European Myeloma Network recommendations on the evaluation and treatment of newly diagnosed patients with multiple myeloma

Multiple myeloma management has undergone profound changes in the past thanks to advances in our understanding of the disease biology and improvements in treatment and supportive care approaches. This article presents recommendations of the European Myeloma Network for newly diagnosed patients based on the GRADE system for level of evidence. All patients with symptomatic disease should undergo risk stratification to classify patients for International Staging System stage (level of evidence: 1A) and for cytogenetically defined high- versus standard-risk groups (2B). Novel-agent-based induction and up-front autologous stem cell transplantation in medically fit patients remains the standard of care (1A). Induction therapy should include a triple combination of bortezomib, with either adriamycin or thalidomide and dexamethasone (1A), or with cyclophosphamide and dexamethasone (2B). Currently, allogeneic stem cell transplantation may be considered for young patients with high-risk disease and preferably in the context of a clinical trial (2B). Thalidomide (1B) or lenalidomide (1A) maintenance increases progression-free survival and possibly overall survival (2B). Bortezomib-based regimens are a valuable consolidation option, especially for patients who failed excellent response after autologous stem cell transplantation (2A). Bortezomib-melphalan-prednisone or melphalan-prednisone-thalidomide are the standards of care for transplant-ineligible patients (1A). Melphalan-prednisone-lenalidomide with lenalidomide maintenance increases progression-free survival, but overall survival data are needed. New data from the phase III study (MM-020/IFM 07-01) of lenalidomide-low-dose dexamethasone reached its primary end point of a statistically significant improvement in progression-free survival as compared to melphalan-prednisone-thalidomide and provides further evidence for the efficacy of lenalidomide-low-dose dexamethasone in transplant-ineligible patients (2B).     

Update on the management of neuromuscular block: focus on sugammadex

Steroidal neuromuscular blocking agents (NMBAs), such as rocuronium, are widely used in clinical anesthesia and emergency medicine to facilitate endotracheal intubation and artificial ventilation and to allow surgical access to body cavities. Reversal of neuromuscular blockade is important for the acceleration of patient recovery and prevention of postoperative residual neuromuscular blockade and reduces the incidence of severe morbidity and mortality associated with anesthesia management. Sugammadex is the first selective relaxant binding agent (SRBA) and has been designed to reverse the steroidal neuromuscular blocking drug rocuronium. Encapsulation of the rocuronium molecule by sugammadex results in a rapid decrease in free rocuronium in the plasma and subsequently at the nicotinic receptor at the motor endplate. After encapsulation, rocuronium is not available to bind to the nicotinic receptor in the neuromuscular junction. This promotes the liberation of acetylcholine receptors, and muscle activity reappears. This new concept of reversal of neuromuscular block induced by rocuronium (or vecuronium) led to impressive results in animal and phase 1 and 2 studies. Sugammadex is currently in phase 3 clinical studies and may be commercially available by 2008.     

Optical coherence tomography: a quantitative tool to screen for papilledema in craniosynostosis

Purpose

Our aim was to evaluate if optical coherence tomography (OCT) can be used as an alternative for fundoscopy to screen for increased intracranial pressure (ICP) in children with craniosynostosis

Methods

We performed a prospective cohort study at the Dutch Craniofacial Centre. We included 38 patients with nonsyndromic scaphocephaly and Crouzon’s syndrome aged 3–8 years old, in whom we scored complaints suggestive of increased ICP and performed fundoscopy and OCT. Main outcome measures total retinal thickness (TRT) which was measured on 58 OCT scans.

Results

Forty-three percent of fundoscopies revealed pathologic changes of the papil in at least one eye. Retinal thickness was increased in patients with an abnormal fundoscopy as compared to patients with a normal papil (TRT p?<?0.001). Patients with Crouzon’s syndrome had a significantly increased retinal thickness as compared to patients with scaphocephaly (TRT p?<?0.001).

