Citations

Abstract This report describes results from our analysis of the activity and biodistribution of a novel pan-ERBB inhibitor, NT113, when used in treating mice with intracranial glioblastoma (GBM) xenografts. Approaches used in this investigation include: bioluminescence imaging (BLI) for monitoring intracranial tumor growth and response to therapy; determination of survival benefit from treatment; analysis of tumor IHC reactivity for indication of treatment effect on proliferation and apoptotic response; Western blot analysis for determination of effects of treatment on ERBB and ERBB signaling mediator activation; and high-performance liquid chromatography for determination of NT113 concentration in tissue extracts from animals receiving oral administration of inhibitor. Our results show that NT113 is active against GBM xenografts in which wild-type EGFR or EGFRvIII is highly expressed. In experiments including lapatinib and/or erlotinib, NT113 treatment was associated with the most substantial improvement in survival, as well as the most substantial tumor growth inhibition, as indicated by BLI and IHC results. Western blot analysis results indicated that NT113 has inhibitory activity, both in vivo and in vitro, on ERBB family member phosphorylation, as well as on the phosphorylation of downstream signaling mediator Akt. Results from the analysis of animal tissues revealed significantly higher NT113 normal brain-to-plasma and intracranial tumor-to-plasma ratios for NT113, relative to erlotinib, indicating superior NT113 partitioning to intracranial tissue compartments. These data provide a strong rationale for the clinical investigation of NT113, a novel ERBB inhibitor, in treating patients with GBM. Mol Cancer Ther; 13(12); 2919–29. ©2014 AACR.

Femoral ExtractionLaser and radiofrequency energy–assisted lead extraction has greatly facilitated this complex procedure. Although success rates are high, in some instances alternate methods of extraction are required. In this review, we discuss techniques for femoral extraction of implanted leads and retained fragments. The major tools available, including commonly used snares and delivery tools, are discussed. We briefly describe combined internal jugular and femoral venous extraction approaches, as well as complimentary utilization of more than one technique via the femoral vein. Animated and procedural sequences are included to help the reader visualize the key components of these techniques.

Background and purposeHereditary diffuse leukoencephalopathy with spheroids (HDLS) is a devastating, hereditary white matter (WM) disorder with heterogeneous neuropsychiatric features. Colony stimulating factor 1 receptor (CSF1R) mutations were looked for in primary progressive multiple sclerosis (PPMS) patients and the clinical features of a family with a novel CSF1R mutation are reported.MethodsCSF1R exons 12−22 in a cohort of 220 PPMS patients from the Swedish and Norwegian national multiple sclerosis registries were sequenced.ResultsOne patient had a novel mutation, c.2562T>A; p.Asn854Lys, in the CSF1R gene. Her symptoms started at the age of 29 years with insidious onset of pyramidal weakness in the left leg. The cerebrospinal fluid examination showed four intrathecal immunoglobulin G bands. A magnetic resonance imaging scan performed 4 years after symptom onset demonstrated patchy deep WM lesions. She was diagnosed as having PPMS and treated with intramuscular interferon beta 1a. Due to slow disease progression, the development of memory decline and cerebellar signs, she was given subcutaneous interferon beta 1a without any benefit. The updated pedigree indicated that five siblings also had the CSF1R gene mutation; one was diagnosed with PPMS. Six more distant relatives also had a neurological disorder; four were clinically diagnosed with PPMS.ConclusionsOur study indicates that a chronic course of HDLS may mimic PPMS. Genetic testing for CSF1R gene mutations in PPMS cases with a positive family history of neurological disorders may establish the diagnosis of HDLS.

BackgroundPast research has explored patients' expectations about the informed consent process. However, it is currently unknown if the complexity of the surgical procedure influences the type of anesthesia‐related risks that patients wish disclosed. This study explored fears of anesthesia‐related complications and whether these changed based on severity of surgery classification.MethodsPatients presenting to our pre‐operative evaluation clinic from February 2013 to May 2013 were asked to participate in a survey‐based study meant to evaluate their perception of five possible anesthetic risks (peripheral nerve injury, death, nausea and vomiting, heart attack and stroke) when confronted with differing levels of surgical severity.ResultsOne thousand surveys were administered, and 894 were returned for an overall response rate of 89%. Fear of death was the greatest concern as compared to the other risk factors independent of the severity of surgery. The level of fear for all risk factors, with the exception of stroke and heart attack, were dependent on the severity of surgery. Fear of death decreased as the severity of surgery decreased (major 46%, moderate 38%, minor 25%). For major surgery, the fear of perioperative death differed significantly with age (P < 0.001); specifically, with increasing age came a lessened fear of death.ConclusionAwareness by anesthesia providers of those fears that patients report may allow for a more personalized approach to providing information that may better allay anxiety. Further, these results may better tailor the informed consent process to one that meets particular patient concerns.

The characteristics of patients who use heroin, cocaine, or both and present with acute asthma exacerbations have not been well studied. In this retrospective study, we aimed to study the demographic characteristics of this patient population, the characteristics of their asthma attack, and the risk factors for the need for invasive mechanical ventilation in this patient population. We reviewed the charts of patients discharged from an inner-city hospital with a diagnosis of acute asthma exacerbation. Individuals who used either heroin or cocaine or both within 24 hours of presenting to the emergency department were identified as a cohort of drug users. The rest were classified as non–drug users. Both groups were compared, and a univariate analysis was performed. To assess the predictive value of drug use for the need for intubation in the presence of confounding factors, logistic regression analysis was performed to identify whether using cocaine or heroin or both was an individual predictor for the need for invasive ventilation. Data from 218 patients were analyzed. Drug users (n = 85) were younger (mean age in years 43.9 vs. 50.5, P < 0.01), predominantly male (63.5% vs. 33.8%, P < 0.01), and more likely to be cigarette smokers (90.6% vs. 57.6%, P < 0.01). A medical history of intubation and admissions to the intensive care unit (ICU) was more common among drug users (56.5% vs. 29.3%, P < 0.01 and 54.1% vs. 38.3%, P < 0.03, respectively). Drug use was associated with increased need for invasive mechanical ventilation (35% vs. 23.3%, P = 0.05). Non–drug users were more likely to be using inhaled corticosteroids (48.9% vs. 32.9%, P = 0.03) and had longitudinal care established with a primary care provider (50.6% vs. 68.9%, P < 0.01). After adjusting for a history of mechanical ventilation, history of ICU admission, use of systemic corticosteroids, smoking, and acute physiological assessment and chronic health evaluation 2 score, drug use remained predictive for the need for mechanical ventilation (P = 0.026). Acute asthma exacerbations triggered by cocaine and heroin should be treated aggressively because they represent a cohort with poor follow-up and undertreated asthma as outpatients and are associated with increased need for invasive mechanical ventilation and ICU admission during acute exacerbation.