63 results on '"Brown VI"'
Search Results
2. A narrative review of economic constructs in commonly used implementation and scale-up theories, frameworks and models
- Author
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Brown Vicki, Tran Huong, Blake Miranda, Laws Rachel, and Moodie Marj
- Subjects
Implementation ,scale-up ,theories ,models ,frameworks ,economic ,Public aspects of medicine ,RA1-1270 - Abstract
Abstract Background Translating research evidence into practice is challenging and, to date, there are relatively few public health interventions that have been effectively and cost-effectively implemented and delivered at scale. Theories, models and frameworks (herein termed ‘frameworks’) have been used in implementation science to describe, guide and explain implementation and scale-up. While economic constructs have been reported as both barriers and facilitators to effective implementation and scale-up of public health interventions, there is currently no published review of how economic constructs are considered within commonly used implementation and scale-up frameworks. This paper aimed to narratively review the economic constructs incorporated in commonly used implementation and scale-up frameworks. Methods Frameworks for inclusion in the narrative review were identified from the literature and thematic content analysis was undertaken using a recursive deductive approach. Emergent key themes and sub-themes were identified and results were summarised narratively within each theme. Results Twenty-six framework publications were included in our analysis, with wide variation between frameworks in the scope and level of detail of the economic constructs included. Four key themes emerged from the data – ‘resources’, ‘benefit’, ‘cost’ and ‘funding’. Only five frameworks incorporated all four identified key themes. Overarching lenses from which to consider key themes included ‘stakeholder perspectives’, ‘stage in the research translation process’ and ‘context’. ‘Resources’ were most frequently considered in relation to the sub-themes of ‘types of resources’ (e.g. labour, time or infrastructure) and ‘availability’ of resources, and the opportunity for ‘economies of scale’. The ‘relative advantage of interventions’ emerged as an interconnecting sub-theme between ‘cost’ and ‘benefit’. ‘Funding’ was most often considered in relation to ‘funding sources’, ‘availability’, ‘sustainability’ or ‘contextual impact’. The concept of ‘opportunity cost’ was considered in relatively few frameworks, despite being fundamental to economic theory. Conclusions Implementation and scale-up frameworks provide a conceptual map to inform the effective and cost-effective implementation of public health interventions delivered at scale. Despite evidence of an emerging focus on the economic considerations of implementation and scale-up within some commonly used frameworks, our findings suggest that there is significant scope for further exploration of the economic constructs related to implementation and scale-up.
- Published
- 2020
- Full Text
- View/download PDF
3. Survey of traffic noise reduction products, materials, and technologies
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Prophecy Consulting Group, LLC; Arizona Department of Transportation, Brown, Vi (Violettee), Arizona Department of Transportation, Prophecy Consulting Group, LLC; Arizona Department of Transportation, Brown, Vi (Violettee), and Arizona Department of Transportation
- Abstract
88 pages
- Published
- 2008
4. A cost evaluation of cross-border truck emissions testing using heavy duty remote sensing equipment
- Author
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Prophecy Consulting Group; Arizona Department of Transportation, Brown, Vi (Violettee), Arizona Department of Transportation, Prophecy Consulting Group; Arizona Department of Transportation, Brown, Vi (Violettee), and Arizona Department of Transportation
- Abstract
54 pages
- Published
- 2008
5. Survey of traffic noise reduction products, materials, and technologies
- Author
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Brown, Vi and Brown, Vi
- Subjects
- Noise control Arizona., Traffic noise Arizona., Bruit Lutte contre Arizona., Circulation Bruit Arizona., Noise control, Traffic noise, noise barriers., Materials., Products., Technology., Arizona
- Abstract
Noise is one of the most pervasive forms of environmental pollution. It is everywhere and affects our lives at home, work and play. By definition, noise is any unwanted or excessive sound. Highway traffic noise is a major issue for transportation agencies. The objective of this study was to identify noise reduction products, materials, and technologies currently available and that may have potential as noise mitigation alternatives. The literature review and survey identified measures that are being used by U.S. transportation organizations as well as international efforts. Some key findings from the literature review show the following best practices: - Pavement Noise Reduction Products - noise or sound walls dominate this category and have been used for decades in the U.S. Findings from the literature revealed a variety of materials to choose from that are both aesthetically attractive, and effective in reducing sound from tire pavement noise. The cost of installing products will need to be evaluated on a case by case basis with the vendor or for each applicable product. - Pavement Noise Reduction Materials - The operating speed of the roadway should be factored into the roadway design for quiet pavements. European studies show that higher porous mixtures tend to clog under slower speeds. Two layer-porous mixes have been found to be effective in Europe and the US. An important attribute for consideration in two layer-porous mix design and placement is aggregate size. - Pavement Noise Reduction Technologies - use of thin-textured surfacings with a negative pavement depression are recommended for urban or low-speed roadway sections. Diamond grinding enhances noise reduction on concrete surfaces in sensitive locations. - Other Pavement Noise Reduction Measures - looking forward, transportation officials are encouraged to develop an integrated approach to roadway noise reduction. Instead of relying on a single measure, the recommended forward strategy is to develop the ability to model the effectiveness of a number of different measures to achieve greater noise reduction.
- Published
- 2008
6. Liquidity Myths.
- Author
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Brown VI, John P. W.
- Subjects
LIQUIDITY (Economics) ,ENERGY industries ,PRICE indexes ,RISK management in business ,MARKETS - Abstract
The article discusses the implications of market illiquidity on the energy industry. Market illiquidity adversely affects risk-management calculations. One of the impacts that illiquidity markets impose on an energy firm's business is increased cost. Another example of how illiquid markets increase the cost of doing business relates to the use of price indices.
- Published
- 2005
7. Medical isotope collection from ISAC targets
- Author
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Kunz Peter, Andreoiu Corina, Brown Victoria, Cervantes Marla, Even Julia, Garcia Fatima H., Gottberg Alexander, Lassen Jens, Radchenko Valery, Ramogida Caterina F., Robertson Andrew K. H., Schaffer Paul, and Sothilingam Rozhannaa
- Subjects
Physics ,QC1-999 - Abstract
The ISAC facility (Isotope Separation and Acceleration) at TRIUMF has recently started to provide isotopes for pre-clinical nuclear medicine studies. By irradiating ISOL (Isotope Separation OnLine) targets with a 480 MeV proton beam from the TRIUMF H- cyclotron, the facility can deliver a large variety of radioactive isotope beams (RIB) for research in the fields of nuclear astrophysics, nuclear structure and material science with half-lives down to a few milliseconds via an electrostatic beamline network. For the collection of medical isotopes, typically with half-lives in the range of hours or days, we have developed a compact apparatus for the implantation of mass-separated RIB on a target disc at energies between 20-55 keV. In this paper, we also discuss two different retrieval methods of the implanted activity from the implantation target: by chemical etching of the target surface and by recoil collection of implanted alpha emitters.
- Published
- 2020
- Full Text
- View/download PDF
8. A Segregation of Memory: The 1921 Tulsa Race Riot.
- Author
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Brown, Vi
- Abstract
The article focuses on the 1921 Tulsa Race Riot in Oklahoma. The event started upon the release of a news article on the "Tulsa Tribune" that reported an alleged attack made by an African American man to a white female in an elevator. The incident resulted into the destruction of the entire African American community and the creation of the Tulsa Race Riot Commission that will investigate the violence in the city.
- Published
- 2003
9. Talent Management Admiring America's Most Admired Companies.
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Brown, Vi
- Abstract
The article presents the ten most admired companies in 2001 in terms of managing the right people in the U.S. It includes the General Electric, Cisco Systems and Berkeshire Hathaway. It is stated that the ten companies dominate the areas in stock market and luring talent. Most companies are challenged in attracting and keeping the right employees for their companies. It stated that the best method for identifying and attracting talent is as individual as each company or business.
- Published
- 2001
10. An African American Pioneer: Charles W. Pierce, B.S.ChE, 1901.
- Author
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Brown, Vi
- Abstract
The article features African American chemical engineer Charles W. Pierce. He was the first chemical engineering graduate of the Armour Institute of Technology and the first African American chemical engineer in the U.S. His career upon graduation from the Illinois Institute of Technology is traced. Events that were occurring in the U.S. that may have shaped his career around the turn of the 20th century are discussed. INSET: SETTING THE STAGE FOR A NEW PROFESSION.
- Published
- 2004
11. CELEBRATING: Black History, Careers and Diversity.
- Author
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Brown, Vi
- Abstract
The author reflects on the importance of honoring black history and African American achievements in science in the U.S. She stressed that the celebration of Black History Month and the study of black history could be attributed to Dr. Carter G. Woodson. She added that there are many talented people who had contributed to employees career. For her, global workforce and not selected races or nations, is essential in the society.
- Published
- 2001
12. RAISING THE STAKES in High Technology at the Department of Commerce.
- Author
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Brown, Vi
- Abstract
An interview with Cheryl Shavers, Undersecretary of Commerce for Technology of the U.S. Department of Commerce, Technology Administration (TA), is presented. She believes that President Bill Clinton considered her for the position because of her 25 years experience in the high-technology industry. Shavers mentions the difficulty of improving the image of TA as an advocate for technology. She describes the Technology Demonstration Center established by TA where the private sector can demonstrate new products that are technologically advanced.
- Published
- 2000
13. A cost evaluation of cross-border truck emissions testing using heavy duty remote sensing equipment : final report 601.
- Author
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Arizona. Department of Transportation, United States. Federal Highway Administration, Brown, Vi, Prophecy Consulting Group, Arizona. Department of Transportation, United States. Federal Highway Administration, Brown, Vi, and Prophecy Consulting Group
- Abstract
T0549A0021, The objective of this research study was to perform a thorough evaluation of the feasibility and cost implications for initial system installation and ongoing program and maintenance costs for a land port of entry truck emissions program utilizing heavy duty remote sensing technology. This study includes funding recommendations to maintain such a program. To meet the study objective, project tasks included the following: 1) develop a work plan for approval by the Technical Advisory Committee; 2) review the literature on cross-border truck traffic, truck emissions, and truck emission testing; 3) prepare a detailed data collection plan; 4) implement the data collection plan and provide detailed discussion and analysis to support the proposed testing program's elements and cost components; and 5) prepare a final report and a four-page research note. Cost data were developed for each alternative and includes figures for capital equipment installation and five years of operation and maintenance expenses. The present worth costs for each data plan utilizing contract labor ranged from $1,320,828 to $2,177,467. If employees of the Arizona Department of Transportation (ADOT) or the Arizona Department of Environmental Quality (ADEQ) are used, the present worth costs range between $1,140,349 and $1,923,247. While it is obvious that the use of employees is less expensive than contract labor, the agency could find it difficult to attract highly skilled employees for a proposed HDRS emissions measurement program at the Arizona-Mexico border. It is important to note that measurement of emissions by remote sensing is still an emerging technology that has limitations in its application. ADOT can partner with ADEQ to determine if a monitoring program is warranted at the border at this time. ADEQ has an established air quality monitoring program throughout the state and has trained staff, equipment, and facilities to support such a program.
