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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.
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 GemelliIRCCSUniversità Cattolica del Sacro Cuore di Roma, Rome, Italy
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
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.
Standard urinalysis might still provide a lot of information, including
evidence of both systemic
and intravesical
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.
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.
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.
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.
teria in the bladder activates the immune system to protect the host
against acute infection and may also inhibit early tumor formation.
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.
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.
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.
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 GemelliIRCCSUniversità Cattolica del Sacro Cuore
di Roma, L.go A. Gemelli, Rome, 8 00168, Italy. E-mail address: (L. Di Gianfrancesco).
Current Urology, (2022) 16, 3, 172174
Received April 1, 2021; Accepted April 20, 2021. 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
recruitment of neutrophils to the affected urothelium.
phils can destroy tumor cells directly or indirectly
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
Yu et al.
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.
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.
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.
These studies also allowed some evidences in clinical practice
and management for patients in follow-up for NMIBC.
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.
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)
in-depth analysis of symptoms, however, can exclude the potential
risks due to intravesical treatment.
The word prognostichas 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.
However, very few studies have directly
investigated whether urinary biomarkers could provide prognostic
information over and above that provided by standard clinico-
pathological factors.
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.
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.
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.
Finally, the economic benefit, in terms of reducing the times of
recovery and reorganization of resources, should be taken into full
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.
Statement of ethics
Not applicable.
Conflict of interest statement
No conflict of interest has been declared by the authors.
Funding source
Author contributions
All authors contributed equally in this study.
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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):172174. doi: 10.1097/CU9.0000000000000131
Di Gianfrancesco et al. Volume 16 Issue 3 2022
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Full-text available
Context: This overview presents the updated European Association of Urology (EAU) guidelines for non-muscle-invasive bladder cancer (NMIBC), TaT1, and carcinoma in situ (CIS). Objective: To provide practical recommendations on the clinical management of NMIBC with a focus on clinical presentation and recommendations. Evidence acquisition: A broad and comprehensive scoping exercise covering all areas of the NMIBC guidelines has been performed annually since the last published version in 2017. Databases covered by the search included Medline, EMBASE, and the Cochrane Libraries. Previous guidelines were updated, and the level of evidence and grade of recommendation were assigned. Evidence synthesis: Tumours staged as Ta, T1, and/or CIS are grouped under the heading of NMIBC. Diagnosis depends on cystoscopy and histological evaluation of the tissue obtained by transurethral resection (TURB) in papillary tumours or by multiple bladder biopsies in CIS. In papillary lesions, a complete TURB is essential for the patient's prognosis and correct diagnosis. Where the initial resection is incomplete, where there is no muscle in the specimen, or where a T1 tumour is detected, a second TURB should be performed within 2-6 wk. The risks of both recurrence and progression may be estimated for individual patients using the European Organisation for Research and Treatment of Cancer (EORTC) scoring system. Stratification of patients into low-, intermediate-, and high-risk groups is pivotal to the recommendation of adjuvant treatment. In patients with tumours presumed to be at a low risk and in those presumed to be at an intermediate risk with a low previous recurrence rate and an expected EORTC recurrence score of <5, one immediate chemotherapy instillation is recommended. Patients with intermediate-risk tumours should receive 1 yr of full-dose bacillus Calmette-Guérin (BCG) intravesical immunotherapy or instillations of chemotherapy for a maximum of 1 yr. In patients with high-risk tumours, full-dose intravesical BCG for 1-3 yr is indicated. In patients at the highest risk of tumour progression, immediate radical cystectomy should be considered. Cystectomy is recommended in BCG-unresponsive tumours. The extended version of the guidelines is available at the EAU website: Conclusions: These abridged EAU guidelines present updated information on the diagnosis and treatment of NMIBC for incorporation into clinical practice. Patient summary: The European Association of Urology Non-muscle-invasive Bladder Cancer (NMIBC) Panel has released an updated version of their guidelines, which contains information on classification, risk factors, diagnosis, prognostic factors, and treatment of NMIBC. The recommendations are based on the current literature (until the end of 2018), with emphasis on high-level data from randomised clinical trials and meta-analyses. Stratification of patients into low-, intermediate-, and high-risk groups is essential for deciding appropriate use of adjuvant intravesical chemotherapy or bacillus Calmette-Guérin (BCG) instillations. Surgical removal of the bladder should be considered in case of BCG-unresponsive tumours or in NMIBCs with the highest risk of progression.
