Publications by authors named "Corey Casper"

115 Publications

Intra-host changes in Kaposi sarcoma-associated herpesvirus genomes in Ugandan adults with Kaposi sarcoma.

Authors:
Jan Clement Santiago Jason D Goldman Hong Zhao Alec P Pankow Fred Okuku Michael W Schmitt Lennie H Chen C Alexander Hill Corey Casper Warren T Phipps James I Mullins

PLoS Pathog 2021 Jan 19;17(1):e1008594. Epub 2021 Jan 19.

University of Washington, Department of Microbiology, Seattle, Washington, United States of America.

Intra-host tumor virus variants may influence the pathogenesis and treatment responses of some virally-associated cancers. However, the intra-host variability of Kaposi sarcoma-associated herpesvirus (KSHV), the etiologic agent of Kaposi sarcoma (KS), has to date been explored with sequencing technologies that possibly introduce more errors than that which occurs in the viral population, and these studies have only studied variable regions. Here, full-length KSHV genomes in tumors and/or oral swabs from 9 Ugandan adults with HIV-associated KS were characterized. Furthermore, we used deep, short-read sequencing using duplex unique molecular identifiers (dUMI)-random double-stranded oligonucleotides that barcode individual DNA molecules before library amplification. This allowed suppression of PCR and sequencing errors to ~10-9/base as well as afforded accurate determination of KSHV genome numbers sequenced in each sample. KSHV genomes were assembled de novo, and rearrangements observed were confirmed by PCR and Sanger sequencing. 131-kb KSHV genome sequences, excluding major repeat regions, were successfully obtained from 23 clinical specimens, averaging 2.3x104 reads/base. Strikingly, KSHV genomes were virtually identical within individuals at the point mutational level. The intra-host heterogeneity that was observed was confined to tumor-associated KSHV mutations and genome rearrangements, all impacting protein-coding sequences. Although it is unclear whether these changes were important to tumorigenesis or occurred as a result of genomic instability in tumors, similar changes were observed across individuals. These included inactivation of the K8.1 gene in tumors of 3 individuals and retention of a region around the first major internal repeat (IR1) in all instances of genomic deletions and rearrangements. Notably, the same breakpoint junctions were found in distinct tumors within single individuals, suggesting metastatic spread of rearranged KSHV genomes. These findings define KSHV intra-host heterogeneity in vivo with greater precision than has been possible in the past and suggest the possibility that aberrant KSHV genomes may contribute to aspects of KS tumorigenesis. Furthermore, study of KSHV with use of dUMI provides a proof of concept for utilizing this technique for detailed study of other virus populations in vivo.
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http://dx.doi.org/10.1371/journal.ppat.1008594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845968PMC
January 2021

ACCELERATE: A Patient-Powered Natural History Study Design Enabling Clinical and Therapeutic Discoveries in a Rare Disorder.

Authors:
Sheila K Pierson Johnson S Khor Jasira Ziglar Amy Liu Katherine Floess Erin NaPier Alexander M Gorzewski Mark-Avery Tamakloe Victoria Powers Faizaan Akhter Eric Haljasmaa Raj Jayanthan Arthur Rubenstein Mileva Repasky Kojo Elenitoba-Johnson Jason Ruth Bette Jacobs Matthew Streetly Linus Angenendt Jose Luis Patier Simone Ferrero Pier Luigi Zinzani Louis Terriou Corey Casper Elaine Jaffe Christian Hoffmann Eric Oksenhendler Alexander Fosså Gordan Srkalovic Amy Chadburn Thomas S Uldrick Megan Lim Frits van Rhee David C Fajgenbaum

Cell Rep Med 2020 Dec 22;1(9):100158. Epub 2020 Dec 22.

Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

Geographically dispersed patients, inconsistent treatment tracking, and limited infrastructure slow research for many orphan diseases. We assess the feasibility of a patient-powered study design to overcome these challenges for Castleman disease, a rare hematologic disorder. Here, we report initial results from the ACCELERATE natural history registry. ACCELERATE includes a traditional physician-reported arm and a patient-powered arm, which enables patients to directly contribute medical data and biospecimens. This study design enables successful enrollment, with the 5-year minimum enrollment goal being met in 2 years. A median of 683 clinical, laboratory, and imaging data elements are captured per patient in the patient-powered arm compared with 37 in the physician-reported arm. These data reveal subgrouping characteristics, identify off-label treatments, support treatment guidelines, and are used in 17 clinical and translational studies. This feasibility study demonstrates that the direct-to-patient design is effective for collecting natural history data and biospecimens, tracking therapies, and providing critical research infrastructure.
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http://dx.doi.org/10.1016/j.xcrm.2020.100158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762771PMC
December 2020

International evidence-based consensus diagnostic and treatment guidelines for unicentric Castleman disease.

Authors:
Frits van Rhee Eric Oksenhendler Gordan Srkalovic Peter Voorhees Megan Lim Angela Dispenzieri Makoto Ide Sophia Parente Stephen Schey Matthew Streetly Raymond Wong David Wu Ivan Maillard Joshua Brandstadter Nikhil Munshi Wilbur Bowne Kojo S Elenitoba-Johnson Alexander Fössa Mary Jo Lechowicz Shanmuganathan Chandrakasan Sheila K Pierson Amy Greenway Sunita Nasta Kazuyuki Yoshizaki Razelle Kurzrock Thomas S Uldrick Corey Casper Amy Chadburn David C Fajgenbaum

