RESUMEN
BACKGROUND: Cancer treatment-related cognitive impairment (CTRCI) can substantially reduce the quality of life of cancer survivors. Many treatments of CTRCI have been evaluated in randomized controlled trials (RCTs), including psychological interventions, pharmacologic interventions, and other therapies. There is a pressing need to establish the benefits and harms of previously studied CTRCI treatments. The proposed systematic review and network meta-analyses will assess the relative efficacy and safety of competing interventions for the management of CTRCI. METHODS: In consultation with the review team, an experienced medical information specialist will draft electronic search strategies for MEDLINE®, Embase, CINAHL, PsycINFO, and the Cochrane Trials Registry. We will seek RCTs of interventions for the treatment of CTRCI in adults with any cancer, except cancers/metastases of the central nervous system. Due to the anticipated high search yields, dual independent screening of citations will be expedited by use of an artificial intelligence/machine learning tool. The co-primary outcomes of interest will be subjective and objective cognitive function. Secondary outcomes of interest will include measures of quality of life, mental and physical health symptoms, adherence to treatment, and harms (overall and treatment-related harms and harms associated with study withdrawal), where feasible, random-effects meta-analyses and network meta-analyses will be pursued. We will address the anticipated high clinical and methodological heterogeneity through meta-regressions, subgroup analyses, and/or sensitivity analyses. DISCUSSION: The proposed systematic review will deliver a robust comparative evaluation of the efficacy and safety of existing therapies for the management of CTRCI. These findings will inform clinical decisions, identify evidence gaps, and identify promising therapies for future evaluation in RCTs.
Asunto(s)
Supervivientes de Cáncer , Disfunción Cognitiva , Neoplasias , Calidad de Vida , Revisiones Sistemáticas como Asunto , Humanos , Supervivientes de Cáncer/psicología , Disfunción Cognitiva/terapia , Disfunción Cognitiva/etiología , Neoplasias/terapia , Neoplasias/complicaciones , Investigación sobre la Eficacia Comparativa , AdultoRESUMEN
INTRODUCTION: A patient experience survey was undertaken for patients completing radiotherapy at the three Northwest of England Radiotherapy Providers. METHODS: A previously reported National Radiotherapy Patient Experience Survey was adapted and undertaken in the Northwest of England. Quantitative data was analysed to establish trends. Frequency distribution was applied to appraise the number of participants selecting each of the pre-determined responses. Thematic analysis of free text responses was conducted. RESULTS: The questionnaire received 653 responses from the 3 providers across seven departments. Thematic analysis revealed 3 themes; logistics, information and operational. CONCLUSION: The results indicate that the majority of patients are satisfied with their treatment and care. Patients' responses indicate areas for improvements. Expectancy theory states that an individual's satisfaction is related to the difference between expected service and the service received. Consequently, when reviewing services and developing improvement it is important to understand patients' expectations. This regional survey starts to capture what people receiving radiotherapy expect from the service and the professionals delivering their treatment. IMPLICATIONS FOR PRACTICE: This survey responses make a case for reviewing the information provision pre and post radiotherapy. This includes clarifying the understanding of consent for treatment including the intended benefits and potential late effects. There is an argument to offer information sessions prior to radiotherapy to achieve more relaxed and informed patients. A recommendation from this work is for the radiotherapy community undertake a national radiotherapy patient experience survey, facilitated via the 11 Radiotherapy ODNs. A national radiotherapy survey has multiple benefits to inform improvements in practice. This includes benchmarking services against national averages. This approach is aligned with the principles of the service specification in terms of reducing variation and increasing quality.
