Whole brain radiotherapy after local treatment of brain metastases in melanoma patients - a randomised phase III trial

<p>Abstract</p> <p>Background</p> <p>Cerebral metastases are a common cause of death in patients with melanoma. Systemic drug treatment of these metastases is rarely effective, and where possible surgical resection and/or stereotactic radiosurgery (SRS) are the preferred treatment options. Treatment with adjuvant whole brain radiotherapy (WBRT) following neurosurgery and/or SRS is controversial. Proponents of WBRT report prolongation of intracranial control with reduced neurological events and better palliation. Opponents state melanoma is radioresistant; that WBRT yields no survival benefit and may impair neurocognitive function. These opinions are based largely on studies in other tumour types in which assessment of neurocognitive function has been incomplete.</p> <p>Methods/Design</p> <p>This trial is an international, prospective multi-centre, open-label, phase III randomised controlled trial comparing WBRT to observation following local treatment of intracranial melanoma metastases with surgery and/or SRS. Patients aged 18 years or older with 1-3 brain metastases excised and/or stereotactically irradiated and an ECOG status of 0-2 are eligible. Patients with leptomeningeal disease, or who have had previous WBRT or localised treatment for brain metastases are ineligible. WBRT prescription is at least 30 Gy in 10 fractions commenced within 8 weeks of surgery and/or SRS. Randomisation is stratified by the number of cerebral metastases, presence or absence of extracranial disease, treatment centre, sex, radiotherapy dose and patient age. The primary endpoint is the proportion of patients with distant intracranial failure as determined by MRI assessment at 12 months. Secondary end points include: survival, quality of life, performance status and neurocognitive function.</p> <p>Discussion</p> <p>Accrual to previous trials for patients with brain metastases has been difficult, mainly due to referral bias for or against WBRT. This trial should provide the evidence that is currently lacking in treatment decision-making for patients with melanoma brain metastases. The trial is conducted by the Australia and New Zealand Melanoma Trials Group (ANZMTG-study 01-07), and the Trans Tasman Radiation Oncology Group (TROG) but international participation is encouraged. Twelve sites are open to date with 43 patients randomised as of the 31st March 2011. The target accrual is 200 patients.</p> <p>Trial registration</p> <p>Australia and New Zealand Clinical Trials Register (ANZCTR): <a href="http://www.anzctr.org.au/ACTRN12607000512426.aspx">ACTRN12607000512426</a></p

Improving Approximate Pure Nash Equilibria in Congestion Games

Congestion games constitute an important class of games to model resource allocation by different users. As computing an exact or even an approximate pure Nash equilibrium is in general PLS-complete, Caragiannis et al. (2011) present a polynomial-time algorithm that computes a ($2 + \epsilon$)-approximate pure Nash equilibria for games with linear cost functions and further results for polynomial cost functions. We show that this factor can be improved to $(1.61+\epsilon)$ and further improved results for polynomial cost functions, by a seemingly simple modification to their algorithm by allowing for the cost functions used during the best response dynamics be different from the overall objective function. Interestingly, our modification to the algorithm also extends to efficiently computing improved approximate pure Nash equilibria in games with arbitrary non-decreasing resource cost functions. Additionally, our analysis exhibits an interesting method to optimally compute universal load dependent taxes and using linear programming duality prove tight bounds on PoA under universal taxation, e.g, 2.012 for linear congestion games and further results for polynomial cost functions. Although our approach yield weaker results than that in Bil\`{o} and Vinci (2016), we remark that our cost functions are locally computable and in contrast to Bil\`{o} and Vinci (2016) are independent of the actual instance of the game

