The Collaborative Network Approach: a model for advancing patient-centric research for Castleman disease and other rare diseases

2019 ◽  
Vol 3 (1) ◽  
pp. 97-105
Author(s):  
Mary Zuccato ◽  
Dustin Shilling ◽  
David C. Fajgenbaum
Keyword(s):  
Rare Diseases ◽  
Treatment Options ◽  
Castleman Disease ◽  
High Impact ◽  
Collaborative Network ◽  
Network Approach ◽  
Grant Applications ◽  
Research Questions ◽  
Novel Strategy ◽  
Patient Centric

Abstract There are ∼7000 rare diseases affecting 30 000 000 individuals in the U.S.A. 95% of these rare diseases do not have a single Food and Drug Administration-approved therapy. Relatively, limited progress has been made to develop new or repurpose existing therapies for these disorders, in part because traditional funding models are not as effective when applied to rare diseases. Due to the suboptimal research infrastructure and treatment options for Castleman disease, the Castleman Disease Collaborative Network (CDCN), founded in 2012, spearheaded a novel strategy for advancing biomedical research, the ‘Collaborative Network Approach’. At its heart, the Collaborative Network Approach leverages and integrates the entire community of stakeholders — patients, physicians and researchers — to identify and prioritize high-impact research questions. It then recruits the most qualified researchers to conduct these studies. In parallel, patients are empowered to fight back by supporting research through fundraising and providing their biospecimens and clinical data. This approach democratizes research, allowing the entire community to identify the most clinically relevant and pressing questions; any idea can be translated into a study rather than limiting research to the ideas proposed by researchers in grant applications. Preliminary results from the CDCN and other organizations that have followed its Collaborative Network Approach suggest that this model is generalizable across rare diseases.

scholarly journals A National Evaluation of State and Territory Roles in Hazard Mitigation: Building Local Capacity to Implement FEMA Hazard Mitigation Assistance Grants

2020 ◽  
Vol 12 (23) ◽  
pp. 13
Author(s):  
Gavin Smith ◽  
Olivia Vila
Keyword(s):  
Emergency Management ◽  
National Survey ◽  
Local Governments ◽  
Technical Assistance ◽  
Hazard Mitigation ◽  
Grant Applications ◽  
Research Questions ◽  
Low Levels ◽  
Resilient Infrastructure ◽  
Survey Responses

This article describes the findings of a national survey of State Hazard Mitigation Officers (SHMOs) in U.S. states and territories in order to gain a greater understanding of the roles that they play in assisting local governments to build the capacity required to successfully develop and implement Federal Emergency Management Agency (FEMA)-funded Hazard Mitigation Assistance (HMA) grants, an important but understudied aspect of hazard mitigation governance. The research questions focus on: (1) How states and territories enable local governments to develop and implement HMA grants and (2) SHMOs’ opinions regarding their perceived capacity and effectiveness in assisting local governments to develop and implement HMA grants. Results show that while states and territories are relatively well-equipped to perform general administrative duties required by FEMA, SHMOs expressed wide variation in their capacity to assist local governments to develop and implement HMA grants. This was particularly evident with regard to the delivery of specific technical assistance measures required to develop HMA grants. Survey responses also highlight modest levels of participation in FEMA-designed efforts to delegate responsibility to states and territories and low levels of participation in programs that offer pre-application funding to local governments to help them develop HMA grant applications. These findings should concern FEMA as the agency embarks on the implementation of the Building Resilient Infrastructure and Communities program, an ambitious pre-disaster hazard mitigation grant initiative.

scholarly journals A Review of Genetic Abnormalities in Unicentric and Multicentric Castleman Disease

Biology ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 251
Author(s):  
Alexandra Butzmann ◽  
Jyoti Kumar ◽  
Kaushik Sridhar ◽  
Sumanth Gollapudi ◽  
Robert S. Ohgami
Keyword(s):  
Plasma Cells ◽  
Treatment Options ◽  
Disease Process ◽  
Castleman Disease ◽  
Mitogen Activated Protein Kinase ◽  
Human Herpes Virus 8 ◽  
Multicentric Castleman Disease ◽  
Molecular Abnormalities ◽  
Genetic Abnormalities ◽  
Mitogen Activated Protein

