The ubiquitin-like molecule interferon-stimulated gene 15 (ISG15) is a potential prognostic marker in human breast cancer

INTRODUCTION: ISG15 is an ubiquitin-like molecule that is strongly upregulated by type I interferons as a primary response to diverse microbial and cellular stress stimuli. However, alterations in the ISG15 signalling pathway have also been found in several human tumour entities. To the best of our knowledge, in the current study we present for the first time a systematic characterisation of ISG15 expression in human breast cancer and normal breast tissue both at the mRNA and protein level. METHOD: Using semiquantitative real-time PCR, cDNA dot-blot hybridisation and immunohistochemistry, we systematically analysed ISG15 expression in invasive breast carcinomas (n = 910) and normal breast tissues (n = 135). ISG15 protein expression was analysed in two independent cohorts on tissue microarrays; in an initial evaluation set of 179 breast carcinomas and 51 normal breast tissues; and in a second large validation set of 646 breast carcinomas and 10 normal breast tissues. In addition, a collection of benign and malignant mammary cell lines (n = 9) were investigated for ISG15 expression. RESULTS: ISG15 was overexpressed in breast carcinoma cells compared with normal breast tissue, both at the RNA and protein level. Recurrence-free (p = 0.030), event-free (p = 0.001) and overall (p = 0.001) survival analyses showed a significant correlation between ISG15 overexpression and unfavourable prognosis. CONCLUSION: Therefore, ISG15 may represent a novel breast tumour marker with prognostic significance and may be helpful in selecting patients for and predicting response to the treatment of human breast cancer

Headache and migraine in children with sickle cell disease are associated with lower hemoglobin and higher pain event rates but not silent cerebral infarction

OBJECTIVE: To identify risk factors for headache and migraine in children with sickle cell disease and test the hypothesis that either or both are independently associated with silent cerebral infarcts.STUDY DESIGN: In this cross-sectional study, we evaluated the health history, laboratory values, and brain magnetic resonance imaging findings of participants with sickle cell disease (hemoglobinSS or hemoglobinSβ°-thalassemia) with no history of overt stroke or seizures. Participants characterized headache severity and quality. Migraine was defined by International Headache Society criteria modified for increased sensitivity in children. Neuroradiology and neurology committees adjudicated the presence of silent cerebral infarction by review of magnetic resonance imaging and standardized examination by pediatric neurologists.RESULTS: The cohort included 872 children (51.1% males), ranging in age from 5 to 15 years (mean age, 9.1 years). Of these children, 317 (36.4%) reported recurrent headaches, and 132 (15.1%) reported migraines. In multivariable logistic regression analyses, both were associated with lower steady-state hemoglobin (P = .01 for headaches; P &lt; .01 for migraines) and higher pain rate (P &lt; .01 for headaches; P &lt; .01 for migraines), defined as the number of admissions requiring opioids in the previous 3 years. The presence of silent cerebral infarction was not associated with recurrent headaches or migraines. Only 1.9% (6 of 317) of children with recurrent headaches received medication for headache prophylaxis.CONCLUSION: Recurrent headaches and migraines are common and undertreated in children with sickle cell disease. Low hemoglobin levels and high pain rates are associated with recurrent headaches and migraines; whereas, silent cerebral infarction is not.</p

Acute silent cerebral ischemia occurs more frequently than silent cerebral infarction in children with sickle cell anemia

