Duke Regional Hospital

OBJECTIVE: To determine mortality, morbidity, and costs attributable to surgical-site infections (SSIs) in the 1990s. DESIGN: A matched follow-up study of a cohort of patients with SSI, matched one-to-one with patients without SSI. SETTING: A 415-bed community hospital. STUDY POPULATION: 255 pairs of patients with and without SSI were matched on age, procedure, National Nosocomial Infection Surveillance System risk index, date of surgery, and surgeon. OUTCOME MEASURES: Mortality, excess length of hospitalization, and extra direct costs attributable to SSI; relative risk for intensive care unit (ICU) admission and for readmission to the hospital. RESULTS: Of the 255 pairs, 20 infected patients (7.8%) and 9 uninfected patients (3.5%) died during the postoperative hospitalization (relative risk [RR], 2.2; 95% confidence interval [CI95], 1.1-4.5). Seventy-four infected patients (29%) and 46 uninfected patients (18%) required ICU admission (RR, 1.6; CI95, 1.3-2.0). The median length of hospitalization was 11 days for infected patients and 6 days for uninfected patients. The extra hospital stay attributable to SSI was 6.5 days (CI95, 5-8 days). The median direct costs of hospitalization were $7,531 for infected patients and $3,844 for uninfected patients. The excess direct costs attributable to SSI were $3,089 (CI95, $2,139-$4,163). Among the 229 pairs who survived the initial hospitalization, 94 infected patients (41%) and 17 uninfected patients (7%) required readmission to the hospital within 30 days of discharge (RR, 5.5; CI95, 4.0-7.7). When the second hospitalization was included, the total excess hospitalization and direct costs attributable to SSI were 12 days and $5,038, respectively. CONCLUSIONS: In the 1990s, patients who develop SSI have longer and costlier hospitalizations than patients who do not develop such infections. They are twice as likely to die, 60% more likely to spend time in an ICU, and more than five times more likely to be readmitted to the hospital. Programs that reduce the incidence of SSI can substantially decrease morbidity and mortality and reduce the economic burden for patients and hospitals.

BACKGROUND: Bloodstream infections occurring in persons residing in the community, regardless of whether those persons have been receiving health care in an outpatient facility, have traditionally been categorized as community-acquired infections. OBJECTIVE: To develop a new classification scheme for bloodstream infections that distinguishes among community-acquired, health care-associated, and nosocomial infections. DESIGN: Prospective observational study. SETTING: One academic medical center and two community hospitals. PATIENTS: All adult patients admitted to the hospital with bloodstream infection. MEASUREMENTS: Demographic characteristics, living arrangements before hospitalization, comorbid medical conditions, factors predisposing to bloodstream infection, date of hospitalization, dates and number of positive blood cultures, results of microbiological susceptibility testing, dates of hospital discharge or death, and mortality rates at 3 to 6 months of follow-up. RESULTS: 504 patients with bloodstream infections were enrolled; 143 (28%) had community-acquired bloodstream infections, 186 (37%) had health care-associated bloodstream infections, and 175 (35%) had nosocomial bloodstream infections. Of the 186 patients with health care-associated bloodstream infection, 29 resided in a nursing home, 64 were receiving home health care, 78 were receiving intravenous or intravascular therapy at home or in a clinic, and 117 had been hospitalized in the 90 days before their bloodstream infection. Cancer was more common in patients with health care-associated or nosocomial bloodstream infection than in patients with community-acquired bloodstream infection. Intravascular devices were the most common source of health care-associated and nosocomial infections, and Staphylococcus aureus was the most frequent pathogen in these types of infections. Methicillin-resistant S. aureus occurred with similar frequency in the groups with health care-associated infection (52%) and nosocomial infection (61%) but was uncommon in the group with community-acquired bloodstream infection (14%) (P = 0.001). Mortality rate at follow-up was greater in patients with health care-associated infection (29% versus 16%; P = 0.019) or nosocomial infection (37% versus 16%; P < 0.001) than in patients with community-acquired infection. CONCLUSIONS: Health care-associated bloodstream infections are similar to nosocomial infections in terms of frequency of various comorbid conditions, source of infection, pathogens and their susceptibility patterns, and mortality rate at follow-up. A separate category for health care-associated bloodstream infections is justified, and this new category will have obvious implications for choices about empirical therapy and infection-control surveillance.

Data for 479 patients were analyzed to assess the impact of methicillin resistance on the outcomes of patients with Staphylococcus aureus surgical site infections (SSIs). Patients infected with methicillin-resistant S. aureus (MRSA) had a greater 90-day mortality rate than did patients infected with methicillin-susceptible S. aureus (MSSA; adjusted odds ratio, 3.4; 95% confidence interval, 1.5-7.2). Patients infected with MRSA had a greater duration of hospitalization after infection (median additional days, 5; P<.001), although this was not significant on multivariate analysis (P=.11). Median hospital charges were 29,455 dollars for control subjects, 52,791 dollars for patients with MSSA SSI, and 92,363 dollars for patients with MRSA SSI (P<.001 for all group comparisons). Patients with MRSA SSI had a 1.19-fold increase in hospital charges (P=.03) and had mean attributable excess charges of 13,901 dollars per SSI compared with patients who had MSSA SSIs. Methicillin resistance is independently associated with increased mortality and hospital charges among patients with S. aureus SSI.

OBJECTIVE: To report results of a randomized pilot clinical feasibility trial of endovascular cooling in patients with ischemic stroke. METHODS: Forty patients with ischemic stroke presenting within 12 hours of symptom onset were enrolled in the study. An endovascular cooling device was inserted into the inferior vena cava of those randomized to hypothermia. A core body temperature of 33 degrees C was targeted for 24 hours. All patients underwent clinical assessment and MRI initially, at days 3 to 5 and days 30 to 37. RESULTS: Eighteen patients were randomized to hypothermia and 22 to receive standard medical management. Thirteen patients reached target temperature in a mean of 77 +/- 44 minutes. Most tolerated hypothermia well. Clinical outcomes were similar in both groups. Mean diffusion-weighted imaging (DWI) lesion growth in the hypothermia group (n = 12) was 90.0 +/- 83.5% compared with 108.4 +/- 142.4% in the control group (n = 11) (NS). Mean DWI lesion growth in patients who cooled well (n = 8) was 72.9 +/- 95.2% (NS). CONCLUSIONS: Induced moderate hypothermia is feasible using an endovascular cooling device in most patients with acute ischemic stroke. Further studies are needed to determine if hypothermia improves outcome.