Blood Adv 2020 Dec;4(23):6039-6050

Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Castleman disease (CD) includes a group of rare and heterogeneous disorders with characteristic lymph node histopathological abnormalities. CD can occur in a single lymph node station, which is referred to as unicentric CD (UCD). CD can also involve multicentric lymphadenopathy and inflammatory symptoms (multicentric CD [MCD]). MCD includes human herpesvirus-8 (HHV-8)-associated MCD, POEMS-associated MCD, and HHV-8-/idiopathic MCD (iMCD). The first-ever diagnostic and treatment guidelines were recently developed for iMCD by an international expert consortium convened by the Castleman Disease Collaborative Network (CDCN). The focus of this report is to establish similar guidelines for the management of UCD. To this purpose, an international working group of 42 experts from 10 countries was convened to establish consensus recommendations based on review of treatment in published cases of UCD, the CDCN ACCELERATE registry, and expert opinion. Complete surgical resection is often curative and is therefore the preferred first-line therapy, if possible. The management of unresectable UCD is more challenging. Existing evidence supports that asymptomatic unresectable UCD may be observed. The anti-interleukin-6 monoclonal antibody siltuximab should be considered for unresectable UCD patients with an inflammatory syndrome. Unresectable UCD that is symptomatic as a result of compression of vital neighboring structures may be rendered amenable to resection by medical therapy (eg, rituximab, steroids), radiotherapy, or embolization. Further research is needed in UCD patients with persisting constitutional symptoms despite complete excision and normal laboratory markers. We hope that these guidelines will improve outcomes in UCD and help treating physicians decide the best therapeutic approach for their patients.
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http://dx.doi.org/10.1182/bloodadvances.2020003334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724917PMC
December 2020

Newly diagnosed and previously treated multicentric Castleman disease respond equally to siltuximab.

Authors:
Frits van Rhee Jean-François Rossi David Simpson Alexander Fosså Angela Dispenzieri John Kuruvilla Yeow Tee Goh Seok-Goo Cho Marcelo Capra Ting Liu Corey Casper James Cavet Raymond S Wong

Br J Haematol 2021 Jan 31;192(1):e28-e31. Epub 2020 Oct 31.

Sir YK Pao Centre for Cancer, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong.

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http://dx.doi.org/10.1111/bjh.17177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820993PMC
January 2021

Maternal Epstein-Barr virus-specific antibodies and risk of infection in Ugandan infants.

Authors:
Rana Minab Wei Bu Hanh Nguyen Abigail Wall Anton M Sholukh Meei-Li Huang Michael Ortego Elizabeth M Krantz Michael Irvine Corey Casper Jackson Orem Andrew T McGuire Jeffrey I Cohen Soren Gantt

J Infect Dis 2020 Oct 23. Epub 2020 Oct 23.

University of British Columbia, Vancouver, Canada.

Background: Epstein-Barr virus (EBV) infection is a major cause of malignancy worldwide. Maternal antibody is thought to prevent EBV infection because it is uncommon in early infancy. Maternal HIV infection is associated with an increased incidence of EBV infection in exposed infants, which we hypothesized results from impaired transfer of EBV-neutralizing maternal antibodies.

Methods: Among Ugandan infants followed for EBV acquisition from birth, we measured antibody binding to EBV glycoproteins (e.g., gp350, gH/gL) involved in B cell and epithelial cell entry, as well as viral neutralization and antibody-dependent cellular cytotoxicity (ADCC) activity in plasma samples prior to infection. These serologic data were analyzed for differences between HIV-exposed uninfected (HEU) and unexposed (HUU) infants, and for associations with incident infant EBV infection.

Results: HEU infants had significantly higher titers than HUU infants for all EBV-binding and neutralizing antibodies measured (p<0.01), but not ADCC activity, which was similar between groups. No antibody measure was associated with a decreased risk of EBV acquisition in the cohort.

Conclusions: Our findings indicate that in this cohort maternal antibody did not protect infants against EBV infection through viral neutralization. The identification of protective non-neutralizing antibody functions would be invaluable for the development of an EBV vaccine.
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http://dx.doi.org/10.1093/infdis/jiaa654DOI Listing
October 2020

Analysis of Ugandan cervical carcinomas identifies human papillomavirus clade-specific epigenome and transcriptome landscapes.

Authors:
Alessia Gagliardi Vanessa L Porter Zusheng Zong Reanne Bowlby Emma Titmuss Constance Namirembe Nicholas B Griner Hilary Petrello Jay Bowen Simon K Chan Luka Culibrk Teresa M Darragh Mark H Stoler Thomas C Wright Patee Gesuwan Maureen A Dyer Yussanne Ma Karen L Mungall Steven J M Jones Carolyn Nakisige Karen Novik Jackson Orem Martin Origa Julie M Gastier-Foster Robert Yarchoan Corey Casper Gordon B Mills Janet S Rader Akinyemi I Ojesina Daniela S Gerhard Andrew J Mungall Marco A Marra

Nat Genet 2020 08 3;52(8):800-810. Epub 2020 Aug 3.

Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, British Columbia, Canada.

Cervical cancer is the most common cancer affecting sub-Saharan African women and is prevalent among HIV-positive (HIV) individuals. No comprehensive profiling of cancer genomes, transcriptomes or epigenomes has been performed in this population thus far. We characterized 118 tumors from Ugandan patients, of whom 72 were HIV, and performed extended mutation analysis on an additional 89 tumors. We detected human papillomavirus (HPV)-clade-specific differences in tumor DNA methylation, promoter- and enhancer-associated histone marks, gene expression and pathway dysregulation. Changes in histone modification at HPV integration events were correlated with upregulation of nearby genes and endogenous retroviruses.
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http://dx.doi.org/10.1038/s41588-020-0673-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498180PMC
August 2020

Estimating the Risk of Human Herpesvirus 6 and Cytomegalovirus Transmission to Ugandan Infants from Viral Shedding in Saliva by Household Contacts.

Authors:
Bryan T Mayer Elizabeth M Krantz Anna Wald Lawrence Corey Corey Casper Soren Gantt Joshua T Schiffer

Viruses 2020 02 3;12(2). Epub 2020 Feb 3.

Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.

