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Following the approval of the first antibody-drug conjugates (ADCs) in the early 2000s, development has increased dramatically, with 14 ADCs now approved and >100 in clinical development. In lung cancer, trastuzumab deruxtecan (T-DXd) is approved in human epidermal growth factor receptor 2 (HER2)-mutated, unresectable or metastatic non-small-cell lung cancer, with ADCs targeting HER3 (patritumab deruxtecan), trophoblast cell-surface antigen 2 [datopotamab deruxtecan and sacituzumab govitecan (SG)] and mesenchymal-epithelial transition factor (telisotuzumab vedotin) in late-stage clinical development. In breast cancer, several agents are already approved and widely used, including trastuzumab emtansine, T-DXd and SG, and multiple late-stage trials are ongoing. Thus, in the coming years, we are likely to see significant changes to treatment algorithms. As the number of available ADCs increases, biomarkers (of response and resistance) to better select patients are urgently needed. Biopsy sample collection at the time of treatment selection and incorporation of translational research into clinical trial designs are therefore critical. Biopsy samples taken peri- and post-ADC treatment combined with functional genomics screens could provide insights into response/resistance mechanisms as well as the impact of ADCs on tumour biology and the tumour microenvironment, which could improve understanding of the mechanisms underlying these complex molecules. Many ADCs are undergoing evaluation as combination therapy, but a high bar should be set to progress clinical evaluation of any ADC-based combination, particularly considering the high cost and potential toxicity implications. Efforts to optimise ADC dosing/duration, sequencing and the potential for ADC rechallenge are also important, especially considering sustainability aspects. The ETOP IBCSG Partners Foundation are driving strong collaborations in this field and promoting the generation/sharing of databases, repositories and registries to enable greater access to data. This will allow the most important research questions to be identified and prioritised, which will ultimately accelerate progress and help to improve patient outcomes.
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Neoplasias de la Mama , Inmunoconjugados , Neoplasias Pulmonares , Humanos , Inmunoconjugados/uso terapéutico , Inmunoconjugados/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/genética , Femenino , Antineoplásicos Inmunológicos/uso terapéutico , Antineoplásicos Inmunológicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/genéticaRESUMEN
OBJECTIVES: (1) to determine whether the standard Dutch word lists for speech audiometry are equally intelligible in normal-hearing listeners (Experiment 1), (2) to investigate whether synthetic speech can be used to create word lists (Experiment 1) and (3) to determine whether the list effect found in Experiment 1 can be reduced by combining two lists into pairs (Experiment 2). DESIGN: Participants performed speech tests in quiet with the original (natural) and synthetic word lists (Experiment 1.). In Experiment 2, new participants performed speech tests with list pairs from the original lists constructed from the results of Experiment 1. STUDY SAMPLES: Twenty-four and twenty-eight normal-hearing adults. RESULTS: There was a significant list effect in the natural speech lists; not in the synthetic speech lists. Variability in intelligibility was significantly higher in the former, with list differences up to 20% at fixed presentation levels. The 95% confidence interval of a list with a score of approximately 70% is around 10%-points wider than of a list pair. CONCLUSIONS: The original Dutch word lists show large variations in intelligibility. List effects can be reduced by combining two lists per condition. Synthetic speech is a promising alternative to natural speech in speech audiometry in quiet.
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BACKGROUND: An interatrial communication is present in most neonates. The majority are considered the "normal" patency of the oval foramen, while a minority are abnormal atrial septal defects. Differentiation between the two with transthoracic echocardiography may be challenging, and no generally accepted method of classification is presently available. We aimed to develop and determine the reliability of a new classification of interatrial communications in newborns. METHODS AND RESULTS: An algorithm was developed based on echocardiographic criteria from 495 newborns (median age 11[8;13] days, 51.5% females). The algorithm defines three main categories: patency of the oval foramen, atrial septal defect, and no interatrial communication as well as several subtypes. We found an interatrial communication in 414 (83.6%) newborns. Of these, 386 (93.2%) were categorised as patency of the oval foramen and 28 (6.8%) as atrial septal defects.Echocardiograms from another 50 newborns (median age 11[8;13] days, 36.0% female), reviewed by eight experts in paediatric echocardiography, were used to assess the inter- and intraobserver variation of classification of interatrial communications into patency of the oval foramen and atrial septal defect, with and without the use of the algorithm. Review with the algorithm gave a substantial interobserver agreement (kappa = 0.66), and an almost perfect intraobserver agreement (kappa = 0.82). Without the use of the algorithm, the interobserver agreement between experienced paediatric cardiologists was low (kappa = 0.20). CONCLUSION: A new algorithm for echocardiographic classification of interatrial communications in newborns produced almost perfect intraobserver and substantial interobserver agreement. The algorithm may prove useful in both research and clinical practice.