BACKGROUND: Open verdicts are often included in with suicides for research purposes and for setting health targets. AIMS: To examine similarities and differences in cases defined by the coroner as suicide and open verdicts and the implications of open verdicts for suicide research. METHOD: All cases of open and suicide verdicts recorded in the Newcastle Coroner's Court in the period 1985-1994 were compared on demographic and medical parameters. RESULTS: Open and suicide verdicts had many similarities, differing only in some respects, of which logistic regression identified the most significant to be a suicide note, method used and age. CONCLUSIONS: Open verdicts should be included in all suicide research after excluding cases in which suicide was unlikely. Objective criteria are needed to facilitate comparison between different studies.

A blinded, retrospective review of 83 soft-tissue masses (49 benign and 34 malignant) was performed to evaluate the ability to distinguish benign from malignant soft-tissue masses with magnetic resonance (MR) imaging. The correct histologic diagnosis was reached in 31% of cases by one reader and in 16% of cases by the second reader. Mean sensitivity was 50% for benign masses and 80% for malignant masses. The majority of both benign and malignant masses had inhomogeneous signal intensity and at least partially irregular borders. Malignant masses uncommonly had smooth borders and homogeneous signal intensity. MR imaging can be used to evaluate the extent of soft-tissue masses, but most masses will require biopsy to determine if they are benign or malignant.

OBJECTIVES: The effectiveness of an exercise intervention for people in early and midstage Parkinson's disease (stages 2 and 3 of Hoehn and Yahr) in improving spinal flexibility and physical performance in a sample of community-dwelling older people is described. DESIGN AND SETTING: Fifty-one men and women, aged 55-84 years, identified through advertisement, local support groups, and local neurologists were enrolled into a randomized, controlled trial. Subjects were assigned randomly to an intervention or a usual care arm (i.e., no specific exercise). Of the original 51 participants, 46 completed the randomized, controlled trial. Participants in the exercise arm (n = 23) received individual instruction three times per week for 10 weeks. Participants in the usual care arm (n = 23) were "wait listed" for intervention. MEASUREMENTS: Changes over 10 weeks in spinal flexibility (i.e., functional axial rotation) and physical performance (i.e., functional reach, timed supine to stand) were the primary outcome measures. RESULTS: MANOVA conducted for the three primary outcome variables demonstrated significant differences (P < or = .05) between the two groups. Further analysis using ANOVA demonstrated significant differences between groups in functional axial rotation and functional reach for the intervention compared with the control group. There was no significant difference in supine to sit time. CONCLUSION: Study results demonstrate that improvements in axial mobility and physical performance can be achieved with a 10-week exercise program for people in the early and midstages of PD.

OBJECTIVE: This study analyzed data from a national survey of Iraq and Afghanistan veterans to improve understanding of mental health services use and perceived barriers. METHODS: The National Post-Deployment Adjustment Survey randomly sampled post-9/11 veterans separated from active duty or in the Reserves or National Guard. The corrected response rate was 56% (N=1,388). RESULTS: Forty-three percent screened positive for posttraumatic stress disorder (PTSD), major depression, or alcohol misuse. Past-year psychiatric treatment was reported by 69% of the PTSD group, 67% of the depression group, and 45% of those with alcohol misuse. Most received care at Veterans Affairs (VA) facilities, although women were more likely than men to seek non-VA services. Veterans with more severe symptoms reported greater treatment utilization. Eighteen percent saw a pastoral counselor (chaplain) in the past year. Veterans with mental health needs who did not access treatment were more likely to believe that they had to solve problems themselves and that medications would not help. Those who had accessed treatment were more likely to express concern about being seen as weak by others. CONCLUSIONS: Veterans in greatest need were more likely to access services. More than two-thirds with probable PTSD obtained past-year treatment, mostly at VA facilities. Treatment for veterans may be improved by increasing awareness of gender differences, integrating mental health and pastoral services, and recognizing that alcohol misuse may reduce utilization. Veterans who had and had not used services endorsed different perceptions about treatment, indicating that barriers to accessing care may be distinct from barriers to engaging in care.

BACKGROUND: We aimed to assess the efficacy and safety of two neutralising monoclonal antibody therapies (sotrovimab [Vir Biotechnology and GlaxoSmithKline] and BRII-196 plus BRII-198 [Brii Biosciences]) for adults admitted to hospital for COVID-19 (hereafter referred to as hospitalised) with COVID-19. METHODS: In this multinational, double-blind, randomised, placebo-controlled, clinical trial (Therapeutics for Inpatients with COVID-19 [TICO]), adults (aged ≥18 years) hospitalised with COVID-19 at 43 hospitals in the USA, Denmark, Switzerland, and Poland were recruited. Patients were eligible if they had laboratory-confirmed SARS-CoV-2 infection and COVID-19 symptoms for up to 12 days. Using a web-based application, participants were randomly assigned (2:1:2:1), stratified by trial site pharmacy, to sotrovimab 500 mg, matching placebo for sotrovimab, BRII-196 1000 mg plus BRII-198 1000 mg, or matching placebo for BRII-196 plus BRII-198, in addition to standard of care. Each study product was administered as a single dose given intravenously over 60 min. The concurrent placebo groups were pooled for analyses. The primary outcome was time to sustained clinical recovery, defined as discharge from the hospital to home and remaining at home for 14 consecutive days, up to day 90 after randomisation. Interim futility analyses were based on two seven-category ordinal outcome scales on day 5 that measured pulmonary status and extrapulmonary complications of COVID-19. The safety outcome was a composite of death, serious adverse events, incident organ failure, and serious coinfection up to day 90 after randomisation. Efficacy and safety outcomes were assessed in the modified intention-to-treat population, defined as all patients randomly assigned to treatment who started the study infusion. This study is registered with ClinicalTrials.gov, NCT04501978. FINDINGS: Between Dec 16, 2020, and March 1, 2021, 546 patients were enrolled and randomly assigned to sotrovimab (n=184), BRII-196 plus BRII-198 (n=183), or placebo (n=179), of whom 536 received part or all of their assigned study drug (sotrovimab n=182, BRII-196 plus BRII-198 n=176, or placebo n=178; median age of 60 years [IQR 50-72], 228 [43%] patients were female and 308 [57%] were male). At this point, enrolment was halted on the basis of the interim futility analysis. At day 5, neither the sotrovimab group nor the BRII-196 plus BRII-198 group had significantly higher odds of more favourable outcomes than the placebo group on either the pulmonary scale (adjusted odds ratio sotrovimab 1·07 [95% CI 0·74-1·56]; BRII-196 plus BRII-198 0·98 [95% CI 0·67-1·43]) or the pulmonary-plus complications scale (sotrovimab 1·08 [0·74-1·58]; BRII-196 plus BRII-198 1·00 [0·68-1·46]). By day 90, sustained clinical recovery was seen in 151 (85%) patients in the placebo group compared with 160 (88%) in the sotrovimab group (adjusted rate ratio 1·12 [95% CI 0·91-1·37]) and 155 (88%) in the BRII-196 plus BRII-198 group (1·08 [0·88-1·32]). The composite safety outcome up to day 90 was met by 48 (27%) patients in the placebo group, 42 (23%) in the sotrovimab group, and 45 (26%) in the BRII-196 plus BRII-198 group. 13 (7%) patients in the placebo group, 14 (8%) in the sotrovimab group, and 15 (9%) in the BRII-196 plus BRII-198 group died up to day 90. INTERPRETATION: Neither sotrovimab nor BRII-196 plus BRII-198 showed efficacy for improving clinical outcomes among adults hospitalised with COVID-19. FUNDING: US National Institutes of Health and Operation Warp Speed.

