Induction chemotherapy in locally advanced squamous cell carcinoma of the head and neck: role, controversy, and future directions.

BackgroundThe value of induction chemotherapy (ICT) remains under investigation despite decades of research. New advancements in the field, specifically regarding the induction regimen of choice, have reignited interest in this approach for patients with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN). Sufficient evidence has accumulated regarding the benefits and superiority of TPF (docetaxel, cisplatin, and fluorouracil) over the chemotherapy doublet cisplatin and fluorouracil. We therefore sought to collate and interpret the available data and further discuss the considerations for delivering ICT safely and optimally selecting suitable post-ICT regimens.DesignWe nonsystematically reviewed published phase III clinical trials on TPF ICT in a variety of LA SCCHN patient populations conducted between 1990 and 2017.ResultsTPF may confer survival and organ preservation benefits in a subgroup of patients with functionally inoperable or poor-prognosis LA SCCHN. Additionally, patients with operable disease or good prognosis (who are not candidates for organ preservation) may benefit from TPF induction in terms of reducing local and distant failure rates and facilitating treatment deintensification in selected populations. The safe administration of TPF requires treatment by a multidisciplinary team at an experienced institution. The management of adverse events associated with TPF and post-ICT radiotherapy-based treatment is crucial. Finally, post-ICT chemotherapy alternatives to cisplatin concurrent with radiotherapy (i.e. cetuximab or carboplatin plus radiotherapy) appear promising and must be investigated further.ConclusionsTPF is an evidence-based ICT regimen of choice in LA SCCHN and confers benefits in suitable patients when it is administered safely by an experienced multidisciplinary team and paired with the optimal post-ICT regimen, for which, however, no consensus currently exists

Variation in plasma oxidative status and testosterone level in relation to egg-eviction effort and age of brood-parasitic common cuckoo nestlings

To avoid competition for parental care, brood-parasitic Common Cuckoo (Cuculus canorus) nestlings evict all of the host's eggs and nestlings within a few days after hatching. Little is known about the physiological effects of eviction behavior on the cuckoo nestling's oxidative balance or about age-related variation in plasma oxidative status and testosterone level of developing birds. We examined whether the cuckoo nestling's plasma oxidative status was related to prior effort in eviction and quantified variation in the level of reactive oxygen metabolites, of nonenzymatic antioxidant capacity, and of testosterone concentration in plasma at various phases of the cuckoo's development. Levels of both reactive oxygen metabolites and antioxidant capacity were greater in older than in younger nestlings, suggesting that younger nestlings effectively counterbalance their increased production of free radicals, whereas, near fledging, levels of reactive oxygen metabolites increase despite improved antioxidant capacity. Possibly, overall energy expenditure increases with age and elevates the production of reactive oxygen species to a rate higher than what the antioxidant system could eliminate. Plasma testosterone level was the highest at nestlings' intermediate phase of growth. High levels of testosterone may be required during the period of fastest growth, and when the growth rate levels off near fledging, testosterone levels may also decline. Cuckoo chicks that evicted more host eggs from steeper nests had higher plasma levels of reactive oxygen metabolites shortly after the eviction period, suggesting that eviction is costly in terms of an increased level of oxidative stress. Para evitar la competencia por el cuidado parental, los polluelos parásitos de nidada de Cuculus canorus desalojan todos los huevos y los polluelos del hospedador a los pocos días después de la eclosión. Se sabe poco sobre los efectos fisiológicos del comportamiento de desalojo en el balance oxidativo de los polluelos de C. canorus o sobre la variación en el estatus oxidativo del plasma y el nivel de testosterona relacionado con la edad de las aves en desarrollo. Examinamos si el estatus oxidativo del plasma de los polluelos de C. canorus se relacionaba con un esfuerzo previo de desalojo y cuantificamos la variación en el nivel de metabolitos reactivos de oxígeno, la capacidad antioxidante no enzimática y la concentración de testosterona en el plasma en varias fases del desarrollo de C. canorus. Tanto los niveles de metabolitos reactivos de oxígeno como la capacidad antioxidante fueron superiores en los polluelos de mayor edad que en los más jóvenes, lo que sugiere que los polluelos de menor edad contrarrestan eficazmente el aumento de la producción de radicales libres, mientras que, cuando se apróximan al abandono del nido, los niveles de metabolitos reactivos de oxígeno aumentan a pesar de una mejora en la capacidad antioxidante. Posiblemente, el gasto total de energía se incrementa con la edad, elevándose la producción de formas reactivas de oxígeno a una tasa mayor de la que el sistema antioxidante puede eliminar. El nivel de testosterona en el plasma fue máximo en la fase intermedia del crecimiento de los polluelos. Pueden requerirse altos niveles de testosterona durante el período de mayor crecimiento y, cuando la tasa de crecimiento se estabiliza cerca del abandono del nido, los niveles de testosterona también podrián disminuir. Los polluelos de C. canorus que desalojaron más huevos del hospedador en nidos con una estructura más empinada tuvieron niveles de plasma de metabolitos reactivos de oxígeno en plasma más altos poco después del período de desalojo, sugiriendo que el desalojo es costoso en términos de un incremento en el nivel de estrés oxidativo

