Clinical Research Publications

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Last Modified, June 28, 2020
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Prevalence of COVID-19 Infection and Outcomes Among Symptomatic Healthcare Workers in Seattle, Washington

Clin Infect Dis

2020 Noah Hoffman; Catherine Liu; Sara Marquis; Keith Jerome; Alex Greninger; Steven Pergam

BACKGROUND: Healthcare workers (HCW) serving on the front lines of the coronavirus disease 2019 (COVID-19) pandemic have been at increased risk for infection due to SARS-CoV-2 in some settings. Healthcare-acquired infection has been reported in similar epidemics, but there are limited data on the prevalence of COVID-19 among HCWs and their associated clinical outcomes in the United States. METHODS: We established two high-throughput employee testing centers in Seattle, Washington with drive-through and walk-through options for symptomatic employees in the University of Washington Medicine system and its affiliated organizations. Using data from these testing centers, we report the prevalence of SARS-CoV-2 infection among symptomatic employees and describe the clinical characteristics and outcomes among employees with COVID-19. RESULTS: Between March 12 and April 23, a total of 3,477 symptomatic employees were tested for COVID-19 at two employee testing centers; 185 (5.3%) employees tested positive for COVID-19. The prevalence of SARS-CoV-2 was similar when comparing frontline HCWs (5.2%) to non-frontline staff (5.5%). Among 174 positive employees reached for follow-up at least 14 days after diagnosis, 6 reported COVID-related hospitalization; all recovered. CONCLUSIONS: During the study period, we observed that the prevalence of positive SARS-CoV-2 tests among symptomatic HCWs was comparable to that of symptomatic non-frontline staff. Reliable and rapid access to testing for employees is essential to preserve the health, safety, and availability of the healthcare workforce during this pandemic and to facilitate the rapid return of SARS-CoV-2 negative employees to work.

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

Mol Ther Methods Clin Dev

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

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.

Clinical Development of BRAF plus MEK Inhibitor Combinations

Trends Cancer

2020 Christina Baik

Genomic profiling shows that many solid tumors are characterized by specific driver aberrations, and this has expanded the therapeutic options for many patients. The mitogen-activated protein kinase (MAPK) pathway is a key cell signaling pathway involved in regulating cellular growth, proliferation, and survival. Driver mutations in the BRAF gene, a key player in the MAPK pathway, are described in multiple tumor types, including subsets of melanoma, non-small cell lung cancer (NSCLC), and anaplastic thyroid cancer (ATC), making BRAF a desirable target for inhibition. BRAF inhibitors have shown efficacy in several cancers; however, most patients eventually develop resistance. To delay or prevent resistance, combination therapy targeting BRAF and MEK, a downstream signaling target of BRAF in the MAPK pathway, was evaluated and demonstrated synergistic benefit. BRAF and MEK inhibitor combinations have been approved for use in various cancers by the US FDA. We review the clinical data for various BRAF plus MEK combination regimens in three cancer types with underlying BRAF driver mutations: melanoma, NSCLC, and ATC. We also discuss practical treatment considerations and management of selected combination therapy toxicities.

Hematopoietic Cell Transplantation for Diamond Blackfan anemia: A report from the Pediatric Group of the Brazilian Bone Marrow Transplantation Society

Eur J Haematol

2020 Mary Flowers

OBJECTIVES: The aim of this study was to analyze the outcomes of children with Diamond-Blackfan anemia (DBA) treated in Brazil with hematopoietic cell transplantation (HCT). METHODS: We performed a retrospective analysis of 44 pediatrics patients transplanted between 1990 and 2018. The median age of patients was 5 years, and 57% were male. Twenty-five received their first HCT from an HLA-matched sibling donor (MSD) and 12 from a HLA matched unrelated bone marrow donor (MUD 10/10, n=12) and 7 other HLA mismatched donors (MMD). RESULTS: After a median follow-up of 4 years, estimate 5-year overall survival (OS) for the entire cohort was 70%, 80% for MSD group, 73% for MUD and 29% for MMD. Thirty-eight out of the 44 evaluable patients engrafted successfully. Primary and secondary graft failure was observed in five and three patients, respectively. Rates of grade II-IV and III-IV acute graft-versus-host disease (aGVHD) were 25 % and 18 % respectively. Nine patients developed chronic GVHD (cGVHD). CONCLUSION: OS rates observed after HLA matched donors transplant for DBA were comparable to those reported from higher income countries and international registries.

