Publications by authors named "Kristin Schroeder"

22 Publications

  • Page 1 of 1

Parental limited English proficiency in pediatric stem cell transplantation: Clinical impact and health care utilization.

Pediatr Blood Cancer 2021 Sep 9;68(9):e29174. Epub 2021 Jun 9.

Division of Hematologic Malignancies and Cellular Therapy, Duke Cancer Institute, Durham, North Carolina, USA.

Background: Limited English proficiency (LEP) is associated with adverse clinical outcomes. The clinical impact of LEP in hematopoietic stem cell transplant (HSCT) has not been studied. The objectives of this study were to compare HSCT outcomes and health care utilization of Hispanic pediatric patients with and without parental LEP.

Methods: We conducted a retrospective review of Hispanic/Latino pediatric patients receiving HSCT at a single institution. Families were identified as LEP or English proficient (EP) based on clinicians' notes, social work documentation, or the signature of a Spanish interpreter on treatment consents.

Results: A total of 83 Hispanic/Latino patients were identified with 53 (65.1%) having parental LEP. More patients in the LEP group had a documented financial burden at pretransplant psychosocial evaluation (72.2% vs. 41.4%, p = .009). LEP patients were more likely to have health insurance coverage through government-sponsored Medicaid (76.9% vs. 27.6%, p < .001). LEP patients were hospitalized on average 13 days longer than EP patients, and LEP patients were more likely to have pretransplant cytomegalovirus (CMV) reactivity (67.3%) than EP patients (p = .001). Overall survival was lower in LEP than EP, but was not statistically significant (p = .193). Multivariable Cox modeling suggested a potentially higher risk of death in LEP versus EP (hazard ratio = 1.56, 95% CI: 0.38, 6.23).

Conclusions: Parental LEP in HSCT is associated with prolonged hospitalization and pretransplant CMV reactivity. These factors are associated with posttransplant complications and death. Our results suggest parental LEP is a risk factor for poor HSCT outcomes. Further study is warranted in a larger cohort.
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http://dx.doi.org/10.1002/pbc.29174DOI Listing
September 2021

Integration of cancer registry and electronic health record data to construct a childhood cancer survivorship cohort, facilitate risk stratification for late effects, and assess appropriate follow-up care.

Pediatr Blood Cancer 2021 Jun 19;68(6):e29014. Epub 2021 Mar 19.

Duke Cancer Institute, Durham, North Carolina, USA.

Background: This retrospective study harnessed an institutional cancer registry to construct a childhood cancer survivorship cohort, integrate electronic health record (EHR) and geospatial data to stratify survivors based on late-effect risk, analyze follow-up care patterns, and determine factors associated with suboptimal follow-up care.

Procedure: The survivorship cohort included patients ≤18 years of age reported to the institutional cancer registry between January 1, 1994 and November 30, 2012. International Classification of Diseases for Oncology, third revision (ICD-O-3) coding and treatment exposures facilitated risk stratification of survivors. The EHR was linked to the cancer registry based on medical record number (MRN) to extract clinic visits.

Results: Five hundred and ninety pediatric hematology-oncology (PHO) and 275 pediatric neuro-oncology (PNO) survivors were included in the final analytic cohort. Two hundred and eight-two survivors (32.6%) were not seen in any oncology-related subspecialty clinic at Duke 5-7 years after initial diagnosis. Factors associated with follow-up included age (p = .008), diagnosis (p < .001), race/ethnicity (p = .010), late-effect risk strata (p = .001), distance to treatment center (p < .0001), and area deprivation index (ADI) (p = .011). Multivariable logistic modeling attenuated the association for high-risk (OR 1.72; 95% CI 0.805, 3.66) and intermediate-risk (OR 1.23, 95% CI 0.644, 2.36) survivors compared to survivors at low risk of late effects among the PHO cohort. PNO survivors at high risk for late effects were more likely to follow up (adjusted OR 3.66; 95% CI 1.76, 7.61).

Conclusions: Nearly a third of survivors received suboptimal follow-up care. This study provides a reproducible model to integrate cancer registry and EHR data to construct risk-stratified survivorship cohorts to assess follow-up care.
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http://dx.doi.org/10.1002/pbc.29014DOI Listing
June 2021

Clinical Outcomes and Patient-Matched Molecular Composition of Relapsed Medulloblastoma.

J Clin Oncol 2021 Mar 27;39(7):807-821. Epub 2021 Jan 27.

Division of Pediatric Hematology and Oncology, University of Texas Southwestern Medical Center, Dallas, TX.

Purpose: We sought to investigate clinical outcomes of relapsed medulloblastoma and to compare molecular features between patient-matched diagnostic and relapsed tumors.

