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\begin{document}

\title{Does the Urinary Mast Cell Mediators Predict the Immune Response to BCG
in Patients with Primary High-Grade Non-Muscle Invasive Bladder Cancer?}



\author[1]{Muhammed Fatih Simsekoglu}%
\author[1]{İslim Kaleler}%
\author[2]{Bulent Onal}%
\author[1]{Cetin Demirdag}%
\author[1]{Sinharib Citgez}%
\author[1]{Ezel Uslu}%
\author[1]{Ahmet Erozenci}%
\author[1]{Zubeyr Talat}%
\affil[1]{Istanbul University-Cerrahpasa Cerrahpasa Faculty of Medicine}%
\affil[2]{Istanbul Universitesi-Cerrahpasa}%


\vspace{-1em}



  
  \date{May 16, 2024}


\begingroup
\let\center\flushleft
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\selectlanguage{english}
\begin{abstract}
Background: Mast cells play a critical role in tumor-associated immune
pathways. We aimed to determine whether the urinary mast cell mediators
predict the immune response in patients with non-muscle invasive bladder
cancer (NMIBC) treated with Bacillus Calmette-Gu\selectlanguage{ngerman}érin (BCG)
immunotherapy. Methods: Nineteen patients who have received
immunotherapy due to NMIBC and 19 healthy participants were enrolled.
Urine samples were collected to assay N-methylhistamine, histamine, and
tryptase levels immediately before the first BCG instillation,
immediately after the third and sixth instillations, and four weeks
after the sixth instillation in patients with NMIBC and at a single
visit in healthy participants. Cystoscopic examinations were performed
on the patient with NMIBC at three-month intervals for two years. The
changes in urinary markers due to BCC response, BCG instillation, and
the presence of NMIBC were assessed. Results: The average age was 56.1 ±
10.5 years in patients with NMIBC. Fourteen patients had high-grade Ta
tumors, and 5 had high-grade T1 tumors. While 12 patients responded, 6
presented with recurrence and 1 with progression. There was no
correlation between the levels of mast cell mediators and BCG response.
The N-methylhistamine and histamine levels were increased significantly
with the onset of immunotherapy, and N-methylhistamine levels were
significantly decreased when immunotherapy was terminated. Pre-BCG
estimated marginal means of N-methylhistamine were significantly higher
in patients with NMIBC than healthy participants. Conclusions: Our study
is the first study to identify the changes in mast cell mediators with
the onset of immunotherapy and with the presence of bladder cancer.
However, these mediators were not found to predict the patients'
response to immunotherapy.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\textbf{Does the Urinary Mast Cell Mediators Predict the Immune Response
to BCG in Patients with Primary High-Grade Non-Muscle Invasive Bladder
Cancer?}

\textbf{Keywords:} BCG; bladder cancer; immunotherapy; mast cell;
mediator

\textbf{Running Title:} Mast Cell Mediators in Bladder Cancer

\begin{enumerate}
\tightlist
\item
  Muhammed Fatih Simsekoglu, Department of Urology, University of
  Istanbul-Cerrahpasa, Cerrahpasa School of Medicine, Istanbul, Turkey
\item
  Islim Kaleler, Department of Biochemistry, University of
  Istanbul-Cerrahpasa, Cerrahpasa School of Medicine, Istanbul, Turkey
\item
  Bulent Onal, Department of Urology, University of Istanbul-Cerrahpasa,
  Cerrahpasa School of Medicine, Istanbul, Turkey
\item
  Cetin Demirdag, Department of Urology, University of
  Istanbul-Cerrahpasa, Cerrahpasa School of Medicine, Istanbul, Turkey
\item
  Sinharib Citgez, Department of Urology, University of
  Istanbul-Cerrahpasa, Cerrahpasa School of Medicine, Istanbul, Turkey
\item
  Ezel Uslu, Department of Biochemistry, University of
  Istanbul-Cerrahpasa, Cerrahpasa School of Medicine, Istanbul, Turkey
\item
  Ahmet Erozenci, Department of Urology, University of
  Istanbul-Cerrahpasa, Cerrahpasa School of Medicine, Istanbul, Turkey
\item
  Zubeyr Talat, Department of Urology, University of
  Istanbul-Cerrahpasa, Cerrahpasa School of Medicine, Istanbul, Turkey
\end{enumerate}

\textbf{Conflict of interest} : The authors declare that they have no
conflict of interest.

\textbf{Funding source} : This study was conducted with the financial
support of the Istanbul University-Cerrahpasa Board of Scientific
Research Projects (Number: 30651)\textbf{Ethical approval:} This study
was approved by the institutional review board of Istanbul
University-Cerrahpasa.

\textbf{Informed consent:} Informed consent was obtained from all
individual participants included in the study.

\textbf{Contribution statement:} All authors contributed the study.

\textbf{Data Availability statements:} The datasets generated during
and/or analyzed during the current study are not publicly available due
(Personal Data Protection Law) but are available from the corresponding
author on reasonable request.

\emph{CORRESPONDING AUTHOR:}

Muhammed Fatih Simsekoglu, M.D.

Cerrahpasa Mah. 34100

Cerrahpasa T\selectlanguage{polish}ı\selectlanguage{english}p Fak\selectlanguage{ngerman}ültesi

Uroloji Anabilim Dal\selectlanguage{polish}ı, \selectlanguage{english}Fatih

34100, Istanbul-Turkey

Telephone: +90 (537) 312 7344

Facsimile: +90 (212) 414 3526

e-mail:\emph{m.fatihsimsekoglu@gmail.com}

\textbf{Abstract}

\textbf{Background:} Mast cells play a critical role in tumor-associated
immune pathways. We aimed to determine whether the urinary mast cell
mediators predict the immune response in patients with non-muscle
invasive bladder cancer (NMIBC) treated with Bacillus Calmette-Gu\selectlanguage{ngerman}érin
(BCG) immunotherapy.

