Predicting adverse events in children with fever and chemotherapy-induced neutropenia: the prospective multicenter SPOG 2003 FN study

PURPOSE To develop a score predicting the risk of adverse events (AEs) in pediatric patients with cancer who experience fever and neutropenia (FN) and to evaluate its performance. PATIENTS AND METHODS Pediatric patients with cancer presenting with FN induced by nonmyeloablative chemotherapy were observed in a prospective multicenter study. A score predicting the risk of future AEs (ie, serious medical complication, microbiologically defined infection, radiologically confirmed pneumonia) was developed from a multivariate mixed logistic regression model. Its cross-validated predictive performance was compared with that of published risk prediction rules. Results An AE was reported in 122 (29%) of 423 FN episodes. In 57 episodes (13%), the first AE was known only after reassessment after 8 to 24 hours of inpatient management. Predicting AE at reassessment was better than prediction at presentation with FN. A differential leukocyte count did not increase the predictive performance. The score predicting future AE in 358 episodes without known AE at reassessment used the following four variables: preceding chemotherapy more intensive than acute lymphoblastic leukemia maintenance (weight = 4), hemoglobin > or = 90 g/L (weight = 5), leukocyte count less than 0.3 G/L (weight = 3), and platelet count less than 50 G/L (weight = 3). A score (sum of weights) > or = 9 predicted future AEs. The cross-validated performance of this score exceeded the performance of published risk prediction rules. At an overall sensitivity of 92%, 35% of the episodes were classified as low risk, with a specificity of 45% and a negative predictive value of 93%. CONCLUSION This score, based on four routinely accessible characteristics, accurately identifies pediatric patients with cancer with FN at risk for AEs after reassessment.

Induction of apoptosis and enhancement of chemosensitivity in human prostate cancer LNCaP cells using bispecific antisense oligonucleotide targeting Bcl-2 and Bcl-xL genes

OBJECTIVE: To determine whether a specifically designed bispecific (Bcl-2/Bcl-xL) antisense oligonucleotide (ASO) induces apoptosis and enhances chemosensitivity in human prostate cancer LNCaP cells, as Bcl-2 and Bcl-xL are both anti-apoptotic genes associated with treatment resistance and tumour progression in many malignancies, including prostate cancer. MATERIALS AND METHODS: Inhibition of Bcl-2 and Bcl-xL expression by the bispecific ASO was evaluated using real-time reverse transcription-polymerase chain reaction and Western blotting, while growth inhibition and induction of apoptosis were analysed by a crystal violet assay, flow cytometry and Western blotting of apoptosis-relevant proteins. The effect of combined treatment with bispecific ASO and chemotherapy or small-interference RNA (siRNA) targeting the clusterin gene was also investigated. RESULTS: Bispecific ASO reduced Bcl-2 and Bcl-xL expression in LNCaP cells in a dose-dependent manner. There was cell growth inhibition, increases in the sub-G0-G1 fraction, and cleavage of caspase-3 and poly(ADP-Ribose) polymerase proteins in LNCaP cells after bispecific ASO treatment. Interestingly, Bcl-2/Bcl-xL bispecific ASO treatment also resulted in the down-regulation of Mcl-1 and up-regulation of Bax. The sensitivity of LNCaP cells to mitoxantrone, docetaxel or paclitaxel was significantly increased, reducing the 50% inhibitory concentration by 45%, 80% or 90%, respectively. Furthermore, the apoptotic induction by Bcl-2/Bcl-xL bispecific ASO was synergistically enhanced by siRNA-mediated inhibition of clusterin, a cytoprotective chaperone that interacts with and inhibits activated Bax. CONCLUSIONS: These findings support the concept of the targeted suppression of Bcl-2 anti-apoptotic family members using multitarget inhibition strategies for prostate cancer, through the effective induction of apoptosis.

Comparison of six radiographic projections to assess femoral head/neck asphericity

