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PDF file, 60KB, Clinical characteristics of GBM tissue microarray.

PDF file, 84KB, Antibodies used for western analysis and subclassification of human glioblastoma stem-like cells.

PDF file, 78KB, Antibodies used for immunohistochemical analysis of human glioblastoma stem-like cell induced mouse xenograft tumors and grade IV astrocytoma tissue microarray.

PDF file, 80KB, Differential neural lineage marker expression associate with survivability of GSC-induced xenografts in immunodeficient mice.

Purpose: Glioblastoma multiforme (GBM) is a poorly treated human brain cancer with few established clinically useful molecular prognostic markers. We characterized glioblastoma stem–like cells (GSC) according to developmental neural lineage markers and correlated their expression with patient survival.Experimental Design: Immunoblot array of neural lineage markers classified five independently isolated human GSC lines into three classes exhibiting differential expression of oligodendrocyte progenitor cells (OPC), astrocyte progenitor cells (APC), and neural progenitor cells (NPC) markers. Immunodeficient mice were orthotopically implanted with each cell line to evaluate tumor infiltration and recipient survival. 2′,3′-Cyclic-nucleotide 3′-phosphodiesterase (CNP) antigenic expression was used to evaluate a clinically annotated GBM tissue microarray with 115 specimens.Results: We report that molecular classification of patient-derived GSCs using neural lineage markers show association with differential xenograft invasiveness, and also show significant correlation to survival in both the mouse model and human patients. Orthotopic implantation into immunodeficient mice showed Ki-67 proliferative index independent xenograft infiltration: class I GSCs (OPC and NPC positive) established focal lesions, class II GSCs (NPC positive) formed minimally invasive lesions, and class III GSCs (APC positive) established highly infiltrative lesions. The OPC marker, CNP also exhibited high expression in focal xenografts versus low expression in invasive xenografts. Differential CNP expression correlated with mouse model survival, and CNP immunoassay of a large GBM tissue microarray also showed significant differential patient survival.Conclusions: GSC classification with developmental neural lineage markers revealed CNP as a novel and potentially useful clinical prognosis marker, and suggests clinical importance for patient-specific GSC analysis. Clin Cancer Res; 18(13); 3628–36. ©2012 AACR.

PDF file, 327KB, Low and high magnification histology and IHC of differential tumor infiltration in mouse xenografts.

PDF file, 91KB.

Guidelines recommend surveillance after resection of colorectal cancer (CRC), but rates of adherence to surveillance are variable and have not been studied at National Cancer Institute (NCI)‐designated Comprehensive Cancer Centers. The aim of this study was to determine rates of adherence to standard postresection CRC surveillance recommendations including physician visits, carcinoembryonic antigen (CEA), computed tomography (CT), and colonoscopy after CRC resection at three NCI‐designated centers. Data on patients with resected CRC from 2010 to 2017 were reviewed. Adherence to physician visits was defined as having at least two visits within 14 months after surgical resection. CEA adherence was defined as having at least four CEA levels drawn within 14 months. CT and colonoscopy adherence were defined as completing each between 10 and 14 months from surgical resection. Chi‐square test and logistic regression analyses were performed for overall adherence and adherence to individual components. A total of 241 CRC patients were included. Overall adherence was 23%. While adherence to physician visits was over 98%, adherence to CEA levels, CT, and colonoscopy were each less than 50%. Center was an independent predictor of adherence to CEA, CT, and/or colonoscopy. Stage III disease predicted CT adherence, while distance traveled of 40 miles or less predicted colonoscopy adherence. Overall adherence to postresection CRC guideline‐recommended care is low at NCI‐designated centers. Adherence rates to surveillance vary by center, stage, and distance traveled for care. Understanding factors associated with adherence is critical to ensure CRC patients benefit from postresection surveillance.

