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DNA Barcoding in Nonhuman Primates Reveals Important Limitations in Retrovirus Integration Site Analysis

Mol Ther Methods Clin Dev

2020 Adair, Jennifer; Humphrys, Daniel; Kiem, Hans-Peter; Schefter, Lauren E; Haworth, Kevin G; Shahbazi, Reza; Enstrom, Mark R

In vivo tracking of retrovirus-tagged blood stem and progenitor cells is used to study hematopoiesis. Two techniques are used most frequently: sequencing the locus of retrovirus insertion, termed integration site analysis, or retrovirus DNA barcode sequencing. Of these, integration site analysis is currently the only available technique for monitoring clonal pools in patients treated with retrovirus-modified blood cells. A key question is how these two techniques compare in their ability to detect and quantify clonal contributions. In this study, we assessed both methods simultaneously in a clinically relevant nonhuman primate model of autologous, myeloablative transplantation. Our data demonstrate that both methods track abundant clones; however, DNA barcode sequencing is at least 5-fold more efficient than integration site analysis. Using computational simulation to identify the sources of low efficiency, we identify sampling depth as the major factor. We show that the sampling required for integration site analysis to achieve minimal coverage of the true clonal pool is likely prohibitive, especially in cases of low gene-modified cell engraftment. We also show that early subsampling of different blood cell lineages adds value to clone tracking information in terms of safety and hematopoietic biology. Our analysis demonstrates DNA barcode sequencing as a useful guide to maximize integration site analysis interpretation in gene therapy patients.

Effective Multi-lineage Engraftment in a Mouse Model of Fanconi Anemia Using Non-genotoxic Antibody-Based Conditioning

Mol Ther Methods Clin Dev

2020 Humbert, Olivier M; Rajawat, Yogendra S; Haworth, Kevin G; Ironside, Christina M; Kiem, Hans-Peter; Srikanthan, Meera A

Conditioning chemotherapy is used to deplete hematopoietic stem cells in the recipient's marrow, facilitating donor cell engraftment. Although effective, a major issue with chemotherapy is the systemic genotoxicity that increases the risk for secondary malignancies. Antibody conjugates targeting hematopoietic cells are an emerging non-genotoxic method of opening the marrow niche and promoting engraftment of transplanted cells while maintaining intact marrow cellularity. Specifically, this platform would be useful in diseases associated with DNA damage or cancer predisposition, such as dyskeratosis congenita, Schwachman-Diamond syndrome, and Fanconi anemia (FA). Our approach utilizes antibody-drug conjugates (ADC) as an alternative conditioning regimen in an FA mouse model of autologous transplantation. Antibodies targeting either CD45 or CD117 were conjugated to saporin (SAP), a ribosomal toxin. FANCA knockout mice were conditioned with either CD45-SAP or CD117-SAP prior to receiving whole marrow from a heterozygous healthy donor. Bone marrow and peripheral blood analysis revealed equivalent levels of donor engraftment, with minimal toxicity in ADC-treated groups as compared with cyclophosphamide-treated controls. Our findings suggest ADCs may be an effective conditioning strategy in stem cell transplantation not only for diseases where traditional chemotherapy is not tolerated, but also more broadly for the field of blood and marrow transplantation.

Mechanisms for the testing effect on patient-reported outcomes

Contemp Clin Trials Commun

2020 Jones, Salene M

The testing effect is when patient-reported outcomes (PRO) improve with repeated administration without intervention. The testing effect can confound interpretation of clinical trials using PROs as endpoints. This study investigated potential mechanisms. The parent study (n = 302) investigated a self-management intervention for depression. We qualitatively analyzed exit interview feedback from the 89 control group participants completing the last assessment. Participants reported several perceived benefits from control group participation including novel mechanisms (study participation was meaningful, emotional support, appreciating outreach), a possible negative testing effect and mechanisms previously identified (behavioral change).

A phased approach to implementing the Breast Imaging Reporting and Data System (BI-RADS) in low-income and middle-income countries


2020 Anderson, Benjamin O; Scheel, John R; Lam, Diana; Duggan, Catherine R

BACKGROUND: Successful breast cancer detection programs rely on standardized reporting and interpreting systems, such as the Breast Imaging Reporting and Data System (BI-RADS), to improve system performance. In low-income and middle-income countries, evolving diagnostic programs have insufficient resources to either fully implement BI-RADS or to periodically evaluate the program's performance, which is a necessary component of BI-RADS. This leads to inconsistent breast ultrasound interpretation and a failure to improve performance. METHODS: The authors applied the Breast Health Global Initiative's phased implementation strategy to implement diagnostic ultrasound and BI-RADS within the context of a limited-resource setting. RESULTS: The authors recommended starting with triage ultrasound to distinguish suspicious masses from normal breast tissue and benign masses such as cysts because the majority of health workers performing ultrasounds at this level have minimal breast imaging experience. Transitioning to full diagnostic ultrasound with condensed or full BI-RADS should occur after performance and quality metrics have been met. CONCLUSIONS: Transitioning through these phases across facilities likely will occur at different times, particularly in rural versus urban settings.