Early radiographic detection of femoroacetabular impingement might prevent initiation and progression of osteoarthritis. The structural abnormality in femoral-induced femoroacetabular impingement (cam type) is frequently asphericity at the anterosuperior head/neck contour. To determine which of six radiographic projections (anteroposterior, Dunn, Dunn/45 degrees flexion, cross-table/15 degrees internal rotation, cross-table/neutral rotation, and cross-table/15 degrees external rotation) best identifies femoral head/neck asphericity, we studied 21 desiccated femurs; 11 with an aspherical femoral head/neck contour and 10 with a spherical femoral head/neck contour. To radiographically quantify femoral head asphericity, we measured the angle where the femoral head/neck leaves sphericity (angle alpha). The aspherical femoral head/neck contours had a greater maximum angle alpha (70 degrees ) compared with the spherical head/neck contours (50 degrees ). The angle alpha varied depending on the radiographic projection: it was greatest in the Dunn view with 45 degrees hip flexion (71 degrees +/- 10 degrees ) and least in the cross-table view in 15 degrees external rotation (51 degrees +/- 7 degrees ). Diagnosis of a pathologic femoral head/neck contour depends on the radiologic projection. The Dunn view in 45 degrees or 90 degrees flexion or a cross-table projection in internal rotation best show femoral head/neck asphericity, whereas anteroposterior or externally rotated cross-table views are likely to miss asphericity. Level of Evidence: Prognostic study, level II-1 (retrospective study).

Survival and failure rates of orthodontic temporary anchorage devices: a systematic review

AIM: The purpose of this study was to systematically review the literature on the survival rates of palatal implants, Onplants((R)), miniplates and mini screws. MATERIAL AND METHODS: An electronic MEDLINE search supplemented by manual searching was conducted to identify randomized clinical trials, prospective and retrospective cohort studies on palatal implants, Onplants((R)), miniplates and miniscrews with a mean follow-up time of at least 12 weeks and of at least 10 units per modality having been examined clinically at a follow-up visit. Assessment of studies and data abstraction was performed independently by two reviewers. Reported failures of used devices were analyzed using random-effects Poisson regression models to obtain summary estimates and 95% confidence intervals (CI) of failure and survival proportions. RESULTS: The search up to January 2009 provided 390 titles and 71 abstracts with full-text analysis of 34 articles, yielding 27 studies that met the inclusion criteria. In meta-analysis, the failure rate for Onplants((R)) was 17.2% (95% CI: 5.9-35.8%), 10.5% for palatal implants (95% CI: 6.1-18.1%), 16.4% for miniscrews (95% CI: 13.4-20.1%) and 7.3% for miniplates (95% CI: 5.4-9.9%). Miniplates and palatal implants, representing torque-resisting temporary anchorage devices (TADs), when grouped together, showed a 1.92-fold (95% CI: 1.06-2.78) lower clinical failure rate than miniscrews. CONCLUSION: Based on the available evidence in the literature, palatal implants and miniplates showed comparable survival rates of >or=90% over a period of at least 12 weeks, and yielded superior survival than miniscrews. Palatal implants and miniplates for temporary anchorage provide reliable absolute orthodontic anchorage. If the intended orthodontic treatment would require multiple miniscrew placement to provide adequate anchorage, the reliability of such systems is questionable. For patients who are undergoing extensive orthodontic treatment, force vectors may need to be varied or the roots of the teeth to be moved may need to slide past the anchors. In this context, palatal implants or miniplates should be the TADs of choice.

Chronic NSAID use and long-term decline of renal function in a prospective rheumatoid arthritis cohort study

OBJECTIVES Non-steroidal anti-inflammatory drugs (NSAIDs) may cause kidney damage. This study assessed the impact of prolonged NSAID exposure on renal function in a large rheumatoid arthritis (RA) patient cohort. METHODS Renal function was prospectively followed between 1996 and 2007 in 4101 RA patients with multilevel mixed models for longitudinal data over a mean period of 3.2 years. Among the 2739 'NSAID users' were 1290 patients treated with cyclooxygenase type 2 selective NSAIDs, while 1362 subjects were 'NSAID naive'. Primary outcome was the estimated glomerular filtration rate according to the Cockroft-Gault formula (eGFRCG), and secondary the Modification of Diet in Renal Disease and Chronic Kidney Disease Epidemiology Collaboration formula equations and serum creatinine concentrations. In sensitivity analyses, NSAID dosing effects were compared for patients with NSAID registration in ≤/>50%, ≤/>80% or ≤/>90% of assessments. FINDINGS In patients with baseline eGFRCG >30 mL/min, eGFRCG evolved without significant differences over time between 'NSAID users' (mean change in eGFRCG -0.87 mL/min/year, 95% CI -1.15 to -0.59) and 'NSAID naive' (-0.67 mL/min/year, 95% CI -1.26 to -0.09, p=0.63). In a multivariate Cox regression analysis adjusted for significant confounders age, sex, body mass index, arterial hypertension, heart disease and for other insignificant factors, NSAIDs were an independent predictor for accelerated renal function decline only in patients with advanced baseline renal impairment (eGFRCG <30 mL/min). Analyses with secondary outcomes and sensitivity analyses confirmed these results. CONCLUSIONS NSAIDs had no negative impact on renal function estimates but in patients with advanced renal impairment.

