Journal of International Medical Research, Ahead of Print.
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Κυριακή 24 Φεβρουαρίου 2019
Effect of alteplase on platelet function and receptor expression
Chronic stress: a critical risk factor for atherosclerosis
Journal of International Medical Research, Ahead of Print.
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Dandy–Walker syndrome associated with syringomyelia in an adult: a case report and literature review
Journal of International Medical Research, Ahead of Print.
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Disease in Childhood
| Theophylline and aminophylline for prevention of acute kidney injury in neonates and children: a systematic review Objective To compare the efficacy and safety of theophylline or aminophylline for prevention of acute kidney injury (AKI) in neonates and children. DesignSystematic review and meta-analysis with application of Grading of Recommendations, Assessment, Development and Evaluation system. Data sourcesPubMed/MEDLINE, Embase, Google Scholar and Cochrane renal group were searched from 1970 to May 2018. Eligibility criteriaRandomised clinical trials and quasi-randomised trials comparing the efficacy and safety of prophylactic theophylline or aminophylline for prevention of AKI in neonates and children were included. The primary outcomes were: incidence of AKI, serum creatinine levels and all-cause mortality. ResultsA total of nine trials were included in the qualitative synthesis. Six trials including 436 term neonates with birth asphyxia who received a single dose of theophylline were finally included in the meta-analysis. The pooled estimate showed 60% reduction in the incidence of AKI in neonates with severe birth asphyxia (RR: 0.40; 95% CI 0.3 to 0.54; heterogeneity: I2=0%) (moderate quality evidence), decrease in serum creatinine over days 2–5 (very low to low quality evidence) without significant difference in all-cause mortality (RR: 0.88; 95% CI 0.52 to 1.50; heterogeneity: I2=0%) (very low-quality evidence). A significant difference in the negative fluid balance, increase in GFR and decrease in urinary β2 microglobulin was seen in favour of theophylline. Conclusion and relevanceA single dose of prophylactic theophylline helps in prevention of AKI/severe renal dysfunction in term neonates with severe birth asphyxia (moderate quality evidence) without increasing the risk of complications and without affecting all-cause mortality (very low-quality evidence). Trial registration numberCRD 42017073600. |
| Pathways to inequalities in child health From birth, children living in disadvantaged socioeconomic circumstances (SECs) suffer from worse health than their more advantaged peers. The pathways through which SECs influence children's health are complex and inter-related, but in general are driven by differences in the distribution of power and resources that determine the economic, material and psychosocial conditions in which children grow up. A better understanding of why children from more disadvantaged backgrounds have worse health and how interventions work, for whom and in what contexts, will help to reduce these unfair differences. Macro-level change is also required, including the reduction of child poverty through improved social security systems and employment opportunities, and continued investment in high-quality and accessible services (eg, childcare, key workers, children's centres and healthy school environments). Child health professionals can play a crucial role by being mindful of the social determinants of health in their daily practice, and through advocating for more equitable and child-focussed resource allocation. |
| Reclaiming the systems approach to paediatric safety Introduction Prior to the emergence of the patient safety movement as a distinct science, it was assumed that the safety of patients was an outcome of good professional acumen, and that if healthcare providers could individually perform well then their patients would remain safe at all times. It is now 20 years since the publication of To Err is Human,1 the first major review of healthcare safety in the USA. In the UK, the publication Organisation with a Memory2 in 2000 supported the view that patient safety required a wider system approach. Both documents reframed safety and error in healthcare as an organisational or system issue rather than one of individual error, whether of omission or of commission. Over the past 20 years, there has been major progress in the understanding of patient safety and the complexity of the systems involved in providing healthcare. In a recent... |
| No association between abdominal pain and Dientamoeba in Dutch and Belgian children Objective To study the association between Dientamoebafragilis colonisation and faecal calprotectin to see whether the parasite is a harmless commensal or a gut pathogen. DesignCross-sectional study of previously collected stool samples. Setting and patientsTwo hundred stool samples originated from children aged 5–19 years with chronic abdominal pain and diarrhoea, who were seen in paediatric clinics in the Netherlands and Belgium and in whom somatic gastrointestinal disorders were excluded. Another 122 samples came from a healthy community-based reference population of the same age. All stool samples were analysed with real-time PCR for the detection of D. fragilis and with an ELISA for calprotectin—a biomarker of gastrointestinal inflammation. Main outcome measuresPrevalence of D. fragilis colonisation and results of stool calprotectin testing. ResultsD. fragilis was detected in 45% (95% CI 38% to 51%) of patients and in 71% (95% CI 63% to 79%) of healthy children. Median (IQR) concentrations of calprotectin in patients and healthy children with a positive PCR result were not different from those with a negative PCR result (40 (40–55) μg/g vs 40 (40–75) μg/g, respectively). ConclusionSince D. fragilis colonisation is most prevalent in healthy children and is not associated with an increase in faecal calprotectin concentration, our data do not support the inference that D. fragilis is a pathogenic parasite. Routinely testing for D. fragilis in children with chronic abdominal pain should therefore be discouraged. |
| Epidemiology of paediatric chronic fatigue syndrome in Australia Objective To estimate the paediatrician-diagnosed incidence of chronic fatigue syndrome (CFS) in Australia, and describe demographic and clinical features, as well as approaches to diagnosis and management. MethodsThe Australian Paediatric Surveillance Unit facilitates monthly national surveillance of uncommon conditions seen by paediatricians. Data from young people aged <18 years diagnosed with CFS were collected. Incidence was estimated based on new cases reported from April 2015 to April 2016. ResultsA total of 164 cases of newly diagnosed CFS in young people aged 4–17 years were identified for inclusion. The estimated national incidence for children aged 4–9 years was 0.25 per 100 000 per annum. In children aged 10–17 years, the estimated incidence of paediatrician-diagnosed cases for Victoria (17.48 per 100 000) was substantially greater than other Australian states (range 1.31–5.51 per 100 000). Most cases were female and Caucasian, most commonly presenting after an infectious illness with symptoms gradual in onset. The majority were diagnosed at least 13 months after symptom onset. Symptoms, associations, investigations and management strategies were highly variable. ConclusionsCurrent findings suggest that, consistent with other countries, the Australian incidence of CFS in children aged <10 years is very low. In contrast, the national incidence of CFS in older children and adolescents (aged 10–17 years) is more unclear, with marked variability between geographical regions apparent. This may be due to variation in service accessibility and clinician understanding of CFS. Accordingly, national initiatives to improve equity of care for children with CFS may be required. |
| Persistence of pneumococcal antibodies after primary immunisation with a polysaccharide-protein conjugate vaccine Introduction Despite immunisation, antibiotics and intensive care management, infection with Streptococcus pneumoniae remains a major cause of morbidity and mortality in children. The WHO currently recommends vaccinating infants with either a 3+0 schedule (6 weeks, 3–4 and 4–6 months of age) or 2+1 schedule (2 doses before 6 months of age, plus a booster dose at 9–15 months of age). This study investigated pneumococcal antibody responses, including persistence of antibodies, after immunisation of healthy infants with a 3+0 schedule. MethodsWe measured pneumococcal antibody concentrations to all 13 antigens included in the 13-valent pneumococcal conjugate vaccine (PCV13) after immunisation with a 3+0 schedule in 91 infants at 7 months and in 311 infants at 13 months of age. The geometric mean concentrations (GMCs) and the proportion of infants with an antibody concentration above the standard threshold correlate of protection (seroprotection rate) were calculated at both time points. ResultsAt 7 months of age, GMCs varied between 0.52 µg/mLand 11.52 µg/mL, and seroprotection rates varied between 69% and 100%. At 13 months of age, GMCs had decreased to between 0.22 µg/mLand 3.09 µg/mL, with the lowest responses against serotype 4, followed by 19A, 3, 6B and 23F. Seroprotection rates at 13 months of age were below 90% for most serotypes, with the lowest rates for serotype 4 (23%) followed by 19A (50%), 23F (61%) and 6B (64%). ConclusionOur study shows that at 13 months of age, many infants vaccinated with a 3+0 schedule have pneumococcal antibody concentrations below the standard threshold correlate of protection. To optimise protection against pneumococcal disease through early childhood and to improve antibody persistence and indirect protective effects, immunisation schedules with booster doses might be necessary. |