\textbf{Methods:} Nineteen patients who have received immunotherapy due
to NMIBC and 19 healthy participants were enrolled. Urine samples were
collected to assay N-methylhistamine, histamine, and tryptase levels
immediately before the first BCG instillation, immediately after the
third and sixth instillations, and four weeks after the sixth
instillation in patients with NMIBC and at a single visit in healthy
participants. Cystoscopic examinations were performed on the patient
with NMIBC at three-month intervals for two years. The changes in
urinary markers due to BCC response, BCG instillation, and the presence
of NMIBC were assessed.

\textbf{Results:} The average age was 56.1 ± 10.5 years in patients with
NMIBC. Fourteen patients had high-grade Ta tumors, and 5 had high-grade
T1 tumors. While 12 patients responded, 6 presented with recurrence and
1 with progression. There was no correlation between the levels of mast
cell mediators and BCG response. The N-methylhistamine and histamine
levels were increased significantly with the onset of immunotherapy, and
N-methylhistamine levels were significantly decreased when immunotherapy
was terminated. Pre-BCG estimated marginal means of N-methylhistamine
were significantly higher in patients with NMIBC than healthy
participants.

\textbf{Conclusions:} Our study is the first study to identify the
changes in mast cell mediators with the onset of immunotherapy and with
the presence of bladder cancer. However, these mediators were not found
to predict the patients' response to immunotherapy.

\textbf{Keywords:} BCG; bladder cancer; immunotherapy; mast cell;
mediator.

\textbf{Introduction}

Bladder cancer is the 10th most common malignancy worldwide {[}1{]}.
Approximately 70-80 \% of patients present with non-muscle invasive
bladder cancer (NMIBC) limited to the mucosa and lamina propria, and the
remaining 20-30 \% of patients present with muscle-invasive or
metastatic disease {[}2{]}. Intravesical Bacillus Calmette-Guérin (BCG)
is the most effective therapy for NMIBC {[}3{]}. Optimal improvements in
recurrence and progression rates can be observed with intravesical BCG
immunotherapy applied after transurethral resection (TUR). However, the
rate of non-responders is seen up to 80 \% in patients treated with BCG
immunotherapy during long follow-up periods {[}4{]}.

The immune microenvironment of bladder tissue plays a critical role in
anti-tumor mechanisms. It is showed that different inflammatory cells
infiltrate oncogenic tissue, including mast cells, neutrophils,
macrophages, and lymphocytes, as a marker of the cancer-induced immune
response {[}5{]}. Different mechanisms have been evaluated about
interactions between bladder cancer, BCG immunotherapy, and immune
response. After intravesical BCG immunotherapy, the antigen 85 complex
adheres to the bladder wall through fibronectin and initiates an acute
immune response in the bladder wall, but many questions remain unclear
{[}6{]}.

Clinical trials based on BCG induced acute immune response have examined
T cells, cytokines, and macrophages. In these trials, bladder mast cell
activity is thought to play a critical role in tumor pathways and
angiogenesis {[}7{]}. The bladder mast cell contains many granules, each
of which can secrete many immunoactive molecules. Of these mediators,
elevated expression of IL 17, N-methylhistamine, histamine, and tryptase
may accept as a marker of mast cell activation {[}7-9{]}. Although one
study has confirmed the predictive value of IL-17+ mast cells in
patients with NMIBC treated with BCG immunotherapy {[}7{]}, there is no
study in the literature investigating urinary N-methylhistamine,
histamine, and tryptase levels. It is considered that the determination
of the mast cell activation can contribute to the increase of our
clinical approach to BCG immunotherapy. Furthermore, the determination
of mast cell activation in patients with NMIBC who receive immunotherapy
will benefit the development of mast cell-based new treatment
approaches.

We aimed to investigate the changes in urinary mast cell mediators level
in patients with NMIBC due to the instillation of BCG and the presence
of NMIBC. In addition, we assessed the differences between responders
and non-responders to immunotherapy in terms of urinary mast cell
mediator levels.

\textbf{Material and Methods}

\textbf{- Study Design and Patient Selection}

The present study protocol was reviewed and approved by the
Institutional Review Board of the Istanbul University-Cerrahpasa School
of Medicine (approval number: 21263603-806.01.03-400654). Informed
consent was obtained by all subjects when they were enrolled. This study
was conducted with the financial support of the Istanbul
University-Cerrahpasa Board of Scientific Research Projects (Number:
30651). The inclusion and exclusion criteria of the study are given
below.

\emph{Inclusion criteria:}

- Patients diagnosed with high-grade NMIBC,

- Patients completing TUR procedures,

- Patients with no contraindication for BCG,

- Demographic data and medical records being available.

\emph{Exclusion criteria:}

- Patients with Ta low-grade bladder cancer,

- Patients with metastatic involvement of any region,

- Patients with any other malignancy.

- Patients on immunosuppressive drugs like chemotherapy, steroids, or
HIV medications.

- Patients with a previous history of tuberculosis infection or BCG
instillation.

Nineteen patients who were planned to be treated with BCG for high-grade
NMIBC between February 2016 and November 2017 and 19 healthy
participants for comparison were enrolled in the study. Healthy
participants were selected randomly, and urinary ultrasonography and
urinary analyses were performed to exclude bladder malignancies.

\textbf{- Treatment Protocol}

The patients with NMIBC received weekly intravesical BCG for six weeks,
at least two weeks after the last TUR session. In each immunotherapy, 40
mg/ml of SII- Onco BCG (Serum Institute of India, Pune, India) was
dissolved with 40 cc of isotonic NaCl and administered through a 12-Fr
urethral catheter. This solution was retained in the bladder for 2
hours, after which urine collection was performed.

