Showing papers by "Gdańsk Medical University published in 2018"
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Kindai University1, University of California, Los Angeles2, Yonsei University3, University of Bologna4, California Pacific Medical Center5, Fourth Military Medical University6, Gdańsk Medical University7, University of Bordeaux8, Hannover Medical School9, Beatson West of Scotland Cancer Centre10, Eisai11, National Taiwan University12
TL;DR: Lenvatinib was non-inferior to sorafenib in overall survival in untreated advanced hepatocellular carcinoma and the safety and tolerability profiles of lenvatinIB were consistent with those previously observed.
3,046 citations
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TL;DR: Recent cumulative data suggest that, without the existence of the immunosenescence/inflamm-aging duo, human longevity would be greatly shortened and it may be more suitable to aim to maintain general homeostasis and function by appropriately improving immune-inflammatory-functions.
Abstract: The immune system is the most important protective physiological system of the organism. It has many connections with other systems and is, in fact, often considered as part of the larger neuro-endocrine-immune axis. Most experimental data on immune changes with aging show a decline in many immune parameters when compared to young healthy subjects. The bulk of these changes is termed immunosenescence. Immunosenescence has been considered for some time as detrimental because it often leads to subclinical accumulation of pro-inflammatory factors and inflamm-aging. Together, immunosenescence and inflamm-aging are suggested to stand at the origin of most of the diseases of the elderly, such as infections, cancer, autoimmune disorders, and chronic inflammatory diseases. However, an increasing number of immune-gerontologists have challenged this negative interpretation of immunosenescence with respect to its significance in aging-related alterations of the immune system. If one considers these changes from an evolutionary perspective, they can be viewed preferably as adaptive or remodeling rather than solely detrimental. Whereas it is conceivable that global immune changes may lead to various diseases, it is also obvious that these changes may be needed for extended survival/longevity. Recent cumulative data suggest that, without the existence of the immunosenescence/inflamm-aging duo (representing two sides of the same phenomenon), human longevity would be greatly shortened. This review summarizes recent data on the dynamic reassessment of immune changes with aging. Accordingly, attempts to intervene on the aging immune system by targeting its rejuvenation, it may be more suitable to aim to maintain general homeostasis and function by appropriately improving immune-inflammatory-functions.
777 citations
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TL;DR: The importance of BDNF for future studies aimed at disclosing mechanisms of activation of signaling pathways, neuro- and gliogenesis, as well as synaptic plasticity is highlighted.
Abstract: Brain-derived neurotrophic factor (BDNF) is one of the most widely distributed and extensively studied neurotrophins in the mammalian brain. Among its prominent functions, one can mention control of neuronal and glial development, neuroprotection, and modulation of both short- and long-lasting synaptic interactions, which are critical for cognition and memory. A wide spectrum of processes are controlled by BDNF, and the sometimes contradictory effects of its action can be explained based on its specific pattern of synthesis, comprising several intermediate biologically active isoforms that bind to different types of receptor, triggering several signaling pathways. The functions of BDNF must be discussed in close relation to the stage of brain development, the different cellular components of nervous tissue, as well as the molecular mechanisms of signal transduction activated under physiological and pathological conditions. In this review, we briefly summarize the current state of knowledge regarding the impact of BDNF on regulation of neurophysiological processes. The importance of BDNF for future studies aimed at disclosing mechanisms of activation of signaling pathways, neuro- and gliogenesis, as well as synaptic plasticity is highlighted.
715 citations
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TL;DR: Fragment size analysis and selective sequencing of specific fragment sizes can boost ctDNA detection and could complement or provide an alternative to deeper sequencing of cfDNA.
Abstract: Existing methods to improve detection of circulating tumor DNA (ctDNA) have focused on genomic alterations but have rarely considered the biological properties of plasma cell-free DNA (cfDNA). We hypothesized that differences in fragment lengths of circulating DNA could be exploited to enhance sensitivity for detecting the presence of ctDNA and for noninvasive genomic analysis of cancer. We surveyed ctDNA fragment sizes in 344 plasma samples from 200 patients with cancer using low-pass whole-genome sequencing (0.4×). To establish the size distribution of mutant ctDNA, tumor-guided personalized deep sequencing was performed in 19 patients. We detected enrichment of ctDNA in fragment sizes between 90 and 150 bp and developed methods for in vitro and in silico size selection of these fragments. Selecting fragments between 90 and 150 bp improved detection of tumor DNA, with more than twofold median enrichment in >95% of cases and more than fourfold enrichment in >10% of cases. Analysis of size-selected cfDNA identified clinically actionable mutations and copy number alterations that were otherwise not detected. Identification of plasma samples from patients with advanced cancer was improved by predictive models integrating fragment length and copy number analysis of cfDNA, with area under the curve (AUC) >0.99 compared to AUC 0.91 compared to AUC < 0.5 without fragmentation features. Fragment size analysis and selective sequencing of specific fragment sizes can boost ctDNA detection and could complement or provide an alternative to deeper sequencing of cfDNA.
602 citations
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TL;DR: Add-on cannabidiol is efficacious for the treatment of patients with drop seizures associated with Lennox-Gastaut syndrome and is generally well tolerated.