| Highlights from the literature Separating craniopagus twins Lucina doesn't normally feature surgical case reports, but this one reported in the NEJM is remarkable (Heuer G et al doi:10.1056/NEJMoa1805132). A highly-skilled team from the Children's Hospital of Philadelphia successfully separated conjoined twin girls, who shared skull bones and a common sagittal sinus, but not brain tissue. They were delivered at 30 weeks, and pre-operatively required tissue expansion techniques over several months to make separation easier. Meticulous planning, which involved computerised modelling and 3-D printing, led to an 11 hours separation procedure at age 10 months. Remodelling the venous sinuses was a particular challenge. The girls have done well, with intact skulls and only mild neurocognitive deficits. Conjoined twins are rare and craniopagus even rarer, so each case has to be looked at afresh as new technologies emerge. EMLA in infants'Magic cream', or topical local anaesthetic EMLA (eutectic mixture of lidocaine/lignocaine and prilocaine), is frequently used for... |
| Air pollution and autism It's clear that genetics plays a major role in the aetiology of autistic spectrum disorder (ASD), but the genuine increase in prevalence over recent decades suggests that environmental factors are also responsible. If ASD is considered to be a neurodevelopmental disorder, rather than a social construct, then antenatal influences during early brain development may be important. Potential prenatal causes suggested thus far are many and varied, including paracetamol (Archivist Oct 2016 doi.org/10.1136/archdischild-2016–3 11 708), antidepressant drugs (Archivist March 2016 doi.org/10.1136/archdischild-2016–3 10 462), ultrasound (Archivist Sept 2018 doi.org/10.1136/archdischild-2018–3 15 816), season of conception (Lucina Dec 2016 doi.org/10.1136/archdischild-2016–3 12 102), and obesity, among many others. Several studies have hinted at a link with maternal air pollution exposure, but these have been inconsistent or inconclusive. ASD definitions have been imprecise, exposure indicators not sufficiently localised, and types of pollution lumped together. Importantly, confounding factors need to be accounted for, as families with the highest psychosocial risks for autism may tend to live... |
| Screentime and child health The media are obsessed with the issue of 21st century children spending too much time staring at screens: some reports have amounted to a moral panic (www.telegraph.co.uk/news/2018/09/26/two-hours-screentime-day-could-damage-childrens-brain-development). The release of a statement from the UK's Royal College of Paediatrics and Child Health (RCPCH) was therefore welcome (rcpch.ac.uk/resources/health-impacts-screen-time-guide-clinicians-parents). It was based on a systematic 'review of reviews' which synthesised the large amount of evidence available (Stiglic N, Viner R. doi: 10. 1136/bmjopen- 2018–0 23 191). Rather than go back to the primary data, they identified 13 reviews of varying quality that had already done this. They assessed each review's conclusions qualitatively, rather than doing further meta-analyses. Screentime use included television (TV), computers, tablets and smartphones. TV-watching predominated in most reviews. Different outcome domains were considered. With regards to obesity or adiposity, they concluded that there was a positive association with TV screentime, but they could not define a 'safe threshold' of time.... |
| At what weight should preterm infants be transferred from incubator to open cot? Scenario A preterm infant born at 28 weeks' gestation is 5 weeks old, weighs 1600 g and nursed in an incubator. During the round, the medical team instructs the nurse to transfer the infant to open cot. The nurse in charge is concerned that weaning the infant from incubator to cot at this weight might affect the temperature stability, weight gain and may delay the discharge of the infant. The third-year paediatric resident offers to review the literature and report the findings to the multidisciplinary team. Structured clinical questionIn a medically stable preterm infant with a birth weight of less than 1600 g, not on any respiratory support, nursed in incubator (patient), whether transferring the infant from incubator to unheated open cot at a lower weight (<1700 g) (intervention) compared with a higher weight (>1700 g) (comparison) will affect the temperature stability, weight gain and length of hospital stay of the... |
| Highlights from this issue Global child healthVitamin A The history of the vitamin A supplementation studies from the initial excitement of the reduction in measles related mortality trials in West Africa 25 years ago has been a chequered one. The routine population supplementation from 6 months to 5 years of age is now established, but the issue over neonatal supplementation and its effect on infant mortality and morbidity has remained unresolved, trials showing different directions of effect, or no effect. The paper from the WHO Vitamin A supplementation group addresses this in a meta-analysis of the 11 published studies. Pooled analysis showed no effect of early (first 2 to 3 days) vitamin A supplementation on mortality at either 6 months (RR 0.97, 95% CI 0.89 to 1.06) or 1 year. There were subtle differences in the sub-analyses stratified by region: in South Asia (but not Africa) where Vitamin A deficiency (defined by established... |
| Fetal hydrops: diagnosis and prognosis The causes and outcomes of fetal hydrops have been well described in the literature over many years. Anti-D immunoglobulin has dramatically reduced the rate (and mortality) of immune hydrops such that non-immune hydrops (NIHF) now accounts for 90% of cases.1 Hydrops is a challenging condition to counsel for due to the relative rarity (1 in 1700–3000 pregnancies) and the fact it is the preterminal manifestation of many different pathophysiological processes.2–4 The paper published in our sister journal Fetal & Neonatal by Gilby et al5 addresses two key questions that all expectant parents faced with this problem would ask: what is the cause of the hydrops and will my baby survive? Diagnosis in NIHF is of paramount importance to accurate counselling. The more refined the phenotype the more accurate information a clinician is able to provide on mortality, morbidity and treatment options. |
| 'Death is not the answer: the challenge of measuring the impact of early warning systems We can all remember individual children in whom a deterioration went unrecognised. Sometimes fatally. Our defences were little more than the pearls offered by senior colleagues of grave warning signs: 'beware grunting in an infant' or 'watch out for a tachycardia after the temperature has fallen'. But this advice was unstructured, and children are so different, and their comorbidities so broad, we failed some of them. Paediatric Early Warning Systems (PEWS) are serious attempts to reduce the unacceptable and dangerous variability in this recognition and response process. Scoring systems should provide age-appropriate thresholds for concern for single parameters or aggregated abnormal physiology and prompt standardised responses. The idea has such natural appeal that PEWS use was soon advocated by a number of national bodies1 2 without evidence. This may have been a mistake. Many of the scores in widespread use were not calibrated or validated.... |
| Biological therapeutic drug monitoring: a step towards precision medicine? Biological medications including monoclonal antibodies against tumour necrosis factor-α (TNF-α), such as infliximab and adalimumab, have revolutionised the treatment of children and young people with autoimmune conditions such as inflammatory bowel disease, juvenile idiopathic arthritis (JIA) and childhood chronic inflammatory uveitis. Emerging evidence is increasingly supporting the use of therapeutic drug monitoring (TDM) to help optimise biological efficacy, safety and cost-effectiveness. The pharmacokinetics of biologics is complex and in contrast to traditional medications; predominantly due to their large molecular size and structural complexity, they do not undergo hepatic metabolisation and are instead broken down by intracellular lysosomal proteolytic degradation. Also, unlike traditional medications, they have immunogenic potential and the formation of antidrug antibodies (ADA) can significantly affect their pharmacokinetic profile. ADA directed against the corresponding biologic can trigger proteolytic elimination in the reticuloendothelial system (RES) leading to increased clearance of these molecules. Conversely, an immune complex that does not... |
| Improving the quality of care delivered to adolescents in Europe: a time to invest Introduction While many governments, non governmental organisations (NGOs) and United Nations (UN) agencies have focused in the past on the health of mothers, infants and young children, there is now growing evidence that the healthcare system should also address the well-being and problems of adolescents, defined by WHO as individuals aged 10–19 years. They represent 1.2 billion individuals in the global population and between 10% and 25% of the population in European countries.1 In September 2015, the UN Secretary-General announced that the 'Every Woman, Every Child' agenda would move forward to 2030 as a Global Strategy for Women's, Children's and Adolescents' Health. In 2017, WHO responded to the large number of health problems affecting adolescents by launching a state-of-the-art review of programmes and interventions targeting the health burden of adolescents around the world, the AA-HA initiative ('Accelerated Action for the Health of Adolescents'). Adolescents' morbidities such as sexually transmitted... |