Finding an alternative diagnosis does not justify increased use of CT-pulmonary angiography

Background: The increased use of computed tomography pulmonary angiography (CTPA) is often justified by finding alternative diagnoses explaining patients' symptoms. However, this has not been rigorously examined.Methods: We retrospectively reviewed CTPA done at our center over an eleven year period (2000 - 2010) in patients with suspected pulmonary embolus (PE). We then reviewed in detail the medical records of a representative sample of patients in three index years - 2000, 2005 and 2008. We determined whether CTPA revealed pulmonary pathology other than PE that was not readily identifiable from the patient's history, physical examination and prior chest X-ray. We also assessed whether the use of pre-test probability guided diagnostic strategy for PE.Results: A total of 12,640 CTPA were performed at our center from year 2000 to 2010. The number of CTPA performed increased from 84 in 2000 to 2287 in 2010, a 27 fold increase. Only 7.6 percent of all CTPA and 3.2 percent of avoidable CTPAs (low or intermediate pre-test probability and negative D-dimer) revealed previously unknown findings of any clinical significance. When we compared 2008 to 2000 and 2005, more CTPAs were performed in younger patients (mean age (years) for 2000: 67, 2005: 63, and 2008: 60, (p=0.004, one-way ANOVA)). Patients were less acutely ill with fewer risk factors for PE. Assessment of pre-test probability of PE and D-dimer measurement were rarely used to select appropriate patients for CTPA (pre-test probability of PE documented in chart (% total) in year 2000: 4.1%, 2005: 1.6%, 2008: 3.1%). Conclusions: Our data do not support the argument that increased CTPA use is justified by finding an alternative pulmonary pathology that could explain patients' symptoms. CTPA is being increasingly used as the first and only test for suspected PE. © 2013 Chandra et al.; licensee BioMed Central Ltd

A graph-search framework for associating gene identifiers with documents

BACKGROUND: One step in the model organism database curation process is to find, for each article, the identifier of every gene discussed in the article. We consider a relaxation of this problem suitable for semi-automated systems, in which each article is associated with a ranked list of possible gene identifiers, and experimentally compare methods for solving this geneId ranking problem. In addition to baseline approaches based on combining named entity recognition (NER) systems with a "soft dictionary" of gene synonyms, we evaluate a graph-based method which combines the outputs of multiple NER systems, as well as other sources of information, and a learning method for reranking the output of the graph-based method. RESULTS: We show that named entity recognition (NER) systems with similar F-measure performance can have significantly different performance when used with a soft dictionary for geneId-ranking. The graph-based approach can outperform any of its component NER systems, even without learning, and learning can further improve the performance of the graph-based ranking approach. CONCLUSION: The utility of a named entity recognition (NER) system for geneId-finding may not be accurately predicted by its entity-level F1 performance, the most common performance measure. GeneId-ranking systems are best implemented by combining several NER systems. With appropriate combination methods, usefully accurate geneId-ranking systems can be constructed based on easily-available resources, without resorting to problem-specific, engineered components

Typology of Web 2.0 spheres: Understanding the cultural dimensions of social media spaces