593 citations
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TL;DR: The aim of the review is to focus on polyphenols of olive oil in context of their biological activities, with a broad spectrum of health-promoting properties, which comprises antioxidant, anti-inflammatory,Anti-allergic, Anti-atherogenic, anti -thrombotic, and anti-mutagenic effects.
Abstract: Beneficial effects of natural plant polyphenols on the human body have been evaluated in a number of scientific research projects. Bioactive polyphenols are natural compounds of various chemical structures. Their sources are mostly fruits, vegetables, nuts and seeds, roots, bark, leaves of different plants, herbs, whole grain products, processed foods (dark chocolate), as well as tea, coffee, and red wine. Polyphenols are believed to reduce morbidity and/or slow down the development of cardiovascular and neurodegenerative diseases as well as cancer. Biological activity of polyphenols is strongly related to their antioxidant properties. They tend to reduce the pool of reactive oxygen species as well as to neutralize potentially carcinogenic metabolites. A broad spectrum of health-promoting properties of plant polyphenols comprises antioxidant, anti-inflammatory, anti-allergic, anti-atherogenic, anti-thrombotic, and anti-mutagenic effects. Scientific studies present the ability of polyphenols to modulate the human immune system by affecting the proliferation of white blood cells, and also the production of cytokines or other factors that participate in the immunological defense. The aim of the review is to focus on polyphenols of olive oil in context of their biological activities.
362 citations
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TL;DR: Axial (λ║) and radial (λ┴) diffusivity seem to provide quite consistent information in healthy subjects, and in pathological conditions with limited edema and inflammatory changes, and DTI remains one of the most promising non-invasive diagnostic tools in medicine.
Abstract: The use of the diffusion tensor imaging (DTI) is rapidly growing in the neuroimaging field. Nevertheless, rigorously performed quantitative validation of DTI pathologic metrics remains very limited owing to the difficulty in co-registering quantitative histology findings with magnetic resonance imaging. The aim of this review is to summarize the existing state-of-the-art knowledge with respect to axial (λ║) and radial (λ┴) diffusivity as DTI markers of axonal and myelin damage, respectively. First, we provide technical background for DTI and briefly discuss the specific organization of white matter in bundles of axonal fibers running in parallel; this is the natural target for imaging based on diffusion anisotropy. Second, we discuss the four seminal studies that paved the way for considering axial (λ║) and radial (λ┴) diffusivity as potential in vivo surrogate markers of axonal and myelin damage, respectively. Then, we present difficulties in interpreting axial (λ║) and radial (λ┴) diffusivity in clinical conditions associated with inflammation, edema, and white matter fiber crossing. Finally, future directions are highlighted. In summary, DTI can reveal strategic information with respect to white matter tracts, disconnection mechanisms, and related symptoms. Axial (λ║) and radial (λ┴) diffusivity seem to provide quite consistent information in healthy subjects, and in pathological conditions with limited edema and inflammatory changes. DTI remains one of the most promising non-invasive diagnostic tools in medicine.
274 citations
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University College London1, University of Milano-Bicocca2, Utrecht University3, University of Brescia4, Paris Descartes University5, University Hospital of Lausanne6, Ghent University7, University of Barcelona8, University of Glasgow9, Karolinska Institutet10, Saarland University11, University of Valencia12, University of Milan13, Oslo University Hospital14, Charité15, University of Birmingham16, Gdańsk Medical University17, University of Zurich18, National and Kapodistrian University of Athens19
TL;DR: These practice guidelines on the management of arterial hypertension are a concise summary of the more extensive ones prepared by the Task Force jointly appointed by the European Society of Hypertension and theEuropean Society of Cardiology.
Abstract: These practice guidelines on the management of arterial hypertension are a concise summary of the more extensive ones prepared by the Task Force jointly appointed by the European Society of Hypertension and the European Society of Cardiology. These guidelines have been prepared on the basis of the best available evidence on all issues deserving recommendations; their role must be educational and not prescriptive or coercive for the management of individual subjects who may differ widely in their personal, medical and cultural characteristics. The members of the Task Force have participated independently in the preparation of these guidelines, drawing on their academic and clinical experience and by objective examination and interpretation of all available literature. A disclosure of their potential conflict of interest is reported on the websites of the ESH and the ESC.
270 citations
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TL;DR: UV touches the brain and central neuroendocrine system to reset body homeostasis, which invites multiple therapeutic applications of UV radiation, for example, in the management of autoimmune and mood disorders, addiction, and obesity.
