Human herpesvirus type 8-associated primary lymphomatous effusion in an elderly HIV-negative patient: clinical and molecular characterization

Primary lymphomatous effusions are defined as lymphomas presenting in the serous body cavities in the absence of clinically identifiable tumor masses. Recently, a peculiar type of primary lymphomatous effusion associated with tumor clone infection by human herpesvirus type 8 (HHV-8) and preferentially arising in HIV-positive patients has been described and termed as primary effusion lymphoma (PEL). This report describes a case of PEL which has developed in a HIV-negative, 92-year-old man with longstanding Mediterranean Kaposi's sarcoma, a disease also associated with HHV-8 infection. The patient presented with pleural and ascitic effusions in the absence of solid masses within the lungs, mediastinum, thoracic wall or abdominal cavity. The effusions consisted of malignant lymphocytes with morphologic features bridging immunoblastic and anaplastic cells. Immunophenotypic studies revealed that the lymphoma population expressed an antigenic profile consistent with PEL, i.e. the absence of common B- and T-cell markers (non-B, non-T phenotype) coupled to CD138 positivity. Molecular analysis demonstrated infection of the tumor clone by HHV-8 as well as monoclonally rearranged immunoglobulin genes, consistent with a B-cell histogenesis of the lymphoma. In addition, this PEL case harbored PAX-5 gene mutations, which have been recently demonstrated as a key feature of the proto-oncogene hypermutation process involved in the pathogenesis of some lymphoma types. Following two courses of etoposide and prednisone, a partial remission was achieved. The patient died of liver failure 3 months after the diagnosis of PEL. Overall, this case report illustrates the need for an integrated diagnostic approach based on clinical features, morphology, immunophenotype, and molecular genetics to primary lymphomatous effusions.     

The use of dendritic cells in cancer immunotherapy

Cancer immunotherapy aims at eliciting an immune response directed against tumor antigens to help fight off residual tumor cells and thereby improve survival and quality of life of cancer patients. Different immunotherapeutic approaches share the use of dendritic cells (DCs) to present tumor-associated antigens to T-lymphocytes. Ex vivo generated DCs can be loaded with antigens and re-infused to the patients, or they can be used for ex vivo expansion of antitumor lymphocytes. Alternatively, methods exist to target antigens to DCs in vivo without need for ex vivo cell manipulations. The clinical studies have shown that DC administration to patients is safe and induces antigen-specific immunity. However, it seldom elicits objective clinical responses in patients with advanced-stage malignancies. Novel insights into DC and lymphocyte regulation are expected to lead to more effective vaccines in the near future. Meanwhile, efforts are directed at identifying the most appropriate clinical targets for active specific immunotherapies. Data suggests that vaccinations may indeed be beneficial when given in the adjuvant setting rather than to treat metastatic cancers. These issues are discussed here together with an overview of the DC-based antitumor immunotherapy studies.     

Antibacterial‐nanocomposite bone filler based on silver nanoparticles and polysaccharides

Injectable bone fillers represent an attractive strategy for the treatment of bone defects. These injectable materials should be biocompatible, capable of supporting cell growth and possibly able to exert antibacterial effects. In this work, nanocomposite microbeads based on alginate, chitlac, hydroxyapatite and silver nanoparticles were prepared and characterized. The dried microbeads displayed a rapid swelling in contact with simulated body fluid and maintained their integrity for more than 30 days. The evaluation of silver leakage from the microbeads showed that the antibacterial metal is slowly released in saline solution, with less than 6% of silver released after 1 week. Antibacterial tests proved that the microbeads displayed bactericidal effects toward Staphylococcus aureus, Pseudomonas aeruginosa and Staphylococcus epidermidis, and were also able to damage pre‐formed bacterial biofilms. On the other hand, the microbeads did not exert any cytotoxic effect towards osteoblast‐like cells. After characterization of the microbeads bioactivity, a possible means to embed them in a fluid medium was explored in order to obtain an injectable paste. Upon suspension of the particles in alginate solution or alginate/hyaluronic acid mixtures, a homogenous and time‐stable paste was obtained. Mechanical tests enabled to quantify the extrusion forces from surgical syringes, pointing out the proper injectability of the material. This novel antibacterial bone filler appears as a promising material for the treatment of bone defects, in particular when possible infections could compromise the bone‐healing process. Copyright © 2016 John Wiley & Sons, Ltd.     

