Publications by authors named "Matthew McKinney"

14 Publications

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Primary Mediastinal (Thymic) Large B-Cell Lymphoma: Fidelity of Diagnosis Using WHO Criteria.

Clin Lymphoma Myeloma Leuk 2020 Dec 30. Epub 2020 Dec 30.

Department of Radiation Oncology Duke University Medical Center, Durham, NC.

Purpose: Diagnosing primary mediastinal (thymic) large B-cell lymphoma (PMBCL) is challenging because it is a clinicopathologic entity that shares characteristics with other lymphomas and lacks pathognomonic features. We sought to investigate the fidelity between a working diagnosis of PMBCL at our institution and the clinicopathologic criteria established within the 2017 World Health Organization (WHO) classification.

Patients And Methods: Medical records and archived tissue of patients treated for stage I-II PMBCL from 1998 to 2018 were retrospectively reviewed for clinical and pathologic conformity with current WHO criteria. Disease was characterized as definitely PMBCL if all of the following were present: anterior mediastinal mass with or without lymph node involvement, no extranodal disease, B-cell antigen expression, Epstein-Barr virus negativity, and at least one supportive feature: female gender under age 40, bulky primary tumor, CD30 weakly positive, compartmentalizing alveolar fibrosis, lack of surface immunoglobulin expression, and MUM1 or CD23 positivity. Disease without supportive features or other pathologic findings more suggestive of other entities was characterized as equivocal for PMBCL. Lack of an anterior mediastinal mass, presence of distant lymph node involvement or extranodal disease, lack of B-cell antigen expression, or Epstein-Barr virus positivity were characterized as definitely not PMBCL. Clinical management and outcomes were also assessed.

Results: Of 63 patients treated for presumed stage I-II PMBCL, 58 (92%) met the criteria for PMBCL. The most common reason for a discordant diagnosis was lack of an anterior mediastinal mass (n = 3). Two additional patients were characterized as having disease equivocal for PMBCL. In retrospect, one patient most likely had a mediastinal gray zone lymphoma due to CD15 positivity and another diffuse large B cell, not otherwise specified, at pathologic review. Five-year progression-free and overall survival were 67% (95% confidence interval, 54-77) and 81% (95% confidence interval, 68-89), respectively, for all patients.

Conclusion: Despite the complexity of the clinicopathologic criteria of PMBCL, most patients (92%) who were treated for stage I-II PMBCL at our institution appear to have been accurately diagnosed.
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http://dx.doi.org/10.1016/j.clml.2020.12.015DOI Listing
December 2020

Results and Clinical Utilization of Foundation Medicine Molecular Tumor Profiling in Uterine and Ovarian Cancers.

Target Oncol 2021 01 5;16(1):109-118. Epub 2021 Jan 5.

Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Duke University, 201 Trent Drive, 203 Baker House, Durham, NC, 27710, USA.

Background: Recent advances in next-generation sequencing have allowed for an increase in molecular tumor profiling.

Objective: We sought to assess the actionability and clinical utilization of molecular tumor profiling results obtained via Foundation Medicine tumor sequencing tests in uterine and ovarian cancers.

Patients And Methods: We performed a single-institution retrospective chart review to obtain demographic and clinical information in patients with uterine and ovarian cancer whose tumors were submitted to Foundation Medicine for molecular tumor profiling over a 7-year period. Alterations identified on testing were stratified according to the OncoKB database actionability algorithm. Descriptive statistics were primarily used to analyze the data.

Results: Tumors from 185 women with gynecologic cancer were submitted for molecular tumor profiling between 2013 and 2019. The majority of tests (144/185; 78%) were ordered after a diagnosis of recurrence. In 60 (32%), no actionable molecular alteration was identified. Thirteen (7%) identified an alteration that directed to a US Food and Drug Administration-approved therapy in that tumor type, while 112 (61%) had alterations with investigational or hypothetical treatment implications. In patients with any actionable finding, treatment was initiated in 27 (15%) based on these results.

Conclusions: The majority of uterine and ovarian cancers (93%) did not have molecular alterations with corresponding Food and Drug Administration-approved treatments. Even in patients with a potentially actionable alteration, gynecologic oncologists were more likely to choose an alternative therapy. Further investigation is warranted to determine which patients with uterine and ovarian cancer are most likely to benefit from molecular tumor profiling and the ideal timing of testing. The potential to identify effective therapeutic options in a minority of patients needs to be balanced with the current limited clinical applicability of these results in most cases.
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http://dx.doi.org/10.1007/s11523-020-00785-zDOI Listing
January 2021

Hodgkin Lymphoma, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology.

