Mitotic activity index and CD25+ lymphocytes predict risk of stage progression in non-muscle invasive bladder cancer.

In urothelial cell type non-muscle invasive urinary bladder carcinoma, TNM stage and WHO grade are widely used to classify patients into low and high­risk groups for prognostic and therapeutic decision-making. However, stage and grade reproducibility and prediction accuracy are wanting. This may lead to suboptimal treatment. We evaluated whether proliferation features, nuclear area of the epithelial cancer cells and the composition of stromal and tumor infiltrating lymphocytes have independent prognostic value. In 183 primary non-muscle invasive bladder cancer patients with long follow-up (median for stage progression cohort: 119 months, range 5-173; median for tumor recurrence cohort: 82, range 3-165) proliferation features Ki67, PPH3 and Mitotic Activity Index (MAI), Mean Nuclear Area (MNA), lymphocyte subsets (CD8+, CD4+, CD25+) and plasma cells (CD138+) were assessed on consecutive sections. Post-resection instillation treatments (none, mitomycin, BCG) were strictly standardized during the intake period. Risk of recurrence was associated with expression of Ki67 (≤ 39 vs. > 39) and Multifocality (p = 0.01). Patients with low Ki67 had a higher recurrence rate than those with high Ki67. Lymphocyte composition did not predict recurrence. Stage progression was strongly associated with high values for MAI (>15) and CD25+ (>0.2%). In a multivariate analysis the combination of MAI and CD25+ was the single most prognostic feature (p<0.001). Validation of these results in additional, independent studies is warranted.

Validation study of MARCKSL1 as a prognostic factor in lymph node-negative breast cancer patients.

Protein expression of Myristoylated alanine-rich C kinase substrate like-1 (MARCKSL1) has been identified as a prognostic factor in lymph-node negative (LN-) breast cancer patients. We aim to validate MARCKSL1 protein expression as a prognostic marker for distant metastasis-free survival (DMFS) in a new cohort of LN- breast cancer patients. MARCKSL1 expression was evaluated in 151 operable T1,2N0M0 LN- breast cancer patients by immunohistochemistry. Median follow-up time was 152 months, range 11-189 months. Results were compared with classical prognosticators (age, tumor diameter, grade, estrogen receptor, and proliferation) using single (Kaplan-Meier) and multivariate (Cox model) survival analysis. Thirteen patients (9%) developed distant metastases. With both single and multiple analysis of all features, MARCKSL1 did not show a significant prognostic value for DMFS (p = 0.498). Of the assessed classical prognosticators, only tumor diameter showed prognostic value (hazard ratio 9.3, 95% confidence interval 2.8-31.0, p <0.001). MARCKSL1 expression could not be confirmed as a prognostic factor in this cohort. Possible reasons include changes in diagnostic and treatment guidelines between the discovery and validation cohorts. Further studies are needed to reveal the potential biological role of this protein in breast cancer.

Quality assurance of human papillomavirus (HPV) testing in the implementation of HPV primary screening in Norway: an inter-laboratory reproducibility study.

BACKGROUND: Human papillomavirus (HPV) testing as primary screening for cervical cancer is currently being implemented in Norway in a randomized controlled fashion, involving three laboratories. As part of the quality assurance programme of the implementation, an evaluation of the inter-laboratory reproducibility of the HPV test was initiated, to ensure satisfactory HPV test reliability in all three laboratories. METHODS: The HPV test used is the cobas 4800 HPV Test, detecting 14 high-risk types with individual HPV genotype results for HPV16 and HPV18. In addition to the three laboratories involved in the implementation, the Norwegian HPV reference laboratory was included as a fourth comparative laboratory. A stratified sample of 500 cervical liquid based cytology (LBC) samples was used in the evaluation, with an aim towards a high-risk HPV positivity of ~25%. Samples were collected at one laboratory, anonymized, aliquoted, and distributed to the other laboratories. RESULTS: Comparison of the test results of all four laboratories revealed a 95.6% agreement, an 86.3% positive agreement and a kappa value of 0.94 (95% CI 0.92-0.97). For negative cytology specimens, there was a 95.8% overall agreement, a 67.4% positive agreement, and a kappa value of 0.88 (95% CI 0.80-0.93). For abnormal cytology specimens, there was a 95.8% overall agreement, a 95.5% positive agreement, and a kappa value of 0.86 (95% CI 0.71-0.97). CONCLUSIONS: The study showed a high inter-laboratory reproducibility of HPV testing, implying satisfactory user performance and reliability in the laboratories involved in the implementation project. This is important knowledge and we recommend similar studies always to be performed prior to the introduction of new screening routines.

Consistent condom use increases spontaneous regression in high-risk non-HPV16 but not in HPV16 CIN2-3 lesions, a prospective population-based cohort study.

BACKGROUND: The major cause of cervical intraepithelial neoplasia (CIN) is persistent infection with human papillomavirus (HPV). Most CIN grade 2 and 3 lesions are treated with cone excision, although a substantial proportion (6-50%) of CIN2-3 lesions will regresses spontaneously. Predictors for regression of CIN2-3 are desirable in order to reduce this overtreatment. METHODS: In this prospective cohort study, 145 consecutive women with first-time onset CIN2-3 in colposcopy-directed biopsies and standardized biopsy-cone excision interval were included. The genotype of the high-risk human papillomaviruses (=hrHPV) and clinical factors including sexual behaviour, parity, contraception and smoking were assessed. Patients were divided into two groups according to lesions containing HPV16 (hrHPV16+) and high-risk non-HPV16 (hrHPV16-) genotypes. RESULTS: Women whose partners consistently used condoms showed a significantly higher regression rate than women using other types of contraception (53% versus 13%, p<0.0001). However, this effect was only seen in hrHPV16- patients (73% regression rate versus 13%, p<0.0001). HrHPV16+ patients had a significantly higher number of sexual partners and more current smokers compared to hrHPV16- patients. The regression rate was not significantly different in CIN2-3 lesions containing HPV16 (hrHPV16+) versus hrHPV16- genotypes. CONCLUSIONS: Heterogeneity among hrHPV genotypes excists. HPV-genotype analyses can identify women who significantly increase their chance of regression by consistent condom use.