Abstract: The skin, a self-regulating protective barrier organ, is empowered with sensory and computing capabilities to counteract the environmental stressors to maintain and restore disrupted cutaneous homeostasis. These complex functions are coordinated by a cutaneous neuro-endocrine system that also communicates in a bidirectional fashion with the central nervous, endocrine, and immune systems, all acting in concert to control body homeostasis. Although UV energy has played an important role in the origin and evolution of life, UV absorption by the skin not only triggers mechanisms that defend skin integrity and regulate global homeostasis but also induces skin pathology (e.g., cancer, aging, autoimmune responses). These effects are secondary to the transduction of UV electromagnetic energy into chemical, hormonal, and neural signals, defined by the nature of the chromophores and tissue compartments receiving specific UV wavelength. UV radiation can upregulate local neuroendocrine axes, with UVB being markedly more efficient than UVA. The locally induced cytokines, corticotropin-releasing hormone, urocortins, proopiomelanocortin-peptides, enkephalins, or others can be released into circulation to exert systemic effects, including activation of the central hypothalamic-pituitary-adrenal axis, opioidogenic effects, and immunosuppression, independent of vitamin D synthesis. Similar effects are seen after exposure of the eyes and skin to UV, through which UVB activates hypothalamic paraventricular and arcuate nuclei and exerts very rapid stimulatory effects on the brain. Thus, UV touches the brain and central neuroendocrine system to reset body homeostasis. This invites multiple therapeutic applications of UV radiation, for example, in the management of autoimmune and mood disorders, addiction, and obesity.
262 citations
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TL;DR: Olaparib in combination with abiraterone provided clinical efficacy benefit for patients with metastatic castration-resistant prostate cancer and preclinical data suggest synergy between olaparIB and androgen pathway inhibitors.
Abstract: Summary Background Patients with metastatic castration-resistant prostate cancer and homologous recombination repair (HRR) mutations have a better response to treatment with the poly(ADP-ribose) polymerase inhibitor olaparib than patients without HRR mutations. Preclinical data suggest synergy between olaparib and androgen pathway inhibitors. We aimed to assess the efficacy of olaparib plus the androgen pathway inhibitor abiraterone in patients with metastatic castration-resistant prostate cancer regardless of HRR mutation status. Methods We carried out this double-blind, randomised, placebo-controlled phase 2 trial at 41 urological oncology sites in 11 countries across Europe and North America. Eligible male patients were aged 18 years or older with metastatic castration-resistant prostate cancer who had previously received docetaxel and were candidates for abiraterone treatment. Patients were excluded if they had received more than two previous lines of chemotherapy, or had previous exposure to second-generation antihormonal drugs. Patients were randomly assigned (1:1) using an interactive voice or web response system, without stratification, to receive oral olaparib 300 mg twice daily or placebo. All patients received oral abiraterone 1000 mg once daily and prednisone or prednisolone 5 mg twice daily. Patients and investigators were masked to treatment allocation. The primary endpoint was investigator-assessed radiographic progression-free survival (rPFS; based on Response Evaluation Criteria in Solid Tumors version 1.1 and Prostate Cancer Clinical Trials Working Group 2 criteria). Efficacy analyses were done in the intention-to-treat population, which included all randomly assigned patients, and safety analyses included all patients who received at least one dose of olaparib or placebo. This trial is registered with ClinicalTrials.gov, number NCT01972217, and is no longer recruiting patients. Findings Between Nov 25, 2014, and July 14, 2015, 171 patients were assessed for eligibility. Of those, 142 patients were randomly assigned to receive olaparib and abiraterone (n=71) or placebo and abiraterone (n=71). The clinical cutoff date for the final analysis was Sept 22, 2017. Median rPFS was 13·8 months (95% CI 10·8–20·4) with olaparib and abiraterone and 8·2 months (5·5–9·7) with placebo and abiraterone (hazard ratio [HR] 0·65, 95% CI 0·44–0·97, p=0·034). The most common grade 1–2 adverse events were nausea (26 [37%] patients in the olaparib group vs 13 [18%] patients in the placebo group), constipation (18 [25%] vs eight [11%]), and back pain (17 [24%] vs 13 [18%]). 38 (54%) of 71 patients in the olaparib and abiraterone group and 20 (28%) of 71 patients in the placebo and abiraterone group had grade 3 or worse adverse events, including anaemia (in 15 [21%] of 71 patients vs none of 71), pneumonia (four [6%] vs three [4%]), and myocardial infarction (four [6%] vs none). Serious adverse events were reported by 24 (34%) of 71 patients receiving olaparib and abiraterone (seven of which were related to treatment) and 13 (18%) of 71 patients receiving placebo and abiraterone (one of which was related to treatment). One treatment-related death (pneumonitis) occurred in the olaparib and abiraterone group. Interpretation Olaparib in combination with abiraterone provided clinical efficacy benefit for patients with metastatic castration-resistant prostate cancer compared with abiraterone alone. More serious adverse events were observed in patients who received olaparib and abiraterone than abiraterone alone. Our data suggest that the combination of olaparib and abiraterone might provide an additional clinical benefit to a broad population of patients with metastatic castration-resistant prostate cancer. Funding AstraZeneca.
259 citations
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TL;DR: Analyzing social media top shared news could contribute to identification of leading fake medical information miseducating the society and encourage authorities to take actions such as put warnings on biased domains or scientifically evaluate those generating fake health news.