Asunto(s)
Evaluación del Resultado de la Atención al Paciente , Pacientes , Humanos , Encuestas y Cuestionarios , InglaterraRESUMEN
Head and neck squamous cell carcinoma (HNSCC) patients treated with high-dose cisplatin concurrently with radiotherapy (hdCis-RT) commonly suffer kidney injury leading to acute and chronic kidney disease (AKD and CKD, respectively). We conducted a retrospective analysis of renal function and kidney injury-related plasma biomarkers in a subset of HNSCC subjects receiving hdCis-RT in a double-blinded, placebo-controlled clinical trial (NCT02508389) evaluating the superoxide dismutase mimetic, avasopasem manganese (AVA), an investigational new drug. We found that 90 mg AVA treatment prevented a significant reduction in estimated glomerular filtration rate (eGFR) three months as well as six and twelve months after treatment compared to 30 mg AVA and placebo. Moreover, AVA treatment may have allowed renal repair in the first 22 days following cisplatin treatment as evidenced by an increase in epithelial growth factor (EGF), known to aid in renal recovery. An upward trend was also observed in plasma iron homeostasis proteins including total iron (Fe-blood) and iron saturation (Fe-saturation) in the 90 mg AVA group versus placebo. These data support the hypothesis that treatment with 90 mg AVA mitigates cisplatin-induced CKD by inhibiting hdCis-induced renal changes and promoting renal recovery.
Asunto(s)
Neoplasias de Cabeza y Cuello , Insuficiencia Renal Crónica , Humanos , Benchmarking , Cisplatino/efectos adversos , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/metabolismo , Hierro/metabolismo , Riñón/metabolismo , Insuficiencia Renal Crónica/inducido químicamente , Insuficiencia Renal Crónica/tratamiento farmacológico , Estudios Retrospectivos , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/patologíaRESUMEN
BACKGROUND: Continued smoking after a diagnosis of cancer negatively impacts cancer outcomes, but the impact of tobacco on newer treatments options is not well established. Collecting and evaluating tobacco use in clinical trials may advance understanding of the consequences of tobacco use on treatment modalities, but little is known about the frequency of reporting and analysis of tobacco use in cancer cooperative clinical trial groups. PATIENTS AND METHODS: A comprehensive literature search was conducted to identify cancer cooperative group clinical trials published from January 2017-October 2019. Eligible studies evaluated either systemic and/or radiation therapies, included ≥100 adult patients, and reported on at least one of: overall survival, disease/progression-free survival, response rates, toxicities/adverse events, or quality-of-life. RESULTS: A total of 91 studies representing 90 trials met inclusion criteria with trial start dates ranging from 1995 to 2015 with 14% involving lung and 5% head and neck cancer patients. A total of 19 studies reported baseline tobacco use; 2 reported collecting follow-up tobacco use. Seven studies reported analysis of the impact of baseline tobacco use on clinical outcomes. There was significant heterogeneity in the reporting of baseline tobacco use: 7 reported never/ever status, 10 reported never/ex-smoker/current smoker status, and 4 reported measuring smoking intensity. None reported verifying smoking status or second-hand smoke exposure. Trials of lung and head and neck cancers were more likely to report baseline tobacco use than other disease sites (83% versus 6%, P < 0.001). CONCLUSIONS: Few cancer cooperative group clinical trials report and analyze trial participants' tobacco use. Significant heterogeneity exists in reporting tobacco use. Routine standardized collection and reporting of tobacco use at baseline and follow-up in clinical trials should be implemented to enable investigators to evaluate the impact of tobacco use on new cancer therapies.
Asunto(s)
Neoplasias , Nicotiana , Adulto , Humanos , Nicotiana/efectos adversos , Uso de Tabaco/efectos adversos , Uso de Tabaco/epidemiología , Neoplasias/epidemiología , Neoplasias/etiología , Neoplasias/terapiaRESUMEN
BACKGROUND: Emergency laparotomy carries a significant risk profile around the time of surgery. This research aimed to establish the feasibility of recruitment to a study using validated scoring tools to assess complications after surgery; and patient-reported outcome measures (PROMs) to assess quality of life and quality of recovery up to a year following emergency laparotomy (EL). METHODS: We used our local National Emergency Laparotomy Audit (NELA) register to identify potential participants at a single NHS centre in England. Complications were assessed at 5, 10 and 30 days after EL. Patient-reported outcome measures were collected at 1, 3, 6 and 12 months after surgery using EQ5D and WHODAS 2.0 questionnaires. RESULTS: Seventy of 129 consecutive patients (54%) agreed to take part in the study. Post-operative morbidity survey data was recorded from 63 and 37 patients at postoperative day 5 and day 10. Accordion Complication Severity Grading data was obtained from 70 patients. Patient-reported outcome measures were obtained from patients at baseline and 1, 3, 6 and 12 months after surgery from 70, 59, 51, 48, to 42 patients (100%, 87%, 77%, 75% and 69% of survivors), respectively. CONCLUSIONS: This study affirms the feasibility of collecting PROMs and morbidity data successfully at various time points following emergency laparotomy, and is the first longitudinal study to describe quality of life up to a year after surgery. This finding is important in the design of a larger observational study into quality of life and recovery after EL.
