Combination of bevacizumab and 2-weekly pegylated liposomal doxorubicin as first-line therapy for locally recurrent or metastatic breast cancer. A multicenter, single-arm phase II trial (SAKK 24/06).

BACKGROUND: Pegylated liposomal doxorubicin (PLD) and bevacizumab are active agents in the treatment of metastatic breast cancer (MBC). We carried out a multicenter, single-arm phase II trial to evaluate the toxicity and efficacy of PLD and bevacizumab as first-line treatment in MBC patients. METHODS: Bevacizumab (10 mg/kg) and PLD (20 mg/m(2)) were infused on days 1 and 15 of a 4-week cycle for a maximum of six cycles. Thereafter, bevacizumab monotherapy was continued at the same dose until progression or toxicity. The primary objective was safety and tolerability, and the secondary objective was to evaluate efficacy of the combination. RESULTS: Thirty-nine of 43 patients were assessable for the primary end point. Eighteen of 39 patients (46%, 95% confidence interval 30% to 63%) had a grade 3 toxicity. Sixteen (41%) had grade 3 palmar-plantar erythrodysesthesia, one had grade 3 mucositis, and one severe cardiotoxicity. Secondary end point of overall response rate among 43 assessable patients was 21%. CONCLUSIONS: In this nonrandomized single-arm trial, the combination of bimonthly PLD and bevacizumab in locally recurrent and MBC patients demonstrated higher than anticipated toxicity while exhibiting only modest activity. Based on these results, we would not consider this combination for further investigation in this setting.

Stimulus statistics shape oscillations in nonlinear recurrent neural networks.

Rhythmic activity plays a central role in neural computations and brain functions ranging from homeostasis to attention, as well as in neurological and neuropsychiatric disorders. Despite this pervasiveness, little is known about the mechanisms whereby the frequency and power of oscillatory activity are modulated, and how they reflect the inputs received by neurons. Numerous studies have reported input-dependent fluctuations in peak frequency and power (as well as couplings across these features). However, it remains unresolved what mediates these spectral shifts among neural populations. Extending previous findings regarding stochastic nonlinear systems and experimental observations, we provide analytical insights regarding oscillatory responses of neural populations to stimulation from either endogenous or exogenous origins. Using a deceptively simple yet sparse and randomly connected network of neurons, we show how spiking inputs can reliably modulate the peak frequency and power expressed by synchronous neural populations without any changes in circuitry. Our results reveal that a generic, non-nonlinear and input-induced mechanism can robustly mediate these spectral fluctuations, and thus provide a framework in which inputs to the neurons bidirectionally regulate both the frequency and power expressed by synchronous populations. Theoretical and computational analysis of the ensuing spectral fluctuations was found to reflect the underlying dynamics of the input stimuli driving the neurons. Our results provide insights regarding a generic mechanism supporting spectral transitions observed across cortical networks and spanning multiple frequency bands.

Franceschetti hereditary recurrent corneal erosion.

PURPOSE: To describe new affected individuals of Franceschetti's original pedigree of hereditary recurrent erosion and to classify a unique entity called Franceschetti corneal dystrophy. DESIGN: Observational case series. METHODS: Slit-lamp examination of 10 affected individuals was conducted. Biomicroscopic examinations were supplemented by peripheral corneal biopsy in 1 affected patient with corneal haze. Tissue was processed for light and electron microscopy and immunohistochemistry was performed. DNA analysis was carried out in 12 affected and 3 nonaffected family members. RESULTS: All affected individuals suffered from severe ocular pain in the first decade of life, attributable to recurrent corneal erosions. Six adult patients developed bilateral diffuse subepithelial opacifications in the central and paracentral cornea. The remaining 4 affected individuals had clear corneas in the pain-free stage of the disorder. Histologic and immunohistochemical examination of the peripheral cornea in a single patient showed a subepithelial, avascular pannus. There was negative staining with Congo red. DNA analysis excluded mutations in the transforming growth factor beta-induced (TGFBI) gene and in the tumor-associated calcium signal transducer 2 (TACSTD2) gene. CONCLUSION: We have extended the pedigree of Franceschetti corneal dystrophy and elaborated its natural history on the basis of clinical examinations. A distinctive feature is the appearance of subepithelial opacities in adult life, accompanied by a decreased frequency of recurrent erosion attacks. Its clinical features appear to distinguish it from most other forms of dominantly inherited recurrent corneal erosion reported in the literature.