In the process of obtaining urine samples from each patient, the first
visit was organized immediately before the first BCG instillation, the
second visit immediately after the third instillation, the third visit
immediately after the sixth instillation, and the last visit four weeks
after the sixth instillation. In healthy participants, urine samples
collection was performed at a single visit after excluding bladder
cancer and urinary tract infection using ultrasonography and urinalysis.

\textbf{- Laboratory analysis}

The samples were immediately centrifuged at 5,000 rpm and 4 °C for 10
min to remove cells and debris and stored in aliquots at --70 °C until
analysis. The urinary N-methylhistamine, histamine, and tryptase levels
were~measured using~test kits by the sandwich enzyme-linked
immunosorbent assay (Genzyme Corporation, Cambridge, MA, USA). The
specific biotinylated detection antibody and avidin horseradish
peroxidase conjugate were added to the wells and incubated. After
removing the non-washing parts, the blue color was created in the boxes
by adding a substrate solution. The reaction was stopped by adding the
stop solution, and the blue color was observed to turn yellow. Optical
density (OD) was determined spectrophotometrically at a wavelength of
450 ± 2 nm. Since the OD value was proportional to mast cell mediator
levels in the samples, the N-methylhistamine, histamine, and tryptase
levels concentrations were calculated using standard curve graphics.

\textbf{- Follow-up}

All patients with NMIBC were planned to undergo two-year maintenance BCG
therapy according to the Southwest Oncology Group Study (SWOG) protocol
{[}10{]}. The patents were examined by cystoscopy and cytology at
three-month intervals for two years {[}11{]}. They underwent CT
urography imaging every six months {[}11{]}. Recurrence was defined as
histopathologically confirmed detection of any tumor after BCG induction
therapy. Progression was defined as an increase in the stage of the
muscle-invasive disease. After two years of follow-up, the patients were
classified as non-responders to immunotherapy in case of recurrence or
progression and responders to immunotherapy if there was no recurrence
or progression.

\textbf{- Statistical Analysis}

Statistical analysis was performed using the SPSS ver. 22.0 (IBM
Corporation, NY, USA). The predictive value of each mast cell mediators
and clinical parameters were assessed by chi-square test. The
differences in the urinary mast cell mediators levels between the
patients with NMIBC and healthy participants were examined using the
Mann--Whitney U test. The relationship between the urinary mast cell
mediator levels and the patients' response to immunotherapy was also
evaluated using the Mann--Whitney U test. The serial changes in the
urinary mast cell mediators measured at four different visits were
analyzed by the Wilcoxon signed-rank, Friedman, and Post-Hoc tests. A
p-value of less than 0.05 was accepted as statistically significant.

\textbf{Results}

The average age at the time of immunotherapy was 56.1 (37-79) years in
patients diagnosed with NMIBC. There were 13 men and 6 women. Fourteen
patients were diagnosed with Ta high-grade and 5 with T1 high-grade
bladder cancer. There was no patient with carcinoma in situ. During the
follow-up, while 18 patients completed two-year maintenance BCG therapy,
one underwent radical cystectomy. The cystoscopic evaluations undertaken
at three-month intervals revealed that 7 of 19 patients did not respond
to immunotherapy (non-responders), and 12 responded well (responders).
Among the non-responders, recurrence was observed in six patients and
progression in one patient. The average time to recurrence or
progression was 9.4 (3-18) months. The mean age was 52.2 ± 10.5 years in
responders and 61.4 ± 10.6 years in non-responders (p = 0.098). The
remaining baseline clinicopathological findings are shown
in\textbf{Table 1} .

The serial changes in estimated marginal means of urinary
N-methylhistamine, histamine, and tryptase levels in responders and
non-responders are shown in \textbf{Figure 1} . There was no
statistically significant difference between the immunotherapy
responders and non-responders in terms of the urinary N-methylhistamine,
histamine, and tryptase changes (p \textgreater{} 0.05). However, a
statistically significant increase was observed in the estimated
marginal means of urinary N-methylhistamine (p = 0.027) and histamine (p
= 0.004) levels measured at the second visit compared to the first visit
in patients treated with BCG (\textbf{Table 2} ). Although there were no
statistically significant differences between the second and third
visits (p = 0.053 and p = 0.26), a statistically significant decrease
was detected in the estimated marginal means of N-methylhistamine levels
measured last visit compared to the third visit (p = 0.013). Concerning
the urinary tryptase levels, no statistically significant differences
were obtained in terms of immunotherapy response and changes of urinary
tryptase levels at different visits in patients treated with BCG (p
\textgreater{} 0.05).

The estimated marginal means of urinary N-methylhistamine, histamine,
and tryptase levels measured at the first visit before immunotherapy in
patients with NMIBC and measured at a single visit in healthy
participants are given in \textbf{Table 2} . There were no statistically
significant differences in the estimated marginal means of urinary
histamine (p = 0.307) and tryptase (p = 0.816) levels between the
patients diagnosed with NMIBC and healthy participants. However, the
estimated marginal means of urinary N-methylhistamine levels were
significantly higher in patients with NMIBC than healthy participants (p
= 0.005).

The mast cell response to initial intravesical BCG immunotherapy between
BCG responders and non-responders is also evaluated. The increase in the
estimated marginal means of urinary N-methylhistamine after initial BCG
was 27.24 nmol/ml in responders and 41.51 nmol/ml in non-responders (p =
0.340). The increase in the estimated marginal means of urinary
histamine was 19.03 nmol/ml in responders and 27.64 nmol/ml in
non-responders (p = 0.801). The increase in the estimated marginal means
of urinary tryptase was 5.21 nmol/ml in responders and 7.51 nmol/ml in
non-responders (p = 0.108) \textbf{(Figure 1).}

\textbf{Discussion}

In the present study, we observed that urinary N-methylhistamine and
histamine levels were increased significantly with the onset of
immunotherapy, and N-methylhistamine levels were significantly decreased
when immunotherapy was terminated. Although we did not find
statistically significant differences between the responders and
non-responders, the estimated marginal means of Pre-BCG
N-methylhistamine were significantly higher in patients with NMIBC than
healthy participants.