Bevacizumab (BEV) is a common treatment for recurrent glioblastoma (GBM). After progression on BEV, there is no consensus on subsequent therapy, as multiple chemotherapy trials have failed to demonstrate discernible activity for salvage. A previous review (995 patients) estimated a progression free survival (PFS) on BEV of 4.2 months (SD±2.1) with an overall survival (OS) after progression on BEV at 3.8 months (SD +/− 1). We endeavored to establish a more rigorous historical control, both as a benchmark for efficacy, and a prognostic tool for clinical practice. A comprehensive literature review was performed utilizing PubMed and societal presentation abstracts. A total 2388 patients from 53 arms of 42 studies were analyzed in three groups: 1) thirty-two studies in which survival post-BEV was determined by subtracting PFS from OS (2045 patients): PFS on BEV =4.38 months (95% CI 4.09–4.68); OS post-BEV =3.36 months (95% CI 3.12–3.66); 2) two studies (94 patients) in which OS post-BEV is reported: OS= 3.26 (95% CI 2.39–4.42); 3) eight studies of salvage therapy after progression on BEV (249 patients): of OS post-BEV =4.46 months (95% CI 3.68–5.54). These estimates provide a firm historical control for PFS on BEV, as well as OS after disease progression on BEV therapy.

Purpose: Glioblastoma multiforme (GBM) is a poorly treated human brain cancer with few established clinically useful molecular prognostic markers. We characterized glioblastoma stem–like cells (GSC) according to developmental neural lineage markers and correlated their expression with patient survival. Experimental Design: Immunoblot array of neural lineage markers classified five independently isolated human GSC lines into three classes exhibiting differential expression of oligodendrocyte progenitor cells (OPC), astrocyte progenitor cells (APC), and neural progenitor cells (NPC) markers. Immunodeficient mice were orthotopically implanted with each cell line to evaluate tumor infiltration and recipient survival. 2′,3′-Cyclic-nucleotide 3′-phosphodiesterase (CNP) antigenic expression was used to evaluate a clinically annotated GBM tissue microarray with 115 specimens. Results: We report that molecular classification of patient-derived GSCs using neural lineage markers show association with differential xenograft invasiveness, and also show significant correlation to survival in both the mouse model and human patients. Orthotopic implantation into immunodeficient mice showed Ki-67 proliferative index independent xenograft infiltration: class I GSCs (OPC and NPC positive) established focal lesions, class II GSCs (NPC positive) formed minimally invasive lesions, and class III GSCs (APC positive) established highly infiltrative lesions. The OPC marker, CNP also exhibited high expression in focal xenografts versus low expression in invasive xenografts. Differential CNP expression correlated with mouse model survival, and CNP immunoassay of a large GBM tissue microarray also showed significant differential patient survival. Conclusions: GSC classification with developmental neural lineage markers revealed CNP as a novel and potentially useful clinical prognosis marker, and suggests clinical importance for patient-specific GSC analysis. Clin Cancer Res; 18(13); 3628–36. ©2012 AACR.

Diabet. Med. 29, 212–219 (2012) Abstract Aims In cohort studies, Type 2 diabetes mellitus has been associated with decreased forced 1 s expiratory volume and forced vital capacity. We examined if forced vital capacity, forced 1 s expiratory volume and diffusion lung capacity correlate with diabetes mellitus across different races in a clinical setting. Methods We examined the medical records of 19 882 adults 18–97 years of age in our centre from 1 January 2000 to 1 May 2009. After excluding patients with diseases causing abnormal lung function, 4164 subjects were available for analysis. We used multiple linear regressions to examine cross-sectional differences in forced vital capacity, forced 1 s expiratory volume and carbon monoxide diffusing capacity between patients with and without diabetes mellitus, after adjustment for age, age2, sex, race, height, height2, smoking, BMI and heart failure. Results Patients with diabetes (n = 560) were older (62 ± 12 vs. 55 ± 16 years), more likely to be men (56 vs. 43%), overweight (BMI 31.7 ± 8.5 vs. 27.3 ± 6.7 kg/m2), have heart failure (33 vs. 14%) and less likely to be Caucasians (65 vs. 76%) and never smokers (66 vs. 72%) compared with patients without diabetes (n = 3604). The mean unadjusted values in patients with diabetes vs. those without were: forced vital capacity 2.78 ± 0.91 vs. 3.19 ± 1.03 l; forced 1 s expiratory volume 2.17 ± 0.74 vs. 2.49 ± 0.0.83 l; and carbon monoxide diffusing capacity 16.67 ± 5.53 vs. 19.18 ± 6.72 ml−1 min−1 mmHg, all P

Among 4164 patients, those with type 2 diabetes mellitus (DM) had lower lung diffusion capacity (DLCO) compared with those without DM (DLCO mean±SE: 15.7±0.3 vs. 17.0±0.2 mL/min/mm Hg, p0.01). Reduced DLCO predicted hospitalization for pneumonia independent of diabetes control, severity and co-morbidities (OR=2.4, CI 1.08-5.31).

