Diagnostic de la maladie coronarienne stable par FFR non invasive, mythe ou réalité [Diagnosis of stable coronary artery disease with non-invasive FFR: myth or reality?].

Decision to revascularize a patient with stable coronary artery disease should be based on the detection of myocardial ischemia. If this decision can be straightforward with significant stenosis or in non-significant stenosis, the decision with intermediate stenosis is far more difficult and require invasive measures of functional impact of coronary stenosis on maximal blood (flow fractional flow reserve=FFR). A recent computer based method has been developed and is able to measure FFR with data acquired during a standard coronary CT-scan (FFRcT). Two recent clinical studies (DeFACTO and DISCOVER-FLOW) show that diagnostic performance of FFRcT was associated with improved diagnostic accuracy versus standard coronary CT-scan for the detection of myocardial ischemia although FFRcT need further development.

Effective Treatment of Invasive Aspergillus fumigatus Infection Using Combinations of Topical and Systemic Antifungals in a Severely Burned Patient.

The authors describe an invasive Aspergillus fumigatus deep-burn wound infection in a severely burned patient that was successfully treated with a combination of topical terbinafine and systemic voriconazole antifungal therapy. To our knowledge, this is the first case report describing the effective control of an invasive deep-burn wound infection using this combination.

Neutrophil-derived APRIL concentrated in tumor lesions by proteoglycans correlates with human B-cell lymphoma aggressiveness.

A PRoliferation-Inducing TNF Ligand (APRIL) costimulates B-cell activation. When overexpressed in mice, APRIL induces B-cell neoplasia, reminiscent of human B-cell chronic lymphoid leukemia (B-CLL). We analyzed APRIL expression in situ in human non-Hodgkin lymphomas. APRIL up-regulation was only observed in high-grade B-cell lymphomas, diffuse large B-cell lymphoma (DLBCL), and Burkitt lymphoma (BL). Up-regulation was seen in 46% and 20% of DLBCL and BL, respectively. In DLBCL, neutrophils, constitutively producing APRIL and infiltrating the tumor tissue, were the main cellular source of APRIL. Rare DLBCL cases showed a predominance of histiocytes or mesenchymal cells as APRIL source. APRIL secreted by neutrophils accumulated on tumor cells via proteoglycan binding. In addition to proteoglycans, DLBCL tumor cells expressed the APRIL signaling receptor, TACI and/or BCMA, indicating that these tumor cells are fully equipped to respond to APRIL. A retrospective clinical analysis revealed a significant correlation between high expression of APRIL in tumor lesions and decreased overall patient survival rate. Hence, APRIL produced by inflammatory cells infiltrating lymphoma lesions may increase tumor aggressiveness and affect disease outcome.

Striking immunodominance hierarchy of naturally occurring CD8+ and CD4+ T cell responses to tumor antigen NY-ESO-1.

Immunodominance has been well-demonstrated in many antiviral and antibacterial systems, but much less so in the setting of immune responses against cancer. Tumor Ag-specific CD8+ T cells keep cancer cells in check via immunosurveillance and shape tumor development through immunoediting. Because most tumor Ags are self Ags, the breadth and depth of antitumor immune responses have not been well-appreciated. To design and develop antitumor vaccines, it is important to understand the immunodominance hierarchy and its underlying mechanisms, and to identify the most immunodominant tumor Ag-specific T cells. We have comprehensively analyzed spontaneous cellular immune responses of one individual and show that multiple tumor Ags are targeted by the patient's immune system, especially the "cancer-testis" tumor Ag NY-ESO-1. The pattern of anti-NY-ESO-1 T cell responses in this patient closely resembles the classical broad yet hierarchical antiviral immunity and was confirmed in a second subject.

Application of the 2008 definitions for invasive fungal diseases to the trial comparing voriconazole versus amphotericin B for therapy of invasive aspergillosis: a collaborative study of the Mycoses Study Group (MSG 05) and the European Organization for Research and Treatment of Cancer Infectious Diseases Group.