Methods: Children and infants enrolled on either SJMB03 (NCT00085202) or SJYC07 (NCT00602667) trials who experienced medulloblastoma relapse were analyzed for clinical outcomes, including anatomic and temporal patterns of relapse and postrelapse survival. A largely independent, paired molecular cohort was analyzed by DNA methylation array and next-generation sequencing.

Results: A total of 72 of 329 (22%) SJMB03 and 52 of 79 (66%) SJYC07 patients experienced relapse with significant representation of Group 3 and wingless tumors. Although most patients exhibited some distal disease (79%), 38% of patients with sonic hedgehog tumors experienced isolated local relapse. Time to relapse and postrelapse survival varied by molecular subgroup with longer latencies for patients with Group 4 tumors. Postrelapse radiation therapy among previously nonirradiated SJYC07 patients was associated with long-term survival. Reirradiation was only temporizing for SJMB03 patients. Among 127 patients with patient-matched tumor pairs, 9 (7%) experienced subsequent nonmedulloblastoma CNS malignancies. Subgroup (96%) and subtype (80%) stabilities were largely maintained among the remainder. Rare subgroup divergence was observed from Group 4 to Group 3 tumors, which is coincident with genetic alterations involving , , and . Subgroup-specific patterns of alteration were identified for driver genes and chromosome arms.

Conclusion: Clinical behavior of relapsed medulloblastoma must be contextualized in terms of up-front therapies and molecular classifications. Group 4 tumors exhibit slower biological progression. Utility of radiation at relapse is dependent on patient age and prior treatments. Degree and patterns of molecular conservation at relapse vary by subgroup. Relapse tissue enables verification of molecular targets and identification of occult secondary malignancies.
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http://dx.doi.org/10.1200/JCO.20.01359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078396PMC
March 2021

Outcomes by Clinical and Molecular Features in Children With Medulloblastoma Treated With Risk-Adapted Therapy: Results of an International Phase III Trial (SJMB03).

J Clin Oncol 2021 Mar 6;39(7):822-835. Epub 2021 Jan 6.

Hartwell Center, St Jude Children's Research Hospital, Memphis, TN.

Purpose: SJMB03 (ClinicalTrials.gov identifier: NCT00085202) was a phase III risk-adapted trial that aimed to determine the frequency and clinical significance of biological variants and genetic alterations in medulloblastoma.

Patients And Methods: Patients 3-21 years old were stratified into average-risk and high-risk treatment groups based on metastatic status and extent of resection. Medulloblastomas were molecularly classified into subgroups (Wingless [WNT], Sonic Hedgehog [SHH], group 3, and group 4) and subtypes based on DNA methylation profiles and overlaid with gene mutations from next-generation sequencing. Coprimary study end points were (1) to assess the relationship between ERBB2 protein expression in tumors and progression-free survival (PFS), and (2) to estimate the frequency of mutations associated with WNT and SHH tumors. Clinical and molecular risk factors were evaluated, and the most robust were used to model new risk-classification categories.

Results: Three hundred thirty eligible patients with medulloblastoma were enrolled. Five-year PFS was 83.2% (95% CI, 78.4 to 88.2) for average-risk patients (n = 227) and 58.7% (95% CI, 49.8 to 69.1) for high-risk patients (n = 103). No association was found between ERBB2 status and PFS in the overall cohort ( = .74) or when patients were stratified by clinical risk ( = .71). Mutations in (96%), (37%), and (24%) were most common in WNT tumors and (38%), (21%), and (19%) in SHH tumors. Methylome profiling classified 53 WNT (17.4%), 48 SHH (15.7%), 65 group 3 (21.3%), and 139 group 4 (45.6%) tumors. A comprehensive clinicomolecular risk factor analysis identified three low-risk groups (WNT, low-risk SHH, and low-risk combined groups 3 and 4) with excellent (5-year PFS > 90%) and two very high-risk groups (high-risk SHH and high-risk combined groups 3 and 4) with poor survival (5-year PFS < 60%).

Conclusion: These results establish a new risk stratification for future medulloblastoma trials.
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http://dx.doi.org/10.1200/JCO.20.01372DOI Listing
March 2021

Delays Experienced by Patients With Pediatric Cancer During the Health Facility Referral Process: A Study in Northern Tanzania.

JCO Glob Oncol 2020 11;6:1757-1765

Department of Oncology, Bugando Medical Centre, Mwanza, Tanzania.

Purpose: It is estimated that 50%-80% of patients with pediatric cancer in sub-Saharan Africa present at an advanced stage. Delays can occur at any time during the care-seeking process from symptom onset to treatment initiation. Referral delay, the time from first presentation at a health facility to oncologist evaluation, is a key component of total delay that has not been evaluated in sub-Saharan Africa.