Human herpesvirus 6 (HHV-6) and cytomegalovirus (CMV) infections are common in early childhood. In a prospective Ugandan birth cohort study, most infants acquired HHV-6 (24/31; 77%) and CMV (20/30; 67%) during follow-up. To assess the transmission risk, we modeled a dose-response relationship between infant HHV-6 and CMV infections and weekly oral viral shedding by mothers and all other ("secondary") children in the home. Oral viral loads that were shed by mothers and secondary children were significantly associated with HHV-6 but not CMV transmission. While secondary children had higher and more frequent HHV-6 shedding than their mothers, they had a lower per-exposure transmission risk, suggesting that transmission to maternal contacts may be more efficient. HHV-6 transmission was relatively inefficient, occurring after <25% of all weekly exposures. Although HHV-6 transmission often occurs following repeated, low dose exposures, we found a non-linear dose-response relationship in which infection risk markedly increases when exposures reached a threshold of > 5 log DNA copies/mL. The lack of association between oral CMV shedding and transmission is consistent with breastfeeding being the dominant route of infant infection for that virus. These affirm saliva as the route of HHV-6 transmission and provide benchmarks for developing strategies to reduce the risk of infection and its related morbidity.
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http://dx.doi.org/10.3390/v12020171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7077293PMC
February 2020

Long-term safety of siltuximab in patients with idiopathic multicentric Castleman disease: a prespecified, open-label, extension analysis of two trials.

Authors:
Frits van Rhee Corey Casper Peter M Voorhees Luis E Fayad Damilola Gibson Karan Kanhai Razelle Kurzrock

Lancet Haematol 2020 Mar 3;7(3):e209-e217. Epub 2020 Feb 3.

Center for Personalized Therapy and Clinical Trials Office, UC San Diego Moore's Cancer Center, La Jolla, CA, USA.

Background: Siltuximab is recommended by international consensus as a first-line treatment for idiopathic multicentric Castleman disease on the basis of durable efficacy and safety data. This study was done to assess the long-term safety and activity of siltuximab over up to 6 years of treatment.

Methods: This study is a prespecified open-label extension analysis of a phase 1 trial (NCT00412321) and a phase 2 trial (NCT01024036), done at 26 hospitals worldwide. Patients in both studies were at least 18 years old with histologically confirmed, symptomatic Castleman disease. This extension study enrolled 60 patients who completed the previous trials without disease progression on siltuximab. Patients received siltuximab infusions of 11 mg/kg every 3 weeks (which could be extended to 6 weeks) for up to 6 years. Descriptive statistics were used to summarise the data. No formal hypothesis testing was performed. The primary endpoint was the safety of siltuximab, assessed at each dosing cycle. The study was registered with ClinicalTrials.gov, number NCT01400503 and with EudraCT, number 2010-022837-27.

Findings: Patient enrolment into the phase 1 trial was from June 20, 2005, to Sept 15, 2009, and enrolment into the phase 2 trial was from Feb 9, 2010, to Feb 3, 2012. Patients were enrolled in this long-term extension from April 1, 2011, to Jan 15, 2014. Median follow-up was 6 years (IQR 5·11-7·76). Median treatment duration, from the beginning of the previous trials to the end of the present study, was 5·5 years (IQR 4·26-7·14). Siltuximab was well tolerated; however, adverse events of grade 3 or worse were reported in 36 (60%) of 60 patients with the most common being hypertension (eight [13%]), fatigue (five [8%]), nausea (four [7%]), neutropenia (four [7%]), and vomiting (three [5%]). 25 (42%) patients reported at least one serious adverse event, which most commonly was an infection (eight [13%]). Only two serious adverse events, polycythaemia and urinary retention, were considered related to siltuximab treatment. 18 patients discontinued before study completion, either to receive siltuximab locally (eight) or because of progressive disease (two), adverse events (two), or other reasons (six). No deaths were reported.

Interpretation: These results show that siltuximab is well tolerated long term and provides important evidence for the feasibility of the life-long use required by patients with idiopathic multicentric Castleman disease.

Funding: Janssen R&D and EUSA Pharma.
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http://dx.doi.org/10.1016/S2352-3026(19)30257-1DOI Listing
March 2020

A phase 1 antigen dose escalation trial to evaluate safety, tolerability and immunogenicity of the leprosy vaccine candidate LepVax (LEP-F1 + GLA-SE) in healthy adults.

Authors:
Malcolm S Duthie Aude Frevol Tracey Day Rhea N Coler Julie Vergara Tom Rolf Zachary K Sagawa Anna Marie Beckmann Corey Casper Steven G Reed

Vaccine 2020 02 30;38(7):1700-1707. Epub 2019 Dec 30.

Infectious Disease Research Institute, Seattle, WA, USA; Host Directed Therapeutics, Seattle, WA, USA; Department of Global Health, University of Washington, Seattle, WA, USA.

Healthy United States-based adult volunteers with no history of travel to leprosy-endemic countries were enrolled for the first-in-human evaluation of LepVax (LEP-F1 + GLA-SE). In total 24 volunteers participated in an open-labelclinicaltrial, with 21 receiving three injections of LepVax consisting of either 2 µg or 10 µg recombinantpolyprotein LEP-F1 mixed with 5 µg of the GLA-SE adjuvant formulation. LepVax doses were provided by intramuscular injection on Days 0, 28, and 56, and safety was evaluated for one year following the final injection. LepVaxwas safe and well tolerated at both antigen doses. Immunological analyses indicated that similar LEP-F1-specific antibody and Th1 cytokine secretion (IFN-γ, IL-2, TNF) were induced by each of the antigen doses evaluated within LepVax. This clinicaltrialof the first definedvaccinecandidate for leprosy demonstrates that LepVax is safe and immunogenic in healthy subjects and supports its advancement to testing in leprosy-endemic regions.
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http://dx.doi.org/10.1016/j.vaccine.2019.12.050DOI Listing
February 2020

The association between HIV infection and cervical cancer presentation and survival in Uganda.