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Tabique Interatrial , Foramen Oval , Defectos del Tabique Interatrial , Niño , Humanos , Recién Nacido , Femenino , Masculino , Reproducibilidad de los Resultados , Defectos del Tabique Interatrial/diagnóstico por imagen , Tabique Interatrial/diagnóstico por imagen , EcocardiografíaRESUMEN
Aim Acquired brain injury (ABI) is a common cause of acquired disability in children. Rehabilitation services are known to be underdeveloped in Ireland. We aimed to estimate the incidence of severe ABI in young people in Ireland. Methods The National Quality Assurance and Information System (NQAIS) database was analysed to identify patients aged 1-16 years who had suffered a "probable severe acquired brain injury requiring rehabilitation" (PSABIR) from 2016 - 2019. PSABIR is defined as the co-occurrence of a medical condition likely to cause ABI with a length of hospital admission longer than 28 days. Results 187 young people in Ireland had PSABIRs from 2016-2019, accounting for 21.4% of all prolonged admissions (incidence 4.55 per 100,000 per year). Median length of stay was 46 days (IQR 35- 80 days). Two children (1%) were discharged directly to specialist rehabilitation; 132 (70.6%) were discharged directly home. Conclusion Severe ABI accounts for a significant proportion of prolonged paediatric admissions, with an average of 47 such events per year. Most young people spend the acute and subacute phases of recovery in a tertiary acute hospital, before being discharged directly home. Rehabilitation services need to be developed in all settings to address unmet need.
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Lesiones Encefálicas , Adolescente , Lesiones Encefálicas/epidemiología , Niño , Hospitalización , Humanos , Incidencia , Irlanda/epidemiología , Alta del PacienteRESUMEN
The murine cell line GRX has been introduced as an experimental tool to study aspects of hepatic stellate cell biology. It was established from livers of C3H/HeN mice that were infected with cercariae of Schistosoma mansoni. Although these cells display a myofibroblast phenotype, they can accumulate intracellular lipids and acquire a fat-storing lipocyte phenotype when treated with retinol, insulin, and indomethacin. We have performed genetic characterization of GRX and established a multi-loci short tandem repeat (STR) signature for this cell line that includes 18 mouse STR markers. Karyotyping further revealed that this cell line has a complex genotype with various chromosomal aberrations. Transmission electron microscopy revealed that GRX cells produce large quantities of viral particles belonging to the gammaretroviral genus of the Retroviridae family as assessed by next generation mRNA sequencing and Western blot analysis. Rolling-circle-enhanced-enzyme-activity detection (REEAD) revealed the absence of retroviral integrase activity in cell culture supernatants, most likely as a result of tetherin-mediated trapping of viral particles at the cell surface. Furthermore, staining against schistosome gut-associated circulating anodic antigens and cercarial O- and GSL-glycans showed that the cell line lacks S. mansoni-specific glycostructures. Our findings will now help to fulfill the recommendations for cellular authentications required by many granting agencies and scientific journals when working with GRX cells. Moreover, the definition of a characteristic STR profile will increase the value of GRX cells in research and provides an important benchmark to identify intra-laboratory cell line heterogeneity, discriminate between different mouse cell lines, and to avoid misinterpretation of experimental findings by usage of misidentified or cross-contaminated cells.
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Células Estrelladas Hepáticas , Macrófagos del Hígado , Animales , Células Estrelladas Hepáticas/metabolismo , Macrófagos del Hígado/metabolismo , Hígado/metabolismo , Ratones , Ratones Endogámicos C3H , Vitamina A/metabolismoRESUMEN
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has created an urgent need for new technologies to treat COVID-19. Here we report a 2'-fluoro protected RNA aptamer that binds with high affinity to the receptor binding domain (RBD) of SARS-CoV-2 spike protein, thereby preventing its interaction with the host receptor ACE2. A trimerized version of the RNA aptamer matching the three RBDs in each spike complex enhances binding affinity down to the low picomolar range. Binding mode and specificity for the aptamer-spike interaction is supported by biolayer interferometry, single-molecule fluorescence microscopy, and flow-induced dispersion analysis in vitro. Cell culture experiments using virus-like particles and live SARS-CoV-2 show that the aptamer and, to a larger extent, the trimeric aptamer can efficiently block viral infection at low concentration. Finally, the aptamer maintains its high binding affinity to spike from other circulating SARS-CoV-2 strains, suggesting that it could find widespread use for the detection and treatment of SARS-CoV-2 and emerging variants.