A few studies have shown valuable changes in the BCG-induced urinary
immune microenvironment. In this field, IL-17+ mast cell, interleukins,
TNF-\selectlanguage{greek}α, \selectlanguage{english}IFN-\selectlanguage{greek}γ, \selectlanguage{english}and soluble ICAM-1 levels have been examined {[}7, 12,
13{]}. But there is no available data in the literature that can
determine mast cell activation in patients with NMIBC treated with BCG.
Our study determined that the urinary N-methylhistamine and histamine
levels increased with BCG immunotherapy, and N-methylhistamine decreased
with the termination of this BCG immunotherapy. Tryptase is considered
an unstable mast cell mediator, and therefore there was no statistically
significant change in the tryptase levels due to BCG immunotherapy.

Clinically useful tools to predict disease recurrence and progression
are much needed. Studies on predicting immunotherapy response started
with measuring purified protein derivative (PPD)-associated BCG
response.~In a study, the median recurrence-free survival was 25 months
in the PPD-negative group and was not available in the PPD positive
group (p \textless{} 0.05) {[}14{]}. But there was only one study about
the mast cell-related immunotherapy response. {[}7{]}. This study has
confirmed the predictive value of IL-17+ mast cells in patients with
NMIBC treated with BCG immunotherapy, and higher numbers of IL-17+ cells
have been found associated with improved event-free survival. However,
there is no available data in the literature to determine urinary
N-methylhistamine, histamine, and tryptase levels in patients with
NMIBC. In our study, the lack of a statistically significant difference
between the mast cell mediators and immunotherapy response can be
explained by the small size of the patient group. The samples'
quantitative differences suggest that statistically significant
differences could be found in further studies designed with larger
patient groups.

There are a few studies on urinary markers in identifying NMIBC
patients. Although some studies have reported promising results in
determining bladder cancer with urinary, immune markers, there was no
mast cell-related markers in the literature {[}15, 16{]}. In our study,
increased urinary N-methylhistamine levels were found in patients with
NMIBC compared to healthy participants. These results can be discussed
in several aspects. The evaluation of the samples obtained at the first
visit before BCG instillation in patients with NMIBC excluded the
BCG-related immunological response. However, the samples were taken
after the re-TUR procedure, suggesting that a resection-induced mast
cell activation may have been effective. Therefore, it can be considered
that resection-associated mast cell activation alone can be effective
against tumor cells.

A few studies suggest that a decrease in immune system function in
elderly patients may weaken the BCG response. Kanematsu et al. were the
first to report significantly reduced protection from tumor recurrence
and reduced tuberculin skin test reactivity in patients aged
\textgreater{}80 years treated with BCG {[}17{]}. A phase 2 study
revealed that patients older than 80 years had the poorest
recurrence-free survival, and thus being over 80 was an independent
predictor of recurrence (hazard ratio: 1.56) {[}18{]}. Furthermore, age
was also an independent predictor of progression by the Club Urologico
Espanol de Tratamiento Oncologico (CUETO) group {[}19{]}. Although in
our study, the mean age was reported higher in immunotherapy
non-responders, these differences were not found statistically
significant due to the low number of patients (p = 0.098).

Despite the promising results, our study has certain limitations. First,
it was a single-center study with a relatively low number of cases.
Second, it is considered that increasing the number of visits could
provide more detailed information about the changes in mast cell
mediators. Third, although all patients with NMIBC were high grade,
excluding other clinical and pathological conditions that could affect
immunotherapy response can be considered another limitation. Future
studies with a larger sample size and longer follow-up are needed to
predict BCG response at the beginning of the treatment.

\textbf{Conclusions}

According to our knowledge, this is the first study to determine that
urinary N-methylhistamine and histamine levels were increased
significantly with receiving immunotherapy, and N-methylhistamine levels
were significantly decreased when immunotherapy was terminated. Although
there are no statistically significant differences between the
immunotherapy responders and non-responders, the estimated marginal
means of Pre-BCG N-methylhistamine levels are significantly higher in
patients with NMIBC than healthy participants. These results are
promising for further studies to be conducted on mast cell activation.

\textbf{Acknowledgments:}

\textbf{Conflict of Interest} : The authors declare that they have no
conflict of interest.

\textbf{Funding Source} : None.

\textbf{Ethical approval:} This study was approved by the institutional
review board of the Medical Faculty of Istanbul University-Cerrahpasa.

\textbf{Informed consent:} Informed consent was obtained from all
individual participants included in the study.

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  Fernandez J, Solsona E, Unda M, et al (2008) Prognostic factors in
  patients with non-muscle-invasive bladder cancer treated with bacillus
  Calmette-Guerin: multivariate analysis of data from four randomized
  CUETO trials. Eur Urol 53:992-1001. doi: 10.1016/j.eururo.2007.10.006.
\end{enumerate}