The regeneration of sensory hair cells in lateral line neuromasts of axolotls was investigated via nearly continuous time-lapse microscopic observation after all preexisting hair cells were killed by a laser microbeam. The laser treatments left neuromasts with one resident cell type, which was supporting cells. Over the course of 1 week, replacement hair cells arose either directly via differentiation of cells present in the epithelium from the beginning of the time-lapse period or via the development of cells produced after one or two divisions of supporting cells. All of the cell divisions that produced hair cells were asymmetrical. During the first hour after the treatment, macrophages and smaller leukocytes were attracted to the laser-treated neuromasts. The smaller leukocytes returned to control levels 48-60 hr after the treatment, whereas macrophages remained active there throughout the period of hair cell replacement. Macrophage incidence peaked 36-48 hr after the laser treatment. Macrophages phagocytosed damaged hair cells and supporting cells, as well as new cells and preexisting cells without recognizable damage. The results provide direct evidence of hair cells arising as progeny produced from the divisions of supporting cells, evidence of hair cells and supporting cells arising from the same cell division, evidence relating to the timing of hair cell differentiation, and indirect evidence pertaining to proposals that hair cells sometimes arise via conversion of cells without an intervening division. The results also suggest that macrophages may influence early stages in the process of hair cell regeneration.

From the Department of Medicine, Emory University Medical School, Atlanta, Georgia * Present address: Department of Medicine, Duke Hospital, Durham, North Carolina.

Background: Our objective was to examine the variation in telemedicine adoption by specialty line and patient demographic characteristics after the initial peak period of the coronavirus disease 2019 pandemic when in-person visits had resumed and visit volume returned to prepandemic levels. Materials and Methods: Aggregated encounter data were extracted for six service lines (dermatology, psychiatry, endocrinology, cardiology, orthopedics, and nonurgent primary care) in an integrated health system across three time periods: July 1 to September 30, 2019 ( n = 239,803), July 1 to September 30, 2020 ( n = 245,648), and December 29, 2019 to October 3, 2020 ( n = 624,886). Risk ratios were calculated to assess the relative use of telemedicine compared with in-person encounters and telemedicine modality (i.e., synchronous audio/video vs. audio-only telephone) by patient race, age, sex, and insurance type. Results: By June 2020, total visit volume returned to prepandemic levels. Differences in patient demographics between July 1 to September 30, 2020 and the previous year's baseline were negligible. Telemedicine adoption varied by medical specialty, from 3.2% (dermatology) to 98.3% (psychiatry) of visits. African American and male patients were less likely to use telemedicine (telephone or video) compared with white and female patients. Among telemedicine encounters, African American, publicly insured, and older patients were less likely to use video compared with white, commercially insured, and younger patients. Discussion: Variation in telemedicine adoption and modality underscores the importance of balancing patient- and clinic-level implementation factors to promote sustainable, equitable telemedicine integration. Conclusion: Understanding current trends in the “new normal” of telemedicine provides valuable insights into future implementation and financing.

Opioid use has risen dramatically in the past three decades. In the USA, opioid overdose has become a leading cause of unintentional death, surpassing motor vehicle accidents. A patient's first exposure to opioids may be during the perioperative period, a time where anesthesiologists have a significant role in pain management. Almost all patients in the USA receive opioids during a surgical encounter. Opioids have many undesirable side effects, including potential for misuse, or opioid use disorder. Anesthesiologists and surgeons employ several methods to decrease unnecessary opioid use, opioid-related adverse events, and side effects in the perioperative period. Multimodal analgesia, enhanced recovery pathways, and regional anesthesia are key tools as we work towards optimal opioid stewardship and the ideal of effective analgesia without undesirable sequelae.