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Aptámeros de Nucleótidos/farmacología , SARS-CoV-2/efectos de los fármacos , Internalización del Virus/efectos de los fármacos , Enzima Convertidora de Angiotensina 2/metabolismo , Aptámeros de Nucleótidos/química , Aptámeros de Nucleótidos/metabolismo , Humanos , Mutación , Pruebas de Neutralización , Conformación de Ácido Nucleico , Unión Proteica/efectos de los fármacos , Dominios y Motivos de Interacción de Proteínas , SARS-CoV-2/fisiología , Técnica SELEX de Producción de Aptámeros , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/metabolismoRESUMEN
INTRODUCTION: In Denmark, non-invasive prenatal testing (NIPT) has been used since 2013. We aimed to evaluate the early clinical use of NIPT in Danish public and private healthcare settings before NIPT became an integrated part of the national guidelines on prenatal screening and diagnosis in 2017. MATERIAL AND METHODS: NIPT data were collected between March 2013 and June 2017 from national public registries and private providers. Results from follow-up samples (chorionic villi, amniotic fluid, postnatal blood or fetal tissue) were included from The Danish Cytogenetics Central Registry and indications and outcome from The Danish Fetal Medicine Database. RESULTS: A total of 3936 NIPT results were included in the study from public hospitals (n = 3463, 88.0%) and private clinics (n = 473, 12.0%). The total number of prenatal tests was 19 713 during the study period: 20% were NIPT analyses (n = 3936) and 80% invasive procedures (n = 15 777). Twenty-five percent of NIPTs in the private clinics were performed before gestational week 11+0 , whereas NIPT in public settings was used only after combined first trimester screening (P < .001). Regardless of indication, the national public sensitivity was 96.9% (95% CI 82.0%-99.8%) for trisomy 21, 100% (95% CI 46.3%-100%) for trisomy 18, 100% (95% CI 5.5%-100%) for trisomy 13, and 87.0% (95% CI 74.5%-92.4%) for any fetal chromosomal aberration. Forty-seven true-positive NIPT results included cases of common aneuplodies (trisomy 21, n = 31; trisomy 18, n = 5; and trisomy 13, n = 1), sex chromosomal aberrations (n = 7) and atypical chromosomal aberrations (n = 3). One false-negative NIPT result occurred (trisomy 21). Of 47 cases, 21 (45%) cases with a true-positive NIPT result resulted in live births by choice; 11 of these children had Down and 4 had Edwards syndrome. CONCLUSIONS: The total number of NIPT analyses was low compared with the number of invasive procedures in the implementation period. In contrast to the generally high termination rate after a positive result following invasive testing in Denmark, a high proportion of true-positive NIPT results from the public setting resulted in live births. NIPT may be an important risk-free alternative to invasive testing for a minority of women in the public setting who wish to use prenatal genetic testing for information only and not for reproductive decision-making.
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Instituciones de Salud , Pruebas Prenatales no Invasivas/estadística & datos numéricos , Sector Privado , Sector Público , Adulto , Aberraciones Cromosómicas , Dinamarca/epidemiología , Síndrome de Down/diagnóstico , Femenino , Humanos , Persona de Mediana Edad , Embarazo , Sensibilidad y Especificidad , Síndrome de la Trisomía 13/diagnóstico , Síndrome de la Trisomía 18/diagnósticoRESUMEN
INTRODUCTION: The objective of this study was to explore the association between detection of fetal growth restriction and maternal-, healthcare provider- and organizational factors. MATERIAL AND METHODS: A historical, observational, multicentre study. All women who gave birth to a child with a birthweight <2.3rd centile from 1 September 2012 to 31 August 2015 in Zealand, Denmark, were included. The population was identified through the Danish Fetal Medicine Database. Medical charts were reviewed to obtain data regarding maternal characteristics and information on the healthcare professionals. Date of authorization for the midwives and obstetricians involved was extracted from the Danish Health Authorization Registry. Multivariable Cox regression models were used to identify predictors of antenatal detection of fetal growth restriction, and analyses were adjusted for hospital, body mass index, parity, the presence of at least one risk factor and experience of the first midwife, number of midwife visits, number of visits to a doctor, the experience of the consultant midwife or the educational level of the doctor, the number of scans and gaps in continuity of midwife-care. Antenatal detection was defined as an ultrasound estimated fetal weight <2.3rd centile (corresponding to -2 standard deviations) prior to delivery. RESULTS: Among 78 544 pregnancies, 3069 (3.9%) had a fetal growth restriction. Detection occurred in 31% of fetal growth-restricted pregnancies. Clinical experience (defined as years since graduation) of the first consultation midwife was positively associated with detection, with a hazard ratio [HR] of 1.15, 95% confidence interval [CI] 1.03-1.28), for every 10 years of additional experience. The hazard of detection increased with the number of midwife consultations (HR 1.15, 95% CI 1.05-1.26) and with multiparity (HR 1.28, 95% CI 1.03-1.58). After adjusting for all covariates, an unexplained difference between hospitals (P = .01) remained. CONCLUSIONS: The low-risk nullipara may constitute an overlooked group of women at increased risk of antenatal non-detection of fetal growth restriction. Being screened by experienced midwives during early pregnancy and having access to multiple midwife consultations may improve future diagnosis.