Authors:
Emily S Wu Renata R Urban Elizabeth M Krantz Noleb M Mugisha Carolyn Nakisige Stephen M Schwartz Heidi J Gray Corey Casper

Gynecol Oncol Rep 2020 Feb 19;31:100516. Epub 2019 Nov 19.

Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, PO Box 19024, Seattle, WA 98109, USA.

Our objective was to determine how HIV infection impacts cervical cancer stage at presentation and overall survival (OS) among Ugandan women. This was a prospective study of 149 women diagnosed with cervical cancer from 2013 to 2015 at the Uganda Cancer Institute. Poisson regression models were fit to calculate prevalence ratios (PR) for the association between HIV infection and late stage at cancer diagnosis. The association between HIV infection and OS after cervical cancer diagnosis was evaluated using Cox proportional hazards models. The cohort included 53 HIV-positive and 96 HIV-negative participants. Median age at diagnosis was 44 years for HIV-positive and 54 years for HIV-negative participants. Seventy-seven percent of HIV-positive participants received antiretroviral therapy. Median baseline CD4 count was 373 cells/mm3 for HIV-positive participants versus 926 cells/mm3 for HIV-negative participants. Thirty-two percent of HIV-positive participants were diagnosed with late stage cervical cancer (III-IV) versus 39% of HIV-negative participants. No association was found between late stage at cancer diagnosis and HIV infection (PR adjusted for age, parity and transport cost 1.0, 95%CI 0.6-1.8). Most women presenting for care received cancer treatment, though almost half who received radiotherapy did not complete treatment. The median OS was 13.7 months for HIV-positive participants and 24.3 months for HIV-negative participants. After adjusting for age and stage, HIV infection was weakly associated with OS (HR 1.3, 95%CI 0.8-2.2). In Uganda, cervical cancer is often incompletely treated and survival remains poor. HIV infection was not associated with cervical cancer stage at diagnosis, but may be weakly associated with shorter survival.
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http://dx.doi.org/10.1016/j.gore.2019.100516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6921151PMC
February 2020

Presentation and Outcomes of Childhood Cancer Patients at Uganda Cancer Institute.

Authors:
Innocent Mutyaba Henry R Wabinga Jackson Orem Corey Casper Warren Phipps

Glob Pediatr Health 2019 18;6:2333794X19849749. Epub 2019 May 18.

Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

. Limited data suggest that children with cancer in sub-Saharan Africa have poor survival. We aimed to describe the presentation, treatment outcomes, and factors associated with survival among children with cancer managed at Uganda Cancer Institute. . We retrospectively evaluated patients with childhood cancer (age ≤19 years) from Kyadondo County treated at Uganda Cancer Institute from 2006 to 2009. Cox's regression and Kaplan-Meier methods were used to study 1-year survival. . Among 310 patients studied, median age was 7 years (range = 0.25-19 years), 64% were boys, and 92% had histological confirmation of cancer diagnosis. The commonest diagnoses were Burkitt lymphoma (BL, N = 87), Kaposi sarcoma (KS, N = 68), non-BL non-Hodgkin lymphoma (NHL, N = 32), acute lymphoblastic leukemia (ALL, N = 28), Wilms (N = 28), and Hodgkin disease (HD, N = 20). Advanced disease at diagnosis was common for all cancers (ranging from 45% for KS to 83% for non-BL NHL). Overall, 33.2% abandoned treatment. One-year survival was 68% for HD (95% confidence interval [CI] = 11.3-40.6), 67% for KS (95% CI = 52.1-77.9), 55% for BL (95% CI = 42-66.9), 44% for Wilms (95% CI = 22.5-63), 43% for non-BL NHL (95% CI = 23.3-61.3), and 20% for ALL (95% CI = 6.4-38.7). In univariate and multivariate analysis, anemia and thrombocytopenia were associated with mortality for several cancers. . Survival among children with cancer in Uganda is poor. Advanced stage disease and loss to follow-up likely contribute to poor outcomes. Anemia and thrombocytopenia may augment traditional staging methods to provide better prognostic factors in Uganda and warrant further evaluation.
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http://dx.doi.org/10.1177/2333794X19849749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6537233PMC
May 2019

Survival of children with endemic Burkitt lymphoma in a prospective clinical care project in Uganda.

Authors:
Suzanne M McGoldrick Innocent Mutyaba Scott V Adams Anna Larsen Elizabeth M Krantz Constance Namirembe Peter Mooka Susan Nabakooza Mariam Ndagire Kelvin Mubiru Martin Nabwana Rose Nankinga Sarah Gerdts Cristin Gordon-Maclean Fadhil Geriga Abrahams Omoding Erica Sessle Joyce Kambugu Thomas S Uldrick Jackson Orem Corey Casper

Pediatr Blood Cancer 2019 09 3;66(9):e27813. Epub 2019 Jun 3.

Departments of Medicine and Global Health, Infectious Disease Research Institute and the University of Washington, Seattle, Washington.

Purpose: "Endemic" Burkitt lymphoma (BL) is a common childhood cancer in Africa. Social and treatment factors may contribute to poor survival. With the aim of improving BL outcomes in Uganda, we undertook a comprehensive project (BL Project) that provided diagnostic support, access to standard chemotherapy, nutritional evaluations, and case management. We evaluated survival of children with BL in the context of the project.

Patients And Methods: Patients followed by the BL Project who consented to research were enrolled in this study. Children with a pathology diagnosis consistent with BL were eligible. Data were collected prospectively. First-line chemotherapy generally consisted of six cycles of cyclophosphamide, vincristine, low-dose methotrexate (COM). We used Kaplan-Meier and Cox regression analyses to evaluate factors associated with overall survival (OS).