The Breast Health Global Initiative 2018 Global Summit on Improving Breast Healthcare Through Resource-Stratified Phased Implementation: Methods and overview


2020 Anderson, Benjamin O; Gralow, Julie R; Duggan, Catherine R; Dvaladze, Allison L

BACKGROUND: The Breast Health Global Initiative (BHGI) established a series of resource-stratified, evidence-based guidelines to address breast cancer control in the context of available resources. Here, the authors describe methodologies and health system prerequisites to support the translation and implementation of these guidelines into practice. METHODS: In October 2018, the BHGI convened the Sixth Global Summit on Improving Breast Healthcare Through Resource-Stratified Phased Implementation. The purpose of the summit was to define a stepwise methodology (phased implementation) for guiding the translation of resource-appropriate breast cancer control guidelines into real-world practice. Three expert consensus panels developedstepwise, resource-appropriate recommendations for implementing these guidelines in low-income and middle-income countries as well as underserved communities in high-income countries. Each panel focused on 1 of 3 specific aspects of breast cancer care: 1) early detection, 2) treatment, and 3) health system strengthening. RESULTS: Key findings from the summit and subsequent article preparation included the identification of phased-implementation prerequisites that were explored during consensus debates. These core issues and concepts are key components for implementing breast health care that consider real-world resource constraints. Communication and engagement across all levels of care is vital to any effectively operating health care system, including effective communication with ministries of health and of finance, to demonstrate needs, outcomes, and cost benefits. CONCLUSIONS: Underserved communities at all economic levels require effective strategies to deploy scarce resources to ensure access to timely, effective, and affordable health care. Systematically strategic approaches translating guidelines into practice are needed to build health system capacity to meet the current and anticipated global breast cancer burden.

Breast cancer treatment: A phased approach to implementation


2020 Anderson, Benjamin O; Menon, Manoj P; Niyonzima, Nixon; Gralow, Julie R; Duggan, Catherine R

Optimal treatment outcomes for breast cancer are dependent on a timely diagnosis followed by an organized, multidisciplinary approach to care. However, in many low- and middle-income countries, effective care management pathways can be difficult to follow because of financial constraints, a lack of resources, an insufficiently trained workforce, and/or poor infrastructure. On the basis of prior work by the Breast Health Global Initiative, this article proposes a phased implementation strategy for developing sustainable approaches to enhancing patient care in limited-resource settings by creating roadmaps that are individualized and adapted to the baseline environment. This strategy proposes that, after a situational analysis, implementation phases begin with bolstering palliative care capacity, especially in settings where a late-stage diagnosis is common. This is followed by strengthening the patient pathway, with consideration given to a dynamic balance between centralization of services into centers of excellence to achieve better quality and decentralization of services to increase patient access. The use of resource checklists ensures that comprehensive therapy or palliative care can be delivered safely and effectively. Episodic or continuous monitoring with established process and quality metrics facilitates ongoing assessment, which should drive continual process improvements. A series of case studies provides a snapshot of country experiences with enhancing patient care, including the implementation of national cancer control plans in Kenya, palliative care in Romania, the introduction of a 1-stop clinic for diagnosis in Brazil, the surgical management of breast cancer in India, and the establishment of a women's cancer center in Ghana.

Breast cancer patient advocacy: A qualitative study of the challenges and opportunities for civil society organizations in low-income and middle-income countries


2020 Anderson, Benjamin O; Gralow, Julie R; Dvaladze, Allison L; Duggan, Catherine R

BACKGROUND: Breast cancer advocacy movements, driven by advocate-led civil society organizations (CSOs), have proven to be a powerful force for the advancement of cancer control in high-income countries (HICs). However, although patient advocacy movements are growing in low-income and middle-income countries (LMICs) in response to an increasing cancer burden, the experiences and needs of advocate-led breast cancer CSOs in LMICs is understudied. METHODS: The authors conducted a qualitative study using in-depth interviews and focus group discussions with 98 participants representing 23 LMICs in Eastern Europe, Central Asia, East and Southern Africa, and Latin America. RESULTS: Despite geographic, cultural, and socioeconomic differences, the common themes that emerged from the data across the 3 regions are strikingly similar: trust, knowledge gaps, stigma, sharing experiences, and sustainability. The authors identified common facilitators (training/education, relationship building/networking, third-party facilitators, and communication) and barriers (mistrust, stigma, organizational fragility, difficulty translating HIC strategies) to establishing trust, collaboration, and advancing cancer advocacy efforts. To the authors' knowledge, the current study is the first to describe the role that coalitions and regional networks play in advancing breast cancer advocacy in LMICs across multiple regions. CONCLUSIONS: The findings of the current study corroborate the importance of investing in 3-way partnerships between CSOs, political leaders, and health experts. When provided with information that is evidence-based and resource appropriate, as well as opportunities to network, advocates are better equipped to achieve their goals. The authors propose that support for CSOs focuses on building trust through increasing opportunities for engagement, disseminating best practices and evidence-based information, and fostering the creation of platforms for partnerships and networks.