RESUMEN
BACKGROUND: Thoracic epidural analgesia (TEA) has been regarded as the standard of care after oesophagectomy for pain control, but has several side-effects. Multimodal (intrathecal diamorphine, paravertebral and rectus sheath catheters) analgesia (MA) may facilitate postoperative mobilization by reducing hypotensive episodes and the need for vasopressors, but uncertainty exists about whether it provides comparable analgesia. This study aimed to determine whether MA provides comparable analgesia to TEA following transthoracic oesophagectomy. METHODS: Consecutive patients undergoing oesophagectomy for cancer between January 2015 and December 2018 were grouped according to postoperative analgesia regimen. Propensity score matching (PSM) was used to account for treatment selection bias. Pain scores at rest and on movement, graded from 0 to 10, were used. The incidence of hypotensive episodes and the requirement for vasopressors were evaluated. RESULTS: The study included 293 patients; 142 (48.5 per cent) received TEA and 151 (51.5 per cent) MA. After PSM, 100 patients remained in each group. Mean pain scores were significantly higher at rest in the MA group (day 1: 1.5 versus 0.8 in the TEA group, P = 0.017; day 2: 1.7 versus 0.9 respectively, P = 0.014; day 3: 1.2 versus 0.6, P = 0.047). Fewer patients receiving MA had a hypotensive episode (25 per cent versus 45 per cent in the TEA group; P = 0.003) and fewer required vasopressors (36 versus 53 per cent respectively; P = 0.016). There was no significant difference in the overall complication rate (71.0 versus 61.0 per cent; P = 0.136). CONCLUSION: MA is less effective than TEA at controlling pain, but this difference may not be clinically significant. However, fewer patients experienced hypotension or required vasopressor support with MA; this may be beneficial within an enhanced recovery programme.
Asunto(s)
Analgesia Epidural/métodos , Analgesia/métodos , Esofagectomía , Dolor Postoperatorio/terapia , Anciano , Neoplasias Esofágicas/cirugía , Esofagectomía/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Dimensión del Dolor , Puntaje de Propensión , Vértebras TorácicasRESUMEN
Following accidental release into marine environments, crude oil progressively weathers, influencing composition, fate, and toxicity. However, published studies draw conflicting conclusions on the effects of oil weathering on ecotoxicity. Using the PETROTOX model, this study characterized the effect of weathering on acute oil toxicity for four aquatic species. Results indicated that predicted acute toxicity decreased with increased oil weathering, due to reductions in overall concentrations and bioavailability of hydrocarbon constituents.
Asunto(s)
Contaminación por Petróleo , Petróleo , Contaminantes Químicos del Agua , Hidrocarburos , Petróleo/toxicidad , Contaminación por Petróleo/análisis , Contaminantes Químicos del Agua/análisis , Contaminantes Químicos del Agua/toxicidad , Tiempo (Meteorología)RESUMEN
Purpose: Many patients diagnosed with head-and-neck cancer are current or former smokers. Despite the well-known adverse effects of smoking, continuation of smoking during cancer treatment is associated with reduced efficacy of that treatment and with cancer recurrence. In the present study, we examined smoking characteristics in patients with head-and-neck cancer near the time of cancer treatment. Methods: A prospective cohort of patients with head-and-neck cancer who attended a dental oncology clinic before receiving cancer treatment at a regional cancer centre were invited to participate in a study that involved completing an interviewer-administered questionnaire to assess smoking characteristics, intention to quit, motivation to quit, and strategies perceived to potentially aid in successful cessation. Results: The study enrolled 493 ever-smokers, with a response rate of 96.1% and a self-reported current smoker rate of 37.1% (n = 183). Most of the current smokers reported high nicotine dependence, with 84.7% (n = 155) indicating a time to first cigarette of 30 minutes or less. Most had previously attempted to quit smoking (77.0%), and many had prior unsuccessful quit attempts before resuming smoking again. Most were interested in quitting smoking (85.8%), and many (70.5%) were seriously considering quitting smoking within the subsequent 30 days. Conclusions: Patients with head-and-neck cancer reported high nicotine dependence and high interest in cessation opportunities near the time of treatment for cancer. Those results might provide support for provision of smoking cessation opportunities.