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Retardo del Crecimiento Fetal/diagnóstico , Diagnóstico Prenatal/estadística & datos numéricos , Adulto , Estudios de Cohortes , Dinamarca/epidemiología , Femenino , Hospitales , Humanos , Partería , Embarazo , Atención Prenatal/estadística & datos numéricos , Modelos de Riesgos ProporcionalesRESUMEN
Autosomal recessive omodysplasia (GPC6-related) is a rare short-limb skeletal dysplasia caused by biallelic mutations in the GPC6 gene. Affected individuals manifest with rhizomelic short stature, decreased mobility of elbow and knee joints as well as craniofacial anomalies. Both upper and lower limbs are severely affected. These manifestations contrast with normal height and limb shortening restricted to the arms in autosomal dominant omodysplasia (FZD2-related). Here, we report 2 affected brothers of Pakistani descent from Denmark with GPC6-related omodysplasia, aiming to highlight the clinical and radiological findings. A homozygous deletion of exon 6 in the GPC6 gene was detected. The pathognomonic radiological findings were distally tapered humeri and femora as well as severe proximal radioulnar diastasis. On close observations, we identified a recurrent and not previously described type of abnormal patterning in all long bones.
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STUDY QUESTION: Is the fetal fraction (FF) of circulating cell-free DNA (cfDNA) affected in pregnancies following ART treatment with either fresh or frozen embryo transfer (ET) compared with natural conception? SUMMARY ANSWER: This study shows a significant reduction in the FF in ART patients compared with naturally conceived pregnancies, which seems to be more pronounced after fresh ET compared with frozen ET. WHAT IS KNOWN ALREADY: Non-invasive prenatal testing (NIPT) is based on cfDNA in maternal blood, of which about 10% is of placental origin and thus represents the fetal karyotype. Validation studies have demonstrated a high sensitivity, specificity and positive predictive value of NIPT for the detection of fetal trisomy 21, 18 and 13. Nevertheless, the FF of cfDNA is an important factor for NIPT test accuracy. Several studies have found a reduction in FF for pregnancies following ART in comparison with natural conception. However, knowledge on how the FF is affected in ART pregnancies after fresh ET compared with frozen ET is very limited. STUDY DESIGN, SIZE, DURATION: The study was designed as a case-control study. A total of 54 women with an ongoing pregnancy following ART treatment were included. After exclusion for different reasons, statistical analyses were based on 23 NIPT samples from pregnant women treated with fresh ET and 26 NIPT samples from pregnant women treated with frozen-thawed ET in a modified natural cycle. Women were included between February 2018 and November 2018. The results were compared with a control group of 238 naturally conceived pregnancies with a high-risk result from the combined first trimester screening (cFTS). PARTICIPANTS/MATERIALS, SETTING, METHODS: The study included women from the Fertility Clinics at Copenhagen University Hospital Hvidovre and Copenhagen University Hospital Rigshospitalet. Blood samples for NIPT analysis were drawn between 11 + 0 and 14 + 2 weeks of gestation and were all analyzed at the NIPT Center at Copenhagen University Hospital Hvidovre. The NIPT-test was performed by massive-parallel whole-genome sequencing. The FF was determined using the SeqFF algorithm. MAIN RESULTS AND THE ROLE OF CHANCE: We found a reduction in FF in ART patients compared with naturally conceived pregnancies, and the reduction was more pronounced for ART pregnancies after fresh ET (mean FF = 0.049) compared with frozen ET (mean FF = 0.063) (multivariate analysis adjusted for maternal BMI, P = 0.02). Another multivariate analysis, adjusted for BMI and multiples of median (MoM) values for pregnancy-associated plasma protein-A (PAPP-A), demonstrated a significantly reduced FF for ART pregnancies (mean FF = 0.056) compared with naturally conceived pregnancies (mean FF = 0.072) (P < 0.0001). We found that FF was significantly reduced with increasing maternal BMI (P < 0.0001) and with decreasing MoM values of PAPP-A (P = 0.003). LIMITATIONS, REASONS FOR CAUTION: A limitation of our study design was the relatively small sample size. Another limitation was that the control group was not matched with the ART-treated women. The majority of the women from the control group had a high risk from cFTS, thereby their biochemical markers were diverging. However, the biochemical markers for the ART-treated women with fresh or frozen ET were not divergent within the subgroups. WIDER IMPLICATIONS OF THE FINDINGS: Concurrent with other studies demonstrating a reduced FF for singleton pregnancies after ART treatment compared with naturally conceived pregnancies, we found a reduction in FF between the two groups. This is one of the first studies to examine FF in ART pregnancies after fresh ET compared with frozen ET, hence the existing knowledge is limited. We find that FF is even more reduced in pregnancies following fresh ET compared with frozen ET, which might possibly reflect the predisposition of being small for gestational age after fresh ET compared with natural cycle frozen ET. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by the A.P. Møller og Hustru Chastine Mc-Kinney Møllers Fond til almene Formaal (the A.P. Møller Foundation for General Purposes). All authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER: NA.
