Do patients with p16-positive oropharyngeal squamous cell carcinoma get more bone metastasis than p16-negative patients?

BACKGROUND: Oropharyngeal squamous cell carcinoma is thought to rarely metastasise to bone. This study hypothesised that in p16-positive disease there is a significant incidence of bony metastasis. METHODS: This was an ambispective cohort review. All patients with oropharyngeal squamous cell carcinoma diagnosed and treated at one centre were included. RESULTS: A total of 180 consecutive patients were identified over 5 years. Fifteen patients were excluded because of lack of p16 status, none of whom had bony metastasis. The final analysis included 165 patients: 48 (29.09 per cent) in the p16-negative group and 117 (70.91 per cent) in the p16-positive group. Ten patients (8.55 per cent) in the p16-positive group developed bony metastasis, compared with zero in the p16-negative group; this difference was statistically significant (p = 0.036). CONCLUSION: Expression of p16 was associated with an increased incidence in bony metastasis in this cohort. This is the first study to explore this specific question.

The Alzheimer's Prevention Initiative Generation Program: Evaluating CNP520 Efficacy in the Prevention of Alzheimer's Disease.

Alzheimer's disease pathology begins decades before the onset of clinical symptoms. This provides an opportunity for interventional clinical trials to potentially delay or prevent the onset of cognitive impairment or dementia. CNP520 (a beta-site-amyloid precursor protein-cleaving enzyme inhibitor) is in clinical development for the treatment of preclinical Alzheimer's disease under the Alzheimer's Prevention Initiative Generation Program. The Alzheimer's Prevention Initiative is a public-private partnership intended to accelerate the evaluation of Alzheimer's disease prevention therapies. The Generation Program comprises two pivotal phase II/III studies with similar designs to assess the efficacy and safety of investigational treatments in a cognitively unimpaired population at increased risk for developing Alzheimer's disease based on age and apolipoprotein E (APOE) genotype (i.e., presence of the APOE ε4 allele). The program has been designed to maximize benefit to Alzheimer's disease research. Generation Study 1 (NCT02565511) and Generation Study 2 (NCT03131453) are currently enrolling; their key features are presented here.

Simple Single-Pass Technique for Ultrathin Descemet Stripping Automated Endothelial Keratoplasty: A Pilot Study.

PURPOSE: To assess intraoperative and postoperative graft thickness (GT) after donor deturgescence for ultrathin Descemet stripping automated endothelial keratoplasty and to evaluate visual outcomes, endothelial cell density, and patient satisfaction at 1 year. METHODS: Prospective interventional case series of patients with Fuchs endothelial dystrophy, Fuchs endothelial dystrophy and cataract, and pseudophakic bullous keratopathy (n = 12 grafts). The donor cornea was allowed to thin out by simple evaporation on an artificial anterior chamber, to the required precut thickness, before a single microkeratome pass. GT after microkeratome cut, at 1 week, 1, 3, 6, and 12, months was measured. Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity, Pelli-Robson contrast sensitivity, endothelial cell density, and score on the visual function questionnaire (VFQ-25) were assessed. RESULTS: Mean intraoperative postmicrokeratome cut GT was 78.9 ± 33.3 µm. Mean GT at 1 week, 1, 3, 6, and 12 months was 70.7, 70.9, 62.8, 66.5, and 58.9 µm, respectively. Mean initial donor corneal thickness was 647 ± 67 µm, and mean precut thickness was 526 ± 4.5 µm (mean thinning time: 17 min). Best-corrected visual acuity at 1 week, 1, 3, 6, and 12 months was 68.8, 76.9, 76.3, 76.9, and 78.6 letters with 9-letter gain at 12 months (P = 0.02). Mean endothelial cell loss at 3, 6, and 12 months was 36.8% ± 6.75%, 37.2% ± 8%, and 37.9% ± 9.75% loss, respectively. At 1 year, 83.3% of patients achieved ≥20/40 (6/12) and 66.7% of patients achieved ≥20/32 (6/9.5). VFQ-25 testing showed an improvement in the visual function. CONCLUSIONS: This pilot study demonstrates a simple graft deturgescence technique that reproducibly creates ultrathin grafts without donor wastage.

Differential bud activation by a net positive root signal explains branching phenotype in prostrate clonal herbs: a model.

