Publications by authors named "Linda M S Resar"

58 Publications

Use of pegylated interferon in young patients with polycythemia vera and essential thrombocythemia.

Pediatr Blood Cancer 2021 Mar 31;68(3):e28888. Epub 2020 Dec 31.

Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.

Myeloproliferative neoplasms (MPN) are rare disorders in young patients, and because of this, standardized treatment recommendations are not available. Pediatric patients are more frequently treated with hydroxyurea than interferon, yet there are no data suggesting this is the best practice. Current treatment guidelines for adults suggest using interferon as upfront therapy in young patients. We reviewed the cases of 13 young patients with polycythemia vera or essential thrombocythemia, who were treated with interferon. Extreme thrombocytosis was well controlled and the medication was tolerated by many. Our work shows the need for prospective studies evaluating interferon in our youngest patients with MPN.
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http://dx.doi.org/10.1002/pbc.28888DOI Listing
March 2021

Inflammation exerts a nonrandom risk in the acquisition and progression of the MPN: Insights from a Mendelian randomization study.

EClinicalMedicine 2020 Apr 18;21:100324. Epub 2020 Apr 18.

Division of Adult Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States.

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http://dx.doi.org/10.1016/j.eclinm.2020.100324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7167502PMC
April 2020

High mobility group A1 (HMGA1) protein and gene expression correlate with ER-negativity and poor outcomes in breast cancer.

Breast Cancer Res Treat 2020 Jan 17;179(1):25-35. Epub 2019 Sep 17.

Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.

Purpose: The high mobility group A1 (HMGA1) chromatin remodeling protein is required for metastatic progression and cancer stem cell properties in preclinical breast cancer models, although its role in breast carcinogenesis has remained unclear. To investigate HMGA1 in primary breast cancer, we evaluated immunoreactivity score (IRS) in tumors from a large cohort of Asian women; HMGA1 gene expression was queried from two independent Western cohorts.

Methods: HMGA1 IRS was generated from breast tumors in Korean women as the product of staining intensity (weak = 1, moderate = 2, strong = 3) and percent positive cells (< 5% = 0, 5-30% = 1, 30-60% = 2, > 60% = 3), and stratified into three groups: low (< 3), intermediate (3-6), high (> 6). We assessed HMGA1 and estrogen receptor (ESR1) gene expression from two large databases (TCGA, METABRIC). Overall survival was ascertained from the METABRIC cohort.

Results: Among 540 primary tumors from Korean women (181 ER-negative, 359 ER-positive), HMGA1 IRS was < 3 in 89 (16.5%), 3-6 in 215 (39.8%), and > 6 in 236 (43.7%). High HMGA1 IRS was associated with estrogen receptor (ER)-negativity (χ = 12.07; P = 0.002) and advanced nuclear grade (χ = 12.83; P = 0.012). In two large Western cohorts, the HMGA1 gene was overexpressed in breast cancers compared to non-malignant breast tissue (P < 0.0001), including Asian, African American, and Caucasian subgroups. HMGA1 was highest in ER-negative tumors and there was a strong inverse correlation between HMGA1 and ESR1 gene expression (Pearson r = - 0.60, P < 0.0001). Most importantly, high HMGA1 predicted decreased overall survival (P < 0.0001) for all women with breast cancer and further stratified ER-positive tumors into those with inferior outcomes.

Conclusions: Together, our results suggest that HMGA1 contributes to estrogen-independence, tumor progression, and poor outcomes. Moreover, further studies are warranted to determine whether HMGA1 could serve as a prognostic marker and therapeutic target for women with breast cancer.
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http://dx.doi.org/10.1007/s10549-019-05419-1DOI Listing
January 2020

Approaches to Bloodless Surgery for Oncology Patients.

Hematol Oncol Clin North Am 2019 10 31;33(5):857-871. Epub 2019 Jul 31.

Department of Medicine (Hematology), Oncology & Institute for Cellular Engineering, The Johns Hopkins Medical Institutions, Center for Bloodless Medicine and Surgery, Ross Building Room 1015, 1800 Orleans Street, Baltimore, MD 21287, USA.

Providing optimal care to surgical oncology patients who cannot be transfused for religious or other reasons can be challenging. However, with careful planning, using a combination of blood-conserving methods, these "bloodless" patients have clinical outcomes that are similar to other patients who can be transfused. Bloodless surgery can be accomplished safely for most patients, including those undergoing technically challenging oncologic surgery. This article reviews best practices used in a bloodless program during the preoperative, intraoperative, and postoperative periods, with the aim of achieving optimal outcomes when transfusion is not an option for surgical oncology patients.
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http://dx.doi.org/10.1016/j.hoc.2019.05.009DOI Listing
October 2019

Genetic Engineering of Primary Mouse Intestinal Organoids Using Magnetic Nanoparticle Transduction Viral Vectors for Frozen Sectioning.