BACKGROUND: Strict definition of invasive aspergillosis (IA) cases is required to allow precise conclusions about the efficacy of antifungal therapy. The Global Comparative Aspergillus Study (GCAS) compared voriconazole to amphotericin B (AmB) deoxycholate for the primary therapy of IA. Because predefined definitions used for this trial were substantially different from the consensus definitions proposed by the European Organization for Research and Treatment of Cancer/Mycoses Study Group in 2008, we recategorized the 379 episodes of the GCAS according to the later definitions. METHODS: The objectives were to assess the impact of the current definitions on the classification of the episodes and to provide comparative efficacy for probable/proven and possible IA in patients treated with either voriconazole or AmB. In addition to original data, we integrated the results of baseline galactomannan serum levels obtained from 249 (65.7%) frozen samples. The original response assessment was accepted unchanged. RESULTS: Recategorization allowed 59 proven, 178 probable, and 106 possible IA cases to be identified. A higher favorable 12-week response rate was obtained with voriconazole (54.7%) than with AmB (29.9%) (P < .0001). Survival was higher for voriconazole for mycologically documented (probable/proven) IA (70.2%) than with AmB (54.9%) (P = .010). Higher response rates were obtained in possible IA treated with voriconazole vs AmB with the same magnitude of difference (26.2%; 95% confidence interval [CI], 7.2%-45.3%) as in mycologically documented episodes (24.3%; 95% CI, 11.9%-36.7%), suggesting that possible cases are true IA. CONCLUSIONS: Recategorization resulted in a better identification of the episodes and confirmed the higher efficacy of voriconazole over AmB deoxycholate in mycologically documented IA.

Mouse mammary tumor virus : a model system for regulation of gene expression

Mouse mammary tumor virus (MMTV) kommt prizipiell in zwei Formen vor. Erstens als integierte virale DNA (endogen vererbt), die in allen Zellen der Maus enthalten ist und zweitens als infektiöse Form, bei der sich die DNA nur im Kern von Brustdrüsenzellen integriert. Die erste Form verhält sich wie ein stummes Gen während die zweite Form aktiv ist, durch Glukocorticoide stimuliert wird und zum Mamma-Karzinom führt. Wir haben beide Typen von viralen Genen molekular geklont und durch Transfektion in verschiedene Zellen in Gewebekultur eingeführt. Wir konnten zeigen, dass sowohl die endogene DNA, wie dir infektiöse DNA in transfektieren Zellen aktiv ist und dass die Expression beider Gene durch Glukocorticoide stimuliert wird. Wir konnten die DNA Squenzen, die für dir Homonstimulierung nötig sind, in einem kleinen Fragment der viralen DNA lokalisieren. Bei der Sequenzanalyse dieses DNA-Stückes haben wir ein neues virales Gen entdeckt, das dir Information für ein Protein von ca. 40000 Moleklargewicht enthählt. Mit Hilfe eines Antikörpers suchen wir in verschiedenen Brustdrüsenzellen und Tumoren nach diesem Proetin, dessen Funktion noch nicht bekannt ist.

IRM cardiaque: imagerie de référence dans le diagnostic de la myocardite aiguë [Cardiac magnetic resonance in acute myocarditis: a new non-invasive diagnostic gold standard?].

Acute myocarditis was until recently one of the most difficult diagnoses in cardiology. The spectrum of signs and symptoms is very wide, the usual non-invasive tests lack specificity and the myocardial biopsy is only performed in a minority of cases to confirm the diagnosis. Due to its unique ability to directly image myocardial necrosis, fibrosis and oedema, cardiac magnetic resonance (CMR) is now considered the primary tool for noninvasive assessment of patients with suspected myocarditis. CMR is also useful for monitoring disease activity under treatment. Myocarditis has been associated with the development of dilated cardiomyopathy; CMR could play a role in the follow-up of such cases to detect the progression toward a dilatative phenotype. Precise mapping of myocardial lesions with cardiac MRI is invaluable to guide myocardial biopsy and increase its diagnostic yield by improving sensitivity.

Immunogenetics of invasive aspergillosis.