Optimization of extracorporeal shock wave lithotripsy delivery rates achieves excellent outcomes in ureteral stones. Results of a prospective, randomized trial

PURPOSE Management of ureteral stones remains controversial. To determine whether optimizing extracorporeal shock wave lithotripsy (ESWL) delivery rates improves treatment of solitary ureteral stones, we compared outcomes of two SW delivery rates in a prospective, randomized trial. MATERIALS AND METHODS From July 2010 to October 2012, 254 consecutive patients were randomized to undergo ESWL at SW delivery rates of either 60 pulses (n=130) or 90 pulses (n=124) per min. The primary endpoint was stone-free rate at 3-month follow-up. Secondary endpoints included stone disintegration, treatment time, complications, and the rate of secondary treatments. Descriptive statistics were used to compare endpoints between the two groups. Adjusted odds ratios and 95% confidence intervals were calculated to assess predictors of success. RESULTS The stone-free rate at 3 months was significantly higher in patients who underwent ESWL at a SW delivery rate of 90 pulses per min than in those receiving 60 pulses (91% vs. 80%, p=0.01). Patients with proximal and mid-ureter stones, but not those with distal ureter stones, accounted for the observed difference (100% vs. 83%; p=0.005; 96% vs. 73%, p=0.03; and 81% vs. 80%, p=0.9, respectively). Treatment time, complications, and the rate of secondary treatments were comparable between the two groups. In multivariable analysis, SW delivery rate of 90 pulses per min, proximal stone location, stone density, stone size and the absence of an indwelling JJ stent were independent predictors of success. CONCLUSIONS Optimization of ESWL delivery rates can achieve excellent results for ureteral stones.

In Vitro Activity of the Novel Antimicrobial Peptide Dendrimer G3KL against Multidrug-Resistant Acinetobacter baumannii and Pseudomonas aeruginosa.

The in vitro activity of the novel antimicrobial peptide dendrimer G3KL was evaluated against 32 Acinetobacter baumannii (including 10 OXA-23, 7 OXA-24, and 11 OXA-58 carbapenemase producers) and 35 Pseudomonas aeruginosa (including 18 VIM and 3 IMP carbapenemase producers) strains and compared to the activities of standard antibiotics. Overall, both species collections showed MIC50/90 values of 8/8 μg/ml and minimum bactericidal concentrations at which 50% or 90% of strains tested are killed (MBC50/90) of 8/8 μg/ml. G3KL is a promising molecule with antibacterial activity against multidrug-resistant and extensively drug-resistant A. baumannii and P. aeruginosa isolates.

All cause and disease specific mortality in patients with knee or hip osteoarthritis: population based cohort study

Objective To examine all cause and disease specific mortality in patients with osteoarthritis of the knee or hip. Design Population based cohort study. Setting General practices in the southwest of England. Participants 1163 patients aged 35 years or over with symptoms and radiological confirmation of osteoarthritis of the knee or hip. Main outcome measures Age and sex standardised mortality ratios and multivariable hazard ratios of death after a median of 14 years’ follow-up. Results Patients with osteoarthritis had excess all cause mortality compared with the general population (standardised mortality ratio 1.55, 95% confidence interval 1.41 to 1.70). Excess mortality was observed for all disease specific causes of death but was particularly pronounced for cardiovascular (standardised mortality ratio 1.71, 1.49 to 1.98) and dementia associated mortality (1.99, 1.22 to 3.25). Mortality increased with increasing age (P for trend <0.001), male sex (adjusted hazard ratio 1.59, 1.30 to 1.96), self reported history of diabetes (1.95, 1.31 to 2.90), cancer (2.28, 1.50 to 3.47), cardiovascular disease (1.38, 1.12 to 1.71), and walking disability (1.48, 1.17 to 1.86). However, little evidence existed for increased mortality associated with previous joint replacement, obesity, depression, chronic inflammatory disease, eye disease, or presence of pain at baseline. The more severe the walking disability, the higher was the risk of death (P for trend <0.001). Conclusion Patients with osteoarthritis are at higher risk of death compared with the general population. History of diabetes, cancer, or cardiovascular disease and the presence of walking disability are major risk factors. Management of patients with osteoarthritis and walking disability should focus on effective treatment of cardiovascular risk factors and comorbidities, as well as on increasing physical activity.

