry (IHC).

\textbf{MATERIALS AND METHODS}

\textbf{Study Population}

The prostate specimens of the study were obtained from the records of
our university hospital. A total of 197 prostatic pre-operative biopsies
and radical prostatectomy specimens from patients treated between 2009
and 2018 were studied. Of 197 samples, 87 belonged to localized prostate
cancer, 46 to metastatic prostate cancer, and the remaining 64 specimens
were from patients with benign prostate hyperplasia. All radical
prostatectomy, TURP (Transurethral resection of the prostate) samples,
and biopsies were initially evaluated by an expert pathologist and then
radical prostatectomy, and biopsies specimens were graded according to
the current international society of urological pathology (ISUP) grading
system (Epstein et al. 2016). The Last update ISUP grade group has been
considered the Gleason score: Grade Group 1= Gleason score \selectlanguage{english}[?]6, Grade
Group 2= Gleason score 3+4=7, Grade Group 3= Gleason score 4+3=7, Grade
Group 4= Gleason score 8, Grade Group 5= Gleason score \selectlanguage{english}[?]9, as well as
modified morphological criteria for Gleason pattern
4\textsuperscript{24}.

Detailed questionnaires were administered at baseline consisting of age,
smoking, family history of prostate cancer, history of hypertension, and
type 2 diabetes mellitus. Fasting height and weight were measured, and
Body mass index (BMI) was calculated in all patients. Fasting Plasma
Glucose (FPG mg/dL), HbA1C (\%, mmol/L), Total cholesterol (mg/dL),
Low-Density Cholesterol (LDL, mg/dL), Triglycerides (mg/dL),
Prostate-Specific Antigen (PSA) of all patients were recorded.

Imaging Techniques including Bone scan, Magnetic Resonance, and
Computerized Tomography were performed in patients diagnosed with
prostate cancer histopathologically after biopsy, according to D'amico
risk classification and EAU (European Association of Urology) guidelines
recommendations.

\textbf{Evaluation of recurrence in localized and metastatic prostate
cancer}

For patients with localized prostate cancer, after radical
prostatectomy, two consecutive serum PSA values higher than 0.2 ng/mL
and/or increment were defined as biochemical recurrence (BCR).
Currently, BCR has been accepted as the first rise (\selectlanguage{english}[?]0.2ng/mL) in
PSA\textsuperscript{25}.

For patients with metastatic prostate cancer, castration resistance
prostate cancer (CRPC) accepted for recurrence. CRPC is defined as
castrating serum testosterone \textless{}50 ng/dl or 1.7 nmol/l plus one
of the following types of progression.

Biochemical progression: Three consecutive rises in PSA 1 week apart,
resulting in two 50\% increases over the nadir, and PSA \textgreater{} 2
ng/ml.

Radiologic progression: The appearance of new lesions: either two or
more new bone lesions on bone scan or a soft tissue lesion using the
Response Evaluation Criteria in Solid Tumours
(RECIST)\textsuperscript{26,27}.

\textbf{Immunohistochemical assay}

Initially, pathological specimens were deparaffinized with dimethyl
benzene and rehydrated through an ethanol gradient (100\%, 95\%, 90\%,
80\%, and 70\%) into water. After washing with PBS (phosphate-buffered
saline three times, slides were boiled in antigen retrieval buffer, 0.01
M sodium citrate-hydrochloric acid (pH=6.0), for 30 min in a microwave
oven. After endogenous peroxidase activity was quenched with 3\% H2O2
after three PBS washes, nonspecific antibody binding was blocked by
incubating the slides with 10\% normal goat nonimmune serum. The
sections were then incubated at 4degC overnight with the rabbit polyclonal
RAGE antibody (Santa-Cruz, CA, USA) at a 1:400 dilution and subsequently
incubated with horseradish peroxidase (HRP) (ChemMateTM DAKO EnVisionTM
Detection Kit) at room temperature for 30 min. After washing in PBS, the
sections were then developed using 3,3-V-diaminobenzidine (Sigma),
washed in running tap water, and lightly counterstained with hematoxylin
before dehydration and coverslip mounting. Negative control experiments
were conducted by replacing the primary antibody with PBS.