Background: Children with autism spectrum disorder (ASD) have urinary metabolites suggesting impairments in several pathways, including oxidative stress, inflammation, mitochondrial dysfunction, and gut microbiome alterations. Sulforaphane, a supplement with indirect antioxidant effects that are derived from broccoli sprouts and seeds, was recently shown to lead to improvements in behavior and social responsiveness in children with ASD. We conducted the current open-label study to determine if we could identify changes in urinary metabolites that were associated with clinical improvements with the goal of identifying a potential mechanism of action. Methods: Children and young adults enrolled in a school for children with ASD and related neurodevelopmental disorders were recruited to participate in a 12-week, open-label study of sulforaphane. Fasting urinary metabolites and measures of behavior (Aberrant Behavior Checklist-ABC) and social responsiveness (Social Responsiveness Scale-SRS) were measured at baseline and at the end of the study. Pearson's correlation coefficient was calculated for the pre- to post-intervention change in each of the two clinical scales (ABS and SRS) versus the change in each metabolite. Results: Fifteen children completed the 12-week study. Mean scores on both symptom measures showed improvements (decreases) over the study period, but only the change in the SRS was significant. The ABC improved - 7.1 points (95% CI - 17.4 to 3.2), and the SRS improved - 9.7 points (95% CI - 18.7 to - 0.8). We identified 77 urinary metabolites that were correlated with changes in symptoms, and they clustered into pathways of oxidative stress, amino acid/gut microbiome, neurotransmitters, hormones, and sphingomyelin metabolism. Conclusions: Urinary metabolomics analysis is a useful tool to identify pathways that may be involved in the mechanism of action of treatments targeting abnormal physiology in ASD. Trial registration: This study was prospectively registered at clinicaltrials.gov (NCT02654743) on January 11, 2016.

OBJECTIVE: To assess the efficacy and safety of the dopamine agonist cabergoline (CAB) in patients with restless legs syndrome (RLS). METHODS: Patients with moderate to severe RLS were randomized into four groups receiving placebo, 0.5 mg, 1 mg, or 2 mg CAB once daily in a double-blind, placebo-controlled, multicenter dose-finding trial followed by an open long-term extension trial of 47 weeks. Efficacy was assessed with the RLS-6 scales and International RLS Study Group severity scale (IRLS). RESULTS: A total of 85 patients (age 56 +/- 10 years, 71% females) were treated. Severity of RLS-6 scale symptoms during the night (the primary endpoint) was markedly improved by all CAB doses compared to placebo (placebo: -1.4 +/- 3.1, 0.5 mg CAB: -4.2 +/- 3.0 [p = 0.0082], 1.0 mg CAB: -4.0 +/- 2.9 [p = 0.0040], 2.0 mg CAB: -4.8 +/- 3.7 [p = 0.0026]). Similar results were found for the RLS severity at bedtime and during the day, IRLS, and satisfaction with sleep. A stable, clinically relevant improvement was achieved in all efficacy measures (severity during the night: change between last assessment and baseline: -5.6 +/- 2.5, rate of remission: 71.2%) throughout 1 year with a mean CAB dose of 2.2 mg per day. During long-term treatment, 6 of 66 treated patients were affected (n = 2) or possibly affected (n = 4) by mild augmentation. Under CAB therapy up to 1 year, 11 of 85 patients discontinued treatment due to a drug-related adverse event. CONCLUSIONS: Cabergoline is an efficacious and well-tolerated option for the treatment of restless legs symptoms during the night and the day.

Abstract Context. —The World Health Organization (WHO) recently published its 4th edition of the classification of tumors of the central nervous system, incorporating a substantial number of important changes to the previous version (WHO 2000). The new WHO classification introduces 7 changes in the grading of central nervous system neoplasms, ranging in significance from minor to major, in categories of anaplastic oligoastrocytomas, meningiomas, choroid plexus tumors, pineal parenchymal tumors, ganglioglioma, cerebellar liponeurocytoma, and hemangiopericytomas. The 4th edition also introduces 10 newly codified entities, variants, and patterns, as well as 1 new genetic syndrome. A number of established brain tumors are reorganized, including medulloblastomas and primitive neuroectodermal tumors, in an attempt to more closely align classification with current understanding of central nervous system neoplasia. Objective. —To summarize and discuss the most significant updates in the 4th edition for the practicing surgical pathologist, including (1) changes in grading among established entities; (2) newly codified tumor entities, variants, patterns, and syndromes; and (3) changes in the classification of existing brain tumors. Data Sources. —The primary source for this review is the WHO Classification of Tumours of the Central Nervous System, 4th edition. Other important sources include the 3rd edition of this book and the primary literature that supported changes in the 4th edition. Conclusions. —The new edition of the WHO blue book reflects advancements in the understanding of brain tumors in terms of classification, grading, and new entities. The changes introduced are substantial and will have an impact on the practice of general surgical pathologists and neuropathologists.

PURPOSE: Consensus recommendations to help ensure safe insulin use in hospitalized patients are presented. SUMMARY: Insulin products are frequently involved in medication errors in hospitals, and insulin is classified as a high-alert medication when used in inpatient settings. In an initiative to promote safer insulin use, the American Society of Health-System Pharmacists (ASHP) Research and Education Foundation convened a 21-member panel representing the fields of pharmacy, medicine, and nursing and consumer advocacy groups for a three-stage consensus-building initiative. The panel's consensus recommendations include the following: development of protocol-driven insulin order sets, elimination of the routine use of correction/sliding-scale insulin doses for management of hyperglycemia, restrictions on the types of insulin products stored in patient care areas, and policies to restrict the preparation of insulin bolus doses and i.v. infusions to the pharmacy department. In addition, the panelists recommended that hospitals better coordinate insulin use with meal intake and glucose testing, prospectively monitor the coordination of insulin delivery and rates of hypoglycemia and hyperglycemia, and provide standardized education and competency assessment for all hospital-based health care professionals responsible for insulin use. CONCLUSION: A 21-member expert panel convened by the ASHP Foundation identified 10 recommendations for enhancing insulin-use safety across the medication-use process in hospitals. Professional organizations, accrediting bodies, and consumer groups can play a critical role in the translation of these recommendations into practice. Rigorous research studies and program evaluations are needed to study the impact of implementation of these recommendations.