Idiopathic recurrent neuroretinitis: effects of long-term immunosuppression.

OBJECTIVE: To determine the efficacy of long-term immunosuppressive therapy in patients with recurrent idiopathic neuroretinitis. METHODS: A retrospective review of 30 patients with recurrent idiopathic neuroretinitis identified 7 who received ongoing immunosuppression with prednisone and/or azathioprine for whom adequate follow-up information was available. We calculated the number of attacks per unit of time for each patient before and after treatment to derive mean attack rates for the group. RESULTS: For the entire group, we found a rate of 0.58 attacks per year prior to the initiation of immunosuppressive treatment, which decreased to 0.16 attacks per year following immunosuppression. This represents a reduction in the attack rate of 0.41, or a 72% decrease in attack frequency. CONCLUSIONS: Our study suggests a possible role for long-term immunosuppressive treatment in patients with recurrent idiopathic neuroretinitis. A longer follow-up interval, more standardized treatment regimens, and additional outcome measures might reveal a greater benefit of treatment.

Airway stenting with the LT-Mold? for severe glotto-subglottic stenosis or intractable aspiration: experience in 65 cases.

The purpose of this study was to assess the safety and efficacy of stenting in upper airway reconstructions for benign laryngotracheal stenosis (LTS) with a newly designed prosthesis, the LT-Mold?. The LT-Mold and its proper use during open surgery and endoscopy are described, and the experience gathered from a prospectively collected database on 65 patients treated for complex LTS or severe aspiration is reported. This series is compared to the results of other stenting methods. All patients were available for evaluation. In all but one case, the prosthesis was removed at the end of the study. The new prosthesis did not induce any stent-related trauma to the supraglottis, glottis and subglottis. Before adding a distal round-shaped silicone cap to the LT-Mold, granulation tissue was usually seen at the stent-mucosal interface at the tracheostoma level. In 14 cases, there has been a spontaneous extrusion of the prosthesis through the mouth; this problem was solved by fixing the prosthesis through the reinforced portion of the prosthesis at the cap level and by adding one fixation stitch in the supraglottis. We have to document the loss of the silicone cap in three cases. This problem was resolved by designing a new prototype with an integrated cap, glued with a slow hardening silicone glue. Fifty-four (83 %) of 65 patients were decannulated after a mean duration of stenting of 3 months (range 1-12 months). The mean follow-up after decannulation was 23 months (range 1 month to 10 years). The experience gathered with the LT-Mold shows that long-term stenting for complex LTS is safely achieved when the prosthesis is used with its distal integrated silicone cap. The softness and smoothness of the prosthesis with a round-shaped configuration of both extremities help avoid ulceration and granulation tissue formation in the reconstructed airway. Adequate fixation is mandatory to avoid extrusion.

Clinical Prognostic Factors Predicting Outcomes Of Patients With Recurrent Gbm And Nomograms

BACKGROUND: Prognostic models and nomograms were recently developed to predict survival of patients with newly diagnosed glioblastoma multiforme (GBM).1 To improve predictions, models should be updated with the most recent patient and disease information. Nomograms predicting patient outcome at the time of disease progression are required. METHODS: Baseline information from 299 patients with recurrent GBM recruited in 8 phase I or II trials of the EORTC Brain Tumor Group was used to evaluate clinical parameters as prognosticators of patient outcome. Univariate (log rank) and multivariate (Cox models) analyses were made to assess the ability of patients' characteristics (age, sex, performance status [WHO PS], and MRC neurological deficit scale), disease history (prior treatments, time since last treatment or initial diagnosis, and administration of steroids or antiepileptics) and disease characteristics (tumor size and number of lesions) to predict progression free survival (PFS) and overall survival (OS). Bootstrap technique was used for models internal validation. Nomograms were computed to provide individual patients predictions. RESULTS: Poor PS and more than 1 lesion had a significant prognostic impact for both PFS and OS. Antiepileptic drug use was significantly associated with worse PFS. Larger tumors (split by the median of the largest tumor diameter >42.5 mm) and steroid use had shorter OS. Age, sex, neurologic deficit, prior therapies, and time since last therapy or initial diagnosis did not show independent prognostic value for PFS or OS. CONCLUSIONS: This analysis confirms that PS but not age is a major prognostic factor for PFS and OS. Multiple or large tumors and the need to administer steroids significantly increase the risk of progression and death. Nomograms at the recurrence could be used to obtain accurate predictions for the design of new targeted therapy trials or retrospective analyses. (1. T. Gorlia et al., Nomograms for predicting survival of patients with newly diagnosed glioblastoma. Lancet Oncol 9 (1): 29-38, 2008.)