J Vis Exp 2019 05 10(147). Epub 2019 May 10.

Department of Medicine, Division of Hematology, Johns Hopkins University School of Medicine; Department of Oncology, Johns Hopkins University School of Medicine; Department of Pathology, Johns Hopkins University School of Medicine; Institute for Cell Engineering, Johns Hopkins University School of Medicine;

Intestinal organoid cultures provide a unique opportunity to investigate intestinal stem cell and crypt biology in vitro, although efficient approaches to manipulate gene expression in organoids have made limited progress in this arena. While CRISPR/Cas9 technology allows for precise genome editing of cells for organoid generation, this strategy requires extensive selection and screening by sequence analysis, which is both time-consuming and costly. Here, we provide a detailed protocol for efficient viral transduction of intestinal organoids. This approach is rapid and highly efficient, thus decreasing the time and expense inherent in CRISPR/Cas9 technology. We also present a protocol to generate frozen sections from intact organoid cultures for further analysis with immunohistochemical or immunofluorescent staining, which can be used to confirm gene expression or silencing. After successful transduction of viral vectors for gene expression or silencing is achieved, intestinal stem cell and crypt function can be rapidly assessed. Although most organoid studies employ in vitro assays, organoids can also be delivered to mice for in vivo functional analyses. Moreover, our approaches are advantageous for predicting therapeutic responses to drugs because currently available therapies generally function by modulating gene expression or protein function rather than altering the genome.
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http://dx.doi.org/10.3791/57040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7837413PMC
May 2019

Greater anemia tolerance among hospitalized females compared to males.

Transfusion 2019 08 7;59(8):2551-2558. Epub 2019 May 7.

Johns Hopkins Health System Blood Management Program, Department of Anesthesiology/Critical Care Medicine, Faculty, Armstrong Institute for Patient Safety and Quality, The Johns Hopkins Medical Institutions, Baltimore, Maryland.

Background: Although females have a lower baseline hemoglobin (Hb) compared to males, it is unknown whether females have a greater tolerance for anemia when hospitalized. We tested the hypothesis that females tolerate severe anemia better than males, with decreased inpatient mortality in this setting.

Study Design And Methods: We conducted a retrospective cohort study in 230,644 adult patients admitted to Johns Hopkins Hospital from January 2009 to June 2016. The relationships between nadir Hb and percentage change in Hb with inpatient mortality were assessed for nontransfused males and females. A multivariable logistic regression was used to determine risk-adjusted differences between males and females for the likelihood of inpatient mortality at nadir Hb levels of 5, 6, and 7 g/dL.

Results: Males had increased mortality when nadir Hb was 6.0 g/dL or less (p < 0.05), whereas females did not. The risk-adjusted likelihood for inpatient mortality was greater for males compared to females at a nadir Hb of 6 g/dL or less (odds ratio, 1.84; 95% confidence interval, 1.09-3.16) (p = 0.02), but this sex-related difference was not significant at a nadir Hb of 5 or 7 g/dL or less. Inpatient mortality increased significantly in both males and females when the percentage decrease in Hb was greater than 50% from baseline (p < 0.05).

Conclusions: Compared to males, females tolerate a lower nadir Hb, but a similar percentage change in Hb, before an increase in inpatient mortality is recognized. The findings suggest that females may be "preconditioned" to tolerate anemia better than males.
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http://dx.doi.org/10.1111/trf.15338DOI Listing
August 2019

Preoperative treatment of anemia and outcomes in surgical Jehovah's Witness patients.

Am J Hematol 2019 02 18;94(2):E55-E58. Epub 2018 Dec 18.

Division of Hematology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland.

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http://dx.doi.org/10.1002/ajh.25359DOI Listing
February 2019

PBOV1 as a potential biomarker for more advanced prostate cancer based on protein and digital histomorphometric analysis.

Prostate 2018 05 9;78(7):547-559. Epub 2018 Mar 9.

Department of Urology, The James Buchanan Brady Urological Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland.

Background: There are few tissue-based biomarkers that can accurately predict prostate cancer (PCa) progression and aggressiveness. We sought to evaluate the clinical utility of prostate and breast overexpressed 1 (PBOV1) as a potential PCa biomarker.