\textbf{Table 1 --} Patient characteristics: \textbf{(a)} baseline
clinical outcomes; \textbf{(b)} tumor characteristics.\selectlanguage{english}
\begin{longtable}[]{@{}lllllllll@{}}
\toprule
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{(a)}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{(a)}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{(a)}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{(a)}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{(a)}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{(a)}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{(a)}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{(a)}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{(a)}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\textbf{Total} \textbf{(n = 19)}\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\textbf{Responders} \textbf{(n = 12)}\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\textbf{Non-responders (n = 7)}\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
P value\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Age \selectlanguage{ngerman}\emph{(years) (mean ± SD)}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
56.1 \selectlanguage{ngerman}± 10.5\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
52.2 \selectlanguage{ngerman}± 10.5\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
51.42 \selectlanguage{ngerman}± 10.6\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.098\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Gender\emph{, n} Female Male\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
6 13\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
4 8\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
2 5\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
0.622\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Complaint Hematuria LUTS Flank pain\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
10 5 4\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
6 2 4\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
4 3 0\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
0.171\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Smoking, \emph{n} Yes No\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
14 5\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
8 4\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
6 1\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
0.603\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Occupational risk, \emph{n} Yes No\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
4 15\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
2 10\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
2 5\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
0.475\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Familial cancer history, \emph{n} Yes No\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
7 12\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
4 8\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
3 4\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
0.526\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{(b)}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{(b)}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{(b)}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{(b)}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{(b)}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{(b)}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{(b)}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{(b)}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{(b)}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Tumor stage T1 Ta\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
5 14\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
1 11\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
4 3\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
0.508\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Tumor size \textless{}3 cm [?]3 cm\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
10 9\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
7 5\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
3 4\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
0.650\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Number of tumors Single Multiple\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
12 7\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
9 3\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
3 4\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
0.603\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Tumor morphology Papillary Non-papillary\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
16 3\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
11 1\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
5 2\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
0.359\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Additional treatment, \emph{n} Maintenance BCG Radical cystectomy\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
18 1\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
12 0\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
6 1\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
0.249\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
SD = standard deviation; LUTS = lower urinary tract symptoms; BCG =
Bacillus Calmette-Gu\selectlanguage{ngerman}érin\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
SD = standard deviation; LUTS = lower urinary tract symptoms; BCG =
Bacillus Calmette-Gu\selectlanguage{ngerman}érin\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
SD = standard deviation; LUTS = lower urinary tract symptoms; BCG =
Bacillus Calmette-Gu\selectlanguage{ngerman}érin\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
SD = standard deviation; LUTS = lower urinary tract symptoms; BCG =
Bacillus Calmette-Gu\selectlanguage{ngerman}érin\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
SD = standard deviation; LUTS = lower urinary tract symptoms; BCG =
Bacillus Calmette-Gu\selectlanguage{ngerman}érin\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
SD = standard deviation; LUTS = lower urinary tract symptoms; BCG =
Bacillus Calmette-Gu\selectlanguage{ngerman}érin\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
SD = standard deviation; LUTS = lower urinary tract symptoms; BCG =