Invasive aspergillosis is one of the most important infections in hematopoietic stem cell transplant recipients, with an incidence rate of 5-15% and an associated mortality of 30-60%. It remains unclear why certain patients develop invasive aspergillosis while others, undergoing identical transplant regimen and similar post transplant immunosuppression, do not. Over the last decade, pattern recognition receptors such as Toll-like receptors (TLRs) and the C-type lectin receptors (CLRs) have emerged as critical components of the innate immune system. By detecting specific molecular patterns from invading microbes and initiating inflammatory and subsequent adaptive immune responses, pattern recognition receptors are strategically located at the molecular interface of hosts and pathogens. Polymorphisms in pattern recognition receptors and downstream signaling molecules have been associated with increased or decreased susceptibility to infections, suggesting that their detection may have an increasing impact on the treatment and prevention of infectious diseases in the coming years. Infectious risk stratification may be particularly relevant for patients with hematologic malignancies, because of the high prevalence and severity of infections in this population. This review summarizes the innate immune mechanisms involved in Aspergillus fumigatus detection and the role of host genetic polymorphisms in susceptibility to invasive aspergillosis.

Melanoma cell expression of Fas(Apo-1/CD95) ligand: implications for tumor immune escape.

Malignant melanoma accounts for most of the increasing mortality from skin cancer. Melanoma cells were found to express Fas (also called Apo-1 or CD95) ligand (FasL). In metastatic lesions, Fas-expressing T cell infiltrates were proximal to FasL+ tumor cells. In vitro, apoptosis of Fas-sensitive target cells occurred upon incubation with melanoma tumor cells; and in vivo, injection of FasL+ mouse melanoma cells in mice led to rapid tumor formation. In contrast, tumorigenesis was delayed in Fas-deficient lpr mutant mice in which immune effector cells cannot be killed by FasL. Thus, FasL may contribute to the immune privilege of tumors.

Assessment of vaccine-induced CD4 T cell responses to the 119-143 immunodominant region of the tumor-specific antigen NY-ESO-1 using DRB1*0101 tetramers.

Abstract: Purpose: NY-ESO-1 (ESO), a tumor-specific antigen of the cancer/testis group, is presently viewed as an important model antigen for the development of generic anticancer vaccines. The ESO119-143 region is immunodominant following immunization with a recombinant ESO vaccine. In this study, we generated DRB1*0101/ESO119-143 tetramers and used them to assess CD4 T-cell responses in vaccinated patients expressing DRB1*0101 (DR1). Experimental Design: We generated tetramers of DRB1*0101 incorporating peptide ESO119-143 using a previously described strategy. We assessed ESO119-143-specific CD4 T cells in peptide-stimulated post-vaccine cultures using the tetramers. We isolated DR1/ESO119-143 tetramer(+) cells by cell sorting and characterized them functionally. We assessed vaccine-induced CD4(+) DR1/ESO119-143 tetramer(+) T cells ex vivo and characterized them phenotypically. Results: Staining of cultures from vaccinated patients with DR1/ESO119-143 tetramers identified vaccine-induced CD4 T cells. Tetramer(+) cells isolated by cell sorting were of T(H)1 type and efficiently recognized full-length ESO. We identified ESO123-137 as the minimal optimal epitope recognized by DR1-restricted ESO-specific CD4 T cells. By assessing DR1/ESO119-143 tetramer(+) cells using T cell receptor (TCR) beta chain variable region (V beta)-specific antibodies, we identified several frequently used V beta. Finally, direct ex vivo staining of patients' CD4 T cells with tetramers allowed the direct quantification and phenotyping of vaccine-induced ESO-specific CD4 T cells. Conclusions: The development of DR1/ESO119-143 tetramers, allowing the direct visualization, isolation, and characterization of ESO-specific CD4 T cells, will be instrumental for the evaluation of spontaneous and vaccine-induced immune responses to this important tumor antigen in DR1-expressing patients

Self-paced Movement Intention Detection from Human Brain Signals: Invasive and Non-invasive EEG