BACKGROUND: Time studies, first developed in the late 19th century, are now being used to evaluate and improve worker efficiency in the hospital setting. This is the first review of hospital time study literature of which we are aware. PURPOSE: We performed a systematic review of the literature to better understand the available time study literature describing the activities of hospital physicians. DATA SOURCES: We searched MEDLINE, EMBASE, EMBASE Classic, PsycINFO, Cochrane Library, CINAHL, and Web of Science. We also manually reviewed the reference lists of retrieved articles and consulted experts in the field to identify additional articles for review. STUDY SELECTION: We selected studies that used time-motion or work-sampling performed via direct observation, included physicians, medical residents, or interns in their study population, and were performed on an inpatient hospital ward. DATA EXTRACTION: We abstracted data on subject population, study site, collection tools, and percentage of time spent on key categories of activity. DATA SYNTHESIS: Our search produced 11 time-motion and 2 work-sampling studies that met our criteria. These studies focused primarily on academic hospitals (92%) and the activities of physicians in training (69%). Other results varied widely. A lack of methodological standardization and dissimilar activity categorizations inhibited our efforts to summarize detailed findings across studies. However, we consistently found that activities indirectly related to a patient's care took more of hospital physicians' time than direct interaction with hospitalized patients. CONCLUSIONS: Time studies, when properly performed, have a great deal to offer in helping us understand and reengineer hospital care. Journal of Hospital Medicine 2010;5:353–359. © 2010 Society of Hospital Medicine.

BACKGROUND: Within the last decade hospitalists have become an integral part of inpatient care in the United States and now care for about half of all Medicare patients requiring hospitalization. However, little data exists describing hospitalist workflow and their activities in daily patient care. OBJECTIVE: To clarify how hospitalists spend their time and how patient volumes affect their workflow. DESIGN: Observers continuously shadowed each of 24 hospitalists for two complete shifts. Observations were recorded using a handheld computer device with customized data collection software. SETTING: Urban, tertiary care, academic medical center. RESULTS: Hospitalists spent 17% of their time on direct patient contact, and 64% on indirect patient care. For 16% of all time recorded, more than one activity was occurring simultaneously (i.e., multitasking). Professional development, personal time, and travel each accounted for about 6% of their time. Communication and electronic medical record (EMR) use, two components of indirect care, occupied 25% and 34% of recorded time respectively. Hospitalists with above average patient loads spent less time per patient communicating with others and working with the EMR than those hospitalists with below average patient loads, but reported delaying documentation until later in the evening or next day. Patient load did not change the amount of time hospitalists spent with each patient. CONCLUSIONS: Hospitalists spend more time reviewing the EMR and documenting in it, than directly with the patient. Multi-tasking occurred frequently and occupied a significant portion of each shift. Journal of Hospital Medicine 2010;5:323–328. © 2010 Society of Hospital Medicine.

Glioblastoma multiforme (GBM) is a poorly treated human brain cancer with few established clinically useful molecular prognostic markers. GBM gene expression and microRNA profiling recently revealed developmental subtypes that potentially correlates with prognosis and treatment response. However, the clinically significant subset of glioblastoma stem-like cells (GSC) still lacks detailed molecular characterization and correlation to patient survival. We report that molecular classification of patient-derived GSCs using neural lineage markers show association with differential xenograft invasiveness, and also demonstrate significant correlation to survival in both the mouse model and human patients. Immunoblot array of neural lineage markers classified five independently isolated human GSC lines into three classes exhibiting differential expression of oligodendrocyte progenitor cells (OPC), astrocyte progenitor cells (APC), and neural progenitor cells (NPC) markers. After orthotopic injection into immunodeficient mice, Ki-67 proliferative index independent xenograft infiltration was observed: class I GSCs (OPC and NPC positive) created focal lesions, class II GSCs (NPC positive) formed minimally invasive lesions, and class III GSCs (APC positive) established highly infiltrative lesions. The OPC marker, cyclic nucleotide phosphodiesterase (CNP), exhibited high expression in focal xenografts versus low expression in invasive xenografts. Differential CNP expression significantly correlated with mouse model survival, and CNP assay of a large clinically annotated human GBM tissue microarray also showed differential patient survival. Therefore, GSC molecular characterization with neural lineage markers revealed a novel and potentially useful clinical prognosis marker, and suggests clinical importance for patient-specific GSC subtyping. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5344. doi:1538-7445.AM2012-5344