Bacillus Calmette-Gu\selectlanguage{ngerman}érin\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
SD = standard deviation; LUTS = lower urinary tract symptoms; BCG =
Bacillus Calmette-Gu\selectlanguage{ngerman}érin\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
SD = standard deviation; LUTS = lower urinary tract symptoms; BCG =
Bacillus Calmette-Gu\selectlanguage{ngerman}érin\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}\selectlanguage{ngerman}\selectlanguage{english}
\begin{longtable}[]{@{}lllllllllllllllllllllll@{}}
\toprule
\textbf{Table 2.} Comparison of estimated marginal means of urinary mast
cell activation markers between the different visits in patients treated
with a six-week course~of Bacillus Calmette-Gu\selectlanguage{ngerman}érin therapy and between
the patients diagnosed with NMIBC (Visit 1) and healthy participants. &
\textbf{Table 2.} Comparison of estimated marginal means of urinary mast
cell activation markers between the different visits in patients treated
with a six-week course~of Bacillus Calmette-Gu\selectlanguage{ngerman}érin therapy and between
the patients diagnosed with NMIBC (Visit 1) and healthy participants. &
\textbf{Table 2.} Comparison of estimated marginal means of urinary mast
cell activation markers between the different visits in patients treated
with a six-week course~of Bacillus Calmette-Gu\selectlanguage{ngerman}érin therapy and between
the patients diagnosed with NMIBC (Visit 1) and healthy participants. &
\textbf{Table 2.} Comparison of estimated marginal means of urinary mast
cell activation markers between the different visits in patients treated
with a six-week course~of Bacillus Calmette-Gu\selectlanguage{ngerman}érin therapy and between
the patients diagnosed with NMIBC (Visit 1) and healthy participants. &
\textbf{Table 2.} Comparison of estimated marginal means of urinary mast
cell activation markers between the different visits in patients treated
with a six-week course~of Bacillus Calmette-Gu\selectlanguage{ngerman}érin therapy and between
the patients diagnosed with NMIBC (Visit 1) and healthy participants. &
\textbf{Table 2.} Comparison of estimated marginal means of urinary mast
cell activation markers between the different visits in patients treated
with a six-week course~of Bacillus Calmette-Gu\selectlanguage{ngerman}érin therapy and between
the patients diagnosed with NMIBC (Visit 1) and healthy participants. &
\textbf{Table 2.} Comparison of estimated marginal means of urinary mast
cell activation markers between the different visits in patients treated
with a six-week course~of Bacillus Calmette-Gu\selectlanguage{ngerman}érin therapy and between
the patients diagnosed with NMIBC (Visit 1) and healthy participants. &
\textbf{Table 2.} Comparison of estimated marginal means of urinary mast
cell activation markers between the different visits in patients treated
with a six-week course~of Bacillus Calmette-Gu\selectlanguage{ngerman}érin therapy and between
the patients diagnosed with NMIBC (Visit 1) and healthy participants. &
\textbf{Table 2.} Comparison of estimated marginal means of urinary mast
cell activation markers between the different visits in patients treated
with a six-week course~of Bacillus Calmette-Gu\selectlanguage{ngerman}érin therapy and between
the patients diagnosed with NMIBC (Visit 1) and healthy participants. &
\textbf{Table 2.} Comparison of estimated marginal means of urinary mast
cell activation markers between the different visits in patients treated
with a six-week course~of Bacillus Calmette-Gu\selectlanguage{ngerman}érin therapy and between
the patients diagnosed with NMIBC (Visit 1) and healthy participants. &
\textbf{Table 2.} Comparison of estimated marginal means of urinary mast
cell activation markers between the different visits in patients treated
with a six-week course~of Bacillus Calmette-Gu\selectlanguage{ngerman}érin therapy and between
the patients diagnosed with NMIBC (Visit 1) and healthy participants. &
\textbf{Table 2.} Comparison of estimated marginal means of urinary mast
cell activation markers between the different visits in patients treated
with a six-week course~of Bacillus Calmette-Gu\selectlanguage{ngerman}érin therapy and between
the patients diagnosed with NMIBC (Visit 1) and healthy participants. &
\textbf{Table 2.} Comparison of estimated marginal means of urinary mast
cell activation markers between the different visits in patients treated
with a six-week course~of Bacillus Calmette-Gu\selectlanguage{ngerman}érin therapy and between
the patients diagnosed with NMIBC (Visit 1) and healthy participants. &
\textbf{Table 2.} Comparison of estimated marginal means of urinary mast
cell activation markers between the different visits in patients treated
with a six-week course~of Bacillus Calmette-Gu\selectlanguage{ngerman}érin therapy and between
the patients diagnosed with NMIBC (Visit 1) and healthy participants. &
\textbf{Table 2.} Comparison of estimated marginal means of urinary mast
cell activation markers between the different visits in patients treated
with a six-week course~of Bacillus Calmette-Gu\selectlanguage{ngerman}érin therapy and between
the patients diagnosed with NMIBC (Visit 1) and healthy participants. &
\textbf{Table 2.} Comparison of estimated marginal means of urinary mast
cell activation markers between the different visits in patients treated
with a six-week course~of Bacillus Calmette-Gu\selectlanguage{ngerman}érin therapy and between
the patients diagnosed with NMIBC (Visit 1) and healthy participants. &
\textbf{Table 2.} Comparison of estimated marginal means of urinary mast
cell activation markers between the different visits in patients treated
with a six-week course~of Bacillus Calmette-Gu\selectlanguage{ngerman}érin therapy and between
the patients diagnosed with NMIBC (Visit 1) and healthy participants. &
\textbf{Table 2.} Comparison of estimated marginal means of urinary mast
cell activation markers between the different visits in patients treated
with a six-week course~of Bacillus Calmette-Gu\selectlanguage{ngerman}érin therapy and between
the patients diagnosed with NMIBC (Visit 1) and healthy participants. &
\textbf{Table 2.} Comparison of estimated marginal means of urinary mast
cell activation markers between the different visits in patients treated
with a six-week course~of Bacillus Calmette-Gu\selectlanguage{ngerman}érin therapy and between