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Ácidos Nucleicos Libres de Células , Estudios de Casos y Controles , Transferencia de Embrión , Femenino , Humanos , Embarazo , Primer Trimestre del Embarazo , Técnicas Reproductivas AsistidasRESUMEN
Background: The incidence of TB among Inuit is the highest in Canada. A significantly shorter latent TB infection (LTBI) treatment with rifapentine and isoniazid once weekly for 12 weeks (3HP) is now available in limited settings in Canada.Methods: A prospective open-label 2-year observational postmarketing study was conducted introducing 3HP for the first time in Canada in Iqaluit followed by a program rollout in Qikiqtarjuaq, Nunavut.Results: A total of 247 people were offered 3HP, 102 in the Iqaluit postmarketing study and 145 in the Qikiqtarjuaq program roll out. Although statistical significance was not reached, more people who started treatment completed treatment in the 3HP group (Iqaluit, 60/73 (82.2%) and Qikiqtarjuaq, 89/115 (77.4%)) than in the historical control 9INHgroup (306/420 = 72.9%) (p = 0.2). Most of the adverse events in 3HP treated patients were associated with mild discomfort but no disruption of normal daily activity. Not drinking alcohol was associated with increased 3HP completion (OR 13.33, 95% CI, 2.27-78.20) as was not taking concomitant medications (OR 7.19, 95% CI, 1.47-35.30).Conclusions: The present study supports the feasibility and safety profile of 3HP for the treatment of LTBI in Nunavut.
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Inuk , Isoniazida/uso terapéutico , Tuberculosis Latente/tratamiento farmacológico , Cumplimiento de la Medicación/etnología , Rifampin/análogos & derivados , Adolescente , Adulto , Consumo de Bebidas Alcohólicas/etnología , Regiones Árticas/epidemiología , Niño , Preescolar , Comorbilidad , Quimioterapia Combinada , Femenino , Humanos , Isoniazida/administración & dosificación , Isoniazida/efectos adversos , Tuberculosis Latente/etnología , Masculino , Persona de Mediana Edad , Nunavut/epidemiología , Vigilancia de Productos Comercializados , Estudios Prospectivos , Rifampin/administración & dosificación , Rifampin/efectos adversos , Rifampin/uso terapéutico , Factores de Riesgo , Factores Socioeconómicos , Adulto JovenRESUMEN
Noninvasive prenatal testing (NIPT) has become a popular screening test for the most common fetal aneuploidies. The performance of NIPT is affected by several factors including maternal obesity, which results in a greater rate of no-calls for obese pregnant women. Guidelines regarding NIPT in prenatal screening have been published, but with few and divergent recommendations on the issue. We aimed to review the medical literature, guidelines from scientific societies and information material from commercial NIPT providers on no-calls and maternal obesity. We systematically identified medical literature and guidelines from scientific societies using the database MEDLINE. Information material from commercial NIPT providers was found via a systematic search on Google.com. Nine medical studies investigating the association between maternal obesity and NIPT no-calls were included. They all showed the same trend: increasing no-call rate with increasing maternal obesity. The no-call rate ranged from 0% to 4.2% for women with body mass index (BMI) 18.5-24.9 and from 5.4% to 70.1% for women BMI ≥40. We identified 17 scientific societies with guidelines and 13 commercial NIPT providers. All were checked for information material on no-calls and maternal obesity. To allow comparison, all guidelines were examined to answer the same three predefined questions. Of the 17 included scientific societies, 13 (76.5%) mentioned the association between maternal obesity and NIPT no-calls, two (11.8%) specified weight limits and three (17.6%) advised against NIPT for severely obese pregnant women. None of the 13 commercial NIPT providers provided specific recommendations, but four (30.8%) cite maternal obesity as a potential cause for a no-call. Because of the increasing number of patients in this group, we advocate updated recommendations to guide decision making in prenatal screening for obese pregnant women.