Nonunion fracture healing: Evaluation of effectiveness of demineralized bone matrix and mesenchymal stem cells in a novel sheep bone nonunion model

Nonunion treatment has a high rate of success, although recalcitrant nonunion may determine the need for amputation. Therefore, new treatment options are continuously investigated in order to further reduce the risk of nonunion recurrence. This study aimed to (a) develop a new large animal model for bone atrophic nonunion and (b) compare the efficacy of demineralized bone matrix (DBM) and DBM in combination with mesenchymal stem cells (MSC) in the new nonunion model. The new model consists of a noncritical, full‐thickness segmental defect created in the sheep tibia, stabilized by an intramedullary nail, and involves the creation of a locally impaired blood supply achieved through periosteum excision and electrocauterization of the stump ends. Six weeks after defect creation, lack of hard tissue callus and established nonunion was observed in all operated tibiae both by radiographic and clinical evaluation. Nonunion was treated with allogeneic DBM or autologous MSC cultivated on DBM particles (DBM + MSC) for 1 day before implantation. Twelve weeks after treatment, radiographic, microtomographic, histologic, and histomorphometric analysis showed the formation of bone callus in DBM group, whereas the fracture healing appeared at an early stage in DBM + MSC group. Torsional strength and stiffness of the DBM group appeared higher than those of DBM + MSC group, although the differences were not statistically significant. In conclusion, a new sheep bone nonunion model resembling the complexity of the clinical condition was developed. DBM is an effective option for nonunion treatment, whereas MSC do not improve the healing process when cultivated on DBM particles before implantation.     

Multidimensional fetal flow imaging with cardiovascular magnetic resonance: a feasibility study

Purpose

To image multidimensional flow in fetuses using golden-angle radial phase contrast cardiovascular magnetic resonance (PC-CMR) with motion correction and retrospective gating.

Methods

A novel PC-CMR method was developed using an ungated golden-angle radial acquisition with continuously incremented velocity encoding. Healthy subjects (n?=?5, 27?±?3 years, males) and pregnant females (n?=?5, 34?±?2 weeks gestation) were imaged at 3 T using the proposed sequence. Real-time reconstructions were first performed for retrospective motion correction and cardiac gating (using metric optimized gating, MOG). CINE reconstructions of multidimensional flow were then performed using the corrected and gated data.

Results

In adults, flows obtained using the proposed method agreed strongly with those obtained using a conventionally gated Cartesian acquisition. Across the five adults, bias and limits of agreement were ??1.0 cm/s and [??5.1, 3.2] cm/s for mean velocities and???1.1 cm/s and [??6.5, 4.3] cm/s for peak velocities. Temporal correlation between corresponding waveforms was also high (R~?0.98). Calculated timing errors between MOG and pulse-gating RR intervals were low (~?20 ms). First insights into multidimensional fetal blood flows were achieved. Inter-subject consistency in fetal descending aortic flows (n =?3) was strong with an average velocity of 27.1?±?0.4 cm/s, peak systolic velocity of 70.0?±?1.8 cm/s and an intra-class correlation coefficient of 0.95 between the velocity waveforms. In one fetal case, high flow waveform reproducibility was demonstrated in the ascending aorta (R =?0.97) and main pulmonary artery (R =?0.99).

Conclusion

Multidimensional PC-CMR of fetal flow was developed and validated, incorporating retrospective motion compensation and cardiac gating. Using this method, the first quantification and visualization of multidimensional fetal blood flow was achieved using CMR.

     

Canakinumab for secondary prevention of atherosclerotic disease

Introduction: The widespread prevalence of cardiovascular disease (CVD) and its impact on morbidity and mortality requires effective secondary prevention measures. For years, inflammation has been advocated as a key mediator of atherosclerosis and its associated complications. Drugs for secondary prevention of CVD events include interventions aimed at risk factors control and antithrombotic management, but there is no drug currently recommended that specifically targets inflammation. Recently, the inflammatory hypothesis of atherosclerosis has been confirmed by a randomized clinical trial of canakinumab, a monoclonal antibody that blocks an inflammatory pathway mediated by interleukin-1β.