Castleman disease (CD) is a rare lymphoproliferative disorder known to represent at least four distinct clinicopathologic subtypes. Large advancements in our clinical and histopathologic description of these diverse diseases have been made, resulting in subtyping based on number of enlarged lymph nodes (unicentric versus multicentric), according to viral infection by human herpes virus 8 (HHV-8) and human immunodeficiency virus (HIV), and with relation to clonal plasma cells (POEMS). In recent years, significant molecular and genetic abnormalities associated with CD have been described. However, we continue to lack a foundational understanding of the biological mechanisms driving this disease process. Here, we review all cases of CD with molecular abnormalities described in the literature to date, and correlate cytogenetic, molecular, and genetic abnormalities with disease subtypes and phenotypes. Our review notes complex karyotypes in subsets of cases, specific mutations in PDGFRB N666S in 10% of unicentric CD (UCD) and NCOA4 L261F in 23% of idiopathic multicentric CD (iMCD) cases. Genes affecting chromatin organization and abnormalities in methylation are seen more commonly in iMCD while abnormalities within the mitogen-activated protein kinase (MAPK) and interleukin signaling pathways are more frequent in UCD. Interestingly, there is a paucity of genetic studies evaluating HHV-8 positive multicentric CD (HHV-8+ MCD) and POEMS-associated CD. Our comprehensive review of genetic and molecular abnormalities in CD identifies subtype-specific and novel pathways which may allow for more targeted treatment options and unique biologic therapies.

scholarly journals A novel preference-informed complementary trial (PICT) design for clinical trial research influenced by strong patient preferences

Trials ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Samina Ali ◽  
◽  
Gareth Hopkin ◽  
Naveen Poonai ◽  
Lawrence Richer ◽  
...  
Keyword(s):  
External Validity ◽  
Treatment Options ◽  
Internal Validity ◽  
Clinical Effectiveness ◽  
Drop Out ◽  
Innovative Design ◽  
Clinical Trial Research ◽  
Research Questions ◽  
Internal And External Validity ◽  
Treatment Population

Abstract Background Patients and their families often have preferences for medical care that relate to wider considerations beyond the clinical effectiveness of the proposed interventions. Traditionally, these preferences have not been adequately considered in research. Research questions where patients and families have strong preferences may not be appropriate for traditional randomized controlled trials (RCTs) due to threats to internal and external validity, as there may be high levels of drop-out and non-adherence or recruitment of a sample that is not representative of the treatment population. Several preference-informed designs have been developed to address problems with traditional RCTs, but these designs have their own limitations and may not be suitable for many research questions where strong preferences and opinions are present. Methods In this paper, we propose a novel and innovative preference-informed complementary trial (PICT) design which addresses key weaknesses with both traditional RCTs and available preference-informed designs. In the PICT design, complementary trials would be operated within a single study, and patients and/or families would be given the opportunity to choose between a trial with all treatment options available and a trial with treatment options that exclude the option which is subject to strong preferences. This approach would allow those with strong preferences to take part in research and would improve external validity through recruiting more representative populations and internal validity. Here we discuss the strengths and limitations of the PICT design and considerations for analysis and present a motivating example for the design based on the use of opioids for pain management for children with musculoskeletal injuries. Conclusions PICTs provide a novel and innovative design for clinical trials with more than two arms, which can address problems with existing preference-informed trial designs and enhance the ability of researchers to reflect shared decision-making in research as well as improving the validity of trials of topics with strong preferences.

scholarly journals The Molecular and Cellular Mechanisms Associated with a Microvascular Inflammation in the Pathogenesis of Heart Failure with Preserved Ejection Fraction

Acta Naturae ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 40-51
Author(s):  
A. G. Ovchinnikov ◽  
T. I. Arefieva ◽  
A. V. Potekhina ◽  
A. Yu. Filatova ◽  
F. T. Ageev ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Severe Disease ◽  
Treatment Options ◽  
Cellular Mechanisms ◽  
Reduced Ejection Fraction ◽  
Hypertrophied Myocardium ◽  
Microvascular Inflammation ◽  
Novel Strategy ◽  
Current Paradigm

