The indispensable role of urinalysis for patients undergoing treatment for nonmuscle invasive bladder cancer

Abstract

Despite several efforts in the search for noninvasive biomarkers to provide prognostic information for noninvasive muscle bladder cancer, none have shown significant potential. In this context, standard urinalysis is still necessary to provide many data. This method is an inexpensive, simple, and easy-to-repeat tool to follow-up patients over time. Urinalysis does not fall within study protocols and allows evaluation of the immune activation/response (even if indirectly). As such, this method can certainly provide useful information for prognosis.

Full text

The indispensable role of urinalysis for patients
undergoing treatment for nonmuscle invasive
bladder cancer
Luca Di Gianfrancesco*, Mauro Ragonese, Giuseppe Palermo, Emilio Sacco, Foschi Nazario,
PierFrancesco Bassi, Marco Racioppi
Clinica Urologica, Fondazione Policlinico Universitario “Agostino Gemelli”IRCCS–Università Cattolica del Sacro Cuore di Roma, Rome, Italy
Abstract
Despite several efforts in the search for noninvasive biomarkers to provide prognostic information for noninvasive muscle bladder can-
cer, none have shown significant potential. In this context, standard urinalysis is still necessary to provide many data. This method is an
inexpensive, simple, and easy-to-repeat tool to follow-up patients over time. Urinalysis does not fall within study protocols and allows
evaluation of the immune activation/response (even if indirectly). As such, this method can certainly provide useful information for
prognosis.
Keywords: Urinalysis; Immune system; Bacteriuria; Prognosis; Inflammatory response; Microbiome
Despite significant efforts to identify noninvasive biomarkers able to
provide prognostic information for nonmuscle invasive bladder can-
cer (NMIBC), no undisputable biomarkers have yet been identified.
[1]
Standard urinalysis might still provide a lot of information, including
evidence of both systemic
[2]
and intravesical
[3]
inflammation factors:
this aspect is very important because the neoplasm stimulates an im-
mune response that also involves the release of inflammatory factors
at both the systemic and local level, and this release is stimulated by
the recruited neutrophils. Macrophages are instrumental in the re-
sponse to both infectious and noninfectious diseases, and their role in
the bladder has been frequently and widely studied, because of the prev-
alence of illnesses, such as urinary tract infection and bladder cancer.
Notably, bladder tissue macrophages are among the most populous
resident immune cells in this organ, and several studies have supported
the idea that resident macrophages and infiltrating monocytes play non-
redundant roles in response to infection, immunotherapy, and inflam-
mation. Advancing the understanding of macrophage behavior in the
bladder is complicated by the difficulty in obtaining tissue-resident cells.
Surmounting this challenge to obtain a greater understanding of macro-
phage ontology, impact on innate and adaptive immunity, and regula-
tion of homeostasis will ultimately contribute to the development
of better therapies for common afflictions of the bladder.
[3]
The role of polymorphonuclear neutrophil granulocytes (PMNs)
displays a surprising dichotomy in antitumoral immune responses:
PMNs have alternatively been shown to both promote tumor growth
and progression under inflammatory conditions, and exert important
antitumor functions, especially in the context of therapeutic interven-
tions. Polymorphonuclear neutrophil granulocytes therefore play an
immunoregulatory role: they represent a major source of the
chemokines interleukin 8, growth-related oncogene α, and macro-
phage inflammatory protein 1α, as well as of inflammatory cyto-
kine migration inhibitory factor. They further induce T-cell che-
motaxis via the accessory function of activated monocytes, which
is indispensable for effective tumor immunotherapy.
[4]
The antibacterial immune responses activated by activation and
release of PMNs are similar to the anticancer inflammatory responses
induced by bacillus Calmette-Guerin (BCG), suggesting that patients
with bacteriuria might better respond to BCG treatment and
achieve longer disease-free intervals than patients without activa-
tion of the immune response by bacteriuria.
Herr
[5]
evaluated the issue of asymptomatic bacteriuria and investi-
gated how this could affect the response to intravesical BCG. Both
bacteria colonizing the bladder and the intravesical immunotherapy
activate the immune response to destroy urothelial cancer cells.
[5]
Bac-
teria in the bladder activates the immune system to protect the host
against acute infection and may also inhibit early tumor formation.