Thymic stromal lymphopoietin plays divergent roles in murine models of atopic and nonatopic airway inflammation.

BACKGROUND: Thymic stromal lymphopoietin (TSLP) is a cytokine primarily produced by epithelial cells, which has been shown to be a potent inducer of T-helper 2 (Th2)-type responses. However, TSLP has pleiotropic effects upon immune cells, and although extensively studied in the context of atopic asthma, its relevance as a therapeutic target and its role in the pathogenesis of nonatopic asthma remains unknown. We sought to investigate the role of TSLP in atopic, nonatopic and viral-induced exacerbations of pulmonary inflammation. METHODS: Using stringently defined murine models of atopic, nonatopic and virally exacerbated forms of pulmonary inflammation, we compared inflammatory responses of C57BL/6 wild-type (WT) and TSLP receptor-deficient (TSLPR KO) mice. RESULTS: Thymic stromal lymphopoietin receptor (TSLPR) signaling was crucial for the development of atopic asthma. Specifically, TSLPR signaling to lung recruited CD4+ T cells enhanced eosinophilia, goblet cell hyperplasia, and overall inflammation within the airways. In contrast, the absence of TSLPR signaling was associated with strikingly exaggerated pulmonary neutrophilic inflammation in a nonatopic model of airway inflammation. The inflammation was associated with excessive levels of interleukin (IL)-17A in the lungs, indicating that TSLP negatively regulates IL-17A. In addition, in a model of influenza-induced exacerbation of atopic airway inflammation, the absence of TSLPR signaling also led to exaggerated neutrophilic inflammation. CONCLUSION: Thymic stromal lymphopoietin plays divergent roles in the pathogenesis of atopic and nonatopic asthma phenotypes by either enhancing Th2 responses or curtailing T-helper 17 responses. These findings raise important caveats for the design of therapeutic interventions targeting TSLP in asthma.

SWIVIT - Swiss video-intubation trial evaluating video-laryngoscopes in a simulated difficult airway scenario: study protocol for a multicenter prospective randomized controlled trial in Switzerland.

BACKGROUND: Video-laryngoscopes are marketed for intubation in difficult airway management. They provide a better view of the larynx and may facilitate tracheal intubation, but there is no adequately powered study comparing different types of video-laryngoscopes in a difficult airway scenario or in a simulated difficult airway situation. METHODS/DESIGN: The objective of this trial is to evaluate and to compare the clinical performance of three video-laryngoscopes with a guiding channel for intubation (Airtraq?, A. P. Advance?, King Vision?) and three video-laryngoscopes without an integrated tracheal tube guidance (C-MAC?, GlideScope?, McGrath?) in a simulated difficult airway situation in surgical patients. The working hypothesis is that each video-laryngoscope provides at least a 90% first intubation success rate (lower limit of the 95% confidence interval >0.9). It is a prospective, patient-blinded, multicenter, randomized controlled trial in 720 patients who are scheduled for elective surgery under general anesthesia, requiring tracheal intubation at one of the three participating hospitals. A difficult airway will be created using an extrication collar and taping the patients' head on the operating table to substantially reduce mouth opening and to minimize neck movement. Tracheal intubation will be performed with the help of one of the six devices according to randomization. Insertion success, time necessary for intubation, Cormack-Lehane grade and percentage of glottic opening (POGO) score at laryngoscopy, optimization maneuvers required to aid tracheal intubation, adverse events and technical problems will be recorded. Primary outcome is intubation success at first attempt. DISCUSSION: We will simulate the difficult airway and evaluate different video-laryngoscopes in this highly realistic and clinically challenging scenario, independently from manufacturers of the devices. Because of the sufficiently powered multicenter design this study will deliver important and cutting-edge results that will help clinicians decide which device to use for intubation of the expected and unexpected difficult airway. TRIAL REGISTRATION: NCT01692535.

Tracheostomy in children.

