Circulating Tumor Cells Prediction in Hormone Receptor Positive HER2-Negative Advanced Breast Cancer: A Retrospective Analysis of the MONARCH 2 Trial

Background: The MONARCH 2 trial (NCT02107703) showed the efficacy of abemaciclib, a cyclin-dependent kinase 4 & 6 inhibitor (CDK4/6i), in combination with fulvestrant for hormone receptor-positive, HER2-negative metastatic breast cancer (MBC). The aim of this analysis was to explore the prediction of circulating tumor cells (CTCs) stratification using machine learning for hypothesis generation of biomarker-driven clinical trials. Patients and Methods: Predicted CTCs were computed in the MONARCH 2 trial through a K nearest neighbor (KNN) classifier trained on a dataset comprising 2436 patients with MBC. Patients were categorized into predicted Stage IVaggressive (pStage IVaggressive, ≥5 predicted CTCs) or predicted Stage IVindolent (pStage IVindolent, <5 predicted CTCs). Prognosis was tested in terms of progression-free-survival (PFS) and overall survival (OS) through Cox regression. Results: Patients classified as predicted pStage IVaggressive and predicted pStage Stage IVindolent were, respectively, 183 (28%) and 461 (72%). After multivariable Cox regression, predicted CTCs were confirmed as independently associated with prognosis in terms of OS, together with ECOG performance status, liver involvement, bone-only disease, and treatment arm. Patients in the pStage Stage IVindolent subgroup treated with abemaciclib experienced the best prognosis both in terms of PFS and OS. The treatment effect of abemaciclib on OS was then explored through subgroup analysis, showing a consistent benefit across all subgroups. Conclusion: This study is the first analysis of CTCs modeling for stage IV disease stratification. These results show the need to expand biomarker profiling in combination with CTCs stratification for improved biomarker-driven drug development

Simultaneous interval regression for K-nearest neighbor

International audienceIn some regression problems, it may be more reasonable to predict intervals rather than precise values. We are interested in finding intervals which simultaneously for all input instances x ∈X contain a β proportion of the response values. We name this problem simultaneous interval regression. This is similar to simultaneous tolerance intervals for regression with a high confidence level γ ≈ 1 and several authors have already treated this problem for linear regression. Such intervals could be seen as a form of confidence envelop for the prediction variable given any value of predictor variables in their domain. Tolerance intervals and simultaneous tolerance intervals have not yet been treated for the K-nearest neighbor (KNN) regression method. The goal of this paper is to consider the simultaneous interval regression problem for KNN and this is done without the homoscedasticity assumption. In this scope, we propose a new interval regression method based on KNN which takes advantage of tolerance intervals in order to choose, for each instance, the value of the hyper-parameter K which will be a good trade-off between the precision and the uncertainty due to the limited sample size of the neighborhood around each instance. In the experiment part, our proposed interval construction method is compared with a more conventional interval approximation method on six benchmark regression data sets

FDG-PET as a predictive biomarker for therapy with everolimus in metastatic renal cell cancer

AbstractThe mTOR (mammalian target of rapamycin) inhibitor, everolimus, affects tumor growth by targeting cellular metabolic proliferation pathways and delays renal cell carcinoma (RCC) progression. Preclinical evidence suggests that baseline elevated tumor glucose metabolism as quantified by FDG-PET ([18F] fluorodeoxy-glucose positron emission tomography) may predict antitumor activity. Metastatic RCC (mRCC) patients refractory to vascular endothelial growth factor (VEGF) pathway inhibition were treated with standard dose everolimus. FDG-PET scans were obtained at baseline and 2weeks; serial computed tomography (CT) scans were obtained at baseline and every 8weeks. Maximum standardized uptake value (SUVmax) of the most FDG avid lesion, average SUVmax of all measured lesions and their corresponding 2-week relative changes were examined for association with 8-week change in tumor size. A total of 63 patients were enrolled; 50 were evaluable for the primary endpoint of which 48 had both PET scans. Patient characteristics included the following: 36 (72%) clear cell histology and median age 59 (range: 37–80). Median pre- and 2-week treatment average SUVmax were 6.6 (1–17.9) and 4.2 (1–13.9), respectively. Response evaluation criteria in solid tumors (RECIST)-based measurements demonstrated an average change in tumor burden of 0.2% (−32.7% to 35.9%) at 8weeks. Relative change in average SUVmax was the best predictor of change in tumor burden (all evaluable P=0.01; clear cell subtype P=0.02), with modest correlation. Baseline average SUVmax was correlated with overall survival and progression-free survival (PFS) (P=0.023; 0.020), but not with change in tumor burden. Everolimus therapy decreased SUVs on follow-up PET scans in mRCC patients, but changes were only modestly correlated with changes in tumor size. Thus, clinical use of FDG-PET-based biomarkers is challenged by high variability.In this phase II trial, FDG-PET was explored as a predictive biomarker for response to everolimus (mTOR inhibition) in metastatic renal cell carcinoma. Everolimus therapy decreased SUVs on follow-up FDG-PET scans in these patients. SUV changes were modestly correlated with changes in tumor size and baseline average SUVmax values were correlated with overall survival