Conclusions

The current study demonstrates that OCT in children with craniosynostosis is feasible. It confirms that retinal thickness increases in case of papilledema. Given the quantitative character, OCT has a high potential as an alternative tool to screen for papilledema in craniosynostosis and other pediatric populations.     

The effect of neuromuscular blockade on oxygen consumption in sedated and mechanically ventilated pediatric patients after cardiac surgery

Objective  To measure the effect of intense neuromuscular blockade (NMB) on oxygen consumption (VO₂) in deeply sedated and mechanically ventilated children on the first day after complex congenital cardiac surgery. Design  Prospective clinical interventional study. Setting  Pediatric intensive care unit of an university medical centre. Measurements and results  Nine mechanically ventilated and sedated children (weight 2.8–8.7 kg) were included. All children were treated with vasoactive drugs. The level of sedation was quantified using the comfort score, Ramsay score and bispectral index (BIS). The intensity of NMB was quantified using acceleromyography and VO₂ was measured using indirect calorimetry. Analgo-sedation using various intravenous agents was targeted at a deep level (comfort score < 18, BIS < 60 and Ramsay score > 4). NMB was achieved by intravenous administration of rocuronium. All measurements were conducted before, during and after recovery from a period of intense NMB. Baseline values were VO₂ 6.1 ml/(kg min) (SD 1.3), comfort score 13 (SD 0.7), BIS 42.5 (SD 14.2), mean blood pressure 54.0 mmHg (SD 10.5), mean heart rate 129.9 bpm (SD 28.9) and mean core temperature 36.7°C (SD 0.5). There were no significant differences in VO₂ or other parameters between baseline, during NMB and the recovery phase. Conclusion  Neuromuscular blocking agents do not reduce oxygen consumption in deeply sedated and mechanically ventilated children after congenital cardiac surgery.     

Staphylococcus aureus carriage among GPs in the Netherlands

Background

The extent to which GPs serve as a reservoir for antibiotic-resistant Staphylococcus aureus is unknown and not well studied.

Aim

To determine the prevalence of nasal S. aureus carriage among GPs in the Netherlands, as well as the antimicrobial resistance and the genotypes of isolated S. aureus.

Design of study

Observational, point-prevalence, and cross-sectional study.

Setting

GPs attending the annual conference of the Dutch College of General Practitioners in 2006.

Method

Nasal swabs were randomly taken from 395 GPs and analysed for the presence of S. aureus. Antimicrobial susceptibility was determined by a microbroth dilution method and the genotypes by spa typing, which was associated with multilocus sequence typing.

Results

Of the GPs, 129/395 (33%; 95% confidence interval [CI] = 28 to 37%) were carriers of S. aureus. No meticillin-resistant S. aureus (MRSA) was found. Resistance was observed to penicillin (71%; 95% CI = 63 to 79%), fusidic acid (7%; 95% CI = 3 to 13%), and clarithromycin (6%; 95% CI = 3 to 12%). In 72% of the isolates, an MRSA-related genotype of S. aureus was found.

Conclusion

The low antibiotic resistance found among S. aureus of GPs suggests that GPs are not a reservoir of antibiotic-resistant S. aureus strains. The relatively high resistance to fusidic acid, which has not previously been described in the Netherlands and is mostly because of antibiotic use, suggests that patients infect GPs and not the other way round. GPs may be at risk for nasal carriage of S. aureus with an MRSA-related genotype.     