Methods: Patient tumor samples were designated by Grade Groups using the 2014 Gleason grading system. Primary radical prostatectomy tumors were obtained from 48 patients and evaluated for PBOV1 levels using Western blot analysis in matched cancer and benign cancer-adjacent regions. Immunohistochemical evaluation of PBOV1 was subsequently performed in 80 cancer and 80 benign cancer-adjacent patient samples across two tissue microarrays (TMAs) to verify protein levels in epithelial tissue and to assess correlation between PBOV1 proteins and nuclear architectural changes in PCa cells. Digital histomorphometric analysis was used to track 22 parameters that characterized nuclear changes in PBOV1-stained cells. Using a training and test set for validation, multivariate logistic regression (MLR) models were used to identify significant nuclear parameters that distinguish Grade Group 3 and above PCa from Grade Group 1 and 2 PCa regions.

Results: PBOV1 protein levels were increased in tumors from Grade Group 3 and above (GS 4 + 3 and ≥ 8) regions versus Grade Groups 1 and 2 (GS 3 + 3 and 3 + 4) regions (P = 0.005) as assessed by densitometry of immunoblots. Additionally, by immunoblotting, PBOV1 protein levels differed significantly between Grade Group 2 (GS 3 + 4) and Grade Group 3 (GS 4 + 3) PCa samples (P = 0.028). In the immunohistochemical analysis, measures of PBOV1 staining intensity strongly correlated with nuclear alterations in cancer cells. An MLR model retaining eight parameters describing PBOV1 staining intensity and nuclear architecture discriminated Grade Group 3 and above PCa from Grade Group 1 and 2 PCa and benign cancer-adjacent regions with a ROC-AUC of 0.90 and 0.80, respectively, in training and test sets.

Conclusions: Our study demonstrates that the PBOV1 protein could be used to discriminate Grade Group 3 and above PCa. Additionally, the PBOV1 protein could be involved in modulating changes to the nuclear architecture of PCa cells. Confirmatory studies are warranted in an independent population for further validation.
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http://dx.doi.org/10.1002/pros.23499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5882516PMC
May 2018

HMGA1 amplifies Wnt signalling and expands the intestinal stem cell compartment and Paneth cell niche.

Nat Commun 2017 04 28;8:15008. Epub 2017 Apr 28.

Division of Hematology, Department of Medicine, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross Research Building, Room 1025, Baltimore, Maryland 21205, USA.

High-mobility group A1 (Hmga1) chromatin remodelling proteins are enriched in intestinal stem cells (ISCs), although their function in this setting was unknown. Prior studies showed that Hmga1 drives hyperproliferation, aberrant crypt formation and polyposis in transgenic mice. Here we demonstrate that Hmga1 amplifies Wnt/β-catenin signalling to enhance self-renewal and expand the ISC compartment. Hmga1 upregulates genes encoding both Wnt agonist receptors and downstream Wnt effectors. Hmga1 also helps to 'build' an ISC niche by expanding the Paneth cell compartment and directly inducing Sox9, which is required for Paneth cell differentiation. In human intestine, HMGA1 and SOX9 are positively correlated, and both become upregulated in colorectal cancer. Our results define a unique role for Hmga1 in intestinal homeostasis by maintaining the stem cell pool and fostering terminal differentiation to establish an epithelial stem cell niche. This work also suggests that deregulated Hmga1 perturbs this equilibrium during intestinal carcinogenesis.
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http://dx.doi.org/10.1038/ncomms15008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5414379PMC
April 2017

Hmga1 deficiency: "SAC-King" the SAC genes to incite chromosomal instability.

Cell Cycle 2017 01 15;16(1):17-18. Epub 2016 Dec 15.

a Department of Medicine , Johns Hopkins University School of Medicine , Baltimore , MD , USA.

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http://dx.doi.org/10.1080/15384101.2016.1214034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5270530PMC
January 2017

Bloodless medicine: current strategies and emerging treatment paradigms.

Transfusion 2016 Oct 29;56(10):2637-2647. Epub 2016 Jul 29.

Department of Anesthesiology/Critical Care Medicine, and the, Baltimore, Maryland.

Background: Advances in our understanding of the risks associated with allogeneic blood transfusions (ABTs) and the growing number of patients who wish to avoid ABTs have led to the emergence of new treatment paradigms for "bloodless" medicine and surgery.