The Coincidence Between Increasing Age, Immunosuppression, and the Incidence of Patients With Glioblastoma

Background: Glioblastoma (GBM) is the most aggressive primary brain tumor in adults and is associated with a median overall survival (mOS) of 16–21 months. Our previous work found a negative association between advanced aging and the survival benefit after treatment with immunotherapy in an experimental brain tumor model. Given the recent phase III clinical success of immunotherapy in patients with many types of cancer, but not for patients with GBM, we hypothesize that aging enhances immunosuppression in the brain and contributes to the lack of efficacy for immunotherapy to improve mOS in patients with malignant glioma. Herein, we compare epidemiological data for the incidence and mortality of patients with central nervous system (CNS) cancers, in addition to immune-related gene expression in the normal human brain, as well as peripheral blood immunological changes across the adult lifespan.Methods: Data were extracted from the National Cancer Institute’s surveillance, epidemiology, and end results (SEER)-, the Broad Institute’s Genotype Tissue Expression project (GTEx)-, and the University of California San Francisco’s 10k Immunomes-databases and analyzed for associations with aging.Results: The proportion of elderly individuals, defined as ≥65 years of age, has predominantly increased for more than 100 years in the United States. Over time, the rise in elderly United States citizens has correlated with an increased incidence and mortality rate associated with primary brain and other CNS cancer. With advanced aging, human mRNA expression for factors associated with immunoregulation including immunosuppressive indoleamine 2,3 dioxygenase 1 (IDO) and programmed death-ligand 1 (PD-L1), as well as the dendritic cell surface marker, CD11c, increase in the brain of normal human subjects, coincident with increased circulating immunosuppressive Tregs and decreased cytolytic CD8+ T cells in the peripheral blood. Strikingly, these changes are maximally pronounced in the 60–69 year old group; consistent with the median age of a diagnosis for GBM.Conclusion: These data demonstrate a significant association between normal human aging and increased immunosuppression in the circulation and CNS; particularly late in life. Our data raise several hypotheses including that, aging: (i) progressively suppresses normal immunosurveillance and thereby contributes to GBM cell initiation and/or outgrowth; (ii) decreases immunotherapeutic efficacy against malignant glioma

Local Transdermal Delivery of Telapristone Acetate Through Breast Skin, Compared With Oral Treatment: A Randomized Double-Blind, Placebo-Controlled Phase II Trial

Oral breast cancer prevention medications entail systemic exposure, limiting acceptance by high-risk women. Delivery through the breast skin, although an attractive alternative, requires demonstration of drug distribution throughout the breast. We conducted a randomized double-blind, placebo-controlled phase II clinical trial comparing telapristone acetate, a progesterone receptor antagonist, administered orally (12 mg/day) or transdermally (12 mg/breast) for 4 ± 1 weeks to women planning mastectomy. Plasma and tissue concentrations, measured at five locations in the mastectomy specimen using liquid chromatography tandem mass spectrometry were compared. In 60 evaluable subjects, median drug concentration (ng/g tissue) was 103 (interquartile range (IQR): 46.3–336) in the oral vs. 2.82 (IQR: 1.4–5.5) in the transdermal group. Despite poor dermal permeation, within-breast drug distribution pattern was identical in both groups (R2 = 0.88, P = 0.006), demonstrating that transdermally and orally delivered drug is distributed similarly through the breast, and is strongly influenced by tissue adiposity (P &lt; 0.0001). Other skin-penetrant drugs should be tested for breast cancer prevention

Membrane chemical stability and seed longevity

Here, we investigate the relationships between the chemical stability of the membrane surface and seed longevity. Dry embryos of long-lived tomato and short-lived onion seeds were labeled with 5-doxyl-stearic acid (5-DS). Temperature-induced loss of the electron spin resonance signal caused by chemical conversion of 5-DS to nonparamagnetic species was used to characterize the membrane surface chemical stability. No difference was found between temperature plots of 5-DS signal intensity in dry onion and tomato below 345 K. Above this temperature, the 5-DS signal remained unchanged in tomato embryos and irreversibly disappeared in onion seeds. The role of the physical state and chemical status of the membrane environment in the chemical stability of membrane surfaces was estimated for model systems containing 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) dried alone or in the presence of trehalose or glucose. Fourier transform infrared spectroscopy was used to follow temperature-induced structural changes in dry POPC. Spin-label technique was used to relate the chemical stability of 5-DS with the dynamic properties of the bilayer and 5-DS motion behavior. In all the models, the decrease in 5-DS signal intensity was always observed above Tm for the membrane surface. The 5-DS signal was irreversibly lost at high temperature when dry POPC was embedded in a glucose matrix. The loss of 5-DS signal was moderate when POPC was dried alone or in the presence of trehalose. Comparison of model and in vivo data shows that the differences in longevity between onion and tomato seeds are caused by differences in the chemical status of the membrane surface rather than the degree of its immobilization