Neural signatures of humans' movement intention can be exploited by future neuroprosthesis. We propose a method for detecting self-paced upper limb movement intention from brain signals acquired with both invasive and noninvasive methods. In the first study with scalp electroencephalograph (EEG) signals from healthy controls, we report single trial detection of movement intention using movement related potentials (MRPs) in a frequency range between 0.1 to 1 Hz. Movement intention can be detected above chance level (p<0.05) on average 460 ms before the movement onset with low detection rate during the on-movement intention period. Using intracranial EEG (iEEG) from one epileptic subject, we detect movement intention as early as 1500 ms before movement onset with accuracy above 90% using electrodes implanted in the bilateral supplementary motor area (SMA). The coherent results obtained with non-invasive and invasive method and its generalization capabilities across different days of recording, strengthened the theory that self-paced movement intention can be detected before movement initiation for the advancement in robot-assisted neurorehabilitation.

Imaging spectrum of the solid pseudopapillary tumor of the pancreas : P42

Solid pseudopapillary tumor of the pancreas (SPPP) is a very rare pancreatic tumor with low malignancy potential, occurring mostly in adolescent females and often not considered in the differential diagnosis of pancreas tumors in children. Patients with SPPP usually present with non specific abdominal symptoms and normal clinical laboratory tests. Between 2005 and 2007, 3 cases of SPPP were evaluated in our institution. The purpose of this communication is to describe the typical imaging findings of the SPPP tumor at US, CT and MRI and to correlate the images with the macro- and microscopic features of the lesion.

A Novel HLA-B18 Restricted CD8+ T Cell Epitope Is Efficiently Cross-Presented by Dendritic Cells from Soluble Tumor Antigen.

NY-ESO-1 has been a major target of many immunotherapy trials because it is expressed by various cancers and is highly immunogenic. In this study, we have identified a novel HLA-B*1801-restricted CD8(+) T cell epitope, NY-ESO-1(88-96) (LEFYLAMPF) and compared its direct- and cross-presentation to that of the reported NY-ESO-1(157-165) epitope restricted to HLA-A*0201. Although both epitopes were readily cross-presented by DCs exposed to various forms of full-length NY-ESO-1 antigen, remarkably NY-ESO-1(88-96) is much more efficiently cross-presented from the soluble form, than NY-ESO-1(157-165). On the other hand, NY-ESO-1(157-165) is efficiently presented by NY-ESO-1-expressing tumor cells and its presentation was not enhanced by IFN-γ treatment, which induced immunoproteasome as demonstrated by Western blots and functionally a decreased presentation of Melan A(26-35); whereas NY-ESO-1(88-96) was very inefficiently presented by the same tumor cell lines, except for one that expressed high level of immunoproteasome. It was only presented when the tumor cells were first IFN-γ treated, followed by infection with recombinant vaccinia virus encoding NY-ESO-1, which dramatically increased NY-ESO-1 expression. These data indicate that the presentation of NY-ESO-1(88-96) is immunoproteasome dependent. Furthermore, a survey was conducted on multiple samples collected from HLA-B18(+) melanoma patients. Surprisingly, all the detectable responses to NY-ESO-1(88-96) from patients, including those who received NY-ESO-1 ISCOMATRIX? vaccine were induced spontaneously. Taken together, these results imply that some epitopes can be inefficiently presented by tumor cells although the corresponding CD8(+) T cell responses are efficiently primed in vivo by DCs cross-presenting these epitopes. The potential implications for cancer vaccine strategies are further discussed.

Deciphering and reversing tumor immune suppression.

Generating an anti-tumor immune response is a multi-step process that is executed by effector T cells that can recognize and kill tumor targets. However, tumors employ multiple strategies to attenuate the effectiveness of T-cell-mediated attack. They achieve this by interfering with nearly every step required for effective immunity, from deregulation of antigen-presenting cells to establishment of a physical barrier at the vasculature that prevents homing of effector tumor-rejecting cells and the suppression of effector lymphocytes through the recruitment and activation of immunosuppressive cells such as myeloid-derived suppressor cells, tolerogenic monocytes, and T regulatory cells. Here, we review the ways in which tumors exert immune suppression and highlight the new therapies that seek to reverse this phenomenon and promote anti-tumor immunity. Understanding anti-tumor immunity, and how it becomes disabled by tumors, will ultimately lead to improved immune therapies and prolonged survival of patients.