the patients diagnosed with NMIBC (Visit 1) and healthy participants. &
\textbf{Table 2.} Comparison of estimated marginal means of urinary mast
cell activation markers between the different visits in patients treated
with a six-week course~of Bacillus Calmette-Gu\selectlanguage{ngerman}érin therapy and between
the patients diagnosed with NMIBC (Visit 1) and healthy participants. &
\textbf{Table 2.} Comparison of estimated marginal means of urinary mast
cell activation markers between the different visits in patients treated
with a six-week course~of Bacillus Calmette-Gu\selectlanguage{ngerman}érin therapy and between
the patients diagnosed with NMIBC (Visit 1) and healthy participants. &
\textbf{Table 2.} Comparison of estimated marginal means of urinary mast
cell activation markers between the different visits in patients treated
with a six-week course~of Bacillus Calmette-Gu\selectlanguage{ngerman}érin therapy and between
the patients diagnosed with NMIBC (Visit 1) and healthy participants.
&\tabularnewline
\midrule
\endhead
& & & & & \textbf{NMIBC} \textbf{(19)} & \textbf{NMIBC} \textbf{(19)} &
\textbf{NMIBC} \textbf{(19)} & \textbf{NMIBC} \textbf{(19)} &
\textbf{NMIBC} \textbf{(19)} & \textbf{NMIBC} \textbf{(19)} &
\textbf{NMIBC} \textbf{(19)} & & & & & & & \textbf{HP} \textbf{(19)} &
\textbf{HP} \textbf{(19)} & \textbf{HP} \textbf{(19)} & &\tabularnewline
& & & \textbf{Visit 1} & \textbf{Visit 1} & \textbf{Visit 1} & &
\textbf{Visit 2} & & \textbf{Visit 3} & & \textbf{Visit 4} & & \emph{P}
\textbf{value\textsuperscript{+}} & \emph{P}
\textbf{value\textsuperscript{+}} & & & & & & \emph{P}
\textbf{value\textsuperscript{*}} & \emph{P}
\textbf{value\textsuperscript{*}} &\tabularnewline
N-methylhistamine \selectlanguage{ngerman}\emph{(nmol/ml) (mean ± SD)} & N-methylhistamine
\selectlanguage{ngerman}\emph{(nmol/ml) (mean ± SD)} & & 112.09 \selectlanguage{ngerman}± 31.17 & 112.09 \selectlanguage{ngerman}± 31.17 &
112.09 \selectlanguage{ngerman}± 31.17 & & 144.59 \selectlanguage{ngerman}± 44.63 & & 118.01 \selectlanguage{ngerman}± 23.15 & & 93.43 \selectlanguage{ngerman}± 25.01 &
& \textbf{0.001} & \textbf{0.001} & 71.78 \selectlanguage{ngerman}± 39.39 & 71.78 \selectlanguage{ngerman}± 39.39 &
71.78 \selectlanguage{ngerman}± 39.39 & 71.78 \selectlanguage{ngerman}± 39.39 & 71.78 \selectlanguage{ngerman}± 39.39 & \textbf{0.005} &
\textbf{0.005} &\tabularnewline
Histamine \selectlanguage{ngerman}\emph{(ng/ml) (mean ± SD)} & Histamine \selectlanguage{ngerman}\emph{(ng/ml) (mean ±
SD)} & & 32.37 \selectlanguage{ngerman}± 14.16 & 32.37 \selectlanguage{ngerman}± 14.16 & 32.37 \selectlanguage{ngerman}± 14.16 & & 54.57 \selectlanguage{ngerman}± 27.45
& & 42.26 \selectlanguage{ngerman}± 27.89 & & 32.79 \selectlanguage{ngerman}± 19.42 & & \textbf{0.001} & \textbf{0.001}
& 29.22 \selectlanguage{ngerman}± 17.18 & 29.22 \selectlanguage{ngerman}± 17.18 & 29.22 \selectlanguage{ngerman}± 17.18 & 29.22 \selectlanguage{ngerman}± 17.18 & 29.22
\selectlanguage{ngerman}± 17.18 & 0.307 & 0.307 &\tabularnewline
Tryptase \selectlanguage{ngerman}\emph{(ng/ml) (mean ± SD)} & Tryptase \selectlanguage{ngerman}\emph{(ng/ml) (mean ±
SD)} & & 68.11 \selectlanguage{ngerman}± 17.41 & 68.11 \selectlanguage{ngerman}± 17.41 & 68.11 \selectlanguage{ngerman}± 17.41 & & 68.71 \selectlanguage{ngerman}± 18.65
& & 42.26 \selectlanguage{ngerman}± 27.89 & & 32.79 \selectlanguage{ngerman}± 19.42 & & 0.206 & 0.206 & 68.48 \selectlanguage{ngerman}± 19.66 &
68.48 \selectlanguage{ngerman}± 19.66 & 68.48 \selectlanguage{ngerman}± 19.66 & 68.48 \selectlanguage{ngerman}± 19.66 & 68.48 \selectlanguage{ngerman}± 19.66 & 0.816 &
0.816 &\tabularnewline
SD = standard deviation; IL= interleukin; TNF-\selectlanguage{greek}α \selectlanguage{english}= tumor necrosis factor
alpha; IFN= interferon-gamma; HP = healthy participants; NMIBC =
non-muscle invasive bladder cancer. * Mann-U Whitney test (between the
first visit of the patients diagnosed with NMIBC and healthy
participants). \textsuperscript{+} Friedman test (between different
visits). & SD = standard deviation; IL= interleukin; TNF-\selectlanguage{greek}α \selectlanguage{english}= tumor
necrosis factor alpha; IFN= interferon-gamma; HP = healthy participants;
NMIBC = non-muscle invasive bladder cancer. * Mann-U Whitney test
(between the first visit of the patients diagnosed with NMIBC and
healthy participants). \textsuperscript{+} Friedman test (between
different visits). & SD = standard deviation; IL= interleukin; TNF-\selectlanguage{greek}α \selectlanguage{english}=
tumor necrosis factor alpha; IFN= interferon-gamma; HP = healthy
participants; NMIBC = non-muscle invasive bladder cancer. * Mann-U
Whitney test (between the first visit of the patients diagnosed with
NMIBC and healthy participants). \textsuperscript{+} Friedman test
(between different visits). & SD = standard deviation; IL= interleukin;
TNF-\selectlanguage{greek}α \selectlanguage{english}= tumor necrosis factor alpha; IFN= interferon-gamma; HP = healthy
participants; NMIBC = non-muscle invasive bladder cancer. * Mann-U
Whitney test (between the first visit of the patients diagnosed with
NMIBC and healthy participants). \textsuperscript{+} Friedman test
(between different visits). & SD = standard deviation; IL= interleukin;
TNF-\selectlanguage{greek}α \selectlanguage{english}= tumor necrosis factor alpha; IFN= interferon-gamma; HP = healthy
participants; NMIBC = non-muscle invasive bladder cancer. * Mann-U
Whitney test (between the first visit of the patients diagnosed with
NMIBC and healthy participants). \textsuperscript{+} Friedman test
(between different visits). & SD = standard deviation; IL= interleukin;
TNF-\selectlanguage{greek}α \selectlanguage{english}= tumor necrosis factor alpha; IFN= interferon-gamma; HP = healthy
participants; NMIBC = non-muscle invasive bladder cancer. * Mann-U
Whitney test (between the first visit of the patients diagnosed with
NMIBC and healthy participants). \textsuperscript{+} Friedman test
(between different visits). & SD = standard deviation; IL= interleukin;
TNF-\selectlanguage{greek}α \selectlanguage{english}= tumor necrosis factor alpha; IFN= interferon-gamma; HP = healthy
participants; NMIBC = non-muscle invasive bladder cancer. * Mann-U
Whitney test (between the first visit of the patients diagnosed with
NMIBC and healthy participants). \textsuperscript{+} Friedman test