Full-text available
Objectives: With the advent of novel genomic and transcriptomic technologies, new urinary biomarkers have been identified and tested for bladder cancer (BCa) surveillance. To summarize the current status of urinary biomarkers for the detection of recurrence and/or progression in the follow-up of non-muscle invasive BCa patients, and to assess the value of urinary biomarkers in predicting response to intravesical Bacillus Calmette-Guerin (BCG) therapy. Methods and materials: A medline/pubmed© literature search was performed. The performance of commercially available and investigational biomarkers has been reviewed. End points were cancer detection (recurrence), cancer progression, and response to BCG therapy. Results: The performance requirements for biomarkers are variable according to the clinical scenario. The clinical role of urinary biomarkers in the follow-up of non-muscle invasive BCa patients remains undefined. The FDA-approved tests provide unsatisfactory sensitivity and specificity levels and their use is limited. Fluorescence in situ hybridization (FISH) has been shown to be useful in specific scenarios, mostly as a reflex test and in the setting of equivocal urinary cytology. FISH and immunocytology could conceivably be used to assess BCG response. Recently developed biomarkers have shown promising results; upcoming large trials will test their utility in specific clinical scenarios in a manner similar to a phased drug development strategy. Conclusions: Current commercially available urinary biomarker-based tests are not sufficiently validated to be widely used in clinical practice. Several novel biomarkers are currently under investigation. Prospective multicenter analyses will be needed to establish their clinical relevance and value.
Full-text available
For over 80 years, cystoscopy has remained the gold-standard for detecting tumours of the urinary bladder. Since bladder tumours have a tendency to recur and progress, many patients are subjected to repeated cystoscopies during long-term surveillance, with the procedure being both unpleasant for the patient and expensive for healthcare providers. The identification and validation of bladder tumour specific molecular markers in urine could enable tumour detection and reduce reliance on cystoscopy, and numerous classes of biomarkers have been studied. Proteins represent the most intensively studied class of biomolecule in this setting. As an aid to researchers searching for better urinary biomarkers, we report a comprehensive systematic review of the literature and a searchable database of proteins that have been investigated to date. Our objective was to classify these proteins as: 1) those with robustly characterised sensitivity and specificity for bladder cancer detection; 2) those that show potential but further investigation is required; 3) those unlikely to warrant further investigation; and 4) those investigated as prognostic markers. This work should help to prioritise certain biomarkers for rigorous validation, whilst preventing wasted effort on proteins that have shown no association whatsoever with the disease, or only modest biomarker performance despite large-scale efforts at validation.
Full-text available
Urologists often insist on sterile urine before invasive outpatient urological procedures, and urine culture and antibiotics are usually given before cystoscopy or instillation of bacille Calmette–Guérin (BCG) therapy, especially in patients who have positive urine cultures. Our experience suggests that cystoscopy and induction BCG therapy can be performed safely, even in patients with asymptomatic bacteriuria, without pretreatment or prophylactic antibiotics. The rate of subsequent febrile urinary tract infection is <4% in both infected and uninfected patients. Pretreatment antibacterial therapy does not appear to be necessary before these two outpatient urological procedures in patients with bladder cancer. Such strategy facilitates timely interventions and reduces the possibility of antibiotic resistance.
Bladder cancer may present management challenges as it frequently recurs and can progress when not expeditiously diagnosed and carefully monitored following initial therapy for non-invasive disease. Cystoscopy and cytology have long been the primary tools for the urologist treating bladder cancer. However, as a host of potential biomarkers have been developed, new avenues for non-invasive testing have become available in the detection, surveillance, and prognostic setting. Analysis of urine for mutational signatures at the genetic and epigenetic levels appears promising but such testing has yet to become widely adopted into clinical practice. Here we review recent advances in bladder cancer biomarker assays, with particular attention to clinical relevance and potential application.
Objective: To determine the initial response to intravesical bacillus Calmette-Guérin and the 3-year recurrence rate of high-risk non-muscle-invasive bladder cancer in patients who have asymptomatic bacteriuria. Methods: Response and recurrence rates were investigated in 505 patients with high-risk non-muscle-invasive bladder cancer after treatment with induction bacillus Calmette-Guérin (TICE strain) therapy. Initial response was determined after 3 months and patients were followed every 3-6 months for 3 years. Before bacillus Calmette-Guérin and each follow-up cystoscopy, urine cultures were obtained, stratified as no growth, <104, >104 or >105 colony-forming unit/mL. Any degree of bacteriuria on culture was classified as asymptomatic bacteriuria. Results: Of the 505 cases, 270 (53%) had asymptomatic bacteriuria. A total of 89% of patients with asymptomatic bacteriuria showed a complete response to bacillus Calmette-Guérin versus 76% of uninfected patients (P = 0.001), and 75% of bacteriuric patients survived tumor-free for 3 years versus 65% of uninfected patients. Conclusions: Chronic bacteriuria might enhance the response of high-risk non-muscle-invasive bladder cancer to intravesical bacillus Calmette-Guérin and result in longer tumor-free survival than uninfected patients.
