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Pailler E.,University Paris - Sud | Pailler E.,Translational Research Laboratory | Auger N.,Gustave Roussy | Lindsay C.R.,University Paris - Sud | And 11 more authors.
Annals of Oncology | Year: 2015

Background: Genetic aberrations affecting the c-ros oncogene 1 (ROS1) tyrosine kinase gene have been reported in a small subset of patients with non-small-cell lung cancer (NSCLC). We evaluated whether ROS1-chromosomal rearrangements could be detected in circulating tumor cells (CTCs) and examined tumor heterogeneity of CTCs and tumor biopsies in ROS1-rearranged NSCLC patients. Patients and methods: Using isolation by size of epithelial tumor cells (ISET) filtration and filter-adapted-fluorescence in situ hybridization (FA-FISH), ROS1 rearrangement was examined in CTCs from four ROS1-rearranged patients treated with the ROS1-inhibitor, crizotinib, and four ROS1-negative patients. ROS1-gene alterations observed in CTCs at baseline from ROS1- rearranged patients were compared with those present in tumor biopsies and in CTCs during crizotinib treatment. Numerical chromosomal instability (CIN) of CTCs was assessed by DNA content quantification and chromosome enumeration. Results: ROS1 rearrangement was detected in the CTCs of all four patients with ROS1 rearrangement previously confirmed by tumor biopsy. In ROS1-rearranged patients, median number of ROS1-rearranged CTCs at baseline was 34.5 per 3 ml blood (range, 24-55). In ROS1-negative patients, median background hybridization of ROS1-rearranged CTCs was 7.5 per 3 ml blood (range, 7-11). Tumor heterogeneity, assessed by ROS1 copy number, was significantly higher in baseline CTCs compared with paired tumor biopsies in the three patients experiencing PR or SD (P < 0.0001). Copy number in ROS1-rearranged CTCs increased significantly in two patients who progressed during crizotinib treatment (P < 0.02). CTCs from ROS1-rearranged patients had a high DNA content and gain of chromosomes, indicating high levels of aneuploidy and numerical CIN. Conclusion: We provide the first proof-of-concept that CTCs can be used for noninvasive and sensitive detection of ROS1 rearrangement in NSCLC patients. CTCs from ROS1-rearranged patients show considerable heterogeneity of ROS1-gene abnormalities and elevated numerical CIN, a potential mechanism to escape ROS1-inhibitor therapy in ROS1-rearranged NSCLC tumors. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


Grieve K.,Center Hospitalier National dOphtalmologie des Quinze Vingts | Palazzo L.,Clinique du Trocadero | Dalimier E.,LLTech SAS | Vielh P.,Translational Research Laboratory | Fabre M.,Translational Research Laboratory
Gastrointestinal Endoscopy | Year: 2015

Background Rapid on-site evaluation of cytologic specimens is a way of determining the adequacy of fine-needle aspiration (FNA). However, alternatives may be useful when the presence of a cytotechnologist and/or pathologist is not possible. Objective To evaluate the feasibility of using full-field optical coherence tomography (FFOCT) for FNA specimen quality assessment. Design FFOCT images were acquired on gastric, pancreatic, pelvic, and lymph-node formalin-fixed FNA specimens and were compared with histology of the same samples. Setting Pathology suite in a hospital. Patients Fourteen patients undergoing gastric, pancreatic, pelvic, or lymph-node EUS-guided FNA biopsy. Interventions FFOCT imaging on formalin-fixed samples before histologic procedures. Main Outcome Measurements FFOCT imaging feasibility and visibility of normal and abnormal features on images. Results FFOCT imaging was possible. Blood, mucus, muscle, collagen, and digestive mucosa could be identified as well as abnormal architectural features including infiltrative pancreatic ductal carcinoma and a neuroendocrine neoplasm. Lesions at the individual cell level could not be detected. Limitations The study was performed on a limited number of cases. Conclusion FFOCT offers rapid, noninvasive, nondestructive imaging of FNA biopsy specimens. In the future, it could be performed in the endoscopy suite to improve detection of satisfactory specimens and obviate the need for rapid on-site evaluation. © 2015 American Society for Gastrointestinal Endoscopy.


