Multivariate Analysis of RNA Chemistry Marks Uncovers Epitranscriptomics-Based Biomarker Signature for Adult Diffuse Glioma Diagnostics.

One of the main challenges in cancer management relates to the discovery of reliable biomarkers, which could guide decision-making and predict treatment outcome. In particular, the rise and democratization of high-throughput molecular profiling technologies bolstered the discovery of "biomarker signatures" that could maximize the prediction performance. Such an approach was largely employed from diverse OMICs data (i.e., genomics, transcriptomics, proteomics, metabolomics) but not from epitranscriptomics, which encompasses more than 100 biochemical modifications driving the post-transcriptional fate of RNA: stability, splicing, storage, and translation. We and others have studied chemical marks in isolation and associated them with cancer evolution, adaptation, as well as the response to conventional therapy. In this study, we have designed a unique pipeline combining multiplex analysis of the epitranscriptomic landscape by high-performance liquid chromatography coupled to tandem mass spectrometry with statistical multivariate analysis and machine learning approaches in order to identify biomarker signatures that could guide precision medicine and improve disease diagnosis. We applied this approach to analyze a cohort of adult diffuse glioma patients and demonstrate the existence of an "epitranscriptomics-based signature" that permits glioma grades to be discriminated and predicted with unmet accuracy. This study demonstrates that epitranscriptomics (co)evolves along cancer progression and opens new prospects in the field of omics molecular profiling and personalized medicine.

[Being diagnosed with COPD: A qualitative study of real life experience]. / Annonce de la BPCO : étude qualitative sur le vécu des patients.

INTRODUCTION: This qualitative study aimed to explore the real life experience of the patients with chronic obstructive pulmonary disease (COPD) at the time they receive the diagnosis. METHODS: Data were collected using face to face interviews in general practice as well as focus groups in a pulmonary rehabilitation centre. RESULTS: Thirty-four patients participated in the study. Most of them were made aware of their disease by a pulmonologist during hospitalisation for an acute exacerbation. Several terms were used to name the disease including emphysema, asthma, chronic bronchitis and COPD (acronym often not explained). At the time of the announcement, patients expressed responses which included for some a sense of stupefaction associated with anxiety and for others guilt and an attitude of denial. If the need for smoking cessation was mentioned by doctors, a lack of information at the time of the announcement was general. The chronic and potentially serious aspects of COPD were not understood or rarely mentioned. CONCLUSION: The announcement of the disease did not always appear to have been of good quality. Ideally, the diagnosis of COPD should be conveyed to people after its identification in a dedicated consultation, combined with better information and a proposal for psychological support.

[Pulmonary intravascular talcosis: A case report]. / Talcose intravasculaire pulmonaire : à propos d'un cas.

INTRODUCTION: Pulmonary intravascular talcosis is a rare condition occurring in intravenous drug users injecting oral medications. Talc results in a foreign-body granulomatous reaction giving a radiological haematogenic miliary appearance mimicking miliary tuberculosis. Drug users represent a population at risk for both these conditions and their distinction may be challenging. CASE REPORT: We reported the case of a man, 33 year-old, intravenous drug addict, detected by the health services because he was the partner of a person who died of contagious and multi-resistant tuberculosis. Chest X-ray and CT scan showed a typical miliary appearance. Despite negative microbiology, clinical diagnosis of miliary tuberculosis was retained. Due to the lack of radiological improvement despite appropriate antibiotic treatment, re-evaluation and trans-bronchial biopsy were undertaken. The presence of granulomas centered by birefringent foreign bodies in polarized light led to a diagnosis of pulmonary intravascular talcosis. CONCLUSION: In the presence of pulmonary miliary in an intravenous drug addict, intravascular talcosis should be suspected.

DOCK4 promotes loss of proliferation in glioblastoma progenitor cells through nuclear beta-catenin accumulation and subsequent miR-302-367 cluster expression.

Glioblastomas (GBM) are lethal primitive brain tumours characterized by a strong intra-tumour heterogeneity. We observed in GBM tissues the coexistence of functionally divergent micro-territories either enriched in more differentiated and non-mitotic cells or in mitotic undifferentiated OLIG2 positive cells while sharing similar genomic abnormalities. Understanding the formation of such functionally divergent micro-territories in glioblastomas (GBM) is essential to comprehend GBM biogenesis, plasticity and to develop therapies. Here we report an unexpected anti-proliferative role of beta-catenin in non-mitotic differentiated GBM cells. By cell type specific stimulation of miR-302, which directly represses cyclin D1 and stemness features, beta-catenin is capable to change its known proliferative function. Nuclear beta-catenin accumulation in non-mitotic cells is due to a feed forward mechanism between DOCK4 and beta-catenin, allowed by increased GSK3-beta activity. DOCK4 over expression suppresses selfrenewal and tumorigenicity of GBM stem-like cells. Accordingly in the frame of GBM median of survival, increased level of DOCK4 predicts improved patient survival.