14. Survey of Traffic Noise Reduction Products, Materials, and Technologies.
- Author
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Arizona. Department of Transportation, United States. Federal Highway Administration, Brown, Vi (Violettee), Prophecy Consulting Group, Arizona. Department of Transportation, United States. Federal Highway Administration, Brown, Vi (Violettee), and Prophecy Consulting Group
- Abstract
T0549A0028, Noise is one of the most pervasive forms of environmental pollution. It is everywhere and affects our lives at, home, work and play. By definition, noise is any unwanted or excessive sound. Highway traffic noise is a, major issue for transportation agencies. The objective of this study was to identify noise reduction products, materials, and technologies currently available and that may have potential as noise mitigation alternatives., The literature review and survey identified measures that are being used by U.S. transportation organizations, as well as international efforts. Some key findings from the literature review show the following best, practices, Pavement Noise Reduction Products – noise or sound walls dominate this category and have been used, for decades in the U.S. Findings from the literature revealed a variety of materials to choose from that are, both aesthetically attractive, and effective in reducing sound from tire pavement noise. The cost of installing, products will need to be evaluated on a case by case basis with the vendor or for each applicable product., Pavement Noise Reduction Materials – The operating speed of the roadway should be factored into the, roadway design for quiet pavements. European studies show that higher porous mixtures tend to clog under, slower speeds. Two layer-porous mixes have been found to be effective in Europe and the US. An, important attribute for consideration in two layer-porous mix design and placement is aggregate size., Pavement Noise Reduction Technologies - use of thin-textured surfacings with a negative pavement, depression are recommended for urban or low-speed roadway sections. Diamond grinding enhances noise, reduction on concrete surfaces in sensitive locations., Other Pavement Noise Reduction Measures – looking forward, transportation officials are encouraged to, develop an integrated approach to roadway noise reduction. Instead of relying on a single measure, the, recommended forward strategy is to develop the ability to model the effectiveness of a number of different, measures to achieve greater noise reduction.
15. Minimal access excision of aortic valve fibroelastoma: a case report and review of the literature
- Author
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Harling Leanne, Athanasiou Thanos, Ashrafian Hutan, Kokotsakis John, Brown Virginia, Nathan Anthony, and Casula Roberto
- Subjects
Fibroelastoma ,Minimally invasive ,Aortic valve ,Surgery ,RD1-811 ,Anesthesiology ,RD78.3-87.3 - Abstract
Abstract Papillary fibroelastomas are rare primary tumours of cardiac origin accounting for approximately 10% of all primary cardiac neoplasms. Due to a high thromboembolic risk, surgical excision is the mainstay of treatment in these patients and median sternotomy the most widely used approach. We describe the case of a 43 year-old lady presenting with acute myocardial infarction secondary to aortic valve papillary fibroelastoma subsequently excised using a minimal access technique. From our experience mini-sternotomy offers excellent exposure and allows for safe resection in such cases, improving cosmesis without compromising either intra or post-operative outcome.
- Published
- 2012
- Full Text
- View/download PDF
16. Biological conversion assay using Clostridium phytofermentans to estimate plant feedstock quality
- Author
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Lee Scott J, Warnick Thomas A, Pattathil Sivakumar, Alvelo-Maurosa Jesús G, Serapiglia Michelle J, McCormick Heather, Brown Virginia, Young Naomi F, Schnell Danny J, Smart Lawrence B, Hahn Michael G, Pedersen Jeffrey F, Leschine Susan B, and Hazen Samuel P
- Subjects
Fuel ,TP315-360 ,Biotechnology ,TP248.13-248.65 - Abstract
Abstract Background There is currently considerable interest in developing renewable sources of energy. One strategy is the biological conversion of plant biomass to liquid transportation fuel. Several technical hurdles impinge upon the economic feasibility of this strategy, including the development of energy crops amenable to facile deconstruction. Reliable assays to characterize feedstock quality are needed to measure the effects of pre-treatment and processing and of the plant and microbial genetic diversity that influence bioconversion efficiency. Results We used the anaerobic bacterium Clostridium phytofermentans to develop a robust assay for biomass digestibility and conversion to biofuels. The assay utilizes the ability of the microbe to convert biomass directly into ethanol with little or no pre-treatment. Plant samples were added to an anaerobic minimal medium and inoculated with C. phytofermentans, incubated for 3 days, after which the culture supernatant was analyzed for ethanol concentration. The assay detected significant differences in the supernatant ethanol from wild-type sorghum compared with brown midrib sorghum mutants previously shown to be highly digestible. Compositional analysis of the biomass before and after inoculation suggested that differences in xylan metabolism were partly responsible for the differences in ethanol yields. Additionally, we characterized the natural genetic variation for conversion efficiency in Brachypodium distachyon and shrub willow (Salix spp.). Conclusion Our results agree with those from previous studies of lignin mutants using enzymatic saccharification-based approaches. However, the use of C. phytofermentans takes into consideration specific organismal interactions, which will be crucial for simultaneous saccharification fermentation or consolidated bioprocessing. The ability to detect such phenotypic variation facilitates the genetic analysis of mechanisms underlying plant feedstock quality.
- Published
- 2012
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17. High dose intermittent sorafenib shows improved efficacy over conventional continuous dose in renal cell carcinoma
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Wang Xiaoen, Zhang Liang, Goldberg S Nahum, Bhasin Manoj, Brown Victoria, Alsop David C, Signoretti Sabina, Mier James W, Atkins Michael B, and Bhatt Rupal S
- Subjects
Renal cell carcinoma ,anti-angiogenic therapy ,arterial spin labeled magnetic resonance imaging ,Medicine - Abstract
Abstract Background Renal cell carcinoma (RCC) responds to agents that inhibit vascular endothelial growth factor (VEGF) pathway. Sorafenib, a multikinase inhibitor of VEGF receptor, is effective at producing tumor responses and delaying median progression free survival in patients with cytokine refractory RCC. However, resistance to therapy develops at a median of 5 months. In an effort to increase efficacy, we studied the effects of increased sorafenib dose and intermittent scheduling in a murine RCC xenograft model. Methods Mice bearing xenografts derived from the 786-O RCC cell line were treated with sorafenib according to multiple doses and schedules: 1) Conventional dose (CD) continuous therapy; 2) high dose (HD) intermittent therapy, 3) CD intermittent therapy and 4) HD continuous therapy. Tumor diameter was measured daily. Microvessel density was assessed after 3 days to determine the early effects of therapy, and tumor perfusion was assessed serially by arterial spin labeled (ASL) MRI at day 0, 3, 7 and 10. Results Tumors that were treated with HD sorafenib exhibited slowed tumor growth as compared to CD using either schedule. HD intermittent therapy was superior to CD continous therapy, even though the total dose of sorafenib was essentially equivalent, and not significantly different than HD continuous therapy. The tumors exposed to HD sorafenib had lower microvessel density than the untreated or the CD groups. ASL MRI showed that tumor perfusion was reduced to a greater extent with the HD sorafenib at day 3 and at all time points thereafter relative to CD therapy. Further the intermittent schedule appeared to maintain RCC sensitivity to sorafenib as determined by changes in tumor perfusion. Conclusions A modification of the sorafenib dosing schedule involving higher dose intermittent treatment appeared to improve its efficacy in this xenograft model relative to conventional dosing. MRI perfusion imaging and histologic analysis suggest that this benefit is related to enhanced and protracted antiangiogenic activity. Thus, better understanding of dosing and schedule issues may lead to improved therapeutic effectiveness of VEGF directed therapy in RCC and possibly other tumors.
- Published
- 2011
- Full Text
- View/download PDF
18. Effect of pentoxifylline on preventing acute kidney injury after cardiac surgery by measuring urinary neutrophil gelatinase - associated lipocalin
- Author
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Yousefshahi Fardin, Abbasi Kiomars, Khatami Mohammad, Soltaninia Hasan, Shafiee Akbar, Karimi Abbasali, Barkhordari Khosro, Haghighat Babak, and Brown Virginia
- Subjects
Surgery ,RD1-811 ,Anesthesiology ,RD78.3-87.3 - Abstract
Abstract Background Based on Acute Kidney Injury Network (AKIN) criteria, we considered acute kidney injury (AKI) as an absolute increase in the serum creatinine (sCr) level of more than or equal to 0.3 mg/dl or 50%. The introduction of Urinary neutrophil gelatinase-associated lipocalin (UNGAL) has conferred earlier diagnosis of AKI. Pentoxifylline (PTX), a non-specific phosphodiesterase inhibitor, can suppress the production of some factors of inflammatory response and presumably prevent AKI. We examined the PTX on the development of AKI in cardiac surgery patients by measuring the levels of UNGAL. Materials and methods We performed a double blind randomized clinical trial, enrolling 28 consecutive patients undergoing elective coronary artery bypass graft (CABG) surgery. Patients were divided into two groups, one to receive PTX 5 mg/kg intravenous bolus injection, followed by 1.5 mg/kg/h continuous intravenous infusion until 3 hours after cessation of CPB and the other group received placebo. UNGAL was measured before, 3 and 24 hours after surgery. In addition serum creatinine was measured before and 24, 48, 72 and 96 hours after surgery and C-reactive protein (CRP) only 24 hours postoperatively. Results Both groups did not differ in demographic and baseline characteristics. 12 patients developed AKI 48 hours after surgery; 5 of them were in the intervention group and 7 in the control group (p= 0.445). There was an increase of UNGAL in both groups postoperatively, although not significant. Mean sCr was significantly increased in the control group at 24 and 48 hours after surgery (24-h mean: 0.79 ± 0.18 mg/dl vs. 1.03 ± 0.43 mg/dl, P value = 0.02; 48-h mean: 1.17 ± 0.24 mg/dl vs. 0.98 ± 0.20 mg/dl, P value = 0.03, respectively). PTX had a positive effect in preventing AKI reflecting in changes in sCr, and the increase of UNGAL was consistent with the emergence of AKI (Pearson's correlation = 0.30). Conclusion Our study demonstrates a weak correlation between UNGAL and sCr after cardiac surgery. The rise of UNGAL in these patients may be reduced by administration of PTX although we did not show significance. PTX could reduce the occurrence of AKI as determined by attenuation of sCr rise without causing hemodynamic instability or increased bleeding. Overall, we suggest future studies with larger sample sizes to elucidate this effect and determine the different aspects of administrating PTX. Trial Registration ISRCTN: IRCT138807302622N1
- Published
- 2011
- Full Text
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19. READER'S FORUM.
