Long-term effects of Garcinia cambogia/Glucomannan on weight loss in people with obesity, PLIN4, FTO and Trp64Arg polymorphisms

Overweight and obesity are considered major health problems that contribute to increase mortality and quality of life. Both conditions have a high prevalence across the world reaching epidemic numbers. Our aim...

http://ift.tt/2DyoI3i

Evaluation of biological potential of selected species of family Poaceae from Bahawalpur, Pakistan

Oxidative stress as well as bacterial and fungal infections are common source of diseases while plants are source of medication for curative or protective purposes. Hence, aim of study was to compare the pharm...

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Thermal-Responsive Polymers for Enhancing Safety of Electrochemical Storage Devices

Abstract

Thermal runway constitutes the most pressing safety issue in lithium-ion batteries and supercapacitors of large-scale and high-power density due to risks of fire or explosion. However, traditional strategies for averting thermal runaway do not enable the charging–discharging rate to change according to temperature or the original performance to resume when the device is cooled to room temperature. To efficiently control thermal runaway, thermal-responsive polymers provide a feasible and reversible strategy due to their ability to sense and subsequently act according to a predetermined sequence when triggered by heat. Herein, recent research progress on the use of thermal-responsive polymers to enhance the thermal safety of electrochemical storage devices is reviewed. First, a brief discussion is provided on the methods of preventing thermal runaway in electrochemical storage devices. Subsequently, a short review is provided on the different types of thermal-responsive polymers that can efficiently avoid thermal runaway, such as phase change polymers, polymers with sol–gel transitions, and polymers with positive temperature coefficients. The results represent the important development of thermal-responsive polymers toward the prevention of thermal runaway in next-generation smart electrochemical storage devices.

Thermal-responsive polymers provide a feasible and reversible strategy to efficiently control thermal runaway due to their ability to sense and subsequently act according to a predetermined sequence when triggered by heat. A short review is provided on using thermal-responsive polymers to efficiently avoid thermal runaway, such as polymers with phase changes, polymers with sol–gel transitions, and polymers with a positive temperature coefficient.

http://ift.tt/2DyUocG

Crystallographic Orientation Dependent Reactive Ion Etching in Single Crystal Diamond

Abstract

Sculpturing desired shapes in single crystal diamond is ever more crucial in the realization of complex devices for nanophotonics, quantum computing, and quantum optics. The crystallographic orientation dependent wet etch of single crystalline silicon in potassium hydroxide (KOH) allows a range of shapes to be formed and has significant impacts on microelectromechanical systems (MEMS), atomic force microscopy (AFM), and microfluidics. Here, a crystal direction dependent dry etching principle in an inductively coupled plasma reactive ion etcher is presented, which selectively reveals desired crystal planes in monocrystalline diamond by controlling the etching conditions. Using this principle, monolithic diamond nanopillars for magnetometry using nitrogen vacancy centers are fabricated. In these nanopillars, a half-tapering angle up to 21° is achieved, the highest angle reported in the literature, which leads to a high photon efficiency and high mechanical strength of the nanopillar. These results represent the first demonstration of a crystallographic orientation dependent reactive ion etching principle, which opens a new window for shaping specific nanostructures which is at the heart of nanotechnology. It is believed that this principle will prove to be valuable for the structuring and patterning of other single crystal materials as well.

A crystal direction dependent dry etching principle in an inductively coupled plasma reactive ion etcher is presented, which allows to selectively reveal desired crystal planes in monocrystalline diamond by controlling the etching conditions. It is believed that this principle will prove to be valuable for the structuring and patterning of other single crystal materials as well.

http://ift.tt/2F6Jyae

Synergism of Geometric Construction and Electronic Regulation: 3D Se-(NiCo)Sx/(OH)x Nanosheets for Highly Efficient Overall Water Splitting

Abstract

The exploration of highly efficient electrocatalysts for both oxygen and hydrogen generation via water splitting is receiving considerable attention in recent decades. Up till now, Pt-based catalysts still exhibit the best hydrogen evolution reaction (HER) performance and Ir/Ru-based oxides are identified as the benchmark for oxygen evolution reaction (OER). However, the high cost and rarity of these materials extremely hinder their large-scale applications. This paper describes the construction of the ultrathin defect-enriched 3D Se-(NiCo)S_x/(OH)_x nanosheets for overall water splitting through a facile Se-induced hydrothermal treatment. Via Se-induced fabrication, highly efficient Se-(NiCo)S_x/(OH)_x nanosheets are successfully fabricated through morphology optimization, defect engineering, and electronic structure tailoring. The as-prepared hybrids exhibit relatively low overpotentials of 155 and 103 mV at the current density of 10 mA cm⁻² for OER and HER, respectively. Moreover, an overall water-splitting device delivers a current density of 10 mA cm⁻² for ≈66 h without obvious degradation.

This communication describes the construction of ultrathin defect-enriched Se-(NiCo)S_x/(OH)_x nanosheets through a facile Se-induced hydrothermal treatment. Benefited from morphological optimization, defect engineering and electronic-structure tailoring, Se-(NiCo)S_x/(OH)_x exhibits highly efficient activity and long-term stability for oxygen evolution, hydrogen evolution, and overall water splitting.

http://ift.tt/2rBZY8J

Endowing Perovskite Nanocrystals with Circularly Polarized Luminescence

Abstract

Perovskite nanocrystals are attracting great interest due to their excellent photonic properties. Here, through a supramolecular self-assembly approach, the perovskite nanocrystals (NCs) with a novel circularly polarized luminescence (CPL) are successfully endowed. It is found that the achiral perovskite NCs can coassemble with chiral gelator in nonpolar solvents, in which the gelator molecules modify the surface of the perovskite NCs. Through such cogelation, the molecular chirality can transfer to the NCs resulting in CPL signals with a dissymmetric factor (g_lum) up to 10⁻³. Furthermore, depending on the molecular chirality of the gelator, the CPL sense can be selected and the mirror-imaged CPL is obtained. Such gels can be further embedded into the polymer film to facilitate flexible CPL devices. It is envisaged that this approach will afford a new insight into the designing of the functional chiroptical materials.

Circularly polarized luminescent perovskite nanocrystals are obtained through supramolecular encapsulating in organogel. Chiral gel made from a chiral lipid gelator can endow various colorful achiral perovskite nanocrystals with chirality that show intense circularly polarized luminescence.

http://ift.tt/2Gc6Cpa

Defect Effects on TiO2 Nanosheets: Stabilizing Single Atomic Site Au and Promoting Catalytic Properties

Abstract

Isolated single atomic site catalysts have attracted great interest due to their remarkable catalytic properties. Because of their high surface energy, single atoms are highly mobile and tend to form aggregate during synthetic and catalytic processes. Therefore, it is a significant challenge to fabricate isolated single atomic site catalysts with good stability. Herein, a gentle method to stabilize single atomic site metal by constructing defects on the surface of supports is presented. As a proof of concept, single atomic site Au supported on defective TiO₂ nanosheets is prepared and it is discovered that (1) the surface defects on TiO₂ nanosheets can effectively stabilize Au single atomic sites through forming the Ti–Au–Ti structure; and (2) the Ti–Au–Ti structure can also promote the catalytic properties through reducing the energy barrier and relieving the competitive adsorption on isolated Au atomic sites. It is believed that this work paves a way to design stable and active single atomic site catalysts on oxide supports.

Single atomic sites of Au are supported on defective TiO₂ nanosheets and it is discovered that the surface defects on TiO₂ nanosheets can effectively stabilize Au single atomic sites through forming a Ti–Au–Ti structure, and this Ti–Au–Ti structure can also promote the catalytic properties through reducing the energy barrier and relieving the competitive adsorption on isolated Au atomic sites.

http://ift.tt/2rAGn8D

Transfusion practices in traumatic brain injury

Purpose of review The aim of this review is to summarize the recent studies looking at the effects of anemia and red blood cell transfusion in critically-ill patients with traumatic brain injury (TBI), describe the transfusion practice variations observed worldwide, and outline the ongoing trials evaluating restrictive versus liberal transfusion strategies for TBI. Recent findings Anemia is common among critically-ill patients with TBI, it is also thought to exacerbate secondary brain injury, and is associated with an increased risk of poor outcome. Conversely, allogenic red blood cell transfusion carries its own risks and complications, and has been associated with worse outcomes. Globally, there are large reported differences in the hemoglobin threshold used for transfusion after TBI. Observational studies have shown differential results for improvements in cerebral oxygenation and metabolism after red blood cell transfusion in TBI. Summary Currently, there is insufficient evidence to make strong recommendations regarding which hemoglobin threshold to use as a transfusion trigger in critically-ill patients with TBI. There is also uncertainty whether the restrictive transfusion strategy used in general critical care can be extrapolated to acutely brain injured patients. Ultimately, the consequences of anemia-induced cerebral injury need to be weighed up against the risks and complications associated with red blood cell transfusion. Correspondence to Victoria A. McCredie, MBChB, PhD, Department of Critical Care Medicine, 2nd Floor McLaughlin Rm 411-J, Toronto Western Hospital, University Health Network, 399 Bathurst St, Toronto, Canada M5T 2S8. Tel: +1 416 302 1959; e-mail: Victoria.McCredie@uhn.ca Copyright © 2018 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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Staff and family response to end-of-life care in the ICU

Purpose of review End-of-life (EOL) care can be stressful for clinicians as well as patients and their relatives. Decisions to withhold or withdraw life-sustaining therapy vary widely depending on culture, beliefs and organizational norms. The following review will describe the current understanding of the problem and give an overview over interventional studies. Recent findings EOL care is a risk factor for clinician burnout; poor work conditions contribute to emotional exhaustion and intent to leave. The impact of EOL care on families is part of the acute Family Intensive Care Unit Syndrome (FICUS) and the Post Intensive Care Syndrome–Family (PICS-F). Family-centered care (FCC) acknowledges the importance of relatives in the ICU. Several interventions have been evaluated, but evidence for their effectiveness is at best moderate. Some interventions even increased family stress. Interventional studies, which address clinician burnout are rare. Summary EOL care is associated with negative outcomes for ICU clinicians and relatives, but strength of evidence for interventions is weak because we lack understanding of associated factors like work conditions, organizational issues or individual attitudes. In order to develop complex interventions that can successfully mitigate stress related to EOL care, more research is necessary, which takes into account all potential determinants. Correspondence to Dr Konrad Reinhart, ML, Senior Professor, Jena University Hospital, Chairman Global Sepsis Alliance, Paul-Schneider-Street 2, 07747 Jena, Germany. E-mail: konrad.reinhart@med.uni-jena.de Copyright © 2018 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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Pediatric trauma transfusion and cognitive aids