Abstract: Objectives Fake news: misinformation and falsehood of health news in social media constitute a potential threat to the public health, but the scope of this issue remains unclear. Our pilot study is an initial attempt to measure a number of the top shared health misinformation stories in the Polish language social media. Methods Using the BuzzSumo Application, a range of the top shared health web links in the Polish language social media was assessed during the period between 2012 and 2017. We used the following keywords which were related to the most common diseases and causes of death: cancer, neoplasm, heart attack, stroke, hypertension, diabetes, vaccinations, HIV, and AIDS. Each link was checked for the presence of fake news. Results 40% of the most frequently shared links contained text we classified as fake news. These were shared more than 450,000 times. The most fallacious content concerned vaccines, while news about cardiovascular diseases was, in general, well sourced and informative. More than 20% of dangerous links from our material was generated by one source. Conclusions Analyzing social media top shared news could contribute to identification of leading fake medical information miseducating the society. It might also encourage authorities to take actions such as put warnings on biased domains or scientifically evaluate those generating fake health news.
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Public Health Research Institute1, Oslo University Hospital2, University of Bristol3, Southmead Hospital4, University of Helsinki5, Meir Medical Center6, Tbilisi State Medical University7, Gdańsk Medical University8, University of Coimbra9, University of Iceland10, RMIT University11, University of Tartu12, Istanbul University13, Sofia Medical University14, Lithuanian University of Health Sciences15, French Institute of Health and Medical Research16
TL;DR: The epidemiology of renal replacement therapy (RRT) for end-stage renal disease (ESRD) in 2016 within 36 countries was described, with the incidence and prevalence higher among men than women, and men had a higher rate of kidney transplantation compared with women.
Abstract: Background This article summarizes the European Renal Association - European Dialysis and Transplant Association (ERA-EDTA) Registry's 2015 Annual Report. It describes the epidemiology of renal replacement therapy (RRT) for end-stage renal disease (ESRD) in 2015 within 36 countries. Methods In 2016 and 2017, the ERA-EDTA Registry received data on patients who were undergoing RRT for ESRD in 2015, from 52 national or regional renal registries. Thirty-two registries provided individual patient-level data and 20 provided aggregated-level data. The incidence, prevalence and survival probabilities of these patients were determined. Results In 2015, 81 373 individuals commenced RRT for ESRD, equating to an overall unadjusted incidence rate of 119 per million population (pmp). The incidence ranged by 10-fold, from 24 pmp in Ukraine to 232 pmp in the Czech Republic. Of the patients commencing RRT, almost two-thirds were men, over half were aged ≥65 years and a quarter had diabetes mellitus as their primary renal diagnosis. Treatment modality at the start of RRT was haemodialysis for 85% of the patients, peritoneal dialysis for 11% and a kidney transplant for 4%. By Day 91 of commencing RRT, 82% of patients were receiving haemodialysis, 13% peritoneal dialysis and 5% had a kidney transplant. On 31 December 2015, 546 783 individuals were receiving RRT for ESRD, corresponding to an unadjusted prevalence of 801 pmp. This ranged throughout Europe by more than 10-fold, from 178 pmp in Ukraine to 1824 pmp in Portugal. In 2015, 21 056 kidney transplantations were performed, equating to an overall unadjusted transplant rate of 31 pmp. This varied from 2 pmp in Ukraine to 94 pmp in the Spanish region of Cantabria. For patients commencing RRT during 2006-10, the 5-year unadjusted patient survival probabilities on all RRT modalities combined was 50.0% (95% confidence interval 49.9-50.1).
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TL;DR: Alectinib significantly improved systemic and CNS efficacy versus chemotherapy for crizotinib-pretreated ALK-positive NSCLC patients, with a favorable safety profile.
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University of Michigan1, University of Lausanne2, The Chinese University of Hong Kong3, Harvard University4, Seoul National University Hospital5, University of California, Irvine6, University of Lyon7, Gdańsk Medical University8, University of Turin9, Hoffmann-La Roche10, University of Colorado Boulder11
TL;DR: Alectinib demonstrated superior CNS activity and significantly delayed CNS progression versus crizotinib in patients with previously untreated, advanced ALK+ NSCLC, irrespective of prior CNS disease or radiotherapy.
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Karolinska Institutet1, University of Tennessee Health Science Center2, Semmelweis University3, Obafemi Awolowo University4, Rio de Janeiro State University5, St George's Hospital6, Gdańsk Medical University7, University of Parma8, Claude Bernard University Lyon 19, University of Ulsan10, Vanderbilt University11, Veterans Health Administration12, Imperial College Healthcare13, University of California, Irvine14, Taylors University15, Federal Fluminense University16, University of Toronto17, Case Western Reserve University18, Sanjay Gandhi Post Graduate Institute of Medical Sciences19, Başkent University20, University of Lausanne21, VU University Amsterdam22, University of Hong Kong23
TL;DR: It is concluded that PEW is a common phenomenon across the spectrum of AKI and CKD, and the well-documented impact of PEW on patient outcomes justifies the need for increased medical attention.
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Greater Baltimore Medical Center1, University of Birmingham2, Children's Hospital of Philadelphia3, Royal Hospital for Sick Children4, Cincinnati Children's Hospital Medical Center5, University of Utah6, Thomas Jefferson University7, University of Zaragoza8, Gdańsk Medical University9, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico10, Necker-Enfants Malades Hospital11, Western General Hospital12, Johns Hopkins University13, University of Amsterdam14, University of Lübeck15, Salisbury University16, Texas Tech University17, University Medical Center Groningen18
TL;DR: A series of recommendations are outlined that document the consensus of a group of international experts on clinical diagnostic criteria, both for classic and non-classic Cornelia de Lange syndrome phenotypes, molecular investigations, long-term management and care planning.