- Author
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Patton, Christi, Brown, Vi, and Perusek, Anne
- Abstract
A letter to the editor is presented in response to the article "A Segregation of Memory: The 1921 Tulsa Race Riot," which appeared in the winter 2003 issue.
- Published
- 2003
20. The Black Women's Health Study.
- Author
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Brown, Vi
- Abstract
The article provides information about the Black Women's Health Study which focuses on the health problems of African American women. Investigators Lynn Rosenberg, Lucile Adams-Campbell and Julie Palmer wanted to design a study that would gather information on many conditions affecting the group. Health problems such as breast cancer, lupus, premature birth, hypertension and colon cancer are the focus of the investigations. Information on study design and participants is provided.
- Published
- 2002
21. WAITING FOR MY TINA TURNER CAREER OPPORTUNITY.
- Author
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Brown, Vi
- Abstract
The article discusses the author's experience when she lost her job due to the company's wide reduction in force scheme. The author a compulsory workshop on career continuation sponsored by the outplacement firm and while waiting for the workshop to start, the author called on many people to let them know that she is no longer employed. During the workshop, she learned job-hunting methods, techniques and the possible tools such as the Internet and Sunday's newspapers to find jobs.
- Published
- 2001
22. DIVERSITY: SAME GENDER ISSUES.
- Author
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Brown, Vi
- Abstract
The article discusses a research on diversity as an issue for women and people of color conducted by Vi Brown, Region B director of the Society of Women Engineers. Brown's research features the definition and perception of diversity and the traditional female and male issue conceived by women engineers and scientists. She also discusses the importance of diversity female gender issues which can affect one's status in the organization since it implies a negative emphasis on differences.
- Published
- 1999
23. Welcome to the FY '05 Yearbook!
- Author
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Brown, Vi
- Abstract
Presents information on the fiscal 2005 yearbook of the Society of Women Engineers (SWE) which documented the efforts and accomplishments of the group in the local, regional and national levels in the U.S. Highlights of the activities of the SWE in the year; Commendation for each professional and student sections that hosted SWE regional conferences; Gratitude to region governors and their conference planning committees for their hospitality and conferences.
- Published
- 2005
24. Strong and Vibrant.
- Author
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Brown, Vi
- Abstract
Presents insights on the significance of the Society of Women Engineers (SWE) to the engineering profession. Initial activities of the SWE for 2005; Accomplishments of SWE; Need for SWE members to practice diversity within the profession.
- Published
- 2005
25. Looking to the Future.
- Author
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Brown, Vi
- Abstract
Presents an overview of articles on engineering careers and employment trends in the U.S. Importance of training and skills to establish a career in the engineering field; Topics discussed in the 2004 Society of Women Engineers (SWE) National Conference held in Milwaukee, Wisconsin; Award received by engineer Stephanie Horne Swindle from SWE.
- Published
- 2005
26. Witamy, Wilkommen, Bienvenido!
- Author
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Brown, Vi
- Abstract
The article talks about the 2004 national conference by the Society of Women Engineers (SWE) which will be held in Milwaukee, Wisconsin. The conference program is divided into three sections, including education, personal growth and technology. A career fair will be featuring almost 200 exhibitors. Violettee V. Brown, president of SWE, encourages everyone in the society to enhance programs and individual interactions.
- Published
- 2004
27. SWE Successes in FY03.
- Author
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Brown, Vi
- Abstract
The article highlights the accomplishments made by the Society of Women Engineers (SWE) in the U.S. in 2003. The traveling exhibit "Petticoats and Slide Rules" opened at Wayne State University in Michigan on October 8, 2002. The SWE Member Services Center allows members to apply, upgrade or renew membership online. The corporate partnership council was introduced in January 2003.
- Published
- 2003
28. Molecular-guided therapy for the treatment of patients with relapsed and refractory childhood cancers: a Beat Childhood Cancer Research Consortium trial.
- Author
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Sholler GLS, Bergendahl G, Lewis EC, Kraveka J, Ferguson W, Nagulapally AB, Dykema K, Brown VI, Isakoff MS, Junewick J, Mitchell D, Rawwas J, Roberts W, Eslin D, Oesterheld J, Wada RK, Pastakia D, Harrod V, Ginn K, Saab R, Bielamowicz K, Glover J, Chang E, Hanna GK, Enriquez D, Izatt T, Halperin RF, Moore A, Byron SA, Hendricks WPD, and Trent JM
- Subjects
- Child, Humans, Antineoplastic Combined Chemotherapy Protocols adverse effects, Neoplasm Recurrence, Local drug therapy, Neoplasm Recurrence, Local etiology, Neuroblastoma drug therapy, Neuroblastoma genetics
- Abstract
Background: Children with relapsed central nervous system (CNS tumors), neuroblastoma, sarcomas, and other rare solid tumors face poor outcomes. This prospective clinical trial examined the feasibility of combining genomic and transcriptomic profiling of tumor samples with a molecular tumor board (MTB) approach to make real‑time treatment decisions for children with relapsed/refractory solid tumors., Methods: Subjects were divided into three strata: stratum 1-relapsed/refractory neuroblastoma; stratum 2-relapsed/refractory CNS tumors; and stratum 3-relapsed/refractory rare solid tumors. Tumor samples were sent for tumor/normal whole-exome (WES) and tumor whole-transcriptome (WTS) sequencing, and the genomic data were used in a multi-institutional MTB to make real‑time treatment decisions. The MTB recommended plan allowed for a combination of up to 4 agents. Feasibility was measured by time to completion of genomic sequencing, MTB review and initiation of treatment. Response was assessed after every two cycles using Response Evaluation Criteria in Solid Tumors (RECIST). Patient clinical benefit was calculated by the sum of the CR, PR, SD, and NED subjects divided by the sum of complete response (CR), partial response (PR), stable disease (SD), no evidence of disease (NED), and progressive disease (PD) subjects. Grade 3 and higher related and unexpected adverse events (AEs) were tabulated for safety evaluation., Results: A total of 186 eligible patients were enrolled with 144 evaluable for safety and 124 evaluable for response. The average number of days from biopsy to initiation of the MTB-recommended combination therapy was 38 days. Patient benefit was exhibited in 65% of all subjects, 67% of neuroblastoma subjects, 73% of CNS tumor subjects, and 60% of rare tumor subjects. There was little associated toxicity above that expected for the MGT drugs used during this trial, suggestive of the safety of utilizing this method of selecting combination targeted therapy., Conclusions: This trial demonstrated the feasibility, safety, and efficacy of a comprehensive sequencing model to guide personalized therapy for patients with any relapsed/refractory solid malignancy. Personalized therapy was well tolerated, and the clinical benefit rate of 65% in these heavily pretreated populations suggests that this treatment strategy could be an effective option for relapsed and refractory pediatric cancers., Trial Registration: ClinicalTrials.gov, NCT02162732. Prospectively registered on June 11, 2014., (© 2024. The Author(s).)
- Published
- 2024
- Full Text
- View/download PDF
29. Eflornithine as Postimmunotherapy Maintenance in High-Risk Neuroblastoma: Externally Controlled, Propensity Score-Matched Survival Outcome Comparisons.
- Author
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Oesterheld J, Ferguson W, Kraveka JM, Bergendahl G, Clinch T, Lorenzi E, Berry D, Wada RK, Isakoff MS, Eslin DE, Brown VI, Roberts W, Zage P, Harrod VL, Mitchell DS, Hanson D, and Saulnier Sholler GL
- Subjects
- Child, Humans, Propensity Score, Neoplasm Recurrence, Local drug therapy, Recurrence, Disease-Free Survival, Eflornithine adverse effects, Neuroblastoma drug therapy
- Abstract
Purpose: Long-term survival in high-risk neuroblastoma (HRNB) is approximately 50%, with mortality primarily driven by relapse. Eflornithine (DFMO) to reduce risk of relapse after completion of immunotherapy was investigated previously in a single-arm, phase II study (NMTRC003B; ClinicalTrials.gov identifier: NCT02395666) that suggested improved event-free survival (EFS) and overall survival (OS) compared with historical rates in a phase III trial (Children Oncology Group ANBL0032; ClinicalTrials.gov identifier: NCT00026312). Using patient-level data from ANBL0032 as an external control, we present new analyses to further evaluate DFMO as HRNB postimmunotherapy maintenance., Patients and Methods: NMTRC003B (2012-2016) enrolled patients with HRNB (N = 141) after standard up-front or refractory/relapse treatment who received up to 2 years of continuous treatment with oral DFMO (750 ± 250 mg/m
2 twice a day). ANBL0032 (2001-2015) enrolled patients with HRNB postconsolidation, 1,328 of whom were assigned to dinutuximab (ch.14.18) treatment. Selection rules identified 92 NMTRC003B patients who participated in (n = 87) or received up-front treatment consistent with (n = 5) ANBL0032 (the DFMO/treated group) and 852 patients from ANBL0032 who could have been eligible for NMTRC003B after immunotherapy, but did not enroll (the NO-DFMO/control group). The median follow-up time for DFMO/treated patients was 6.1 years (IQR, 5.2-7.2) versus 5.0 years (IQR, 3.5-7.0) for NO-DFMO/control patients. Kaplan-Meier and Cox regression compared EFS and OS for overall groups, 3:1 (NO-DFMO:DFMO) propensity score-matched cohorts balanced on 11 baseline demographic and disease characteristics with exact matching on MYCN , and additional sensitivity analyses., Results: DFMO after completion of immunotherapy was associated with improved EFS (hazard ratio [HR], 0.50 [95% CI, 0.29 to 0.84]; P = .008) and OS (HR, 0.38 [95% CI, 0.19 to 0.76]; P = .007). The results were confirmed with propensity score-matched cohorts and sensitivity analyses., Conclusion: The externally controlled analyses presented show a relapse risk reduction in patients with HRNB treated with postimmunotherapy DFMO.- Published