The RAGE detection was arbitrarily determined as to extent of
immunoreactivity: 0, \textless{}5\%; 1, 5\%-10\%; 2, 10\%-50\%; 3,
50\%-75\%; 4, \textgreater{}75\%. Staining intensity was scored as 0,
negative; 1, weak; 2, moderate; 3, strong (figure 1). For each case, the
total immunohistostaining score, also known as the staining index (SI)
was calculated by multiplying the percentage of positive cells with the
staining intensity score, yielding a value between 0 and 12. For
statistical analysis, staining intensity scores 0 and 1 defined as
negative expression (--), 2 to 12 scores defined as positive expression
(+)\textsuperscript{28}.

\textbf{Statistical Analyses}

Statistical analyses were performed using IBM SPSS Statistics for
Windows, Version 23.0. a statistical software package (Armonk, NY: IBM
Corp; 2015). Frequency distribution of demographic and
clinical-pathological characteristics across the groups were compared
using Pearson' s chi-square tests. For comparison of continuous
variables between two groups, the Student's t-test or Mann-Whitney U
test was used, depending on whether or not the statistical hypotheses
were fulfilled. Survival curves were generated using Kaplan-Meier
methods, and the log-rank analysis was carried out to evaluate the
survival differences between groups. All statistical tests were 2-sided,
and p\textless{} 0.05 was considered statistically significant.

\textbf{RESULTS}

Demographical and Biochemical and Immunohistochemical Parameters

Demographical, biochemical parameters and RAGE scores of three subgroups
(BPH, LPCa, MetPCa) were demonstrated in table 1.

There were no significant RAGE expressions on the specimens of a total
of 64 patients with BPH. RAGE expressions score of 24 diabetic and 40
non-diabetic patients with BPH were 0.5+-0.65 (range 0-4) and 0.6+-0.9
(range 0-4), respectively (diabetic vs.non-diabetic
p\textgreater{}0.05). All biochemical parameters and RAGE scores of
diabetic or non-diabetic patients with BPH were demonstrated in table 1.

There were 87 patients (diabetic 41; non-diabetic 46) with LPCa. RAGE
scores of diabetic (n=41) and nondiabetic patients (n=46) with LPCa were
found to be 4.7+-3.1 (range 1-12) and 1.5+-1.8 (range 0-9), respectively
(diabetic vs. non-diabetic p=0.01). All biochemical parameters and RAGE
scores of diabetic or nondiabetic patients with LPCa were demonstrated
in table 1. There were 46 (diabetic 30, non-diabetic 16) patients with
MetPCa. RAGE scores of diabetic (n=30) and nondiabetic patients (n=16)
with MetPCa were found to be 4.9+-3.6 (0-12) 1.6+-1.5 (range 0-6),
(diabetic vs.non-diabetic, p=0.00).

There was no difference between the patients' group (BPH, LPCa, MetPCa)
for the age, fasting plasma glucose, HbA1c, and diabetes duration
(except for diabetic patients).

\textbf{Correlations of RAGE expression with patients' survival rate}

There was a total of 46 patients with MetPca. Of 46, 27 patients had
RAGE positive on specimens, and 19 had a negative expression on
specimens. When compared each other with respect to cancer recurrence,
cancer-specific mortality, and follow-up period (month); recurrence rate
(81,4\% vs 78.9\%, p=0.8), cancer-specific mortality (33.3\% vs 26.3\%,
p=0.58) were statistically found to be non -significant. (See table 2,
figure 2-3).

For the patients (total n=87) with localized prostate cancer, there were
47 patients with RAGE positive, 35 patients with RAGE negative. Five
patients in the LPCa group had a positive surgical margin, so these
patients were not included in the survival analysis. Comparison of these
two groups patients, we did not find a significant difference for the
cancer recurrence, duration of the follow-up, but we discovered that
biochemical recurrence rate was found significantly higher in RAGE
positive patients (p=0.00; table 2, figure 4).

\textbf{DISCUSSION}

In the present study, we found an increased rate of RAGE expressions on
the specimens of the localized and metastatic prostate cancer tissue
samples to those of the patients with BPH. Additionally, we not only
confirmed previous studies of RAGE expression in Prostate cancer samples
but also compared the malignant prostate neoplasias (localized or
metastatic) with benign prostate hyperplasia. A similar study has been
previously reported on the overexpression of RAGE in patients with
prostate neoplasias but not in a Turkish population\textsuperscript{29}.