[6]
On the basis of this concept, the use of BCG for the prevention of re-
currence of high risk nonmuscle invasive tumors has been proposed.
[7]
Moreover, studies of the urinary microbiota identified remark-
able differences between healthy populations and those with uro-
logic diseases. Microorganisms are likely to have a profound effect
on urologic health, both positive and negative, because of their
metabolic output and other contributions. In addition, bacteria are
also used in the prevention of bladder cancer recurrence.
[8]
How-
ever, this has only been demonstrated in few small sampled studies
where specific probiotics were given to patients with NMIBC recur-
rence: this is definitely not the standard of care, nor is it recom-
mended by any clinical guidelines.
In a retrospective study, Herr et al.
[9]
showed that patients with
chronic bacteriuria, with or without BCG, seemed to have a lower
rate of bladder tumor recurrence than uninfected patients. The in-
nate immune response against microbes is initiated by cytokine
*Corresponding Author: Luca Di Gianfrancesco, Clinica Urologica, Fondazione
Policlinico Universitario “Agostino Gemelli”IRCCS–Università Cattolica del Sacro Cuore
di Roma, L.go A. Gemelli, Rome, 8 00168, Italy. E-mail address:
luca.digian@libero.it (L. Di Gianfrancesco).
Current Urology, (2022) 16, 3, 172–174
Received April 1, 2021; Accepted April 20, 2021.
http://dx.doi.org/10.1 097/CU9.00000000000001 31
Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. This is
an open-access article distributed under the terms of the Creative Commons
Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it
is permissible to download and share the work provided it is properly cited. The
work cannot be changed in any way or used commercially without permission
from the journal.
Special Topic: Advances in Bladder Cancer Therapy
172
Commentary

recruitment of neutrophils to the affected urothelium.
[10]
Neutro-
phils can destroy tumor cells directly or indirectly
[11,12]
;patients
with bacteriuria have more neutrophils in the blood than uninfected
patients, and recent studies have demonstrated the number of circu-
lating neutrophils as an independent prognostic parameter of cancer
outcomes.
[13,14]
Yu et al.
[15]
showed that elevated absolute neutro-
phil counts and the presence of pyuria are signs of local immune ac-
tivity in patients with chronic asymptomatic bacteriuria.
The action of neutrophils and macrophages has been extensively
evaluated directly on histological specimens. Jallad et al.
[16]
analyzed
the prognostic value of inflammation/granuloma in 215 BCG-treated
NMIBC patients over a 5-year period, and the correlations between his-
topathological results and disease recurrence and progression were
assessed. The mean recurrence-free survival rates were higher in
the granuloma and inflammation groups (65 and 56 months, re-
spectively) than in the normal histology group (20 months; log-rank
p= 0.001). The same trend was seen for progression-free survival, with
higher rates in granuloma and inflammation groups (75 and 82 months,
respectively) compared with the normal histology group (33 months)
(log-rank p< 0.001). Moreover, the absence of inflammation/
granuloma was significantly associated with recurrence on multi-
variate analysis (log-rank p< 0.001). The authors highlighted how
inflammation/granuloma in histology samples after intravesical BCG treat-
ment for NMIBC could be considered as a positive marker of response,
while their absence increased the risk of recurrence and progression.
In an apparent contradiction, Herr et al.
[9]
demonstrated how BCG
treatment had a destructive role against the urinary microbiome, up to
eradicate bacterial infection. The authors reported how intravesical
BCG therapy was associated with clearance of uropathogens in NMIBC
patients, possibly because of augmented innate host immunity.
[16]
These studies also allowed some evidences in clinical practice
and management for patients in follow-up for NMIBC.
[7,17]
Urol-
ogists often insist on the patient having sterile urine before under-
going invasive outpatient urological procedures, and urine culture
and antibiotics are usually given before cystoscopy or BCG instilla-
tion, especially in patients with a positive urine cultures. This
evidence-based experience suggests that cystoscopy and induction
BCG therapycan be performed safely, even in patients with asymp-
tomatic bacteriuria, without pretreatment or prophylactic antibi-
otics. Pretreatment antibacterial therapy further does not seem to
be necessary before these 2 outpatient urological procedures in pa-
tients with bladder cancer. Such strategy facilitates timely interven-
tions and reduces the possibility of antibiotic resistance.