Outcomes Among Homeless Patients With Non-Small-Cell Lung Cancer: A County Hospital Experience

JCO Oncol Pract

2020 Christina Baik; Qian (Vicky) Wu; Isaac Jenkins; Hannah Linden

PURPOSE: Lung cancer remains the leading cause of cancer death in the United States, with outcomes likely worsened by the presence of poorer outcomes among vulnerable populations such as the homeless. We hypothesized that homeless patients experience delays in biopsy, decreased appointment adherence, and increased overall mortality rates. METHODS: We conducted a retrospective electronic medical record-based review of all patients with non-small-cell lung cancer (NSCLC; N = 133) between September 2012 and September 2018 at an academic county hospital in Seattle, Washington. RESULTS: Of the 133 patients treated for NSCLC, 22 (17%) were homeless at the time of their treatment. Among homeless patients with localized lung cancer, the mean time from radiographic finding to biopsy was 248 days, compared with 116 days among housed patients (P = .37). Homeless patients with advanced disease missed a mean of 26% of appointments in the year after diagnosis, compared with 16% among housed patients (P = .03). Homeless patients with advanced NSCLC had a median survival of 0.58 years, versus 1.30 years in housed patients (P = .48). CONCLUSION: To our knowledge, this is the first US study comparing outcomes among homeless and housed patients with NSCLC within the same institution; we found homeless patients had longer delays to biopsy, increased rates of missed appointments, and a trend toward decreased survival. This study shows potential areas where interventions could be implemented to improve lung cancer outcomes in this patient population.

Cytokines and Co-stimulation in Acute Graft-versus-Host Disease

Blood

2020 Geoffrey Hill; Motoko Koyama

Allogeneic hematopoietic stem cell transplantation (alloSCT) is an important curative therapy for high-risk hematological malignancies, but the development of severe and/or steroid-refractory acute graft-versus-host disease (aGVHD) remains a significant limitation to optimal outcomes. New approaches to prevent and treat aGVHD remain an unmet need that can be best addressed by understanding the complex disease pathophysiology. It is now clear that chemoradiotherapy utilized prior to alloSCT induces the release of endogenous alarmins (e.g. HMGB-1, ATP, IL-1α, IL-33) from recipient tissue. Exogenous pathogen-derived molecules (e.g. LPS, nucleic acids) also translocate from the gastrointestinal tract lumen. Together, these danger signals activate antigen presenting cells (APC) to efficiently present alloantigen to donor T cells whilst releasing cytokines (e.g. IL-12, IL-23, IL-6, IL-27, IL-10, TGFb) that expand and differentiate both pathogenic and regulatory donor T cells. Concurrent co-stimulatory signals at the APC-T cell interface (e.g. CD80/CD86-CD28, CD40-CD40L, OX40L-OX40, CD155/CD112-DNAM-1) and subsequent co-inhibitory signals (e.g. CD80/CD86-CTLA4, PDL1/2-PD1, CD155/CD112-TIGIT) are critical to the acquisition of effector T cell function and ensuing secretion of pathogenic cytokines (e.g. IL-17, IFNg, TNF, GM-CSF) and cytolytic degranulation pathway effectors (e.g. perforin/granzyme). This review focuses on the combination of cytokine and costimulatory networks at the T cell surface that culminates in effector function and subsequent aGVHD in target tissue. Together, these pathways now represent robust and clinically tractable targets for preventing the initiation of deleterious immunity after alloSCT.