- 2024
- Full Text
- View/download PDF
30. Allogeneic hematopoietic cell transplantation for blastic plasmacytoid dendritic cell neoplasm: a CIBMTR analysis.
- Author
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Murthy HS, Zhang MJ, Chen K, Ahmed S, Deotare U, Ganguly S, Kansagra A, Michelis FV, Nishihori T, Patnaik M, Abid MB, Aljurf M, Arai Y, Bacher U, Badar T, Badawy SM, Ballen K, Battiwalla M, Beitinjaneh A, Bejanyan N, Bhatt VR, Brown VI, Martino R, Cahn JY, Castillo P, Cerny J, Chhabra S, Copelan E, Daly A, Dholaria B, Diaz Perez MA, Freytes CO, Grunwald MR, Hashmi S, Hildebrandt GC, Jamy O, Joseph J, Kanakry CG, Khera N, Krem MM, Kuwatsuka Y, Lazarus HM, Lekakis LJ, Liu H, Modi D, Munshi PN, Mussetti A, Palmisiano N, Patel SS, Rizzieri DA, Seo S, Shah MV, Sharma A, Sohl M, Solomon SR, Ulrickson M, Ustun C, van der Poel M, Verdonck LF, Wagner JL, Wang T, Wirk B, Zeidan A, Litzow M, Kebriaei P, Hourigan CS, Weisdorf DJ, Saber W, and Kharfan-Dabaja MA
- Subjects
- Humans, Middle Aged, Transplantation, Homologous, Neoplasm Recurrence, Local, Acute Disease, Chronic Disease, Recurrence, Dendritic Cells pathology, Hematopoietic Stem Cell Transplantation adverse effects, Myeloproliferative Disorders pathology
- Abstract
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy with a poor prognosis and considered incurable with conventional chemotherapy. Small observational studies reported allogeneic hematopoietic cell transplantation (allo-HCT) offers durable remissions in patients with BPDCN. We report an analysis of patients with BPDCN who received an allo-HCT, using data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). We identified 164 patients with BPDCN from 78 centers who underwent allo-HCT between 2007 and 2018. The 5-year overall survival (OS), disease-free survival (DFS), relapse, and nonrelapse mortality (NRM) rates were 51.2% (95% confidence interval [CI], 42.5-59.8), 44.4% (95% CI, 36.2-52.8), 32.2% (95% CI, 24.7-40.3), and 23.3% (95% CI, 16.9-30.4), respectively. Disease relapse was the most common cause of death. On multivariate analyses, age of ≥60 years was predictive for inferior OS (hazard ratio [HR], 2.16; 95% CI, 1.35-3.46; P = .001), and higher NRM (HR, 2.19; 95% CI, 1.13-4.22; P = .02). Remission status at time of allo-HCT (CR2/primary induction failure/relapse vs CR1) was predictive of inferior OS (HR, 1.87; 95% CI, 1.14-3.06; P = .01) and DFS (HR, 1.75; 95% CI, 1.11-2.76; P = .02). Use of myeloablative conditioning with total body irradiation (MAC-TBI) was predictive of improved DFS and reduced relapse risk. Allo-HCT is effective in providing durable remissions and long-term survival in BPDCN. Younger age and allo-HCT in CR1 predicted for improved survival, whereas MAC-TBI predicted for less relapse and improved DFS. Novel strategies incorporating allo-HCT are needed to further improve outcomes., (Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
- Published
- 2023
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31. A phase II trial of nifurtimox combined with topotecan and cyclophosphamide for refractory or relapsed neuroblastoma and medulloblastoma.
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Eslin D, Zage PE, Bergendahl G, Lewis E, Roberts W, Kraveka J, Mitchell D, Isakoff MS, Rawwas J, Wada RK, Fluchel M, Brown VI, Ginn K, Higgins T, BeeravallyNagulapally A, Dykema K, Hanna G, Ferguson W, and Saulnier Sholler GL
- Subjects
- Child, Humans, Topotecan adverse effects, Nifurtimox therapeutic use, Neoplasm Recurrence, Local pathology, Cyclophosphamide, Antineoplastic Combined Chemotherapy Protocols adverse effects, Medulloblastoma drug therapy, Neuroblastoma drug therapy, Neuroblastoma etiology, Cerebellar Neoplasms
- Abstract
Children with relapsed/refractory (R/R) neuroblastoma (NB) and medulloblastoma (MB) have poor outcomes. We evaluated the efficacy of nifurtimox (Nfx) in a clinical trial for children with R/R NB and MB. Subjects were divided into three strata: first relapse NB, multiply R/R NB, and R/R MB. All patients received Nfx (30 mg/kg/day divided TID daily), Topotecan (0.75 mg/m
2 /dose, days 1-5) and Cyclophosphamide (250 mg/m2 /dose, days 1-5) every 3 weeks. Response was assessed after every two courses using International Neuroblastoma Response Criteria and Response Evaluation Criteria in Solid Tumors (RECIST) criteria. One hundred and twelve eligible patients were enrolled with 110 evaluable for safety and 76 evaluable for response. In stratum 1, there was a 53.9% response rate (CR + PR), and a 69.3% total benefit rate (CR + PR + SD), with an average time on therapy of 165.2 days. In stratum 2, there was a 16.3% response rate, and a 72.1% total benefit rate, and an average time on study of 158.4 days. In stratum 3, there was a 20% response rate and a 65% total benefit rate, an average time on therapy of 105.0 days. The most common side effects included bone marrow suppression and reversible neurologic complications. The combination of Nfx, topotecan and cyclophosphamide was tolerated, and the objective response rate plus SD of 69.8% in these heavily pretreated populations suggests that this combination is an effective option for patients with R/R NB and MB. Although few objective responses were observed, the high percentage of stabilization of disease and prolonged response rate in patients with multiply relapsed disease shows this combination therapy warrants further testing., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)- Published
- 2023
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32. HLA Class I Genotype Is Associated with Relapse Risk after Allogeneic Stem Cell Transplantation for NPM1-Mutated Acute Myeloid Leukemia.
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Narayan R, Niroula A, Wang T, Kuxhausen M, He M, Meyer E, Chen YB, Bhatt VR, Beitinjaneh A, Nishihori T, Sharma A, Brown VI, Kamoun M, Diaz MA, Abid MB, Askar M, Kanakry CG, Gragert L, Bolon YT, Marsh SGE, Gadalla SM, Paczesny S, Spellman S, and Lee SJ
- Subjects
- Adult, Humans, Retrospective Studies, Chronic Disease, Genotype, Nuclear Proteins genetics, Recurrence, Hematopoietic Stem Cell Transplantation, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute therapy
- Abstract
Mutation-bearing peptide ligands from mutated nucleophosmin-1 (NPM1) protein have been empirically found to be presented by HLA class I in acute myeloid leukemia (AML). We hypothesized that HLA genotype may impact allogeneic hematopoietic stem cell transplantation (allo-HCT) outcomes in NPM1-mutated AML owing to differences in antigen presentation. We evaluated the effect of the variable of predicted strong binding to mutated NPM1 peptides using HLA class I genotypes from matched donor-recipient pairs on transplant recipients' overall survival (OS) and disease-free survival (DFS) as part of the primary objectives and cumulative incidence of relapse and nonrelapse mortality (NRM) as part of secondary objectives. Baseline and outcome data reported to the Center for International Blood and Marrow Transplant Research from a study cohort of adult patients (n = 1020) with NPM1-mutated de novo AML in first (71%) or second (29%) complete remission undergoing 8/8 matched related (18%) or matched unrelated (82%) allo-HCT were analyzed retrospectively. Class I alleles from donor-recipient pairs were analyzed for predicted strong HLA binding to mutated NPM1 using netMHCpan 4.0. A total of 429 (42%) donor-recipient pairs were classified as having predicted strong-binding HLA alleles (SBHAs) to mutated NPM1. In multivariable analyses adjusting for clinical covariates, the presence of predicted SBHAs was associated with a lower risk of relapse (hazard ratio [HR], .72; 95% confidence interval [CI], .55 to .94; P = .015). OS (HR, .81; 95% CI, .67 to .98; P = .028) and DFS (HR, .84; 95% CI, .69 to 1.01; P = .070) showed a suggestion of better outcomes if predicted SBHAs were present but did not meet the prespecified P value of <.025. NRM did not differ (HR, 1.04; P = .740). These hypothesis-generating data support further exploration of HLA genotype-neoantigen interactions in the allo-HCT context., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. All rights reserved.)
- Published
- 2023
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33. Impact of pre-transplant induction and consolidation cycles on AML allogeneic transplant outcomes: a CIBMTR analysis in 3113 AML patients.
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Boyiadzis M, Zhang MJ, Chen K, Abdel-Azim H, Abid MB, Aljurf M, Bacher U, Badar T, Badawy SM, Battiwalla M, Bejanyan N, Bhatt VR, Brown VI, Castillo P, Cerny J, Copelan EA, Craddock C, Dholaria B, Perez MAD, Ebens CL, Gale RP, Ganguly S, Gowda L, Grunwald MR, Hashmi S, Hildebrandt GC, Iqbal M, Jamy O, Kharfan-Dabaja MA, Khera N, Lazarus HM, Lin R, Modi D, Nathan S, Nishihori T, Patel SS, Pawarode A, Saber W, Sharma A, Solh M, Wagner JL, Wang T, Williams KM, Winestone LE, Wirk B, Zeidan A, Hourigan CS, Litzow M, Kebriaei P, de Lima M, Page K, and Weisdorf DJ
- Subjects
- Adult, Humans, Transplantation, Homologous, Transplantation Conditioning, Neoplasm Recurrence, Local etiology, Retrospective Studies, Hematopoietic Stem Cell Transplantation adverse effects, Leukemia, Myeloid, Acute
- Abstract
We investigated the impact of the number of induction/consolidation cycles on outcomes of 3113 adult AML patients who received allogeneic hematopoietic cell transplantation (allo-HCT) between 2008 and 2019. Patients received allo-HCT using myeloablative (MAC) or reduced-intensity (RIC) conditioning in first complete remission (CR) or with primary induction failure (PIF). Patients who received MAC allo-HCT in CR after 1 induction cycle had 1.3-fold better overall survival (OS) than 2 cycles to CR and 1.47-fold better than ≥3 cycles. OS after CR in 2 or ≥3 cycles was similar. Relapse risk was 1.65-fold greater in patients receiving ≥3 cycles to achieve CR. After RIC allo-HCT, the number of induction cycles to CR did not affect OS. Compared to CR in 1 cycle, relapse risk was 1.24-1.41-fold greater in patients receiving 2 or ≥3 cycles. For patients receiving only 1 cycle to CR, consolidation therapy prior to MAC allo-HCT was associated with improved OS vs. no consolidation therapy. Detectable MRD at the time of MAC allo-HCT did not impact outcomes while detectable MRD preceding RIC allo-HCT was associated with an increased risk of relapse. For allo-HCT in PIF, OS was significantly worse than allo-HCT in CR after 1-3 cycles., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
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- 2023
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34. Correction to: Impact of pre-transplant induction and consolidation cycles on AML allogeneic transplant outcomes: a CIBMTR analysis in 3113AML patients.