The association between diabetes mellitus and the development of
prostate cancer has been studied in numerous studies, but this
relationship has been still controversial\textsuperscript{6,7,30,31}.
Some of these studies\textsuperscript{32,33} documented that there was a
decreased risk of prostate cancer in patients with type 2 diabetes
mellitus whereas; others documented an elevated risk of prostate cancer
in these patients\textsuperscript{11,34,35}. Lower androgen levels have
been suggested as an explanation for the inverse correlation between
diabetes and prostate cancer\textsuperscript{36}. Furthermore, it was
reported that low PSA levels were related to diabetes mellitus, and
lower PSA values could cause fewer biopsies and result in decreased
diagnose of prostate cancer in patients with type 2 diabetes
mellitus\textsuperscript{37,38}. Contrary to these
studies\textsuperscript{35,38,45}, in this study, we did not find low
PSA levels in diabetic patients than non-diabetic patients (p=0.06). But
we know that the measurement of PSA levels seems to be influenced by
number factors including demographic, lifestyle, and health
characteristics\textsuperscript{46}. Variation of the serum PSA
measurements could be an alternative explanation for the inverse
correlation between diabetes and prostate cancer. On the other hand,
preliminary studies were reporting that obesity, hyperinsulinemia,
inflammatory cytokines, dyslipidemia, and common factors associated with
type 2 DM were revealed as risk factors for various cancer types,
including prostate cancer\textsuperscript{39}.

It is well known that AGE and interactions of their receptor (RAGE) are
produced increasingly in diabetes mellitus, and they induce oxidative
stress, inflammatory reaction, apoptosis, autophagy which resultant with
cancer development\textsuperscript{40-42}. The previous study claimed
that RAGE/NF-\selectlanguage{greek}κ\selectlanguage{english}B signaling pathways facilitated the prostate cancer
metastasis\textsuperscript{43}. They studied the HMGB1 (high mobility
group box 1) and RAGE expression on 36 prostate tissue specimens (12
BPH, 12 LPCa, 12 MetPCa) by immunohistochemically, and they showed the
HMGB1 and RAGE expression were increased on tissues of LPCa and MetPCa
and less detectable on muscles of BPH. In another study, they reported
that RAGE expression was strongly correlated with progression and poor
prognosis of prostate cancer\textsuperscript{44}. They also found that
RAGE's positive expression was significantly higher in prostate cancer
than BPH (p=0.002). They suggested that the RAGE expressions were
positively correlated with tumor stage, lymph node metastasis, and
distant metastasis. Inconsistent with this study, the other
study\textsuperscript{29} demonstrated that RAGE expression rates were
significantly high on tissues of untreated prostate cancer and
hormone-refractory prostate cancer tissue.

In the present study, we focused on diabetic patients because diabetes
mellitus is the most known causative underlying factor in the occurrence
of glycated end products and RAGE expression on tissues. Consistent with
these regards, RAGE expressions were found to be more intense on
prostate cancer tissues (localized or metastatic) among patients with
Diabetes Mellitus than hyperplasia. When we compared the diabetic LPCa
patients with diabetic MetPCa patients, RAGE expression on specimens of
the metastatic disease was higher than localized cancer. But this was
not significant statistically related to sample size. Our finding is
consistent with the study\textsuperscript{44} mentioned above that
overexpression of RAGE was strongly correlated with the metastatic
diseases\textsuperscript{44,47}. We could not find any significant
difference in cancer recurrence, cancer metastasis, and clinical
survival in diabetic and non-diabetic.

When we screen the studies related to the RAGE expression and cancer
progress, the relationship between RAGE expression and patient outcome
has still been a controversial issue. In certain cohort studies, it has
been reported that there was a weak connection between the RAGE
expression and cancer course of other cancer types, including
colorectal, esophageal carcinoma\textsuperscript{48,49}. Further
investigations with a large number of patients and more extended
follow-up periods may support our hypothesis with more satisfactory
results.

One of the major limitations of this study is the small sample size for
all three (BPH-LPCa-MetPCa) subgroups. Besides, this is a retrospective
study, so some parameters, including a history of medications, smoking,
are missing. Another limitation of our study is that diabetic and
non-diabetic patients with prostate cancer (localized or metastatic)
cannot be compared in terms of prognosis and survival because the number
of diabetic patients is insufficient for statistical analysis.