Tumors are complex collections of heterogeneous cells with recruited vasculature, inflammatory cells, and stromal elements. Neoplastic cells frequently display a hierarchy in differentiation status. Recent studies suggest that brain tumors have a limited population of neoplastic cells called cancer stem cells with the capacity for sustained self-renewal and tumor propagation. Brain tumor stem cells contribute to therapeutic resistance and tumor angiogenesis. In this minireview, we summarize recent data regarding critical signaling pathways involved in brain tumor stem cell biology and discuss how targeting these molecules may contribute to the development of novel anti-glioma therapies. Tumors are complex collections of heterogeneous cells with recruited vasculature, inflammatory cells, and stromal elements. Neoplastic cells frequently display a hierarchy in differentiation status. Recent studies suggest that brain tumors have a limited population of neoplastic cells called cancer stem cells with the capacity for sustained self-renewal and tumor propagation. Brain tumor stem cells contribute to therapeutic resistance and tumor angiogenesis. In this minireview, we summarize recent data regarding critical signaling pathways involved in brain tumor stem cell biology and discuss how targeting these molecules may contribute to the development of novel anti-glioma therapies. Cancers can be considered organ systems with aberrant activation of developmental and wound response pathways. Recent evidence suggests that within some tumors there is a cell subpopulation with the special capacity for sustained self-renewal and tumor propagation in vivo. Cells fulfilling these criteria were originally reported in acute myeloid leukemia (1Bhatia M. Wang J.C. Kapp U. Bonnet D. Dick J.E. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 5320-5325Crossref PubMed Scopus (727) Google Scholar), but similar populations were soon successively identified within various solid tumors (2Cho R.W. Clarke M.F. Curr. Opin. Genet. Dev. 2008; 18: 48-53Crossref PubMed Scopus (205) Google Scholar). The proper terminology regarding these cells remains unsettled, with most groups using terms such as CSCs, 2The abbreviations used are: CSCcancer stem cellNSCneural stem cellRTKreceptor tyrosine kinaseEGFRepidermal growth factor receptorBMPbone morphogenetic proteinBMPRBMP receptormiRNAmicroRNAVEGFvascular endothelial growth factor. tumor-initiating/propagating cells, and stem-like cancer cells. Although CSCs are a source of controversy, the concept recognizes the well described heterogeneity of tumor cells. Many critics contest the hypothesis on the grounds of a potential stem cell origin, challenge of current markers, or CSC frequency, none of which are implicit requirements of the CSC hypothesis (3Jordan C.T. Cell Stem Cell. 2009; 4: 203-205Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar). cancer stem cell neural stem cell receptor tyrosine kinase epidermal growth factor receptor bone morphogenetic protein BMP receptor microRNA vascular endothelial growth factor. Malignant gliomas are essentially universally lethal despite conventional therapy, with surgical resection and chemoradiation limited to palliation. Glioma CSCs were among the first solid tumor CSCs described (4Singh S.K. Hawkins C. Clarke I.D. Squire J.A. Bayani J. Hide T. Henkelman R.M. Cusimano M.D. Dirks P.B. Nature. 2004; 432: 396-401Crossref PubMed Scopus (6142) Google Scholar) and remain one of the most widely used CSC models. Glioma CSCs share significant similarities with normal NSCs, including the expression of stem cell markers (CD133, Nestin, Musashi, and Sox2) and the capacity to differentiate into multiple lineages (5Bao S. Wu Q. McLendon R.E. Hao Y. Shi Q. Hjelmeland A.B. Dewhirst M.W. Bigner D.D. Rich J.N. Nature. 2006; 444: 756-760Crossref PubMed Scopus (4948) Google Scholar), but the overlap is incomplete. Notably, glioma CSCs are also highly resistant to chemoradiotherapies (5Bao S. Wu Q. McLendon R.E. Hao Y. Shi Q. Hjelmeland A.B. Dewhirst M.W. Bigner D.D. Rich J.N. Nature. 2006; 444: 756-760Crossref PubMed Scopus (4948) Google Scholar, 6Ma S. Lee T.K. Zheng B.J. Chan K.W. Guan X.Y. Oncogene. 2008; 27: 1749-1758Crossref PubMed Scopus (661) Google Scholar), underscoring the importance of developing more efficient therapies against CSCs and prompting researchers to elucidate the molecular mechanisms regulating CSCs. Here, we summarize recent findings regarding the signaling pathways that are critical to glioma CSC biology. CSC behaviors are constantly affected by external signals from their niche, including neighboring stromal, immune, and non-stem tumor cells. Extracellular and paracrine effects are mediated commonly from cell-surface ligand-receptor systems. Accumulating evidence has demonstrated that multiple glioma CSC functions hinge on major receptor-mediated pathways (Fig. 1). The RTK family mediates the effects of multiple oncogenic growth factor pathways, among which the EGFR is one of the best characterized in gliomas. Malignant glioma cells frequently have increased EGFR signaling as a result of either amplified EGFR copy number or expression of the constitutively active variant EGFRvIII. Transduction of murine Nestin+ NSCs with EGFRvIII induces glioma-like lesions (7Bachoo R.M. Maher E.A. Ligon K.L. Sharpless N.E. Chan S.S. You M.J. Tang Y. DeFrances J. Stover E. Weissleder R. Rowitch D.H. Louis D.N. DePinho R.A. Cancer Cell. 2002; 1: 269-277Abstract Full Text Full Text PDF PubMed Scopus (550) Google Scholar). Similarly, a recent publication showed that the combination of AKT/phosphoinositide 3-hydroxykinase activation and constitutive EGFR activity is sufficient to transform murine NSCs (8Li L. Dutra A. Pak E. Labrie III, J.E. Gerstein R.M. Pandolfi P.P. Recht L.D. Ross A.H. Neuro-oncology. 2009; 11: 9-21Crossref PubMed Scopus (71) Google Scholar). Although the origin of glioma CSCs is under study (9Alcantara Llaguno S. Chen J. Kwon C.H. Jackson E.L. Li Y. Burns D.K. Alvarez-Buylla A. Parada L.F. Cancer Cell. 2009; 15: 45-56Abstract Full Text Full Text PDF PubMed Scopus (498) Google Scholar), these data suggest a possible role for EGFR pathways in glioma and possibly CSC biology. In cell culture studies, the proliferation and neurosphere generation (an in vitro assay to assess the self-renewal of CSCs) of human glioma CSCs were dependent on the EGFR (10Soeda A. Inagaki A. Oka N. Ikegame Y. Aoki H. Yoshimura S.-i. Nakashima S. Kunisada T. Iwama T. J. Biol. Chem. 2008; 283: 10958-10966Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar), like NSCs. The signal initiated by RTKs is transduced and amplified through downstream molecule cascades, such as the pro-survival AKT/phosphoinositide 3-hydroxykinase pathway. Upon activation by RTK pathways, AKT promotes survival, proliferation, invasion, and secretion of pro-angiogenic factors. We recently demonstrated that glioma CSCs are more dependent on AKT signals than matched non-stem glioma cells (54Eyler C.E. Foo W.C. LaFiura K.M. McLendon R.E. Hjelmeland A.B. Rich J.N. Stem Cells. 