| Early neonatal vitamin A supplementation and infant mortality: an individual participant data meta-analysis of randomised controlled trials Background Biannual vitamin A supplementation is a well-established survival tool for preschool children 6 months and older in vitamin A deficient populations but this schedule misses the opportunity to intervene on most young infant deaths. Randomised trials of neonatal vitamin A supplementation (NVAS) in the first few days of life to assess its impact on under 6-month mortality in low/middle-income countries have had varying results. MethodsInvestigators of 11 published randomised placebo-controlled NVAS trials (n=163 567 children) reanalysed their data according to an agreed plan and pooled the primary outcomes of mortality from supplementation through 6 and 12 months of age using random effects models and meta-regression. One investigator withdrew but allowed use of the data. FindingsOverall there was no effect of NVAS on infant survival through 6 (risk ratio (RR) 0.97; 95% CI 0.89 to 1.06) or 12 months of age (RR 1.00; 95% CI 0.93 to 1.08) but results varied by study population characteristics. NVAS significantly reduced 6-month mortality among the trials conducted in Southern Asia (RR 0.87; 95% CI 0.77 to 0.98), in contexts with moderate or severe vitamin A deficiency (defined as 10% or higher proportion of women with serum retinol <0.7 µmol/L or 5% or more women with night blindness) (RR 0.87; 95% CI 0.80 to 0.94), early infant mortality was 30 or more per 1000 live births (RR 0.91; 95% CI 0.85 to 0.98), 75% or more of infant mortality occurred in the first 6 months of life (RR 0.92; 95% CI 0.84 to 1.01), or where >32% mothers had no schooling (RR 0.88; 95% CI 0.80 to 0.96). NVAS did not reduce mortality in the first 6 months of life in trials conducted in Africa, in contexts characterised by a low prevalence of vitamin A deficiency, lower rates of infant mortality and where maternal education was more prevalent. There was a suggestion of increased infant mortality in trials conducted in Africa (RR 1.07; 95% CI 1.00 to 1.15). Individual-level characteristics such as sex, birth weight, gestational age and size, age at dosing, parity, time of breast feeding initiation, maternal education and maternal vitamin A supplementation did not modify the impact of NVAS. ConclusionNVAS reduced infant mortality in South Asia, in contexts where the prevalence of maternal vitamin A deficiency is moderate to severe and early infant mortality is high; but it had no beneficial effect on infant survival in Africa, in contexts where the prevalence of maternal vitamin A deficiency is lower, early infant mortality is low. |
| Mass antibiotic distribution to reduce mortality among preschool children? Worldwide, under-fives mortality has halved since 1990 from 93 to 41 deaths per 1000 live births in 2016. However, progress has been very uneven. Child mortality is still highest in Africa (76 per 1000 live births) (figure 1) and neonatal mortality has declined at a slower rate so is now approaching 50% of all under-fives mortality.1 Research and programmatic efforts are focussed on reducing child mortality in the highest burden areas. An intriguing and controversial idea to reduce mortality has arisen from mass antimicrobial distribution programmes for the prevention of blindness caused by trachoma. Trachoma has a predilection for the poorest, most remote communities with low levels of hygiene. Chlamydia trachomatis is spread by direct contact with fluid from an infected person's eyes or nose, or indirect contact with these fluids via clothing or flies. It is endemic across Africa from South Sudan and Ethiopia... |
| Linear growth following complicated severe malnutrition: 1-year follow-up cohort of Kenyan children Background Stunting is the most common manifestation of childhood undernutrition worldwide. Children presenting with severe acute malnutrition (SAM) are often also severely stunted. We evaluated linear growth and its determinants after medically complicated SAM. MethodsWe performed secondary analysis of clinical trial data (NCT00934492) from HIV-uninfected Kenyan children aged 2–59 months hospitalised with SAM. Outcome was change in height/length-for-age z-score (HAZ) between enrolment and 12 months later. Exposures were demographic, clinical, anthropometric characteristics and illness episodes during follow-up. ResultsAmong 1169 children with HAZ values at month 12 (66% of those in original trial), median (IQR) age 11 (7–17) months and mean (SD) HAZ –2.87 (1.6) at enrolment, there was no change in mean HAZ between enrolment and month 12: –0.006Z (95% CI –0.07 to 0.05Z). While 262 (23%) children experienced minimal HAZ change (within ±0.25 HAZ), 472 (40%) lost >0.25 and 435 (37%) gained >0.25 HAZ. After adjusting for regression to the mean, inpatient or outpatient episodes of diarrhoea and inpatient severe pneumonia during follow-up were associated with HAZ loss. Premature birth and not being cared by the biological parent were associated with HAZ gain. Increases in mid-upper arm circumference and weight-for-age were associated with HAZ gain and protected against HAZ loss. Increase in weight-for-height was not associated with HAZ gain but protected against HAZ loss. No threshold of weight gain preceding linear catch-up growth was observed. ConclusionsInterventions to improve dietary quality and prevent illness over a longer period may provide opportunities to improve linear growth. |
| Child mortality: how does the USA compare? In March 2015, an Archives editorial featured a Lancet paper describing neonatal, infant and child mortality trends, comparing UK data to other European countries and Canada, but not the USA (doi: 10.1136/archdischild-2014–3 07 678). The UK was improving more slowly than the comparator countries. Now American authors have done something similar (Khan S et al doi:10.1001/jamapediatrics.2018.3317). Using the US National Centre for Health Statistics database, and comparing to equivalent data from England/Wales (E&W) and Canada, they found that the US is actually doing much worse than the UK. They looked at annual mortality rates for all individuals up to age 24, from 1999 to 2015, throughout the US. As seen in other countries, there was a striking decline in overall mortality rates for most age groups over the 16 year period, except for young adults aged 20–24 where there was a decline until 2012 and then a slight increase. In all age... |
| Research priorities for childhood chronic conditions: a workshop report Background Chronic conditions are the leading cause of mortality, morbidity and disability in children. However, children and caregivers are rarely involved in identifying research priorities, which may limit the value of research in supporting patient-centred practice and policy. ObjectiveTo identify priorities of patients, caregivers and health professionals for research in childhood chronic conditions and describe the reason for their choices. SettingAn Australian paediatric hospital and health consumer organisations. MethodsRecruited participants (n=73) included patients aged 8 to 14 years with a chronic condition (n=3), parents/caregivers of children aged 0 to 18 years with a chronic condition (n=19), representatives from consumer organisations (n=13) and health professionals including clinicians, researches (n=38) identified and discussed research priorities. Transcripts were thematically analysed. ResultsSeventy-eight research questions were identified. Five themes underpinned participants' priorities: maintaining a sense of normality (enabling participation in school, supporting social functioning, promoting understanding and acceptance), empowering self-management and partnership in care (overcoming communication barriers, gaining knowledge and skills, motivation for treatment adherence, making informed decisions, access and understanding of complementary and alternative therapies),strengthening ability to cope (learning to have a positive outlook, preparing for home care management, transitioning to adult services), broadening focus to family (supporting sibling well-being, parental resilience and financial loss, alleviating caregiver burden), and improving quality and scope of health and social care (readdressing variability and inequities, preventing disease complications and treatment side effects, identifying risk factors, improving long-term outcomes, harnessing technology, integrating multidisciplinary services). ConclusionResearch priorities identified by children, caregivers and health professionals emphasise a focus on life participation, psychosocial well-being, impact on family and quality of care. These priorities may be used by funding and policy organisations in establishing a paediatric research agenda. |
The Emerging World of TCR-T Cell Trials Against Cancer: A Systematic Review
Technology in Cancer Research &Treatment, Volume 18, Issue , January 2019.
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Modification of drug-binding proteins associated with the efflux pump in MDR-MTB in course of evolution: an unraveled clue based on in silico approach
Modification of drug-binding proteins associated with the efflux pump in MDR-MTB in course of evolution: an unraveled clue based on in silico approach
Modification of drug-binding proteins associated with the efflux pump in MDR-MTB in course of evolution: an unraveled clue based on in silico approach, Published online: 25 February 2019; doi:10.1038/s41429-019-0146-3
Modification of drug-binding proteins associated with the efflux pump in MDR-MTB in course of evolution: an unraveled clue based on in silico approach
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A dual pathway inhibition strategy using BKM120 combined with vemurafenib is poorly tolerated in BRAF V600E/K mutant advanced melanoma
Abstract
Single or dual agent inhibition of the MAPK pathway can induce objective responses in up to 70% of BRAF mutant melanoma patients, but these responses are transient in most patients (e. g. Long et al., 2015). Aberrant signaling in the PI3K pathway has been implicated in both melanoma oncogenesis and in BRAF inhibitor resistance (e. g. Dankort et al., 2009; Goel et al., 2006). PTEN loss, which leads to increased PI3K activity, is common in patients treated with the BRAF inhibitor vemurafenib (McArthur et al., 2011) and decreased PTEN expression has been identified as a predictor of decreased PFS in patients treated with the drug (Nathanson et al., 2013).
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Osteochondritis dissecans (OCD) in Horses - Molecular Background of its Pathogenesis and Perspectives for Progenitor Stem Cell Therapy.
| Related Articles |
Osteochondritis dissecans (OCD) in Horses - Molecular Background of its Pathogenesis and Perspectives for Progenitor Stem Cell Therapy.