In conclusion, In the present study, we found a high rate of RAGE
expression in malignant prostate neoplasias (localized or metastatic) to
the benign prostate hyperplasia, furthermore (beside) those with type 2
diabetes mellitus as expected revealed higher scores than the
non-diabetics. Disease progression and survival parameters were worse in
the patients with high RAGE levels, but it was not statistically
significant. We already do not know the exact mechanisms and clinical
consequences or any reasonable diabetic metabolic control on the
prostate cancer prognosis. Further studies are needed.

\textbf{ACKNOWLEDGMENT}

The authors would like to thank the Cukurova University Research for
funding this study.

\textbf{CONFLICTS OF INTEREST}

We declare that there was no conflict of interest.

\textbf{AUTHOR CONTRIBUTIONS}

G. Akkus, V. Izol and F. Ok, data analysis/interpretation, critical
revision of article, approval of article; M. Evran, M. Inceman and S.
Erdogan, data analysis/interpretation, manuscript writing/editing; H. M.
Kaplan, data extraction, statistics, data analysis/interpretation,
manuscript writing/editing; M. Sert and T. Tetiker, concept/design, data
analysis/interpretation, manuscript writing/editing.

\textbf{ETHICAL APPROVAL}

Permission was obtained from the Medical Research Ethics Committee of
Cukurova University Faculty of Medicine for the study (approval
number-March 4, 2016; 2/51).

This study was conducted in accordance with the Declaration of Helsinki
in its latest version. This article does not contain any studies with
animals performed by any of the authors.