Study Design And Methods: Here, we review prior studies and summarize current strategies for bloodless care used at our institution. We advocate three basic principles: 1) diagnosing and aggressively treating anemia, 2) minimizing blood loss from laboratory testing and invasive procedures, and 3) identifying and managing bleeding diatheses. Anemia is treated with erythropoiesis-stimulating agents as well as iron, folate, and B12 when indicated. Low-volume phlebotomy tubes are used for laboratory testing. Autologous blood salvage is used for childbirth and surgical patients who have the potential for substantial bleeding.

Results: Although there have been few retrospective studies and no prospective studies to guide management, prior studies suggest that outcomes for surgical patients managed without ABTs are comparable to those of historic controls.

Conclusions: Given the emerging evidence that patients who avoid ABTs do as well if not better than patients who accept ABTs, further efforts are needed to determine whether all patients could benefit from bloodless strategies. Bloodless approaches in selected patients could reduce risks, improve outcomes, and decrease costs for all patients.
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http://dx.doi.org/10.1111/trf.13736DOI Listing
October 2016

Patent foramen ovale in adults with sickle cell disease and stroke.

Am J Hematol 2016 09 20;91(9):E358-60. Epub 2016 Jul 20.

Hematology Division, the Johns Hopkins University School of Medicine, Baltimore, Maryland.

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http://dx.doi.org/10.1002/ajh.24440DOI Listing
September 2016

Ultramassive transfusion: give blood, save a life.

Transfusion 2016 Mar;56(3):546-8

Department of Medicine (Hematology), Oncology & Institute for Cellular Engineering, The Johns Hopkins Medical Institutions, Baltimore, MD.

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http://dx.doi.org/10.1111/trf.13403DOI Listing
March 2016

The Efficacy and Utility of Acute Normovolemic Hemodilution.

Anesth Analg 2015 Dec;121(6):1412-4

From the *Department of Anesthesiology/Critical Care Medicine and †Department of Medicine (Hematology), Oncology, and the Institute for Cellular Engineering, The Johns Hopkins Medical Institutions, Baltimore, Maryland.

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http://dx.doi.org/10.1213/ANE.0000000000000935DOI Listing
December 2015

Hemoglobin thresholds for transfusion in pediatric patients at a large academic health center.

Transfusion 2015 Dec 29;55(12):2890-7. Epub 2015 Sep 29.

Department of Pediatrics, the Johns Hopkins Medical Institutions, Baltimore, Maryland.

Background: Although prior studies support the use of a hemoglobin (Hb) transfusion trigger of 7 to 8 g/dL for most hospitalized adults, there are few studies in pediatric populations. We therefore investigated transfusion practices and Hb triggers in hospitalized children.

Study Design And Methods: We performed a historical cohort study comparing transfusion practices in hospitalized children by service within a single academic institution. Blood utilization data from transfused patients (n = 3370) were obtained from electronic records over 4 years. Hb triggers and posttransfusion Hb levels were defined as the lowest and last Hb measured during hospital stay, respectively, in transfused patients. The mean and percentile distribution for Hb triggers were compared to the evidence-based restrictive transfusion threshold of 7 g/dL.

Results: Mean Hb triggers were above the restrictive trigger (7 g/dL) for eight of 12 pediatric services. Among all of the services, there were significant differences between the mean Hb triggers (>2.5 g/dL, p<0.0001) and between the posttransfusion Hb levels (>3 g/dL, p < 0.0001). The variation between the 10th and 90th percentiles for triggers (up to 4 g/dL, p < 0.0001) and posttransfusion Hb levels (up to 6 g/dL, p < 0.0001) were significant. Depending on the service, between 25 and 90% of transfused patients had Hb triggers higher than the restrictive range.

Conclusions: Red blood cell (RBC) transfusion therapy varies significantly in hospitalized children with mean Hb triggers above a restrictive threshold for most services. Our findings suggest that transfusions may be overused and that implementing a restrictive transfusion strategy could decrease the use of RBC transfusions, thereby reducing the associated risks and costs.
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http://dx.doi.org/10.1111/trf.13296DOI Listing
December 2015

Through a Gender Lens: A View of Gender and Leadership Positions in a Department of Medicine.

J Womens Health (Larchmt) 2015 Oct 22;24(10):837-42. Epub 2015 Jul 22.

4 Division of Hematology, Departments of Medicine, Oncology, and Institute for Cellular Engineering, Johns Hopkins University School of Medicine , Baltimore, Maryland.

Background: Despite increasing numbers in academic medicine, women remain underrepresented in top leadership positions. The objectives of this study were to characterize leadership positions held by department of medicine (DOM) faculty at all ranks at one Academic Health Center and to compare leadership positions held by male and female faculty.