(between different visits). & SD = standard deviation; IL= interleukin;
TNF-\selectlanguage{greek}α \selectlanguage{english}= tumor necrosis factor alpha; IFN= interferon-gamma; HP = healthy
participants; NMIBC = non-muscle invasive bladder cancer. * Mann-U
Whitney test (between the first visit of the patients diagnosed with
NMIBC and healthy participants). \textsuperscript{+} Friedman test
(between different visits). & SD = standard deviation; IL= interleukin;
TNF-\selectlanguage{greek}α \selectlanguage{english}= tumor necrosis factor alpha; IFN= interferon-gamma; HP = healthy
participants; NMIBC = non-muscle invasive bladder cancer. * Mann-U
Whitney test (between the first visit of the patients diagnosed with
NMIBC and healthy participants). \textsuperscript{+} Friedman test
(between different visits). & SD = standard deviation; IL= interleukin;
TNF-\selectlanguage{greek}α \selectlanguage{english}= tumor necrosis factor alpha; IFN= interferon-gamma; HP = healthy
participants; NMIBC = non-muscle invasive bladder cancer. * Mann-U
Whitney test (between the first visit of the patients diagnosed with
NMIBC and healthy participants). \textsuperscript{+} Friedman test
(between different visits). & SD = standard deviation; IL= interleukin;
TNF-\selectlanguage{greek}α \selectlanguage{english}= tumor necrosis factor alpha; IFN= interferon-gamma; HP = healthy
participants; NMIBC = non-muscle invasive bladder cancer. * Mann-U
Whitney test (between the first visit of the patients diagnosed with
NMIBC and healthy participants). \textsuperscript{+} Friedman test
(between different visits). & SD = standard deviation; IL= interleukin;
TNF-\selectlanguage{greek}α \selectlanguage{english}= tumor necrosis factor alpha; IFN= interferon-gamma; HP = healthy
participants; NMIBC = non-muscle invasive bladder cancer. * Mann-U
Whitney test (between the first visit of the patients diagnosed with
NMIBC and healthy participants). \textsuperscript{+} Friedman test
(between different visits). & SD = standard deviation; IL= interleukin;
TNF-\selectlanguage{greek}α \selectlanguage{english}= tumor necrosis factor alpha; IFN= interferon-gamma; HP = healthy
participants; NMIBC = non-muscle invasive bladder cancer. * Mann-U
Whitney test (between the first visit of the patients diagnosed with
NMIBC and healthy participants). \textsuperscript{+} Friedman test
(between different visits). & SD = standard deviation; IL= interleukin;
TNF-\selectlanguage{greek}α \selectlanguage{english}= tumor necrosis factor alpha; IFN= interferon-gamma; HP = healthy
participants; NMIBC = non-muscle invasive bladder cancer. * Mann-U
Whitney test (between the first visit of the patients diagnosed with
NMIBC and healthy participants). \textsuperscript{+} Friedman test
(between different visits). & SD = standard deviation; IL= interleukin;
TNF-\selectlanguage{greek}α \selectlanguage{english}= tumor necrosis factor alpha; IFN= interferon-gamma; HP = healthy
participants; NMIBC = non-muscle invasive bladder cancer. * Mann-U
Whitney test (between the first visit of the patients diagnosed with
NMIBC and healthy participants). \textsuperscript{+} Friedman test
(between different visits). & SD = standard deviation; IL= interleukin;
TNF-\selectlanguage{greek}α \selectlanguage{english}= tumor necrosis factor alpha; IFN= interferon-gamma; HP = healthy
participants; NMIBC = non-muscle invasive bladder cancer. * Mann-U
Whitney test (between the first visit of the patients diagnosed with
NMIBC and healthy participants). \textsuperscript{+} Friedman test
(between different visits). & SD = standard deviation; IL= interleukin;
TNF-\selectlanguage{greek}α \selectlanguage{english}= tumor necrosis factor alpha; IFN= interferon-gamma; HP = healthy
participants; NMIBC = non-muscle invasive bladder cancer. * Mann-U
Whitney test (between the first visit of the patients diagnosed with
NMIBC and healthy participants). \textsuperscript{+} Friedman test
(between different visits). & SD = standard deviation; IL= interleukin;
TNF-\selectlanguage{greek}α \selectlanguage{english}= tumor necrosis factor alpha; IFN= interferon-gamma; HP = healthy
participants; NMIBC = non-muscle invasive bladder cancer. * Mann-U
Whitney test (between the first visit of the patients diagnosed with
NMIBC and healthy participants). \textsuperscript{+} Friedman test
(between different visits). & SD = standard deviation; IL= interleukin;
TNF-\selectlanguage{greek}α \selectlanguage{english}= tumor necrosis factor alpha; IFN= interferon-gamma; HP = healthy
participants; NMIBC = non-muscle invasive bladder cancer. * Mann-U
Whitney test (between the first visit of the patients diagnosed with
NMIBC and healthy participants). \textsuperscript{+} Friedman test
(between different visits). & SD = standard deviation; IL= interleukin;
TNF-\selectlanguage{greek}α \selectlanguage{english}= tumor necrosis factor alpha; IFN= interferon-gamma; HP = healthy
participants; NMIBC = non-muscle invasive bladder cancer. * Mann-U
Whitney test (between the first visit of the patients diagnosed with
NMIBC and healthy participants). \textsuperscript{+} Friedman test
(between different visits). & SD = standard deviation; IL= interleukin;
TNF-\selectlanguage{greek}α \selectlanguage{english}= tumor necrosis factor alpha; IFN= interferon-gamma; HP = healthy
participants; NMIBC = non-muscle invasive bladder cancer. * Mann-U
Whitney test (between the first visit of the patients diagnosed with
NMIBC and healthy participants). \textsuperscript{+} Friedman test
(between different visits). & SD = standard deviation; IL= interleukin;
TNF-\selectlanguage{greek}α \selectlanguage{english}= tumor necrosis factor alpha; IFN= interferon-gamma; HP = healthy
participants; NMIBC = non-muscle invasive bladder cancer. * Mann-U
Whitney test (between the first visit of the patients diagnosed with
NMIBC and healthy participants). \textsuperscript{+} Friedman test
(between different visits). &\tabularnewline
\bottomrule
\end{longtable}

\textbf{Figure Legend}

\textbf{Figure 1.} Serial changes in the estimated marginal means of
urinary N-methylhistamine, histamine and tryptase levels in patients
treated with a six-week course~of bacillus Calmette-Gu\selectlanguage{ngerman}érin therapy.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1/Figure-1}

\end{center}
\end{figure}

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