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Pruebas Prenatales no Invasivas , Obesidad Materna , Índice de Masa Corporal , Femenino , Humanos , Obesidad Materna/clasificación , Guías de Práctica Clínica como Asunto , Embarazo , Sociedades CientíficasRESUMEN
Systemic inflammation is associated with arteriosclerotic disease progression and worse stroke outcome in patients with carotid arteriosclerotic disease. We hypothesize that systemic inflammation is mediated by impaired carotid baroreceptor and chemoreceptor function induced by carotid arteriosclerosis rather than by the generalized inflammatory arteriosclerotic process.Heart rate variability (HRV), serum levels of inflammatory markers, demographic and life style factors, and concomitant diseases with potential impact on systemic inflammation were determined in 105 patients with asymptomatic carotid stenosis of varying degree. Multivariate linear regression analyses were performed to ascertain independent determinants of carotid stenosis severity, autonomic function, and inflammation.Systemic inflammation (C-reactive protein, beta = .255; P = .014), age (beta = .232; P < .008), and arterial hypertension (beta = .206; P = .032) were associated with carotid stenosis severity. Only carotid stenosis severity and not generalized arteriosclerotic disease, concomitant diseases (arterial hypertension, diabetes mellitus, dyslipidemia, hypothyroidism), life style factors (smoking, obesity), or age was associated with a reduction in vagal tone (HRV HF band power beta = - .193; P < 0.049). Systemic inflammation was related to a reduction in vagal tone (HRV HF band power, beta = - .214; P = .031), and not to generalized arteriosclerotic disease, concomitant diseases (arterial hypertension, diabetes mellitus, dyslipidemia), life style factors (smoking, obesity), and age.In conclusion, systemic inflammation is associated with carotid rather than with generalized arteriosclerotic disease. The association between systemic inflammation and carotid arteriosclerosis is mediated by a reduction in vagal tone which indicates a major role of carotid arteriosclerosis-mediated autonomic dysfunction in the pathogenesis of systemic inflammation in arteriosclerotic disease.
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Arteriosclerosis/complicaciones , Enfermedades del Sistema Nervioso Autónomo/complicaciones , Estenosis Carotídea/complicaciones , Inflamación/complicaciones , Adulto , Anciano , Anciano de 80 o más Años , Arteriosclerosis/sangre , Enfermedades del Sistema Nervioso Autónomo/sangre , Estenosis Carotídea/sangre , Femenino , Frecuencia Cardíaca , Humanos , Inflamación/sangre , Estilo de Vida , Masculino , Persona de Mediana EdadRESUMEN
The exact biological mechanism governing the radioresistant phenotype of prostate tumours at a high risk of recurrence despite the delivery of advanced radiotherapy protocols remains unclear. This study analysed the protein expression profiles of a previously generated isogenic 22Rv1 prostate cancer model of radioresistance using DigiWest multiplex protein profiling for a selection of 90 signalling proteins. Comparative analysis of the profiles identified a substantial change in the expression of 43 proteins. Differential PARP-1, AR, p53, Notch-3 and YB-1 protein levels were independently validated using Western Blotting. Pharmacological targeting of these proteins was associated with a mild but significant radiosensitisation effect at 4Gy. This study supports the clinical relevance of isogenic in vitro models of radioresistance and clarifies the molecular radiation response of prostate cancer cells.