Methods: Over a 3-month period, caregivers of children diagnosed with cancer at a regional cancer center (Bugando Medical Centre [BMC]) in Tanzania were consecutively surveyed to determine the number and type of health facilities visited before presentation, interventions received, and transportation used to reach each facility.

Results: Forty-nine caregivers were consented and included in the review. A total of 124 facilities were visited before BMC, with 31% of visits (n = 38) resulting in a referral. The median referral delay was 89 days (mean, 122 days), with a median of two facilities (mean, 2.5 facilities) visited before presentation to BMC. Visiting a traditional healer first significantly increased the time taken to reach BMC compared with starting at a health center/dispensary (103 236 days; = .02). Facility visits in which a patient received a referral to a higher-level facility led to significantly decreased time to reach BMC ( < .0001). Only 36% of visits to district hospitals and 20.6% of visits to health centers/dispensaries yielded a referral, however.

Conclusion: The majority of patients were delayed during the referral process, but receipt of a referral to a higher-level facility significantly shortened delay time. Referral delay for pediatric patients with cancer could be decreased by raising awareness of cancer and strengthening the referral process from lower-level to higher-level facilities.
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http://dx.doi.org/10.1200/GO.20.00407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713565PMC
November 2020

The cost-effectiveness of treating childhood cancer in 4 centers across sub-Saharan Africa.

Cancer 2021 Mar 27;127(5):787-793. Epub 2020 Oct 27.

Unit for Policy and Economic Research in Childhood Cancer, The Hospital for Sick Children, Toronto, Ontario, Canada.

Background: The treatment of childhood cancer often is assumed to be costly in African settings, thereby limiting advocacy and policy efforts. The authors determined the cost and cost-effectiveness of maintaining childhood cancer centers across 4 hospitals throughout sub-Saharan Africa.

Methods: Within hospitals representing 4 countries (Kenya, Nigeria, Tanzania, and Zimbabwe), cost was determined either retrospectively or prospectively for all inputs related to operating a pediatric cancer unit (eg, laboratory costs, medications, and salaries). Cost-effectiveness was calculated based on the annual number of newly diagnosed patients, survival rates, and life expectancy.

Results: Cost per new diagnosis ranged from $2400 to $31,000, attributable to variances with regard to center size, case mix, drug prices, admission practices, and the treatment abandonment rate, which also affected survival. The most expensive cost input was found to be associated with medication in Kenya, and medical personnel in the other 3 centers. The cost per disability-adjusted life-year averted ranged from 0.3 to 3.6 times the per capita gross national income. Childhood cancer treatment therefore was considered to be very cost-effective by World Health Organization standards in 2 countries and cost-effective in 1 additional country. In all centers, abandonment of treatment was common; modeling exercises suggested that public funding of treatment, additional psychosocial personnel, and modifications of inpatient policies would increase survival rates while maintaining or even improving cost-effectiveness.

Conclusions: Across various African countries, childhood cancer treatment units represent cost-effective interventions. Cost-effectiveness can be increased through the control of drug prices, appropriate policy environments, and decreasing the rate of treatment abandonment. These results will inform national childhood cancer strategies across Africa.
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http://dx.doi.org/10.1002/cncr.33280DOI Listing
March 2021

Cancer incidence and treatment utilization patterns at a regional cancer center in Tanzania from 2008-2016: Initial report of 2,772 cases.

Cancer Epidemiol 2020 08 10;67:101772. Epub 2020 Jul 10.

Bugando Medical Centre, Mwanza, Tanzania; Duke Global Health Institute, Duke University, Durham, NC, USA; Department of Pediatric Hematology/Oncology, Duke University, Durham, NC, USA. Electronic address:

Purpose: To describe cancer incidence and treatment utilization patterns at the regional cancer referral center for the Lake Zone of northwestern Tanzania from 2008 to 2016.

Methods: This descriptive, retrospective study reviewed all cancer cases recorded in the Bugando Cancer Registry (BCR), a clinical and pathology based registry at the only cancer referral hospital in the region. Primary tumor site, method of diagnosis, HIV status, and cancer treatment were reported. Using census data, the 2012 GLOBOCAN estimates for Tanzania were scaled to the Lake Zone and adjusted for 2016 population growth. These estimates were then compared to BCR cases using one-sample tests of proportion.

Results: A total of 2772 cases were reported from 2008-2016. Among these, the majority of cases (82.5 %, n = 2286) were diagnosed among adults. Most cases (85 %, n = 1923) were diagnosed by histology or cytology. Among adults, the most common cancers diagnosed were cervix (22.7 %, n=520), breast (12.6 %, n=288), and prostate (8.5 %, n=195). Among children, the most common cancers were non-Burkitt non-Hodgkin lymphoma (17.3 %, n=84), Burkitt lymphoma (16.5 %, n=80), and Wilms tumor (14.6 %, n=71). The 1116 BCR cases represent 12.2 % of the 9165 expected number of cancer cases for the Lake Zone (p < 0.001). 1494 cases (53.9 %) received some form of treatment - surgery, chemotherapy, radiation, or hormone therapy - while 1278 cases (46.1 %) had no treatment recorded.