Stem Cell Rev. 2019 Feb 23;:
Authors: Bourebaba L, Röcken M, Marycz K
Abstract
Osteochondrosis (osteochondrosis dissecans; OCD) is a disease syndrome of growing cartilage related to different clinical entities such as epiphysitis, subchondral cysts and angular carpal deformities, which occurs in growing animals of all species, including horses. Nowadays, these disorders are affecting increasing numbers of young horses worldwide. As a complex multifactorial disease, OCD is initiated when failure in cartilage canals because of existing ischemia, chondrocyte biogenesis impairment as well as biochemical and genetic disruptions occur. Recently, particular attention have been accorded to the definition of possible relations between OCD and some metabolic disorders; in this way, implication of mitochondrial dysfunctions, endoplasmic reticulum disruptions, oxidative stress or endocrinological affections are among the most considered axes for future researches. As one of the most frequent cause of impaired orthopaedic potential, which may result in a sharp decrease in athletic performances of the affected animals, and lead to the occurrence of complications such as joint fragility and laminitis, OCD remains as one of the primary causes of considerable economic losses in all sections of the equine industry. It would therefore be important to provide more information on the exact pathophysiological mechanism(s) underlying early OC(D) lesions, in order to implement innovative strategies involving the use of progenitor stem cells, which are considered nowadays as a promising approach to regenerative medicine, with the potential to treat numerous orthopaedic disorders, including osteo-degenerative diseases, for prevention and reduction of incidence of the disease, not only in horses, but also in human medicine, as the equine model is already widely accepted by the scientific community and approved by the FDA, for the research and application of cellular therapies in the treatment of human conditions.
PMID: 30796679 [PubMed - as supplied by publisher]
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Reassessing the impact of intraoperative electrocorticography on postoperative outcome of patients undergoing standard temporal lobectomy for MRI-negative temporal lobe epilepsy.
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Reassessing the impact of intraoperative electrocorticography on postoperative outcome of patients undergoing standard temporal lobectomy for MRI-negative temporal lobe epilepsy.
J Neurosurg. 2019 Feb 22;:1-10
Authors: Grewal SS, Alvi MA, Perkins WJ, Cascino GD, Britton JW, Burkholder DB, So E, Shin C, Marsh RW, Meyer FB, Worrell GA, Van Gompel JJ
Abstract
OBJECTIVEAlmost 30% of the patients with suspected temporal lobe epilepsy (TLE) have normal results on MRI. Success rates for resection of MRI-negative TLE are less favorable, ranging from 36% to 76%. Herein the authors describe the impact of intraoperative electrocorticography (ECoG) augmented by opioid activation and its effect on postoperative seizure outcome.METHODSAdult and pediatric patients with medically resistant MRI-negative TLE who underwent standardized ECoG at the time of their elective anterior temporal lobectomy (ATL) with amygdalohippocampectomy between 1990 and 2016 were included in this study. Seizure recurrence comprised the primary outcome of interest and was assessed using Kaplan-Meier and multivariable Cox regression analysis plots based on distribution of interictal epileptiform discharges (IEDs) recorded on scalp electroencephalography, baseline and opioid-induced IEDs on ECoG, and extent of resection.RESULTSOf the 1144 ATLs performed at the authors' institution between 1990 and 2016, 127 (11.1%) patients (81 females) with MRI-negative TLE were eligible for this study. Patients with complete resection of tissue generating IED recorded on intraoperative ECoG were less likely to have seizure recurrence compared to those with incomplete resection on univariate analysis (p < 0.05). No difference was found in seizure recurrence between patients with bilateral independent IEDs and unilateral IEDs (p = 0.15), presence or absence of opioid-induced epileptiform activation (p = 0.61), or completeness of resection of tissue with opioid-induced IEDs on intraoperative ECoG (p = 0.41).CONCLUSIONSThe authors found that incomplete resection of IED-generating tissue on intraoperative ECoG was associated with an increased chance of seizure recurrence. However, they found that induction of epileptiform activity with intraoperative opioid activation did not provide useful intraoperative data predictive of improving operative results for temporal lobectomy in MRI-negative epilepsy.
PMID: 30797216 [PubMed - as supplied by publisher]
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Prediction of postoperative deficits using an improved diffusion-weighted imaging maximum a posteriori probability analysis in pediatric epilepsy surgery.
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Prediction of postoperative deficits using an improved diffusion-weighted imaging maximum a posteriori probability analysis in pediatric epilepsy surgery.
J Neurosurg Pediatr. 2019 Feb 22;:1-12
Authors: Lee MH, O'Hara NB, Nakai Y, Luat AF, Juhasz C, Sood S, Asano E, Jeong JW
Abstract
OBJECTIVEThis study is aimed at improving the clinical utility of diffusion-weighted imaging maximum a posteriori probability (DWI-MAP) analysis, which has been reported to be useful for predicting postoperative motor, language, and visual field deficits in pediatric epilepsy surgery. The authors determined the additive value of a new clustering mapping method in which average direct-flip distance (ADFD) reclassifies the outliers of original DWI-MAP streamlines by referring to their minimum distances to the exemplar streamlines (i.e., medoids).METHODSThe authors studied 40 children with drug-resistant focal epilepsy (mean age 8.7 ± 4.8 years) who had undergone resection of the presumed epileptogenic zone and had five categories of postoperative deficits (i.e., hemiparesis involving the face, hand, and/or leg; dysphasia requiring speech therapy; and/or visual field cut). In pre- and postoperative images of the resected hemisphere, DWI-MAP identified a total of nine streamline pathways: C1 = face motor area, C2 = hand motor area, C3 = leg motor area, C4 = Broca's area-Wernicke's area, C5 = premotor area-Broca's area, C6 = premotor area-Wernicke's area, C7 = parietal area-Wernicke's area, C8 = premotor area-parietal area, and C9 = occipital lobe-lateral geniculate nucleus. For each streamline of the identified pathway, the minimal ADFD to the nine exemplars corrected the pathway membership. Binary logistic regression analysis was employed to determine how accurately two fractional predictors, Δ1-9 (postoperative volume change of C1-9) and γ1-9 (preoperatively planned volume of C1-9 resected), predicted postoperative motor, language, and visual deficits.RESULTSThe addition of ADFD to DWI-MAP analysis improved the sensitivity and specificity of regression models for predicting postoperative motor, language, and visual deficits by 28% for Δ1-3 (from 0.62 to 0.79), 13% for Δ4-8 (from 0.69 to 0.78), 13% for Δ9 (from 0.77 to 0.87), 7% for γ1-3 (from 0.81 to 0.87), 1% for γ4-8 (from 0.86 to 0.87), and 24% for γ9 (from 0.75 to 0.93). Preservation of the eloquent pathways defined by preoperative DWI-MAP analysis with ADFD (up to 97% of C1-4,9) prevented postoperative motor, language, and visual deficits with sensitivity and specificity ranging from 88% to 100%.CONCLUSIONSThe present study suggests that postoperative functional outcome substantially differs according to the extent of resected white matter encompassing eloquent cortex as determined by preoperative DWI-MAP analysis. The preservation of preoperative DWI-MAP-defined pathways may be crucial to prevent postoperative deficits. The improved DWI-MAP analysis may provide a complementary noninvasive tool capable of guiding the surgical margin to minimize the risk of postoperative deficits for children.
PMID: 30797207 [PubMed - as supplied by publisher]
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Patient preference study comparing hypofractionated versus conventionally fractionated whole-breast irradiation after breast-conserving surgery.
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Patient preference study comparing hypofractionated versus conventionally fractionated whole-breast irradiation after breast-conserving surgery.
Jpn J Clin Oncol. 2019 Feb 23;:
Authors: Kawaguchi H, Tsujino K, Miki M, Matsumoto Y, Ota Y, Hirokaga K, Takao S, Soejima T, Sasaki R
Abstract
OBJECTIVE: To compare patient preferences and acute adverse events of hypofractionated (HF) and conventionally fractionated (CF) whole-breast irradiation (WBI) after breast-conserving surgery in our institution.
METHODS: We conducted a patient preference study comparing CF-WBI (50 Gy/25 fractions) and HF-WBI (41.6 Gy/16 fractions) after breast-conserving surgery. Eligible patients selected either type of fractionation following an explanation from the radiation oncologist. In this report, we analyzed the selection rate and acute toxicities.
RESULTS: Between June 2009 and December 2013, 348 patients (349 breasts) were identified as eligible for the study. Among them, 259 patients (260 breasts [74.5%]) selected CF-WBI and 89 patients (89 breasts [25.5%]) selected HF-WBI. Factors significantly associated with the selection of HF-WBI were older age (P = 0.028) and no adjuvant chemotherapy (P = 0.041). Regarding acute adverse events, Grade 2 (G2) or higher radiation dermatitis was less frequently observed in HF-WBI than in CF-WBI (13.8% vs. 29.4%; P = 0.004). In addition, G2 or higher breast pain was only observed in the CF-WBI group (6.9%; P = 0.012). There were no significant differences in the presence of fatigue, wound pain or radiation pneumonitis of G2 or higher between the groups.
CONCLUSIONS: In this study, in which patients themselves selected the irradiation method, more patients tended to select CF-WBI. The frequency of G2 or higher dermatitis and breast pain was significantly lower in the HF-WBI group than in the CF-WBI group. Our results support the evidence for recommending HF-WBI after breast-conserving surgery while presenting aspects of patient preferences.