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Boyiadzis M, Zhang MJ, Chen K, Abdel-Azim H, Abid MB, Aljurf M, Bacher U, Badar T, Badawy SM, Battiwalla M, Bejanyan N, Bhatt VR, Brown VI, Castillo P, Cerny J, Copelan EA, Craddock C, Dholaria B, Perez MAD, Ebens CL, Gale RP, Ganguly S, Gowda L, Grunwald MR, Hashmi S, Hildebrandt GC, Iqbal M, Jamy O, Kharfan-Dabaja MA, Khera N, Lazarus HM, Lin R, Modi D, Nathan S, Nishihori T, Patel SS, Pawarode A, Saber W, Sharma A, Solh M, Wagner JL, Wang T, Williams KM, Winestone LE, Wirk B, Zeidan A, Hourigan CS, Litzow M, Kebriaei P, de Lima M, Page K, and Weisdorf DJ
- Published
- 2023
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35. Chronic pain in children and adolescents diagnosed with cancer: the challenge of mitigating the pain and the potential of integrating exercise into pain management.
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Caru M, Alberts NM, Freeman MC, Dandekar SC, Rao P, McKeone DJ, Brown VI, McGregor LM, and Schmitz KH
- Subjects
- Humans, Child, Adolescent, Pain Management, Exercise, Decision Making, Chronic Pain etiology, Chronic Pain therapy, Neoplasms complications
- Abstract
Background: Pain is one of the most common and distressing symptoms experienced by children and adolescents diagnosed with cancer. It is vital that children and adolescents receive adequate pain management early on in their cancer treatments to mitigate pain and cancer-related symptoms. Exercise training shows particular promise in the management of acute and chronic pain among children and adolescents diagnosed with cancer., Methods: This position paper comes to outline the challenge of mitigating pain in children and adolescents diagnosed with cancer, and the potential benefits of integrating exercise training to the management of chronic pain in this population in need., Results: Integrating exercise training into the care and pain management of children and adolescents diagnosed with cancer who have chronic pain would have the advantage of addressing several shortcomings of pain medication. Pain medication aims to temporarily manage or reduce pain; it does not have the potential to directly improve a patient's physical condition in the way that exercise training can. The current paucity of data available on the use of exercise training as a complementary treatment to pain medications to reduce chronic pain in children and adolescents diagnosed with cancer allows only for hypotheses on the effectiveness of this pain management modality., Conclusion: More research on this important topic is necessary and mitigating pain effectively while also reducing the use of opioid pain medication is an important goal shared by patients, their families, clinicians, and researchers alike. Future research in this area has great potential to inform clinical care, clinical care guidelines, and policy-making decisions for pain management in children and adolescents diagnosed with cancer who experience chronic pain., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
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- 2023
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36. A pilot study of genomic-guided induction therapy followed by immunotherapy with difluoromethylornithine maintenance for high-risk neuroblastoma.
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Kraveka JM, Lewis EC, Bergendahl G, Ferguson W, Oesterheld J, Kim E, Nagulapally AB, Dykema KJ, Brown VI, Roberts WD, Mitchell D, Eslin D, Hanson D, Isakoff MS, Wada RK, Harrod VL, Rawwas J, Hanna G, Hendricks WPD, Byron SA, Snuderl M, Serrano J, Trent JM, and Saulnier Sholler GL
- Subjects
- Humans, Eflornithine adverse effects, Pilot Projects, Induction Chemotherapy, Retrospective Studies, Immunotherapy, Immunologic Factors, Genomics, RNA therapeutic use, Neuroblastoma drug therapy, Neuroblastoma genetics, Antineoplastic Agents therapeutic use
- Abstract
Background: Survival for patients with high-risk neuroblastoma (HRNB) remains poor despite aggressive multimodal therapies., Aims: To study the feasibility and safety of incorporating a genomic-based targeted agent to induction therapy for HRNB as well as the feasibility and safety of adding difluoromethylornithine (DFMO) to anti-GD2 immunotherapy., Methods: Twenty newly diagnosed HRNB patients were treated on this multicenter pilot trial. Molecular tumor boards selected one of six targeted agents based on tumor-normal whole exome sequencing and tumor RNA-sequencing results. Treatment followed standard upfront HRNB chemotherapy with the addition of the selected targeted agent to cycles 3-6 of induction. Following consolidation, DFMO (750 mg/m
2 twice daily) was added to maintenance with dinutuximab and isotretinoin, followed by continuation of DFMO alone for 2 years. DNA methylation analysis was performed retrospectively and compared to RNA expression., Results: Of the 20 subjects enrolled, 19 started targeted therapy during cycle 3 and 1 started during cycle 5. Eighty-five percent of subjects met feasibility criteria (receiving 75% of targeted agent doses). Addition of targeted agents did not result in toxicities requiring dose reduction of chemotherapy or permanent discontinuation of targeted agent. Following standard consolidation, 15 subjects continued onto immunotherapy with DFMO. This combination was well-tolerated and resulted in no unexpected adverse events related to DFMO., Conclusion: This study demonstrates the safety and feasibility of adding targeted agents to standard induction therapy and adding DFMO to immunotherapy for HRNB. This treatment regimen has been expanded to a Phase II trial to evaluate efficacy., (© 2022 The Authors. Cancer Reports published by Wiley Periodicals LLC.)- Published
- 2022
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37. Clinical Characteristics and Outcomes of COVID-19 in Pediatric and Early Adolescent and Young Adult Hematopoietic Stem Cell Transplant Recipients: A Cohort Study.
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Bhatt NS, Sharma A, St Martin A, Abid MB, Brown VI, Diaz Perez MA, Frangoul H, Gadalla SM, Herr MM, Krem MM, Lazarus HM, Martens MJ, Mehta PA, Nishihori T, Prestidge T, Pulsipher MA, Rangarajan HG, Williams KM, Winestone LE, Yin DE, Riches ML, Dandoy CE, and Auletta JJ
- Subjects
- Adolescent, COVID-19 Testing, Child, Cohort Studies, Humans, Oxygen, Young Adult, COVID-19 epidemiology, Hematopoietic Stem Cell Transplantation adverse effects
- Abstract
Adult hematopoietic stem cell transplantation (HSCT) recipients are at a high risk of adverse outcomes after COVID-19. Although children have had better outcomes after COVID-19 compared to adults, data on risk factors and outcomes of COVID-19 among pediatric HSCT recipients are lacking. We describe outcomes of HSCT recipients who were ≤21 years of age at COVID-19 diagnosis and were reported to the Center for International Blood and Marrow Transplant Research between March 27, 2020, and May 7, 2021. The primary outcome was overall survival after COVID-19 diagnosis. We determined risk factors of COVID-19 as a secondary outcome in a subset of allogeneic HSCT recipients. A total of 167 pediatric HSCT recipients (135 allogeneic; 32 autologous HSCT recipients) were included. Median time from HSCT to COVID-19 was 15 months (interquartile range [IQR] 7-45) for allogeneic HSCT recipients and 16 months (IQR 6-59) for autologous HSCT recipients. Median follow-up from COVID-19 diagnosis was 53 days (range 1-270) and 37 days (1-179) for allogeneic and autologous HSCT recipients, respectively. Although COVID-19 was mild in 87% (n = 146/167), 10% (n = 16/167) of patients required supplemental oxygen or mechanical ventilation. The 45-day overall survival was 95% (95% confidence interval [CI], 90-99) and 90% (74-99) for allogeneic and autologous HSCT recipients, respectively. Cox regression analysis showed that patients with a hematopoietic cell transplant comorbidity index (HCT-CI) score of 1-2 were more likely to be diagnosed with COVID-19 (hazard ratio 1.95; 95% CI, 1.03-3.69, P = .042) compared to those with an HCT-CI of 0. Pediatric and early adolescent and young adult HSCT recipients with pre-HSCT comorbidities were more likely to be diagnosed with COVID-19. Overall mortality, albeit higher than the reported general population estimates, was lower when compared with previously published data focusing on adult HSCT recipients., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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38. Natural Killer Cell Alloreactivity Predicted By Killer Cell Immunoglobulin-Like Receptor Ligand Mismatch Does Not Impact Engraftment in Umbilical Cord Blood and Haploidentical Stem Cell Transplantation.
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Otegbeye F, Vina MAF, Wang T, Bolon YT, Lazaryan A, Beitinjaneh A, Bhatt VR, Castillo P, Marsh SGE, Hildebrandt GC, Assal A, Brown VI, Hsu J, Spellman S, de Lima M, and Lee SJ
- Subjects
- Histocompatibility Antigens immunology, Humans, Ligands, Receptors, KIR immunology, Fetal Blood, Hematopoietic Stem Cell Transplantation, Killer Cells, Natural immunology
- Abstract
Natural killer cell alloreactivity is determined by killer cell immunoglobulin-like receptor (KIR) ligands in donor and recipient pairs. A small, single institution study suggested that the risk of primary graft failure after cord blood hematopoietic cell transplantation (CBT) can be predicted by host-versus-graft (HvG)-directed natural killer cell alloreactivity. In the haploidentical transplantation (Haplo HCT) cohort, graft failures were observed only in graft-versus-host (GvH) KIR ligand mismatched pairs. A subsequent study was designed to explore the association between HvG and GvH KIR ligand mismatching and engraftment in both CBT and Haplo HCT using the large, multicenter transplant population of the Center for International Blood and Transplant Research database. Nine hundred single CBT (sCBT), 954 double CBT (dCBT), and 671 Haplo HCT performed between 2008 and 2017 for acute leukemias and myelodysplastic syndrome were examined. Several models of KIR-L interactions were analyzed by multiple regression analyses for their association with engraftment, overall survival (OS), and transplant-related mortality (TRM). In sCBT, although HvG or bidirectional KIR ligand mismatch (KIR-L-MM) was initially associated with higher TRM in the first 6 months after transplantation, this effect was nullified after 6 months such that long-term survival was not different compared to GvH KIR-L-MM or KIR-L matched (KIR-L-M) pairs. There was no significant difference in neutrophil and platelet engraftment. In dCBT, no significant differences were seen in engraftment, OS and TRM. In the Haplo cohort there was faster platelet recovery in the GvH KIR-L-MM/KIR-L-M pairs versus HvG KIR-L-MM or bidirectional mismatch (HR 1.23, P= .0116). There was no significant association with OS, TRM, or neutrophil engraftment. In this large registry study, KIR-L mismatching did not significantly impact engraftment, TRM, or survival in CBT and Haplo HCT, although an association with platelet engraftment in Haplo HCT was demonstrated., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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39. Genomic and Transcriptomic Analysis of Relapsed and Refractory Childhood Solid Tumors Reveals a Diverse Molecular Landscape and Mechanisms of Immune Evasion.