Situational analysis of breast health care systems: Why context matters


2020 Scheel, John R; Anderson, Benjamin O; Duggan, Catherine R; Duncan, Jennifer A; Dvaladze, Allison L

BACKGROUND: Implementation of evidence-based, resource-appropriate guidelines for breast cancer control should be preceded by a baseline assessment or situational analysis to assess breast health infrastructure, workforce capacity, patient pathways, existing practices, accessibility, and costs. METHODS: To support the assessment of breast health care systems within the broader context in which they exist, the Breast Health Global Initiative (BHGI) developed, tested, and refined a set of situational analysis tools with which to guide the assessment of breast health care capacity, identify the relative strengths and weaknesses of the health system, and support stakeholders in prioritizing actionable items to advance breast cancer care using evidence-based strategies tailored to their setting. The tools address 6 domains of breast health care delivery: 1) breast cancer early detection practices; 2) breast cancer awareness programs; 3) the availability of breast cancer surgery; 4) the availability of pathology; 5) the availability of radiotherapy, and 6) the availability of systemic therapy services. The current study also describes the more comprehensive International Atomic Energy Agency Programme of Action for Cancer Therapy (PACT) integrated missions for PACT (imPACT) review. RESULTS: As of 2020, 5 formal BHGI situational analyses have been performed in India, Brazil, Panama, Tanzania, and Uganda. As of August 2019, a total of 100 imPACT reviews have been conducted in 91 countries. These assessments can contribute to more informed policymaking. CONCLUSIONS: Situational analyses are a prerequisite for the development of resource-appropriate strategies with which to advance breast cancer control in any setting and should assess services across the entire breast health care continuum as well as the broader structural, sociocultural, personal, and financial contexts within which they operate.

Health system strengthening: Integration of breast cancer care for improved outcomes


2020 Duggan, Catherine R; Dvaladze, Allison L; Anderson, Benjamin O

The adoption of the goal of universal health coverage and the growing burden of cancer in low- and middle-income countries makes it important to consider how to provide cancer care. Specific interventions can strengthen health systems while providing cancer care within a resource-stratified perspective (similar to the World Health Organization-tiered approach). Four specific topics are discussed: essential medicines/essential diagnostics lists; national cancer plans; provision of affordable essential public services (either at no cost to users or through national health insurance); and finally, how a nascent breast cancer program can build on existing programs. A case study of Zambia (a country with a core level of resources for cancer care, using the Breast Health Global Initiative typology) shows how a breast cancer program was built on a cervical cancer program, which in turn had evolved from the HIV/AIDS program. A case study of Brazil (which has enhanced resources for cancer care) describes how access to breast cancer care evolved as universal health coverage expanded. A case study of Uruguay shows how breast cancer outcomes improved as the country shifted from a largely private system to a single-payer national health insurance system in the transition to becoming a country with maximal resources for cancer care. The final case study describes an exciting initiative, the City Cancer Challenge, and how that may lead to improved cancer services.

Breast cancer early detection: A phased approach to implementation


2020 Duggan, Catherine R; Dvaladze, Allison L; Anderson, Benjamin O; Scheel, John R

When breast cancer is detected and treated early, the chances of survival are very high. However, women in many settings face complex barriers to early detection, including social, economic, geographic, and other interrelated factors, which can limit their access to timely, affordable, and effective breast health care services. Previously, the Breast Health Global Initiative (BHGI) developed resource-stratified guidelines for the early detection and diagnosis of breast cancer. In this consensus article from the sixth BHGI Global Summit held in October 2018, the authors describe phases of early detection program development, beginning with management strategies required for the diagnosis of clinically detectable disease based on awareness education and technical training, history and physical examination, and accurate tissue diagnosis. The core issues address include finance and governance, which pertain to successful planning, implementation, and the iterative process of program improvement and are needed for a breast cancer early detection program to succeed in any resource setting. Examples are presented of implementation, process, and clinical outcome metrics that assist in program implementation monitoring. Country case examples are presented to highlight the challenges and opportunities of implementing successful breast cancer early detection programs, and the complex interplay of barriers and facilitators to achieving early detection for breast cancer in real-world settings are considered.

Last Modified, December 03, 2019