PMID: 30796835 [PubMed - as supplied by publisher]
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The dawn of robotic surgery in otolaryngology: head and neck surgery.
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The dawn of robotic surgery in otolaryngology: head and neck surgery.
Jpn J Clin Oncol. 2019 Feb 23;:
Authors: Nakayama M, Holsinger FC, Chevalier D, Orosco RK
Abstract
Transoral robotic surgery (TORS) utilizing the da Vinci robotic system has opened a new era for minimally-invasive surgery (MIS) in Otolaryngology-Head and Neck Surgery. Awareness of the historical steps in developing robotic surgery (RS) and understanding its current application within our field can help open our imaginations to future of the surgical robotics. We compiled a historical perspective on the evolution of surgical robotics, the road to the da Vinci surgical system, and conducted a review of TORS regarding clinical applications and limitations, prospective clinical trials and current status in Japan. We also provided commentary on the future of surgical robotics within our field. Surgical robotics grew out of the pursuit of telerobotics and the advances in robotics for non-medical applications. Today in our field, cancers and diseases of oropharynx and supraglottis are the most common indications for RS. It has proved capable of preserving the laryngopharyngeal function without compromising oncologic outcomes, and reducing the intensity of adjuvant therapy. TORS has become a standard modality for MIS, and will continue to evolve in the future. As robotic surgical systems evolve with improved capabilities in visual augmentation, spatial navigation, miniaturization, force-feedback and cost-effectiveness, we will see further advances in the current indications, and an expansion of indications. By promoting borderless international collaborations that put 'patients first', the bright future of surgical robotics will synergistically expand to the limits of our imaginations.
PMID: 30796834 [PubMed - as supplied by publisher]
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Efficacy and safety of TC dose-dense chemotherapy as first-line treatment of epithelial ovarian cancer: a single-institution retrospective cohort study.
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Efficacy and safety of TC dose-dense chemotherapy as first-line treatment of epithelial ovarian cancer: a single-institution retrospective cohort study.
Jpn J Clin Oncol. 2019 Feb 23;:
Authors: Vrdoljak J, Boban T, Petrić Miše B, Boraska Jelavić T, Bajić Ž, Tomić S, Vrdoljak E
Abstract
BACKGROUND: The optimal first-line therapy of advanced ovarian cancer still remains questionable: standard paclitaxel-carboplatin (TC), dose-dense TC, intraperitoneal chemotherapy or TC plus bevacizumab. In this study, we present the real-life results of dose-dense treatment of the single-institution on Caucasian population.
METHODS: A retrospective cohort study was used on consecutive samples of 74 patients treated with the conventional 3-weekly TC protocol (2008-11) and on 70 treated with TC dose-dense protocol (2012-16). The primary endpoint of this study was overall survival (OS). Secondary endpoints were progression free-survival (PFS) and toxicity. We made adjustments for age, pathohistological type, tumor grade, stage and postoperative residual disease by Cox regression.
RESULTS: After adjustment for pre-planned clinical and sociodemographic factors, patients treated with dose-dense protocol showed a significantly lower hazard for dying from any cause, than patients treated with conventional protocol (HR = 0.50; 95% CI 0.26-0.98; P = 0.042). Median OS, at 60 months follow-up had not been reached in the dose-dense group, while in the standard treatment group was 48 months (95% CI 33-62). Unadjusted PFS was significantly longer in the dose-dense group (HR = 0.58; 95% CI 0.38-0.88; P = 0.011), but not after the adjustment (P = 0.096). Generally, the level of toxicity was similar in both groups of patients. The need for blood transfusions and usage of filgrastim was significantly higher in the TC dd group. The incidence of neutropenia and thrombocytopenia Grade 3 or 4 were not significantly different in both regimens.
CONCLUSIONS: Our retrospective study has shown the superior efficacy and comparable toxicity of dose-dense chemotherapy regimen over the conventional regimen in treatment of ovarian cancer on Caucasian population at a single-institution.
PMID: 30796833 [PubMed - as supplied by publisher]
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A randomized phase III trial of denosumab before curettage for giant cell tumor of bone: Japan Clinical Oncology Group Study JCOG1610.
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A randomized phase III trial of denosumab before curettage for giant cell tumor of bone: Japan Clinical Oncology Group Study JCOG1610.
Jpn J Clin Oncol. 2019 Feb 23;:
Authors: Urakawa H, Mizusawa J, Tanaka K, Eba J, Hiraga H, Kawai A, Nishida Y, Hosaka M, Iwamoto Y, Fukuda H, Ozaki T
Abstract
A randomized phase III trial was planned to commence in October 2017. Resectable giant cell tumor of bone (GCTB) without possible postoperative large bone defect has been treated by curettage with local adjuvant treatment, with the local recurrence rate found to be as high as 24.6-30.8%. The aim of this study is to confirm the superiority of preoperative denosumab for patients with GCTB without possible postoperative large bone defect. A total of 106 patients will be accrued from 34 Japanese institutions over 5 years. The primary endpoint is relapse-free survival (RFS). Secondary endpoints include overall survival, joint-preserved survival, local RFS, metastasis-free survival, adverse events, serious adverse events, surgical and postoperative complications, and discontinuation of denosumab. This trial is conducted by the Bone and Soft Tissue Tumor Study Group in the Japan Clinical Oncology Group and has been registered in the UMIN Clinical Trials Registry as UMIN000029451 [https://ift.tt/1lXJedE].
PMID: 30796832 [PubMed - as supplied by publisher]
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Cervical laser vaporization for women with cervical intraepithelial neoplasia-3.
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Cervical laser vaporization for women with cervical intraepithelial neoplasia-3.
Jpn J Clin Oncol. 2019 Feb 23;:
Authors: Shimada C, Todo Y, Yamazaki H, Minobe S, Kato H
Abstract
OBJECTIVE: This study evaluated outcomes of laser vaporization of the cervix for women with cervical intraepithelial neoplasia (CIN)-3.
METHODS: We retrospectively reviewed 161 consecutive patients with CIN3 who were treated with cervical laser vaporization between January 2008 and December 2012. At each follow-up visit, histologically confirmed CIN2, CIN3 and invasive carcinoma were defined as treatment failures, as were high-grade squamous intraepithelial lesion (HSIL) or atypical squamous cells that cannot exclude HSIL with subsequent treatment or lost to follow-up. Primary endpoints included long-term follow-up (at least 5 years of regular hospital visits) and treatment failure rate. Treatment failure rates were estimated by the Kaplan-Meier method.
RESULTS: Patients' median age was 31 years old. Median follow-up period was 67 months (interquartile range: 52-74 months). Over 5 years, 70.8% continued their follow-up visits, but significantly more patients aged ≥35 years did so (86.4%) than did those aged ≤34 years (61.8%, P = 0.0009). Treatment failure was observed in 14 (8.7%) patients, 1 of whom progressed to invasive cancer (0.6%). Cumulative treatment failure rates were 1-year: 5.1%, 2-year: 6.4% and 5-year: 9.5%. Among patients who suffered treatment failures, 57.1% initial failures occurred within the first year and 71.4% within the first 2 years.
CONCLUSIONS: Long-term oncologic outcomes of cervical vaporization in CIN3 remain at a suboptimal level. The importance of a minimum of 5 years of regular hospital visits should be emphasized to patients with CIN3 who are candidates for cervical laser vaporization, especially those aged ≤34 years.
PMID: 30796831 [PubMed - as supplied by publisher]
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Preliminary safety and efficacy of first-line pertuzumab combined with trastuzumab and taxane therapy for HER2-positive locally recurrent or metastatic breast cancer (PERUSE).
Preliminary safety and efficacy of first-line pertuzumab combined with trastuzumab and taxane therapy for HER2-positive locally recurrent or metastatic breast cancer (PERUSE).
Ann Oncol. 2019 Feb 23;:
Authors: Bachelot T, Ciruelos E, Schneeweiss A, Puglisi F, Peretz-Yablonski T, Bondarenko I, Paluch-Shimon S, Wardley A, Merot JL, du Toit Y, Easton V, Lindegger N, Miles D
Abstract
BACKGROUND: Pertuzumab combined with trastuzumab and docetaxel is the standard first-line therapy for HER2-positive metastatic breast cancer, based on results from the phase III CLEOPATRA trial. PERUSE was designed to assess the safety and efficacy of investigator-selected taxane with pertuzumab and trastuzumab in this setting.
PATIENTS AND METHODS: In the ongoing multicentre single-arm phase IIIb PERUSE study, patients with inoperable HER2-positive advanced breast cancer (locally recurrent/metastatic) (LR/MBC) and no prior systemic therapy for LR/MBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks [q3w]) and pertuzumab (840 mg loading dose, then 420 mg q3w) until disease progression or unacceptable toxicity. The primary end point was safety. Secondary end points included overall response rate (ORR) and progression-free survival (PFS).