A dynamic network approach for the study of human phenotypes

The use of networks to integrate different genetic, proteomic, and metabolic datasets has been proposed as a viable path toward elucidating the origins of specific diseases. Here we introduce a new phenotypic database summarizing correlations obtained from the disease history of more than 30 million patients in a Phenotypic Disease Network (PDN). We present evidence that the structure of the PDN is relevant to the understanding of illness progression by showing that (1) patients develop diseases close in the network to those they already have; (2) the progression of disease along the links of the network is different for patients of different genders and ethnicities; (3) patients diagnosed with diseases which are more highly connected in the PDN tend to die sooner than those affected by less connected diseases; and (4) diseases that tend to be preceded by others in the PDN tend to be more connected than diseases that precede other illnesses, and are associated with higher degrees of mortality. Our findings show that disease progression can be represented and studied using network methods, offering the potential to enhance our understanding of the origin and evolution of human diseases. The dataset introduced here, released concurrently with this publication, represents the largest relational phenotypic resource publicly available to the research community.Comment: 28 pages (double space), 6 figure

Inhaled tobramycin solution-associated recurrent eosinophilia and severe persistent bronchospasm in a patient with cystic fibrosis: a case report

BACKGROUND: Delivery of tobramycin by inhalation to the lungs of patients with cystic fibrosis (CF) who are infected with Pseudomonas aeruginosa has been proven to be effective and safe. The aerosol administration allows high concentrations of tobramycin to be delivered to the site of infection with limited systemic absorption. In rare patients, systemic absorption of inhaled tobramycin may be significant enough to produce toxic effects, such as renal and vestibular toxicities. CASE PRESENTATION: We report a patient with CF who developed recurrent eosinophilia and severe persistent bronchospasm following repeated administration of preservative-free tobramycin by inhalation, beginning at 16 months of age. Also, he developed similar signs and symptoms when he was administered tobramycin intravenously on one occasion at 5 1/2 years. The patient had a history of environmental allergies. Temporal sequence of his signs and symptoms after each administration of tobramycin (similar to re-challenge testing), and his improvement after discontinuation of the drug strongly suggest an adverse drug reaction. CONCLUSION: Hypersensitivity reaction should be considered in patients who develop recurrent eosinophilia and deterioration of pulmonary function following the use of tobramycin by inhalation or by intravenous administration

Probing electron-phonon interactions away from the Fermi level with resonant inelastic x-ray scattering

Interactions between electrons and lattice vibrations are responsible for a wide range of material properties and applications. Recently, there has been considerable interest in the development of resonant inelastic x-ray scattering (RIXS) as a tool for measuring electron-phonon ( e -ph) interactions. Here, we demonstrate the ability of RIXS to probe the interaction between phonons and specific electronic states both near to, and away from, the Fermi level. We perform carbon K -edge RIXS measurements on graphite, tuning the incident x-ray energy to separately probe the interactions of the π ∗ and σ ∗ electronic states. Our high-resolution data reveal detailed structure in the multiphonon RIXS features that directly encodes the momentum dependence of the e -ph interaction strength. We develop a Green’s-function method to model this structure, which naturally accounts for the phonon and interaction-strength dispersions, as well as the mixing of phonon momenta in the intermediate state. This model shows that the differences between the spectra can be fully explained by contrasting trends of the e -ph interaction through the Brillouin zone, being concentrated at the Γ and K points for the π ∗ states while being significant at all momenta for the σ ∗ states. Our results advance the interpretation of phonon excitations in RIXS and extend its applicability as a probe of e -ph interactions to a new range of out-of-equilibrium situations

Shear localization and recrystallization in dynamic deformation of 8090 Al-Li alloy

The microstructural evolution in localized shear deformation was investigated in an 8090 Al-Li alloy by split Hopkinson pressure bar (strain rate of approximately 10(3) s(-1)) at ambient temperature and 77 K. The alloy was tested in the peak-, over-, under-, and natural-aged conditions, that provide a wide range of microstructural parameters and mechanical properties. Two types of localized shear bands were distinguished by optical microscopy: the deformed shear band and the white-etching shear band. They form at different stages of deformation during localization. There are critical strains for the occurrence of deformed and white-etching localized shear deformation, at the imposed strain rate. Observations by transmission electron microscopy reveal that the white-etching bands contain fine equiaxed grains; it is proposed that they are the result of recrystallization occurring during localization. The deformed-type bands are observed after testing at 77 K in all heat treatment conditions, but they are not as well defined as those developed at ambient temperature. Cracking often occurs along the localized shear at ambient temperature. The decrement in temperature is favorable for the nucleation, growth and coalescence of the microcracks along the shear bands, inducing fracture