Results: Between July 2012 and June 2017, 341 patients with suspected BL presented to the BL Project. One hundred eighty patients with a pathology-based diagnosis were included in this study. The median age was seven years (interquartile range, 5-9), 74% lived ≥100 km from the Uganda Cancer Institute, 61% had late-stage disease, 84% had ECOG performance status < 3, 63% reported B-symptoms, and 22% showed neurologic symptoms. Fewer than 10% abandoned therapy. The four-year OS rate was 44% (95% CI, 36%-53%). In a multivariate model, ECOG status was significantly associated with mortality.

Conclusion: The BL Project reduced effects of lacking supportive care and oncology resources, and allowed patients from Uganda to receive curative intent therapy with minimal loss to follow-up. Nonetheless, OS remains unacceptably low. Improved therapeutic approaches to endemic BL are urgently needed in Africa.
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http://dx.doi.org/10.1002/pbc.27813DOI Listing
September 2019

Humoral Immune Correlates for Prevention of Postnatal Cytomegalovirus Acquisition.

Authors:
Frances M Saccoccio Jennifer A Jenks Hannah L Itell Shuk Hang Li Madison Berry Justin Pollara Corey Casper Soren Gantt Sallie R Permar

J Infect Dis 2019 07;220(5):772-780

Division of Pediatric Infectious Diseases, Duke University, Durham, North Carolina.

Background: Development of a cytomegalovirus (CMV) vaccine is a high priority. However, the ability of antibodies to protect against CMV infection is not well characterized. Studies of maternal antibodies in infants offer the potential to identify humoral correlates of protection against postnatal acquisition.

Methods: This hypothesis-generating study analyzed 29 Ugandan mother-infant pairs that were followed weekly for CMV acquisition. Seventeen mothers and no infants were infected with human immunodeficiency virus (HIV). We evaluated the association between CMV-specific immunoglobulin G (IgG) responses in mothers at the time of delivery and their infants' CMV status at 6 months of age. We also assessed levels of CMV-specific IgG in infants at 6 weeks of age. CMV-specific IgG responses in the mother-infant pairs were then analyzed on the basis of perinatal HIV exposure.

Results: We found similar levels of multiple CMV glycoprotein-specific IgG binding specificities and functions in mothers and infants, irrespective of perinatal HIV exposure or infant CMV status at 6 months of age. However, the glycoprotein B-specific IgG titer, measured by 2 distinct assays, was higher in infants without CMV infection and was moderately associated with delayed CMV acquisition.

Conclusions: These data suggest that high levels of glycoprotein B-specific IgG may contribute to the partial protection against postnatal CMV infection afforded by maternal antibodies, and they support the continued inclusion of glycoprotein B antigens in CMV vaccine candidates.
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http://dx.doi.org/10.1093/infdis/jiz192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6667799PMC
July 2019

The cost effectiveness of treating Burkitt lymphoma in Uganda.

Authors:
Avram E Denburg Nazeefah Laher Innocent Mutyaba Suzanne McGoldrick Joyce Kambugu Erica Sessle Jackson Orem Corey Casper

Cancer 2019 06 6;125(11):1918-1928. Epub 2019 Mar 6.

Fred Hutchinson Cancer Research Center, Seattle Children's Hospital, Seattle, Washington.

Background: Perceptions of high cost and resource intensity remain political barriers to the prioritization of childhood cancer treatment programs in many low- and middle-income countries (LMICs). Little knowledge exists of the actual cost and cost-effectiveness of such programs. To improve outcomes for children with Burkitt lymphoma (BL), the most common childhood cancer in Africa, the Uganda Cancer Institute implemented a comprehensive BL treatment program in 2012. We undertook an economic evaluation of the program to ascertain the cost-effectiveness of BL therapy in a specific LIC setting.

Methods: We compared the treatment of BL to usual care in a cohort of 122 patients treated between 2012 and 2014. Costs included variable, fixed, and family costs. Our primary measure of effectiveness was overall survival (OS). Patient outcomes were determined through prospective capture and retrospective chart abstraction. The cost per disability-adjusted life-year (DALY) averted was calculated using the World Health Organization's Choosing Interventions That Are Cost-Effective (WHO-CHOICE) methodology.

Results: The 2-year OS with treatment was 55% (95% CI, 45% to 64%). The cost per DALY averted in the treatment group was US$97 (Int$301). Cumulative estimate of national DALYs averted through treatment was 8607 years, and the total national annual cost of treatment was US$834,879 (Int$2,590,845). The cost of BL treatment fell well within WHO-CHOICE cost-effectiveness thresholds. The ratio of cost per DALY averted to per capita gross domestic product was 0.14, reflecting a very cost-effective intervention.

Conclusion: This study demonstrates that treating BL with locally tailored protocols is very cost-effective by international standards. Studies of this kind will furnish crucial evidence to help policymakers prioritize the allocation of LMIC health system resources among noncommunicable diseases, including childhood cancer.
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http://dx.doi.org/10.1002/cncr.32006DOI Listing
June 2019

Engagement in HIV Care and Access to Cancer Treatment Among Patients With HIV-Associated Malignancies in Uganda.

Authors:
Daniel H Low Warren Phipps Jackson Orem Corey Casper Rachel A Bender Ignacio

J Glob Oncol 2019 02;5:1-8

Fred Hutchinson Cancer Research Center, Seattle, WA.

Purpose: Health system constraints limit access to HIV and cancer treatment programs in sub-Saharan Africa. Limited access and continuity of care affect morbidity and mortality of patients with cancer and HIV. We assessed barriers in the care cascade of comorbid HIV and cancer.

Patients And Methods: Structured interviews were conducted with 100 adult patients with HIV infection and new diagnoses of cancer at the Uganda Cancer Institute. Participants completed follow-up questionnaires after 1 year to assess ongoing engagement with and barriers to care.