We reviewed the records of 108 patients who had a tracheostomy performed over a 10-year period from July 1979 to April 1989. Median age at tracheostomy was 6 months (1 week-15 years). Indications for surgery were acquired subglottic stenosis (31.4%), bilateral vocal cord paralysis (22.2%), congenital airway malformations (22.2%) and tumours (11.1%). No epiglottis and no emergency situation had to be managed by tracheostomy. Operation was uneventful in all, but 8 patients (7.4%) developed a pneumothorax in the postoperative period. Twenty-one (19.5%) had severe complications during the cannulation period (tube obstruction in 11 patients with cardiorespiratory arrest in 4; dislocation of the tube in 6 patients). Fifteen patients (13.8%) had severe complications after decannulation (2 had a cardiorespiratory arrest); all 15 had to be recannulated. At the end of the study period 85 patients (78.7%) were successfully decannulated with a median period of tracheostomy of 486 days (8 days-6.6 years). The median hospital stay was 159 days (13 days-2.7 years). All patients could be discharged. Eight patients (7.4%) died but no death was related to tracheostomy. In summary the mortality rate is lower than reported in previous reviews and tracheostomy is a safe operation even in small children but cannula-related complications may lead to life-threatening events. The management of tracheostomized small children and infants in a highly staffed and monitored intensive care unit has allowed better handling of complications and has resulted in a reduction in cannula-related deaths.

Breeding strategies for recurrent selection of maize

The objectives of this work were to analyze theoretical genetic gains of maize due to recurrent selection among full-sib and half-sib families, obtained by Design I, Full-Sib Design and Half-Sib Design, and genotypic variability and gene loss with long term selection. The designs were evaluated by simulation, based on average estimated gains after ten selection cycles. The simulation process was based on seven gene systems with ten genes (with distinct degrees of dominance), three population classes (with different gene frequencies), under three environmental conditions (heritability values), and four selection strategies. Each combination was repeated ten times, amounting to 25, 200 simulations. Full-sib selection is generally more efficient than half-sib selection, mainly with favorable dominant genes. The use of full-sib families derived by Design I is generally more efficient than using progenies obtained by Full-Sib Design. Using Design I with 50 males and 200 females (effective size of 160) did not result in improved populations with minimum genotypic variability. In the populations with lower effective size (160 and 400) the loss of favorable genes was restricted to recessive genes with reduced frequencies.

Subgroup And Quality Of Life Analyses Of The Phase Iii Clinical Trial Of Novottf-100a Versus Best Standard Chemotherapy For Recurrent Glioblastoma

BACKGROUND: NovoTTF is a portable device delivering low-intensity, intermediate-frequency, electric fields using noninvasive, disposable scalp electrodes. These fields physically interfere with cell division. Preliminary studies in recurrent and newly diagnosed glioblastoma (GBM) have shown promising results. A phase III study in recurrent GBM has recently been concluded. METHODS: Adults (KPS ≥ 70%) with recurrent GBM (any recurrence) were randomized (stratified by surgery and center) to either NovoTTF administered continuously (20-24 hours/day, 7 days/week) or the best available chemotherapy (best physician choice [BPC]). Primary endpoint was overall survival (OS); 6-month progression-free survival (PFS6), 1-year survival, and QOL were secondary endpoints. RESULTS: Two hundred thirty-seven patients were randomized (28 centers in the United States and Europe) to either NovoTTF alone (120 patients) or BPC (117 patients). Patient characteristics were balanced, median age was 54 years (range, 23-80 years), median KPS was 80% (range, 50-100). One quarter had surgery for recurrence, and over half were at their second or more recurrence. A survival advantage for the device group was seen in patients treated according to protocol (median OS, 7.8 months vs. 6.1 months; n = 185; p = 0.01). Moreover, subgroup analysis in patients with better prognostic baseline characteristics (KPS ≥ 80%; age ≤ 60; 1st-3rd recurrence) demonstrated a robust survival benefit for NovoTTF patients compared to matched BPC patients (median OS, 8.8 months vs. 6.6 months; n = 110; p < 0.01). In this group, 1-year survival was 35% vs. 20% and PFS6 was 25.6% vs. 7.7%. Interestingly, in patients who failed bevacizumab prior to the trial, OS was also significantly extended by NovoTTF (4.4 months vs. 3.1 months; n = 23 vs. n = 21; p < 0.02). Quality of life was equivalent or superior in NovoTTF patients. CONCLUSIONS: NovoTTF, a noninvasive, novel cancer treatment modality shows significant therapeutic efficacy with improved quality of life. The impact of NovoTTF was more pronounced when patients with better baseline prognostic factors were treated. A large scale phase III clinical trial in newly diagnosed GBM is currently being conducted.