Asunto(s)
Fumar Cigarrillos , Neoplasias de Cabeza y Cuello , Cese del Hábito de Fumar , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Neoplasias de Cabeza y Cuello/epidemiología , Neoplasias de Cabeza y Cuello/etiología , Neoplasias de Cabeza y Cuello/terapia , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Estudios Prospectivos , Humo , Fumar/epidemiologíaRESUMEN
BACKGROUND: The optimal duration of filgrastim as primary febrile neutropenia (FN) prophylaxis in early breast cancer patients is unknown, with 5, 7 or 10 days being commonly prescribed. This trial evaluates whether 5 days of filgrastim was non-inferior to 7/10 days. PATIENTS AND METHODS: In this randomised, open-label trial, early breast cancer patients who were to receive filgrastim as primary FN prophylaxis were randomly allocated to 5 versus 7 versus 10 days of filgrastim for all chemotherapy cycles. A protocol amendment in November 2017 allowed subsequent patients (N = 324) to be randomised to either 5 or 7/10 days. The primary outcome was a composite of either FN or treatment-related hospitalisations. Secondary outcomes included chemotherapy dose reductions, delays and discontinuations. Analyses were carried out by per protocol (primary) and intention-to-treat, and the non-inferiority margin was set at 3% for the risk of having FN and/or hospitalisation per cycle of chemotherapy. RESULTS: Patients (N = 466) were randomised to receive 5 (184, 39.5%), or 7/10 (282, 60.5%) days of filgrastim. In our primary analysis, the difference in risk of either FN or treatment-related hospitalisation per cycle was -1.52% [95% confidence interval (CI): -3.22% to 0.19%] suggesting non-inferiority of a 5-day filgrastim schedule compared with 7/10-days. The difference in events per cycle for FN was 0.11% (95% CI: -1.05 to 1.27) while for treatment-related hospitalisations it was -1.68% (95% CI: -2.73% to -0.63%). The overall proportions of patients having at least one occurrence of either FN or treatment-related hospitalisation were 11.8% and 14.96% for the 5- and 7/10-day groups, respectively (risk difference: -3.17%, 95% CI: -9.51% to 3.18%). CONCLUSION: Five days of filgrastim was non-inferior to 7/10 days. Given the cost and toxicity of this agent, 5 days should be considered standard of care. CLINICALTRIALS. GOV REGISTRATION: NCT02428114 and NCT02816164.
Asunto(s)
Neoplasias de la Mama , Neutropenia Febril Inducida por Quimioterapia , Neutropenia Febril , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Neutropenia Febril Inducida por Quimioterapia/epidemiología , Neutropenia Febril Inducida por Quimioterapia/etiología , Neutropenia Febril Inducida por Quimioterapia/prevención & control , Neutropenia Febril/inducido químicamente , Neutropenia Febril/epidemiología , Neutropenia Febril/prevención & control , Filgrastim/uso terapéutico , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Humanos , Polietilenglicoles/uso terapéutico , Proteínas Recombinantes/uso terapéuticoRESUMEN
We introduce a filter using a noise-free quantum buffer with large optical bandwidth that can both filter temporal-spectral modes as well as interconvert them and change their frequency. We theoretically show that such quantum buffers optimally filter out temporal-spectral noise, producing identical single photons from many distinguishable noisy single-photon sources with the minimum required reduction in brightness. We then experimentally demonstrate a noise-free quantum buffer in a warm atomic system that is well matched to quantum dots. Based on these experiments, simulations show that our buffer can outperform all intensity (incoherent) filtering schemes for increasing indistinguishability.