- Author
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Byron SA, Hendricks WPD, Nagulapally AB, Kraveka JM, Ferguson WS, Brown VI, Eslin DE, Mitchell D, Cornelius A, Roberts W, Isakoff MS, Oesterheld JE, Wada RK, Rawwas J, Neville K, Zage PE, Harrod VL, Bergendahl G, VanSickle E, Dykema K, Bond J, Chou HC, Wei JS, Wen X, Reardon HV, Roos A, Nasser S, Izatt T, Enriquez D, Hegde AM, Cisneros F, Christofferson A, Turner B, Szelinger S, Keats JJ, Halperin RF, Khan J, Saulnier Sholler GL, and Trent JM
- Subjects
- Adolescent, Adult, Child, Child, Preschool, Female, Follow-Up Studies, Gene Expression Regulation, Neoplastic, Humans, Infant, Longitudinal Studies, Male, Neoplasm Recurrence, Local drug therapy, Neoplasm Recurrence, Local genetics, Neoplasm Recurrence, Local immunology, Neoplasms drug therapy, Neoplasms genetics, Neoplasms immunology, Prognosis, Survival Rate, Transcriptome, Young Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Biomarkers, Tumor genetics, Drug Resistance, Neoplasm, Immune Evasion, Mutation, Neoplasm Recurrence, Local pathology, Neoplasms pathology
- Abstract
Children with treatment-refractory or relapsed (R/R) tumors face poor prognoses. As the genomic underpinnings driving R/R disease are not well defined, we describe here the genomic and transcriptomic landscapes of R/R solid tumors from 202 patients enrolled in Beat Childhood Cancer Consortium clinical trials. Tumor mutational burden (TMB) was elevated relative to untreated tumors at diagnosis, with one-third of tumors classified as having a pediatric high TMB. Prior chemotherapy exposure influenced the mutational landscape of these R/R tumors, with more than 40% of tumors demonstrating mutational signatures associated with platinum or temozolomide chemotherapy and two tumors showing treatment-associated hypermutation. Immunogenomic profiling found a heterogenous pattern of neoantigen and MHC class I expression and a general absence of immune infiltration. Transcriptional analysis and functional gene set enrichment analysis identified cross-pathology clusters associated with development, immune signaling, and cellular signaling pathways. While the landscapes of these R/R tumors reflected those of their corresponding untreated tumors at diagnosis, important exceptions were observed, suggestive of tumor evolution, treatment resistance mechanisms, and mutagenic etiologies of treatment. SIGNIFICANCE: Tumor heterogeneity, chemotherapy exposure, and tumor evolution contribute to the molecular profiles and increased mutational burden that occur in treatment-refractory and relapsed childhood solid tumors., (©2021 American Association for Cancer Research.)
- Published
- 2021
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40. A subset analysis of a phase II trial evaluating the use of DFMO as maintenance therapy for high-risk neuroblastoma.
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Lewis EC, Kraveka JM, Ferguson W, Eslin D, Brown VI, Bergendahl G, Roberts W, Wada RK, Oesterheld J, Mitchell D, Foley J, Zage P, Rawwas J, Rich M, Lorenzi E, Broglio K, Berry D, and Saulnier Sholler GL
- Subjects
- Child, Preschool, Disease-Free Survival, Eflornithine therapeutic use, Female, Humans, Maintenance Chemotherapy, Male, Prognosis, Standard of Care, Treatment Outcome, Eflornithine administration & dosage, Neuroblastoma drug therapy
- Abstract
Neuroblastoma is a sympathetic nervous system tumor, primarily presenting in children under 6 years of age. The long-term prognosis for patients with high-risk neuroblastoma (HRNB) remains poor despite aggressive multimodal therapy. This report provides an update to a phase II trial evaluating DFMO as maintenance therapy in HRNB. Event-free survival (EFS) and overall survival (OS) of 81 subjects with HRNB treated with standard COG induction, consolidation and immunotherapy followed by 2 years of DFMO on the NMTRC003/003b Phase II trial were compared to a historical cohort of 76 HRNB patients treated at Beat Childhood Cancer Research Consortium (BCC) hospitals who were disease-free after completion of standard upfront therapy and did not receive DFMO. The 2- and 5-year EFS were 86.4% [95% confidence interval (CI) 79.3%-94.2%] and 85.2% [77.8%-93.3%] for the NMTRC003/003b subset vs 78.3% [69.5%-88.3%] and 65.6% [55.5%-77.5%] for the historical control group. The 2- and 5-year OS were 98.8% [96.4-100%] and 95.1% [90.5%-99.9%] vs 94.4% [89.3%-99.9%] and 81.6% [73.0%-91.2%], respectively. DFMO maintenance for HRNB after completion of standard of care therapy was associated with improved EFS and OS relative to historical controls treated at the same institutions. These results support additional investigations into the potential role of DFMO in preventing relapse in HRNB., (© 2020 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)
- Published
- 2020
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41. Increased overall and bacterial infections following myeloablative allogeneic HCT for patients with AML in CR1.
- Author
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Ustun C, Kim S, Chen M, Beitinjaneh AM, Brown VI, Dahi PB, Daly A, Diaz MA, Freytes CO, Ganguly S, Hashmi S, Hildebrandt GC, Lazarus HM, Nishihori T, Olsson RF, Page KM, Papanicolaou G, Saad A, Seo S, William BM, Wingard JR, Wirk B, Yared JA, Perales MA, Auletta JJ, Komanduri KV, Lindemans CA, and Riches ML
- Subjects
- Adult, Hematopoietic Stem Cell Transplantation methods, Humans, Leukemia, Myeloid, Acute complications, Myeloablative Agonists therapeutic use, Remission Induction, Time Factors, Transplantation Conditioning adverse effects, Transplantation Conditioning methods, Transplantation, Homologous adverse effects, Treatment Outcome, Bacterial Infections etiology, Hematopoietic Stem Cell Transplantation adverse effects, Infections etiology, Leukemia, Myeloid, Acute therapy, Myeloablative Agonists adverse effects
- Abstract
Presumably, reduced-intensity/nonmyeloablative conditioning (RIC/NMA) for allogeneic hematopoietic cell transplantation (alloHCT) results in reduced infections compared with myeloablative conditioning (MAC) regimens; however, published evidence is limited. In this Center for International Blood and Marrow Transplant Research study, 1755 patients (aged ≥40 years) with acute myeloid leukemia in first complete remission were evaluated for infections occurring within 100 days after T-cell replete alloHCT. Patients receiving RIC/NMA (n = 777) compared with those receiving MAC (n = 978) were older and underwent transplantation more recently; however, the groups were similar regarding Karnofsky performance score, HCT-comorbidity index, and cytogenetic risk. One or more infections occurred in 1045 (59.5%) patients (MAC, 595 [61%]; RIC/NMA, 450 [58%]; P = .21) by day 100. The median time to initial infection after MAC conditioning occurred earlier (MAC, 15 days [range, <1-99 days]; RIC/NMA, 21 days [range, <1-100 days]; P < .001). Patients receiving MAC were more likely to experience at least 1 bacterial infection by day 100 (MAC, 46% [95% confidence interval (CI), 43-49]; RIC/NMA, 37% [95% CI, 34-41]; P = .0004), whereas at least a single viral infection was more prevalent in the RIC/NMA cohort (MAC, 34% [95% CI, 31-37]; RIC/NMA, 39% [95% CI, 36-42]; P = .046). MAC remained a risk factor for bacterial infections in multivariable analysis (relative risk, 1.44; 95% CI, 1.23-1.67; P < .0001). Moreover, the rate of any infection per patient-days at risk in the first 100 days (infection density) after alloHCT was greater for the MAC cohort (1.21; 95% CI, 1.11-1.32; P < .0001). RIC/NMA was associated with reduced infections, especially bacterial infections, in the first 100 days after alloHCT., (© 2019 by The American Society of Hematology.)
- Published
- 2019
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42. Dasatinib Plus Intensive Chemotherapy in Children, Adolescents, and Young Adults With Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: Results of Children's Oncology Group Trial AALL0622.
- Author
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Slayton WB, Schultz KR, Kairalla JA, Devidas M, Mi X, Pulsipher MA, Chang BH, Mullighan C, Iacobucci I, Silverman LB, Borowitz MJ, Carroll AJ, Heerema NA, Gastier-Foster JM, Wood BL, Mizrahy SL, Merchant T, Brown VI, Sieger L, Siegel MJ, Raetz EA, Winick NJ, Loh ML, Carroll WL, and Hunger SP
- Subjects
- Adolescent, Adult, Age Factors, Antineoplastic Combined Chemotherapy Protocols adverse effects, Child, Child, Preschool, Dasatinib administration & dosage, Dasatinib adverse effects, Disease-Free Survival, Female, Hematopoietic Stem Cell Transplantation methods, Humans, Infant, Male, Survival Rate, Young Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy
- Abstract
Purpose Addition of imatinib to intensive chemotherapy improved survival for children and young adults with Philadelphia chromosome-positive acute lymphoblastic leukemia. Compared with imatinib, dasatinib has increased potency, CNS penetration, and activity against imatinib-resistant clones. Patients and Methods Children's Oncology Group (COG) trial AALL0622 (Bristol Myers Squibb trial CA180-204) tested safety and feasibility of adding dasatinib to intensive chemotherapy starting at induction day 15 in patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia age 1 to 30 years. Allogeneic hematopoietic stem-cell transplantation (HSCT) was recommended for patients at high risk based on slow response and for those with a matched family donor regardless of response after at least 11 weeks of therapy. Patients at standard risk based on rapid response received chemotherapy plus dasatinib for an additional 120 weeks. Patients with overt CNS leukemia received cranial irradiation. Results Sixty eligible patients were enrolled. Five-year overall (OS) and event-free survival rates (± standard deviations [SD]) were 86% ± 5% and 60% ± 7% overall, 87% ± 5% and 61% ± 7% for standard-risk patients (n = 48; 19% underwent HSCT), and 89% ± 13% and 67% ± 19% for high-risk patients (n = 9; 89% underwent HSCT), respectively. Five-year cumulative incidence (± SD) of CNS relapse was 15% ± 6%. Outcomes (± SDs) were similar to those in COG AALL0031, which used the same chemotherapy with continuous imatinib: 5-year OS of 81% ± 6% versus 86% ± 5% ( P = .63) and 5-year disease-free survival of 68% ± 7% versus 60% ± 7% ( P = 0.31) for AALL0031 versus AALL0622, respectively. IKZF1 deletions, present in 56% of tested patients, were associated with significantly inferior OS and event-free survival overall and in standard-risk patients. Conclusion Dasatinib was well tolerated with chemotherapy and provided outcomes similar to those with imatinib in COG AALL0031, where all patients received cranial irradiation. Our results support limiting HSCT to slow responders and suggest a potential role for transplantation in rapid responders with IKZF1 deletions.