Regulation of branching within perennial prostrate clonal herbs differs from the annual orthotropic species, Arabidopsis and pea, as the dominant signal transported from roots is a branching promoter, not an inhibitor. Trifolium repens, an exemplar of such prostrate species, was used to investigate the interaction between roots and branch development. This study tests whether or not current knowledge when synthesized into a predictive model is sufficient to simulate the branching pattern developing on the shoot distal to a basal root. The major concepts underpinning the model are: (i) bud outgrowth (activation) is stimulated in a dose-dependent manner by branching promoter signals from roots, (ii) the distribution of this net root stimulus (NRS) is uniform throughout the shoot system distal to the basal root but declines geometrically in intensity upon continued enlargement of this shoot system, and (iii) each bud has an outgrowth potential, equal to the activation level of the apical bud in which it forms, that moderates its response to NRS. The validity of these concepts was further tested by running simulations of the branching of a phylogenetically-distanced prostrate perennial monocotyledonous species, Tradescantia fluminensis. For both species the model reasonably accounted for the observed pattern of branching. The outgrowth potential of buds plays an important role in limiting the number of hierarchies of branching that can develop on a plant. In conclusion, for both species, the model accounted for the major factors involved in the correlative regulation of branching and is possibly also pertinent for all prostrate clonal species.

Preclinical trials in autosomal dominant AD: implementation of the DIAN-TU trial.

The Dominantly Inherited Alzheimer's Network Trials Unit (DIAN-TU) was formed to direct the design and management of interventional therapeutic trials of international DIAN and autosomal dominant Alzheimer's disease (ADAD) participants. The goal of the DIAN-TU is to implement safe trials that have the highest likelihood of success while advancing scientific understanding of these diseases and clinical effects of proposed therapies. The DIAN-TU has launched a trial design that leverages the existing infrastructure of the ongoing DIAN observational study, takes advantage of a variety of drug targets, incorporates the latest results of biomarker and cognitive data collected during the observational study, and implements biomarkers measuring Alzheimer's disease (AD) biological processes to improve the efficiency of trial design. The DIAN-TU trial design is unique due to the sophisticated design of multiple drugs, multiple pharmaceutical partners, academics servings as sponsor, geographic distribution of a rare population and intensive safety and biomarker assessments. The implementation of the operational aspects such as home health research delivery, safety magnetic resonance imagings (MRIs) at remote locations, monitoring clinical and cognitive measures, and regulatory management involving multiple pharmaceutical sponsors of the complex DIAN-TU trial are described.

Alzheimer's disease therapeutic trials: EU/US Task Force report on recruitment, retention, and methodology.

While we may not be able to find a cure for Alzheimer's disease (AD) in the near future, several drugs presently in trials have shown promise as possible modifiers of disease progression. However, we may not be able to demonstrate efficacy due to issues of recruitment, retention, site-to-site variability, and other methodological issues. It is thus incumbent on the scientific community to find solutions to these problems, particularly as the field moves toward preventing illness or treating the disease in its prodromal stages, where these methodological issues will become even more critical. We need to better understand why participants agree or refuse to enter drug trials, and why both primary care physicians and Alzheimer's specialists agree or refuse to involve their patients. We also need to quantify the impact of requiring imaging studies, extensive questionnaires, cognitive testing, and lumbar punctures on recruitment and retention. With these concerns in mind, an international task force meeting of experts from academia and industry in the United States, European Union, and Japan in San Diego, California on November 2, 2011 to focus on recruitment, retention and other methodological issues related to clinical trials for AD. Based on the recommendations of this Task force meeting, this Perspectives article critically reflects on the most critical and timely methodological issues related to recruitment and retention in prevention and therapeutic trials in AD, which are paralleled by a paradigm shift in the diagnostic conceptualization of this disease, as reflected by recently new proposed diagnostic criteria involving preclinical stages of the disease.

A grid overlay framework for analysis of medical images and its application to the measurement of stroke lesions.

OBJECTIVES: To create and evaluate an interactive software tool for measuring imaging data in situations where hand-drawn region-of-interest measurements are unfeasible, for example, when the structure of interest is patchy with ill-defined boundaries. METHODS: An interactive grid overlay software tool was implemented that enabled coding of voxels dependent on their imaging appearance with a series of user-defined classes. The Grid Analysis Tool (GAT) was designed to automatically extract quantitative imaging data, grouping the results by tissue class. Inter- and intra-observer reproducibility was evaluated by six observers of various backgrounds in a study of acute stroke patients. RESULTS: The software tool enabled a more detailed classification of the stroke lesion than would be possible with a region-of-interest approach. However, inter-observer coefficients of variation (CVs) were relatively high, reaching 70% in "possibly abnormal" tissue and around 15-20% in normal appearing tissues, while intra-observer CVs were no more than 13% in "possibly abnormal" tissue and generally less than 1% in normal-appearing tissues. CONCLUSIONS: The grid-overlay method overcomes some of the limitations of conventional Region Of Interest (ROI) approaches, providing a viable alternative for segmenting patchy lesions with ill-defined boundaries, but care is required to ensure acceptable reproducibility if the method is applied by multiple observers. KEY POINTS: Computer software developed to overcome limitations of conventional regions of interest measurements • This software is suitable for patchy lesions with ill-defined borders • Allows a more detailed assessment of imaging data.