Hyperprogressive Disease After Treatment With Checkpoint Inhibitors: Time for Prospective Studies

JAMA Oncol

2020 Rafael Santana-Davila

N/A

Donor-derived acute promyelocytic leukemia presenting as myeloid sarcoma in a transplanted kidney

Leukemia

2020 Shreeram Akilesh; Risa Wong; Pamela Becker

N/A

Dickkopf-related protein 3 is a novel biomarker for chronic GVHD after allogeneic hematopoietic cell transplantation

Blood Adv

2020 Mary Flowers; Yoshihiro Inamoto; Richard Lawler; Lynn Onstad; Laura Tabellini; Stephanie Lee; Paul Martin

To identify plasma biomarkers associated with fibrotic mechanisms of chronic graft-versus-host disease (GVHD), we used multiplex mass spectrometry with pooled samples for biomarker discovery in comparing proteomic profiles between patients with newly diagnosed sclerotic chronic GVHD (n = 21), those with newly diagnosed nonsclerotic chronic GVHD (n = 33), and those without chronic GVHD (n = 20). Immunoassay was used to measure protein concentrations of individual discovery samples and 186 independent verification samples. The discovery mass spectrometry analysis identified 2 candidate proteins with at least 1.5-fold difference in sclerotic GVHD: Dickkopf-related protein 3 (DKK3) and interleukin-1 receptor accessory protein (IL1RAP). Analysis of individual discovery samples by immunoassay showed that DKK3, a modulator of the Wnt signaling pathway, was a biomarker for both sclerotic and nonsclerotic chronic GVHD. Verification analysis of 186 patients confirmed that elevated plasma DKK3 concentrations were associated with chronic GVHD, regardless of the presence or absence of sclerosis, and that the area under the receiver operating characteristic curve was 0.85 for association of DKK3 concentrations with chronic GVHD. Multiple linear regression analysis showed that chronic GVHD with or without steroid treatment and patient age were independently associated with DKK3 concentrations. Patients with high DKK3 concentrations had a higher nonrelapse mortality than those with low concentrations. The lower IL1RAP concentrations in patients with sclerotic GVHD compared with other conditions in the discovery cohort were not confirmed in the verification cohort. DKK3 is a novel biomarker for chronic GVHD. Further studies are needed to determine the biological functions of DKK3 in the pathogenesis of chronic GVHD.

Implementation of Germline Testing for Prostate Cancer: Philadelphia Prostate Cancer Consensus Conference 2019

J Clin Oncol

2020 Evan Yu; Daniel Lin; Heather Cheng; Colin Pritchard

PURPOSE: Germline testing (GT) is a central feature of prostate cancer (PCA) treatment, management, and hereditary cancer assessment. Critical needs include optimized multigene testing strategies that incorporate evolving genetic data, consistency in GT indications and management, and alternate genetic evaluation models that address the rising demand for genetic services. METHODS: A multidisciplinary consensus conference that included experts, stakeholders, and national organization leaders was convened in response to current practice challenges and to develop a genetic implementation framework. Evidence review informed questions using the modified Delphi model. The final framework included criteria with strong (> 75%) agreement (Recommend) or moderate (50% to 74%) agreement (Consider). RESULTS: Large germline panels and somatic testing were recommended for metastatic PCA. Reflex testing-initial testing of priority genes followed by expanded testing-was suggested for multiple scenarios. Metastatic disease or family history suggestive of hereditary PCA was recommended for GT. Additional family history and pathologic criteria garnered moderate consensus. Priority genes to test for metastatic disease treatment included BRCA2, BRCA1, and mismatch repair genes, with broader testing, such as ATM, for clinical trial eligibility. BRCA2 was recommended for active surveillance discussions. Screening starting at age 40 years or 10 years before the youngest PCA diagnosis in a family was recommended for BRCA2 carriers, with consideration in HOXB13, BRCA1, ATM, and mismatch repair carriers. Collaborative (point-of-care) evaluation models between health care and genetic providers was endorsed to address the genetic counseling shortage. The genetic evaluation framework included optimal pretest informed consent, post-test discussion, cascade testing, and technology-based approaches. CONCLUSION: This multidisciplinary, consensus-driven PCA genetic implementation framework provides novel guidance to clinicians and patients tailored to the precision era. Multiple research, education, and policy needs remain of importance.