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  criteria in solid tumours: revised RECIST guideline (version 1.1). EJC
  2009; 45:228--47.
\item
  Xu XC, Abuduhadeer X, Zhang WB, et al (2013). Knockdown of RAGE
  inhibits growth and invasion of gastric cancer Cells. \emph{Eur J
  Histochem} , 29, 240-6.
\item
  Ishiguro H, Nakaigawa N, Miyoshi Y, Fujinami K, Kubota Y, Uemura H.
  Receptor for advanced glycation end products (RAGE) and its ligand,
  amphoterin are overexpressed and associated with prostate cancer
  development.~The Prostate.~2005; 64:92--100.
\item
  Cai H, Xu Z, Xu T, et al. Diabetes mellitus~is associated with
  elevated risk of mortality amongst patients with~prostate cancer: a
  meta-analysis of 11 cohort studies. Diabetes Metab Res Rev. 2015;
  31(4):336-43
\item
  Chen M, Luo Y, Yang S, et al. Association of~diabetes
  mellitus~with~prostate cancer~grade and~prostate-specific antigen in
  Chinese biopsy population. ~\emph{Diabetes research and clinical
  practice} ~141 (2018): 80-87.
\item
  Tsilidis KK, Allen NE, Appleby PN, et al. Diabetes mellitus~and risk
  of~prostate cancer~in the European Prospective Investigation
  into~Cancer~and Nutrition. Int J Cancer 2015;136(2):372-81
\item
  Xu H, Jiang HW, Ding GX, et al. Diabetes mellitus~and~prostate
  cancer~risk of different grade or stage: a systematic review and
  meta-analysis. Diabetes Clin Res Pract 2013; 99(3):241-9
\item
  Moreira DM, Anderson T, Gerber L, et al. The association of diabetes
  mellitus and high-grade prostate cancer in a multiethnic biopsy
  series.~Cancer Causes Control.~2011; 22:977--983
\item
  Fukushima H, Masuda H, Kawakami S, et al. Effect of diabetes mellitus
  on high-grade prostate cancer detection among Japanese obese patients
  with prostate-specific antigen less than 10~ng/mL.~Urology.~2012;
  79:1329--1334.
\item
  Betancourt-Albrecht M, Cunningham GR. Hypogonadism and diabetes.~Int J
  Impot Res.~2003; 15(Suppl 4): S14--S20.
\item
  Peskoe SB, Joshu CE, Rohrmann S, et al. Circulating total testosterone
  and PSA concentrations in a nationally representative sample of men
  without a diagnosis of prostate cancer.~Prostate.~2015; 75:1167--1176.
\item
  Barrett-Connor E. Lower endogenous androgen levels and dyslipidemia in
  men with non-insulin-dependent diabetes mellitus.~Ann Intern
  Med.~1992; 117:807--811.
\item
  Mokdad AH, Ford ES, Bowman BA, et al. Prevalence of obesity, diabetes,
  and obesity-related health risk factors, 2001.~Jama.~2003; 289:76--79.
\item
  Drinda S, Franke S, Ruster M, et al. Identification of the receptor
  for advanced glycation end products in synovial tissue of patients
  with rheumatoid arthritis.~Rheumatol Int.~2005; 25:411--413.
\item
  Hu P, Lai D, Lu P, Gao J, He H. ERK and Akt signaling pathways are
  involved in advanced glycation end product-induced autophagy in rat
  vascular smooth muscle cells.~Int J Mol Med.~2012; 29:613--618.
\item
  Yuan X, Zhang Z, Gong K, Zhao P, Qin J, Liu N. Inhibition of reactive
  oxygen species/extracellular signal-regulated kinases pathway by
  pioglitazone attenuates advanced glycation end products-induced
  proliferation of vascular smooth muscle cells in rats.~Biol Pharm
  Bull.~2011; 34:618--623.
\item
  Zhang J, Shao S, Han D, et al. High mobility group box 1 promotes the
  epithelial-to-mesenchymal transition in prostate cancer PC3 cells via
  the RAGE/NF-\selectlanguage{greek}κ\selectlanguage{english}B signaling pathway. Int J Oncol. 2018; 53(2):659-671
\item
  Zhao C, Bao J, Lu Y, et al. Co-expression of RAGE and HMGB1 is
  associated with cancer progression and poor patient outcome of
  prostate cancer. Am J Cancer Res. \emph{American journal of cancer
  research} ~4.4 (2014): 369.
\item
  Baillargeon J, Pollock BH, Kristal AR, et al. The association of body
  mass index and prostate-specific antigen in a population-based
  study.~Cancer.~2005; 103:1092--1095.
\item
  McGinley KF, McMahon GC, Brown GA. ~Impact of the US Preventive
  Services Task Force Grade D recommendation: assessment of evaluations
  for elevated prostate-specific antigen and prostate biopsies in a
  large urology group practice following statement revision.~\emph{~Rev
  Urol} . 2015; 17(3):171-177.
\item
  Staquicini FI, Card\selectlanguage{ngerman}ó-Vila M, Kolonin MG, et al. Vascular
  ligand-receptor mapping by direct combinatorial selection in cancer
  patients.~Proc Natl Acad Sci U S A.~2011; 108(46):18637--42.
\item
  Tateno T, Ueno S, Hiwatashi K, et al. Expression of receptor for
  advanced glycation end products (RAGE) is related to prognosis in
  patients with esophageal squamous cell carcinoma. Ann Surg Oncol.
  2009; 16(2):440-6
\item
  Fahmueller YN, Nagel D, Hoffmann RT, et al. Immunogenic cell death
  biomarkers HMGB1, RAGE, and DNAse indicate response to
  radioembolization therapy and prognosis in colorectal cancer patients.
  Int J Cancer 2013; 132(10):2349-58
\end{enumerate}