Chronic divalproex sodium use and brain atrophy in Alzheimer disease.

OBJECTIVE: We evaluated the effect of the divalproex sodium formulation of valproic acid on brain volumes using MRI in people with mild to moderate Alzheimer disease (AD) and assessed for changes associated with behavioral and cognitive effects. METHODS: Eighty-nine of 313 participants randomized to divalproex or placebo in a 24-month, parallel-group trial received MRI scans at baseline and 12 months. Interval MRI annual percent changes in whole brain, ventricular, and hippocampal volumes were the primary outcomes of interest. Change from baseline in clinical outcomes was assessed at 6-month intervals. RESULTS: There were no baseline differences between active treatment and placebo groups in age, education, brain volumes, clinical rating scores, or APOE ε4 carrier status. The group treated with divalproex showed a greater rate of decline in left and right hippocampal and brain volumes (-10.9% and -12.4% vs -5.6% and -6.3%, and -3.5% vs -1.4%, respectively), and a greater rate of ventricular expansion (24.5% vs 9.9%) (p < 0.001). Mini-Mental State Examination scores showed a more rapid decline with divalproex through month 12 (placebo = -2.0 ± 4.3, divalproex = -3.9 ± 4.0) (p = 0.037), although there were no changes on other cognitive, behavioral, or functional ratings at 12 and 24 months. CONCLUSIONS: Divalproex treatment was associated with accelerated brain volume loss over 1 year and perhaps with greater cognitive impairment. The long-term clinical effects of these changes are not known.

A randomized, double-blind, placebo-controlled trial of simvastatin to treat Alzheimer disease.

BACKGROUND: Lowering cholesterol is associated with reduced CNS amyloid deposition and increased dietary cholesterol increases amyloid accumulation in animal studies. Epidemiologic data suggest that use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) may decrease the risk of Alzheimer disease (AD) and a single-site trial suggested possible benefit in cognition with statin treatment in AD, supporting the hypothesis that statin therapy is useful in the treatment of AD. OBJECTIVE: To determine if the lipid-lowering agent simvastatin slows the progression of symptoms in AD. METHODS: This randomized, double-blind, placebo-controlled trial of simvastatin was conducted in individuals with mild to moderate AD and normal lipid levels. Participants were randomly assigned to receive simvastatin, 20 mg/day, for 6 weeks then 40 mg per day for the remainder of 18 months or identical placebo. The primary outcome was the rate of change in the Alzheimer's Disease Assessment Scale-cognitive portion (ADAS-Cog). Secondary outcomes measured clinical global change, cognition, function, and behavior. RESULTS: A total of 406 individuals were randomized: 204 to simvastatin and 202 to placebo. Simvastatin lowered lipid levels but had no effect on change in ADAS-Cog score or the secondary outcome measures. There was no evidence of increased adverse events with simvastatin treatment. CONCLUSION: Simvastatin had no benefit on the progression of symptoms in individuals with mild to moderate AD despite significant lowering of cholesterol. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that simvastatin 40 mg/day does not slow decline on the ADAS-Cog.

The relative efficiency of time-to-threshold and rate of change in longitudinal data.

Randomized, placebo-controlled trials often use time-to-event as the primary endpoint, even when a continuous measure of disease severity is available. We compare the power to detect a treatment effect using either rate of change, as estimated by linear models of longitudinal continuous data, or time-to-event estimated by Cox proportional hazards models. We propose an analytic inflation factor for comparing the two types of analyses assuming that the time-to-event can be expressed as a time-to-threshold of the continuous measure. We conduct simulations based on a publicly available Alzheimer's disease data set in which the time-to-event is algorithmically defined based on a battery of assessments. A Cox proportional hazards model of the time-to-event endpoint is compared to a linear model of a single assessment from the battery. The simulations also explore the impact of baseline covariates in either analysis.