Purpose of review Trauma is the most common cause of pediatric mortality. Much of the research that led to life-saving interventions in adults, however, has not been replicated in the pediatric population. Children have important physiologic and anatomic differences from adults, which impact hemostasis and transfusion. Hemorrhage is a leading cause of death in trauma, and children have important differences in their coagulation profiles. Transfusion strategies, including the massive transfusion protocol and use of antifibrinolytics, are still controversial. In addition to the blood that is lost from the injury itself, trauma leads to inflammation and to a dysfunction in hemostasis, causing coagulopathy. Recent findings In one study in which children suffered from mainly blast and penetrating injuries in a combat setting (PEDTRAX trial), the early administration of tranexamic acid was associated with decreased mortality. Some authors suggest that this result may not apply to blunt trauma, which is much more common in children in noncombat settings. Using thromboelastography to guide the administration of recombinant Factor VIIa has been done in selected cases and may represent a future avenue of research. Summary This article explores new research from the past year in pediatric trauma, starting with the physiologic differences in pediatric red blood cells and coagulation profiles. We also looked at the dramatic change in thinking over the past decade in the tolerable level of anemia in critically ill pediatric patients, as well as scales for determining the need for massive transfusion and exploring if the concepts of damage control resuscitation apply to children. Other strategies, such as avoiding hypothermia, and the selective administration of antifibriniolytics, are important in pediatric trauma as well. Future research that is pediatric focused is needed for the optimal care of our youngest patients. Correspondence: Anna Clebone, MD, Assistant Professor, Department of Anesthesia and Critical Care, University of Chicago, 5841 S. Maryland Ave. MC-4028, Chicago, IL 60637, USA. Tel: +773 702 6700; e-mail: aclebone@dacc.uchicago.edu Copyright © 2018 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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Spirituality at the end of life

Purpose of review There is increasing emphasis on medical care of the whole patient. This holistic approach encompasses supporting the spiritual or religious needs of the patient. Particularly at the end of life, spiritual concerns may come to the fore as patients recognize and accept their impending death. Physicians may also recognize this spiritual distress but may not be clear on how to provide spiritual support. Recent findings Tools to screen for spiritual concerns are available for physicians to use. Some physicians wish to go further, supporting patients at the end of life in their spiritual quest. Other physicians express concern about causing more distress to patients in a time of significant need. Descriptions of educational tools, as well as the difference between spiritual generalists and spiritual specialists have emerged. Integration of chaplains into the medical team caring for patients at the end of life will also enhance care of the whole patient. Summary The increasing emphasis on whole patient care is leading to increasing focus on spiritual concerns of patients. Although not every patient has an interest in spiritual conversation, most do and medical teams will need to become more educated about appropriate spiritual engagement. Correspondence to Cynthiane J. Morgenweck, MD, MA, Center for Bioethics and Medical Humanities, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA. Tel: +1 414 955 8498; e-mail: cmorg@mcw.edu Copyright © 2018 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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American Society for Enhanced Recovery and Perioperative Quality Initiative Joint Consensus Statement on Nutrition Screening and Therapy Within a Surgical Enhanced Recovery Pathway

Perioperative malnutrition has proven to be challenging to define, diagnose, and treat. Despite these challenges, it is well known that suboptimal nutritional status is a strong independent predictor of poor postoperative outcomes. Although perioperative caregivers consistently express recognition of the importance of nutrition screening and optimization in the perioperative period, implementation of evidence-based perioperative nutrition guidelines and pathways in the United States has been quite limited and needs to be addressed in surgery-focused recommendations. The second Perioperative Quality Initiative brought together a group of international experts with the objective of providing consensus recommendations on this important topic with the goal of (1) developing guidelines for screening of nutritional status to identify patients at risk for adverse outcomes due to malnutrition; (2) address optimal methods of providing nutritional support and optimizing nutrition status preoperatively; and (3) identifying when and how to optimize nutrition delivery in the postoperative period. Discussion led to strong recommendations for implementation of routine preoperative nutrition screening to identify patients in need of preoperative nutrition optimization. Postoperatively, nutrition delivery should be restarted immediately after surgery. The key role of oral nutrition supplements, enteral nutrition, and parenteral nutrition (implemented in that order) in most perioperative patients was advocated for with protein delivery being more important than total calorie delivery. Finally, the role of often-inadequate nutrition intake in the posthospital setting was discussed, and the role of postdischarge oral nutrition supplements was emphasized. Accepted for publication October 27, 2017. Funding: The Perioperative Quality Initiative (POQI) meeting received financial assistance from the American Society for Enhanced Recovery (ASER). Conflicts of Interest: See Disclosures at the end of the article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://ift.tt/KegmMq). For the Perioperative Quality Initiative (POQI) 2 Workgroup, see Supplemental Digital Content, Appendix 1, http://ift.tt/2n5LfOn. Reprints will not be available from the authors. Address correspondence to Timothy E. Miller, MB, ChB, FRCA, Division of General, Vascular and Transplant Anesthesia, Duke University Medical Center, Box 3094, Durham, NC 27710. Address e-mail to timothy.miller2@duke.edu. © 2018 International Anesthesia Research Society

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Age Does Not Affect Metoprolol’s Effect on Perioperative Outcomes (From the POISE Database)

BACKGROUND: Perioperative β-blockade reduces the incidence of myocardial infarction but increases that of death, stroke, and hypotension. The elderly may experience few benefits but more harms associated with β-blockade due to a normal effect of aging, that of a reduced resting heart rate. The tested hypothesis was that the effect of perioperative β-blockade is more significant with increasing age. METHODS: To determine whether the effect of perioperative β-blockade on the primary composite event, clinically significant hypotension, myocardial infarction, stroke, and death varies with age, we interrogated data from the perioperative ischemia evaluation (POISE) study. The POISE study randomly assigned 8351 patients, aged ≥45 years, in 23 countries, undergoing major noncardiac surgery to either 200 mg metoprolol CR daily or placebo for 30 days. Odds ratios or hazard ratios for time to events, when available, for each of the adverse effects were measured according to decile of age, and interaction term between age and treatment was calculated. No adjustment was made for multiple outcomes. RESULTS: Age was associated with higher incidences of the major outcomes of clinically significant hypotension, myocardial infarction, and death. Age was associated with a minimal reduction in resting heart rate from 84.2 (standard error, 0.63; ages 45–54 years) to 80.9 (standard error, 0.70; ages >85 years; P

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Using the Ventrain With a Small-Bore Catheter: Ventilation or Just Oxygenation?

No abstract available

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The Effects of Agrin Isoforms on Diabetic Neuropathic Pain in a Rat Streptozotocin Model

BACKGROUND: Diabetes mellitus affects 9.3% of the US population and increases risks of surgery and complications. Diabetic neuropathic pain (DNP), one of the main consequences of diabetes mellitus, is extremely difficult to treat. Current medications yield limited benefits and/or have severe adverse effects. Therefore, new, effective treatment is needed. METHODS: Streptozotocin at 55 mg/kg was injected intraperitoneally in rats to induce diabetes mellitus. Diabetic rats exhibiting neuropathic pain underwent intrathecal injection of purified agrin proteins at various doses and were then tested for tactile allodynia to evaluate whether DNP was inhibited. The agrin effects were also analyzed with patch-clamp recording on spinal cord slices. RESULTS: Fifty–kilo Dalton agrin (Agr50) at 0.2 and 2 ng suppressed DNP when given intrathecally, while 25- and 75-kDa agrin (Agr25, Agr75) had little effect. The suppressive effect of Agr50 lasted 4 hours after a single bolus injection. The difference in effects of Agr50 on mean withdrawal threshold (4.6 ± 2.2 g before treatment to 26 ± 0 g after treatment) compared with that of Agr25 (4.9 ± 2.0 g to 4.9 ± 2.0 g) and Agr75 (5.3 ± 2.3 g to 9.2 ± 2.5 g) was highly significant (P

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Electroencephalography and Brain Oxygenation Monitoring in the Perioperative Period

Maintaining brain function and integrity is a pivotal part of anesthesiological practice. The present overview aims to describe the current role of the 2 most frequently used monitoring methods for evaluation brain function in the perioperative period, ie, electroencephalography (EEG) and brain oxygenation monitoring. Available evidence suggests that EEG-derived parameters give additional information about depth of anesthesia for optimizing anesthetic titration. The effects on reduction of drug consumption or recovery time are heterogeneous, but most studies show a reduction of recovery times if anesthesia is titrated along processed EEG. It has been hypothesized that future EEG-derived indices will allow a better understanding of the neurophysiological principles of anesthetic-induced alteration of consciousness instead of the probabilistic approach most often used nowadays. Brain oxygenation can be either measured directly in brain parenchyma via a surgical burr hole, estimated from the venous outflow of the brain via a catheter in the jugular bulb, or assessed noninvasively by near-infrared spectroscopy. The latter method has increasingly been accepted clinically due to its ease of use and increasing evidence that near-infrared spectroscopy–derived cerebral oxygen saturation levels are associated with neurological and/or general perioperative complications and increased mortality. Furthermore, a goal-directed strategy aiming to avoid cerebral desaturations might help to reduce these complications. Recent evidence points out that this technology may additionally be used to assess autoregulation of cerebral blood flow and thereby help to titrate arterial blood pressure to the individual needs and for bedside diagnosis of disturbed autoregulation. Accepted for publication December 8, 2017. Funding: None. Conflicts of Interest: See Disclosures at the end of the article. Reprints will not be available from the authors. Address correspondence to Thomas W. L. Scheeren, MD, PhD, Department of Anaesthesiology, University Medical Center Groningen, PO Box 30 001, 9700 RB Groningen, the Netherlands. Address e-mail to t.w.l.scheeren@umcg.nl. © 2018 International Anesthesia Research Society

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In Response

No abstract available

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Comparison of Intranasal Dexmedetomidine and Oral Pentobarbital Sedation for Transthoracic Echocardiography in Infants and Toddlers: A Prospective, Randomized, Double-Blind Trial

