Designing phase II clinical trials to target subgroup of interest in a heterogeneous population: A case study using an R package.

Phase II trials that evaluate target therapies based on a biomarker must be well designed in order to assess anti-tumor activity as well as clinical utility of the biomarker. Classical phase II designs do not deal with this molecular heterogeneity and can lead to an erroneous conclusion in the whole population, whereas a subgroup of patients may well benefit from the new therapy. Moreover, the target population to be evaluated in a phase III trial may be incorrectly specified. Alternative approaches are proposed in the literature that make it possible to include two subgroups according to biomarker status (negative/positive) in the same study. Jones, Parashar and Tournoux et al. propose different stratified adaptive two-stage designs to identify a subgroup of interest in a heterogeneous population that could possibly benefit from the experimental treatment at the end of the first or second stage. Nevertheless, these designs are rarely used in oncology research. After introducing these stratified adaptive designs, we present an R package (ph2hetero) implementing these methods. A case study is provided to illustrate both the designs and the use of the R package. These stratified adaptive designs provide a useful alternative to classical two-stage designs and may also provide options in contexts other than biomarker studies.

DNA replication stress response involving PLK1, CDC6, POLQ, RAD51 and CLASPIN upregulation prognoses the outcome of early/mid-stage non-small cell lung cancer patients.

Lung cancer is the leading cause of cancer deaths worldwide. Clinical staging classification is generally insufficient to provide a reliable prognosis, particularly for early stages. In addition, prognostic factors are therefore needed to better forecast life expectancy and optimize adjuvant therapeutic strategy. Recent evidence indicates that alterations of the DNA replication program contribute to neoplasia from its early stages and that cancer cells are frequently exposed to endogenous replication stress. We therefore hypothesized that genes involved in the replication stress response may represent an under-explored source of biomarkers. Expressions of 77 DNA replication-associated genes implicated in different aspects of chromosomal DNA replication, including licensing, firing of origins, elongation, replication fork maintenance and recovery, lesion bypass and post-replicative repair were determined in primary tumors and adjacent normal tissues from 93 patients suffering from early- or mid-stage non-small cell lung cancer (NSCLC). We then investigated a statistically significant interaction between gene expressions and survival of early-stage NSCLC patients.The expression of five genes, that is, POLQ, PLK1, RAD51, CLASPIN and CDC6 was associated with overall, disease-free and relapse-free survival. The expression levels are independent of treatment and stage classification. Except RAD51, their prognostic role on survival persists after adjustment on age, sex, treatment, stage classification and conventional proliferation markers, with a hazard ratio of 36.3 for POLQ (95%CI 2.6-517.4, P=0.008), 23.5 for PLK1 (95%CI 1.9-288.4, P=0.01), 20.7 for CLASPIN (95%CI 1.5-275.9, P=0.02) and 18.5 for CDC6 (95%CI 1.3-267.4, P=0.03). We also show that a five-gene signature including POLQ, PLK1, RAD51, CLASPIN and CDC6 separates patients into low- and high-risk groups, with a hazard ratio of 14.3 (95% CI 5.1-40.3, P<0.001). This 'replication stress' metamarker may be a reliable predictor of survival for NSCLC, and may also help understand the molecular mechanisms underlying tumor progression.

[Pathologic Doppler flowmetry of the uterine artery and histologic changes of the placenta]. / Doppler pathologique aux artères utérines et altérations histologiques du placenta.

The usefulness of velocimetric study of the uterine arteries during high-risk pregnancies and in particular in the presence of presumed or confirmed maternal pathology is now recognized. Is it possible to identify a link between hemodynamic disturbances affecting the uterine arteries and histological abnormalities of the placenta? This was the aim of the present study. Histological examination of the placenta was routinely requested after delivery when uterine artery Doppler had been pathological during pregnancy (index and/or notch). Fifty five placentas were studied, all but one being pathological. This essentially involved ischemic lesions (including retroplacental hematomas), for which Doppler investigation appears to be a good indicator. Forty placentas were hypotrophic and 2 hypertrophic. Thus uterine artery Doppler during pregnancy appears to accurately reflect the histological state of the placenta and possibly even its functional value.