Arnedos M.,Gustave Roussy Cancer Campus | Arnedos M.,French Institute of Health and Medical Research | Vielh P.,French Institute of Health and Medical Research | Vielh P.,Translational Research Laboratory | And 5 more authors.
Journal of Pathology | Year: 2014

Molecular characterization of frequent cancers has shown that these entities actually include a very large number of rare genomic diseases. The progression of each of these rare diseases is being driven by specific genomic alterations, leading to abnormal proteins that can be targeted. Based on this observation, several personalized medicine programmes have been launched. They consist in profiling the tumour samples from each patient, identifying key oncogenic drivers, and treating the patient accordingly. Several preliminary data suggest that this approach is feasible and could lead to anti-tumour effects that are currently modest. Several reasons could explain why personalized medicine programmes only report modest activity to targeted agents. First, the identification of key oncogenic drivers among several genomic alterations can be challenging. Second, the intratumour heterogeneity could lead to the emergence of resistant clones. Finally, several genomic alterations could contribute to cancer progression. These observations are leading to the second generation of personalized medicine trials, where targeted therapies are combined with each other and with immunotherapeutics, and where patients are selected to present a tumour with a low level of genetic instability. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Sheppard K.E.,University of Melbourne | Sheppard K.E.,Molecular Oncology Laboratory | McArthur G.A.,University of Melbourne | McArthur G.A.,Molecular Oncology Laboratory | And 2 more authors.
Clinical Cancer Research | Year: 2013

The recent clinical success of targeted therapies in melanoma directed at the oncogene BRAF validates the concept of targeting oncogenes. The p16-cyclin D-CDK4/6-retinoblastoma protein pathway (CDK4 pathway) is dysregulated in 90% of melanomas, and is, therefore, an obvious therapeutic target for this disease. The main outcome of CDK4 activation is the phosphorylation and, thus, inhibition of the retinoblastoma protein leading to G1-S cell-cycle transition. In addition, CDK4 directly phosphorylates other proteins that promote cell-cycle progression and inhibit both cell senescence and apoptosis. In preclinical studies, the response to CDK4 inhibition correlates with genomic changes that increase CDK4 activity, most notably where the tumor suppressor CDKN2A (p16INK4A) is deleted. A central question is whether melanomas with activating events in the CDK4 pathway have become "addicted" to this signaling pathway, in which case inhibition of CDK4 would not simply induce cell-cycle arrest but induce cell death and tumor regression. Recently, a number of selective CDK4/6 inhibitors have entered clinical trials, and these compounds are showing great promise in that they are well tolerated and show clinical benefit. This review discusses the CDK4 pathway, its dysregulation in melanoma, the consequences of CDK4 pathway inhibition, and potential novel combinational strategies for the treatment of melanoma. © 2013 American Association for Cancer Research.


Newbold A.,Peter MacCallum Cancer Center | Martin B.P.,Peter MacCallum Cancer Center | Cullinane C.,Translational Research Laboratory | Cullinane C.,University of Melbourne | Bots M.,Center for Experimental Molecular Medicine
Cold Spring Harbor Protocols | Year: 2014

Positron emission tomography (PET) can be used to monitor the uptake of the labeled glucose analog fluorodeoxyglucose (18F-FDG), a process that is generally believed to reflect viable tumor cell mass. The use of 18F-FDG PET can be helpful in documenting over time the reduction in tumor mass volume in response to anticancer drug therapy in vivo. In this protocol, we describe how to monitor the response of murine B-cell lymphomas to an inducer of apoptosis, the anticancer drug vorinostat (a histone deacetylase inhibitor). B-cell lymphoma cells are injected into recipient mice and, on tumor formation, the mice are treated with vorinostat. The tracer 18F-FDG is then injected into the mice at several time points, and its uptake is monitored using PET. Because the uptake of 18F-FDG is not a direct measure of apoptosis, an additional direct method proving that apoptotic cells are present should also be performed. © 2014 Cold Spring Harbor Laboratory Press.


Lee B.,Peter MacCallum Cancer Center | Sandhu S.,Peter MacCallum Cancer Center | McArthur G.,Peter MacCallum Cancer Center | McArthur G.,University of Melbourne | And 2 more authors.
Current Opinion in Oncology | Year: 2015

PURPOSE OF REVIEW: This review highlights recent clinical developments in the therapeutic targeting of cell cycle control in melanoma with cyclin-dependent kinase inhibitors, checkpoint kinases, MDM2, MDM4 and p53 inhibitors. RECENT FINDINGS: The high prevalence of activating genetic aberrations along the p16:cyclinD-CDK4/6:RB pathway in melanoma and increasing evidence that alterations in this pathway are linked to melanomagenesis, make targeting the p16:cyclinD-CDK4/6:RB pathway in melanoma logical and highly attractive. The presence of elevated CDK4 activity appears to correlate with greater CDK4/6 inhibitor therapeutic activity, whereas the loss of RB1 has been linked to CDK inhibitor resistance. Other novel compounds targeting cell cycle control via reactivating wild-type p53 and checkpoint kinases are also currently under investigation in melanoma. SUMMARY: Cell cycle control is a promising target in the management of melanoma with early data reporting therapeutic benefit with cyclin-dependent kinase inhibitors, MDM2, and p53 reactivation compounds. Many of these drugs have entered phase I and II clinical trial development. Preliminary data from these studies are discussed in this review along with future treatment strategies for maximizing treatment outcomes in advanced melanoma. VIDEO ABSTRACT: Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.