Results: The median time from new-onset cancer symptoms to initiation of cancer care at the Uganda Cancer Institute was 209 days (interquartile range, 113 to 384 days). Persons previously established in HIV care waited less overall to initiate cancer care ( P = .04). Patients established in HIV care experienced shorter times from initial symptoms to seeking of cancer care ( P = .02) and from seeking of care to cancer diagnosis ( P = .048). Barriers to receiving care for HIV and cancer included difficulty traveling to multiple clinics/hospitals (46%), conflicts between HIV and cancer appointments (23%), prohibitive costs (21%), and difficulty adhering to medications (15%). Reporting of any barriers to care was associated with premature discontinuation of cancer treatment ( P = .003).

Conclusion: Patients with HIV-associated malignancies reported multiple barriers to receiving care for both conditions, although knowledge of HIV status and engagement in HIV care before presentation with malignancy reduced subsequent time to the start of cancer treatment. This study provides evidence to support creation and evaluation of integrated HIV and cancer care models.
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http://dx.doi.org/10.1200/JGO.18.00187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6426497PMC
February 2019

Genome-wide discovery of somatic coding and noncoding mutations in pediatric endemic and sporadic Burkitt lymphoma.

Authors:
Bruno M Grande Daniela S Gerhard Aixiang Jiang Nicholas B Griner Jeremy S Abramson Thomas B Alexander Hilary Allen Leona W Ayers Jeffrey M Bethony Kishor Bhatia Jay Bowen Corey Casper John Kim Choi Luka Culibrk Tanja M Davidsen Maureen A Dyer Julie M Gastier-Foster Patee Gesuwan Timothy C Greiner Thomas G Gross Benjamin Hanf Nancy Lee Harris Yiwen He John D Irvin Elaine S Jaffe Steven J M Jones Patrick Kerchan Nicole Knoetze Fabio E Leal Tara M Lichtenberg Yussanne Ma Jean Paul Martin Marie-Reine Martin Sam M Mbulaiteye Charles G Mullighan Andrew J Mungall Constance Namirembe Karen Novik Ariela Noy Martin D Ogwang Abraham Omoding Jackson Orem Steven J Reynolds Christopher K Rushton John T Sandlund Roland Schmitz Cynthia Taylor Wyndham H Wilson George W Wright Eric Y Zhao Marco A Marra Ryan D Morin Louis M Staudt

Blood 2019 03 7;133(12):1313-1324. Epub 2019 Jan 7.

Lymphoid Malignancies Branch, Center for Cancer Research and.

Although generally curable with intensive chemotherapy in resource-rich settings, Burkitt lymphoma (BL) remains a deadly disease in older patients and in sub-Saharan Africa. Epstein-Barr virus (EBV) positivity is a feature in more than 90% of cases in malaria-endemic regions, and up to 30% elsewhere. However, the molecular features of BL have not been comprehensively evaluated when taking into account tumor EBV status or geographic origin. Through an integrative analysis of whole-genome and transcriptome data, we show a striking genome-wide increase in aberrant somatic hypermutation in EBV-positive tumors, supporting a link between EBV and activation-induced cytidine deaminase (AICDA) activity. In addition to identifying novel candidate BL genes such as , , and , we demonstrate that EBV-positive tumors had significantly fewer driver mutations, especially among genes with roles in apoptosis. We also found immunoglobulin variable region genes that were disproportionally used to encode clonal B-cell receptors (BCRs) in the tumors. These include IGHV4-34, known to produce autoreactive antibodies, and IGKV3-20, a feature described in other B-cell malignancies but not yet in BL. Our results suggest that tumor EBV status defines a specific BL phenotype irrespective of geographic origin, with particular molecular properties and distinct pathogenic mechanisms. The novel mutation patterns identified here imply rational use of DNA-damaging chemotherapy in some patients with BL and targeted agents such as the CDK4/6 inhibitor palbociclib in others, whereas the importance of BCR signaling in BL strengthens the potential benefit of inhibitors for PI3K, Syk, and Src family kinases among these patients.
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http://dx.doi.org/10.1182/blood-2018-09-871418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428665PMC
March 2019

Quantitative RNAseq analysis of Ugandan KS tumors reveals KSHV gene expression dominated by transcription from the LTd downstream latency promoter.

Authors:
Timothy M Rose A Gregory Bruce Serge Barcy Matt Fitzgibbon Lisa R Matsumoto Minako Ikoma Corey Casper Jackson Orem Warren Phipps

PLoS Pathog 2018 12 17;14(12):e1007441. Epub 2018 Dec 17.

Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.

KSHV is endemic in Uganda and the HIV epidemic has dramatically increased the incidence of Kaposi sarcoma (KS). To investigate the role of KSHV in the development of KS, we obtained KS biopsies from ART-naïve, HIV-positive individuals in Uganda and analyzed the tumors using RNAseq to globally characterize the KSHV transcriptome. Phylogenetic analysis of ORF75 sequences from 23 tumors revealed 6 distinct genetic clusters with KSHV strains exhibiting M, N or P alleles. RNA reads mapping to specific unique coding sequence (UCDS) features were quantitated using a gene feature file previously developed to globally analyze and quantitate KSHV transcription in infected endothelial cells. A pattern of high level expression was detected in the KSHV latency region that was common to all KS tumors. The clear majority of transcription was derived from the downstream latency transcript promoter P3(LTd) flanking ORF72, with little evidence of transcription from the P1(LTc) latency promoter, which is constitutive in KSHV-infected lymphomas and tissue-culture cells. RNAseq data provided evidence of alternate P3(LTd) transcript editing, splicing and termination resulting in multiple gene products, with 90% of the P3(LTd) transcripts spliced to release the intronic source of the microRNAs K1-9 and 11. The spliced transcripts encode a regulatory uORF upstream of Kaposin A with alterations in intervening repeat sequences yielding novel or deleted Kaposin B/C-like sequences. Hierarchical clustering and PCA analysis of KSHV transcripts revealed three clusters of tumors with different latent and lytic gene expression profiles. Paradoxically, tumors with a latent phenotype had high levels of total KSHV transcription, while tumors with a lytic phenotype had low levels of total KSHV transcription. Morphologically distinct KS tumors from the same individual showed similar KSHV gene expression profiles suggesting that the tumor microenvironment and host response play important roles in the activation level of KSHV within the infected tumor cells.
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http://dx.doi.org/10.1371/journal.ppat.1007441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6312348PMC
December 2018

Correlates of GLA family adjuvants' activities.