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Biomarcadores de Tumor/metabolismo , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/radioterapia , Análisis por Matrices de Proteínas/métodos , Tolerancia a Radiación , Línea Celular Tumoral , Supervivencia Celular , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Humanos , Masculino , Modelos Biológicos , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Neoplasias de la Próstata/tratamiento farmacológico , Receptor Notch3/metabolismo , Receptores Androgénicos/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Proteína 1 de Unión a la Caja Y/metabolismoRESUMEN
OBJECTIVE: Metastasized non-small cell lung cancer (NSCLC) with an anaplastic lymphoma kinase (ALK) rearrangement is usually sensitive to a range of ALK-tyrosine kinase inhibitors. ALK-positive NSCLC have been identified in pivotal phase III trials with fluorescence in situ hybridization (ALK FISH+). These tumors are also expressing the fusion product (ALK immunohistochemistry (IHC)+). However, discrepant cases occur, including ALK IHCâ¯+â¯FISH-. The aim of this study was to collect ALK IHCâ¯+â¯cases and compare within this group response to crizotinib treatment of ALK FISHâ¯+â¯cases with ALK FISH- cases. MATERIALS AND METHODS: In this European prospective multicenter research study patients with Stage IV ALK IHCâ¯+â¯NSCLC treated with crizotinib were enrolled. Tumor slides were validated centrally for ALK IHC and ALK FISH. RESULTS: Registration of 3523 ALK IHC tests revealed a prevalence of 2.7% (nâ¯=â¯94) ALK IHCâ¯+â¯cases. Local ALK FISH analysis resulted in 48 concordant (ALK IHC+/FISH+) and 16 discordant (ALK IHC+/FISH-) cases. Central validation revealed 37 concordant and 7 discordant cases, 5 of which had follow-up. Validation was hampered by limited amount of tissue in biopsy samples. The PFS at 1â¯year for ALK concordant and discordant was 58% and 20%, respectively (HRâ¯=â¯2.4; 95% CI: 0.78-7.3; pâ¯=â¯0.11). Overall survival was significantly better for concordant cases than discordant cases after central validation (HR=4.5; 95% CI= 1.2-15.9; p=0.010. CONCLUSION: ALK IHCâ¯+â¯FISH- NSCLC is infrequent and associated with a worse outcome on personalized treatment. A suitable predictive testing strategy may be to screen first with IHC and then confirm with FISH instead of considering ALK IHC equivalent to ALK FISH according to the current guidelines.
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Quinasa de Linfoma Anaplásico/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Crizotinib/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Quinasa de Linfoma Anaplásico/genética , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Femenino , Reordenamiento Génico , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Inhibidores de Proteínas Quinasas/uso terapéutico , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
INTRODUCTION: Tympanostomy tube insertion is very frequent in Denmark. Using electronic patient-reported outcome (ePRO) data, we investigated Danish ear, nose og throat (ENT) specialists' adherence to the 2015 national clinical guideline (NCG) on first-time tympanostomy tube (TT) insertion in children aged 0-5 years with otitis media (OM). METHODS: Data on children aged 0-5 years with OM undergoing first-time TT insertion were extracted from the Danish ENT Specialists Organisation (DØNHO) database. Pre-operative questionnaires were used to obtain information on symptom duration, and the number of acute OM (AOM) episodes was analysed. The following criteria were established to define NCG adherence: 1) A symptom duration of three months or longer, 2) three or more AOM episodes within six months and 3) four or more AOM episodes within 12 months. These criteria are in accordance with the NCG definition of chronic OM with effusion (COME) and recurrent AOM (RAOM). RESULTS: A total of 1,495 children were included in the study. In total, 91.0% of the parents reported a symptom duration of three months or more and/or RAOM within 6-12 months prior to TT insertion in accordance with the adherence criteria; 4.6% reported a symptom duration of less than three months with few or no episodes of AOM and did not meet the recommended TT insertion criteria. Finally, 4.4% of the parents were undecided with respect to symptom duration, number of AOM episodes or both at 6-12 months prior to TT insertion. CONCLUSIONS: Using solely ePRO data, we found that Danish practicing ENT specialists adhere to the 2015 NCG in regard to OM symptom duration and RAOM. FUNDING: none. TRIAL REGISTRATION: not relevant.