\textbf{TABLE 1} Demographic, biochemical, histopathological parameters
and RAGE score of all three groups and subgroups (BPH-LPCa-MetPCa)\selectlanguage{english}
\begin{longtable}[]{@{}lllllllllllll@{}}
\toprule
\begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
BPH (n=64)\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
BPH (n=64)\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
p\textsuperscript{*}\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
LPCa (n=87)\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
LPCa (n=87)\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
p\textsuperscript{**}\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
MetPCa (n=46)\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
MetPCa (n=46)\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
p\textsuperscript{***}\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
P Value\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
P Value\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
P Value\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
DM (n=24)\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
NDM (n=40)\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
DM (n=41)\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
NDM (n=46)\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
DM (n=30)\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
NDM (n=16)\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
BPH vs LPCa\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
BPH vs MetPCa\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
LPCa vs MetPCa\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Age (y)\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
68.1\selectlanguage{ngerman}±9.4\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
67.0\selectlanguage{ngerman}±8.6\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
NG\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
60.2\selectlanguage{ngerman}±3.4\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
57.2\selectlanguage{ngerman}±5.2\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
NG\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
68.1\selectlanguage{ngerman}±8.1\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
70.5\selectlanguage{ngerman}±7.6\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
NG\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
NG\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
NG\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
NG\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
BMI (kg/m\textsuperscript{2})\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
28.2\selectlanguage{ngerman}±3.3\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
24.4\selectlanguage{ngerman}±1.8\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
0.001\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
28.2\selectlanguage{ngerman}±2.6\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
27.0\selectlanguage{ngerman}±3.1\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
0.06\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
26.9\selectlanguage{ngerman}±3.5\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
23.8\selectlanguage{ngerman}±2.1\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
0.001\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
0.001\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
0.94\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
0.002\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
FPG (mg/dL)\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
142.6\selectlanguage{ngerman}±47.4\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
95.4\selectlanguage{ngerman}±10.1\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
0.001\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
135.8\selectlanguage{ngerman}±32.7\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
90.4\selectlanguage{ngerman}±7.0\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
0.001\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
136.8\selectlanguage{ngerman}±37.5\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
90.9\selectlanguage{ngerman}±9.4\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
0.001\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
0.81\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
0.29\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
0.14\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
HbA1c (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
6.9\selectlanguage{ngerman}±1.4\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
5.3\selectlanguage{ngerman}±0.3\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
0.001\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
6.7\selectlanguage{ngerman}±1.3\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
5.4\selectlanguage{ngerman}±0.3\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
0.001\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
6.5\selectlanguage{ngerman}±1.1\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
5.3\selectlanguage{ngerman}±0.3\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
0.001\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
0.45\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
0.33\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
0.74\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
DMt (y)\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
7.7\selectlanguage{ngerman}±4.1\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
6.5\selectlanguage{ngerman}±3.0\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
0.18\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
PSA (ng/mL)\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
7.2\selectlanguage{ngerman}±8.0\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
5.2\selectlanguage{ngerman}±7.7\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
0.03\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
11.3\selectlanguage{ngerman}±7.6\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
11.9\selectlanguage{ngerman}±12.4\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
0.72\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
1075.0\selectlanguage{ngerman}±2157.3\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
518.8\selectlanguage{ngerman}±13282.6\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
0.03\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
0.001\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
0.001\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
0.001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
RAGE score\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
0.5\selectlanguage{ngerman}±0.6\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
0.6\selectlanguage{ngerman}±0.9\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
0.69\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
4.7\selectlanguage{ngerman}±3.1\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
1.5\selectlanguage{ngerman}±1.8\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
0.01\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
4.9\selectlanguage{ngerman}±3.6\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
1.6\selectlanguage{ngerman}±1.5\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
0.001\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
0.001\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
0.001\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
0.19\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textsuperscript{*}: p value demonstrate the comparement of the diabetic
and nondiabetic patients with BPH

\textsuperscript{**}: p value demonstrate the comparement of the
diabetic and nondiabetic patients with LPCa

\textsuperscript{***}: p value demonstrate the comparement of the
diabetic and nondiabetic patients with MetPCa

DM: Diabetes Mellitus, NDM: Non-Diabetes Mellitus NG: Non significant

BMI: body mass index, FPG: fasting plasma glucose, PSA: prostate
specific antigen, DMt: Diabetes Mellitus Duration time