Mifamurtide for the treatment of nonmetastatic osteosarcoma

International audienceINTRODUCTION: The standard treatment for osteosarcoma requires both macroscopic surgical wide resection and postoperative multi-drug chemotherapy in neoadjuvant and adjuvant settings. However, the 5-year event-free survival has remained at a plateau of 60-70% of patients with nonmetastatic osteosarcoma for more than 30 years. AREAS COVERED: Mifamurtide (liposomal muramyl tripeptide phosphatidylethanolamine; L-MTP-PE) is a new agent. L-MTP-PE is a nonspecific immunomodulator, which is a synthetic analog of a component of bacterial cell walls. L-MTP-PE activates macrophages and monocytes as a potent activator of immune response in addition to standard chemotherapy. It also improves the overall survival from 70 to 78% and results in a one-third reduction in the risk of death from osteosarcoma. This review summarizes the most recent findings about L-MTP-PE and its therapeutic application for nonmetastatic osteosarcoma. EXPERT OPINION: Recently, L-MTP-PE has been approved in Europe for the treatment of nonmetastatic osteosarcoma with chemotherapy. L-MTP-PE in combination with traditional treatment is expected to go mainstream and to be beneficial for patients with osteosarcoma. Information about potential benefit regarding mifamurtide use in the neoadjuvant setting (i.e., before surgery) and/or usefulness of L-MTP-PE in metastatic in relapsed and metastatic osteosarcoma requires analysis of expanded access and/or future clinical trials of L-MTP-PE in high-burden and low-burden situations

The Comparative Oncology Trials Consortium: Using Spontaneously Occurring Cancers in Dogs to Inform the Cancer Drug Development Pathway

Chand Khanna and colleagues describe the work of the Comparative Oncology Trials Consortium (COTC), which provides infrastructure and resources to integrate naturally occurring dog cancer models into the development of new human cancer drugs, devices, and imaging techniques

Relationship between smoking and obesity:a cross-sectional study of 499,504 middle-aged adults in the UK general population

Background: There is a general perception that smoking protects against weight gain and this may influence commencement and continuation of smoking, especially among young women.&lt;p&gt;&lt;/p&gt; Methods: A cross-sectional study was conducted using baseline data from UK Biobank. Logistic regression analyses were used to explore the association between smoking and obesity; defined as body mass index (BMI) &gt;30kg/m2. Smoking was examined in terms of smoking status, amount smoked, duration of smoking and time since quitting and we adjusted for the potential confounding effects of age, sex, socioeconomic deprivation, physical activity, alcohol consumption, hypertension and diabetes.&lt;p&gt;&lt;/p&gt; Results: The study comprised 499,504 adults aged 31 to 69 years. Overall, current smokers were less likely to be obese than never smokers (adjusted OR 0.83 95% CI 0.81-0.86). However, there was no significant association in the youngest sub-group (≤40 years). Former smokers were more likely to be obese than both current smokers (adjusted OR 1.33 95% CI 1.30-1.37) and never smokers (adjusted OR 1.14 95% CI 1.12-1.15). Among smokers, the risk of obesity increased with the amount smoked and former heavy smokers were more likely to be obese than former light smokers (adjusted OR 1.60, 95% 1.56-1.64, p&lt;0.001). Risk of obesity fell with time from quitting. After 30 years, former smokers still had higher risk of obesity than current smokers but the same risk as never smokers.&lt;p&gt;&lt;/p&gt; Conclusion: Beliefs that smoking protects against obesity may be over-simplistic; especially among younger and heavier smokers. Quitting smoking may be associated with temporary weight gain. Therefore, smoking cessation interventions should include weight management support.&lt;p&gt;&lt;/p&gt