Biomarkers in Recurrent Grade III Glioma Patients Treated with Bevacizumab and Irinotecan

<p>Predictive biomarkers and prognostic models are required to identify recurrent grade III glioma patients who benefit from existing treatment. In this study of 62 recurrent grade III glioma patients, a range of clinical and paraclinical factors are tested for association with progression-free survival, overall survival, and response to bevacizumab and irinotecan therapy. Significant factors from univariate screening are included in multivariate analysis. Biomarkers previously advanced as predictive or prognostic in the first-line setting did not affect outcome in this patient cohort. Based on the optimized model for overall survival, comprising performance status and p53 expression, a prognostic index is established.</p

Types of <i>TOP1</i> gene copy number increases by <i>TOP1</i> status.

<p>Red line denotes <i>TOP1</i> gene signal and green dot denotes centromeric signal. Examples are based on CRC cell line metaphase results – trisomy (SW620), pentasomy (Colo-205), 20q isochromosome formation (HT-29) and 20q gain (KM12).</p

Metaphases of CRC cell lines with <i>TOP1</i> gene copy number increases.

<p>A: Colo-205, B: HT-29 (lower right corner: digitally enlarged isochromosome), C: KM12, D: SW620. Note: Due to the existence of two chromatids in each metaphase chromosome, the observed number of gene signals is double that of what is observed in an interphase nucleus.</p

Molecular prediction of adjuvant cisplatin efficacy in Non-Small Cell Lung Cancer (NSCLC)—validation in two independent cohorts

<div><p>Introduction</p><p>Effective predictive biomarkers for selection of patients benefiting from adjuvant platinum-based chemotherapy in non-small cell lung cancer (NSCLC) are needed. Based on a previously validated methodology, molecular profiles of predicted sensitivity in two patient cohorts are presented.</p><p>Methods</p><p>The profiles are correlations between <i>in vitro</i> sensitivity to cisplatin and vinorelbine and baseline mRNA expression of the 60 cell lines in the National Cancer Institute panel. An applied clinical samples filter focused the profiles to clinically relevant genes. The profiles were tested on 1) snap-frozen tumors from 133 patients with completely resected stage 1B-2 NSCLC randomized to adjuvant cisplatin and vinorelbine (ACV, n = 71) or no adjuvant treatment (OBS, n = 62) and 2) formalin-fixed paraffin-embedded (FFPE) tumors from 95 patients with completely resected stage 1A-3B NSCLC receiving adjuvant cisplatin and vinorelbine.</p><p>Results</p><p>The combined cisplatin and vinorelbine profiles showed: 1) univariate Hazard Ratio (HR) for sensitive versus resistant of 0.265 (95% CI:0.079–0.889, p = 0.032) in the ACV cohort and a HR of 0.28 in a multivariate model (95% CI:0.08–1.04, p = 0.0573); 2) significant prediction at 3 year survival from surgery in univariate (HR = 0.138 (95% CI:0.035–0.537), p = 0.004) and multivariate analysis (HR = 0.14 (95% CI:0.030–0.6), p = 0.0081). No discrimination was found in the OBS cohort (HR = 1.328, p = 0.60). The cisplatin predictor alone had similar figures with 1) univariate HR of 0.37 (95% CI:0.12–1.15, p = 0.09) in the ACV cohort and 2) univariate HR of 0.14 (95% CI:0.03–0.59, p = 0.0076) to three years. Functional analysis on the cisplatin profile revealed a group of upregulated genes related to RNA splicing as a part of DNA damage repair and apoptosis.</p><p>Conclusions</p><p>Profiles derived from snap-frozen and FFPE NSCLC tissue were prognostic and predictive in the patients that received cisplatin and vinorelbine but not in the cohort that did not receive adjuvant treatment.</p></div

Kaplan-Meier curves of the cohorts receiving adjuvant cisplatin and vinorelbine, disease-specific survival.

<p>The curves show the cohort receiving adjuvant chemotherapy (ACV) in JBR.10 (1A) divided by a score of 50 and of the RH-cohort also receiving ACV (1B) divided by a score of 50. Underneath each curve is a description of events and patients at risk at different time points. Red: Combined cisplatin and vinorelbine score > 50, predicted high-likelihood responders to ACV; black: Combined cisplatin and vinorelbine score ≤ 50, predicted low-likelihood responders to ACV.</p

Definition of ploidy ranges from unaffacted colon mucosa specimens and estimation of ploidy in tumor samples.

a<p>% denotes the percentage of specimens in category relative to the total number of specimens (151).</p>b<p>CEN-20 aneusomy was defined as specimens with CEN-20 signals in a higher ploidy range than CEN-2. CEN-2 aneusomy was similarly defined, although vice versa.</p

uPAR immunohistochemistry in urothelial neoplasia of the bladder.

<p>The figure shows examples of different uPAR scores at the invasive front of the tumour: uPAR score = 0 (no uPAR positive cells detected), uPAR score = 3 (between 5% and 10% positive cells), and uPAR score = 6 (>70% positively stained cells). Tissue sections stained with a pAb against uPAR. uPAR expression was scored semi-quantitatively. The antibody was visualised with NovaRed. uPAR immunoreactivity was scored separately in cancer cells, macrophages and myofibroblasts. The black squares in A, C and E are shown in higher magnification in B, D and F. uPAR immunoreactivity was primarily seen in myofibroblasts (<b>yellow</b> arrow in D and F) and macrophages (<b>green</b> arrow in D and F) in the surrounding stroma. uPAR positive neutrophils served as internal control (<b>red</b> arrow in B, D and F). Tu: tumour, Ca: cancer, St: stroma. Bar in A, C and E ~ 50μm. Bar in B, D and F ~ 25μm.</p

Expected disease-specific survival based on a multivariable model in the ACV cohort of JBR.10.

<p>Curves shown for expected disease-specific survival based on the multivariate time-dependent model from JBR.10 with values of the combined profiles (DRP) of 10, 25, 50, 75 and 90 for a model including gender male, age 62 years, histology adenocarcinoma and stage 1 (A) and stage 2 (B).</p

Kaplan-Meier plots illustrating patient outcome according to <i>TOP1</i> status.

<p>A (left): OS, B (right): TTR.</p

Distribution of uPAR positivity at the invasive front (A) and tumour core (B), respectively.

<p>uPAR positivity in both myofibroblasts and macrophages, but not cancer cells, increases significantly with tumour stage. The x-axis shows the tumour stage and the y-axis the percentage of uPAR positive cells. P-values shown are for the χ2-test.</p