MET immunolabelling is a useful predictive tool for MET gene amplification in glioblastoma.

AIMS: MET gene amplification is rare in glioblastoma (GBM) and represents a potential target for MET inhibitors. An immunohistochemical screening may be useful to identify MET amplification. The aim of our study was to establish how MET immunolabelling correlates with MET amplification. METHODS: Three cohorts including 108 GBM (cohort 1, prospective), 104 GBM (cohort 2, retrospective) and 52 GBM (cohort 3, prospective) were investigated for MET expression by immunohistochemistry. MET amplification was assessed by comparative genomic hybridization on microarray (CGH-array) in all cohorts and by fluorescent in situ hybridization (FISH) in cohorts 2 and 3. Active form of MET was assessed using p-MET (Y1349) immunohistochemistry. RESULTS: Diffuse MET amplification detectable by CGH-array was associated with diffuse, strong MET immunolabelling (four cases in cohort 1 and one case in cohort 2). Focal MET amplification detectable only by FISH was observed in small foci of strongly immunopositive cells in two GBM (cohort 2). In both cohorts, MET amplification was never detected in GBM devoid of strongly immunopositive cells. MET overexpression, observed in 23% of unamplified GBM, was associated with a predominant weak-to-moderate staining intensity and with necrosis (P < 0.005). p-MET was detected in all MET-amplified GBM and in perinecrotic areas of nonamplified GBM. A strong MET immunostaining intensity, at least focal and distant from necrosis, showed 100% sensitivity and 84% specificity for predicting MET amplification in cohort 3. CONCLUSIONS: MET amplification is characterized by strongly immunopositive cells. Only GBM showing strong MET immunostaining is appropriate for the assessment of MET amplification.

[Evolution of pain during respiratory rehabilitation after major lung resection]. / Évolution de la douleur en soins de suites et rééducation après résection pulmonaire majeure.

INTRODUCTION: Lung resection for cancer is the cause of significant postoperative pain. The aim of this study was to determine whether pulmonary rehabilitation could induce a resurgence of pain. METHODS: In 2014 and 2015, pulmonary rehabilitation was offered to all patients referred to our institution after lung resection for cancer. Patients were assessed at entry and departure for nociceptive pain, neuropathic pain (DN4), for quality of life using questionnaire EORTC QlQ-C30 and for anxiety and depression (HAD questionnaire). Pain was studied before and after the sessions of cycloergometer, gym and massages. RESULTS: During the period, 99 patients were admitted to our institution following lung resection for cancer. Medians changed during pulmonary rehabilitation from 3 to 1 for nociceptive pain (p<0.001), 3 to 3 for DN4 (NS), 50 to 67 for the quality of life score (p<0.001), 7 to 5 for the anxiety (p<0.001) and 5 to 3 for depression (p<0.0001). Pain remained stable during the sessions of cycloergometer and gym, and decreased during massage. Patients undergoing thoracotomy or video-assisted thoracic surgery evolved identically. CONCLUSION: Postoperative pulmonary rehabilitation after lung resection for cancer was not harmful. It was associated with a decrease in nociceptive pain and was without effect on neuropathic pain.

Meningeal SWI/SNF related, matrix-associated, actin-dependent regulator of chromatin, subfamily B member 1 (SMARCB1)-deficient tumours: an emerging group of meningeal tumours.