Heart failure withpreserved ejection fraction (HFpEF) is a severe disease with an often unfavorable outcome. The prevalence of HFpEF continues to increase, while effective treatment options remain elusive. All the medical strategies used toimprove the outcome in a heart failure with reduced ejection fraction proved ineffective in HFpEF, which was probably due to the different mechanisms ofdevelopment of these two types of heart failure and the diversity of the HFpEF phenotypes. According to the current paradigm of HFpEF development, a chronic mild pro-inflammatory statecauses a coronary microvascular endothelial inflammation, with further myocardial fibrosis and diastolic dysfunction progression. This inflammatory paradigm of HFpEF has been confirmed with someevidence, and suppressing the inflammation may become a novel strategy for treating and managing HFpEF. This review summarizes current concepts about a microvascular inflammation in hypertrophied myocardium and provides a translational perspective of the anti-inflammatory and immunomodulatory approaches in HFpEF.

scholarly journals The Molecular and Cellular Mechanisms Associated with a Microvascular Inflammation in the Pathogenesis of Heart Failure with Preserved Ejection Fraction

Acta Naturae ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 40-51
Author(s):  
A. G. Ovchinnikov ◽  
T. I. Arefieva ◽  
A. V. Potekhina ◽  
A. Yu. Filatova ◽  
F. T. Ageev ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Severe Disease ◽  
Treatment Options ◽  
Cellular Mechanisms ◽  
Reduced Ejection Fraction ◽  
Hypertrophied Myocardium ◽  
Microvascular Inflammation ◽  
Novel Strategy ◽  
Current Paradigm

Heart failure withpreserved ejection fraction (HFpEF) is a severe disease with an often unfavorable outcome. The prevalence of HFpEF continues to increase, while effective treatment options remain elusive. All the medical strategies used toimprove the outcome in a heart failure with reduced ejection fraction proved ineffective in HFpEF, which was probably due to the different mechanisms ofdevelopment of these two types of heart failure and the diversity of the HFpEF phenotypes. According to the current paradigm of HFpEF development, a chronic mild pro-inflammatory statecauses a coronary microvascular endothelial inflammation, with further myocardial fibrosis and diastolic dysfunction progression. This inflammatory paradigm of HFpEF has been confirmed with someevidence, and suppressing the inflammation may become a novel strategy for treating and managing HFpEF. This review summarizes current concepts about a microvascular inflammation in hypertrophied myocardium and provides a translational perspective of the anti-inflammatory and immunomodulatory approaches in HFpEF.

scholarly journals The Impact of Applied Research: Student Research as a High Impact Practice in Freshman Environmental Science

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Billy Morris
Keyword(s):  
Applied Research ◽  
Environmental Science ◽  
Research Question ◽  
High Impact ◽  
Stem Majors ◽  
Research Questions ◽  
And Performance ◽  
Science Major ◽  
High Impact Practice ◽  
The Impact

Abstract: Non-STEM-majors in a freshman elective Science course, Environmental Science 1, were given the opportunity to identify a research question using the course objectives as a guideline. Their research questions and investigations served to fulfill the lab component of the course in lieu of a lab manual. Students were asked to choose a question of interest that could be researched on campus. Student partnerships were encouraged, and a class of 17 students produced 11 research projects. Frequent interactions with the Instructor and peers resulted in lively discussions, new questions, and high levels of student engagement and performance. This approach to laboratory work in a non-science major course can be duplicated when access to resources and instructor/student ratio allows.

scholarly journals Serum Proteomics Reveals Distinct Subtypes Associated with Treatment Response in Idiopathic Multicentric Castleman Disease

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3716-3716
Author(s):  
Dustin Shilling ◽  
Jason R Ruth ◽  
Christopher Sheild Nabel ◽  
Sheila K Pierson ◽  
Mary Guilfoyle ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Disease Activity ◽  
Hodgkin Lymphoma ◽  
Research Funding ◽  
Treatment Options ◽  
Castleman Disease ◽  
Employment Equity ◽  
Multicentric Castleman Disease ◽  
Serum Proteomics ◽  
Equity Ownership