[18]
With this in mind, it is always recommended to ask the patient
about any urinary symptoms; this aspect is always very challenging
because the symptoms that the patient complains of can also be re-
lated to the neoplasm (such as in cases of carcinoma in situ)
[19]
;an
in-depth analysis of symptoms, however, can exclude the potential
risks due to intravesical treatment.
[20]
The word “prognostic”has been variably applied to urinary bio-
markers. Most urinary biomarkers increase in concentration with
both stage and grade of disease and could therefore be considered
as prognostic indicators.
[21]
However, very few studies have directly
investigated whether urinary biomarkers could provide prognostic
information over and above that provided by standard clinico-
pathological factors.
[22]
Indeed, bladder tumor antigen, carcino-
embryonic antigen, matrix metalloproteinase-9, tenascin-C, cystatin-B,
and the soluble extracellular domains of epidermal growth factor
receptor and epithelial cell adhesion molecule have been reported
as independent prognostic indicators, although these data require
independent validation. Moreover, Shariat et al.
[23]
reported that
the pretreatment urinary nuclear matrix protein 22
®
levels slightly
improved the ability of nomograms to predict later recurrence.
Moreover, benign conditions and previous BCG instillations may
influence the results of many urinary marker tests.
[24]
Nevertheless, positive results of cytology, UroVysion, nuclear
matrix protein 22
®
, fibroblast growth factor receptor 3/telomerase
reverse transcriptase, and microsatellite analysis in patients with
negative cystoscopy and upper tract workup may be used to iden-
tify patients more likely to experience disease recurrence and
possible progression.
[25,26]
Finally, the economic benefit, in terms of reducing the times of
recovery and reorganization of resources, should be taken into full
consideration.
[27]
This method is an inexpensive, simple, and easy-to-repeat tool to
follow-up patients over time. Urinalysis does not fall within study
protocols, and allows evaluation of the immune activation/response
(even if indirectly). As such, this method can certainly provide useful
information for prognosis.
Acknowledgments
None.
Statement of ethics
Not applicable.
Conflict of interest statement
No conflict of interest has been declared by the authors.
Funding source
None.
Author contributions
All authors contributed equally in this study.
References
[1] Henning GM, Barashi NS, Smith ZL. Advances in biomarkers for detection,
surveillance, and prognosis of bladder cancer. Clin Genitourin Cancer 2021;
19(3):194–198.
[2] Mbeutcha A, Shariat SF, Rieken M, et al. Prognostic significance of
markers of systemic inflammatory response in patients with non-muscle-
invasive bladder cancer. Urol Oncol 2016;34(11):483.e17–483.e24.
[3] Lacerda Mariano L, Ingersoll MA. Bladder resident macrophages: Mucosal
sentinels. Cell Immunol 2018;330:136–141.
[4] Suttmann H, Riemensberger J, Bentien G, et al. Neutrophil granulocytes
are required for effective bacillus Calmette-Guérin immunotherapy of
bladder cancer and orchestrate local immune responses. Cancer Res 2006;
66(16):8250–8257.
[5] Herr H. Does asymptomatic bacteriuria affect the response to intravesical
bacillus Calmette-Guérin? Int J Urol 2020;27(1):72–74.
[6] Ingersoll MA, Albert ML. From infection to immunotherapy: Host
immune responses to bacteria at the bladder mucosa. Mucosal Immunol
2013;6(6):1041–1053.
[7] Babjuk M, Burger M, Compérat EM, et al. European association of
urology guidelines on non-muscle-invasive bladder cancer (TaT1 and
carcinoma in situ) - 2019 update. Eur Urol 2019;76(5):639–657.
[8] Whiteside SA, Razvi H, Dave S, Reid G,Burton JP. The microbiome ofthe
urinary tract - A role beyond infection. Nat Rev Urol 2015;12(2):81–90.
[9] Herr HW. Intravesical bacille Calmette-Guérin eradicates bacteriuria in
antibiotic-naïve bladder cancer patients. Eur Urol 2013;63(5):832–835.
[10] Powell DR, Huttenlocher A. Neutrophils in the tumor microenvironment.
Trends Immunol 2016;37(1):41–52.
[11] Brincks EL, Risk MC, Griffit h TS. PMN and anti-tumor immunity - The case
of bladder cancer immunotherapy. Semin Cancer Biol 2013;23(3):183–189.