BACKGROUND: Acquisition of transthoracic echocardiographic (TTEcho) images in children often requires sedation. The optimal sedative for TTEcho has not been determined. Children with congenital heart disease are repeatedly exposed to sedatives and anesthetics that may affect brain development. Dexmedetomidine, which in animals alters brain structure to a lesser degree, may offer advantages in this vulnerable population. METHODS: A prospective, randomized, double-blind trial enrolled 280 children 3–24 months of age undergoing outpatient TTEcho, comparing 2.5 µg·kg−1 intranasal dexmedetomidine to 5 mg·kg−1 oral pentobarbital. Rescue sedation, for both groups, was intranasal dexmedetomidine 1 µg·kg−1. The primary outcome was adequate sedation within 30 minutes without rescue sedation, assessed by blinded personnel. Secondary outcomes included number of sonographer pauses, image quality in relation to motion artifacts, and parental satisfaction. RESULTS: Success rates with a single dose were not different between sedation techniques; 85% in the pentobarbital group and 84% in the dexmedetomidine group (P = .8697). Median onset of adequate sedation was marginally faster with pentobarbital (16.5 [interquartile range, 13–21] vs 18 [16–23] minutes for dexmedetomidine [P = .0095]). Time from drug administration to discharge was not different (P = .8238) at 70.5 (64–83) minutes with pentobarbital and 70 (63–82) minutes with dexmedetomidine. Ninety-five percent of sedation failures with pentobarbital and 100% of dexmedetomidine failures had successful rescue sedation with intranasal dexmedetomidine. CONCLUSIONS: Intranasal dexmedetomidine was comparable to oral pentobarbital sedation for TTEcho sedation in infants and did not increase the risk of clinically important adverse events. Intranasal dexmedetomidine appears to be an effective "rescue" sedative for both failed pentobarbital and dexmedetomidine sedation. Dexmedetomidine could be a safer option for repeated sedation in children, but further studies are needed to assess long-term consequence of repeated sedation in this high-risk population. Accepted for publication December 1, 2017. Funding: This research was funded by a grant from the Children's Heart Association of Cincinnati and departmental support. The authors declare no conflicts of interest. Clinical trial registration: NCT02250820. LMA is a registered trademark of Teleflex Incorporated or its affiliates. Reprints will not be available from the authors. Address correspondence to Jeffrey W. Miller, MD, Department of Anesthesiology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, MLC 2001, Cincinnati, OH. Address e-mail to Jeff.Miller@cchmc.org. © 2018 International Anesthesia Research Society

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NKX6.1 hypermethylation predicts the outcome of stage II colorectal cancer patients undergoing chemotherapy

Abstract

Colorectal cancer (CRC) is a common malignancy worldwide. CRC patients in the same stage often present with dramatically different clinical scenarios. Thus, robust prognostic biomarkers are urgently needed to guide therapies and improve treatment outcomes. The NKX6.1 gene has been identified as a hypermethylation marker in cervical cancer, functioning as a metastasis suppressor by regulating epithelial–mesenchymal transition. Here, we investigated whether hypermethylation of NKX6.1 might be a prognostic biomarker for CRC. By analyzing the methylation and expression of NKX6.1 in CRC tissues and CRC cell lines. We quantitatively examined the NKX6.1 methylation levels in 151 pairs of CRC tissues by using methylation-specific polymerase chain reaction analysis and found that NKX6.1 was hypermethylated in 35 of 151 CRC tissues (23%). NKX6.1 gene expression was inversely correlated with the DNA methylation level in CRC cell lines in vitro. Then, we analyzed the association of NKX6.1 methylation with clinical characteristics of these CRC patients. Our data demonstrated that patients with NKX6.1 methylation presented poorer 5-year overall survival (P=0.0167) and disease-free survival (P=0.0083) than patients without NKX6.1 methylation after receiving adjuvant chemotherapy. Most importantly, these data revealed that stage II CRC patients with NKX6.1 methylation had poorer 5-year disease-free survival (P=0.0322) than patients without NKX6.1 methylation after adjuvant chemotherapy. Our results demonstrate that methylation of NKX6.1 is a novel prognostic biomarker in CRC and that it may be used as a predictor of the response to chemotherapy. This article is protected by copyright. All rights reserved.

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Localization and dimer stability of a newly identified microbial rhodopsin from a polar, non-motile green algae

The eukaryotic plasma membrane localized light-gated proton-pumping rhodopsins possesses great optogenetic applications for repolarization (silencing) of the neuronal activity simply by light illumination. Ver...

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Outcomes of children aged 6–59 months with severe acute malnutrition at the GADO Outpatient Therapeutic Center in Cameroon

We aimed to assess outcomes [rates of recovery, default, case fatality; rate of weight gain and rate of Mean Upper Arm Circumference (MUAC) gain] of children aged 6–59 months with severe acute malnutrition (SA...

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Considerations for skin carcinogenesis experiments using inducible transgenic mouse models

This study was designed to estimate the percentage of non-malignant skin tumours (papillomas) progressing to malignant squamous cell carcinomas (SCCs) in a carcinogenesis study using established transgenic mou...

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Medical student attitudes towards older people: a critical review of quantitative measures

Further research into medical student attitudes towards older people is important, and requires accurate and detailed evaluative methodology. The two objectives for this paper are: (1) From the literature, to ...

http://ift.tt/2DFSnuA

Evaluation of tumor volume reduction of nasal carcinomas versus sarcomas in dogs treated with definitive fractionated megavoltage radiation: 15 cases (2010–2016)

Local control is a major challenge in treating canine nasal tumors, and cytoreduction following radiation therapy has been recommended to extend survival and to delay local recurrence. Our objective was to com...

http://ift.tt/2F89Vwy

Critical Evaluation of Causality Assessment of Herb-Drug Interactions in Patients

Abstract

Aim

The aim of this review was to assess the severity of adverse drug reactions (ADRs) due to herb-drug interactions in patients taking herbs and prescribed medications based on published evidence.

Method

Electronic databases of PubMed, the Cochrane Library, Medline and Scopus were searched for randomized or non-randomized clinical studies, case-control and case reports of herb-drug interactions (HDI). The data was extracted and the causal relationship of ADRs as consequences of HDI assessed using Horn's drug interaction probability scale (DIPS) or Roussel Uclaf Causality Assessment Method (RUCAM) scoring systems. The mechanism of interaction was ascertained using Stockley's herbal medicine interaction companion.

Results

Forty-nine case reports and two observational studies with 15 cases of ADRs were recorded. The majority of the patients were diagnosed with cardiovascular diseases (30.60%), cancer (22.45%) and renal transplants (16.32%) receiving mostly warfarin, alkylating agents and cyclosporine, respectively.

Conclusion

HDI occurred in patients resulting in clinical ADRs with different severity. Patients may poorly respond to therapeutic agents or develop toxicity due to severe HDI which in either scenario may increase the cost of treatment and /or lead to or prolong patient hospitalisation. It is warranted to increase patient awareness of the potential interaction between herbs and prescribed medicines and their consequences to curb HDI as a potential health problem.

http://ift.tt/2n5AKKk

Clinicopathological and 123I-FP-CIT SPECT correlations in patients with dementia

Abstract

The relationship between clinicopathologic diagnosis and ¹²³I-FP-CIT SPECT in 18 patients with dementia (12 with Lewy body disease) from one center in the United States was assessed. The sensitivity and specificity of abnormal ¹²³I-FP-CIT SPECT with reduced striatal uptake on visual inspection for predicting Lewy body disease were 91.7% and 83.3%, respectively. The mean calculated putamen to occipital ratio (mPOR) based on regions of interest was significantly reduced in Lewy body disease compared to non-Lewy body disease cases (P = 0.002). In this study, abnormal ¹²³I-FP-CIT SPECT was strongly associated with underlying Lewy body disease pathology, supporting the utility of ¹²³I-FP-CIT SPECT in the clinical diagnosis of dementia with Lewy bodies.

http://ift.tt/2DEr5EQ

Hydration prevents chronic hyperglycaemic patients from neurological deterioration post-ischaemic stroke

Objectives

To determine whether chronic hyperglycaemia predisposes patients to dehydration, which may promote neurological deterioration, and to investigate whether dehydration control improves functional outcome.

Patients and Methods

This study included 355 patients hospitalized with acute ischaemic stroke and diabetes mellitus who fulfilled the glycaemic gap ≤0. We used the following cut-offs: (i) no chronic hyperglycaemia (glycated haemoglobin A1c [HbA1c] < 7%) and (ii) chronic hyperglycaemia (HbA1c ≥ 7%). The chronic hyperglycaemic patients were randomly divided into the control group and the hydration group. Hydration therapy was only initiated in the hydration group. The blood urea nitrogen (BUN)/creatinine (Cr) ratio was used as an indicator of dehydration. Stroke severity on admission and discharge was assessed by means of National Institutes of Health Stroke Scale (NIHSS).

Results

The mean baseline BUN/Cr ratios were higher in the control group and hydration group than in the no chronic hyperglycaemia group. The mean BUN/Cr ratio decreased from 91.22 ± 29.95 on the first day to 77.03 ± 18.23 on the third day (P < .001) in the hydration group. On the third day after admission, there was no significant difference in the BUN/Cr ratio between the hydration group and the no chronic hyperglycaemia group (P = .831). Moreover, neurological deterioration was highest in the control group (33.6%, 36/107), followed by the hydration group (10.5%, 11/105) and the no chronic hyperglycaemia group (5.6%, 8/143).

Conclusions

Chronic hyperglycaemia was associated with the admission NIHSS score and neurological deterioration after excluding the effect of stress hyperglycaemia. Furthermore, hydration therapy may help prevent neurological deterioration.

http://ift.tt/2Fa4YTP

Electroclinical findings and long-term outcomes in epileptic patients with inv dup (15)

Objective

To define the electroclinical phenotype and long-term outcomes in a cohort of patients with inv dup (15) syndrome.

Material and Methods

The electroclinical data of 45 patients (25 males) affected by inv dup (15) and seizures were retrospectively analysed, and long-term follow-up of epilepsy was evaluated.