Abstract Human herpesvirus-8(HHV-8)-negative/idiopathic multicentric Castleman disease (iMCD) is a rare and poorly understood disorder diagnosed in ~1,000 individuals in the USA each year. It involves polyclonal lymphoproliferation, constitutional symptoms, systemic inflammation and an uncontrollable cytokine storm resulting in life-threatening multi-organ failure. Diagnosis and treatment can be difficult due to limited etiological understanding and heterogeneous presentation - clinical, laboratory, and histopathological abnormalities overlap with infectious, autoimmune and oncological diseases. iMCD symptoms and disease progression are largely believed to be driven by interleukin-6 (IL-6). However, approximately 66% of iMCD patients did not respond to anti-IL-6 therapy, siltuximab, the only FDA-approved iMCD therapy, in its phase II study (NCT01024036). Few treatment options exist for anti-IL-6 refractory patients because alternative driver cytokines and signaling pathways are not known. Herein we report the largest study to-date of iMCD serum proteomes with correlative anti-IL6 response data from 92 iMCD patients in disease flare (n=75 of which were collected as part of NCT01024036), in order to: (1) molecularly define iMCD, (2) identify predictors of response to anti-IL6 therapy, and (3) gain insights into the pathogenesis of iMCD. Proteomes of HHV8-positive MCD (n=20), Hodgkin lymphoma (n=20), rheumatoid arthritis (n=20) and healthy individuals (n=44) were also analyzed. Of the ~1,300 analytes measured using SomaLogic SOMAscan, 1,178 passed QC and were included in analyses. Each analyte was log2 transformed and capped at the 2.5th and 97.5th percentiles. Clinical and laboratory data collected at the time of sample draw were used to calculate disease activity following a modified CHAP scale: C-reactive protein, hemoglobin and albumin; missing performance status. Response to siltuximab was determined in NCT01024036. Data analysis was performed using the Medidata Rave Omics machine learning platform and R v3.4.4. Clustering of baseline proteomic data for iMCD patients identified six clusters that ranged in size from seven to 27 subjects. No associations with race, site, sex, age, or batch were found. Analytes identified among the strongest differentiators include cytokines, chemokines and inflammatory molecules. Interestingly, the largest cluster was associated with response to siltuximab (p<0.05; 65% (11/17) vs 19% (5/27) in all others), higher disease activity (p<0.01), and higher IL-6 levels (p<0.01). Analysis of data for the entire study population separated HHV-8-positive MCD, Hodgkin lymphoma, and rheumatoid arthritis into distinct clusters. Of note, iMCD patients did not form a single or unique cluster, reinforcing the heterogeneity of the disease, and a subset of iMCD patients demonstrated similar, but not overlapping, proteomic profiles to those of Hodgkin lymphoma. These results indicate that previously undiscovered proteomically-distinct iMCD subtypes or disease states exist, which can be used to inform treatment options. Given that iMCD may have a sudden and severe onset, predictive markers of anti-IL6 therapy response are critical for timely administration of the correct treatment. Additionally, overlapping proteomic profiles of a subset of iMCD patients with Hodgkin lymphoma provide etiological insights. More broadly, this study represents the first use of high-quality serum proteomics data to study a rare non-malignant lymphoproliferative disorder and to assist with molecularly defining a heterogeneous disease, developing candidate diagnostic biomarkers, predicting response or failure to therapy, and identifying novel candidate therapeutic targets. Disclosures Guilfoyle: Janssen Pharmaceuticals, Inc.: Employment. Tendler:Janssen Pharmaceuticals, Inc.: Employment, Equity Ownership. Reddy:Janssen Pharmaceuticals, Inc.: Employment, Equity Ownership. Weinblatt:Amgen: Consultancy, Research Funding; Sanofi/Regeneron: Consultancy, Research Funding; Crescendo Bioscience: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; UCB Pharmaceuticals: Consultancy, Research Funding. Bower:Merck: Honoraria; ViiV: Honoraria; Gilead: Honoraria; Janssen Pharmaceuticals: Honoraria. Masaki:Ono: Research Funding; Phizer: Research Funding; Astellas: Research Funding; Eisai: Research Funding; Kyowa Hakko Kirin: Research Funding. Beineke:Medidata Solutions: Employment, Equity Ownership. Miljovska:Medidata Solutions: Employment. Katz:Medidata Solutions: Employment. Shenoy:Medidata Solutions: Consultancy. Oromendia:Medidata Solutions: Employment, Equity Ownership. Mezey:Medidata Solutions: Consultancy. Wiser:Medidata Solutions: Employment, Equity Ownership. Benbanaste:Medidata Solutions: Employment, Equity Ownership. Lee:Medidata Solutions: Employment. Fosså:Janssen Pharmaceuticals, Inc.: Honoraria. Fajgenbaum:Janssen Pharmaceuticals, Inc.: Research Funding.