2008; 26: 3027-3036Crossref PubMed Scopus (203) Google Scholar). Pharmacologic inhibitors of AKT attenuate glioma CSC neurosphere formation, induce apoptosis, and substantially delay intracranial tumor formation. These data suggest that AKT inhibition may specifically target the CSC population to reduce tumor malignancy. BMPs are a family of growth factors named for their central roles in bone and cartilage formation (11Reddi A.H. Cytokine Growth Factor Rev. 1997; 8: 11-20Crossref PubMed Scopus (255) Google Scholar). Most BMPs elicit their actions through binding to cell-surface receptor kinases (the BMPRs). The canonical effectors of BMPRs are the Smad proteins. Activating phosphorylation of receptor Smad1/5/8 enables these proteins to bind to the co-activator Smad4, translocate into the nucleus, and regulate transcription. BMPs are crucial factors that regulate proliferation and apoptosis in NSCs and usually promote the differentiation of NSCs (12Panchision D.M. McKay R.D. Curr. Opin. Genet. Dev. 2002; 12: 478-487Crossref PubMed Scopus (172) Google Scholar). Interestingly, a prodifferentiation BMP response mechanism seems to be preserved in some glioma CSCs, as CSCs express BMPRs, and BMPs inhibit the proliferation of these cells (13Piccirillo S.G. Reynolds B.A. Zanetti N. Lamorte G. Binda E. Broggi G. Brem H. Olivi A. Dimeco F. Vescovi A.L. Nature. 2006; 444: 761-765Crossref PubMed Scopus (984) Google Scholar). BMP ligands deplete the CSC population by inducing the differentiation of CSCs into astroglial and neuron-like cells. Treating CSCs with BMPs in vivo markedly delays tumor growth and reduces tumor invasion. These data suggest that selective activation of BMP pathways may reduce the tumorigenic capacity of CSCs. Similar to the previous report, Lee et al. (14Lee J. Son M.J. Woolard K. Donin N.M. Li A. Cheng C.H. Kotliarova S. Kotliarov Y. Walling J. Ahn S. Kim M. Totonchy M. Cusack T. Ene C. Ma H. Su Q. Zenklusen J.C. Zhang W. Maric D. Fine H.A. Cancer Cell. 2008; 13: 69-80Abstract Full Text Full Text PDF PubMed Scopus (358) Google Scholar) reported that glioma CSCs differentiate upon BMP treatment. However, CSCs from one patient displayed enhanced proliferation rather than differentiation upon BMP treatment. This CSC sample displayed a fetal BMPR expression pattern due to epigenetic silencing of Bmpr1b. Restoration of BMPR1B expression sensitized CSCs to BMP-mediated differentiation, suggesting that the expression pattern of BMPR may determine BMP-mediated CSC behavior. Thus, an individual tumor's genomic and epigenetic characteristics may determine the response to anti-CSC treatment. The binding of Hedgehog ligands to their receptors activates transducers termed GLIs (named for their discovery in gliomas), which then translocate into the nucleus to activate or repress downstream targets. The Hedgehog pathway is one of the key regulators of embryogenesis and is critical for several different types of normal stem cells, including NSCs (15Park Y. Rangel C. Reynolds M.M. Caldwell M.C. Johns M. Nayak M. Welsh C.J. McDermott S. Datta S. Dev. Biol. 2003; 253: 247-257Crossref PubMed Scopus (137) Google Scholar, 16Wechsler-Reya R.J. Scott M.P. Neuron. 1999; 22: 103-114Abstract Full Text Full Text PDF PubMed Scopus (1074) Google Scholar). Mutations in the Hedgehog pathway are associated with medulloblastomas, primary brain tumors common in children, and several genetic medulloblastoma models incorporate aberrant Hedgehog signaling. Hedgehog signaling is also active in gliomas and contributes to CSC function (17Dahmane N. Sanchez P. Gitton Y. Palma V. Sun T. Beyna M. Weiner H. Ruiz i Altaba A. Development (Camb.). 2001; 128: 5201-5212PubMed Google Scholar, 18Clement V. Sanchez P. de Tribolet N. Radovanovic I. Ruiz i Altaba A. Curr. Biol. 2007; 17: 165-172Abstract Full Text Full Text PDF PubMed Scopus (913) Google Scholar, 19Bar E.E. Chaudhry A. Lin A. Fan X. Schreck K. Matsui W. Piccirillo S. Vescovi A.L. DiMeco F. Olivi A. Eberhart C.G. Stem Cells. 2007; 25: 2524-2533Crossref PubMed Scopus (530) Google Scholar). Hedgehog ligands are required for CSC self-renewal as well as tumorigenesis. Treatment of glioma CSCs with the Hedgehog inhibitor cyclopamine or transduction with GLI RNA interference inhibits proliferation and self-renewal while increasing apoptosis. The importance of Hedgehog signaling is further underscored by the observation that Hedgehog inhibition augments the efficacy of the standard-of-care chemotherapy agent temozolomide to abolish CSC proliferation and induce cell death. In vivo, Hedgehog pathway inhibition blocks CSC tumor growth (18Clement V. Sanchez P. de Tribolet N. Radovanovic I. Ruiz i Altaba A. Curr. Biol. 2007; 17: 165-172Abstract Full Text Full Text PDF PubMed Scopus (913) Google Scholar). Bar et al. (19Bar E.E. Chaudhry A. Lin A. Fan X. Schreck K. Matsui W. Piccirillo S. Vescovi A.L. DiMeco F. Olivi A. Eberhart C.G. Stem Cells. 2007; 25: 2524-2533Crossref PubMed Scopus (530) Google Scholar) also showed that cyclopamine treatment depletes CSCs, as viable cells after treatment failed to propagate tumors in vivo. In agreement with our study (5Bao S. Wu Q. McLendon R.E. Hao Y. Shi Q. Hjelmeland A.B. Dewhirst M.W. Bigner D.D. Rich J.N. Nature. 2006; 444: 756-760Crossref PubMed Scopus (4948) Google Scholar), they found that CSCs respond poorly to radiotherapy. However, cyclopamine treatment improves the effects of radiation on CSC survival (19Bar E.E. Chaudhry A. Lin A. Fan X. Schreck K. Matsui W. Piccirillo S. Vescovi A.L. DiMeco F. Olivi A. Eberhart C.G. Stem Cells. 2007; 25: 2524-2533Crossref PubMed Scopus (530) Google Scholar). Together, these data suggest that the Hedgehog pathway is important for glioma CSCs and that pharmacologic inhibitors may improve traditional therapy efficiency against gliomas. Notch proteins are single-pass transmembrane receptors that mediate cell-cell communication. Upon ligand binding, Notch is cleaved by the γ-secretase complex to release its intracellular domain from the cell membrane. Cleaved Notch translocates into the nucleus to function as a transcription factor. The importance of the Notch signaling pathway is evident by its high conservation throughout evolution. During development, Notch promotes the proliferation of normal NSCs while suppressing their differentiation (20Gaiano N. Fishell G. Annu. Rev. Neurosci. 2002; 25: 471-490Crossref PubMed Scopus (505) Google Scholar, 21Solecki D.J. Liu X.L. Tomoda T. Fang Y. Hatten M.E. Neuron. 2001; 31: 557-568Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar). Notch is required for neural progenitors both in vitro and in vivo (22Androutsellis-Theotokis A. Leker R.R. Soldner F. Hoeppner D.J. Ravin R. Poser S.W. Rueger M.A. Bae S.K. Kittappa R. McKay R.D. Nature. 2006; 442: 823-826Crossref PubMed Scopus (860) Google Scholar). Notch signaling has been implicated in brain tumor biology as well. Expression of Notch-1 and its ligands Delta-like-1 and Jagged-1 is critical to high grade gliomas and medulloblastomas (23Purow B.W. Haque R.M. Noel M.W. Su Q. Burdick M.J. Lee J. Sundaresan T. Pastorino S. Park J.K. Mikolaenko I. Maric D. Eberhart C.G. Fine H.A. Cancer Res. 2005; 65: 2353-2363Crossref PubMed Scopus (482) Google Scholar, 24Fan X. Mikolaenko I. Elhassan I. Ni X. Wang Y. Ball D. Brat D.J. Perry A. Eberhart C.G. Cancer Res. 2004; 64: 7787-7793Crossref PubMed Scopus (344) Google Scholar, 25Hallahan A.R. Pritchard J.I. Hansen S. Benson M. Stoeck J. Hatton B.A. Russell I.D. Cancer Res. 2004; 64: PubMed Scopus Google Scholar). The potential role of Notch signaling in brain tumor CSCs first in medulloblastomas, with CSCs high of Notch and to Notch pathway inhibitors X. Matsui W. L. D. J. Li Eberhart C.G. Cancer Res. 2006; PubMed Scopus Google Scholar). Notch functions were to glioma CSCs, as Notch signaling expression of the stem cell in gliomas. Notch expression in a lesions in the to glioma formation A.H. 2006; 8: PubMed Scopus Google Scholar). In activation of Notch signaling in the glioma cell the formation of Zheng G. L. Liu P. D.D. Zheng L. Zhang L. H. Chen Cell. 2008; PubMed Scopus Google Scholar). epigenetic and are regulators of normal cells and cancer cells. are of of multiple downstream and are implicated in glioma CSC survival, proliferation, and (Fig. 1). The has been for its role in the proliferation of both normal stem cells and tumor cells. stem cells were from cells through the of several transcription including K. S. Cell. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar), a role in stem cell may as a critical and malignancy. expression with the grade of in gliomas J. E. H.A. 1999; Full Text Full Text PDF PubMed Scopus (71) Google Scholar). We recently that glioma CSCs express of and that is required both for of glioma CSCs in vitro and for their tumorigenic capacity in vivo J. Wang H. Li Wu Q. McLendon R.E. Hjelmeland A.B. Rich J.N. 2008; PubMed Scopus Google Scholar). These data from human patient are by glioma models. of in of in tumors that human gliomas K.M. F. L. C. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). differentiation and promotes self-renewal of tumor from a H. H. H. D.J. Chen Perry G. K.L. R. You M.J. C. Wang Ligon K.L. L. DePinho R.A. Nature. 2008; PubMed Scopus Google Scholar). with and is to be a in the self-renewal and differentiation in stem cells. is also one of the factors that stem cells K. S. Cell. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). is highly in human glioma and cell and its expression with glioma grade D. Liu S. Wang F. Li G. Zhang Y. X. Hao A. 2008; Scopus Google Scholar). The role of in glioma CSCs is well but of in glioma cells the expression of the These data suggest that may inhibit the differentiation of glioma CSCs D. Liu S. Wang F. Li G. Zhang Y. X. Hao A. 2008; Scopus Google Scholar) and contribute to CSC is a transcription factor that is in the central During brain development, is in neural cells that to and Sun T. Ma N. M. Rowitch D.H. Cell. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, Chen Neuron. 2001; 31: Full Text Full Text PDF PubMed Scopus Google Scholar, H. S. M. H. R. M. Y. Dev. PubMed Scopus Google Scholar, Q. D.J. Cell. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). that is in and is required for tumor suggesting a to gliomas and CSCs K.L. J.A. J. Louis D.N. Rowitch D.H. J. 2004; PubMed Scopus Google Scholar, K.L. E. S. S. Liu H. J.A. R.M. M. Louis D.N. DePinho R.A. D.J. Rowitch D.H. Neuron. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). is required in both normal NSCs and glioma CSCs. the of neural progenitors and is for the differentiation potential of neural progenitors Q. D.J. Cell. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, S.K. Lee Ruiz Dev. 2005; PubMed Scopus (172) Google Scholar). function is mediated through the of glioma CSCs in through of K.L. E. S. S. Liu H. J.A. R.M. M. Louis D.N. DePinho R.A. D.J. Rowitch D.H. Neuron. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). to the which usually function as epigenetic has been implicated in stem cell in multiple and is a of self-renewal P. Cancer Cell. 2007; 12: Full Text Full Text PDF PubMed Scopus Google Scholar). is also a that is frequently in cancer including gliomas. cells from and researchers demonstrated that is required for both and NSCs S.W. D. E. T. M. J. M. Cancer Cell. 2007; 12: Full Text Full Text PDF PubMed Scopus Google Scholar). NSCs to high grade gliomas in vivo, NSCs are to tumors have cells the Nestin, that they may have CSCs. and NSCs of a role of in differentiation of normal and stem cells. Although remains is also critical for CSCs from human to CSCs from T. S. A. Aoki R. A. Y. Y. H. H. Iwama A. Cancer Res. 2008; PubMed Scopus Google Scholar). are that can target through mechanisms on target are intracellular regulators a can regulate In cancer can function as the or the to be important in glioma cell to be in and inhibition of its function induces apoptosis J.A. Cancer Res. 2005; 65: PubMed Scopus Google Scholar). recent the roles of in glioma CSCs. The of and are in grade and gliomas in with normal brain J. C. M. G. Alvarez-Buylla A. 2008; PubMed Scopus Google Scholar). of these inhibits proliferation while inducing differentiation of glioma CSCs, a tumor role for these in CSCs. Similarly, is in glioma CSCs in with non-stem glioma cells H. G. G. N. G. D. Res. 2008; PubMed Scopus Google Scholar). expression of inhibits the growth of glioma CSCs and neurosphere formation. The CSCs and their is CSCs signals from through receptors but also signals to the In this CSCs are to the that signals regulating CSCs. is the best of such (Fig. is a of solid tumors and a key role in and as well as Malignant gliomas are characterized by with with enhanced tumor of tumor and the importance of CSCs in glioma is that CSCs and are We showed in with matched non-stem cancer cells, glioma CSCs have a capacity for through amplified secretion of one of the most important pro-angiogenic factors S. Wu Q. S. Hao Y. Li Hjelmeland A.B. Shi Q. McLendon R.E. Bigner D.D. Rich J.N. Cancer Res. 2006; PubMed Scopus Google Scholar). Treating glioma CSCs with the their to promote both in vitro and in vivo, which in markedly inhibits the of CSCs. The mechanism the of in CSCs is but has been that factors such as and important roles in this also be by the of activation of EGFR result in high expression in gliomas. The pro-angiogenic of CSCs is critical for their and but also like normal NSCs, glioma CSCs are in normal NSCs and CSCs are to be in which regulate self-renewal and NSCs are in by the M. L. V. M. L. F. Cell Stem Cell. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar, Q. Wang Y. E. Lin G. S.K. S. Cell Stem Cell. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar), and this is by medulloblastoma CSCs C. H. M. C. M.W. D. M. A. S.S. A. A. R.J. Cancer Cell. 2007; 11: Full Text Full Text PDF PubMed Scopus Google Scholar). of CSCs and endothelial cells tumor and This and glioma CSCs may the of therapy on gliomas. of like and have demonstrated in A. J.E. J.A. Rich J.N. S. S. M. Bigner D.D. A.H. Cancer Res. 2007; 13: PubMed Scopus Google Scholar, E. Zhang Chen M. M. M.M. S. J. Louis D.N. P. T. Cancer Cell. 2007; 11: Full Text Full Text PDF PubMed Scopus Google Scholar). is possible that these the of CSCs, the of tumor The of glioma CSCs a of our of cancer biology. than a of neoplastic cells, gliomas to have a this glioma CSCs cells with an capacity for for anti-glioma therapies. glioma CSCs are also highly resistant to traditional the development of novel against CSCs an have been through recent studies of signaling pathways that are in CSCs and non-stem cancer cells. In to the signaling oncogenic signals protein kinase or tumor may important roles in glioma CSCs. CSCs may be more dependent on oncogenic signaling and targeting these may be a anti-CSC therapeutic to cancer cells but also a for the of CSCs. Thus, they may inhibit tumor growth in of and CSC inhibition by of vascular