Background: Children with sickle cell anemia (HbSS) are at high risk of overt stroke and clinically silent cerebral infarction (SCI). SCI is an infarct-like lesion visualized on magnetic resonance imaging (MRI) of the brain that produces no corresponding motor or sensory deficits. The prevalence of SCI in HbSS is approximately 20 – 30% by 16 years of age, but less is known about its incidence. The Cooperative Study of Sickle Cell Disease (CSSCD) found the incidence of new or more extensive SCI in children with HbSS to be 7 events per 100 patient-years. Given that SCI is clinically silent, the only way to determine its incidence (the number of new events occurring in a specific time-period) is to screen with two sequential MRIs of the brain. MRI can also detect acute cerebral ischemia in asymptomatic patients using diffusion-weighted imaging (DWI). The incidence of acute silent cerebral ischemic events (ASCIEs) is not known. A clinical trial setting provides a unique opportunity to determine the incidence of ASCIEs and SCI in children with HbSS.Objectives: To determine the incidence rates of (1) ASCIEs in children with HbSS without prior evidence of focal neurological deficits and (2) new, recurrent SCI in children with HbSS who have pre-existing SCI.Methods: We studied a cohort of children with HbSS and sickle-β0-thalassemia who had brain MRIs for the Silent Infarct Transfusion Trial. All participants had no prior history of overt stroke, seizures, or transient ischemic attacks. ASCIE was defined as an infarct-like lesion on brain MRI without corresponding motor or sensory deficits that appeared as a focus of T2 hyperintensity with restricted diffusion on DWI sequences. SCI was defined an infarct-like lesion without corresponding motor or sensory deficits that appeared as a focus of T2 hyperintensity without restricted diffusion. Given that acute cerebral ischemia appears as a focus of restricted diffusion on DWI for 10 days, we assumed that each MRI scan provided 10 patient-days of observation for detecting ASCIE. Therefore, the incidence of ASCIEs was calculated using a single MRI per patient. The incidence of new or more extensive SCI in children with pre-existing SCI was determined in those who had two MRIs each (screening and pre-randomization). We statistically compared the incidence rates of ASCIEs and SCI obtained by these two different methods. For all ASCIEs and new SCI events, a medical history tool was completed at the local site at the time of MRI of the brain.Results: In total, 972 MRIs were studied (745 screening, 227 pre-randomization). There were 844 MRIs with DWI sequences, providing 23.1 patient-years of observation in 640 children (52% male; mean age 9.7 years). ASCIEs were detected on 1.2% (10 of 844 MRIs), corresponding to an incidence of 43.3 (95% CI: 20.7 – 79.6) events per 100 patient-years. Nine of the 10 ASCIEs were detected incidentally; 1 ASCIE occurred in a participant who was recovering from a recent episode of acute chest syndrome (onset 5 days before MRI) complicated by severe anemia and hypertension. Standard neurological examination was normal in all cases. Two of the 10 participants with ASCIEs had follow-up MRIs of the brain 4 to 10 months later; one had SCI in the same location as the previously detected acute ischemia, but the other had no residual lesion in the same location. Thus, not all ASCIEs produce detectable SCI. A total of 220 participants (55% male; mean age 10.0 years) had both screening and pre-randomization MRIs. The mean interval between the two MRIs was 124.3 days (range: 14 – 645), providing 74.9 patient-years of observation. All screening MRIs showed baseline SCI. New, recurrent SCI was detected on pre-randomization MRI in 8 participants, corresponding to an incidence of 10.7 events per 100 patient-years (95% CI: 4.6 – 21.0). The incidence of ASCIEs was 4-fold higher than recurrent SCI (43.2 vs. 10.7 events per 100 patient-years; P=0.001).Conclusions: The incidence of recurrent SCI was similar to CSSCD findings. However, we show that children with HbSS experience acute cerebral ischemic events far more frequently than previously recognized. These acute ischemic events are mostly clinically silent, potentially reversible radiographically, and not associated with antecedent medical events

Predicting Recovery and Outcome after Pediatric Stroke: Results from the International Pediatric Stroke Study.

OBJECTIVE To characterize predictors of recovery and outcome following pediatric arterial ischemic stroke, hypothesizing that age influences recovery after stroke. METHODS We studied children enrolled in the International Pediatric Stroke Study between January 1, 2003 and July 31, 2014 with 2-year follow-up after arterial ischemic stroke. Outcomes were defined at discharge by clinician grading and at 2 years by the Pediatric Stroke Outcome Measure. Demographic, clinical, and radiologic outcome predictors were examined. We defined changes in outcome from discharge to 2 years as recovery (improved outcome), emerging deficit (worse outcome), or no change. RESULTS Our population consisted of 587 patients, including 174 with neonatal stroke and 413 with childhood stroke, with recurrent stroke in 8.2% of childhood patients. Moderate to severe neurological impairment was present in 9.4% of neonates versus 48.8% of children at discharge compared to 8.0% versus 24.7% after 2 years. Predictors of poor outcome included age between 28 days and 1 year (compared to neonates, odds ratio [OR] = 3.58, p < 0.05), underlying chronic disorder (OR = 2.23, p < 0.05), and involvement of both small and large vascular territories (OR = 2.84, p < 0.05). Recovery patterns differed, with emerging deficits more common in children <1 year of age (p < 0.05). INTERPRETATION Outcomes after pediatric stroke are generally favorable, but moderate to severe neurological impairments are still common. Age between 28 days and 1 year appears to be a particularly vulnerable period. Understanding the timing and predictors of recovery will allow us to better counsel families and target therapies to improve outcomes after pediatric stroke. ANN NEUROL 2020;87:840-852

Acute Silent Cerebral Ischemic Events in Children With Sickle Cell Anemia

Background: Irregular, sporadic episodes of ischemic brain injury are known to occur in sickle cell anemia (SCA), resulting in overt stroke and silent cerebral infarction. Ongoing ischemia in other organs is common in SCA but has never been documented in the brain. Objective: To test the hypothesis that acute silent cerebral ischemic events (ASCIEs) are frequent and potentially transient. Design: Cross-sectional and cohort study of children with SCA screened by magnetic resonance imaging (MRI) of the brain for a randomized clinical trial. Setting: Clinical trial setting in tertiary care centers. Patients: Asymptomatic children with SCA without known stroke, neurologic injury, or epilepsy not receiving treatment with transfusions or hydroxyurea. Main Outcome Measure: Incidence of ASCIEs calculated using single diffusion-weighted MRI scans (acute ischemic events that occurred within 10 days of the MRI). Results: Acute silent cerebral ischemic events were detected on 1.3% of MRIs (10 of 771) in 652 children (mean age, 10.0 years), with an incidence of 47.3 events per 100 patient-years (95% CI, 22.7-87.2). Two of 10 children with ASCIEs had follow-up MRIs of the brain; only 1 had silent cerebral infarction in the same location as the previously detected ASCIE. Conclusions: Children with SCA experience ongoing (chronic, intermittent) cerebral ischemia, sometimes reversible, far more frequently than previously recognized. The brain in SCA is at constant threat of ischemia.</p