Abstract: Cornelia de Lange syndrome (CdLS) is an archetypical genetic syndrome that is characterized by intellectual disability, well-defined facial features, upper limb anomalies and atypical growth, among numerous other signs and symptoms It is caused by variants in any one of seven genes, all of which have a structural or regulatory function in the cohesin complex Although recent advances in next-generation sequencing have improved molecular diagnostics, marked heterogeneity exists in clinical and molecular diagnostic approaches and care practices worldwide Here, we outline a series of recommendations that document the consensus of a group of international experts on clinical diagnostic criteria, both for classic CdLS and non-classic CdLS phenotypes, molecular investigations, long-term management and care planning
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TL;DR: The concept of inflammaging is described, being a chronic, systemic, low grade and therefore for a long time subclinical, inflammatory process, and how it is integrated in the context of ARD.
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Adria Airways1, University of Oxford2, Ghent University Hospital3, Western General Hospital4, Gdańsk Medical University5, RWTH Aachen University6, University of Würzburg7, Winterthur Museum, Garden and Library8, Royal London Hospital9, Erasmus University Medical Center10, Innlandet Hospital Trust11, Autonomous University of Barcelona12, University of Paris13, Katholieke Universiteit Leuven14, Oulu University Hospital15, Royal Devon and Exeter Hospital16, Józef Piłsudski University of Physical Education in Warsaw17, University of Genoa18
TL;DR: An evidence-based approach to the diagnosis and management of parastomal hernias reveals the lack of evidence on several topics, which need to be addressed by multicenter trials.
Abstract: International guidelines on the prevention and treatment of parastomal hernias are lacking. The European Hernia Society therefore implemented a Clinical Practice Guideline development project. The guidelines development group consisted of general, hernia and colorectal surgeons, a biostatistician and a biologist, from 14 European countries. These guidelines conformed to the AGREE II standards and the GRADE methodology. The databases of MEDLINE, CINAHL, CENTRAL and the gray literature through OpenGrey were searched. Quality assessment was performed using Scottish Intercollegiate Guidelines Network checklists. The guidelines were presented at the 38th European Hernia Society Congress and each key question was evaluated in a consensus voting of congress participants. End colostomy is associated with a higher incidence of parastomal hernia, compared to other types of stomas. Clinical examination is necessary for the diagnosis of parastomal hernia, whereas computed tomography scan or ultrasonography may be performed in cases of diagnostic uncertainty. Currently available classifications are not validated; however, we suggest the use of the European Hernia Society classification for uniform research reporting. There is insufficient evidence on the policy of watchful waiting, the route and location of stoma construction, and the size of the aperture. The use of a prophylactic synthetic non-absorbable mesh upon construction of an end colostomy is strongly recommended. No such recommendation can be made for other types of stomas at present. It is strongly recommended to avoid performing a suture repair for elective parastomal hernia. So far, there is no sufficient comparative evidence on specific techniques, open or laparoscopic surgery and specific mesh types. However, a mesh without a hole is suggested in preference to a keyhole mesh when laparoscopic repair is performed. An evidence-based approach to the diagnosis and management of parastomal hernias reveals the lack of evidence on several topics, which need to be addressed by multicenter trials. Parastomal hernia prevention using a prophylactic mesh for end colostomies reduces parastomal herniation. Clinical outcomes should be audited and adverse events must be reported.
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University of Zurich1, University of California, San Diego2, University of Bremen3, University of Turin4, University Hospital Heidelberg5, University of Southern California6, Hannover Medical School7, Gdańsk Medical University8, Martin Luther University of Halle-Wittenberg9, Technische Universität München10, Leipzig University11, Charité12, HealthPartners13, University of Cologne14, University of Göttingen15, University of Kiel16, University of Ulm17, Otto-von-Guericke University Magdeburg18, John Radcliffe Hospital19, Winterthur Museum, Garden and Library20, Turku University Hospital21, Medical University of Warsaw22, University Hospital of Basel23, Catholic University of the Sacred Heart24, Greifswald University Hospital25, Heidelberg University26, University of Adelaide27, Charles University in Prague28, University of Florida29, Leiden University30, Mayo Clinic31, Imperial College London32
TL;DR: It is demonstrated that TTS can either be benign or a life-threating condition depending on the inciting stress factor, and a new classification based on triggers is proposed, which can serve as a clinical tool to predict short- and long-term outcomes of TTS.
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TL;DR: Fostamatinib produced clinically‐meaningful responses in ITP patients including those who failed splenectomy, thrombopoietic agents, and/or rituximab and is a novel ITP treatment option that targets an important mechanism of ITP pathogenesis.