RESULTS: Overall, 1436 patients received at least one treatment dose (initially docetaxel in 775 patients, paclitaxel in 589, nab-paclitaxel in 65; seven discontinued before starting taxane). Median age was 54 years; 29% had received prior trastuzumab. Median treatment duration was 16 months for pertuzumab and trastuzumab, and 4 months for taxane. Compared with docetaxel-containing therapy, paclitaxel-containing therapy was associated with more neuropathy (all-grade peripheral neuropathy 31% vs 16%) but less febrile neutropenia (1% vs 11%) and mucositis (14% vs 25%). At this preliminary analysis (52 months' median follow-up), median PFS was 20.6 (95% CI 18.9-22.7) months overall (19.6, 23.0 and 18.1 months with docetaxel, paclitaxel and nab-paclitaxel, respectively). ORR was 80% (95% CI 78-82%) overall (docetaxel 79%, paclitaxel 83%, nab-paclitaxel 77%).
CONCLUSIONS: Preliminary findings from PERUSE suggest that the safety and efficacy of first-line pertuzumab, trastuzumab and taxane for HER2-positive LR/MBC are consistent with results from CLEOPATRA. Paclitaxel appears to be a valid alternative taxane backbone to docetaxel, offering similar PFS and ORR with a predictable safety profile.
PMID: 30796821 [PubMed - as supplied by publisher]
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Impact of Subtype on Survival of Young Patients With Stage IV Breast Cancer.
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Impact of Subtype on Survival of Young Patients With Stage IV Breast Cancer.
Clin Breast Cancer. 2019 Jan 29;:
Authors: Ogiya R, Sagara Y, Niikura N, Freedman RA
Abstract
BACKGROUND: Although younger age is a negative prognostic factor for patients with early stage breast cancer, data regarding the outcomes of young patients with stage IV disease are limited. We evaluated differences in overall survival (OS) according to age and disease subtype among patients with stage IV breast cancer.
PATIENTS AND METHODS: Using Surveillance, Epidemiology, and End Results (SEER) data, we identified 6,302 patients aged < 60 years with de novo stage IV breast cancer between 2010 and 2014. We examined age-specific OS among hormone receptor (HR)-positive (HR+)/human epidermal growth factor receptor 2 (HER2)-negative (HER2-), HR+/HER2-positive (HER2+), HR-negative (HR-)/HER2+, and triple-negative cases using log-rank tests and Cox proportional hazards models, adjusting for relevant clinical and demographic variables.
RESULTS: Compared with patients aged 40 to 59 years, patients aged < 40 years (n = 944; 15%) had a higher proportion of HER2+ cancers and a lower proportion of HR+/HER2- disease (P < .001), but a similar proportion of triple-negative disease. Patients aged < 40 years also experienced significantly longer survival, with a median OS of 45 months (vs. 33 months). Further, after stratification by subtype, patients aged < 40 years experienced significantly longer survival, except in the setting of triple-negative disease. These survival differences persisted in adjusted analyses.
CONCLUSIONS: Compared with those aged 40 to 59 years, patients with de novo metastatic breast cancer aged < 40 years experienced significantly longer survival, except in the setting of triple-negative disease. Distinct treatment-related or biological factors may exist between earlier stage and metastatic breast cancers; further examination of the potential reasons for our findings are warranted.
PMID: 30795886 [PubMed - as supplied by publisher]
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Everolimus in combination with Imatinib overcomes resistance in Chronic myeloid leukaemia.
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Everolimus in combination with Imatinib overcomes resistance in Chronic myeloid leukaemia.
Med Oncol. 2019 Feb 22;36(3):30
Authors: Alves R, Gonçalves AC, Jorge J, Alves J, Alves da Silva A, Freitas-Tavares P, Nascimento Costa JM, Almeida AM, Sarmento-Ribeiro AB
Abstract
Although Imatinib and other tyrosine kinase inhibitors (TKIs) have excellent results, the appearance of resistance is a problem in chronic myeloid leukaemia (CML). PI3K/AKT/mTOR pathway is activated by BCR-ABL playing a crucial rule in CML. This study aimed to evaluate the therapeutic potential of Everolimus, in CML models sensitive and resistant to Imatinib. We used one CML cell line sensitive to Imatinib (K562) and two resistant (K562-RC and K56-RD). Cell lines were treated with Everolimus alone and in combination with Imatinib. Cell viability was analysed by resazurin assay. Cell death and cell cycle were analysed by flow cytometry. Additionally, we also studied peripheral blood samples obtained from 52 patients under TKI treatment. Everolimus reduced cell line viability in sensitive (IC50 = 20 µM) and resistant models (K562-RC, IC50 = 25 µM; K562-RD, IC50 = 30 µM). This drug induced cell death by apoptosis and cell cycle arrest in G0/G1 phase. Everolimus also reduced cell viability by increasing apoptosis of haematopoietic stem cells (CD34+ cells) with low cytotoxicity to lymphocytes. Everolimus at 25 µM increased apoptotic cells 18.7% in CD34+ cells and only 8% in lymphocytes. The response to Everolimus was influenced by TKI treatment, with a better response in samples from patients under 2nd and 3rd generation TKI and with less toxicity to lymphocytes. Our results reveal that Everolimus induce cell death in CML cells sensitive and resistant to Imatinib, with low cytotoxicity to normal cells, suggesting that Everolimus could be an alternative targeted therapeutic approach in CML patients, even in cases of Imatinib resistance.
PMID: 30796703 [PubMed - in process]
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A Theoretical Model for the Cell Cycle and Drug Induced Cell Cycle Arrest of FUCCI Systems with Cell-to-Cell Variation during Mitosis.
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A Theoretical Model for the Cell Cycle and Drug Induced Cell Cycle Arrest of FUCCI Systems with Cell-to-Cell Variation during Mitosis.
Pharm Res. 2019 Feb 22;36(4):57
Authors: Bae H, Go YH, Kwon T, Sung BJ, Cha HJ
Abstract
PURPOSE: Since the molecular mechanism of the cell cycle was established, various theoretical models of this process have been developed. A recent study revealed significant variability in cell cycle duration between mother and daughter cells, but this observation has not been incorporated into the theoretical models.
METHODS: We used fluorescent ubiquitination-based cell cycle indicator (FUCCI) systems and live-monitored the heterogeneity of cell cycle progression within daughter cells, which accounts for dephasing synchrony. To incorporate the variable cell cycle durations into a model, we modified a two-ordinary differential equation (ODE) model based on reciprocal activation between CDK1 and APC.
RESULTS: Our model reproduced the experimental population profile, in which cell cycle synchrony dephased due to variability. Based on this model, we determined parameters for CDK1 and APC in the cell cycle profile after treatment with antimitotic drugs and associated the parameters with the drugs' mode of action as cell cycle inhibitors.
CONCLUSION: This suggests that this model is useful for determining the mode of action of unknown small molecules on the cell cycle.
PMID: 30796530 [PubMed - in process]
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LINC00261 is an epigenetically-regulated tumor suppressor that is essential for activation of the DNA damage response.
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LINC00261 is an epigenetically-regulated tumor suppressor that is essential for activation of the DNA damage response.
Cancer Res. 2019 Feb 22;:
Authors: Shahabi S, Kumaran V, Castillo J, Cong Z, Nandagopal G, Mullen DJ, Alvarado A, Ramos Correa M, Saizan A, Goel R, Bhat A, Lynch SK, Zhou B, Borok Z, Marconett CN
Abstract
Lung cancer is the leading cause of cancer-related death in the United States. Long non-coding RNAs (lncRNAs) are a class of regulatory molecules whose role in lung carcinogenesis is poorly understood. In this study, we profiled lncRNA expression in lung adenocarcinoma (LUAD) cell lines, compared their expression to that of purified alveolar epithelial type II cells (the purported cell of origin for LUAD), cross-referenced these with lncRNAs altered in primary human tumors, and interrogated for lncRNA whose expression correlated with patient survival. We identified LINC00261, a lncRNA with unknown function in LUAD, adjacent to the pioneering transcription factor FOXA2. Loss of LINC00261 was observed in multiple tumor types, including liver, breast, and gastric cancer. Reintroduction of LINC00261 into human LUAD cell lines inhibited cell migration and slowed proliferation by inducing a G2/M cell cycle arrest while upregulating DNA damage pathway genes and inducing phosphorylation-mediated activation of components of the DNA damage pathway. FOXA2 was able to induce LINC00261 expression, and the entire locus underwent hypermethylation in LUAD, leading to loss of expression. We have thus identified an epigenetically deregulated lncRNA, whose loss of expression in LUAD promotes the malignant phenotype and blocks activation of the DNA damage machinery, predisposing lung cells to cancer development.