Conclusions: This comprehensive report of the BCR reveals cancer epidemiology and treatment utilization patterns typical of hospitals in low-resource settings. Despite being the only cancer center in the Lake Zone, BMC evaluates a small percentage of the expected number of cancer patients for the region. The BCR remains an important resource to guide clinical care and academic activities for the Lake Zone.
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http://dx.doi.org/10.1016/j.canep.2020.101772DOI Listing
August 2020

Using digital health to facilitate compliance with standardized pediatric cancer treatment guidelines in Tanzania: protocol for an early-stage effectiveness-implementation hybrid study.

BMC Cancer 2020 Mar 29;20(1):254. Epub 2020 Mar 29.

Department of Population Health Sciences, 215 Morris St, Durham, NC, 27701, USA.

Background: In high-income countries (HICs), increased rates of survival among pediatric cancer patients are achieved through the use of protocol-driven treatment. Compared to HICs, differences in infrastructure, supportive care, and human resources, make compliance with protocol-driven treatment challenging in low- and middle-income countries (LMICs). For successful implementation of protocol-driven treatment, treatment protocols must be resource-adapted for the LMIC context, and additional supportive tools must be developed to promote protocol compliance. In Tanzania, an LMIC where resource-adapted treatment protocols are available, digital health applications could promote protocol compliance through incorporation of systematic decision support algorithms, reminders and alerts related to patient visits, and up-to-date data for care coordination. However, evidence on the use of digital health applications in improving compliance with protocol-driven treatment for pediatric cancer is limited. This study protocol describes the development and evaluation of a digital health application, called mNavigator, to facilitate compliance with protocol-driven treatment for pediatric cancer in Tanzania.

Methods: mNavigator is a digital case management system that incorporates nationally-approved and resource-adapted treatment protocols for two pediatric cancers in Tanzania, Burkitt lymphoma and retinoblastoma. mNavigator is developed from an open-source digital health platform, called CommCare, and guided by the Consolidated Framework for Implementation Research. From July 2019-July 2020 at Bugando Medical Centre in Mwanza, Tanzania, all new pediatric cancer patients will be registered and managed using mNavigator as the new standard of care for patient intake and outcome assessment. Pediatric cancer patients with a clinical diagnosis of Burkitt lymphoma or retinoblastoma will be approached for participation in the study evaluating mNavigator. mNavigator users will document pre-treatment and treatment details for study participants using digital forms and checklists that facilitate compliance with protocol-driven treatment. Compliance with treatment protocols using mNavigator will be compared to historical compliance rates as the primary outcome. Throughout the implementation period, we will document factors that facilitate or inhibit mNavigator implementation.

Discussion: Study findings will inform implementation and scale up of mNavigator in tertiary pediatric cancer facilities in Tanzania, with the goal of facilitating protocol-driven treatment.

Trial Registration: The study protocol was registered in ClinicalTrials.gov (NCT03677128) on September 19, 2018.
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http://dx.doi.org/10.1186/s12885-020-6611-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7104518PMC
March 2020

The whole-genome landscape of Burkitt lymphoma subtypes.

Blood 2019 11;134(19):1598-1607

Department of Immunology and.

Burkitt lymphoma (BL) is an aggressive, MYC-driven lymphoma comprising 3 distinct clinical subtypes: sporadic BLs that occur worldwide, endemic BLs that occur predominantly in sub-Saharan Africa, and immunodeficiency-associated BLs that occur primarily in the setting of HIV. In this study, we comprehensively delineated the genomic basis of BL through whole-genome sequencing (WGS) of 101 tumors representing all 3 subtypes of BL to identify 72 driver genes. These data were additionally informed by CRISPR screens in BL cell lines to functionally annotate the role of oncogenic drivers. Nearly every driver gene was found to have both coding and non-coding mutations, highlighting the importance of WGS for identifying driver events. Our data implicate coding and non-coding mutations in IGLL5, BACH2, SIN3A, and DNMT1. Epstein-Barr virus (EBV) infection was associated with higher mutation load, with type 1 EBV showing a higher mutational burden than type 2 EBV. Although sporadic and immunodeficiency-associated BLs had similar genetic profiles, endemic BLs manifested more frequent mutations in BCL7A and BCL6 and fewer genetic alterations in DNMT1, SNTB2, and CTCF. Silencing mutations in ID3 were a common feature of all 3 subtypes of BL. In vitro, mass spectrometry-based proteomics demonstrated that the ID3 protein binds primarily to TCF3 and TCF4. In vivo knockout of ID3 potentiated the effects of MYC, leading to rapid tumorigenesis and tumor phenotypes consistent with those observed in the human disease.
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http://dx.doi.org/10.1182/blood.2019001880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6871305PMC
November 2019

Pediatric Cancer in Northern Tanzania: Evaluation of Diagnosis, Treatment, and Outcomes.