Authors:
Steven G Reed Darrick Carter Corey Casper Malcolm S Duthie Christopher B Fox

Semin Immunol 2018 10 23;39:22-29. Epub 2018 Oct 23.

Infectious Disease Research Institute, 1616 Eastlake Ave E, Suite 400, Seattle, WA 98102 USA. Electronic address:

Lipopolysaccharide (LPS) is a well-defined agonist of Toll-like receptor (TLR) 4 that activates innate immune responses and influences the development of the adaptive response during infection with Gram-negative bacteria. Many years ago, Dr. Edgar Ribi separated the adjuvant activity of LPS from its toxic effects, an effort that led to the development of monophosphoryl lipid A (MPL). MPL, derived from Salmonella minnesota R595, has progressed through clinical development and is now used in various product-enabling formulations to support the generation of antigen-specific responses in several commercial and preclinical vaccines. We have generated several synthetic lipid A molecules, foremost glucopyranosyl lipid adjuvant (GLA) and second-generation lipid adjuvant (SLA), and have advanced these to clinical trial for various indications. In this review we summarize the potential and current positioning of TLR4-based adjuvant formulations in approved and emerging vaccines.
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http://dx.doi.org/10.1016/j.smim.2018.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6289613PMC
October 2018

Second coming: the re-emergence and modernization of immunotherapy by vaccines as a component of leprosy control.

Authors:
Malcolm S Duthie Corey Casper Steven G Reed

Future Microbiol 2018 10 12;13:1449-1451. Epub 2018 Oct 12.

From the Infectious Disease Research Institute, 1616 Eastlake Ave E, Suite 400, Seattle, WA 98102, USA.

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http://dx.doi.org/10.2217/fmb-2018-0186DOI Listing
October 2018

Peer Mentoring at the Uganda Cancer Institute: A Novel Model for Career Development of Clinician-Scientists in Resource-Limited Settings.

Authors:
Warren Phipps Rachel Kansiime Philip Stevenson Jackson Orem Corey Casper Rhoda A Morrow

J Glob Oncol 2018 09;4:1-11

Warren Phipps, Corey Casper, and Rhoda A. Morrow, University of Washington; Warren Phipps, Philip Stevenson, Jackson Orem, Corey Casper, and Rhoda A. Morrow, Fred Hutchinson Cancer Research Center; Corey Casper, Infectious Diseases Research Institute, Seattle, WA; and Rachel Kansiime and Jackson Orem, Uganda Cancer Institute, Kampala, Uganda.

Cancer centers are beginning to emerge in low- and middle-income countries despite having relatively few oncologists and specialists in related fields. Uganda, like many countries in sub-Saharan Africa, has a cadre of highly motivated clinician-scientists-in-training who are committed to developing the capacity for cancer care and research. However, potential local mentors for these trainees are burdened with uniquely high demands on their time for clinical care, teaching, institutional development, advocacy, and research. Facilitated peer mentoring helps to fill skills and confidence gaps and teaches mentoring skills so that trainees can learn to support one another and regularly access a more senior facilitator/role model. With an added consultant component, programs can engage limited senior faculty time to address specific training needs and to introduce junior investigators to advisors and even potential dyadic mentors. Two years after its inception, our facilitated peer mentoring career development program at the Uganda Cancer Institute in Kampala is successfully developing a new generation of researchers who, in turn, are now providing role models and mentors from within their group. This program provides a practical model for building the next generation of clinical scientists in developing countries.
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http://dx.doi.org/10.1200/JGO.17.00134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6223430PMC
September 2018

Association Between HIV Infection and Cancer Stage at Presentation at the Uganda Cancer Institute.

Authors:
Manoj P Menon Anna Coghill Innocent O Mutyaba Warren T Phipps Fred M Okuku John M Harlan Jackson Orem Corey Casper

J Glob Oncol 2018 09 16;4:1-9. Epub 2017 Oct 16.

Manoj P. Menon, Anna Coghill, Warren T. Phipps, and Corey Casper, Fred Hutchinson Cancer Research Center; Manoj P. Menon, Warren T. Phipps, John M. Harlan, and Corey Casper, University of Washington, Seattle, WA; and Innocent O. Mutyaba, Fred M. Okuku, and Jackson Orem, Uganda Cancer Institute, Kampala, Uganda.

Purpose: The HIV epidemic has contributed to the increasing incidence of cancer in sub-Saharan Africa, where most patients with cancer present at an advanced stage. However, improved access to HIV care and treatment centers in sub-Saharan Africa may facilitate earlier diagnosis of cancer among patients who are HIV positive. To test this hypothesis, we characterized the stage of cancer and evaluated the factors associated with advanced stage at presentation among patients in Uganda.

Methods: We conducted a retrospective analysis of adult patients with any of four specific cancers who presented for care in Kampala, Uganda, between 2003 and 2010. Demographic, clinical, and laboratory data were abstracted from the medical record, together with the outcome measure of advanced stage of disease (clinical stage III or IV). We identified measures for inclusion in a multivariate logistic regression model.

Results: We analyzed 731 patients with both AIDS-defining cancers (cervical [43.1%], and non-Hodgkin lymphoma [18.3%]), and non-AIDS-defining cancers (breast [30.0%] and Hodgkin lymphoma [8.6%]). Nearly 80% of all patients presented at an advanced stage and 37% had HIV infection. More than 90% of patients were symptomatic and the median duration of symptoms before presentation was 5 months. In the multivariate model, HIV-positive patients were less likely to present at an advanced stage as were patients with higher hemoglobin and fewer symptoms.