- Published
- 2018
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43. Hematopoietic Stem Cell Transplantation Activity in Pediatric Cancer between 2008 and 2014 in the United States: A Center for International Blood and Marrow Transplant Research Report.
- Author
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Khandelwal P, Millard HR, Thiel E, Abdel-Azim H, Abraham AA, Auletta JJ, Boulad F, Brown VI, Camitta BM, Chan KW, Chaudhury S, Cowan MJ, Angel-Diaz M, Gadalla SM, Gale RP, Hale G, Kasow KA, Keating AK, Kitko CL, MacMillan ML, Olsson RF, Page KM, Seber A, Smith AR, Warwick AB, Wirk B, and Mehta PA
- Subjects
- Adolescent, Allografts, Autografts, Child, Child, Preschool, Female, Humans, Infant, Male, Retrospective Studies, Brain Neoplasms therapy, Calcineurin Inhibitors administration & dosage, Hematopoietic Stem Cell Transplantation, Methotrexate administration & dosage, Neuroblastoma therapy, Transplantation Conditioning methods
- Abstract
This Center for International Blood and Marrow Transplant Research report describes the use of hematopoietic stem cell transplantation (HSCT) in pediatric patients with cancer, 4408 undergoing allogeneic (allo) and3076 undergoing autologous (auto) HSCT in the United States between 2008 and 2014. In both settings, there was a greater proportion of boys (n = 4327; 57%), children < 10 years of age (n = 4412; 59%), whites (n = 5787; 77%), and children with a performance score ≥ 90% at HSCT (n = 6187; 83%). Leukemia was the most common indication for an allo-transplant (n = 4170; 94%), and among these, acute lymphoblastic leukemia in second complete remission (n = 829; 20%) and acute myeloid leukemia in first complete remission (n = 800; 19%) werethe most common. The most frequently used donor relation, stem cell sources, and HLA match were unrelated donor (n = 2933; 67%), bone marrow (n = 2378; 54%), and matched at 8/8 HLA antigens (n = 1098; 37%) respectively. Most allo-transplants used myeloablative conditioning (n = 4070; 92%) and calcineurin inhibitors and methotrexate (n = 2245; 51%) for acute graft-versus-host disease prophylaxis. Neuroblastoma was the most common primary neoplasm for an auto-transplant (n = 1338; 44%). Tandem auto-transplants for neuroblastoma declined after 2012 (40% in 2011, 25% in 2012, and 8% in 2014), whereas tandem auto-transplants increased for brain tumors (57% in 2008 and 77% in 2014). Allo-transplants from relatives other than HLA-identical siblings doubled between 2008 and 2014 (3% in 2008 and 6% in 2014). These trends will be monitored in future reports of transplant practices in the United States., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)
- Published
- 2017
- Full Text
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44. Transplant Outcomes for Children with T Cell Acute Lymphoblastic Leukemia in Second Remission: A Report from the Center for International Blood and Marrow Transplant Research.
- Author
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Burke MJ, Verneris MR, Le Rademacher J, He W, Abdel-Azim H, Abraham AA, Auletta JJ, Ayas M, Brown VI, Cairo MS, Chan KW, Diaz Perez MA, Dvorak CC, Egeler RM, Eldjerou L, Frangoul H, Guilcher GMT, Hayashi RJ, Ibrahim A, Kasow KA, Leung WH, Olsson RF, Pulsipher MA, Shah N, Shah NN, Thiel E, Talano JA, and Kitko CL
- Subjects
- Academic Medical Centers, Acute Disease, Adolescent, Child, Child, Preschool, Chronic Disease, Female, Graft vs Host Disease immunology, Graft vs Host Disease mortality, Graft vs Host Disease pathology, Humans, International Cooperation, Male, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma immunology, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma mortality, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma pathology, Prospective Studies, Recurrence, Remission Induction, Severity of Illness Index, Survival Analysis, Transplantation, Homologous, Treatment Outcome, Bone Marrow Transplantation methods, Graft vs Host Disease drug therapy, Immunosuppressive Agents therapeutic use, Myeloablative Agonists therapeutic use, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma therapy, Transplantation Conditioning methods
- Abstract
Survival for children with relapsed T cell acute lymphoblastic leukemia (T-ALL) is poor when treated with chemotherapy alone, and outcomes after allogeneic hematopoietic cell transplantation (HCT) is not well described. Two hundred twenty-nine children with T-ALL in second complete remission (CR2) received an HCT after myeloablative conditioning between 2000 and 2011 and were reported to the Center for International Blood and Marrow Transplant Research. Median age was 10 years (range, 2 to 18). Donor source was umbilical cord blood (26%), matched sibling bone marrow (38%), or unrelated bone marrow/peripheral blood (36%). Acute (grades II to IV) and chronic graft-versus-host disease occurred in, respectively, 35% (95% confidence interval [CI], 27% to 45%) and 26% (95% CI, 20% to 33%) of patients. Transplant-related mortality at day 100 and 3-year relapse rates were 13% (95% CI, 9% to 18%) and 30% (95% CI, 24% to 37%), respectively. Three-year overall survival and disease-free survival rates were 48% (95% CI, 41% to 55%) and 46% (95% CI, 39% to 52%), respectively. In multivariate analysis, patients with bone marrow relapse, with or without concurrent extramedullary relapse before HCT, were most likely to relapse (hazard ratio, 3.94; P = .005) as compared with isolated extramedullary disease. In conclusion, HCT for pediatric T-ALL in CR2 demonstrates reasonable and durable outcomes, and consideration for HCT is warranted., (Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
45. Targeting the PI3K/AKT/mTOR signaling axis in children with hematologic malignancies.
- Author
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Barrett D, Brown VI, Grupp SA, and Teachey DT
- Subjects
- Animals, Antineoplastic Agents therapeutic use, Child, Hematologic Neoplasms drug therapy, Humans, Lymphoproliferative Disorders drug therapy, Molecular Targeted Therapy, Phosphoinositide-3 Kinase Inhibitors, Proto-Oncogene Proteins c-akt antagonists & inhibitors, Signal Transduction, TOR Serine-Threonine Kinases antagonists & inhibitors, Antineoplastic Agents pharmacology, Hematologic Neoplasms metabolism, Lymphoproliferative Disorders metabolism, Phosphatidylinositol 3-Kinases metabolism, Proto-Oncogene Proteins c-akt metabolism, TOR Serine-Threonine Kinases metabolism
- Abstract
The phosphatidylinositiol 3-kinase (PI3K), AKT, mammalian target of rapamycin (mTOR) signaling pathway (PI3K/AKT/mTOR) is frequently dysregulated in disorders of cell growth and survival, including a number of pediatric hematologic malignancies. The pathway can be abnormally activated in childhood acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), and chronic myelogenous leukemia (CML), as well as in some pediatric lymphomas and lymphoproliferative disorders. Most commonly, this abnormal activation occurs as a consequence of constitutive activation of AKT, providing a compelling rationale to target this pathway in many of these conditions. A variety of agents, beginning with the rapamycin analogue (rapalog) sirolimus, have been used successfully to target this pathway in a number of pediatric hematologic malignancies. Rapalogs demonstrate significant preclinical activity against ALL, which has led to a number of clinical trials. Moreover, rapalogs can synergize with a number of conventional cytotoxic agents and overcome pathways of chemotherapeutic resistance for drugs commonly used in ALL treatment, including methotrexate and corticosteroids. Based on preclinical data, rapalogs are also being studied in AML, CML, and non-Hodgkin's lymphoma. Recently, significant progress has been made using rapalogs to treat pre-malignant lymphoproliferative disorders, including the autoimmune lymphoproliferative syndrome (ALPS); complete remissions in children with otherwise therapy-resistant disease have been seen. Rapalogs only block one component of the pathway (mTORC1), and newer agents are under preclinical and clinical development that can target different and often multiple protein kinases in the PI3K/AKT/mTOR pathway. Most of these agents have been tolerated in early-phase clinical trials. A number of PI3K inhibitors are under investigation. Of note, most of these also target other protein kinases. Newer agents are under development that target both mTORC1 and mTORC2, mTORC1 and PI3K, and the triad of PI3K, mTORC1, and mTORC2. Preclinical data suggest these dual- and multi-kinase inhibitors are more potent than rapalogs against many of the aforementioned hematologic malignancies. Two classes of AKT inhibitors are under development, the alkyl-lysophospholipids (APLs) and small molecule AKT inhibitors. Both classes have agents currently in clinical trials. A number of drugs are in development that target other components of the pathway, including eukaryotic translation initiation factor (eIF) 4E (eIF4E) and phosphoinositide-dependent protein kinase 1 (PDK1). Finally, a number of other key signaling pathways interact with PI3K/AKT/mTOR, including Notch, MNK, Syk, MAPK, and aurora kinase. These alternative pathways are being targeted alone and in combination with PI3K/AKT/mTOR inhibitors with promising preclinical results in pediatric hematologic malignancies. This review provides a comprehensive overview of the abnormalities in the PI3K/AKT/mTOR signaling pathway in pediatric hematologic malignancies, the agents that are used to target this pathway, and the results of preclinical and clinical trials, using those agents in childhood hematologic cancers.
- Published
- 2012
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46. Long-term protection from syngeneic acute lymphoblastic leukemia by CpG ODN-mediated stimulation of innate and adaptive immune responses.