J Glob Oncol 2018 09 9;4:1-10. Epub 2017 Jun 9.

Kristin Schroeder, Anthony Saxton, Christina Chao, Daniel S. Wechsler, and Nelson Chao, Duke University, Durham, NC; Jessica McDade, Seattle Children's, Seattle, WA; Nestory Masalu and Beda Likonda, Bugando Medical Centre, Mwanza, Tanzania; and Colin Chao, Eastern Virginia Medical School, Norfolk, VA.

Purpose: The majority of new diagnoses of pediatric cancer are made in resource-poor countries, where survival rates range from 5% to 25% compared with 80% in high-resource countries. Multiple factors, including diagnostic and treatment capacities and complex socioeconomic factors, contribute to this variation. This study evaluated the available resources and outcomes for pediatric patients with cancer at the first oncology treatment center in northern Tanzania.

Methods: Qualitative interviews were completed from July to August 2015 to determine available staff, hospital, diagnostic, treatment, and supportive care resources. A retrospective review of hospital admissions and clinic visits from January 2010 to August 2014 was completed. A total of 298 patients were identified, and data from 182 patient files were included in this review.

Results: Diagnostic, treatment, and supportive capacities are limited for pediatric cancer care. The most common diagnoses were Burkitt lymphoma (n = 32), other non-Hodgkin lymphoma (n = 26), and Wilms tumor (n = 25). A total of 40% of patients (n = 72) abandoned care. There was a 20% 2-year event-free survival rate, which was significantly affected by patient age, method of diagnosis, and year of diagnosis.

Conclusion: To our knowledge, this is the first review of pediatric cancer outcomes in northern Tanzania. The study identified areas for future development to improve pediatric cancer outcomes, which included strengthening of training and diagnostic capacities, development of registries and research databases, and the need for additional research to reduce treatment abandonment.
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http://dx.doi.org/10.1200/JGO.2016.009027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6180837PMC
September 2018

Qualitative Analysis of Palliative Care for Pediatric Patients With Cancer at Bugando Medical Center: An Evaluation of Barriers to Providing End-of-Life Care in a Resource-Limited Setting.

J Glob Oncol 2018 07;4:1-10

B. Emily Esmaili and Kearsley A. Stewart, Duke University; Kristin M. Schroeder, Duke University Medical Center, Durham, NC; and Nestory A. Masalu, Bugando Medical Center, Mwanza, Tanzania.

Purpose Palliative care remains an urgent, neglected need in the developing world. Global disparities in end-of-life care for children, such as those with advanced cancers, result from barriers that are complex and largely unstudied. This study describes these barriers at Bugando Medical Center, one of three consultant hospitals in Tanzania, to identify areas for palliative care development suitable to this context. Methods In-depth interviews were conducted with 20 caregivers of pediatric patients with cancer and 14 hospital staff involved in pediatric end-of-life care. This was combined with 1 month of participant observation through direct clinical care of terminally ill pediatric patients. Results Data from interviews as well as participant observation revealed several barriers to palliative care: financial, infrastructure, knowledge and cultural (including perceptions of pediatric pain), and communication challenges. Although this study focused on barriers, what also emerged were the unique advantages of end-of-life care in this setting, including community cohesiveness and strong faith background. Conclusion This study provides a unique but focused description of barriers to palliative care common in a low-resource setting, extending beyond resource needs. This multidisciplinary qualitative approach combined interviews with participant observation, providing a deeper understanding of the logistical and cultural challenges in this setting. This new understanding will inform the design of more effective-and more appropriate-palliative care policies for young patients with cancer in the developing world.
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http://dx.doi.org/10.1200/JGO.17.00047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6223406PMC
July 2018

Immunological tolerance as a barrier to protective HIV humoral immunity.

Curr Opin Immunol 2017 Aug 17;47:26-34. Epub 2017 Jul 17.

Department of Immunology & Microbiology, University of Colorado School of Medicine, Aurora, CO 80045, United States. Electronic address:

HIV-1 infection typically eludes antibody control by our immune system and is not yet prevented by a vaccine. While many viral features contribute to this immune evasion, broadly neutralizing antibodies (bnAbs) against HIV-1 are often autoreactive and it has been suggested that immunological tolerance may restrict a neutralizing antibody response. Indeed, recent Ig knockin mouse studies have shown that bnAb-expressing B cells are largely censored by central tolerance in the bone marrow. However, the contribution of peripheral tolerance in limiting the HIV antibody response by anergic and potentially protective B cells is poorly understood. Studies using mouse models to elucidate how anergic B cells are regulated and can be recruited into HIV-specific neutralizing antibody responses may provide insight into the development of a protective HIV-1 vaccine.
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http://dx.doi.org/10.1016/j.coi.2017.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5646169PMC
August 2017

Breaching peripheral tolerance promotes the production of HIV-1-neutralizing antibodies.