Asunto(s)
Consultores , Degeneración Macular Húmeda , Inhibidores de la Angiogénesis , Bevacizumab , HumanosRESUMEN
AIM: To determine the level of confidence general practitioners (GPs) have in radiology reports provided by neuroradiologists and to elicit the preferences of GPs regarding report format and level of detail. MATERIALS AND METHODS: Electronic surveys comprising anonymised neuroradiology reports were sent to GP practices served by a tertiary neuroscience centre. After reviewing the reports, GPs were asked to complete a two-part questionnaire. Firstly, GPs indicated their level of confidence, using a five-tiered Likert scale, in their understanding of: (a) the body of text; (b) the meaning of the report; and (c) the significance of the report. Secondly, GPs provided free-text suggestions for improving the report and highlighted any phrases that they did not understand. RESULTS: One hundred GPs responded from a group of 439 that received a survey (response rate 23%). Although the majority of GPs were fairly confident in their understanding of reports, fewer than one-third of GPs were entirely confident. Approximately 10% of GPs were not confident at all in their understanding of the reports. Causes of confusion included the use of detailed anatomy, acronyms, radiological terminology, and a lack of a conclusion and an action plan. CONCLUSION: General practice is a time-sensitive discipline that demands clear communication. In neuroradiology reports, GPs do not find detailed anatomy, acronyms, or radiological terminology helpful. Rather, GPs want a clear conclusion and action plan.
Asunto(s)
Médicos Generales , Imagen por Resonancia Magnética , Neuroimagen , Actitud del Personal de Salud , Encéfalo/diagnóstico por imagen , Encefalopatías/diagnóstico por imagen , Documentación/normas , Médicos Generales/psicología , Médicos Generales/estadística & datos numéricos , Humanos , Imagen por Resonancia Magnética/métodos , Imagen por Resonancia Magnética/normas , Imagen por Resonancia Magnética/estadística & datos numéricos , Neuroimagen/normas , Neuroimagen/estadística & datos numéricos , Encuestas y Cuestionarios , Terminología como AsuntoRESUMEN
Thoracic epidural (TE) analgesia has been the standard of care for transthoracic esophagectomy patients since the 1990s. Multimodal anesthesia using intrathecal diamorphine, local anesthetic infusion catheters (LAC) into the paravertebral space and rectus sheaths and intravenous opioid postoperatively represent an alternative option for postoperative analgesia. While TE can provide excellent pain control, it may inhibit early postoperative recovery by causing hypotension and reducing mobilization. The aim of this study is to determine whether multimodal analgesia with LAC was effective with respect to adequate pain management, and compare its impact on hypotension and mobility. Patients receiving multimodal LAC analgesia were matched using propensity score matching to patients undergoing two-phase trans-thoracic esophagectomy with a TE over a two-year period (from January 2015 to December 2016). Postoperative endpoints that had been evaluated prospectively, including pain scores on movement and at rest, inotrope or vasoconstrictor requirements, and hypotension (systolic BP < 90 mmHg), were compared between cohorts. Out of 14 patients (13 male) that received LAC were matched to a cohort of 14 patients on age, sex, and comorbidity. Mean and maximum pain scores at rest and movement on postoperative days 0 to 3 were equivalent between the groups. In both cohorts, 50% of patients had a pain score of more than 7 on at least one occasion. Fewer patients in the LAC group required vasoconstrictor infusion (LAC: 36% vs. TE: 57%, P = 0.256) to maintain blood pressure or had episodes of hypotension (LAC: 43% vs. TE: 79%, P = 0.05). The LAC group was more able to ambulate on the first postoperative day (LAC: 64% vs. TE: 43%, P = 0.14) but these differences were not statistically significant. Within the epidural cohort, three patients had interruption of epidural due to dislodgement or failure of block compared to no disruption in the multimodal local anesthesia catheters group (P = 0.05). Therefore, multimodal anesthesia using spinal diamorphine with combined paravertebral and rectus sheath local anesthetic catheters appears to provide comparable pain relief post two-phase esophagectomy and may provide more reliable and safe analgesia than the current standard of care.