scholarly journals Essential List of Medicinal Products for Rare Diseases – Recommendations from the IRDiRC Rare Disease Treatment Access Working Group

2021 ◽  
Author(s):  
William A. Gahl ◽  
Durhane Wong-Rieger ◽  
Virginie Hivert ◽  
Rachel Yang ◽  
Galliano Zanello ◽  
...  
Keyword(s):  
Rare Disease ◽  
Health Care Providers ◽  
Rare Diseases ◽  
Working Group ◽  
Treatment Options ◽  
Care Providers ◽  
Medicinal Products ◽  
Treatment Access ◽  
Disease Treatment ◽  
Middle Income

Abstract Background Treatments are often unavailable for rare disease patients, especially in low-and-middle-income countries. Reasons for this include lack of financial support for therapies and onerous regulatory requirements for approval of drugs. Other barriers include lack of reimbursement, administrative infrastructure, and knowledge about diagnosis and drug treatment options. The International Rare Diseases Research Consortium set up the Rare Disease Treatment Access Working Group with the first objective to develop an essential list of medicinal products for rare diseases. Results The Working Group extracted 215 drugs with Orphan designation in the FDA, EMA databases and/or China’s Rare Diseases Catalog. The drugs were organized in seven disease categories: metabolic, neurologic, hematologic, anti-inflammatory, endocrine, pulmonary, and immunologic, plus a miscellaneous category. Conclusions The proposed list of essential medicinal products for rare diseases is intended to initiate discussion and collaboration among patient advocacy groups, health care providers, industry and government agencies to enhance access to appropriate medicines for all rare disease patients throughout the world.

scholarly journals ‘Quality in, quality out’, a stepwise approach to evidence-based medicine for rare diseases promoted by multiple endocrine neoplasia type 1

2018 ◽  
Vol 7 (11) ◽  
pp. R260-R274 ◽  
Author(s):  
Dirk-Jan van Beek ◽  
Rachel S van Leeuwaarde ◽  
Carolina R C Pieterman ◽  
Menno R Vriens ◽  
Gerlof D Valk ◽  
...  
Keyword(s):  
Data Collection ◽  
Rare Diseases ◽  
Multiple Endocrine Neoplasia ◽  
Multiple Endocrine Neoplasia Type ◽  
Evidence Based ◽  
Stepwise Approach ◽  
Endocrine Neoplasia ◽  
Research Questions ◽  
Based Medicine

Rare diseases pose specific challenges in the field of medical research to provide physicians with evidence-based guidelines derived from studies with sufficient quality. An example of these rare diseases is multiple endocrine neoplasia type 1 (MEN1), which is an autosomal dominant endocrine tumor syndrome with an estimated occurrence rate of 2–3 per 100,000. For this complex disease, characterized by multiple endocrine tumors, it proves difficult to perform both adequate and feasible studies. The opinion of patients themselves is of utmost importance to identify the gaps in the evidence-based medicine regarding clinical care. In the search for scientific answers to clinical research questions, the aim for best available evidence is obvious. Observational studies within patient cohorts, although prone to bias, seem the most feasible study design regarding the disease prevalence. Knowledge and adaptation to all types of bias is demanded in the strive for answers. Guided by our research on MEN1 patients, we elaborate on strategies to identify sufficient patients, to maximize and maintain patient enrolment and to standardize the data collection process. Preferably, data collection is performed prospectively, however, under certain conditions, data storage in a longitudinal retrospective database with a disease-specific framework is suitable. Considering the global challenges on observational research on rare diseases, we propose a stepwise approach from clinical research questions to scientific answers.

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