Results

Epilepsy onset was marked by generalized seizures in 53% of patients, epileptic spasms in 51%, focal seizures in 26%, atypical absences in 11% and epileptic falls in 9%. The epileptic syndromes defined were: generalized epilepsy (26.7%), focal epilepsy (22.3%), epileptic encephalopathy with epileptic spasms as the only seizure type (17.7%) and Lennox-Gastaut syndrome (33.3%). Drug-resistant epilepsy was detected in 55.5% of patients. There was a significant higher prevalence of seizure-free patients in those with seizure onset after the age of 5 years and with focal epilepsy, with respect to those with earlier epilepsy onset because most of these later developed an epileptic encephalopathy (69.2% vs 34.4%; P = .03), usually Lennox-Gastaut Syndrome in type. In fact, among patients with early-onset epilepsy, those presenting with epileptic spasms as the only seizure type associated with classical hypsarrhythmia achieved seizure freedom (P < .001) compared to patients with spasms and other seizure types associated with modified hypsarrhythmia.

Conclusions

Epilepsy in inv dup (15) leads to a more severe burden of disease. Frequently, these patients show drug resistance, in particular when epilepsy onset is before the age of five and features epileptic encephalopathy.

http://ift.tt/2DGf9Cv

In silico identification, synthesis and biological evaluation of novel tetrazole inhibitors of MurB

Abstract

In the context of antibacterial drug discovery resurgence, novel therapeutic targets and new compounds with alternative mechanisms of action are of paramount importance. We focused on UDP-N-acetylenolpyruvylglucosamine reductase (i.e. MurB), an underexploited target enzyme that is involved in early steps of bacterial peptidoglycan biosynthesis. On the basis of the recently reported crystal structure of MurB in complex with NADP⁺, a pharmacopohore model was generated and used in a virtual screening campaign with combined structure-based and ligand-based approaches. In order to explore chemical space around hit compounds, further similarity search and organic synthesis was employed to obtain several compounds with micromolar IC₅₀ values on MurB. The best inhibitors in the reported series of 5-substituted tetrazol-2-yl acetamides were compounds 13, 26 and 30 with IC₅₀ values of 34, 28 and 25 μM, respectively. None of the reported compounds possessed in vitro antimicrobial activity against S. aureus and E. coli.

This article is protected by copyright. All rights reserved.

Combined ligand-based and structure-based approaches were used in MurB inhibitor design. Model based on crystal structure of MurB in complex with NADP⁺ was used in a virtual screening campaign to identify a tetrazole hit compound. Chemical space around the hit compound was further explored to encompass novel inhibitors of E.coli MurB displaying IC₅₀ values from 25 to 34 μM.

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Preparation and evaluation of effect on E. coli and S. aureus of radiolabeled Ampicillin loaded graphene oxide nanoflakes

Abstract

Ampicillin is a one of effective antibiotics against Gram-positive and Gram-negative bacteria. The present study aims to label ampicillin loaded graphene oxide nanoflake (AMP-GO) with ^99mTc and evaluate of its in vitro binding to S. aureus and E. coli. Firstly, ampicillin was loaded onto graphene oxide nanoflake prepared. AMP-GO was characterized by Fourier Transform Infrared Spectroscopy (FTIR) and Scanning Electron Microscope (SEM) techniques, and the amount of loaded ampicillin onto GO was determined by UV-Vis absorption spectroscopy. AMP and AMP-GO were labeled with ^99mTc using stannous chloride reducing agent. Labeling efficiency of ^99mTc-AMP-GO was found to be 97.66±2.06%. ^99mTc-AMP-GO has higher binding efficiencies to both S. aureus and E. coli than ^99mTc-AMP. ^99mTc-AMP-GO could be promising candidate as agent infection nuclear imaging. Furthermore in vivo studies of ^99mTc-AMP-GO with infected rats are planned to be done.

This article is protected by copyright. All rights reserved.

Ampicillin-Graphene oxide (AMP-GO) nanoparticles by evaluating their in vitro binding in S. aureus and E. coli for infection nuclear imaging.

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A review discussing fluciclovine (18F) PET/CT imaging in the detection of recurrent prostate cancer

Future Oncology, Ahead of Print.


http://ift.tt/2ruKEuA

The prognostic analysis of different metastatic patterns in extensive-stage small-cell lung cancer patients: a large population-based study

Future Oncology, Ahead of Print.


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Magnesium attenuates endothelin-1-induced vasoreactivity and enhances vasodilation in mouse pulmonary arteries: Modulation by chronic hypoxic pulmonary hypertension

Abstract

Pulmonary hypertension (PH) is characterized by enhanced vasoreactivity and sustained pulmonary vasoconstriction, arising from the aberrant Ca²⁺ homeostasis in pulmonary arterial smooth muscle cells. In addition to Ca²⁺, magnesium, the most abundant intracellular divalent cation, also plays critical roles in many cellular processes that regulate cardiovascular functions. Recent findings suggested that magnesium regulates vascular functions by altering the vascular responses to vasodilator and vasoactive agonists, and affects endothelial function by modulating endothelium-dependent vasodilation in hypertension. Administration of magnesium also decreased pulmonary arterial pressure and improved cardiac output in PH animal models. However, the role of magnesium in the regulation of pulmonary vascular function related to PH has not been studied. This study examined the effects of magnesium on endothelin-1 (ET-1)-induced vasoconstriction, acetylcholine (Ach)-induced vasodilatation, and the generation of nitric oxide (NO) in pulmonary arteries (PAs) of normoxic and chronic hypoxia (CH)-treated mice. Our data showed that removal of extracellular magnesium suppressed vasoreactivity of PAs to both ET-1 and Ach. High concentration of magnesium (4.8 mm) inhibited ET-1-induced vasoconstriction in endothelium intact or disrupted PAs of normoxic and CH mice, and enhanced the Ach-induced NO production in PAs of normoxic mice. Moreover, magnesium enhanced Ach-induced vasodilatation in PAs of normoxic mice, and the enhancement was completely abolished after CH exposure. Hence, this study demonstrated that increasing magnesium concentration can attenuate ET-1-induced contractile response, and improve vasodilatation via release of NO from endothelium; and chronic exposure to hypoxia can cause endothelial dysfunction resulting in the suppression of magnesium-dependent modulation of vasodilatation.

This article is protected by copyright. All rights reserved

http://ift.tt/2rwo84l

Transcutaneous electromyographic respiratory muscle recordings to quantify patient–ventilator interaction in mechanically ventilated children

To explore the feasibility of transcutaneous electromyographic respiratory muscle recordings to automatically quantify the synchronicity of patient–ventilator interaction in the pediatric intensive care unit.

http://ift.tt/2DH3Zh3

Neuromyelitis optica spectrum disorder secondary to treatment with anti-PD-1 antibody nivolumab: the first report

Abstract

Background

Immune checkpoint blockade is developed as standard treatment for non-small cell lung cancer. However immune-related adverse events (irAE) have still unknown complications. Here, we report a patient with lung squamous cell carcinoma who developed neuromyelitis optica spectrum disorder with nivolumab.

Case presentation

A 75-year-old Japanese man with lung squamous cell carcinoma was administered nivolumab as second-line treatment. Two months after treatment with nivolumab, he presented acute paralysis in the bilateral lower limbs, sensory loss. Spinal magnetic resonance imaging showed T2 hyperintense lesions between C5-6 and Th12-L1. He was diagnosed with neuromyelitis optica spectrum disorder (NMOSD) by anti-aquaporin-4 antibody-positive in the serum and other examinations. After treatment, steroid reactivity was poor.

Conclusion

This is the first patient who developed anti-AQP4 antibody-positive NMOSD as a nivolumab-induced irAE. Clinicians should be aware of this kind of potential neurological complication by using immune check point inhibitor and start the treatment of this irAE as soon as possible.

http://ift.tt/2G9H4cp

Shifting breast cancer surveillance from current hospital setting to a community based setting: a cost-effectiveness study

Abstract

Background

This study explores the effectiveness and cost-effectiveness of surveillance after breast cancer treatment provided in a hospital-setting versus surveillance embedded in the community-based National Breast Cancer Screening Program (NBCSP).

Methods

Using a decision tree, strategies were compared on effectiveness and costs from a healthcare perspective over a 5-year time horizon. Women aged 50–75 without distant metastases that underwent breast conserving surgery in 2003–2006 were selected from the Netherlands Cancer Registry (n = 14,093). Key input parameters were mammography sensitivity and specificity, risk of loco regional recurrence (LRR), and direct healthcare costs. Primary outcome measure was the proportion true test results (TTR), expressed as the positive and negative predictive value (PPV, NPV). The incremental cost-effectiveness ratio (ICER) is defined as incremental costs per TTR forgone.

Results

For the NBCSP-strategy, 13,534 TTR (8 positive; 13,526 negative), and 12,923 TTR (387 positive; 12,536 negative) were found for low and high risks respectively. For the hospital-based strategy, 26,663 TTR (13 positive; 26,650 negative) and 24,883 TTR (440 positive; 24,443 negative) were found for low and high risks respectively. For low risks, the PPV and NPV for the NBCSP-based strategy were 3.31% and 99.88%, and 2.74% and 99.95% for the hospital strategy respectively. For high risks, the PPV and NPV for the NBCSP-based strategy were 64.10% and 98.87%, and 50.98% and 99.71% for the hospital-based strategy respectively. Total expected costs of the NBCSP-based strategy were lower than for the hospital-based strategy (low risk: €1,271,666 NBCSP vs €2,698,302 hospital; high risk: €6,939,813 NBCSP vs €7,450,150 hospital), rendering ICERs that indicate cost savings of €109 (95%CI €95–€127) (low risk) and €43 (95%CI €39–€56) (high risk) per TTR forgone.