Abstract: Spleen tyrosine kinase (Syk) signaling is central to phagocytosis-based, antibody-mediated platelet destruction in adults with immune thrombocytopenia (ITP). Fostamatinib, an oral Syk inhibitor, produced sustained on-treatment responses in a phase 2 ITP study. In two parallel, phase 3, multicenter, randomized, double-blind, placebo-controlled trials (FIT1 and FIT2), patients with persistent/chronic ITP were randomized 2:1 to fostamatinib (n = 101) or placebo (n = 49) at 100 mg BID for 24 weeks with a dose increase in nonresponders to 150 mg BID after 4 weeks. The primary endpoint was stable response (platelets ≥50 000/μL at ≥4 of 6 biweekly visits, weeks 14-24, without rescue therapy). Baseline median platelet count was 16 000/μL; median duration of ITP was 8.5 years. Stable responses occurred in 18% of patients on fostamatinib vs. 2% on placebo (P = .0003). Overall responses (defined retrospectively as ≥1 platelet count ≥50 000/μL within the first 12 weeks on treatment) occurred in 43% of patients on fostamatinib vs. 14% on placebo (P = .0006). Median time to response was 15 days (on 100 mg bid), and 83% responded within 8 weeks. The most common adverse events were diarrhea (31% on fostamatinib vs. 15% on placebo), hypertension (28% vs. 13%), nausea (19% vs. 8%), dizziness (11% vs. 8%), and ALT increase (11% vs. 0%). Most events were mild or moderate and resolved spontaneously or with medical management (antihypertensive, anti-motility agents). Fostamatinib produced clinically-meaningful responses in ITP patients including those who failed splenectomy, thrombopoietic agents, and/or rituximab. Fostamatinib is a novel ITP treatment option that targets an important mechanism of ITP pathogenesis.
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TL;DR: This review synthesizes the main features that render melatonin a promising candidate for the management of several dermatoses associated with substantial oxidative damage and why it promises to be useful in skin cancer prevention, skin photo- and radioprotection, and as an inducer of repair mechanisms that facilitate the recovery of human skin from environmental damage.
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TL;DR: This systematic review and meta‐analysis investigated the relationship between MSI and overall survival and clinicopathological characteristics of patients with gastric cancer.
Abstract: Background
Several associations between microsatellite instability (MSI) and other clinicopathological factors have been reported in gastric cancer, but the results have been ambiguous. This systematic review and meta-analysis investigated the relationship between MSI and overall survival and clinicopathological characteristics of patients with gastric cancer.
Methods
A systematic literature search of the PubMed, Cochrane and Ovid databases until 31 January 2016 was performed in accordance with the PRISMA statement. The articles were screened independently according to PICO (population, intervention, comparator, outcome) eligibility criteria. All eligible articles were evaluated independently by two reviewers for risk of bias according to the Quality In Prognosis Study tool.
Results
Overall, 48 studies with a total of 18 612 patients were included. MSI was found in 9·2 per cent of patients (1718 of 18 612), and was associated with female sex (odds ratio (OR) 1·57, 95 per cent c.i. 1·31 to 1·89; P < 0·001), older age (OR 1·58, 2·20 to 1·13; P < 0·001), intestinal Lauren histological type (OR 2·23, 1·94 to 2·57; P < 0·001), mid/lower gastric location (OR 0·38, 0·32 to 0·44; P < 0·001), lack of lymph node metastases (OR 0·70, 0·57 to 0·86, P < 0·001) and TNM stage I–II (OR 1·77, 1·47 to 2·13; P < 0·001). The pooled hazard ratio for overall survival of patients with MSI versus those with non-MSI gastric cancer from 21 studies was 0·69 (95 per cent c.i. 0·56 to 0·86; P < 0·001).
Conclusion
MSI in gastric cancer was associated with good overall survival, reflected in several favourable clinicopathological tumour characteristics.
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Royal Hospital for Sick Children1, University of Melbourne2, Boston Children's Hospital3, Institut Gustave Roussy4, University of Padua5, University of Franche-Comté6, Cliniques Universitaires Saint-Luc7, Stanford University8, Copenhagen University Hospital9, Gdańsk Medical University10, Oregon Health & Science University11, University of Geneva12, University of Copenhagen13, Newcastle University14, University of Birmingham15
TL;DR: The addition of sodium thiosulfate, administered 6 hours after cisplatin chemotherapy, resulted in a lower incidence of cisPlatin‐induced hearing loss among children with standard‐risk hepatoblastoma, without jeopardizing overall or event‐free survival.
Abstract: Background Cisplatin chemotherapy and surgery are effective treatments for children with standard-risk hepatoblastoma but may cause considerable and irreversible hearing loss. This trial c...
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TL;DR: The data suggest that a focus on KDMs will miss most resistance mechanisms; broader gene testing strategies and functional validation is warranted to devise new therapeutic strategies for drug resistance.