J Exp Med 2017 Aug 11;214(8):2283-2302. Epub 2017 Jul 11.

Department of Immunology and Microbiology, University of Colorado Denver, School of Medicine, Anschutz Medical Campus, Aurora, CO 80045

A subset of characterized HIV-1 broadly neutralizing antibodies (bnAbs) are polyreactive with additional specificities for self-antigens and it has been proposed immunological tolerance may present a barrier to their participation in protective humoral immunity. We address this hypothesis by immunizing autoimmune-prone mice with HIV-1 Envelope (Env) and characterizing the primary antibody response for HIV-1 neutralization. We find autoimmune mice generate neutralizing antibody responses to tier 2 HIV-1 strains with alum treatment alone in the absence of Env. Importantly, experimentally breaching immunological tolerance in wild-type mice also leads to the production of tier 2 HIV-1-neutralizing antibodies, which increase in breadth and potency following Env immunization. In both genetically prone and experimentally induced mouse models of autoimmunity, increased serum levels of IgM anti-histone H2A autoantibodies significantly correlated with tier 2 HIV-1 neutralization, and anti-H2A antibody clones were found to neutralize HIV-1. These data demonstrate that breaching peripheral tolerance permits a cross-reactive HIV-1 autoantibody response able to neutralize HIV-1.
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http://dx.doi.org/10.1084/jem.20161190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5551567PMC
August 2017

Pathogenic Chikungunya Virus Evades B Cell Responses to Establish Persistence.

Cell Rep 2016 08 21;16(5):1326-1338. Epub 2016 Jul 21.

Department of Immunology and Microbiology, School of Medicine, University of Colorado, Aurora, CO 80045, USA. Electronic address:

Chikungunya virus (CHIKV) and related alphaviruses cause epidemics of acute and chronic musculoskeletal disease. To investigate the mechanisms underlying the failure of immune clearance of CHIKV, we studied mice infected with an attenuated CHIKV strain (181/25) and the pathogenic parental strain (AF15561), which differ by five amino acids. Whereas AF15561 infection of wild-type mice results in viral persistence in joint tissues, 181/25 is cleared. In contrast, 181/25 infection of μMT mice lacking mature B cells results in viral persistence in joint tissues, suggesting that virus-specific antibody is required for clearance of infection. Mapping studies demonstrated that a highly conserved glycine at position 82 in the A domain of the E2 glycoprotein impedes clearance and neutralization of multiple CHIKV strains. Remarkably, murine and human antibodies targeting E2 domain B failed to neutralize pathogenic CHIKV strains efficiently. Our data suggest that pathogenic CHIKV strains evade E2 domain-B-neutralizing antibodies to establish persistence.
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http://dx.doi.org/10.1016/j.celrep.2016.06.076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5003573PMC
August 2016

Validation and Quality Assessment of the Kilimanjaro Cancer Registry.

J Glob Oncol 2016 Dec 27;2(6):381-386. Epub 2016 Apr 27.

, Durham Veterans Affairs Center for Research in Primary Care; , , , , and , Duke University, Durham, NC; , Bugando Medical Centre, Mwanza; and , , , , , , , , and , Kilimanjaro Christian Medical Centre, Moshi, Tanzania.

Purpose: Global cancer burden has increasingly shifted to low- and middle-income countries and is particularly pronounced in Africa. There remains a lack of comprehensive cancer information as a result of limited cancer registry development. In Moshi, Tanzania, a regional cancer registry exists at Kilimanjaro Christian Medical Center. Data quality is unknown. Our objective was to evaluate the completeness and quality of the Kilimanjaro Cancer Registry (KCR).

Methods: In October 2015, we conducted a retrospective review of KCR by validating the internal consistency of registry records with medical and pathology records. We randomly sampled approximately 100 total registry cases. Four reviewers not associated with the KCR manually collected data elements from medical records and compared them with KCR data.

Results: All 100 reviewed registry cases had complete cancer site and morphology included in the registry. Six had a recorded stage. For the majority (n = 92), the basis of diagnosis was pathology. Pathology reports were found in the medical record for 40% of patients; for the remainder, these were stored separately in the pathology department. Of sampled registry cases, the KCR and medical records were 98% and 94% concordant for primary cancer site and morphology, respectively. For 28%, recorded diagnosis dates were within 14 days of what was found in the medical record, and for 32%, they were within 30 days.