Areas covered: This article reviews the pharmacology of canakinumab, its current clinical development status and upcoming regulatory perspectives.

Expert opinion: In the CANTOS trial, canakinumab 150 mg met the pre-specified criteria of statistical significance, showing a reduction in combined cardiovascular events, myocardial infarction, re-hospitalization due to urgent revascularization and any coronary revascularization, but no impact on all-cause or cardiovascular death. There were more death attributed to sepsis or infection with canakinumab than placebo, but fewer reports of arthritis, gout, osteaoarthritis and cancer-related death. Because interleukin-1β is only one of the potential pro-inflammatory pathways that may serve as a target for atherothrombotic protection, other anti-inflammatory drugs may be the object of future investigations. If approved, the initial penetration of canakinumab will face hurdles in view of cost issues, but costs are likely to decrease if the drug loses its present status of orphan drug with the new indication.     

Triple Vectors Expand AAV Transfer Capacity in the Retina

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Assessment of Remote Myocardium Heterogeneity in Patients with Ventricular Tachycardia Using Texture Analysis of Late Iodine Enhancement (LIE) Cardiac Computed Tomography (cCT) Images

Purpose

Diffuse remodeling of myocardial extra-cellular matrix is largely responsible for left ventricle (LV) dysfunction and arrhythmias. Our hypothesis is that the texture analysis of late iodine enhancement (LIE) cardiac computed tomography (cCT) images may improve characterization of the diffuse extra-cellular matrix changes. Our aim was to extract volumetric extracellular volume (ECV) and LIE texture features of non-scarred (remote) myocardium from cCT of patients with recurrent ventricular tachycardia (rVT), and to compare these radiomic features with LV-function, LV-remodeling, and underlying cardiac disease.

Procedures

Forty-eight patients suffering from rVT were prospectively enrolled: 5/48 with idiopathic VT (IVT), 23/48 with post-ischemic dilated cardiomyopathy (ICM), 9/48 with idiopathic dilated cardiomyopathy (IDCM), and 11/48 with scars from a previous healed myocarditis (MYO). All patients underwent echocardiography to assess LV systolic and diastolic function and cCT with pre-contrast, angiographic, and LIE scan to obtain end-diastolic volume (EDV), ECV, and first-order texture parameters of Hounsfield Unit (HU) of remote myocardium in LIE [energy, entropy, HU-mean, HU-median, standard deviation (SD), and mean absolute deviation (MAD)].

Results

Energy, HU mean, and HU median by cCT texture analysis correlated with ECV (rho?=?0.5650, rho?=?0.5741, rho?=?0.5068; p?<?0.0005). cCT-derived ECV, HU-mean, HU-median, SD, and MAD correlated directly to EDV by cCT and inversely to ejection fraction by echocardiography (p?<?0.05). SD and MAD correlated with diastolic function by echocardiography (rho?=?0.3837, p?=?0.0071; rho?=?0.3330, p?=?0.0208). MYO and IVT patients were characterized by significantly lower values of SD and MAD when compared with ICM and IDCM patients, independently of LV-volume systolic and diastolic function.

Conclusions

Texture analysis of LIE may expand cCT capability of myocardial characterization. Myocardial heterogeneity (SD and MAD) was associated with LV dilatation, systolic and diastolic function, and is able to potentially identify the different patterns of structural remodeling characterizing patients with rVT of different etiology.

     

Combining electromagnetic navigation and 3‐D mapping to reduce fluoroscopy time and achieve optimal CRT response

Implantation of cardiac resynchronization therapy (CRT) devices can be challenging, time consuming, and associated with high‐dose x‐ray exposure. We present the technique in which an electromagnetic navigation system (MediGuideTM, St. Jude Medical) and an electroanatomical three‐dimensional mapping system (EnSite NavX, St Jude Medical) are usefully combined for implanting implantable cardioverter defibrillator CRT devices with strong reduction of x‐ray exposure, and for targeting the most delayed regions in the activation maps avoiding scars for optimal CRT response.     

Kinematic Analysis of a Drinking Task in Chronic Hemiparetic Patients Using Features Analysis and Statistical Parametric Mapping

Objective

To compare sitting posture and movement strategies between chronic hemiparetic and healthy subjects while performing a drinking task, using statistical parametric mapping (SPM) and feature analysis.