\textbf{TABLE 2} Survival analysis of patients with metastatic and
localized prostate cancer according to RAGE expression\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
\textbf{MetPCa}\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
\textbf{RAGE Negative} (n=19)\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
\textbf{RAGE Positive} (n=27)\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
\textbf{p Value}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Follow-up period (months) \selectlanguage{ngerman}± SD\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
49,6\selectlanguage{ngerman}±36,7\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
43,8\selectlanguage{ngerman}±27,9\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0,54\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Recurrence n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
15 (78,9)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
22 (81,4)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0,83\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Mean RFS (months) \selectlanguage{ngerman}± SE (\%95 CI)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
32.7\selectlanguage{ngerman}±7.6 (17.8-47.7)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
25.9\selectlanguage{ngerman}±4.7 (16.6-35.2)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0,55\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1-year RFS (\%) \selectlanguage{ngerman}± SE\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
63,2\selectlanguage{ngerman}±11,1\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
67,6\selectlanguage{ngerman}±9,5\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
3-year RFS (\%) \selectlanguage{ngerman}± SE\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
35,5\selectlanguage{ngerman}±11,2\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
10,6\selectlanguage{ngerman}±6,9\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
All-cause mortality n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
6 (31,6)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
9 (33,3)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0,90\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Mean OS (months) \selectlanguage{ngerman}± SE (\%95 CI)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
79,2\selectlanguage{ngerman}±10,1 (59,4-98,9)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
74,9\selectlanguage{ngerman}±7,9 (59,3-90,5)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0,65\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
3-year OS (\%) \selectlanguage{ngerman}± SE\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
68,7\selectlanguage{ngerman}±11,8\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
80,2\selectlanguage{ngerman}±9,1\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
5-year OS (\%) \selectlanguage{ngerman}± SE\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
68,7\selectlanguage{ngerman}±11,8\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
71,3\selectlanguage{ngerman}±11,6\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Cancer-specific mortality n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
5 (26,3)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
9 (33,3)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0,58\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Mean CSS (months) \selectlanguage{ngerman}± SE (\%95 CI)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
83,4\selectlanguage{ngerman}±9,8 (64,2-10,7)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
74,9\selectlanguage{ngerman}±7,9 (59,3-90,5)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0,43\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
3-year CSS (\%) \selectlanguage{ngerman}± SE\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
73,2\selectlanguage{ngerman}±11,7\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
80,2\selectlanguage{ngerman}±9,1\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
5-year CSS (\%) \selectlanguage{ngerman}± SE\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
73,2\selectlanguage{ngerman}±11,7\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
71,3\selectlanguage{ngerman}±11,6\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{LPCa}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
(n=35)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
(n=47)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Follow-up period (months) \selectlanguage{ngerman}± SD\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
54,5\selectlanguage{ngerman}±12,1\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
57,5\selectlanguage{ngerman}±12,8\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0,30\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
BCR n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
3 (8,6)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
8 (17)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{0,00}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Mean BCRFS (months) \selectlanguage{ngerman}± SE (\%95 CI)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
70.4\selectlanguage{ngerman}±1.9 (66.6-74.2)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
63,1\selectlanguage{ngerman}±3,2 (56,9-69,3)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0,26\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
3-year BCRFS (\%) \selectlanguage{ngerman}± SE\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
97,1\selectlanguage{ngerman}±2,8\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
87,2\selectlanguage{ngerman}±4,9\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
5-year BCRFS (\%) \selectlanguage{ngerman}± SE\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
85,6\selectlanguage{ngerman}±8,9\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
80,5\selectlanguage{ngerman}±6,5\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

SD; standard deviation, SE; standard error, RFS; recurrence free
survival, OS; overall survival, CSS; cancer specific survival BCR;
biochemical recurrence, BCRFS; biochemical recurrence free survival, CI;
confidence interval

\textbf{Figure legends}

\textbf{FIGURE 1} Examples of Immunohistochemical staining (IHC) of RAGE
in BPH and adenocarcinoma tissues.

Negative expression of RAGE in BPH (RAGE scoring=0)10xmagnification

1a) Negative expression of RAGE in adenocarcinoma (RAGE scoring=0)
20xmagnification 1b) Weak positive expression of RAGE in adenocarcinoma
(RAGE scoring=1) 20xmagnification 1c)Moderate positive expression of
RAGE in adenocarcinoma (RAGE scoring=2) 10xmagnification 1d)Strong
positive expression of RAGE in adenocarcinoma (RAGE scoring=3)
20xmagnification

\textbf{FIGURE 2} Kaplan-Meier survival curves for cancer specific
survival analysis of RAGE groups in metastatic prostate cancer. Log-rank
test p=0,43.

\textbf{FIGURE 3} Kaplan-Meier survival curves for recurrence-free
survival analysis of RAGE groups in metastatic prostate cancer. Log-rank
test p=0,55.

\textbf{FIGURE 4} Kaplan-Meier survival curves for biochemical
recurrence-free survival analysis of RAGE groups in localized prostate
cancer. Log-rank test p=0,26.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1/Figure-1}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-2/Figure-2}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-3/Figure-3}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-4/Figure-4}

\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
\end{document}