J Natl Compr Canc Netw 2020 06;18(6):755-781

30National Comprehensive Cancer Network.

The NCCN Clinical Practice Guidelines in Oncology for Hodgkin Lymphoma (HL) provide recommendations for the management of adult patients with HL. The NCCN panel meets at least annually to review comments from reviewers within their institutions, examine relevant data, and reevaluate and update their recommendations. Current management of classic HL involves initial treatment with chemotherapy alone or combined modality therapy followed by restaging with PET/CT to assess treatment response. Overall, the introduction of less toxic and more effective regimens has significantly advanced HL cure rates. This portion of the NCCN Guidelines focuses on the management of classic HL.
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http://dx.doi.org/10.6004/jnccn.2020.0026DOI Listing
June 2020

Genomic Landscape of Cell-Free DNA in Patients with Colorectal Cancer.

Cancer Discov 2018 02 1;8(2):164-173. Epub 2017 Dec 1.

The University of Texas MD Anderson Cancer Center, Houston, Texas.

"Liquid biopsy" approaches analyzing cell-free DNA (cfDNA) from the blood of patients with cancer are increasingly utilized in clinical practice. However, it is not yet known whether cfDNA sequencing from large cohorts of patients with cancer can detect genomic alterations at frequencies similar to those observed by direct tumor sequencing, and whether this approach can generate novel insights. Here, we report next-generation sequencing data from cfDNA of 1,397 patients with colorectal cancer. Overall, frequencies of genomic alterations detected in cfDNA were comparable to those observed in three independent tissue-based colorectal cancer sequencing compendia. Our analysis also identified a novel cluster of extracellular domain (ECD) mutations in , mediating resistance by blocking binding of anti-EGFR antibodies. Patients with ECD mutations displayed striking tumor heterogeneity, with 91% harboring multiple distinct resistance alterations (range, 1-13; median, 4). These results suggest that cfDNA profiling can effectively define the genomic landscape of cancer and yield important biological insights. This study provides one of the first examples of how large-scale genomic profiling of cfDNA from patients with colorectal cancer can detect genomic alterations at frequencies comparable to those observed by direct tumor sequencing. Sequencing of cfDNA also generated insights into tumor heterogeneity and therapeutic resistance and identified novel ectodomain mutations. .
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http://dx.doi.org/10.1158/2159-8290.CD-17-1009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5809260PMC
February 2018

Assessing the impact of revegetation and weed control on urban sensitive bird species.

Ecol Evol 2017 06 2;7(12):4200-4208. Epub 2017 May 2.

Centre for Biodiversity and Conservation Science School of Biological Sciences The University of Queensland Brisbane Qld Australia.

Nature in cities is concentrated in urban green spaces, which are key areas for urban biodiversity and also important areas to connect people with nature. To conserve urban biodiversity within these natural refugia, habitat restoration such as weed control and revegetation is often implemented. These actions are expected to benefit biodiversity, although species known to be affected by urbanization may not be interacting with restoration in the ways we anticipate. In this study, we use a case study to explore how urban restoration activities impact different bird species. Birds were grouped into urban sensitivity categories and species abundance, and richness was then calculated using a hierarchical species community model for individual species responses, with "urban class" used as the hierarchical parameter. We highlight variable responses of birds to revegetation and weed control based on their level of urban sensitivity. Revegetation of open grassy areas delivers significant bird conservation outcomes, but the effects of weed control are neutral or in some cases negative. Specifically, the species most reliant on remnant vegetation in cities seem to remain stable or decline in abundance in areas with weed control, which we suspect is the result of a simplification of the understorey. The literature reports mixed benefits of weed control between taxa and between locations. We recommend, in our case study site, that weed control be implemented in concert with replanting of native vegetation to provide the understory structure preferred by urban sensitive birds. Understanding the impacts of revegetation and weed control on different bird species is important information for practitioners to make restoration decisions about the allocation of funds for conservation action. This new knowledge can be used both for threatened species and invasive species management.
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http://dx.doi.org/10.1002/ece3.2960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5478067PMC
June 2017

Enteropathy-associated T cell lymphoma subtypes are characterized by loss of function of SETD2.

J Exp Med 2017 05 19;214(5):1371-1386. Epub 2017 Apr 19.

Duke Center for Genomics and Computational Biology, Duke University, Durham, NC 27708.