Methods: This was a cross-sectional survey to collect information on all leadership positions from 16 divisions in the DOM at the Johns Hopkins University School of Medicine in early 2012, including type of position, method used to fill the position, and financial compensation. Chi-square testing was used to compare leadership position characteristics by rank and gender.

Results: The study included 474 DOM faculty at the rank of instructor or higher; 38% were women. Of the 258 leadership positions identified, 35% were held by women. More leadership positions among assistant professors were held by women compared with men (56% of positions vs. 44%), with women assistant professors more likely to hold a leadership position than men (p=0.03). Numbers of women faculty declined at higher ranks, with leadership positions remaining proportionate to faculty representation. Most division director positions (88%) were held by men, and most leadership positions were compensated (89%) and appointed by the DOM chair or a division director (80%).

Conclusions: Leadership positions held by women and men were proportionate to faculty representation, although the top leadership positions were held almost exclusively by men. While female assistant professors were more likely to hold leadership positions than male assistant professors, these positions appear to be low status positions and it is not clear that they contribute to professional advancement, as few women hold the rank of full professor. Effective interventions are needed to address the gender disparity in top leadership positions.
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http://dx.doi.org/10.1089/jwh.2014.5054DOI Listing
October 2015

Characterizing metabolic changes in human colorectal cancer.

Anal Bioanal Chem 2015 Jun 6;407(16):4581-95. Epub 2015 May 6.

Department of Chemistry, Washington State University, Pullman, WA, 99164, USA.

Colorectal cancer (CRC) remains a leading cause of cancer death worldwide, despite the fact that it is a curable disease when diagnosed early. The development of new screening methods to aid in early diagnosis or identify precursor lesions at risk for progressing to CRC will be vital to improving the survival rate of individuals predisposed to CRC. Metabolomics is an advancing area that has recently seen numerous applications to the field of cancer research. Altered metabolism has been studied for many years as a means to understand and characterize cancer. However, further work is required to establish standard procedures and improve our ability to identify distinct metabolomic profiles that can be used to diagnose CRC or predict disease progression. The present study demonstrates the use of direct infusion traveling wave ion mobility mass spectrometry to distinguish metabolic profiles from CRC samples and matched non-neoplastic epithelium as well as metastatic and primary tumors at different stages of disease (T1-T4). By directly infusing our samples, the analysis time was reduced significantly, thus increasing the speed and efficiency of this method compared to traditional metabolomics platforms. Partial least squares discriminant analysis was used to visualize differences between the metabolic profiles of sample types and to identify the specific m/z features that led to this differentiation. Identification of the distinct m/z features was made using the human metabolome database. We discovered alterations in fatty acid biosynthesis and oxidative, glycolytic, and polyamine pathways that distinguish tumors from non-malignant colonic epithelium as well as various stages of CRC. Although further studies are needed, our results indicate that colonic epithelial cells undergo metabolic reprogramming during their evolution to CRC, and the distinct metabolites could serve as diagnostic tools or potential targets in therapy or primary prevention. Graphical Abstract Colon tissue biopsy samples were collected from patients after which metabolites were extracted via sonication. Two-dimensional data were collected via IMS in tandem with MS (IMMS). Data were then interpreted statistically via PLS-DA. Scores plots provided a visualization of statistical separation and groupings of sample types. Loading plots allowed identification of influential ion features. Lists of these features were exported and analyzed for specific differences. Direct comparisons of the ion features led to the identification and comparative analyses of candidate biomarkers. These differences were then expressed visually in charts and tables.
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http://dx.doi.org/10.1007/s00216-015-8662-xDOI Listing
June 2015

How I treat priapism.

Blood 2015 Jun 25;125(23):3551-8. Epub 2015 Mar 25.

The James Buchanan Brady Urological Institute and Department of Urology, The Johns Hopkins University School of Medicine, Baltimore, MD;

Priapism is a disorder of persistent penile erection unrelated to sexual interest or desire. This pathologic condition, specifically the ischemic variant, is often associated with devastating complications, notably erectile dysfunction. Because priapism demonstrates high prevalence in patients with hematologic disorders, most commonly sickle cell disease (SCD), there is significant concern for its sequelae in this affected population. Thus, timely diagnosis and management are critical for the prevention or at least reduction of cavernosal tissue ischemia and potential damage consequent to each episode. Current guidelines and management strategies focus primarily on reactive treatments. However, an increasing understanding of the molecular pathophysiology of SCD-associated priapism has led to the identification of new potential therapeutic targets. Future agents are being developed and explored for use in the prevention of priapism.
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http://dx.doi.org/10.1182/blood-2014-09-551887DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4458797PMC
June 2015

IBRUTinib: BRUTe force against bortezomib-resistant myeloma cells.