Abstract: Purpose: Despite initial benefit from tyrosine kinase inhibitors (TKIs), patients with advanced non-small cell lung cancer (NSCLC) harboring ALK (ALK+) and ROS1 (ROS1+) gene fusions ultimately progress. Here, we report on the potential resistance mechanisms in a series of patients with ALK+ and ROS1+ NSCLC progressing on different types and/or lines of ROS1/ALK-targeted therapy.Experimental Design: We used a combination of next-generation sequencing (NGS), multiplex mutation assay, direct DNA sequencing, RT-PCR, and FISH to identify fusion variants/partners and copy-number gain (CNG), kinase domain mutations (KDM), and copy-number variations (CNVs) in other cancer-related genes. We performed testing on 12 ROS1+ and 43 ALK+ patients.Results: One of 12 ROS1+ (8%) and 15 of 43 (35%) ALK + patients harbored KDM. In the ROS1+ cohort, we identified KIT and β-catenin mutations and HER2-mediated bypass signaling as non-ROS1-dominant resistance mechanisms. In the ALK+ cohort, we identified a novel NRG1 gene fusion, a RET fusion, 2 EGFR, and 3 KRAS mutations, as well as mutations in IDH1, RIT1, NOTCH, and NF1 In addition, we identified CNV in multiple proto-oncogenes genes including PDGFRA, KIT, KDR, GNAS, K/HRAS, RET, NTRK1, MAP2K1, and others.Conclusions: We identified a putative TKI resistance mechanism in six of 12 (50%) ROS1 + patients and 37 of 43 (86%) ALK+ patients. Our data suggest that a focus on KDMs will miss most resistance mechanisms; broader gene testing strategies and functional validation is warranted to devise new therapeutic strategies for drug resistance. Clin Cancer Res; 24(14); 3334-47. ©2018 AACR.
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TL;DR: The significance of the microRNAs on the relationship between the HIFs under both physiological and pathophysiological conditions is reviewed and miRNAs that endogenously regulate gene expression via the RNA interference pathway are shown to play critical roles in the hypoxia response pathways.
Abstract: The decline of oxygen tension in the tissues below the physiological demand leads to the hypoxic adaptive response. This physiological consequence enables cells to recover from this cellular insult. Understanding the cellular pathways that mediate recovery from hypoxia is therefore critical for developing novel therapeutic approaches for cardiovascular diseases and cancer. The master regulators of oxygen homeostasis that control angiogenesis during hypoxia are hypoxia-inducible factors (HIFs). HIF-1 and HIF-2 function as transcriptional regulators and have both unique and overlapping target genes, whereas the role of HIF-3 is less clear. HIF-1 governs the acute adaptation to hypoxia, whereas HIF-2 and HIF-3 expressions begin during chronic hypoxia in human endothelium. When HIF-1 levels decline, HIF-2 and HIF-3 increase. This switch from HIF-1 to HIF-2 and HIF-3 signaling is required in order to adapt the endothelium to prolonged hypoxia. During prolonged hypoxia, the HIF-1 levels and activity are reduced, despite the lack of oxygen-dependent protein degradation. Although numerous protein factors have been proposed to modulate the HIF pathways, their application for HIF-targeted therapy is rather limited. Recently, the miRNAs that endogenously regulate gene expression via the RNA interference (RNAi) pathway have been shown to play critical roles in the hypoxia response pathways. Furthermore, these classes of RNAs provide therapeutic possibilities to selectively target HIFs and thus modulate the HIF switch. Here, we review the significance of the microRNAs on the relationship between the HIFs under both physiological and pathophysiological conditions.
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Imperial College London1, Central European Institute of Technology2, University of the Witwatersrand3, University of São Paulo4, University of Manchester5, University of Western Australia6, Saint Joseph's University7, Hamad Medical Corporation8, Sultan Qaboos University9, Medical University of Vienna10, Oslo University Hospital11, Institute of Chartered Accountants of Nigeria12, Gdańsk Medical University13, Hebrew University of Jerusalem14, Ljubljana University Medical Centre15, McGill University Health Centre16, Ege University17, University of Belgrade18, National University of Singapore19, University of Latvia20, University of Ioannina21, Capital Medical University22, National Health Laboratory Service23, Heidelberg University24, Kyrgyz State Medical Academy25, University of Basel26, Academy of Medical Sciences, United Kingdom27, Universiti Teknologi MARA28, University of Copenhagen29, University of Debrecen30, Vilnius University31, Sofia Medical University32, University of Zagreb33, University of Benin34, Mashhad University of Medical Sciences35, United Arab Emirates University36, National Taiwan University37, Khoo Teck Puat Hospital38, University of Malta39, The Chinese University of Hong Kong40, National Institutes of Health41, Universidad Autónoma de Guadalajara42, Tallinn University of Technology43, Slovak Medical University44, University of Helsinki45, Osaka University46, Medical University of Łódź47, Linköping University48, University of the Philippines49, Technische Universität München50, Hacettepe University51, Nanyang Technological University52, University of Milan53
TL;DR: FH is a recognised public health concern, with overall suboptimal identification and under-treatment, and efforts and initiatives to improve FH knowledge and management are underway, but support from health authorities and better funding are greatly needed.
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National Institutes of Health1, The Royal Marsden NHS Foundation Trust2, University of Bologna3, University of Barcelona4, Johns Hopkins University5, Charité6, Heidelberg University7, University of Alberta8, Ghent University9, University of California, Los Angeles10, University of Miami11, University of Siena12, Centre Hospitalier Universitaire de Bordeaux13, University of Milan14, Northwestern University15, Masaryk University16, University of Bergen17, Gdańsk Medical University18, University of Texas MD Anderson Cancer Center19, University of Giessen20, City of Hope National Medical Center21, University of New Mexico22, University of Turin23, NewYork–Presbyterian Hospital24, MedImmune25
TL;DR: Moxetumomab pasudotox treatment achieved a high rate of independently assessed durable response and MRD eradication in heavily pretreated patients with HCL, with acceptable tolerability.