Predominant time scales in fission processes in reactions of S, Ti and Ni with W: zeptosecond versus attosecond.

The inhibition of fusion by quasifission is crucial in limiting the formation of superheavy elements in collisions of heavy nuclei. Time scales of ∼10(-18) s inferred for fissionlike events from recent crystal blocking measurements were interpreted to show either that quasifission itself is slower than previously believed, or that the fraction of slow fusion-fission is higher than expected. New measurements of mass-angle distributions for (48)Ti and (64)Ni bombarding W targets show that in these reactions quasifission is the dominant process, typically occurring before the system formed after contact has made a single rotation, corresponding to time scales of ≤10(-20) s.

Existing branches correlatively inhibit further branching in Trifolium repens: possible mechanisms.

In Trifolium repens removal of any number of existing branches distal to a nodal root stimulates development of axillary buds further along the stem such that the complement of branches distal to a nodal root remains constant. This study aimed to assess possible mechanisms by which existing branches correlatively inhibit the outgrowth of axillary buds distal to them. Treatments were applied to basal branches to evaluate the roles of three postulated inhibitory mechanisms: (I) the transport of a phloem-mobile inhibitory feedback signal from branches into the main stem; (II) the polar flow of auxin from branches into the main stem acting to limit further branch development; or (III) the basal branches functioning as sinks for a net root-derived stimulatory signal (NRS). Results showed that transport of auxin, or of a non-auxin phloem-mobile signal, from basal branches did not influence regulation of correlative inhibition and were consistent with the possibility that the intra-plant distribution of NRS could be involved in the correlative inhibition of distal buds by basal branches. This study supports existing evidence that regulation of branching in T. repens is dominated by a root-derived stimulatory signal, initially distributed via the xylem, the characterization of which will progress the generic understanding of branching regulation.

Report of the task force on designing clinical trials in early (predementia) AD.

BACKGROUND: A large number of promising candidate disease-modifying treatments for Alzheimer disease (AD) continue to advance into phase II and phase III testing. However, most completed trials have failed to demonstrate efficacy, and there is growing concern that methodologic difficulties may contribute to these clinical trial failures. The optimal time to intervene with such treatments is probably in the years prior to the onset of dementia, before the neuropathology has progressed to the advanced stage corresponding to clinical dementia. METHOD: An international task force of individuals from academia, industry, nonprofit foundations, and regulatory agencies was convened to discuss optimal trial design in early (predementia) AD. RESULTS: General consensus was reached on key principles involving the scope of the AD diagnosis, the selection of subjects for trials, outcome measures, and analytical methods. CONCLUSION: A consensus has been achieved in support of the testing of candidate treatments in the early (predementia) AD population.

Brain choline concentration. Early quantitative marker of ischemia and infarct expansion?

OBJECTIVE: Better prediction of tissue prognosis in acute stroke might improve treatment decisions. We hypothesized that there are metabolic ischemic disturbances measurable noninvasively by proton magnetic resonance spectroscopy ((1)H MRS) that occur earlier than any structural changes visible on diffusion-tensor imaging (DTI), which may therefore serve for territorial identification of tissue at risk. METHODS: We performed multivoxel (1)H MRS plus DTI within a maximum of 26 hours, and DTI at 3-7 days, after ischemic stroke. We compared choline, lactate, N-acetylaspartate, and creatine concentrations in normal-appearing voxels that became infarcted (infarct expansion) with normal-appearing voxels around the infarct that remained "healthy" (nonexpansion) on follow-up DTI. Each infarct expansion voxel was additionally classified as either complete infarct expansion (infarcted tissue on follow-up DTI covered > or =50% of the voxel) or partial infarct expansion (<50% of voxel). RESULTS: In 31 patients (NIH Stroke Scale score 0-28), there were 108 infarct nonexpansion voxels and 113 infarct expansion voxels (of which 80 were complete expansion and 33 partial expansion voxels). Brain choline concentration increased for each change in expansion category from nonexpansion, via partial expansion to complete expansion (2,423, 3,843, 4,158 IU; p < 0.05). Changes in lactate, N-acetylaspartate, and creatine concentrations in expansion category were insignificant although for lactate there was a tendency to such association. CONCLUSIONS: Choline concentration measurable with (1)H MRS was elevated in peri-ischemic normal-appearing brain that became infarcted by 3-7 days. The degree of elevation was associated with the amount of infarct expansion. (1)H MRS might identify DTI-normal-appearing tissue at risk of conversion to infarction in early stroke.