Cell Cycle 2015 ;14(9):1349-50

a Department of Medicine ; The Johns Hopkins University School of Medicine , Baltimore , MD USA.

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http://dx.doi.org/10.1080/15384101.2015.1022058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4614695PMC
April 2016

Bloodless medicine: what to do when you can't transfuse.

Hematology Am Soc Hematol Educ Program 2014 Dec 18;2014(1):553-8. Epub 2014 Nov 18.

Department of Anesthesiology/Critical Care Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD.

A better understanding of risks associated with allogeneic blood transfusions (ABTs), along with a growing population of patients who do not accept transfusions, have led to the emergence of new treatment paradigms with "bloodless medicine." In this chapter, we review prior studies describing management and outcomes in patients who refuse transfusion (referred to as "bloodless patients" herein) and summarize the approaches used at our institution. Bloodless management for surgical patients includes treatment of preoperative anemia, use of autologous blood salvage, and minimizing blood loss with procedures. Other adjuncts for both medical and surgical patients include minimizing blood loss from laboratory testing using pediatric phlebotomy tubes and conservative testing. Anemia can be treated with erythropoiesis-stimulating agents, as well as iron, folate, and B12 when indicated. Although there are limited retrospective studies and no prospective studies to guide management, prior reports suggest that outcomes for surgical patients managed without ABTs are comparable to historic controls. A recent risk-adjusted, propensity-matched, case-control study of outcomes of all hospitalized patients who refused ABT at a large academic health center showed that bloodless management was not an independent predictor of adverse outcomes. Surprisingly, there was a lower overall mortality in the bloodless group and discharge hemoglobin levels were similar for both bloodless and control groups. Further research is now needed to optimize therapy and identify novel interventions to manage bloodless patients. Lessons learned from bloodless patients are likely to benefit all patients given recent evidence suggesting that patients who avoid ABTs do as well, if not better, than those who accept transfusions.
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http://dx.doi.org/10.1182/asheducation-2014.1.553DOI Listing
December 2014

Efficacy of education followed by computerized provider order entry with clinician decision support to reduce red blood cell utilization.

Transfusion 2015 Jul 3;55(7):1628-36. Epub 2015 Feb 3.

Department of Anesthesiology/Critical Care Medicine, Baltimore, Maryland.

Background: Two necessary components of a patient blood management program are education regarding evidence-based transfusion guidelines and computerized provider order entry (CPOE) with clinician decision support (CDS). This study examines changes in red blood cell (RBC) utilization associated with each of these two interventions.

Study Design And Methods: We reviewed 5 years of blood utilization data (2009-2013) for 70,118 surgical patients from 10 different specialty services at a tertiary care academic medical center. Three distinct periods were compared: 1) before blood management, 2) education alone, and 3) education plus CPOE. Changes in RBC unit utilization were assessed over the three periods stratified by surgical service. Cost savings were estimated based on RBC acquisition costs.

Results: For all surgical services combined, RBC utilization decreased by 16.4% with education alone (p = 0.001) and then changed very little (2.5% increase) after subsequent addition of CPOE (p = 0.64). When we compared the period of education plus CPOE to the pre-blood management period, the overall decrease was 14.3% (p = 0.008; 2102 fewer RBC units/year, or a cost avoidance of $462,440/year). Services with the highest massive transfusion rates (≥10 RBC units) exhibited the least reduction in RBC utilization.

Conclusions: Adding CPOE with CDS after a successful education effort to promote evidence-based transfusion practice did not further reduce RBC utilization. These findings suggest that education is an important and effective component of a patient blood management program and that CPOE algorithms may serve to maintain compliance with evidence-based transfusion guidelines.
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http://dx.doi.org/10.1111/trf.13003DOI Listing
July 2015

HMGA1 drives metabolic reprogramming of intestinal epithelium during hyperproliferation, polyposis, and colorectal carcinogenesis.

J Proteome Res 2015 Mar 23;14(3):1420-31. Epub 2015 Feb 23.

Department of Chemistry, Washington State University , 100 Dairy Road, Pullman, Washington 99164, United States.