Abstract: This is a pivotal, multicenter, open-label study of moxetumomab pasudotox, a recombinant CD22-targeting immunotoxin, in hairy cell leukemia (HCL), a rare B cell malignancy with high CD22 expression. The study enrolled patients with relapsed/refractory HCL who had ≥2 prior systemic therapies, including ≥1 purine nucleoside analog. Patients received moxetumomab pasudotox 40 µg/kg intravenously on days 1, 3, and 5 every 28 days for ≤6 cycles. Blinded independent central review determined disease response and minimal residual disease (MRD) status. Among 80 patients (79% males; median age, 60.0 years), durable complete response (CR) rate was 30%, CR rate was 41%, and objective response rate (CR and partial response) was 75%; 64 patients (80%) achieved hematologic remission. Among complete responders, 27 (85%) achieved MRD negativity by immunohistochemistry. The most frequent adverse events (AEs) were peripheral edema (39%), nausea (35%), fatigue (34%), and headache (33%). Treatment-related serious AEs of hemolytic uremic syndrome (7.5%) and capillary leak syndrome (5%) were reversible and generally manageable with supportive care and treatment discontinuation (6 patients; 7.5%). Moxetumomab pasudotox treatment achieved a high rate of independently assessed durable response and MRD eradication in heavily pretreated patients with HCL, with acceptable tolerability.
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TL;DR: This manuscript is written by members of the Children’s Oncology Group (COG) in North America, the International Childhood Liver Tumors Strategy Group (SIOPEL) in Europe, and the Japanese Study Group for Pediatric liver Tumor (JPLT) and represents an international consensus update to the 2005 PRETEXT definitions.
Abstract: Imaging is crucial in the assessment of children with a primary hepatic malignancy. Since its inception in 1992, the PRETEXT (PRE-Treatment EXTent of tumor) system has become the primary method of risk stratification for hepatoblastoma and pediatric hepatocellular carcinoma in numerous cooperative group trials across the world. The PRETEXT system is made of two components: the PRETEXT group and the annotation factors. The PRETEXT group describes the extent of tumor within the liver while the annotation factors help to describe associated features such as vascular involvement (either portal vein or hepatic vein/inferior vena cava), extrahepatic disease, multifocality, tumor rupture and metastatic disease (to both the lungs and lymph nodes). This manuscript is written by members of the Children's Oncology Group (COG) in North America, the International Childhood Liver Tumors Strategy Group (SIOPEL) in Europe, and the Japanese Study Group for Pediatric Liver Tumor (JPLT; now part of the Japan Children's Cancer Group) and represents an international consensus update to the 2005 PRETEXT definitions. These definitions will be used in the forthcoming Trial to Pediatric Hepatic International Tumor Trial (PHITT).
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TL;DR: It is proposed that the production of Aβ as an AMP will be beneficial on first microbial challenge but will become progressively detrimental as the infection becomes chronic and reactivates from time to time.
Abstract: Alzheimer's disease (AD) is the most frequent type of dementia. The pathological hallmarks of the disease are extracellular senile plaques composed of beta-amyloid peptide (Aβ) and intracellular neurofibrillary tangles composed of pTau. These findings led to the "beta-amyloid hypothesis" that proposes that Aβ is the major cause of AD. Clinical trials targeting Aβ in the brain have mostly failed, whether they attempted to decrease Aβ production by BACE inhibitors or by antibodies. These failures suggest a need to find new hypotheses to explain AD pathogenesis and generate new targets for intervention to prevent and treat the disease. Many years ago, the "infection hypothesis" was proposed, but received little attention. However, the recent discovery that Aβ is an antimicrobial peptide (AMP) acting against bacteria, fungi, and viruses gives increased credence to an infection hypothesis in the etiology of AD. We and others have shown that microbial infection increases the synthesis of this AMP. Here, we propose that the production of Aβ as an AMP will be beneficial on first microbial challenge but will become progressively detrimental as the infection becomes chronic and reactivates from time to time. Furthermore, we propose that host measures to remove excess Aβ decrease over time due to microglial senescence and microbial biofilm formation. We propose that this biofilm aggregates with Aβ to form the plaques in the brain of AD patients. In this review, we will develop this connection between Infection - Aβ - AD and discuss future possible treatments based on this paradigm.
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Maastricht University1, University of Turin2, Cliniques Universitaires Saint-Luc3, Netherlands Cancer Institute4, University of Duisburg-Essen5, Gdańsk Medical University6, Ghent University Hospital7, VU University Medical Center8, Università Campus Bio-Medico9, University of Manchester10, The Royal Marsden NHS Foundation Trust11, Ludwig Maximilian University of Munich12, University of Bern13, Institut Gustave Roussy14
TL;DR: Recommendations are given for methods and time-points of diagnostics and imaging before the start of treatment planning and for the mandatory and optional imaging to be used for planning itself, and opinions on normal tissue delineation and organisational and responsibility questions in the process of target volume delineation.