[12] Priø TK, Bruunsgaard H, Røge B, Pedersen BK. Asymptomatic bacteriuria
in elderly humans is associated with increased levels of circulating TNF
receptors and elevated numbers of neutrophils. Exp Gerontol 2002;
37(5):693–699.
Di Gianfrancesco et al. Volume 16 Issue 3 2022 www.currurol.org
173

[13] Brandau S. The dichotomy of neutrophil granulocytes in cancer. Semin
Cancer Biol 2013;23(3):139–140.
[14] Donskov F. Immunomonitoring and prognostic relevance of neutrophils in
clinical trials. Semin Cancer Biol 2013;23(3):200–207.
[15] Yu Y, Zielinski MD, Rolfe MA, et al. Similar neutrophil-driven inflammatory
and antibacterial responses in elderly patients with symptomatic and
asymptomatic bacteriuria. Infect Immun 2015;83(10):4142–4153.
[16] Jallad S, Goubet S, Symes A, Larner T, Thomas P. Prognostic value of
inflammation or granuloma after intravesival BCG in non-muscle-invasive
bladder cancer. BJU Int 2014;113(5b):E22–E27.
[17] Herr HW. Outpatient urological procedures in antibiotic-naive patients
with bladder cancer with asymptomatic bacteriuria. BJU Int 2012;110
(11 Pt B):E658–E660.
[18] Herr HW. Cystoscopy and intravesical bacille Calmette-Guérin therapy in
antibiotic-naïve patients with bladder cancer with asymptomatic bacteriuria:
An update. Arab J Urol 2016;14(2):75–77.
[19] Danielsson G, Malmström PU, Jahnson S, Wijkström H, Nyberg T, Thulin
H. Bladder health in patients treated with BCG instillations for T1G2–G3
bladder cancer - A follow-up five years after the start of treatment. Scand J
Urol 2018;52(5–6):377–384.
[20] Sylvester RJ, Van Der MEIJDEN AP, Lamm DL. Intravesical bacillus
Calmette-Guerin reduces the risk of progression in patients with superficial
bladder cancer: A meta-analysis of the published results of randomized
clinical trials. JUrol2002;168(5):1964–1970.
[21] Soria F, Droller MJ, Lotan Y, et al. An up-to-date catalog of available
urinary biomarkers for the surveillance of non-muscle invasive bladder
cancer. WorldJUrol2018;36(12):1981–1995.
[22] Lotan Y, Shariat SF, Schmitz-Dräger BJ, et al. Considerations on
implementing diagnostic markers into clinical decision making in bladder
cancer. Urol Oncol 2010;28(4):441–448.
[23] Shariat SF, Zippe C, Lüdecke G, et al. Nomograms including nuclear
matrix protein 22 for prediction of disease recurrence and progression in
patients with Ta, T1 or CIS transitional cell carcinoma of the bladder.
JUrol2005;173(5):1518–1525.
[24] Lokeshwar VB, Habuchi T, Grossman HB, et al. Bladder tumor markers
beyond cytology: International Consensus Panel on bladder tumor
markers. Urology 2005;66(6 Suppl 1):35–63.
[25] Todenhöfer T, Hennenlotter J, Guttenberg P, et al. Prognostic relevance of
positive urine markers in patients with negative cystoscopy during surveillance
of bladder cancer. BMC Cancer 2015;15:155.
[26] D'Costa JJ, Goldsmith JC, Wilson JS, Bryan RT, Ward DG. A systematic
review of the diagnostic and prognostic value of urinary protein biomarkers
in urothelial bladder cancer. Bladder Cancer 2016;2(3):301–317.
[27] Mowatt G, Zhu S, Kilonzo M, et al. Systematic review of the clinical
effectiveness and cost-effectiveness of photodynamic diagnosis and urine
biomarkers (FISH, ImmunoCyt, NMP22) and cytology for the detection
and follow-up of bladder cancer. Health Technol Assess 2010;14(4):
1–331, iii–iv.
How to cite this article: Di Gianfrancesco L, Ragonese M, Palermo G, Sacco E,
Nazario F, Bassi P, Racioppi M. The indispensable role of urinalysis for pa-
tients undergoing treatment for nonmuscle invasive bladder cancer. Curr
Urol 2022;16(3):172–174. doi: 10.1097/CU9.0000000000000131
Di Gianfrancesco et al. Volume 16 Issue 3 2022 www.currurol.org
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