Enteropathy-associated T cell lymphoma (EATL) is a lethal, and the most common, neoplastic complication of celiac disease. Here, we defined the genetic landscape of EATL through whole-exome sequencing of 69 EATL tumors. was the most frequently silenced gene in EATL (32% of cases). The JAK-STAT pathway was the most frequently mutated pathway, with frequent mutations in as well as , , , and We also identified mutations in , , and Type I EATL and type II EATL (monomorphic epitheliotropic intestinal T cell lymphoma) had highly overlapping genetic alterations indicating shared mechanisms underlying their pathogenesis. We modeled the effects of SETD2 loss in vivo by developing a T cell-specific knockout mouse. These mice manifested an expansion of γδ T cells, indicating novel roles for SETD2 in T cell development and lymphomagenesis. Our data render the most comprehensive genetic portrait yet of this uncommon but lethal disease and may inform future classification schemes.
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http://dx.doi.org/10.1084/jem.20160894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5413324PMC
May 2017

The Genetic Basis of Hepatosplenic T-cell Lymphoma.

Cancer Discov 2017 04 25;7(4):369-379. Epub 2017 Jan 25.

Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina.

Hepatosplenic T-cell lymphoma (HSTL) is a rare and lethal lymphoma; the genetic drivers of this disease are unknown. Through whole-exome sequencing of 68 HSTLs, we define recurrently mutated driver genes and copy-number alterations in the disease. Chromatin-modifying genes, including , and , were commonly mutated in HSTL, affecting 62% of cases. HSTLs manifest frequent mutations in (31%), (9%), and (9%), for which there currently exist potential targeted therapies. In addition, we noted less frequent events in , and was the most frequently silenced gene in HSTL. We experimentally demonstrated that acts as a tumor suppressor gene. In addition, we found that mutations in and activate critical signaling pathways important to cell survival in HSTL. Our work thus defines the genetic landscape of HSTL and implicates gene mutations linked to HSTL pathogenesis and potential treatment targets. We report the first systematic application of whole-exome sequencing to define the genetic basis of HSTL, a rare but lethal disease. Our work defines as a tumor suppressor gene in HSTL and implicates genes including and in the disease. .
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http://dx.doi.org/10.1158/2159-8290.CD-16-0330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5402251PMC
April 2017

GNA13 loss in germinal center B cells leads to impaired apoptosis and promotes lymphoma in vivo.

Blood 2016 06 17;127(22):2723-31. Epub 2016 Mar 17.

Duke Cancer Institute and Department of Medicine, Duke University Medical Center, Durham, NC; Duke Center for Genomic and Computational Biology, Duke University, Durham, NC;

GNA13 is the most frequently mutated gene in germinal center (GC)-derived B-cell lymphomas, including nearly a quarter of Burkitt lymphoma and GC-derived diffuse large B-cell lymphoma. These mutations occur in a pattern consistent with loss of function. We have modeled the GNA13-deficient state exclusively in GC B cells by crossing the Gna13 conditional knockout mouse strain with the GC-specific AID-Cre transgenic strain. AID-Cre(+) GNA13-deficient mice demonstrate disordered GC architecture and dark zone/light zone distribution in vivo, and demonstrate altered migration behavior, decreased levels of filamentous actin, and attenuated RhoA activity in vitro. We also found that GNA13-deficient mice have increased numbers of GC B cells that display impaired caspase-mediated cell death and increased frequency of somatic hypermutation in the immunoglobulin VH locus. Lastly, GNA13 deficiency, combined with conditional MYC transgene expression in mouse GC B cells, promotes lymphomagenesis. Thus, GNA13 loss is associated with GC B-cell persistence, in which impaired apoptosis and ongoing somatic hypermutation may lead to an increased risk of lymphoma development.
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http://dx.doi.org/10.1182/blood-2015-07-659938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4991089PMC
June 2016

Merkel cell carcinoma with partial B-cell blastic immunophenotype: a potential mimic of cutaneous richter transformation in a patient with chronic lymphocytic lymphoma.

Am J Dermatopathol 2014 Feb;36(2):148-52

*Department of Pathology, Duke University Medical Center, Durham, NC; †Eastern Dermatology and Pathology, Greenville, NC; and ‡Division of Hematologic Malignancies, Department of Medicine, Duke University Medical Center, Durham, NC.