Corneal graft surgery combined with subconjunctival bevacizumab (avastin).

PURPOSE: To describe the use of subconjunctival bevacizumab (Avastin) as an adjunctive treatment in a vascularized cornea at the time of lamellar keratoplasty to reduce the risk of graft rejection. MATERIALS AND METHODS: After a significant ocular high-velocity thermal injury, a patient developed extensive corneal scarring and a traumatic cataract. To improve vision, a corneal graft was indicated, but the presence of extensive neovascularization increased the risk of early graft rejection. RESULTS: Bevacizumab was injected subconjunctivally before surgery to reduce the corneal vessel load. There was a dramatic response in terms of vessel regression, but this was short lived and the vessels quickly regrew. The subconjunctival bevacizumab injection was repeated at the time of combined cataract extraction and lamellar corneal graft surgery, and the feeder vessels were cauterized at the limbus. After 6 months, the graft remained clear of vessels. CONCLUSIONS: This case is of interest because the eye was treated twice with subconjunctival bevacizumab with good short-term results in both instances but different longer-term outcomes in terms of vessel regrowth. This case suggests that the antiangiogenic effects of bevacizumab may be effectively harnessed at the time of a definitive surgical procedure, which reduces the stimulus for vessel regrowth.

Low energy proton beam induces efficient cell killing in A549 lung adenocarcinoma cells.

The aim of the current study was to determine the signaling differences between gamma- and proton beam-irradiations. A549 lung adenocarcinoma cells were irradiated with 2 Gy proton beam or gamma-radiation. Proton beam was found to be more cytotoxic than gamma-radiation. Proton beam-irradiated cells showed phosphorylation of H2AX, ATM, Chk2, and p53. The mechanism of excessive cell killing in proton beam-irradiated cells was found to be upregulation of Bax and downregulation of Bcl-2. The noteworthy finding of this study is the biphasic activation of the sensor proteins, ATM, and DNA-PK and no activation of ATR by proton irradiation.

Axillary bud outgrowth potential is determined by parent apical bud activity.

Axillary buds within a plant shoot system are known to differ in their ability to respond to treatments favouring their development. This ability is referred to as their outgrowth potential. Using two species of prostrate nodally-rooting herbs, dicotyledonous Trifolium repens and monocotyledonous Tradescantia fluminensis, grown throughout in a strictly vegetative state, this study tested two hypotheses. Hypothesis 1: that each axillary bud exhibits an outgrowth potential that is directly related to the growth rate of its parent apical bud, and Hypothesis 2: that the growth rate attained by an axillary bud depends upon both its outgrowth potential and the local supply of stimulatory root-derived signal (NRS) available to it. Activation levels (growth rates) of apical buds were varied by differential exposure to nodal roots and the outgrowth responses of axillary buds recently emerged from them were then measured under standardized conditions of NRS supply. Hypothesis 1 was shown to be correct for both species. Hypothesis 2, tested only in T. repens, was supported by results showing that an axillary bud's outgrowth potential and the NRS supply to it each independently influenced its growth rate, there being no significant interaction between the two. These results emphasize the significant role the physiological state/activity of apical buds has on the outgrowth potential of axillary buds formed within them. The fact that similar relationships were observed on axillary buds on stems of differing developmental maturity and branching hierarchy, and in two taxonomically diverse species, suggests they might be widespread among morphologically similar species.

Two distinct quasifission modes in the 32S + 232Th reaction.

Comprehensive fission measurements, including mass-angle distributions, for the reaction of 32S with the prolate deformed nucleus 232Th at near-barrier energies show two distinct components in both mass and angle; surprisingly, both have characteristics of quasifission. Their relative probabilities vary rapidly with the ratio of the beam energy to the capture barrier, suggesting a relationship with deformation aligned (sub-barrier), or antialigned (above-barrier), configurations at contact.

Disentangling effects of nuclear structure in heavy element formation.

Forming the same heavy compound nucleus with different isotopes of the projectile and target elements allows nuclear structure effects in the entrance channel (resulting in static deformation) and in the dinuclear system to be disentangled. Using three isotopes of Ti and W, forming 232Cm, with measurement spanning the capture barrier energies, alignment of the heavy prolate deformed nucleus is shown to be the main reason for the broadening of the mass distribution of the quasifission fragments as the beam energy is reduced. The complex, consistently evolving mass-angle correlations that are observed carry more information than the integrated mass or angular distributions, and should severely test models of quasifission.