Impact of chorioamnionitis and preeclampsia on neurodevelopmental outcome in preterm infants below 32 weeks gestational age

ABSTRACT Aim: Intrauterine conditions may interfere with fetal brain development. We compared the neurodevelopmental outcome between infants <32 weeks gestational age after maternal preeclampsia or chorioamnionitis and controls. Methods: Case-control study on infants with maternal preeclampsia, chorioamnionitis and controls (each n = 33) matched for gestational age. Neurodevelopment at two years was assessed with the Bayley Scales of Infant Development II. Results: Ninety-nine infants were included with a median gestational age of 29 weeks (range 25-32). Median mental developmental index (MDI) was 96 in the control, 90 in the chorioamnionitis and 86 in the preeclampsia group. Preeclampsia infants had a lower MDI compared with the control group (univariate p = 0.021, multivariate p = 0.183) and with the chorioamnionitis group (univariate p = 0.242; multivariate p = 0.027). Median psychomotor index was 80.5 in the control, 80 in the preeclampsia and 85 in the chorioamnionitis group, and was not different between these three groups (p > 0.05). Chorioamnionitis or preeclampsia exposure was not associated with major neurodevelopmental impairments (cerebral palsy, MDI<70, PDI<70). Conclusion: The results of this preliminary study suggest that preeclampsia and chorioamnionitis play a relatively minor role among risk factors for adverse neurodevelopment outcome. Postnatal factors such as ventilation and bronchopulmonary dysplasia may have a greater impact on neurodevelopmental outcome.

Age at hip or knee joint replacement surgery predicts likelihood of revision surgery

We compared revision and mortality rates of 4668 patients undergoing primary total hip and knee replacement between 1989 and 2007 at a University Hospital in New Zealand. The mean age at the time of surgery was 69 years (16 to 100). A total of 1175 patients (25%) had died at follow-up at a mean of ten years post-operatively. The mean age of those who died within ten years of surgery was 74.4 years (29 to 97) at time of surgery. No change in comorbidity score or age of the patients receiving joint replacement was noted during the study period. No association of revision or death could be proven with higher comorbidity scoring, grade of surgeon, or patient gender. We found that patients younger than 50 years at the time of surgery have a greater chance of requiring a revision than of dying, those around 58 years of age have a 50:50 chance of needing a revision, and in those older than 62 years the prosthesis will normally outlast the patient. Patients over 77 years old have a greater than 90% chance of dying than requiring a revision whereas those around 47 years are on average twice as likely to require a revision than die. This information can be used to rationalise the need for long-term surveillance and during the informed consent process.

Clinical long-term outcome after implantation of titanium nitride-oxide coated stents compared with paclitaxel- or sirolimus-eluting stents: propensity-score matched analysis

We performed a propensity score matched analysis to explore whether TiNOX stents are superior to paclitaxel- (PES) and sirolimus-eluting stents (SES) in routine clinical practice.

Outcome and patterns of failure after postoperative intensity modulated radiotherapy for locally advanced or high-risk oral cavity squamous cell carcinoma

Background To determine the outcome and patterns of failure in oral cavity cancer (OCC) patients after postoperative intensity modulated radiotherapy (IMRT) with concomitant systemic therapy. Methods All patients with locally advanced (AJCC stage III/IV) or high-risk OCC (AJCC stage II) who underwent postoperative IMRT at our institution between December 2006 and July 2010 were retrospectively analyzed. The primary endpoint was locoregional recurrence-free survival (LRRFS). Secondary endpoints included distant metastasis-free survival (DMFS), overall survival (OS), acute and late toxicities. Results Overall 53 patients were analyzed. Twenty-three patients (43%) underwent concomitant chemotherapy with cisplatin, two patients with carboplatin (4%) and four patients were treated with the monoclonal antibody cetuximab (8%). At a median follow-up of 2.3 (range, 1.1–4.6) years the 3-year LRRFS, DMFS and OS estimates were 79%, 90%, and 73% respectively. Twelve patients experienced a locoregional recurrence. Eight patients, 5 of which had both a flap reconstruction and extracapsular extension (ECE), showed an unusual multifocal pattern of recurrence. Ten locoregional recurrences occurred marginally or outside of the high-risk target volumes. Acute toxicity grades of 2 (27%) and 3 (66%) and late toxicity grades of 2 (34%) and 3 (11%) were observed. Conclusion LRRFS after postoperative IMRT is satisfying and toxicity is acceptable. The majority of locoregional recurrences occurred marginally or outside of the high-risk target volumes. Improvement of high-risk target volume definition especially in patients with flap reconstruction and ECE might transfer into better locoregional control.