PMID: 30796052 [PubMed - as supplied by publisher]
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Nanotechnology in the diagnosis and treatment of lung cancer.
Nanotechnology in the diagnosis and treatment of lung cancer.
Pharmacol Ther. 2019 Feb 20;:
Authors: Cryer AM, Thorley AJ
Abstract
Lung cancer is an umbrella term for a subset of heterogeneous diseases that are collectively responsible for the most cancer-related deaths worldwide. Despite the tremendous progress made in understanding lung tumour biology, advances in early diagnosis, multimodal therapy and deciphering molecular mechanisms of drug resistance, overall curative outcomes remain low, especially in metastatic disease. Nanotechnology, in particular nanoparticles (NPs), continue to progressively impact the way by which tumours are diagnosed and treated. The unique physicochemical properties of materials at the nanoscale grant access to a diverse molecular toolkit that can be manipulated for use in respiratory oncology. This realisation has resulted in several clinically approved NP formulations and many more in clinical trials. However, NPs are not a panacea and have yet to be utilised to maximal effect in lung cancer, and medicine in a wider context. This review serves to: describe the complexity of lung cancer, the current diagnostic and therapeutic environment, and highlight the recent advancements of nanotechnology based approaches in diagnosis and treatment of respiratory malignancies. Finally, a brief outlook on the future directions of nanomedicine is provided; presently the full potential of the field is yet to be realised. By gleaning lessons and integrating advancements from neighbouring disciplines, nanomedicine can be elevated to a position where the current barriers that stymie full clinical impact are lifted.
PMID: 30796927 [PubMed - as supplied by publisher]
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Immunotherapy-based combination strategies for treatment of gastrointestinal cancers: current status and future prospects.
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Immunotherapy-based combination strategies for treatment of gastrointestinal cancers: current status and future prospects.
Front Med. 2019 Feb 22;:
Authors: Zhou C, Zhang J
Abstract
Strategies in comprehensive therapy for gastrointestinal (GI) cancer have been optimized in the last decades to improve patients' outcomes. However, treatment options remain limited for late-stage or refractory diseases. The efficacy of immune checkpoint inhibitors (ICIs) for treatment of refractory GI cancer has been confirmed by randomized clinical trials. In 2017, pembrolizumab was approved by the US Food and Drug Administration as the first agent for treatment of metastatic solid tumors with mismatch repair deficiency, especially for colorectal cancer. Given the different mechanisms, oncologists have focused on determining whether ICIs-based combination strategies could achieve higher efficacy than conventional therapy alone in late-stage or even front-line treatment of GI cancer. This review discusses the current status of combining immune checkpoint inhibitors with molecular targeted therapy, chemotherapy, or radiotherapy in GI cancer in terms of mechanisms, safety, and efficacy to provide basis for future research.
PMID: 30796606 [PubMed - as supplied by publisher]
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Introduction of Novel Structured Reporting Systems for PET Radiotracers with Potential Theranostic Applications.
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Introduction of Novel Structured Reporting Systems for PET Radiotracers with Potential Theranostic Applications.
J Nucl Med. 2019 Feb 22;:
Authors: Werner RA, Bundschuh R, Bundschuh L, Fanti S, Javadi MS, Higuchi T, Weich A, Pienta KJ, Buck AK, Pomper MG, Gorin MA, Herrmann K, Lapa C, Rowe SP
Abstract
Standardized reporting is more and more routinely implemented in clinical practice and such structured reports have a major impact on a large variety of medical fields, e.g. laboratory medicine, pathology, and, recently, radiology. Notably, the field of nuclear medicine is constantly evolving, as novel radiotracers for numerous clinical applications are developed. Thus, framework systems for standardized reporting in this field may a) increase clinical acceptance of new radiotracers, b) allow for inter- and intra-center comparisons for quality assurance, and c) may be used in (global) multi-center studies to ensure comparable results and enable efficient data abstraction. In the last two years, several standardized framework systems for positron emission tomography (PET) radiotracers with potential theranostic applications have been proposed. These include systems for prostate-specific membrane antigen (PSMA)-targeted PET agents for the diagnosis and treatment of prostate cancer (PCa) and somatostatin receptor (SSTR)-targeted PET agents for the diagnosis and treatment of neuroendocrine neoplasias. In the present review, those standardized framework systems for PSMA- and SSTR-targeted PET will be briefly introduced followed by an overview of their advantages and limitations. In addition, potential applications will be defined, approaches to validate such concepts will be proposed, and future perspectives will be discussed.
PMID: 30796171 [PubMed - as supplied by publisher]
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Comparison of the Clinicopathological Characteristics and Genetic Alterations Between Patients with Gastric Cancer with or Without Helicobacter pylori Infection.
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Comparison of the Clinicopathological Characteristics and Genetic Alterations Between Patients with Gastric Cancer with or Without Helicobacter pylori Infection.
Oncologist. 2019 Feb 22;:
Authors: Fang WL, Huang KH, Chang SC, Lin CH, Chen MH, Chao Y, Lo SS, Li AF, Wu CW, Shyr YM
Abstract
BACKGROUND: Helicobacter pylori (HP) can induce epithelial cells and intestinal metaplasia with genetic damage that makes them highly susceptible to the development of gastric cancer (GC).
MATERIALS AND METHODS: Between 2005 and 2010, 356 patients with gastric cancer who received curative surgery were enrolled. Analysis of HP, Epstein-Barr virus (EBV) infection, PIK3CA amplification, and mutation analysis of 68 mutations in eight genes using a mass spectrometric single-nucleotide polymorphism genotyping technology was conducted. The clinicopathological characteristics of patients with or without HP infection were compared.
RESULTS: Among the 356 patients, 185 (52.0%) had HP infection. For intestinal-type GC, patients with HP infection were more likely to be younger and had fewer PI3K/AKT pathway genetic mutations than those without HP infection. For diffuse-type GC, patients with HP infection were characterized by less male predominance, less lymphoid stroma, fewer microsatellite instability-high tumors, and fewer PI3K/AKT pathway genetic mutations than those without HP infection. Patients with HP infection had less tumor recurrence and a better 5-year overall survival (87.7% vs. 73.9%, p = .012) and disease-free survival (64.1% vs. 51.3%, p = .013) than those without HP infection, especially for intestinal-type GC. For EBV-negative GC, patients with HP infection had fewer PI3K/AKT pathway mutations and a better 5-year overall survival and disease-free survival than those without HP infection. Multivariate analysis demonstrated that HP infection was an independent prognostic factor regarding overall survival and disease-free survival.
CONCLUSION: Patients with GC with HP infection were associated with fewer PI3K/AKT pathway genetic mutations and better survival than those without HP infection, especially for EBV-negative and intestinal-type GC.
IMPLICATIONS FOR PRACTICE: Patients with gastric cancer with Helicobacter pylori (HP) infection had fewer PI3K/AKT pathway genetic mutations, less tumor recurrence, and better survival than those without HP infection, especially for Epstein-Barr virus (EBV)-negative and intestinal-type gastric cancer. HP infection is an independent prognostic factor regarding overall survival and disease-free survival. Future in vivo and in vitro studies of the correlation among HP infection, PI3K/AKT pathway, and EBV infection in gastric cancer are required.
PMID: 30796154 [PubMed - as supplied by publisher]
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The ongoing French metastatic breast cancer (MBC) cohort: the example-based methodology of the Epidemiological Strategy and Medical Economics (ESME).
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The ongoing French metastatic breast cancer (MBC) cohort: the example-based methodology of the Epidemiological Strategy and Medical Economics (ESME).
BMJ Open. 2019 Feb 21;9(2):e023568
Authors: Pérol D, Robain M, Arveux P, Mathoulin-Pélissier S, Chamorey E, Asselain B, Berchery D, Gourgou S, Breton M, Delaine-Clisant S, Mons M, Diéras V, Carton M, Guizard AV, Laborde L, Laurent C, Loeb A, Mouret-Reynier MA, Parent D, Perrocheau G, Campion L, Velten M, Cailliot C, Ezzalfani M, Simon G
Abstract
PURPOSE: The currently ongoing Epidemiological Strategy and Medical Economics (ESME) research programme aims at centralising real-life data on oncology care for epidemiological research purposes. We draw on results from the metastatic breast cancer (MBC) cohort to illustrate the methodology used for data collection in the ESME research programme.
PARTICIPANTS: All consecutive ≥18 years patients with MBC treatment initiated between 2008 and 2014 in one of the 18 French Comprehensive Cancer Centres were selected. Diagnostic, therapeutic and follow-up data (demographics, primary tumour, metastatic disease, treatment patterns and vital status) were collected through the course of the disease. Data collection is updated annually.