Merkel cell polyomavirus (MCPyV) is a DNA virus whose pathogenic mechanisms in Merkel cell carcinoma (MCC) are still being unraveled. Emerging reports of an association between MCPyV and chronic lymphocytic lymphoma (CLL) have begun to broaden our understanding of the oncogenic mechanisms of this virus and the known association between these 2 malignancies. Herein, we report a case of MCC demonstrating a B-cell immunophenotype arising in a patient with CLL being treated with rituximab. In this context, we discuss the differential diagnostic considerations, especially with cutaneous Richter transformation (diffuse large B-cell lymphoma). We also assessed for the presence of MCPyV in both the patient's MCC and the CLL. Finally, we provide a large meta-analysis of patients with CLL and MCC. Patients with both MCC and CLL have a dismal prognosis, with greater than 50% overall mortality within the first year and a half after MCC diagnosis.
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http://dx.doi.org/10.1097/DAD.0b013e31829ed784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3931981PMC
February 2014

PAK1 mediates resistance to PI3K inhibition in lymphomas.

Clin Cancer Res 2013 Mar 8;19(5):1106-15. Epub 2013 Jan 8.

Duke Institute for Genome Sciences and Policy and Department of Medicine, Duke Cancer Institute, Duke University Medical Center, Duke University, Durham, North Carolina, USA.

Purpose: The phosphoinositide 3-kinase (PI3K) pathway is known to play an active role in many malignancies. The role of PI3K inhibition in the treatment of lymphomas has not been fully delineated. We sought to identify a role for therapeutic PI3K inhibition across a range of B-cell lymphomas.

Experimental Design: We selected three small molecule inhibitors to test in a panel of 60 cell lines that comprised diverse lymphoma types. We tested the selective PI3K inhibitor BKM120 and the dual PI3K/mTOR inhibitors BEZ235 and BGT226 in these cell lines. We applied gene expression profiling to better understand the molecular mechanisms associated with responsiveness to these drugs.

Results: We found that higher expression of the PAK1 gene was significantly associated with resistance to all three PI3K inhibitors. Through RNA-interference-mediated knockdown of the PAK1 gene, we showed a dramatic increase in the sensitivity to PI3K inhibition. We further tested a small-molecule inhibitor of PAK1 and found significant synergy between PI3K and PAK1 inhibition.

Conclusion: Thus, we show that PI3K inhibition is broadly effective in lymphomas and PAK1 is a key modulator of resistance to PI3K inhibition.
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http://dx.doi.org/10.1158/1078-0432.CCR-12-1060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3594365PMC
March 2013

The genetic landscape of mutations in Burkitt lymphoma.

Nat Genet 2012 Dec 11;44(12):1321-5. Epub 2012 Nov 11.

Duke Institute for Genome Sciences and Policy, Duke University, Durham, NC, USA.

Burkitt lymphoma is characterized by deregulation of MYC, but the contribution of other genetic mutations to the disease is largely unknown. Here, we describe the first completely sequenced genome from a Burkitt lymphoma tumor and germline DNA from the same affected individual. We further sequenced the exomes of 59 Burkitt lymphoma tumors and compared them to sequenced exomes from 94 diffuse large B-cell lymphoma (DLBCL) tumors. We identified 70 genes that were recurrently mutated in Burkitt lymphomas, including ID3, GNA13, RET, PIK3R1 and the SWI/SNF genes ARID1A and SMARCA4. Our data implicate a number of genes in cancer for the first time, including CCT6B, SALL3, FTCD and PC. ID3 mutations occurred in 34% of Burkitt lymphomas and not in DLBCLs. We show experimentally that ID3 mutations promote cell cycle progression and proliferation. Our work thus elucidates commonly occurring gene-coding mutations in Burkitt lymphoma and implicates ID3 as a new tumor suppressor gene.
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http://dx.doi.org/10.1038/ng.2468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3674561PMC
December 2012

Distribution of Chaetodactylus krombeini (Acari: Chaetodactylidae) within Osmia cornifrons (Hymenoptera: Megachilidae) nests: implications for population management.

Exp Appl Acarol 2013 Jun 26;60(2):153-61. Epub 2012 Oct 26.

Department of Entomology, West Virginia University, Morgantown, WV 26506, USA.