Although significant progress has been made in the diagnosis and treatment of colorectal cancer (CRC), it remains a leading cause of cancer death worldwide. Early identification and removal of polyps that may progress to overt CRC is the cornerstone of CRC prevention. Expression of the High Mobility Group A1 (HMGA1) gene is significantly elevated in CRCs as compared with adjacent, nonmalignant tissues. We investigated metabolic aberrations induced by HMGA1 overexpression in small intestinal and colonic epithelium using traveling wave ion mobility mass spectrometry (TWIMMS) in a transgenic model in which murine Hmga1 was misexpressed in colonic epithelium. To determine if these Hmga1-induced metabolic alterations in mice were relevant to human colorectal carcinogenesis, we also investigated tumors from patients with CRC and matched, adjacent, nonmalignant tissues. Multivariate statistical methods and manual comparisons were used to identify metabolites specific to Hmga1 and CRC. Statistical modeling of data revealed distinct metabolic patterns in Hmga1 transgenics and human CRC samples as compared with the control tissues. We discovered that 13 metabolites were specific for Hmga1 in murine intestinal epithelium and also found in human CRC. Several of these metabolites function in fatty acid metabolism and membrane composition. Although further validation is needed, our results suggest that high levels of HMGA1 protein drive metabolic alterations that contribute to CRC pathogenesis through fatty acid synthesis. These metabolites could serve as potential biomarkers or therapeutic targets.
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http://dx.doi.org/10.1021/pr501084sDOI Listing
March 2015

Risk-adjusted clinical outcomes in patients enrolled in a bloodless program.

Transfusion 2014 Oct 18;54(10 Pt 2):2668-77. Epub 2014 Jun 18.

Department of Anesthesiology/Critical Care Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland.

Background: Although clinical outcomes have been reported for patients who do not accept allogeneic blood transfusion (ABT), many previous studies lack a control group, fail to use risk adjustment, and focus exclusively on cardiac surgery.

Study Design And Methods: We report a risk-adjusted, propensity score-matched, retrospective case-control study of clinical outcomes for inpatients who did not accept ABT (bloodless, n = 294) and those who did accept ABT (control, n = 1157). Multidisciplinary specialized care was rendered to the bloodless patients to conserve blood and optimize clinical outcomes. Differences in hemoglobin (Hb), mortality, five morbid outcomes, and hospital charges and costs were compared. Subgroups of medical and surgical patients were analyzed, and independent predictors of outcome were determined by multivariate analysis.

Results: Overall, mortality was lower in the bloodless group (0.7%) than in the control group (2.7%; p = 0.046), primarily attributed to the surgical subgroup. After risk adjustment, bloodless care was not an independent predictor of the composite adverse outcome (death or any morbid event; p = 0.91; odds ratio, 1.02; 95% confidence interval, 0.68-1.53). Discharge Hb concentrations were similar in the bloodless (10.8 ± 2.7 g/dL) and control (10.9 ± 2.3 g/dL) groups (p = 0.42). Total and direct hospital costs were 12% (p = 0.02) and 18% (p = 0.02) less, respectively, in the bloodless patients, a difference attributed to the surgical subgroup.

Conclusions: Using appropriate blood conservation measures for patients who do not accept ABT results in similar or better outcomes and is associated with equivalent or lower costs. This specialized care may be beneficial even for those patients who accept ABT.
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http://dx.doi.org/10.1111/trf.12752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234090PMC
October 2014

Hydroxyurea therapy for priapism prevention and erectile function recovery in sickle cell disease: a case report and review of the literature.

Int Urol Nephrol 2014 Sep 14;46(9):1733-1736. Epub 2014 May 14.

Urology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Prolonged ischemic priapism in patients with sickling hemoglobinopathies is a urologic emergency requiring immediate intervention to avoid irreversible anoxic penile injury, corporal fibrosis, and erectile dysfunction. Therapeutic options, however, are limited and often ineffective. Here, we report recovery of erectile function with hydroxyurea therapy in an adolescent with hemoglobin SS following a prolonged episode of priapism and subsequent severe erectile dysfunction. This case suggests a potential role of hydroxyurea in reversing end organ damage in patients with hemoglobin SS and also supports basic science work indicating involvement of the NO-dependent pathway in the pathogenesis of sickle cell disease-associated priapism.
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http://dx.doi.org/10.1007/s11255-014-0737-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4335636PMC
September 2014

The high mobility group A1 molecular switch: turning on cancer - can we turn it off?

Expert Opin Ther Targets 2014 May 31;18(5):541-53. Epub 2014 Mar 31.

The Johns Hopkins University School of Medicine, Hematology Division , Ross Research Building, Room 1015, 720 Rutland Avenue, Baltimore MD 21205 , USA.