Conclusion: The KCR has a high level of concordance for classification and coding when data are retrieved for validation. This parameter is one of the most important for measuring data quality in a regional cancer registry.
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http://dx.doi.org/10.1200/JGO.2015.002873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5493247PMC
December 2016

A high-throughput in vitro drug screen in a genetically engineered mouse model of diffuse intrinsic pontine glioma identifies BMS-754807 as a promising therapeutic agent.

PLoS One 2015 6;10(3):e0118926. Epub 2015 Mar 6.

Department of Pediatrics, Duke University Medical Center, Durham, NC, United States of America; Department of Pathology, Duke University Medical Center, Durham, NC, United States of America; Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, United States of America.

Diffuse intrinsic pontine gliomas (DIPGs) represent a particularly lethal type of pediatric brain cancer with no effective therapeutic options. Our laboratory has previously reported the development of genetically engineered DIPG mouse models using the RCAS/tv-a system, including a model driven by PDGF-B, H3.3K27M, and p53 loss. These models can serve as a platform in which to test novel therapeutics prior to the initiation of human clinical trials. In this study, an in vitro high-throughput drug screen as part of the DIPG preclinical consortium using cell-lines derived from our DIPG models identified BMS-754807 as a drug of interest in DIPG. BMS-754807 is a potent and reversible small molecule multi-kinase inhibitor with many targets including IGF-1R, IR, MET, TRKA, TRKB, AURKA, AURKB. In vitro evaluation showed significant cytotoxic effects with an IC50 of 0.13 μM, significant inhibition of proliferation at a concentration of 1.5 μM, as well as inhibition of AKT activation. Interestingly, IGF-1R signaling was absent in serum-free cultures from the PDGF-B; H3.3K27M; p53 deficient model suggesting that the antitumor activity of BMS-754807 in this model is independent of IGF-1R. In vivo, systemic administration of BMS-754807 to DIPG-bearing mice did not prolong survival. Pharmacokinetic analysis demonstrated that tumor tissue drug concentrations of BMS-754807 were well below the identified IC50, suggesting that inadequate drug delivery may limit in vivo efficacy. In summary, an unbiased in vitro drug screen identified BMS-754807 as a potential therapeutic agent in DIPG, but BMS-754807 treatment in vivo by systemic delivery did not significantly prolong survival of DIPG-bearing mice.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0118926PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4352073PMC
February 2016

Central nervous system tumor distribution at a tertiary referral center in Uganda.

World Neurosurg 2014 Sep-Oct;82(3-4):258-65. Epub 2014 Jun 19.

Division of Hematology-Oncology, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA. Electronic address:

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http://dx.doi.org/10.1016/j.wneu.2014.06.040DOI Listing
March 2015

Molecular variants and mutations in medulloblastoma.

Pharmgenomics Pers Med 2014 4;7:43-51. Epub 2014 Feb 4.

Pediatric Clinical Services, Preston Robert Tisch Brain Tumor Center at Duke, Duke University Medical Center, Durham, NC, USA.

Medulloblastoma is the commonest malignant brain tumor in children. Treatment with surgery, irradiation, and chemotherapy has improved outcomes in recent years, but patients are frequently left with devastating neurocognitive and other sequelae following such therapy. While the prognosis has traditionally been based on conventional histopathology and clinical staging (based on age, extent of resection, and presence or absence of metastasis), it has become apparent in recent years that the inherent biology of the tumor plays a significant part in predicting survival and sometimes supersedes clinical or pathologic risk factors. The advent of deep sequencing gene technology has provided invaluable clues to the molecular makeup of this tumor and allowed neuro-oncologists to understand that medulloblastoma is an amalgamation of several distinct disease entities with unique clinical associations and behavior. This review is a concise summary of the pathology, genetic syndromes, recent advances in molecular subgrouping, and the associated gene mutations and copy number variations in medulloblastoma. The association of molecular alterations with patient prognosis is also discussed, but it should be remembered that further validation is required in prospective clinical trials utilizing uniform treatment approaches.
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http://dx.doi.org/10.2147/PGPM.S38698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3921827PMC
June 2014

Children are not just little adults: recent advances in understanding of diffuse intrinsic pontine glioma biology.

Pediatr Res 2014 Jan 5;75(1-2):205-9. Epub 2013 Nov 5.

1] Department of Pediatrics, Duke University, Durham, North Carolina [2] Department of Pathology, Duke University, Durham, North Carolina.