Conclusion

Despite expected cost-savings of over 50% in the NBCSP-based strategy, it is nearly 50% lower accurate than the hospital-based strategy, compromising the goal of early detection of LRR to an extent that is unlikely to be acceptable.

http://ift.tt/2rEe35F

Neural Representations Beyond “Plus X”

Abstract

In this paper we defend structural representations, more specifically neural structural representation. We are not alone in this, many are currently engaged in this endeavor. The direction we take, however, diverges from the main road, a road paved by the mathematical theory of measure that, in the 1970s, established homomorphism as the way to map empirical domains of things in the world to the codomain of numbers. By adopting the mind as codomain, this mapping became a boon for all those convinced that a representation system should bear similarities with what was being represented, but struggled to find a precise account of what such similarities mean. The euforia was brief, however, and soon homomorphism revealed itself to be affected by serious weaknesses, the primary one being that it included systems embarrassingly alien to representations. We find that the defense attempts that have followed, adopt strategies that share a common format: valid structural representations come as "homomorphism plus X", with various "X", provided in descriptive format only. Our alternative direction stems from the observation of the overlooked departure from homomorphism as used in the theory of measure and its later use in mental representations. In the former case, the codomain or the realm of numbers, is the most suited for developing theorems detailing the existence and uniqueness of homomorphism for a wide range of empirical domains. In the latter case, the codomain is the realm of the mind, possibly more vague and more ill-defined than the empirical domain itself. The time is ripe for articulating the mapping between represented domains and the mind in formal terms, by exploiting what is currently known about coding mechanisms in the brain. We provide a sketch of a possible development in this direction, one that adopts the theory of neural population coding as codomain. We will show that our framework is not only not in disagreement with the "plus X" proposals, but can lead to natural derivation of several of the "X".

http://ift.tt/2DD5pJ5

Fc-mediated Anomalous Biodistribution of Therapeutic Antibodies in Immunodeficient Mouse Models

A critical benchmark in the development of antibody-based therapeutics is demonstration of efficacy in preclinical mouse models of human disease, many of which rely on immunodeficient mice. However, relatively little is known about how the biology of various immunodeficient strains impacts the in vivo fate of these drugs. Here we used immunoPET radiotracers prepared from humanized, chimeric and murine monoclonal antibodies against four therapeutic oncologic targets to interrogate their biodistribution in four different strains of immunodeficient mice bearing lung, prostate, and ovarian cancer xenografts. The immunodeficiency status of the mouse host as well as both the biological origin and glycosylation of the antibody contributed significantly to the anomalous biodistribution of therapeutic monoclonal antibodies in an Fc receptor-dependent manner. These findings may have important implications for the preclinical evaluation of Fc-containing therapeutics and highlight a clear need for biodistribution studies in the early stages of antibody drug development.

http://ift.tt/2E2uYRN

Keratin 19 expression in hepatocellular carcinoma is regulated by fibroblast-derived HGF via a MET-ERK1/2-AP1 and SP1 axis

Keratin (KRT) 19 is a poor prognostic marker for hepatocellular carcinoma (HCC), however regulatory mechanisms underlying its expression remain unclear. We have previously reported the presence of fibrous tumor stroma in KRT19-positive HCC, suggesting that crosstalk between cancer-associated fibroblasts (CAF) and tumor epithelial cells could regulate KRT19 expression. This was investigated in this study using an in vitro model of paracrine interaction between HCC cell lines (HepG2, SNU423) and hepatic stellate cells (HSC), a major source of hepatic myofibroblasts. HSCs upregulated transcription and translation of KRT19 in HCC cells via paracrine interactions. Mechanistically, hepatocyte growth factor (HGF) from HSCs activated c-MET and the MEK-ERK1/2 pathway which upregulated KRT19 expression in HCC cells. Further, AP1 (JUN/FOSL1) and SP1, downstream transcriptional activators of ERK1/2, activated KRT19 expression in HCC cells. In clinical specimens of human HCC (n=339), HGF and KRT19 protein expression correlated with CAF levels. In addition, HGF or MET protein expression was associated with FOSL1 and KRT19 expression and was found to be a poor prognostic factor. Analysis of data from The Cancer Genome Atlas also revealed KRT19 expression was closely associated with CAF and MET-mediated signaling activities. These results provide insights into the molecular background of KRT19-positive HCC that display an aggressive phenotype.

http://ift.tt/2DwgBE2

Myeloma Cells are Activated in Bone Marrow Microenvironment by the CD180/MD-1 Complex which Senses Lipopolysaccharide

Multiple myeloma (MM) cells acquire dormancy and drug resistance via interaction with bone marrow stroma cells (BMSC) in a hypoxic microenvironment. Elucidating the mechanisms underlying the regrowth of dormant clones may contribute to further improvement of the prognosis of MM patients. In this study, we find that the CD180/MD-1 complex, a non-canonical LPS receptor, is expressed on MM cells but not on normal counterparts, and its abundance is markedly upregulated under adherent and hypoxic conditions. Bacterial LPS and anti-CD180 antibody, but not other TLR ligands, enhanced the growth of MM cells via activation of MAP kinases ERK and JNK in positive correlation with expression levels of CD180. Administration of LPS significantly increased the number of CD180/CD138 double-positive cells in a murine xenograft model when MM cells were inoculated with direct attachment to BMSC. Knockdown of CD180 canceled the LPS response in vitro and in vivo. Promoter analyses identified IKZF1 (Ikaros) as a pivotal transcriptional activator of the CD180 gene. Both cell adhesion and hypoxia activated transcription of the CD180 gene by increasing Ikaros expression and its binding to the promoter region. Pharmacological targeting of Ikaros by the immunomodulatry drug lenalidomide ameliorated the response of MM cells to LPS in a CD180-dependent manner in vitro and in vivo. Thus, the CD180/MD-1 pathway may represent a novel mechanism of growth regulation of MM cells in a BM milieu and may be a therapeutic target of preventing the regrowth of dormant MM cells.

http://ift.tt/2E2jaPk

Downregulation of membrane trafficking proteins and lactate conditioning determine loss of dendritic cell function in lung cancer

Restoring antigen presentation for efficient and durable activation of tumor-specific CD8+ T cell responses is pivotal to immunotherapy, yet the mechanisms that cause subversion of dendritic cells (DC) functions are not entirely understood, limiting the development of targeted approaches. In this study, we show that bone fide DC resident in lung tumor tissues or DC exposed to factors derived from whole lung tumors become refractory to endosomal and cytosolic sensor stimulation and fail to secrete IL-12 and IFN-I. Tumor conditioned DC exhibited downregulation of the SNARE VAMP3, a regulator of endosomes trafficking we found to be required for cross-presentation of tumor antigens and DC-mediated tumor rejection. Dissection of cell-extrinsic suppressive pathways identified lactic acid in the tumor microenvironment as sufficient to inhibit type-I interferon downstream of TLR3 and STING. DC conditioning by lactate also impacted adaptive function, accelerating antigen degradation and impairing cross-presentation. Importantly, DC conditioned by lactate failed to prime anti-tumor responses in vivo. These findings provide a new mechanistic viewpoint to the concept of DC suppression and hold potential for future therapeutic approaches.

http://ift.tt/2Dty3Jn

Tumor-stroma IL-1{beta}-IRAK4 feedforward circuitry drives tumor fibrosis, chemoresistance, and poor prognosis in pancreatic cancer

Targeting the desmoplastic stroma of pancreatic ductal adenocarcinoma (PDAC) holds promise to augment the effect of chemotherapy, but success in the clinic has thus far been limited. Preclinical mouse models suggest that near-depletion of cancer-associated fibroblasts (CAF) carries a risk of accelerating PDAC progression, underscoring the need to concurrently target key signaling mechanisms that drive the malignant attributes of both CAF and PDAC cells. We previously reported that inhibition of interleukin-1 receptor associated kinase 4 (IRAK4) suppresses NF-κB activity and promotes response to chemotherapy in PDAC cells. In this study, we report that CAF in PDAC tumors robustly express activated IRAK4 and NF-κB. IRAK4 expression in CAF promoted NF-κB activity, drove tumor fibrosis, and supported PDAC cell proliferation, survival, and chemoresistance. Cytokine array analysis of CAF and microarray analysis of PDAC cells identified IL-1β as a key cytokine that activated IRAK4 in CAF. Targeting IRAK4 or IL-1β rendered PDAC tumors less fibrotic and more sensitive to gemcitabine. In clinical specimens of human PDAC, high stromal IL-1β expression associated strongly with poor overall survival. Together, our studies establish a tumor-stroma IL-1β-IRAK4 feedforward signal that can be therapeutically disrupted to increase chemotherapeutic efficacy in PDAC.

http://ift.tt/2E2uYkL

Anti-estrogen therapy increases plasticity and cancer stemness of prolactin-induced ER{alpha}+ mammary carcinomas

Although anti-estrogen therapies are successful in many patients with estrogen receptor alpha-positive (ERα+) breast cancer, 25-40% fail to respond. Although multiple mechanisms underlie evasion of these treatments, including tumor heterogeneity and drug-resistant cancer stem cells (CSCs), further investigations have been limited by the paucity of preclinical ERα+ tumor models. Here we examined a mouse model of prolactin-induced aggressive ERα+ breast cancer, which mimics the epidemiologic link between prolactin exposure and increased risk for metastatic ERα+ tumors. Like a subset of ERα+ patient cancers, the prolactin-induced adenocarcinomas contained two major tumor subpopulations that expressed markers of normal luminal and basal epithelial cells. CSC activity was distributed equally across these two tumor subpopulations. Treatment with the selective estrogen receptor downregulator (SERD), ICI 182,780 (ICI), did not slow tumor growth, but induced adaptive responses in CSC activity, increased markers of plasticity including target gene reporters of Wnt/Notch signaling and epithelial-mesenchymal transition, and increased double positive (K8/K5) cells. In primary tumorsphere cultures, ICI stimulated CSC self-renewal, and was able to overcome the dependence of self-renewal upon Wnt or Notch signaling individually, but not together. Our findings demonstrate that treatment of aggressive mixed lineage ERα+ breast cancers with a SERD does not inhibit growth, but rather evokes tumor cell plasticity and regenerative CSC activity, predicting likely negative impacts on patient tumors with these characteristics.

http://ift.tt/2DyaEGE

Timing of probiotic milk consumption during pregnancy and effects on the incidence of preeclampsia and preterm delivery: a prospective observational cohort study in Norway

Objectives

To investigate whether the timing of probiotic milk intake before, during early or late pregnancy influences associations with preeclampsia and preterm delivery.

Design

Population based prospective cohort study.

Setting

Norway, between 1999 and 2008.

Participants

70 149 singleton pregnancies resulting in live-born babies from the Norwegian Mother and Child Cohort Study (no chronic disease, answered questionnaires, no placenta previa/cerclage/serious malformation of fetus, first enrolment pregnancy). Only nulliparous women (n=37 050) were included in the preeclampsia analysis. Both iatrogenic and spontaneous preterm delivery (between gestational weeks 22+0 and 36+6) with spontaneous term controls (between gestational weeks 39+0 and 40+6) were included in the preterm delivery analysis resulting in 34 458 cases.

Main outcome measures

Adjusted OR for preeclampsia and preterm delivery according to consumption of probiotic milk at three different time periods (before pregnancy, during early and late pregnancy).