AIMS: Bi-allelic inactivation of SWI/SNF related, matrix-associated, actin-dependent regulator of chromatin, subfamily B member 1 (SMARCB1; also known as INI1) and loss of immunohistochemical expression of SMARCB1 define the group of SMARCB1-deficient tumours. Initially highlighted in malignant rhabdoid tumours, this inactivation has subsequently been observed in several intra and extracranial tumours. To date, primary meningeal SMARCB1-deficient tumours have not been described. We report two cases of meningeal SMARCB1-deficient tumours occurring in adults. METHODS: We performed immunohistochemical analyses, comparative genomic hybridization, fluorescence in situ hybridization and targeted next-generation sequencing. RESULTS: The first meningeal tumour was a solitary mass, composed of rhabdoid, adenoid, chordoid and sarcomatoid areas. The second case presented as multiple, bilateral, supra and infratentorial nodules, was composed of fusiform and ovoid cells embedded in a myxoid stroma. Tumour cells were positive for epithelial membrane antigen (EMA), vimentin and CD34 and negative for SMARCB1 and meningothelial, melanocytic, muscular, glial markers. In the first case, one allele of SMARCB1 was completely deleted, whereas in the second case, loss of expression of SMARCB1 was observed as a consequence of a homozygous deletion of SMARCB1. CONCLUSIONS: The phenotype and genotype of these two cases did not fit diagnostically with entities already known to be SMARCB1-deficient tumours. As both tumours shared common features, they are regarded as belonging to an emerging group of primary meningeal SMARCB1-deficient tumours, not described to date. To facilitate the identification and characterization of these tumours, we recommend SMARCB1 immunohistochemistry for primary meningeal tumours which are difficult to classify, especially if immunopositive for EMA and CD34.

[Impact of pulmonary rehabilitation after lung resection for cancer on patients' level of anxiety and depression]. / Impact de la réhabilitation respiratoire sur l'anxiété et la dépression après chirurgie thoracique pour cancer.

INTRODUCTION: Pulmonary rehabilitation (PR) for patients undergoing lung resection for cancer remains controversial. We studied the effects of PR, its impact on quality of life and the level of anxiety and depression. METHODS: In 2011 and 2012, PR was offered to all patients referred to our institution after lung resection for cancer. Patients were evaluated between admission and discharge by a 6 minutes walking test (6MWD), a Visual Analogue Pain Intensity Scale, a quality of life questionnaire (EORTC QLQ C30) and by the Hospital Anxiety and Depression Scale (HAD). The same questionnaires were mailed 6 months after completing PR. RESULTS: Between early 2011 and late 2012, 133 patients were admitted to our institution following lung resection for cancer. Of these, 59 (44%) patients completed PR and returned their questionnaires 6 months after discharge. During PR of these 59 patients, the mean quality of life score increased from 56.3 to 65.9 (P<0.05), the median anxiety score decreased from 5.5 to 4 (P<0.05) and that of depression from 3 to 2 (P<0.05). At 6 months post-discharge, the mean quality of life score remained stable at 66.3 (P=0.8), the median anxiety score reverted to 6 (P<0.05) and the median depression score reverted to 4.5 (P<0.05). CONCLUSION: This observational study during PR, showed that quality of life and the levels of anxiety and depression were improved at the end of the course. After returning home, the average quality of life score remained stable but the level of anxiety and depression increased.

[Histological and molecular analysis of brain metastases]. / Analyse histologique et moléculaire des métastases cérébrales.

The first step in the diagnosis of a metastatic brain lesion is to exclude a primary central nervous sytem tumour, followed by verification or identification of the primary tumor site, in order to guide the clinician to specific therapy. In addition to morphological features, ancillary immunohistochemical study is most effective for the evaluation of a metastatic neoplasm of unknown primary. Although the main principles are same, there are slight variations in the approach to the secondary lesion in the central nervous system versus other regions. Indeed, immunohistochemical approach focuses on the most common tumor types associated with secondary brain colonization: lung cancer, breast cancer and melanoma. Several studies have reported that targeted therapies are capable of reducing brain metastases in melanoma or non-small cell lung cancer, sometimes with a high dramatic response. These results have clearly impacted routine neuropathological practice. It is likely that molecular subtyping of central nervous system metastases will play an increasing role in the future. In accordance with the recommendations of Inca (French national cancer institute), the pathologist develops appropriate strategies for molecular and immunohistochemical analysis, in order to provide results as soon as possible. This article summarizes the diagnosic approach to brain metastases, with a focus on the recent emergence of targeted therapies.

[Pleuro-pericarditis developed under a leflunomide therapy]. / Pleuro-péricardite développée au décours d'un traitement par léflunomide.

Leflunomide is an immunosuppressant drug used in rheumatoid arthritis and psoriatic arthritis. This product may cause rare but serious interstitial lung disease that appear at the beginning of treatment. This is why leflunomide should be prescribed and monitored in hospital. We present the case of a 71 years old woman who presented a pleuro-pericarditis with an increase of CA 125 during a treatment with leflunomide. This is the second case reported in the literature. The outcome was favorable after discontinuation of leflunomide.

Fibronectin expression in glioblastomas promotes cell cohesion, collective invasion of basement membrane in vitro and orthotopic tumor growth in mice.