- Author
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Seif AE, Barrett DM, Milone M, Brown VI, Grupp SA, and Reid GS
- Subjects
- Animals, Immunologic Memory, Lymphocyte Activation, Mice, Mice, Inbred BALB C, Mice, Inbred NOD, Mice, SCID, Mice, Transgenic, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma immunology, Reverse Transcriptase Polymerase Chain Reaction, T-Lymphocytes immunology, T-Lymphocytes metabolism, Th1 Cells immunology, Th1 Cells metabolism, Cytotoxicity, Immunologic immunology, Immunity, Innate drug effects, Immunotherapy, Adoptive, Oligodeoxyribonucleotides pharmacology, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy
- Abstract
Acute lymphoblastic leukemia (ALL) is the most common childhood cancer and remains a major cause of mortality in children with recurrent disease and in adults. Despite observed graft-versus-leukemia effects after stem cell transplantation, successful immune therapies for ALL have proven elusive. We previously reported immunostimulatory oligodeoxynucleotides containing CpG motifs (CpG ODN) enhance allogeneic T(h)1 responses and reduce leukemic burden of primary human ALL xenografts. To further the development of CpG ODN as a novel ALL therapy, we investigated the antileukemia activity induced by CpG ODN in a transplantable syngeneic pre-B ALL model. CpG ODN induced early killing of leukemia by innate immune effectors both in vitro and in vivo. Mice were treated with CpG ODN starting 7 days after injection with leukemia to mimic a minimal residual disease state and achieved T cell-dependent remissions of more than 6 months. In addition, mice in remission after CpG ODN treatment were protected from leukemia rechallenge, and adoptive transfer of T cells from mice in remission conferred protection against leukemia growth. To our knowledge, this is the first demonstration that CpG ODN induce a durable remission and ongoing immune-mediated protection in ALL, suggesting this treatment may have clinical utility in patients with minimal residual disease.
- Published
- 2009
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47. Mammalian target of rapamycin inhibitors and their potential role in therapy in leukaemia and other haematological malignancies.
- Author
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Teachey DT, Grupp SA, and Brown VI
- Subjects
- Autoimmune Diseases drug therapy, Autoimmune Diseases metabolism, Hematologic Neoplasms metabolism, Humans, Leukemia drug therapy, Leukemia metabolism, Lymphoproliferative Disorders drug therapy, Lymphoproliferative Disorders metabolism, Signal Transduction drug effects, TOR Serine-Threonine Kinases, Antineoplastic Agents therapeutic use, Hematologic Neoplasms drug therapy, Protein Kinase Inhibitors therapeutic use, Protein Kinases metabolism, Sirolimus therapeutic use
- Abstract
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that functions as a key regulator of cell growth, protein synthesis, and cell-cycle progression through interactions with a number of signalling pathways, including PI3K/AKT, ras, TCL1, and BCR/ABL. Many haematological malignancies have aberrant activation of the mTOR and related signalling pathways. Accordingly, mTOR inhibitors, a class of signal transduction inhibitors that were originally developed as immunosuppressive agents, are being investigated in preclinical models and clinical trials for a number of haematological malignancies. Sirolimus and second-generation mTOR inhibitors, such as temsirolimus and everolimus, are safe and relatively well-tolerated, making them potentially attractive as single agents or in combination with conventional cytotoxics and other targeted therapies. Promising early clinical data suggests activity of mTOR inhibitors in a number of haematological diseases, including acute lymphoblastic leukaemia, chronic myeloid leukaemia, mantle cell lymphoma, anaplastic large cell lymphoma, and lymphoproliferative disorders. This review describes the rationale for using mTOR inhibitors in a variety of haematological diseases with a focus on their use in leukaemia.
- Published
- 2009
- Full Text
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48. mTOR inhibitors are synergistic with methotrexate: an effective combination to treat acute lymphoblastic leukemia.
- Author
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Teachey DT, Sheen C, Hall J, Ryan T, Brown VI, Fish J, Reid GS, Seif AE, Norris R, Chang YJ, Carroll M, and Grupp SA
- Subjects
- Animals, Cell Line, Tumor, Cyclin D, Cyclins metabolism, Drug Resistance, Neoplasm, Drug Synergism, Humans, Mice, Mice, Inbred NOD, Mice, SCID, Neoplasm Transplantation, Precursor Cell Lymphoblastic Leukemia-Lymphoma metabolism, TOR Serine-Threonine Kinases, Tetrahydrofolate Dehydrogenase metabolism, Transplantation, Heterologous, Antimetabolites, Antineoplastic administration & dosage, Methotrexate administration & dosage, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Protein Kinase Inhibitors administration & dosage, Protein Kinases metabolism
- Abstract
We have previously demonstrated that mTOR inhibitors (MTIs) are active in preclinical models of acute lymphoblastic leukemia (ALL). MTIs may increase degradation of cyclin D1, a protein involved in dihydrofolate reductase (DHFR) synthesis. Because resistance to methotrexate may correlate with high DHFR expression, we hypothesized MTIs may increase sensitivity of ALL to methotrexate through decreasing DHFR by increasing turn-over of cyclin D1. We tested this hypothesis using multiple ALL cell lines and nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice xenografted with human ALL. We found MTIs and methotrexate were synergistic in combination in vitro and in vivo. Mice treated with both drugs went into a complete and durable remission whereas single agent treatment caused an initial partial response that ultimately progressed. ALL cells treated with MTIs had markedly decreased expression of DHFR and cyclin D1, providing a novel mechanistic explanation for a combined effect. We found methotrexate and MTIs are an effective and potentially synergistic combination in ALL.
- Published
- 2008
- Full Text
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49. Targeting Notch signaling in autoimmune and lymphoproliferative disease.
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Teachey DT, Seif AE, Brown VI, Bruno M, Bunte RM, Chang YJ, Choi JK, Fish JD, Hall J, Reid GS, Ryan T, Sheen C, Zweidler-McKay P, and Grupp SA
- Subjects
- Animals, Antibodies, Antinuclear blood, Antibodies, Antinuclear immunology, Dipeptides adverse effects, Dipeptides therapeutic use, Disease Models, Animal, Drug Evaluation, Preclinical, Enzyme Inhibitors adverse effects, Enzyme Inhibitors therapeutic use, Humans, Immunoglobulin G blood, Immunoglobulin G immunology, Lupus Erythematosus, Systemic blood, Lupus Erythematosus, Systemic diagnostic imaging, Lupus Erythematosus, Systemic immunology, Lymph Nodes diagnostic imaging, Lymph Nodes immunology, Lymph Nodes metabolism, Lymphocyte Activation drug effects, Lymphocyte Activation immunology, Lymphoproliferative Disorders blood, Lymphoproliferative Disorders diagnostic imaging, Lymphoproliferative Disorders immunology, Mice, Mice, Inbred CBA, Mice, Inbred MRL lpr, Nephritis blood, Nephritis diagnostic imaging, Nephritis drug therapy, Nephritis immunology, Random Allocation, Receptors, Notch immunology, Signal Transduction immunology, Spleen diagnostic imaging, Spleen immunology, Spleen metabolism, T-Lymphocytes metabolism, Ultrasonography, Dipeptides pharmacology, Enzyme Inhibitors pharmacology, Lupus Erythematosus, Systemic drug therapy, Lymphoproliferative Disorders drug therapy, Receptors, Notch antagonists & inhibitors, Signal Transduction drug effects, T-Lymphocytes immunology
- Abstract
Patients with autoimmune lymphoproliferative syndrome (ALPS) and systemic lupus erythematosis (SLE) have T-cell dysregulation and produce abnormal, activated T lymphocytes and an atypical peripheral T-cell population, termed double negative T cells (DNTs). T-cell functions, including DNT transition in T-cell development and T-cell activation, are critically dependent on Notch signaling. We hypothesized that inhibiting Notch signaling would be effective in ALPS and SLE by reducing the production of abnormal DNTs and by blocking aberrant T-cell activation. We tested this hypothesis using murine models of ALPS and SLE. Mice were randomized to treatment with the notch pathway inhibitor (gamma-secretase inhibitor), N-S-phenyl-glycine-t-butyl ester (DAPT), or vehicle control. Response to treatment was assessed by measurement of DNTs in blood and lymphoid tissue, by monitoring lymph node and spleen size with ultrasound, by quantifying cytokines by bead-array, by ELISA for total IgG and anti-double-stranded DNA (dsDNA) specific antibodies, and by histopathologic assessment for nephritis. We found a profound and statistically significant decrease in all disease parameters, comparing DAPT-treated mice to controls. Using a novel dosing schema, we avoided the reported toxicities of gamma-secretase inhibitors. Inhibiting the Notch signaling pathway may thus present an effective, novel, and well-tolerated treatment for autoimmune and lymphoproliferative diseases.
- Published
- 2008
- Full Text
- View/download PDF
50. Novel molecular and cellular therapeutic targets in acute lymphoblastic leukemia and lymphoproliferative disease.
- Author
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Brown VI, Seif AE, Reid GS, Teachey DT, and Grupp SA
- Subjects
- Adjuvants, Immunologic therapeutic use, Animals, Enzyme Inhibitors therapeutic use, Humans, Immunotherapy methods, Lymphoproliferative Disorders metabolism, Precursor Cell Lymphoblastic Leukemia-Lymphoma metabolism, Protein Kinases metabolism, Receptor, Notch1 metabolism, TOR Serine-Threonine Kinases, Lymphoproliferative Disorders therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy, Signal Transduction drug effects
- Abstract
While the outcome for pediatric patients with lymphoproliferative disorders (LPD) or lymphoid malignancies, such as acute lymphoblastic leukemia (ALL), has improved dramatically, patients often suffer from therapeutic sequelae. Additionally, despite intensified treatment, the prognosis remains dismal for patients with refractory or relapsed disease. Thus, novel biologically targeted treatment approaches are needed. These targets can be identified by understanding how a loss of lymphocyte homeostasis can result in LPD or ALL. Herein, we review potential molecular and cellular therapeutic strategies that (i) target key signaling networks (e.g., PI3K/AKT/mTOR, JAK/STAT, Notch1, and SRC kinase family-containing pathways) which regulate lymphocyte growth, survival, and function; (ii) block the interaction of ALL cells with stromal cells or lymphoid growth factors secreted by the bone marrow microenvironment; or (iii) stimulate innate and adaptive immune responses.
- Published
- 2008
- Full Text
- View/download PDF
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