Results

Probiotic milk intake in late pregnancy (but not before or in early pregnancy) was significantly associated with lower preeclampsia risk (adjusted OR: 0.80 (95% CI 0.68 to 0.94) p-value: 0.007). Probiotic intake during early (but not before or during late pregnancy) was significantly associated with lower risk of preterm delivery (adjusted OR: 0.79 (0.64 to 0.97) p-value: 0.03).

Conclusions

In this observational study, we found an association between timing of probiotic milk consumption during pregnancy and the incidence of the adverse pregnancy outcomes preeclampsia and preterm delivery. If future randomised controlled trials could establish a causal association between probiotics consumption and reduced risk of preeclampsia and preterm delivery, recommending probiotics would be a promising public health measure to reduce these adverse pregnancy outcomes.

http://ift.tt/2F9zWeD

Rare differential for large bowel obstruction

http://ift.tt/2DFuyTw

Pressure dressings in mastoid and middle ear surgery: are they necessary? A retrospective review of patient outcomes

Background

The application of mastoid pressure dressings following mastoid and middle ear surgery is widely practised to reduce the risk of haematoma and seroma. There are a number of minor morbidities associated with use of the dressings, as well as a financial cost associated with an overnight stay in hospital or a return appointment for removal of the dressings. The benefit of having these dressings in situ overnight is questionable.

Methods

A retrospective review of 133 patients who had their mastoid dressing removed 2 h after their procedure was undertaken at our Hospital. The patient records were scanned for procedure-related morbidities, and perioperative data were analysed.

Results

No haematomas or seromas occurred in any of the 133 patients studied. Minor morbidities associated with prolonged use of mastoid pressure dressings were avoided.

Conclusion

Removal of mastoid pressure dressings 2 h following ear surgery is safe and effective. Furthermore, a mastoid dressing should not be a factor in the decision as to whether to treat a patient as a day case or overnight admission.

http://ift.tt/2F9PO14

Uptake of adjuvant breast cancer treatments recommended by multi-disciplinary meetings

Background

Adjuvant therapy for breast cancer is routinely discussed and recommended in multi-disciplinary meetings (MDMs). Current literature explores how treatments received by patients differ from national guidelines; however, it does not explore whether treatment is concordant with MDMs. This study provides an Australian perspective on the uptake of MDM recommendations and reasons for non-concordance.

Methods

A retrospective cohort study of patients with breast cancer presented at The Royal Melbourne Hospital MDM in 2010 and 2014 to investigate the concordance between MDM recommendations and treatment received.

Results

The study group comprised 441 patients (161 from 2010 and 280 from 2014). A total of 375 patients were included in the analyses. Overall, 82% of patients had perfect concordance between recommended and received treatment for all modes of adjuvant therapy. Concordance to endocrine therapy was higher for invasive cancers than ductal carcinoma in situ (97% versus 81%, P < 0.0001). Concordance to radiotherapy was high and did not differ according to type of cancer or surgery (ranging from 88 to 91%). Concordance to chemotherapy recommendations was high overall (92%) and did not vary with nodal status. Women aged over 65 years were least likely to be recommended for adjuvant therapy but most likely to concordant with the recommendation.

Conclusions

Uptake of MDM-recommended treatments is high. There is a minority of patients in whom MDM recommendations are not followed, highlighting that there are extra steps between recommendations at an MDM and decisions with patients. More attention to this issue is appropriate, and the reasons for non-concordance warrant further study.

http://ift.tt/2DCZx2v

Liver resection for hepatocellular carcinoma: personal experiences in a series of 1330 consecutive cases in China

Background

Liver resection to treat early stage hepatocellular carcinoma (HCC) is widely practised but surgery for intermediate and advanced stages of HCC is not included in the treatment algorithm of the Barcelona Clinic Liver Cancer, which has been adopted in official guidelines; nevertheless, resection beyond early stages is frequently undertaken and documented.

Methods

Between January 2001 and December 2014, all the HCC patients who underwent liver resection for the first time by Dr Yiqun Yan and his surgical team were enrolled. Clinical data were prospectively collected as well as the follow-up results.

Results

A total of 1330 consecutive patients were included in the study, of which 452 (34.0%) suffered complications after liver resection with a mortality of 0.7%. The overall survival rates at 1-, 3- and 5-year were 91.2, 63.3 and 36.9%, respectively, while the disease-free survival rates at 1-, 3- and 5-year were 67.7, 33.7 and 13.8%, respectively. Cases were classified into Barcelona Clinic Liver Cancer stage A (548 patients, 41.2%), stage B (613 patients, 46.1%) and stage C (169 patients, 12.7%). The overall survival time at 5-year were 49.8, 32.8 and 10.6%, respectively, in patients with stage A, B and C tumours.

Conclusion

Liver resection to treat HCC is safe in patients with preserved liver function and good functional status. Liver resection should be the first line therapy in patients with single (regardless of tumour size) and resectable 2–3 tumours as well as vascular tumour thrombus if the tumour thrombus does not invade the major trunks.

http://ift.tt/2F7Exhs

Hybrid capture-based genomic profiling of circulating tumor DNA from patients with advanced cancers of the gastrointestinal tract or anus

Purpose: Genomic profiling of tumor biopsies from advanced gastrointestinal (GI) and anal cancers is increasingly used to inform treatment. In some cases, tissue biopsy can be prohibitive, and we sought to investigate whether analysis of blood-derived circulating tumor DNA (ctDNA) may provide a minimally invasive alternative. Experimental Design: Hybrid capture-based genomic profiling of 62 genes was performed on blood-based ctDNA from 417 patients with GI carcinomas to assess the presence of genomic alterations (GA) and compare with matched tissue samples. Results: Evidence of ctDNA was detected in 344/417 (82%) samples, and of these ≥1 one reportable GA was detected in 89% (306/344) of samples. Frequently altered genes were TP53 (72%), KRAS (35%), PIK3CA (14%), BRAF (8%), and EGFR (7%). In temporally matched ctDNA and tissue samples available from 25 patients, 86% of alterations detected in tissue were also detected in ctDNA, including 95% of short variants, but only 50% of amplifications. Conversely, 63% of alterations detected in ctDNA were also detected in matched tissue. Examples demonstrating clinical utility are presented. Conclusions: Genomic profiling of ctDNA detected potentially clinically relevant GAs in a significant subset of patients with GI carcinomas. In these tumor types, most alterations detected in matched tissue were also detected in ctDNA, and, with the exception of amplifications, ctDNA sequencing routinely detected additional alterations not found in matched tissue, consistent with tumor heterogeneity. These results suggest feasibility and utility of ctDNA testing in advanced GI cancers as a complementary approach to tissue testing, and further investigation is warranted.

http://ift.tt/2DAFlzp

Nitric Oxide Production by Myeloid Derived Suppressor Cells Plays a Role in Impairing Fc Receptor-Mediated Natural Killer Cell Function.

Purpose: Monoclonal antibodies (mAb) are used to treat solid and hematological malignancies, and work in part through Fc receptors (FcR) on natural killer cells (NK). However, FcR mediated functions of NK cells from cancer patients are significantly impaired. Identifying the mechanisms of this dysfunction and impaired response to mAb therapy could lead to combination therapies and enhance mAb therapy.  Experimental Design: Co-cultures of autologous NK cells and MDSC from cancer patients were used to study the effect of MDSC on NK cell FcR mediated functions including antibody dependent cellular cytotoxicity, cytokine production, and signal transduction in vitro. Mouse breast cancer models were utilized to study the effect of MDSC on antibody therapy in vivo and test the efficacy of combination therapies including a mAb and a MDSC targeting agent.  Results: Cancer patient MDSC were found to significantly inhibit NK cell FcR mediated functions including ADCC, cytokine production, and signal transduction in a contact independent manner. In addition, adoptive transfer of MDSC abolished the efficacy of mAb therapy in a mouse model of pancreatic cancer. Inhibition of iNOS restored NK cell functions and signal transduction. Finally, non-specific elimination of MDSC or inhibition of iNOS in vivo significantly improved the efficacy of mAb therapy in a mouse model of breast cancer. Conclusions: MDSC antagonize NK cell FcR mediated function and signal transduction leading to impaired response to mAb therapy in part through nitric oxide production. Thus, elimination of MDSC or inhibition of nitric oxide production offers a strategy to improve mAb therapy.

http://ift.tt/2n7oclt

Acquired resistance of ER- positive breast cancer to endocrine treatment confers an adaptive sensitivity to TRAIL through post-translational downregulation of c-FLIP

Purpose: One-third of ER-positive breast cancer patients who initially respond to endocrine therapy become resistant to treatment. Such treatment failure is associated with poor prognosis and remains an area of unmet clinical need.  Here we identify a specific post-translational modification that occurs during endocrine resistance and which results in tumour susceptibility to the apoptosis inducer TNF-Related Apoptosis-Inducing Ligand (TRAIL). This potentially offers a novel stratified approach to targeting endocrine resistant breast cancer. Experimental Design: Cell line and primary-derived xenograft models of endocrine resistance were investigated for susceptibility to TRAIL.  Tumour viability, cancer stem cell (CSC) viability (tumourspheres), tumour growth kinetics and metastatic burden were assessed.  Western blots for the TRAIL-pathway inhibitor, c-FLIP, and upstream regulators were performed.  Results were confirmed in primary culture of 26 endocrine-resistant and endocrine-naïve breast tumours. Results: Breast cancer cell lines with acquired resistance to tamoxifen-(TAMR) or faslodex were more sensitive to TRAIL than their endocrine-sensitive controls.  Moreover, TRAIL eliminated CSC-like activity in TAMR cells, resulting in prolonged remission of xenografts in vivo. In primary culture, TRAIL significantly depleted CSCs in 85% endocrine-resistant, compared with 8% endocrine-naïve tumours, while systemic administration of TRAIL in endocrine-resistant patient-derived xenografts reduced tumour growth, CSC-like activity and metastases. Acquired TRAIL sensitivity correlated with a reduction in intra-cellular levels of c-FLIP, and an increase in Jnk-mediated phosphorylation of E3-ligase, ITCH, which degrades c-FLIP. Conclusions:These results identify a novel mechanism of acquired vulnerability to an extrinsic cell death stimulus, in endocrine resistant breast cancers, which has both therapeutic and prognostic potential.

http://ift.tt/2DyMnoi

What is it about a cancer diagnosis that would worry people? A population-based survey of adults in England

Abstract

Background

Surveys indicate quite high prevalence of cancer worry in the general population, but little is known about what it is about cancer that worries people. A better understanding of the origins of cancer worry may help elucidate previously found inconsistencies in its behavioural effect on cancer prevention, screening uptake, and help-seeking for symptoms. In this study, we explore the prevalence and population distribution of general cancer worry and worries about specific aspects of cancer previously identified.