Diffuse intrinsic pontine glioma (DIPG) is a high-grade glioma that originates in the pons and is seen exclusively in children. Despite numerous efforts to improve treatment, DIPG remains incurable with 90% of children dying within 2 y of diagnosis, making it one of the leading causes of death in children with brain tumors. With the advent of new genomic tools, the genetic landscape of DIPG is slowly being unraveled. The most common genetic alterations include a K27M mutation in H3.3 or H3.1, which are found in up to 78% of DIPGs, whereas p53 mutations are found in up to 77%. Other recently discovered alterations include amplification of components of the receptor tyrosine kinase/Ras/phosphatidylinositol 3-kinase signaling pathway, particularly platelet-derived growth factor receptor A. Recapitulating such alterations, genetically engineered DIPG preclinical models have been developed, and DIPG xenograft models have also been established. Both models have strengths and weaknesses but can help with the prioritization of novel agents for clinical trials for children with DIPG. As we move forward, it is important that we continue to study the complex and unique biology of DIPG and develop improved preclinical models to increase our understanding of DIPG pathogenesis, allowing translation into successful therapies in the not too distant future.
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http://dx.doi.org/10.1038/pr.2013.194DOI Listing
January 2014

The role of somatic hypermutation in the generation of pathogenic antibodies in SLE.

Autoimmunity 2013 Mar 9;46(2):121-7. Epub 2013 Jan 9.

Department of Internal Medicine 3, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.

The formation of antibodies against double-stranded (ds)DNA is considered to be the serologic hallmark of systemic lupus erythematosus (SLE) and anti-dsDNA antibodies play an important role in the pathogenesis of the disease. Anti-dsDNA antibodies from lupus mice and SLE patients arise by somatic mutation. Importantly, autoantibodies in which somatic mutations have been reverted to germ-line V regions did not show any measurable autoreactivity, suggesting that anti-dsDNA autoantibodies develop from non-autoreactive B-cells by somatic hypermutation, presumably during the germinal center reaction. As the random nature of somatic hypermutation will inevitably create autoreactive B cells, self-tolerance checkpoints at the postmutational stage of B cell differentiation have to exist that normally prevent the induction of pathogenic anti-dsDNA specificities. This review summarizes the proposed mechanisms for the generation of anti-dsDNA in murine lupus and in SLE patients.
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http://dx.doi.org/10.3109/08916934.2012.748751DOI Listing
March 2013

The effects of macrophage source on the mechanism of phagocytosis and intracellular survival of Leishmania.

Microbes Infect 2011 Nov 30;13(12-13):1033-44. Epub 2011 Jun 30.

Molecular and Cellular Biology Program, University of Iowa, Iowa City, IA 52242, USA.

Leishmania spp. protozoa are obligate intracellular parasites that replicate in macrophages during mammalian infection. Efficient phagocytosis and survival in macrophages are important determinants of parasite virulence. Macrophage lines differ dramatically in their ability to sustain intracellular Leishmania infantum chagasi (Lic). We report that the U937 monocytic cell line supported the intracellular replication and cell-to-cell spread of Lic during 72 h after parasite addition, whereas primary human monocyte-derived macrophages (MDMs) did not. Electron microscopy and live cell imaging illustrated that Lic promastigotes anchored to MDMs via their anterior ends and were engulfed through symmetrical pseudopods. In contrast, U937 cells bound Lic in diverse orientations, and extended membrane lamellae to reorient and internalize parasites through coiling phagocytosis. Lic associated tightly with the parasitophorous vacuole (PV) membrane in both cell types. PVs fused with LAMP-1-expressing compartments 24 h after phagocytosis by MDMs, whereas U937 cell PVs remained LAMP-1 negative. The expression of one phagocytic receptor (CR3) was higher in MDMs than U937 cells, leading us to speculate that parasite uptake proceeds through dissimilar pathways between these cells. We hypothesize that the mechanism of phagocytosis differs between primary versus immortalized human macrophage cells, with corresponding differences in the subsequent intracellular fate of the parasite.
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http://dx.doi.org/10.1016/j.micinf.2011.05.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3185139PMC
November 2011

Predictors of relapse during treatment and treatment completion among marijuana-dependent adolescents in an intensive outpatient substance abuse program.

Subst Abus 2004 Mar;25(1):53-9

Department of Psychiatry, Duke University Medical Center, Box 3374, Durham, NC 27710, USA.

The present study assessed possible predictors of relapse while in treatment and treatment completion among marijuana-dependent adolescents (N = 59) in an intensive outpatient substance abuse treatment program. Comorbid depression was associated with an increased likelihood of relapse and a higher total number of relapses. As expected, relapse while in treatment was associated with a reduced likelihood of successfully completing the treatment program. Comorbid attention deficit hyperactivity disorder (ADHD) was also associated with a lower likelihood of successful program completion. These findings add to a slowly growing literature regarding adolescent substance abuse treatment, and may help clinicians identify marijuana-dependent adolescents at greater risk of relapse or noncompliance.
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http://dx.doi.org/10.1300/J465v25n01_08DOI Listing
March 2004
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