title: Markers predicting response to bacillus Calmette-Guérin immunotherapy in high-risk bladder cancer patients: a systematic review.
abstract: BACKGROUND
  Currently, bacillus Calmette-Guérin (BCG) intravesical instillations are standard treatment for patients with high-grade non-muscle-invasive bladder cancer; however, no markers are available to predict BCG response.
  
  
  OBJECTIVE
  To review the contemporary literature on markers predicting BCG response, to discuss the key issues concerning the identification of predictive markers, and to provide recommendations for further research studies.
  
  
  METHODS
  We performed a systematic review of the literature using PubMed and Embase databases in the period 1996-2010. The free-text search was extended by adding the following keywords: recurrence, progression, survival, molecular marker, prognosis, TP53, Ki-67, RB, fibronectin, immunotherapy, cytokine, interleukin, natural killer, macrophage, PMN, polymorphism, SNP, single nucleotide polymorphism, and gene signature.
  
  
  RESULTS
  If thresholds for the detection of urinary interleukin (IL)-8, IL-18, and tumour necrosis factor apoptosis-inducing ligand levels are standardised, measurement of these cytokines holds promise in the assessment of BCG therapy outcome. Studies on immunohistochemical markers (ie, TP53, Ki-67, and retinoblastoma) display contradictory results, probably because of the small patient groups that were used and seem unsuitable to predict BCG response. Exploring combinations of protein levels might prove to be more helpful to establish the effect of BCG therapy. Single nucleotide polymorphisms, either in cytokines or in genes involved in DNA repair, need to be investigated in different ethnicities before their clinical relevance can be determined. Measurement of urinary IL-2 levels seems to be the most potent marker of all the clinical parameters reviewed.
  
  
  CONCLUSIONS
  IL-2 levels are currently the most promising predictive markers of BCG response. For future studies focusing on new biomarkers, it is essential to make more use of new biomedical techniques such as microRNA profiling and genomewide sequencing.
authors: Department of Pathology, Erasmus Medical Centre Rotterdam, The Netherlands.
authors: Tahlita C M
authors: TC
authors: Zuiverloon
authors: Annemieke J M
authors: AJ
authors: Nieuweboer
authors: Hedvig
authors: H
authors: Vékony
authors: Wim J
authors: WJ
authors: Kirkels
authors: Chris H
authors: CH
authors: Bangma
authors: Ellen C
authors: EC
authors: Zwarthoff
mesh_terms: D000283:Administration, Intravesical; D001500:BCG Vaccine / Q000008:administration & dosage* / Q000009:adverse effects; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D019317:Evidence-Based Medicine; D006801:Humans; D007167:Immunotherapy / Q000009:adverse effects / Q000379:methods*; D018579:Patient Selection; D011237:Predictive Value of Tests; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*
chemical_list: D001500:BCG Vaccine; D014408:Biomarkers, Tumor