Methods

A population-based survey of 2048 English adults (18–70 years, April–May 2016), using face-to-face interviews to assess demographic characteristics, general cancer worry and twelve sources of cancer worry (adapted from an existing scale), including the emotional, physical, and social consequences of a diagnosis.

Results

In general, a third of respondents (37%) never worried about cancer, 57% worried occasionally/sometimes, and 6% often/very often. In terms of specific worries, two thirds would be 'quite a bit' or 'extremely' worried about the threat to life and emotional upset a diagnosis would cause. Half would worry about surgery, radiotherapy, chemotherapy, and loss of control over life. Worries about the social consequences were less commonly anticipated: just under half would worry about financial problems or their social roles, and a quarter would be worried about effects on identity, important relationships, gender role, and sexuality. Women and younger people reported more frequent worry about getting cancer, and would be more worried about the emotional, physical, and social consequences of a cancer diagnosis (p < .001). Those from ethnic minority backgrounds reported less frequent worry about getting cancer than their white counterparts, but would be equally worried about the emotional and physical impact of a cancer diagnosis, and worried more about the social consequences of a cancer diagnosis (p < .05).

Conclusions

The majority of English adults worry at least occasionally about getting cancer, and would be most worried about the emotional and physical impact of a cancer diagnosis. Distinguishing between the various worries that cancer can evoke may help inform efforts to allay undue worries in those who are deterred by them from engaging with cancer prevention and early detection.

http://ift.tt/2n6REcb

Secondary Hyperparathyroidism in HIV-Infected Patients in Central Europe

Horm Metab Res
DOI: 10.1055/s-0043-125073

Secondary hyperparathyroidism (sHPT) might be a contributor to increased risk of osteoporosis in adult HIV patients but there is little data available on this issue in this particular population. The aim of the study was to investigate the prevalence of sHPT in an HIV-infected population with normal kidney function and to evaluate its risk factors in HIV patients. This cross-sectional study was carried out in a single HIV center in Germany using routine data from patients with normal kidney function attending the clinic between January 1st and December 31st, 2016. In total, 1263 patients were included [998 (79.0%) male, median age 48 (IQR 38–54) years]. In 214 patients (16.9%) elevated PTH levels with low or normal calcium levels were found. Multivariate logistic regression modeling showed significant associations with elevated PTH for African ethnicity [OR: 2.12 (95% CI: 1.42–3.16); p<0.001], low 25-hydroxyvitamin D levels [OR: 1.82 (95% CI: 1.32–2.51); p<0.001], low calcium levels [OR 1.69 (95% CI: 1.22–2.33); p=0.001], and use of tenofovir disoproxil fumarate [OR 2.33 (95% CI: 1.62–3.36); p<0.001]. Additional to common risk factors like vitamin D insufficiency and hypocalcemia, we found a significant association between the use of TDF and sHPT. Prospective data are needed to ascertain whether PTH-mediated bone loss is the underlying mechanism of TDF bone-toxicity. Additional screening of PTH even in HIV-infected patients with normal or low calcium levels may help to identify patients at increased risk of bone mineral density loss.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

http://ift.tt/2Dzrv03

Loss in working years after a breast cancer diagnosis

Loss in working years after a breast cancer diagnosis

Loss in working years after a breast cancer diagnosis, Published online: 23 January 2018; doi:10.1038/bjc.2017.456

Loss in working years after a breast cancer diagnosis

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A novel Epstein–Barr virus-latent membrane protein-1-specific T-cell receptor for TCR gene therapy

A novel Epstein–Barr virus-latent membrane protein-1-specific T-cell receptor for TCR gene therapy

A novel Epstein–Barr virus-latent membrane protein-1-specific T-cell receptor for TCR gene therapy, Published online: 23 January 2018; doi:10.1038/bjc.2017.475

A novel Epstein–Barr virus-latent membrane protein-1-specific T-cell receptor for TCR gene therapy

http://ift.tt/2rAo5oa

Back from the dead: TIL apoptosis in cancer immune evasion

Back from the dead: TIL apoptosis in cancer immune evasion

Back from the dead: TIL apoptosis in cancer immune evasion, Published online: 23 January 2018; doi:10.1038/bjc.2017.483

Back from the dead: TIL apoptosis in cancer immune evasion

http://ift.tt/2Gc1iT1

A core matrisome gene signature predicts cancer outcome

A core matrisome gene signature predicts cancer outcome

A core matrisome gene signature predicts cancer outcome, Published online: 23 January 2018; doi:10.1038/bjc.2017.458

A core matrisome gene signature predicts cancer outcome

http://ift.tt/2rtp6ye

Comment on ‘Human papillomavirus association is the most important predictor for surgically treated patients with oropharyngeal cancer’

Comment on 'Human papillomavirus association is the most important predictor for surgically treated patients with oropharyngeal cancer'

Comment on 'Human papillomavirus association is the most important predictor for surgically treated patients with oropharyngeal cancer', Published online: 23 January 2018; doi:10.1038/bjc.2017.416

Comment on 'Human papillomavirus association is the most important predictor for surgically treated patients with oropharyngeal cancer'

http://ift.tt/2Gc0Kwr

Development and validation of a plasma-based melanoma biomarker suitable for clinical use

Development and validation of a plasma-based melanoma biomarker suitable for clinical use

Development and validation of a plasma-based melanoma biomarker suitable for clinical use, Published online: 23 January 2018; doi:10.1038/bjc.2017.477

Development and validation of a plasma-based melanoma biomarker suitable for clinical use

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Reply to ‘Comment on ‘Human papillomavirus association is the most important predictor for surgically treated patients with oropharyngeal cancer”

Reply to 'Comment on 'Human papillomavirus association is the most important predictor for surgically treated patients with oropharyngeal cancer"

Reply to 'Comment on 'Human papillomavirus association is the most important predictor for surgically treated patients with oropharyngeal cancer", Published online: 23 January 2018; doi:10.1038/bjc.2017.464

Reply to 'Comment on 'Human papillomavirus association is the most important predictor for surgically treated patients with oropharyngeal cancer"

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Postmenopausal breast cancer and oestrogen associations with the IgA-coated and IgA-noncoated faecal microbiota

Postmenopausal breast cancer and oestrogen associations with the IgA-coated and IgA-noncoated faecal microbiota

Postmenopausal breast cancer and oestrogen associations with the IgA-coated and IgA-noncoated faecal microbiota, Published online: 23 January 2018; doi:10.1038/bjc.2017.435

Postmenopausal breast cancer and oestrogen associations with the IgA-coated and IgA-noncoated faecal microbiota

http://ift.tt/2E493tA

Case of complete mesh migration into the stomach after mesh hiatoplasty for a hiatal hernia

Abstract

Mesh migration is a rare complication of surgery for a hiatal hernia. Here, we present the case of a 72-year-old who complained of dysphasia and bodyweight loss. Upper gastrointestinal endoscopy revealed incarcerated mesh in the lumen of the esophagogastric junction. Surgery was performed under both endoscopy and laparoscopy, and the mesh was successfully removed via gastrostomy. To the best of our knowledge, our case is the first in which mesh that had migrated into the esophagogastric junction was removed by a combination of laparoscopic and endoscopic procedure, although the cases of 17 patients in which mesh migrated into the stomach after mesh hiatoplasty have previously been reported in the literature.

http://ift.tt/2DBS1oS

Whole Versus Partial Bladder Radiation: Use of an Image-guided Hypofractionated IMRT Bladder-preservation Protocol

Objectives: To report our institutional experience using definitive chemoradiation via whole bladder (WB) and partial bladder (PB) treatment in muscle-invasive bladder cancer. Combining intensity-modulated radiation therapy with image-guidance can improve the therapeutic ratio. Materials and Methods: Retrospective analysis of 26 patients with clinical stage T2-4 N0-2 M0 urothelial cancer treated in 2009 to 2012; 16 received WB radiation and 10 received PB radiation. PB/tumor boost volume included visibly thickened bladder wall or tumor localized on cystoscopy. WB radiation delivered 45 to 50.4 Gy to bladder/lymph nodes, then sequential 19.8 to 21.6 Gy tumor boost (1.8 Gy/fx). PB radiation was 45 to 50 Gy to lymph nodes (1.8 to 2 Gy/fx) and simultaneous integrated boost to 55 to 62.5 Gy to tumor only (2.2 to 2.5 Gy/fx). The primary endpoint was local control, defined as no muscle-invasive recurrence. Secondary endpoints were overall survival, toxicity, and cost. Results: Mean age was 77 and median follow-up was 20 months. Freedom from local recurrence was 86% at 2 years (PB 100%, WB 77%). Overall survival was 80% at 1 year (PB 88%, WB 75%), and 55% at 2 years (PB 70%, WB 48%, P=0.38). Failure was predominantly distant. Toxicities were minimal (3 late grade 3 ureteral, 1 acute grade 4 renal), and all resolved. No cystectomies were performed for toxicity. Hypofractionation reduces treatment time and costs by one third. Conclusions: Image-guided hypofractionated PB radiation provides local control with similar survival to WB therapy, with minimal toxicity. Hypofractionation also offers time and cost advantages. Our results need to be validated in a larger, multi-institutional cohort.

http://ift.tt/2DxlRrd

Hypofractionated Versus Standard Fractionated Proton-beam Therapy for Low-risk Prostate Cancer: Interim Results of a Randomized Trial PCG GU 002

Objective: To identify differences in terms of quality of life, the American Urological Association Symptom Index (AUA), or adverse events (AEs) among patients with prostate cancer treated with either standard fractionation or hypofractionation proton-beam therapy. Materials and Methods: Patients were prospectively randomized to receive 38 Gy relative biological effectiveness (RBE) in 5 treatments (n=49) or 79.2 Gy RBE in 44 treatments (n=33). All patients had low-risk prostate cancer and were treated with proton therapy using fiducial markers and daily image guidance. Results: Median follow-up for both groups was 18 months; 33 patients had follow-up of 2 years or longer. Baseline median (range) AUA was 4.7 (0 to 13) for the 38 Gy RBE arm and 4.8 (0 to 17) for the 79.2 Gy RBE arm. We observed no difference between the groups regarding the Expanded Prostate Index Composite urinary, bowel, or sexual function scores at 3, 6, 12, 18, or 24 months after treatment. The only significant difference was the AUA score at 12 months (8 for the 38 Gy RBE arm vs. 5 for the 79.2 Gy RBE arm; P=0.04); AUA scores otherwise were similar between groups. No grade 3 or higher AEs occurred in either arm. Conclusions: Patients treated with proton therapy in this randomized trial tolerated treatment well, with excellent quality-of-life scores, persistent low AUA, and no grade 3 or higher AEs on either arm. We showed no apparent clinical difference in outcomes with hypofractionated proton-beam therapy compared with standard fractionation on the basis of this interim analysis.

