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Calais da Silva et al. J Cancer Metastasis Treat 2017;3:116-26 Journal of
DOI: 10.20517/2394-4722.2017.25
Cancer Metastasis and Treatment

www.jcmtjournal.com
Topic: Cancer Immunotherapy Open Access

Systemic humoral responses of non-

muscle-invasive bladder cancer during

BCG treatment: less is more

Fernando M. Calais da Silva , Paula A. Videira 2,3,4 , Dário Ligeiro , Maria Guadalupe Cabral , Richard Sylvester ,
6
5
3
1
Fernando E. Calais da Silva , Hélder Trindade 5
1
1 Grupo Português Génito-Urinário, Hospital São José, 1050-059 Lisboa, Portugal.
2 UCIBIO, Departamento Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, 2829-516 Caparica, Portugal.
3 Centro de Estudos de Doenças Crónicas, CEDOC, NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, 1169-056
Lisbon, Portugal.
4 CDG & Allies, Professionals and Patient Associations International Network (CDG & Allies - PPAIN), Faculdade de Ciências e Tecnologia,
Universidade Nova de Lisboa, 2829-516 Caparica, Portugal.
5 Centro de Sangue e Transplantação de Lisboa, IPST, IP., 1749-005 Lisboa, Portugal.
6 EAU Guidelines Office, 24 1040 Brussels, Belgium.
Correspondence to: Dr. Paula A. Videira, UCIBIO, Departamento Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade Nova de
Lisboa, 2829-516 Caparica, Portugal. E-mail: p.videira@fct.unl.pt; Dr. Fernando M. Calais da Silva, Grupo Português Génito-Urinário, Hospital
São José, 1050-059 Lisboa, Portugal. E-mail: fernando.calais@gmail.com

How to cite this article: Calais da Silva FM, Videira PA, Ligeiro D, Cabral MG, Sylvester R, Calais da Silva FE, Trindade H. Systemic humoral
responses of non-muscle-invasive bladder cancer during BCG treatment: less is more. J Cancer Metastasis Treat 2017;3:116-26.
ABSTRACT
Article history: Aim: Intravesical Bacille Calmette-Guérin (BCG) is the mainstay adjuvant treatment of
Received: 06-04-2017 non-muscle-invasive bladder cancer. However, one third of the patients on BCG regimen
Accepted: 23-05-2017 relapse within the first year of treatment. This study aimed at identifying biomarkers to
Published: 14-07-2017 predict response to BCG treatment. Methods: Gene expression was analyzed in blood
cells of 58 patients treated with BCG through six consecutive weekly instillations and then
Key words: at month 3, 6, 9, and 12. Cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-10,
Bladder cancer, interferon (IFN)-γ, IL-1β, IL-2, IL-4, and IL-6; chemokines CCL2, CCL3, CCL8, CXCL9,
Bacille Calmette-Guérin, and IP-10; and mediators of cytotoxicity CTLA4, Fas-L, Perf, GNLY, NOS2A, and HMOX-
immunomodulatory molecules, 1 were analyzed before the 1st and the 6th week instillation and 24 h after to assess fast
multivariate analysis (within 24 h) and prolonged changes resulting from treatment. Results: BCG instillation
led to fast-increased expression of IL-1β, TNF-α, and IL-10 genes. When compared to
relapsing patients, patients with no relapses within one year showed significantly lower
expression of IL-1β at 1st week and less IFN-γ, HMOX-1, and GNLY at week 6. HMOX-1
and GNLY were independent predictive biomarkers, and values above the cut-off ≥ 110
and ≥ 13.0 ‰ mRNA, respectively, were considered prejudicial factors. Patients with two
HMOX-1 and GNLY factors had highest (66.7%) relapsing risk. Conclusion: Assessing
immunomodulators’ expression in blood allows the establishment of predictive cut-off
values and identification of probabilities for patients’ relapses after BCG treatment.

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