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Adhesión a Directriz/estadística & datos numéricos , Ventilación del Oído Medio/normas , Otolaringología/normas , Preescolar , Dinamarca , Femenino , Humanos , Lactante , Masculino , Ventilación del Oído Medio/estadística & datos numéricos , Otitis Media/cirugía , Otolaringología/estadística & datos numéricos , Medición de Resultados Informados por el Paciente , Encuestas y CuestionariosAsunto(s)
Alcoholismo , Consumo de Bebidas Alcohólicas , Etanol , Estudios de Seguimiento , Objetivos , HumanosRESUMEN
INTRODUCTION: A subgroup of patients with benign colonic neoplasia is unsuitable for standard endoscopic treatment modalities. These patients may benefit from a combined endoscopic and laparoscopic surgical (CELS) approach. A CELS procedure may even be an option for some patients with a small malignant lesion where resection of the colon may be associated with an excessively high risk of proced-ure-related morbidity and mortality. METHODS: All patients considered for a CELS procedure were evaluated at a multidisciplinary team conference. The CELS procedures were performed as laparoscopy-assisted endoscopic mucosal resections or endoscopy-assisted laparoscopic resections. RESULTS: A total of 25 patients were included. Five patients had a malignant and 20 patients had a benign lesion. Two patients with histologically verified malignant lesions pre-operatively had CELS performed due to severe co-morbidity. In one patient with initially benign biopsies, the resected CELS specimen revealed adenocarcinoma. This patient subsequently underwent oncological resection (no residual disease). In the last two cases, the lesions were assessed during CELS and they exhibited endoscopically malignant features. Consequently, both patients underwent immediate oncological segmental colon resection. CONCLUSIONS: CELS is a feasible treatment for colonic neoplasia where endoscopic resection alone is not technically possible. In case of severe co-morbidity ruling out segmental resection in patients diagnosed with T1 or T2 colorectal cancer, CELS treatment may be considered. FUNDING: none. TRIAL REGISTRATION: This study was assessed by The National Committee on Health Research Ethics (SJ-593), which concluded that the study required no approval from the Committee. The study was approved by the Danish Data Protection Agency (REG-126-2017). .
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Adenoma/cirugía , Neoplasias del Colon/cirugía , Pólipos del Colon/cirugía , Colonoscopía/métodos , Laparoscopía/métodos , Adulto , Anciano , Anciano de 80 o más Años , Colon/patología , Dinamarca , Femenino , Humanos , Tiempo de Internación , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
INTRODUCTION: The aim of this clinical pilot study was to examine the accuracy of noninvasive fetal RHD genotyping in early pregnancy (8+0 to 11+6 weeks) and to clarify whether targeted administration of Rhesus immunoglobulin (RhIg) is possible for women undergoing an induced abortion such that unnecessary injections can be avoided. The study examines the correlation between gestational age and the amount of cell-free fetal DNA in maternal plasma, the fetal fraction of DNA and whether transportation time or body mass index affects these parameters. MATERIAL AND METHODS: Fifty-two RhD-negative women undergoing a surgically induced abortion were included. A maternal blood sample was collected prior to the abortion and a tissue sample was collected from the placental part of the abortion material after the intervention. Fetal RhD type was determined by PCR analysis of cell-free fetal DNA extracted from maternal plasma and on DNA from the tissue sample, with the latter providing a reference standard. Copies of RHD/mL were determined on RHD-positive samples and the fetal fraction of DNA was calculated. RESULTS: We demonstrated complete concordance between results from plasma and tissue, with 31 RhD-positive and 21 RhD-negative samples, corresponding to 40% being RhD-negative, specificity 100% [95% confidence interval (CI) 88.8-100] and sensitivity 100% (95% CI 83.9-100). We found no significant correlation between gestational age and the amount or the fraction of cell-free fetal DNA in maternal plasma, nor did we find that transportation time or BMI significantly affected these factors in this setup. CONCLUSIONS: Fetal RHD genotyping can be accurately performed from the 8th week of gestation and unnecessary injections of RhIg can be avoided for women undergoing an induced abortion. A larger study is needed to determine a more accurate sensitivity for the analysis early in pregnancy.
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Aborto Inducido , Sistema del Grupo Sanguíneo Rh-Hr/genética , Globulina Inmune rho(D)/uso terapéutico , Adulto , Femenino , Genotipo , Humanos , Proyectos Piloto , Reacción en Cadena de la Polimerasa , Embarazo , Sensibilidad y EspecificidadRESUMEN
Objective: The aim of this study was to compare the laeverin level in maternal serum from first trimester (11-14 weeks) of pregnancy between normal pregnancies and pregnancies that later developed preeclampsia (PE). Material and methods: This was a case-cohort study. The laeverin concentration was measured in cases with preterm PE (n = 55), term PE (n = 95), and a reference group of randomly selected women with normal pregnancy outcome (n = 200) in stored serum samples collected from the double-test as part of the combined first trimester trisomy 21 screening program. The samples were thawed and analyzed for laeverin. The median gestational age at blood sampling was 77 days (range 57-96 days). Multiple regression analysis was performed to establish a normal median. Concentrations were converted to multiples of the median (MoM) and groups were compared using the Mann-Whitney U-test. Results: In the reference group, laeverin was significantly correlated with gestational age (r = 0.18, p = .01) and its concentration ranged from 41-393 µg/L. No significant differences in the median laeverin MoM were found between the reference group (1.01 MoM) and cases with preterm PE (0.98 MoM) or term PE (0.96 MoM). Conclusions: First trimester maternal serum laeverin level cannot be used to predict preeclampsia.