http://ift.tt/2E3yueQ

The Birth of the Illegitimate Linear No-Threshold Model: An Invalid Paradigm for Estimating Risk Following Low-dose Radiation Exposure

This paper examines the birthing process of the linear no-threshold model with respect to genetic effects and carcinogenesis. This model was conceived >70 years ago but still remains a foundational element within much of the scientific thought regarding exposure to low-dose ionizing radiation. This model is used today to provide risk estimates for cancer resulting from any exposure to ionizing radiation down to zero dose, risk estimates that are only theoretical and, as yet, have never been conclusively demonstrated by empirical evidence. We are literally bathed every second of every day in low-dose radiation exposure due to natural background radiation, exposures that vary annually from a few mGy to 260 mGy, depending upon where one lives on the planet. Irrespective of the level of background exposure to a given population, no associated health effects have been documented to date anywhere in the world. In fact, people in the United States are living longer today than ever before, likely due to always improving levels of medical care, including even more radiation exposure from diagnostic medical radiation (eg, x-ray and computed tomography imaging examinations) which are well within the background dose range across the globe. Yet, the persistent use of the linear no-threshold model for risk assessment by regulators and advisory bodies continues to drive an unfounded fear of any low-dose radiation exposure, as well as excessive expenditures on putative but unneeded and wasteful safety measures.

http://ift.tt/2DxF4Ju

Total Lifetime and Cancer-related Costs for Elderly Patients Diagnosed With Anal Cancer in the United States

Objective: To determine the lifetime and phase-specific cost of anal cancer management and the economic burden of anal cancer care in elderly (66 y and older) patients in the United States. Patients and Methods: For this study, we used Surveillance Epidemiology and End Results-Medicare linked database (1992 to 2009). We matched newly diagnosed anal cancer patients (by age and sex) to noncancer controls. We estimated survival time from the date of diagnosis until death. Lifetime and average annual cost by stage and age at diagnosis were estimated by combining survival data with Medicare claims. The average lifetime cost, proportion of patients who were elderly, and the number of incident cases were used to estimate the economic burden. Results: The average lifetime cost for patients with anal cancer was US$50,150 (N=2227) (2014 US dollars). The average annual cost in men and women was US$8025 and US$5124, respectively. The overall survival after the diagnosis of cancer was 8.42 years. As the age and stage at diagnosis increased, so did the cost of cancer-related care. The anal cancer–related lifetime economic burden in Medicare patients in the United States was US$112 million. Conclusions: Although the prevalence of anal cancer among the elderly in the United States is small, its economic burden is considerable.

http://ift.tt/2DZQrut

To What Extent Does Radiotherapy Improve the Quality of Life of Patients With Bone Metastasis?: A Prospective, Single-Institutional Study

Purpose/Objectives: Radiation therapy (RT) is an effective method of palliating painful bone metastases and improves the quality of life (QoL) of these patients. The purpose of this trial is 2-fold: to quantify the impact of RT in the QoL of patients with bone metastasis and to compare the QoL results between the most used schemes of RT at our Centre. Materials and Methods: A consecutive sample of patients with bone metastasis treated with RT in the Complejo Hospitalario de Navarra, Spain, was addressed between January 2011 and November 2012. The QoL was measured with the Quality of Life Questionnaire-C15-Palliative questionnaire, a short version of the European Organisation for Research and Treatment of Cancer-Quality of Life Questionnaire-C30 for palliative care. Two assessments were proposed for each patient: one on the first day of the treatment and the other one a month after the end of the radiotherapy sessions. One hundred and sixteen patients completed the first questionnaire and 75 completed the second one (65%). Results: Significant differences appeared in 9 domains, with better QoL in the second assessment. Five areas (physical functioning, global, fatigue, nausea, dyspnea, and constipation) showed little change (between 5 and 9 points), 3 (emotional functioning, insomnia, and appetite loss) showed moderate change (10 to 20 points), and 1 (pain) showed a very positive change (>30 points). When we compare the QoL scores between the 2 most used schemes of RT (30 Gy/10 fractions vs. 20 Gy/4 to 5 fractions), there are no significant differences in any QoL areas (and in 2 areas P was near 0.05). Conclusions: Palliative RT is a very active treatment for patients with bone metastasis regardless of age, location, primary tumor, or RT scheme. RT significantly improves the QoL, fundamentally by controlling pain and reducing analgesic use. Shorter schemes of RT produce at least—if not better—the same effect on QL than longer schemes (30 Gy).

http://ift.tt/2DvS7L8

A Phase II Study of Biweekly Cisplatin, Fixed-Dose-Rate Gemcitabine and Infusional 5-Fluorouracil in Patients With Metastatic Pancreatic and Biliary Cancers

Objectives: Combinations of gemcitabine, 5-fluorouracil (5-FU), and platinum have demonstrated improved outcomes compared with singlet chemotherapy in pancreatic and biliary cancers. This phase II study examined efficacy and safety of a novel schedule of cisplatin, fixed-dose-rate gemcitabine and infusional 5-FU. Materials and Methods: Patients with metastatic adenocarcinoma of the pancreas or biliary tract, previously untreated or having received 1 cytotoxic regimen for advanced disease, were treated with gemcitabine 1000 mg/m2 intravenously (IV) over 100 minutes, cisplatin 35 mg/m2 IV over 30 minutes, and 5-FU 2400 mg/m2 IV over 48 hours on day 1 of a 14-day cycle. Patients were treated until disease progression or for 12 cycles. After 12 cycles, patients with stable or responding disease could continue gemcitabine and 5-FU. The primary endpoint was objective response. Results: Thirty-nine patients were treated: 8 with biliary cancer (all untreated) and 31 with pancreatic cancer (17 untreated, 14 previously treated). Best response in 25 untreated patients was partial response in 40%, stable disease in 40%, and progressive disease in 20%. In 14 previously treated pancreatic patients, best response was partial response in 7%, stable disease in 50%, and progressive disease in 43%. Median overall survival in untreated patients was 10.3 versus 4.9 months in previously treated patients. Adverse events were primarily uncomplicated hematologic toxicity, ≥grade 3 neutropenia (54%), anemia (21%), and thrombocytopenia (13%). Conclusion: Biweekly cisplatin, fixed-dose-rate gemcitabine, and infusional 5-FU demonstrated a high response rate and were well tolerated, encouraging further investigation of this regimen in metastatic pancreatic and biliary cancers.

http://ift.tt/2E211Ba

The Evolving Role of Tumor Treating Fields in Managing Glioblastoma: Guide for Oncologists

Glioblastoma (GBM) is a devastating brain tumor with poor prognosis despite advances in surgery, radiation, and chemotherapy. Survival of patients with glioblastoma remains poor, with only 1 in 4 patients alive at 2 years, and a 5-year survival rate of about 5%. Recurrence is nearly universal and, after recurrence, prognosis is poor with very short progression-free survival and overall survival (OS). Various salvage chemotherapy strategies have been applied with limited success. Tumor Treating Fields (TTFields) are a novel treatment modality approved for treatment of either newly diagnosed or recurrent GBM. TTFields therapy involves a medical device and transducer arrays to provide targeted delivery of low intensity, intermediate frequency, alternating electric fields to produce antimitotic effects selective for rapidly dividing tumor cells with limited toxicity. In the phase 3 EF-14 trial, TTFields plus temozolomide provided significantly longer progression-free survival and OS compared with temozolomide alone in patients with newly diagnosed GBM after initial chemoradiotherapy. The addition of TTFields to standard therapy improved median OS from 15.6 to 20.5 months (P=0.04). In the phase 3 EF-11 trial, for recurrent GBM, TTFields provided comparable efficacy as investigator's choice systemic therapy, with improved patient-reported quality of life and a lower incidence of serious adverse events. Primary toxicity associated with TTFields is skin irritation generally managed with array relocation and topical treatments including antibiotics and steroids. TTFields therapy has demonstrated proven efficacy in management of GBM, including improvement in OS for patients with newly diagnosed GBM, and is under current investigation in other brain and extracranial tumors.

http://ift.tt/2DubYuo

Clinical Outcomes of Patients With Gastrointestinal Malignancies Participating in Phase I Clinical Trials

Objectives: Early-phase clinical trials play a pivotal role in drug development. However, limited data are available on outcomes of gastrointestinal (GI) cancer patients enrolled in phase I clinical trials. Here, we evaluated the characteristics associated with survival in GI cancer patients participating in phase I clinical trials and attempted to validate previously established prognostic models. Materials and Methods: All consecutive patients with advanced GI tumors who participated in phase I clinical trials at our institution from January 2007 to December 2013 and received at least 1 dose of the study drug were included. Cox regression models were used to estimate multivariable-adjusted hazard ratio (HR) and 95% confidence interval. Results: In 243 study patients (median age, 62 y [range, 26 to 82 y]; 55% male), treatment included chemotherapy only (14%), targeted therapy (41%), chemotherapy+targeted therapy (42%), and others (2%) for the following disease types: pancreatic (42%), colorectal (34%), gastroesophageal (10%), hepatobiliary (13%), and others (2%). Response rate was 4%, with 38% achieving stable disease and 42% having progressive disease. Median survival was 5.8 months (range, 0.2 to 52.4 mo). Our multivariable Cox regression analyses included the following as predictors of survival: Eastern Cooperative Oncology Group performance score ≥1 (HR=1.76), prior systemic therapies ≥2 (HR=1.63), lactate dehydrogenase >618 IU/L (HR=1.85), sodium >135 mmol/L (HR=0.46), and white blood count >6×109/L (HR=1.5). Our data set was consistent with previous prognostic scores. Conclusions: This is the largest study to assess clinical outcomes in this patient population. Phase I trials provide clinical benefit to patients with advanced GI malignancies and should be recommended as a treatment option in appropriate patients.

http://ift.tt/2E4t5UO