Introduction: Emerging evidence demonstrates that the high mobility group A1 (HMGA1) chromatin remodeling protein is a key molecular switch required by cancer cells for tumor progression and a poorly differentiated, stem-like state. Because the HMGA1 gene and proteins are expressed at high levels in all aggressive tumors studied to date, research is needed to determine how to 'turn off' this master regulatory switch in cancer.

Areas Covered: In this review, we describe prior studies that underscore the central role of HMGA1 in refractory cancers and we discuss approaches to target HMGA1 in cancer therapy.

Expert Opinion: Given the widespread overexpression of HMGA1 in diverse, aggressive tumors, further research to develop technology to target HMGA1 holds immense promise as potent anticancer therapy. Previous work in preclinical models indicates that delivery of short hairpin RNA or interfering RNA molecules to 'switch off' HMGA1 expression dramatically impairs cancer cell growth and tumor progression. The advent of nanoparticle technology to systemically deliver DNA or RNA molecules to tumors brings this approach even closer to clinical applications, although further efforts are needed to translate these advances into therapies for cancer patients.
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http://dx.doi.org/10.1517/14728222.2014.900045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4404637PMC
May 2014

Hitting the bull's eye: targeting HMGA1 in cancer stem cells.

Expert Rev Anticancer Ther 2014 Jan;14(1):23-30

Department of Medicine, Pathobiology Graduate Program, Hematology Division, Oncology, the Institute for Cellular Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Emerging evidence suggests that when cancer cells hijack normal stem cell properties, they acquire the ability to invade, metastasize to distant sites and evade therapy. Thus, eliminating cancer cells with stem cell properties, or cancer stem cells, is of prime importance for the successful treatment of cancer, regardless of the tissue of origin. Previous efforts to target cancer stem cells (CSCs), however, have been largely unsuccessful. Recent studies led to the discovery of a novel role for the high mobility group A1 (HMGA1) protein as a master regulator in both CSCs and normal embryonic stem cells. Here, we present exciting new work unveiling HMGA1 as a promising target for therapies directed at eradicating CSCs.
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http://dx.doi.org/10.1586/14737140.2013.859988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4333104PMC
January 2014

More common than you think: common variable immune deficiency.

Case Rep Hematol 2013 5;2013:153767. Epub 2013 Dec 5.

Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA ; Hematology Division, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA ; Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA ; The Institute for Cellular Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA ; The Johns Hopkins University School of Medicine, Ross Research Building, Room 1025, 720 Rutland Avenue, Baltimore, MD 21205, USA.

We report a challenging case of a 16-year-old male who presented with thrombocytopenia and eluded a definitive diagnosis for over 2 years. He was initially diagnosed with a viral illness, although he later developed adenopathy and splenomegaly. An evaluation by an oncologist was unrevealing. He worked on a farm with livestock exposure and was later diagnosed with an atypical, zoonotic infection. Despite appropriate antibiotic therapy, the thrombocytopenia and splenomegaly persisted. Further evaluation revealed that he has a relatively common immunologic disorder. He is currently doing well on appropriate therapy for this disorder.
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http://dx.doi.org/10.1155/2013/153767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3870096PMC
January 2014

Patent foramen ovale in patients with sickle cell disease and stroke: case presentations and review of the literature.

Case Rep Hematol 2013 16;2013:516705. Epub 2013 Jul 16.

Hematology Division, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA ; Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Although individuals with sickle cell disease (SCD) are at increased risk for stroke, the underlying pathophysiology is incompletely understood. Intracardiac shunting via a patent foramen ovale (PFO) is associated with cryptogenic stroke in individuals without SCD. Recent evidence suggests that PFOs are associated with stroke in children with SCD, although the role of PFOs in adults with stroke and SCD is unknown. Here, we report 2 young adults with SCD, stroke, and PFOs. The first patient had hemoglobin SC and presented with a transient ischemic attack and a subsequent ischemic stroke. There was no evidence of cerebral vascular disease on imaging studies and the PFO was closed. The second patient had hemoglobin SS and two acute ischemic strokes. She had cerebral vascular disease with moyamoya in addition to a peripheral deep venous thrombosis (DVT). Chronic transfusion therapy was recommended, and the DVT was managed with warfarin. The PFO was not closed, and the patients' neurologic symptoms were stabilized. We review the literature on PFOs and stroke in SCD. Our cases and the literature review illustrate the dire need for further research to evaluate PFO as a potential risk factor for stroke in adults with SCD.
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http://dx.doi.org/10.1155/2013/516705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3730376PMC
August 2013