Glioblastoma multiforme (GBM) are highly invasive and angiogenic malignancies with a median survival time from diagnosis of <15 months. Previous work has revealed robust overexpression of fibronectin (FN) mRNA in GBM, although immunohistochemical staining of FN in these tumors is typically associated with the angiogenic vasculature. Here we sought to examine the expression of tumor cell FN and address its possible involvement in the invasive phenotype of GBM. We found that FN was expressed and assembled into fibrillar arrays in human tumors and in established GBM lines. Cultured cells spontaneously formed dense cellular networks and spheroid-like domes. Depletion of FN by targeted-short hairpin RNA expression disrupted matrix assembly and multicellular network organization by exerting profound effects on cell adhesion and motility. Although FN depletion enhanced persistent directional migration of single cells, it compromised collective invasion of spheroids through a laminin-rich matrix and sensitized cells to ionizing radiation. In orthotopic grafts, FN depletion significantly reduced tumor growth and angiogenesis. Together our results show that FN produced by the tumor cells has a role in GBM pathophysiology and they provide insights into the implications that targeting FN interactions may have for combating this dreaded disease.

[Vaccination coverage against influenza and pneumococcus for patients admitted to a pulmonary care service]. / Couverture vaccinale grippale et pneumococcique dans un SSR de pneumologie.

INTRODUCTION: The aim of this work was to study the vaccination coverage against influenza and pneumococcus in patients admitted to a pulmonary care department. METHODS: Between September 2010 and August 2011, we conducted a prospective observational study of patients admitted to our institution. A history of vaccination against influenza and pneumococcus was sought systematically using a standardized questionnaire. RESULTS: Of 476 patients admitted to the pulmonary service at our institution, 246 had COPD, 175 had undergone thoracic surgery and 55 had a chronic respiratory disease other than COPD. The average age of our patients was 67 years (60-76) and the sex-ratio was 1.6 (291M and 185 F). Amongst the target population for influenza vaccination, coverage was 73%. The main reason for patients not to have been vaccinated against influenza was patient refusal or intolerance (59%). Amongst the target population for antipneumococcal vaccination, the coverage was 53%. The main reason for the lack of vaccination against pneumococcus was that no offer of vaccination had been made by a physician (92.5%). CONCLUSION: Vaccination coverage was low, in particular for pneumococcus. Pulmonary departments are strategic sites which could take action to systematically improve vaccination coverage.

[Malignant pleural mesothelioma after radiation treatment for Hodgkin lymphoma]. / Mésothéliome pleural malin après irradiation pour maladie de Hodgkin.

Malignant mesothelioma is a relatively uncommon malignancy. Although the pathogenesis is primarily related to asbestos, the role of ionizing radiation is more controversial. We report the case of a 41-year-old male who developed pleural mesothelioma. He had both, a prior short asbestos exposure and a thoracic radiotherapy for Hodgkin's disease 26years before. The evidence for radiotherapy as cause for mesothelioma is expanding and the diagnosis of mesothelioma in patients who had previous irradiation should be kept in mind.

[Pulmonary rehabilitation after lung resection for tumor - a feasibility study]. / Intérêt de la réhabilitation respiratoire après résection pulmonaire pour tumeur.

INTRODUCTION: To investigate the safety, feasibility and effectiveness of an inpatient pulmonary rehabilitation program (i-PR) after lung resection (LR) for cancer. METHODS: Between January 2007 and December 2009, we conducted a prospective observational study on patients admitted in our institution. An i-PR was offered to all patients. They completed respiratory function tests and a quality of life (QoL) questionnaire at the start and after completing the i-PR. RESULTS: During the study, 154 out of 175 patients who underwent LR and who were admitted in our center followed an i-PR. The remaining 21 patients were excluded because of emergency re-hospitalisation (10 patients), anticipated departure (six patients) or refusal to participate (five patients). Most functional parameters in the 154 treated patients improved between the beginning and the end of their stay: FVC (69.9% versus 79.6%; P<0.0001); FEV(1) (61.2% versus 69.9%; P<0.0001); timed walk-6MWT (356 m versus 444 m; P<0.0001) and constant work cycle ergometry test (281 s versus 683 s; P<0.0001). Also, the EORTC QLQ-C30 and the EORTC QLQ-LC13 improved during the stay, especially global health status (50.5 versus 64.5; P<0.0001). CONCLUSION: Postoperative PR is safe and could positively impact on functional status and QoL among this population.