It has taken the past decade to commonly acknowledge that online space is tethered to real place. From euphoric conceptualizations of social media spaces as a novel, unprecedented and revolutionary entity, the dust has settled, allowing for talk of boundaries and ties to real-world settings. Metaphors have been instrumental in this pursuit, shaping perceptions and affecting actions within this extended structural realm. Specifically, they have been harnessed to architect Web 2.0 spaces, be it chatrooms, electronic frontiers, homepages, or information highways for policy and practice. While metaphors are pervasive in addressing and

Meditation on the Soles of the Feet Practice Provides Some Control of Aggression for Individuals with Alzheimer’s Disease

Alzheimer’s disease is a progressive neurodegenerative condition that affects cognition, mental and physical health, and functionality of older people. As the disease progresses from the mild to moderate stage, there is a concomitant increase in several behavioral variables, chiefly agitation, anger, and aggression. Currently, there are no evidence-based treatments for these behaviors in this population. Three individuals with moderate Alzheimer’s disease were taught an informal mindfulness practice, meditation on the Soles of the Feet (SoF), as a self-management strategy within a multiple-baseline design across participants. All three were able to learn and use the SoF practice to manage their verbal and physical aggression. Their use of the SoF practice was correlated with decreased perceived psychological stress for their spouses and caregivers, as well as for the participants, but to a much smaller degree. In terms of social validity, the participants, their spouses, and caregivers rated the SoF practice as acceptable, effective, with no unintended effects, and indicated that they would recommend the practice to others. However, they also rated SoF as effortful for the participants because it involves the participants remembering to use the practice with rising anger, a requirement particularly challenging for those with memory problems. The SoF practice may enable individuals in the early stages of dementia to manage their anger and aggression. The data were derived from an internally valid experimental design, suggestive of initial proof-of-concept, but needs to be replicated before any clinical implications can be imputed from this study

Fulvestrant-induced expression of ErbB3 and ErbB4 receptors sensitizes oestrogen receptor-positive breast cancer cells to heregulin β1

Introduction We have previously reported that induction of epidermal growth factor receptor and ErbB2 in response to antihormonal agents may provide an early mechanism to allow breast cancer cells to evade the growth-inhibitory action of such therapies and ultimately drive resistant cell growth. More recently, the other two members of the ErbB receptor family, ErbB3 and ErbB4, have been implicated in antihormone resistance in breast cancer. In the present study, we have investigated whether induction of ErbB3 and/or ErbB4 may provide an alternative resistance mechanism to antihormonal action in a panel of four oestrogen receptor (ER)-positive breast cancer cell lines. Methods MCF-7, T47D, BT474 and MDAMB361 cell lines were exposed to fulvestrant (100 nM) for seven days, and effects on ErbB3/4 expression and signalling, as well as on cell growth, were assessed. Effects of heregulin β1 (HRGβ1) were also examined in the absence and presence of fulvestrant to determine the impact of ER blockade on the capacity of this ErbB3/4 ligand to promote signalling and cell proliferation. Results Fulvestrant potently reduced ER expression and transcriptional activity and significantly inhibited growth in MCF-7, T47D, BT474 and MDAMB361 cells. However, alongside this inhibitory activity, fulvestrant also consistently induced protein expression and activity of ErbB3 in MCF-7 and T47D cells and ErbB4 in BT474 and MDAMB361 cell lines. Consequently, fulvestrant treatment sensitised all cell lines to the actions of the ErbB3/4 ligand HRGβ1 with enhanced ErbB3/4-driven signalling activity, reexpression of cyclin D1 and significant increases in cell proliferation being observed when compared to untreated cells. Indeed, in T47D and MDAMB361 HRGβ1 was converted from a ligand having negligible or suppressive growth activity into one that potently promoted cell proliferation. Consequently, fulvestrant-mediated growth inhibition was completely overridden by HRGβ1 in all four cell lines. Conclusions These findings suggest that although antihormones such as fulvestrant may have potent acute growth-inhibitory activity in ER-positive breast cancer cells, their ability to induce and sensitise cells to growth factors may serve to reduce and ultimately limit their inhibitory activity