Asunto(s)
Analgesia Epidural/métodos , Analgesia/métodos , Analgésicos Opioides/administración & dosificación , Esofagectomía/efectos adversos , Heroína/administración & dosificación , Dolor Postoperatorio/tratamiento farmacológico , Toracotomía/efectos adversos , Anciano , Analgesia/instrumentación , Catéteres , Esofagectomía/métodos , Esofagectomía/rehabilitación , Femenino , Humanos , Inyecciones Espinales , Masculino , Persona de Mediana Edad , Dolor Postoperatorio/etiología , Estudios Retrospectivos , Toracotomía/métodos , Toracotomía/rehabilitación , Resultado del TratamientoRESUMEN
Interventions to increase physical activity in pregnancy are challenging for morbidly obese women. Targeting sedentary behaviors may be a suitable alternative to increase energy expenditure. We aimed to determine total energy expenditure, and energy expended in sedentary activities in morbidly obese and lean pregnant women. We administered the Pregnancy Physical Activity Questionnaire (nonobjective) and the Actical accelerometer (objective) to morbidly obese (BMI ≥ 40 kg/m²) and lean (BMI ≤ 25 Kg/m²) pregnant women recruited in early (<24 weeks), and late (≥24 weeks) gestation. Data are mean (SD). Morbidly obese pregnant women reported expending significantly more energy per day in early (n = 140 vs 109; 3198.4 (1847.1) vs 1972.3 (10284.8) Kcal/d, P < .0001) and late (n = 104 vs 64; 3078.2 (1356.5) vs 1947.5 (652.0) Kcal/d, P < .0001) pregnancy, and expended significantly more energy in sedentary activities, in early (816.1 (423.5) vs 540.1 (244.9) Kcal/d, P < .0001) and late (881.6 (455.4) vs 581.1 (248.5) Kcal/d, P < .0001) pregnancy, than lean pregnant women. No differences were observed in the proportion of energy expended sedentary between lean and morbidly obese pregnant women. The greater total energy expenditure in morbidly obese pregnant women was corroborated by Actical accelerometer in early (n = 14 per group, obese 1167.7 (313.6) Kcal; lean 781.1 (210.1) Kcal, P < .05), and in late (n = 14 per group, obese 1223.6 (351.5) Kcal; lean 893.7 (175.9) Kcal, P < .05) pregnancy. In conclusion, non-objective and objective measures showed morbidly obese pregnant women expended more energy per day than lean pregnant. Further studies are needed to determine whether sedentary behaviors are a suitable target for intervention in morbidly obese pregnancy.
Asunto(s)
Composición Corporal , Índice de Masa Corporal , Metabolismo Energético , Ejercicio Físico , Obesidad Mórbida/fisiopatología , Estudios de Casos y Controles , Femenino , Humanos , Oligopéptidos , Embarazo , Encuestas y CuestionariosRESUMEN
Sepsis-associated encephalopathy (SAE) induces neuroinflammation, which is associated with cognitive impairment (CI). CI is also correlated with aging. We used contrast-enhanced magnetic resonance imaging (MRI), perfusion MRI, and MR spectroscopy to assess long-term alterations in BBB permeability, microvascularity, and metabolism, respectively, in a rat lipopolysaccharide-induced SAE model. Free radical-targeted molecular MRI was used to detect brain radical levels at 24 h and 1 week post-LPS injection. CE-MRI showed increased Gd-DTPA uptake in LPS rat brains at 24 h in cerebral cortex, hippocampus, thalamus, and perirhinal cortex regions. Increased MRI signal intensities were observed in LPS rat brains in cerebral cortex, perirhinal cortex, and hippocampus regions 1 week post-LPS. Long-term BBB dysfunction was detected in the cerebral cortex at 6 weeks post-LPS. Increased relative cerebral blood flow (rCBF) in cortex and thalamus regions at 24 h, decreased cortical and hippocampal rCBF at 6 weeks, decreased cortical rCBF at 3 and 12 weeks, and increased thalamus rCBF at 6 weeks post-LPS, were detected. MRS indicated that LPS-exposed rat brains had decreased: NAA/Cho metabolite ratios at 1, 3, 6, and 12 weeks; Cr/Cho at 1, 3, and 12 weeks; and Myo-Ins/Cho at 1, 3, and 6 weeks post-LPS. Free radical imaging detected increased radical levels in LPS rat brains at 24 h and 1 week post-LPS. LPS-exposed rats were compared to saline-treated controls. We clearly demonstrated BBB dysfunction, impaired vascularity, and decreased brain metabolites, as measures of long-term neuroinflammatory indicators, as well as increased free radicals in a LPS-induced rat SAE model.