FINDING TO DATE: With a recruitment target of 30 000 patients with MBC by 2019, we currently screened a total of 45 329 patients, and >16 700 patients with a metastatic disease treatment initiated after 2008 have been selected. 20.7% of patients had an hormone receptor (HR)-negative MBC, 73.7% had a HER2-negative MBC and 13.9% were classified as triple-negative BC (ie, HER2 and HR status both negative). Median follow-up duration from MBC diagnosis was 48.55 months for the whole cohort.
FUTURE PLANS: These real-world data will help standardise the management of MBC and improve patient care. A dozen of ancillary research projects have been conducted and some of them are already accepted for publication or ready to be issued. The ESME research programme is expanding to ovarian cancer and advanced/metastatic lung cancer. Our ultimate goal is to achieve a continuous link to the data of the cohort to the French national Health Data System for centralising data on healthcare reimbursement (drugs, medical procedures), inpatient/outpatient stays and visits in primary/secondary care settings.
TRIAL REGISTRATION NUMBER: NCT03275311; Pre-results.
PMID: 30796119 [PubMed - in process]
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Causes of Massive Vulvar Edema in Patients with Severe Ovarian Hyperstimulation Syndrome: A Case Report and Literature Review.
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Causes of Massive Vulvar Edema in Patients with Severe Ovarian Hyperstimulation Syndrome: A Case Report and Literature Review.
Am J Case Rep. 2019 Feb 23;20:238-241
Authors: Kovač V, Reljič M, Bizjak T
Abstract
BACKGROUND Ovarian hyperstimulation syndrome (OHSS) is a potentially serious complication of ovulation stimulation. Modest vulvar edema is frequently seen in a severe form of OHSS; however, cases of massive bilateral vulvar edema are rare and pathogenesis is uncertain. CASE REPORT We report a 31-year-old patient with massive vulvar edema and severe OHSS after IVF treatment with GnRH antagonist and gonadotropins. Five days after embryo transfer, she was hospitalized because of severe clinical manifestation of OHSS and on the fifth day after admission she developed a massive bilateral vulvar edema. After conventional medical therapy of OHSS, vulvar edema spontaneously resolved. CONCLUSIONS Hypoproteinemia with low oncotic pressure and certain personal tissue characteristics may play the main role in the pathogenesis of massive vulvar edema in OHSS.
PMID: 30796195 [PubMed - in process]
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Child Neurology Open
Autism Spectrum Disorder and Neonatal Serum Magnesium Levels in Preterm Infants
Child Neurology OpenHide PreviewAbstract
Premature birth is associated with increased risk of autism spectrum disorder. Antenatal maternal magnesium administration is known to reduce subsequent risk of cerebral palsy including among premature infants, suggesting a potentially broader neuroprotective role for magnesium. Our objective was to determine whether magnesium could be protective against autism spectrum disorders in premature infants. A cohort of 4855 preterm children was identified, magnesium levels from 24 to 48 hours of life recorded, and subsequent autism spectrum disorder status determined. Adjusted relative risk of autism spectrum disorder with each 1 mg/dL increase in neonatal magnesium level was 1.15 (95% confidence interval: 0.86-1.53). Analysis of variance indicated that magnesium levels varied by gestational age and maternal antenatal magnesium supplementation, but not autism spectrum disorder status (F1,4824 = 1.43, P = .23). We found that neonatal magnesium levels were not associated with decreased autism spectrum disorder risk. Future research into autism spectrum disorder risks and treatments in premature infants is needed.
Functional Gains in Children With Spastic Hemiplegia Following a Tendon Achilles Lengthening Using Computerized Adaptive Testing—A Pilot Study
Child Neurology OpenHide PreviewAbstract
This pilot study evaluated the outcomes of tendon Achilles lengthening in 12 children (mean age: 11.2 years) with spastic hemiplegia.
Cerebral Palsy Computer Adaptive Tests, the timed up-and-go, the Gross Motor Function Measure, the Gillette Functional Assessment Questionnaire, and the Pediatric Outcomes Data Collection Instrument were administered at baseline and at 6, 12, and 24 months postsurgery.
Significant improvement at the latest follow-up (12-24 months following surgery) was seen in all domains of the Cerebral Palsy Computer Adaptive Test: activity (P = .017), lower extremity (P = .005), global (P = .005), pain (P = .005), and fatigue (P = .028), as well as in the Gross Motor Function Measure-standing domain (P = .02) and the mobility domain of the Pediatric Outcomes Data Collection Instrument (P = .04).
Clinical Profile of Pediatric Neurological Disorders: Outpatient Department, Khartoum, Sudan
Child Neurology OpenHide PreviewAbstract
There is no available data from Sudan reflecting the magnitude of the neurological disorders and disabilities in the pediatric age-group. This study aims to evaluate the pattern of neurological disorders among Sudanese children.
This is a retrospective survey of children with epilepsy and other neurodisability disorders seen at pediatric neurology outpatient clinic, during the period from January 2007 to August 2013. The data of 9600 patients were analyzed.
A total of 6019 patients were included in the study. The majority of the patients had epilepsy that amounted to 52.8%, followed by cerebral palsy (19.1%), congenital anomalies of the central nervous system (6.2%), neuromuscular disorders (3.2%), stroke (2.4%), ataxia and movement disorders (1.9%), assumed genetic syndromes (1.2%), and others.
A New Observation of an Atypical and Severe Variant of the Guillain-Barre Syndrome in a Child: Remaining Challenges for Diagnosis, Nosologic Classification, and Therapeutic Course
Child Neurology OpenHide PreviewAbstract
Guillain-Barré syndrome is a rare acute polyradiculoneuropathy. Several variants and unusual presentations have been described, particularly in pediatrics. In most cases, making an early diagnosis is challenging due to the treatments that consist in the rapid administration of intravenous immunoglobulin or plasma exchange. The authors present the case of a 7-year-old boy with an atypical and severe axonal Guillain-Barré syndrome, associated with Mycoplasma pneumonia. When he was admitted, febrile respiratory failure was the main focus, and then he presented signs of acute polyneuropathy with cranial nerve palsy and brief hyperreflexia. Mechanical ventilation was required for 48 days as well as 2 cycles of intravenous immunoglobulin. The authors describe all the medical challenges that the authors encountered. This case highlights the fact that respiratory distress can be the main clinical symptom in children. This delays the establishment of a correct diagnosis, even more so when neurological manifestations are abundant and unusual.
Assessing Children With Disabilities Using WHO International Classification of Functioning, Disability and Health Child and Youth Version Activities and Participation D Codes
Child Neurology Open Newly Identified Characteristics and Suggestions for Diagnosis and Treatment of Diffuse Leptomeningeal Glioneuronal/Neuroepithelial Tumors: A Case Report and Review of the Literature
Child Neurology OpenHide PreviewAbstract
Diffuse leptomeningeal glioneuronal tumor is unique for communicating hydrocephalus, diffuse leptomeningeal enhancement, cystic changes, absence of tumor cells in cerebral spinal fluid, and a cell population of both glial and neuronal copositivity. It has likely been misdiagnosed as mixed glioneuronal tumors, oligodendrogliomas, and neuroepithelial tumors. Children with signs of this tumor are often worked up for infection, rheumatologic disease, or disseminated primary malignancy, resulting in unnecessary testing and treatment. We describe a 14-year-old female with recurrent headaches, hydrocephalus, and diffuse leptomeningeal enhancement discovered to be neoplastic 1 year after initial presentation, owing to extensive and unrevealing infectious and immunologic workups. Biopsies revealed atypical cells with markers of both glial and neuronal cells, positivity for OLIG-2, and focal p53 positivity. Great response was seen with temozolomide and craniospinal irradiation. Additionally, we postulate additional diagnostic indicators that may aid in earlier diagnosis and treatment decisions.
Connexin 43 and Its Hemichannels Mediate Hypoxia–Ischemia-Induced Cell Death in Neonatal Rats
Child Neurology OpenHide PreviewAbstract
Wistar rat pups had the left common carotid artery cut, and they were exposed to 8% oxygen with free access to food and water until they were killed at 1, 12, 24, and 48 hours after the hypoxia–ischemia (HI) insult. Connexin 43 (Cx43), hemichannel (HC1), and caspase 3 (Casp3) in cerebral HI tissues were examined by immunohistochemistry and Western blot analyses. Astrocytes cell line, astrocytes transduced with a retroviral empty vector (Psup astrocyte), or a Cx43-specific small hairpin RNA (shRNA) construct (shRNA astrocytes) was treated with oxygen–glucose deprivation (OGD) insult. The viability of astrocytes was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The results showed the expression of Cx43, HC1, and Casp3 in rats' brain, and astrocytes and Psup astrocytes increased significantly after 24 hours of HI/OGD insult. Cell viability decreased after 24 hours of the insult. The results suggest that Cx43 and hemichannel are likely to mediate the astrocytic death after HI insult.
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