Functional MRI correlates of the recall of unresolved life events in borderline personality disorder

BACKGROUND: Patients with borderline personality disorder (BPD) frequently report unresolved life events but it is still poorly understood, how these experiences are represented in the brain. Using functional magnetic resonance imaging (fMRI), the present study aimed at investigating the neural correlates of the recall of unresolved life events in patients with BPD and healthy controls. METHOD: Twenty female BPD patients and 21 healthy control subjects underwent fMRI. During measurement subjects recalled unresolved and resolved negative life events. Individual cue words were used to stimulate autobiographical memory. After scanning, subjects rated their emotional states during the recall of both types of memories. RESULTS: When contrasting unresolved and resolved life events, patients showed significant bilateral activation of frontotemporal areas including the insula, amygdala, and the anterior cingulate cortex, the left posterior cingulate cortex, right occipital cortex, the bilateral cerebellum and the midbrain. In healthy subjects, no differential brain activation was related to these conditions. The 2 x 2 factorial analysis (DeltaBPD - Deltacontrols) revealed similar results with bilateral activation of the frontal cortex including parts of the insula and of the orbitofrontal cortex, temporal activation including the amygdala, activation of the right occipital cortex, and parts of the cerebellum. Patients but not controls reported higher levels of anxiety and helplessness during the unresolved versus resolved memory condition. CONCLUSIONS: The activation of both, the amygdala and prefrontal areas, might reflect an increased effortful but insufficient attempt to control intensive emotions during the recall of unresolved life events in patients with BPD.     

IgE‐expressing memory B cells and plasmablasts are increased in blood of children with asthma,food allergy,and atopic dermatitis

Despite the critical role of soluble IgE in the pathology of IgE‐mediated allergic disease, little is known about abnormalities in the memory B cells and plasma cells that produce IgE in allergic patients. We here applied a flow cytometric approach to cross‐sectionally study blood IgE+ memory B cells and plasmablasts in 149 children with atopic dermatitis, food allergy, and/or asthma and correlated these to helper T(h)2 cells and eosinophils. Children with allergic disease had increased numbers of IgE+CD27‐ and IgE+CD27+ memory B cells and IgE+ plasmablasts, as well as increased numbers of eosinophils and Th2 cells. IgE+ plasmablast numbers correlated positively with Th2 cell numbers. These findings open new possibilities for diagnosis and monitoring of treatment in patients with allergic diseases.     

Targeted Molecular Imaging to Detect Vascular Disease

Major challenges with vascular imaging are related to the deep-seated nature of blood vessels, small dimensions of the lumen, and poor access into the arterial wall. Current imaging techniques are limited to detecting structural abnormalities. To detect minute abnormalities in the vascular lumen or arterial wall, imaging techniques need to be modified to improve their spatial resolution and sensitivity as well as to develop unique homing mechanisms to target biomarkers expressed in the lumen or the wall of the blood vessels. Molecular imaging has the potential to detect pathologic biomarkers that would otherwise be difficult to be detected by current imaging techniques. This review provides an overview of the uses of molecular imaging to detect two major vascular conditions, thrombosis and atherosclerosis. Molecular imaging has the potential to screen for early stages of disease, follow the course of the disease, and detect the presence of vulnerable plaque or occult thromboses that require aggressive intervention.     

Tissue Engineering of Human Heart Valve Leaflets: A Novel Bioreactor for a Strain-Based Conditioning Approach

Current mechanical conditioning approaches for heart valve tissue engineering concentrate on mimicking the opening and closing behavior of the leaflets, either or not in combination with tissue straining. This study describes a novel approach by mimicking only the diastolic phase of the cardiac cycle, resulting in tissue straining. A novel, yet simplified, bioreactor system was developed for this purpose by applying a dynamic pressure difference over a closed tissue engineered valve, thereby inducing dynamic strains within the leaflets. Besides the use of dynamic strains, the developing leaflet tissues were exposed to prestrain induced by the use of a stented geometry. To demonstrate the feasibility of this strain-based conditioning approach, human heart valve leaflets were engineered and their mechanial behavior evaluated. The actual dynamic strain magnitude in the leaflets over time was estimated using numerical analyses. Preliminary results showed superior tissue formation and non-linear tissue-like mechanical properties in the strained valves when compared to non-loaded tissue strips. In conclusion, the strain-based conditioning approach, using both prestrain and dynamic strains, offers new possibilities for bioreactor design and optimization of tissue properties towards a tissue-engineered aortic human heart valve replacement.