Chaetodactylus krombeini (Baker) (Acari: Chaetodactylidae) is a cleptoparasitic mite that negatively affects propagation of Osmia spp. (Hymenoptera: Megachilidae) for orchard pollination in the USA. This study was conducted to determine the effect of C. krombeini on mortality of male and female Osmia cornifrons, the Japanese hornfaced bee. A total of 107 O. cornifrons nests were examined to determine within-nest distribution of C. krombeini with regression analyses. A total of 30 mite-free O. cornifrons nests were observed and within-nest distribution of male and female O. cornifrons was determined with non-linear regression analyses. In addition, cocoons from 20 mite-infested O. cornifrons cells were examined to determine whether C. krombeini could be found inside cocoons of O. cornifrons. The results of this study showed that female O. cornifrons and C. krombeini were found more frequently in the inner part of the nest, and male O. cornifrons were found mostly in the center of the nest. No C. krombeini were found inside O. cornifrons cocoons. These results indicate that C. krombeini have a greater negative impact on mortality in the egg and larval stages of female O. cornifrons than in male O. cornifrons. Implications for management of C. krombeini and O. cornifrons populations for orchard pollination are discussed in this article.
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http://dx.doi.org/10.1007/s10493-012-9629-7DOI Listing
June 2013

Erythropoietin for oncology supportive care.

Exp Cell Res 2011 May 17;317(9):1246-54. Epub 2011 Mar 17.

Department of Medicine, Duke University School of Medicine, Durham, NC, USA.

Recombinant human erythropoietin (rhEPO), the prototype erythropoiesis-stimulating agent developed in the 1980s, was among the first recombinant human proteins to be marketed for clinical use in the oncology setting. Anemia is a frequent concern in patients with cancer receiving myelosuppressive chemotherapy and the availability of rhEPO as an alternative to red blood cell transfusions to treat symptomatic anemia created excitement among clinicians, particularly during an era of mounting concern for transfusion-transmissible infections. Early studies of rhEPO for chemotherapy-induced anemia in patients with non-myeloid malignancies showed these agents improved hemoglobin levels and reduced transfusion rates. rhEPO therapy was reported to decrease fatigue and improve quality of life, although the magnitude and clinical meaningfulness of these effects have been debated. More recent clinical trials since 2003 linking rhEPO therapy to increased risk of tumor progression, thrombo-vascular events and mortality prompted implementation of use restrictions to minimize potential for harm. Scientific research to understand the basic mechanisms of the biologic effects of erythropoietin at the cellular receptor and signaling level has revealed pleiotropic cytokine effects extending beyond erythropoiesis regulation. The importance of erythropoietin receptor signaling in normal, non-erythroid tissues and in pre-clinical tumor models has been under intense investigation and scrutiny, as potential mechanisms of the adverse outcomes associated with rhEPO therapy have been debated. Further research will be required to clarify the complex interplay between the diverse hematopoietic and non-hematopoietic effects of erythropoietin in normal and malignant tissues and to optimize the clinical use of rhEPO in the supportive care of cancer patients.
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http://dx.doi.org/10.1016/j.yexcr.2011.03.003DOI Listing
May 2011

Induction of Wilms' tumor protein (WT1)-specific antitumor immunity using a truncated WT1-expressing adenovirus vaccine.

Clin Cancer Res 2009 Apr 7;15(8):2789-96. Epub 2009 Apr 7.

Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.

Purpose: Wilms' tumor protein (WT1) is overexpressed in most leukemias and many solid tumors and is a promising target for tumor immunotherapy. WT1 peptide-based cancer vaccines have been reported but have limited application due to HLA restriction of the peptides. We sought to vaccinate using adenoviral (Ad) vectors encoding tumor-associated antigens such as WT1 that can stimulate tumor-associated antigen-specific immunity across a broad array of HLA types and multiple class I and class II epitopes.

Experimental Design: We developed a novel Ad vector encoding a truncated version of WT1 (Ad-tWT1) lacking the highly conserved COOH terminus zinc finger domains and tested its ability to stimulate WT1-specific immune responses and antitumor immunity in two murine models of WT1-expressing tumors.

Results: Despite encoding a transcription factor, we found that Ad-tWT1-transduced murine and human dendritic cells showed cytoplasmic expression of the truncated WT1 protein. In addition, vaccination of C57BL/6 mice with Ad-tWT1 generated WT1-specific cell-mediated and humoral immune responses and conferred protection against challenge with the leukemia cell line, mWT1-C1498. Moreover, in a tumor therapy model, Ad-tWT1 vaccination of TRAMP-C2 tumor-bearing mice significantly suppressed tumor growth.

Conclusions: This is the first report of a WT1-encoding Ad vector that is capable of inducing effective immunity against WT1-expressing malignancies. Based on these findings, Ad-tWT1 warrants investigation in human clinical trials to evaluate its applications as a vaccine for patients with WT1-expressing cancers.
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http://dx.doi.org/10.1158/1078-0432.CCR-08-2589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3631522PMC
April 2009