Asunto(s)
Medios de Contraste , Endotoxemia/diagnóstico por imagen , Endotoxemia/metabolismo , Imagen por Resonancia Magnética/métodos , Encefalopatía Asociada a la Sepsis/diagnóstico por imagen , Animales , Barrera Hematoencefálica , Circulación Cerebrovascular/fisiología , Modelos Animales de Enfermedad , Endotoxemia/fisiopatología , Espectroscopía de Resonancia Magnética/métodos , Masculino , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Valores de Referencia , Encefalopatía Asociada a la Sepsis/metabolismo , Encefalopatía Asociada a la Sepsis/fisiopatologíaRESUMEN
Pancreatic cancer has a devastating prognosis, with an overall 5-year survival rate of ~8%, restricted treatment options and characteristic molecular heterogeneity. SerpinB2 expression, particularly in the stromal compartment, is associated with reduced metastasis and prolonged survival in pancreatic ductal adenocarcinoma (PDAC) and our genomic analysis revealed that SERPINB2 is frequently deleted in PDAC. We show that SerpinB2 is required by stromal cells for normal collagen remodelling in vitro, regulating fibroblast interaction and engagement with collagen in the contracting matrix. In a pancreatic cancer allograft model, co-injection of PDAC cancer cells and SerpinB2-/- mouse embryonic fibroblasts (MEFs) resulted in increased tumour growth, aberrant remodelling of the extracellular matrix (ECM) and increased local invasion from the primary tumour. These tumours also displayed elevated proteolytic activity of the primary biochemical target of SerpinB2-urokinase plasminogen activator (uPA). In a large cohort of patients with resected PDAC, we show that increasing uPA mRNA expression was significantly associated with poorer survival following pancreatectomy. This study establishes a novel role for SerpinB2 in the stromal compartment in PDAC invasion through regulation of stromal remodelling and highlights the SerpinB2/uPA axis for further investigation as a potential therapeutic target in pancreatic cancer.
Asunto(s)
Carcinoma Ductal Pancreático/patología , Neoplasias Pancreáticas/patología , Inhibidor 2 de Activador Plasminogénico/metabolismo , Microambiente Tumoral , Animales , Carcinoma Ductal Pancreático/metabolismo , Fibroblastos/metabolismo , Fibroblastos/patología , Perfilación de la Expresión Génica , Humanos , Ratones , Microscopía Electrónica de Rastreo , Neoplasias Pancreáticas/metabolismo , TranscriptomaRESUMEN
The aim of this study was to describe the abnormalities identified with conventional MRI in children with neuropsychiatric systemic lupus erythematosus (NPSLE). This was single-centre (Great Ormond Street Hospital, London) retrospective case series of patients with juvenile NPSLE seen in 2003-2013. Brain MR images of the first episode of active NPSLE were reviewed. All patients fulfilled the 1999 ACR case definitions for NPSLE syndromes. Presenting neuropsychiatric manifestations, immunological findings and treatment are reported. Results are expressed as median and ranges or percentages. Fisher's exact test was used to identify clinical predictors of abnormal MRI. A total of 27 patients (22 females), median age 11 years (4-15), were identified. Presenting clinical symptoms included the following: headaches (85.1 %), mood disorder/depression (62.9 %), seizures (22.2 %), acute psychosis (18.5 %), cognitive dysfunction (14.8 %), movement disorder (14.8 %), acute confusional state (14.8 %), aseptic meningitis (7.4 %), demyelinating syndrome (3.7 %), myelopathy (3.7 %), dysautonomia (3.7 %) and cranial neuropathy (3.7 %). The principal MR findings were as follows: (1) absence of MRI abnormalities despite signs and symptoms of active NPSLE (59 %); (2) basilar artery territory infarction (3 %); (3) focal white matter hyperintensities on T2-weighted imaging (33 %); (4) cortical grey matter lesions (3 %); and (5) brain atrophy (18.5 %). The presence of an anxiety disorder strongly associated with abnormal MRI findings (p = 0.008). In over half the children with NPSLE, no conventional MRI abnormalities were observed; white matter hyperintensities were the most commonly described abnormalities. Improved MR techniques coupled with other alternative diagnostic imaging modalities may improve the detection rate of brain involvement in juvenile NPSLE.