Using a modification of the histologic grading system of the NSABP, we observed a trend towards higher levels of estrogen (E2R) and progesterone receptor (PR) content in well (grade I) and moderately (grade II) differentiated mammary carcinomas. This relationship between receptor content and histologic grade is enhanced by considering estrogen and progesterone receptor simultaneously. The rank correlation between the quantitative levels of E2R and PR was 0.74 among histologic grade I tumors and 0.64 among histologic grade II tumors. Among the grade III carcinomas, the majority of tumors displayed either a paucity of measurable receptor or a divergence between levels of estrogen versus progesterone receptor (r = 0.19). The use of ultrastructural evaluation of features of differentiation is discussed in the evaluation of grade III tumors and in the evaluation of specific histologic types of mammary carcinoma.

OBJECTIVE: To assess survival and functional outcome in patients endotracheally intubated after ischemic stroke (IS) or spontaneous intracerebral hemorrhage (ICH). BACKGROUND: Endotracheal intubation is both a necessary life support intervention and a measure of severity in IS or ICH. Knowledge of associated clinical variables may improve the estimation of early prognosis and guide management in these patients. METHODS: We reviewed 131 charts of patients with IS or ICH who were admitted to the Neurosciences Intensive Care Unit at Duke University Medical Center between July 1994 and June 1997 and required endotracheal intubation. Stroke risk factors, stroke type (IS or ICH) and location (hemispheric, brainstem, or cerebellum), circumstances surrounding intubation, neurologic assessment (Glasgow Coma Score [GCS] and brainstem reflexes), comorbidities, and disposition at discharge were documented. Survivors were interviewed for Barthel Index (BI) scores. RESULTS: Survival was 51% at 30 days and 39% overall. Variables that significantly correlated with 30-day survival in multivariate analysis included GCS at intubation (p = 0.03) and absent pupillary light response (p = 0.008). Increase in the GCS also correlated with improved functional outcome measured by the BI (p = 0.0003). In patients with IS, age and GCS at intubation predicted survival, and in patients with ICH, absent pupillary light response predicted survival. CONCLUSIONS: Predictors for mortality differ between patients with IS and ICH; however, decreased level of consciousness is the most important determinant of increased mortality and poor functional outcome. Absent pupillary light responses also correspond with a poor prognosis for survival, but further validation of this finding is needed.