Objective: Investigate symptoms and how they affect daily life in patients with Non-Muscle Invasive Bladder Cancer (NMIBC) treated with Bacillus Calmette-Guérin (BCG) instillations. Materials and methods: Patients treated with BCG were included. After an initial transurethral resection (TURB) followed by a second-look resection, the patients were given an induction course with BCG for 6 weeks followed by maintenance therapy for 2 years. The patients answered a questionnaire before, during and after the treatment. The questionnaire contained questions about specific symptoms combined with bother questions on how each symptom affected patients’ life. Results: In total, 113 of 116 patients responded to the first questionnaire. Thirty per cent of all patients were bothered by disease-specific symptoms before the start of BCG. Few patients reported fever, haematuria, illness or urinary tract symptoms. No difference in symptoms was found between patients with or without concomitant CIS (carcinoma in situ). Patients younger than 65 years of age reported a greater worry about the symptom burden in the future than those who were older. Patients younger than 65 years reported a decreased level of mental well-being. Conclusion: Patients with bladder cancer T1G2–G3 had disease-specific symptoms present already before the start of the BCG. The burden of symptoms was reduced over time and showed that the bladder might recover. BCG instillations had side-effects that negatively affected the patient’s well-being. It is important to record the patients’ baseline bladder and voiding status before as well as during the BCG-instillation period in order to understand symptoms caused by the treatment.
Macrophages are instrumental in the response to infectious and noninfectious diseases, however, their role in the bladder is poorly understood. Indeed, the bladder is a mucosal tissue frequently overlooked in research, despite the prevalence 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 recent studies support that resident macrophages and infiltrating monocytes play nonredundant roles in response to infection, immunotherapy, and inflammation. Advancing our understanding of macrophage behavior in the bladder is complicated by the difficulty in obtaining tissue-resident cells. Surmounting this challenge, however, for a greater understanding of macrophage ontology, impact on innate and adaptive immunity, and regulation of homeostasis, will ultimately contribute to better therapies for common afflictions of the bladder.
Background: The neutrophil-to-lymphocyte ratio (NLR) and the C-reactive protein (CRP) are markers of systemic inflammatory response, which have been associated with the prognosis of multiple malignancies, but their relationships with oncologic outcomes of non-muscle-invasive bladder cancer (NMIBC) have not been well studied yet. Patients and methods: We retrospectively reviewed the medical records of 1,117 patients with NMIBC who underwent a transurethral resection of the bladder. Univariable and multivariable competing risk regression models were used to assess the association of preoperative NLR and CRP with disease recurrence and progression to muscle-invasive disease. The median follow-up was 64 months. Results: In total, 360 patients (32.2%) had a high NLR (≥2.5) and 145 (13.0%) had a high CRP (≥5mg/l). On multivariable analyses, a high NLR was associated with both disease recurrence (subhazard ratio [SHR] = 1.27, P = 0.013) and progression (SHR = 1.72, P = 0.007), and high CRP was associated with disease progression (SHR = 1.72, P = 0.031). Adding NLR and CRP to the multivariable model predicting disease progression lead to a relevant change in discrimination (+2.0%). In a subgroup analysis of 300 patients treated with bacillus Calmette-Guerin, both high NLR and high CRP were associated with disease progression (SHR = 2.80, P = 0.026 and SHR = 3.51, P = 0.021, respectively), and NLR was associated with disease recurrence (SHR = 1.46, P = 0.046). There was also an increase in the discrimination of the model predicting progression after bacillus Calmette-Guerin following the inclusion of both markers (+2.4%). Conclusion: In patients with NMIBC, markers of systemic inflammation response are associated with disease recurrence and progression. The inclusion of such markers in prognostic models does enhance their accuracy.
Neutrophils are the first responders to sites of acute tissue damage and infection. Recent studies suggest that in addition to neutrophil apoptosis, resolution of neutrophil inflammation at wounds can be mediated by reverse migration from tissues and transmigration back into the vasculature. In settings of chronic inflammation, neutrophils persist in tissues, and this persistence has been associated with cancer progression. However, the role of neutrophils in the tumor microenvironment remains controversial, with evidence for both pro- and anti-tumor roles. Here we review the mechanisms that regulate neutrophil recruitment and resolution at sites of tissue damage, with a specific focus on the tumor microenvironment. We discuss the current understanding as to how neutrophils alter the tumor microenvironment to support or hinder cancer progression, and in this context outline gaps in understanding and important areas of inquiry.