Yeasts and bacterial biosurfactants as demulsifiers for petroleum derivative in seawater emulsions

Abstract Oil sludge or waste generated in transport, storage or refining forms highly stable mixtures due to the presence and additives with surfactant properties and water forming complex emulsions. Thus, demulsification is necessary to separate this residual oil from the aqueous phase for oil processing and water treatment/disposal. Most used chemical demulsifiers, although effective, are environmental contaminants and do not meet the desired levels of biodegradation. We investigated the application of microbial biosurfactants as potential natural demulsifiers of petroleum derivatives in water emulsions. Biosurfactants crude extracts, produced by yeasts (Candida guilliermondii, Candida lipolytica and Candida sphaerica) and bacteria (Pseudomonas aeruginosa, Pseudomonas cepacia and Bacillus sp.) grown in industrial residues, were tested for demulsification capacity in their crude and pure forms. The best results obtained were for bacterial biosurfactants, which were able to recover about 65% of the seawater emulsified with motor oil compared to 35–40% only for yeasts products. Biosurfactants were also tested with oil-in-water (O/W) and water-in-oil (W/O) kerosene model emulsions. No relationship between interfacial tension, cell hydrophobicity and demulsification ratios was observed with all the biosurfactants tested. Microscopic illustrations of the emulsions in the presence of the biosurfactants showed the aspects of the emulsion and demulsification process. The results obtained demonstrate the potential of these agents as demulsifiers in marine environments

Discovery of a Glucocorticoid Receptor (GR) Activity Signature Using Selective GR Antagonism in ER-Negative Breast Cancer

Purpose: Although high glucocorticoid receptor (GR) expression in early-stage estrogen receptor (ER)-negative breast cancer is associated with shortened relapse-free survival (RFS), how associated GR transcriptional activity contributes to aggressive breast cancer behavior is not well understood. Using potent GR antagonists and primary tumor gene expression data, we sought to identify a tumor-relevant gene signature based on GR activity that would be more predictive than GR expression alone. Experimental Design: Global gene expression and GR ChIP-sequencing were performed to identify GR-regulated genes inhibited by two chemically distinct GR antagonists, mifepristone and CORT108297. Differentially expressed genes from MDA-MB-231 cells were cross-evaluated with significantly expressed genes in GR-high versus GR-low ER-negative primary breast cancers. The resulting subset of GR-targeted genes was analyzed in two independent ER-negative breast cancer cohorts to derive and then validate the GR activity signature (GRsig). Results: Gene expression pathway analysis of glucocorticoid-regulated genes (inhibited by GR antagonism) revealed cell survival and invasion functions. GR ChIP-seq analysis demonstrated that GR antagonists decreased GR chromatin association for a subset of genes. A GRsig that comprised n = 74 GR activation-associated genes (also reversed by GR antagonists) was derived from an adjuvant chemotherapy-treated Discovery cohort and found to predict probability of relapse in a separate Validation cohort (HR = 1.9; P = 0.012). Conclusions: The GRsig discovered herein identifies highrisk ER-negative/GR-positive breast cancers most likely to relapse despite administration of adjuvant chemotherapy. Because GR antagonism can reverse expression of these genes, we propose that addition of a GR antagonist to chemotherapy may improve outcome for these high-risk patients. (C) 2018 AACR

The Lung Image Database Consortium (LIDC): An Evaluation of Radiologist Variability in the Identification of Lung Nodules on CT Scans

RATIONALE AND OBJECTIVES: The purpose of this study was to analyze the variability of experienced thoracic radiologists in the identification of lung nodules on CT scans and thereby to investigate variability in the establishment of the “truth” against which nodule-based studies are measured. MATERIALS AND METHODS: Thirty CT scans were reviewed twice by four thoracic radiologists through a two-phase image annotation process. During the initial “blinded read” phase, radiologists independently marked lesions they identified as “nodule ≥ 3mm (diameter),” “nodule < 3mm,” or “non-nodule ≥ 3mm.” During the subsequent “unblinded read” phase, the blinded read results of all radiologists were revealed to each of the four radiologists, who then independently reviewed their marks along with the anonymous marks of their colleagues; a radiologist’s own marks then could be deleted, added, or left unchanged. This approach was developed to identify, as completely as possible, all nodules in a scan without requiring forced consensus. RESULTS: After the initial blinded read phase, a total of 71 lesions received “nodule ≥ 3mm” marks from at least one radiologist; however, all four radiologists assigned such marks to only 24 (33.8%) of these lesions. Following the unblinded reads, a total of 59 lesions were marked as “nodule ≥ 3 mm” by at least one radiologist. 27 (45.8%) of these lesions received such marks from all four radiologists, 3 (5.1%) were identified as such by three radiologists, 12 (20.3%) were identified by two radiologists, and 17 (28.8%) were identified by only a single radiologist. CONCLUSION: The two-phase image annotation process yields improved agreement among radiologists in the interpretation of nodules ≥ 3mm. Nevertheless, substantial variabilty remains across radiologists in the task of lung nodule identification