Frazzi R.,Translational Research Laboratory | Tigano M.,Translational Research Laboratory
International Journal of Molecular Sciences | Year: 2014

Lymphoma and leukemia represent a serious threat to human health and life expectancy. Resveratrol is, among the natural-derived chemopreventive molecules, one of the most effective and better studied. In this paper the main mechanisms of cell death triggered by- or linked to- resveratrol are reviewed and discussed. The main focus is on lymphoma and leukemia experimental models where resveratrol has been tested and investigated at the cellular, molecular or physiological levels. The most relevant in vivo challenges involving resveratrol are also reported and analyzed in order to define the key features of this polyphenol and the potential for the treatment of hematologic tumors. © 2014 by the authors; licensee MDPI, Basel, Switzerland.


Harry S.R.,Vanderbilt University | Hicks D.J.,Translational Research Laboratory | Amiri K.I.,Translational Research Laboratory | Wright D.W.,Vanderbilt University
Chemical Communications | Year: 2010

A new intracellular mRNA imaging probe has been developed that incorporates thiol-terminated hairpin oligonucleotides covalently bound to the surface of citrate-capped gold nanoparticles. The hairpin DNA-coated gold nanoparticles (hAuNPs) positively identifies tyrosinase mRNA in cultured melanoma cells. © The Royal Society of Chemistry 2010.


Basak R.,Translational Research Laboratory | Nair N.K.,Translational Research Laboratory | Mittra I.,Translational Research Laboratory
Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis | Year: 2016

There is extensive literature to show that nucleic acids can be taken up by cells under experimental conditions and that foetal DNA can be detected in maternal tissues. The uptaken DNA can integrate into host cell genomes and can be transcribed and translated into proteins. They can also cause chromosomal damage and karyotype alterations. Cell-free nucleic acids (cfNAs)-based non-invasive DNA diagnostic techniques are being extensively researched in the field of cancer with the potential to advance new prognostic parameters and direct treatment decisions. However, whether extracellular cfNAs that are released into circulation from dying cells as a consequence of normal physiology have any functional significance has not been explored. A recent study has demonstrated that circulating cfNAs have the ability to cause DNA damage and mutagenesis by illegitimately integrating into healthy cells of the body, thereby acting as mobile genetic elements. Fluorescently-labeled cfNAs isolated from sera of cancer patients and healthy volunteers were shown to be readily taken up by host cells followed by activation of a DNA-damage-repair-response which led their large scale integration into the host cell genomes. The latter caused dsDNA breaks and apoptosis in cells in vitro and in those of vital organs when injected intravenously into mice. Cell-free chromatin was consistently more active than cell-free DNA, while cfNAs derived from cancer patients were significantly more active than those from healthy volunteers. This study suggests that circulating extracellular cfNAs act as physiological continuously arising DNA mutagens with implications for ageing, cancer and a host of other degenerative human pathologies. © 2016 Elsevier B.V.


Abedi-Ardekani B.,Translational Research Laboratory | Vielh P.,Translational Research Laboratory
Acta Cytologica | Year: 2014

Objective: The role of pathology has evolved from the first microscopic definitions of diseases by Virchow to the new concept of molecular cytopathology. The management of diseases is now a multidisciplinary approach with the translation of morphological, imagery and molecular findings to therapeutic protocols. Obtaining the most reliable diagnostic material is the essential part of the medical management of patients. Study Design: Here, we try to gain a concise insight into the available data regarding the role of cytology in the application of molecular techniques, focusing on cancer cytopathology. Results: Obtaining cytological material is now feasible by different methods, and in some cases it is the only possible approach to a lesion which is not easily accessible for tissue sampling. The methods of obtaining cytological material have evolved in recent years in parallel with rapid advances in high-throughput molecular techniques, opening new windows for the diagnosis and management of diseases. Conclusions: Different kinds of cytological material are reliable for the application of molecular techniques. Cytological material obtained in a liquid base has advantages such as the better preservation of cytomorphological features and the use of the remaining liquid for nucleic acid extraction even after long storage and the application of molecular methods. © 2014 S. Karger AG, Basel.

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