Conclusion: Patients with limited access to primary care may present with advanced cancer because of a delay in diagnosis. However, patients with HIV now have better access to clinical care. Use of this growing infrastructure to increase cancer screening and referral is promising and deserves continued support, because the prognosis of HIV-positive patients with advanced cancer is characterized by poor survival globally.
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http://dx.doi.org/10.1200/JGO.17.00005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6180750PMC
September 2018

HIV Status and Associated Clinical Characteristics Among Adult Patients With Cancer at the Uganda Cancer Institute.

Authors:
Rachel Bender Ignacio Matine Ghadrshenas Daniel Low Jackson Orem Corey Casper Warren Phipps

J Glob Oncol 2018 09 16;4:1-10. Epub 2017 Nov 16.

Rachel Bender Ignacio, Corey Casper, and Warren Phipps, Fred Hutchinson Cancer Research Center; Rachel Bender Ignacio, Matine Ghadrshenas, Daniel Low, Corey Casper, and Warren Phipps, University of Washington; Corey Casper, Infectious Diseases Research Institute, Seattle, WA; and Jackson Orem, Uganda Cancer Institute, Kampala, Uganda.

Purpose: HIV increases cancer incidence and mortality. In Uganda, the HIV epidemic has led to an elevated incidence of AIDS-defining cancers (ADCs) and non-AIDS-defining cancers (NADCs). Limited information exists about how frequently HIV infection complicates the presentation and manifestations of cancer in sub-Saharan Africa.

Methods: We abstracted medical records from patients with cancer who were age 18 years or older who registered at the Uganda Cancer Institute from June through September 2015 to determine the burden of HIV. We used χ tests and generalized linear models to evaluate factors associated with HIV positivity. A sensitivity analysis estimated HIV prevalence in those untested.

Results: Among 1,137 patients with cancer, 23% were HIV infected, 48% were HIV negative, and 29% had no recorded HIV status. Of those with recorded HIV status, 32% were HIV positive. Forty-two percent (149 of 361 patients) with ADCs were documented as HIV infected (51% of those with documented status) compared with 14% (108 of 776 patients) of those with NADCs (21% of those with documented status). In multivariable analysis, HIV infection was associated with ADC diagnosis (adjusted prevalence ratio [aPR] compared with NADC, 2.2; 95% CI, 1.5 to 3.0), younger age (aPR, 0.9 per decade increase; 95% CI, 0.8 to 1.0), and worse performance status scores (aPR, 1.2 per point ECOG increase; 95% CI, 1.0 to 1.5). When sensitivity analysis accounted for undocumented HIV status, the expected prevalence of HIV infection was 29% (range, 23% to 32%), and almost one fourth of expected HIV cases were undiagnosed or unrecorded.

Conclusion: The prevalence of HIV infection among Ugandan patients with cancer is substantially higher than in the general population. Patients with cancer and HIV tend to be younger and have poorer performance status. Greater awareness of the dual burden of cancer and HIV in Uganda and universal testing of patients with cancer may improve outcomes of HIV-associated malignancies.
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http://dx.doi.org/10.1200/JGO.17.00112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6181185PMC
September 2018

International, evidence-based consensus treatment guidelines for idiopathic multicentric Castleman disease.

Authors:
Frits van Rhee Peter Voorhees Angela Dispenzieri Alexander Fosså Gordan Srkalovic Makoto Ide Nikhil Munshi Stephen Schey Matthew Streetly Sheila K Pierson Helen L Partridge Sudipto Mukherjee Dustin Shilling Katie Stone Amy Greenway Jason Ruth Mary Jo Lechowicz Shanmuganathan Chandrakasan Raj Jayanthan Elaine S Jaffe Heather Leitch Naveen Pemmaraju Amy Chadburn Megan S Lim Kojo S Elenitoba-Johnson Vera Krymskaya Aaron Goodman Christian Hoffmann Pier Luigi Zinzani Simone Ferrero Louis Terriou Yasuharu Sato David Simpson Raymond Wong Jean-Francois Rossi Sunita Nasta Kazuyuki Yoshizaki Razelle Kurzrock Thomas S Uldrick Corey Casper Eric Oksenhendler David C Fajgenbaum

Blood 2018 11 4;132(20):2115-2124. Epub 2018 Sep 4.

Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Castleman disease (CD) describes a group of heterogeneous hematologic disorders with characteristic histopathological features. CD can present with unicentric or multicentric (MCD) regions of lymph node enlargement. Some cases of MCD are caused by human herpesvirus-8 (HHV-8), whereas others are HHV-8-negative/idiopathic (iMCD). Treatment of iMCD is challenging, and outcomes can be poor because no uniform treatment guidelines exist, few systematic studies have been conducted, and no agreed upon response criteria have been described. The purpose of this paper is to establish consensus, evidence-based treatment guidelines based on the severity of iMCD to improve outcomes. An international Working Group of 42 experts from 10 countries was convened by the Castleman Disease Collaborative Network to establish consensus guidelines for the management of iMCD based on published literature, review of treatment effectiveness for 344 cases, and expert opinion. The anti-interleukin-6 monoclonal antibody siltuximab (or tocilizumab, if siltuximab is not available) with or without corticosteroids is the preferred first-line therapy for iMCD. In the most severe cases, adjuvant combination chemotherapy is recommended. Additional agents are recommended, tailored by disease severity, as second- and third-line therapies for treatment failures. Response criteria were formulated to facilitate the evaluation of treatment failure or success. These guidelines should help treating physicians to stratify patients based on disease severity in order to select the best available therapeutic option. An international registry for patients with CD (ACCELERATE, #NCT02817997) was established in October 2016 to collect patient outcomes to increase the evidence base for selection of therapies in the future.
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http://dx.doi.org/10.1182/blood-2018-07-862334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6238190PMC
November 2018

Nonprimary Maternal Cytomegalovirus Infection After Viral Shedding in Infants.

Authors:
Isabelle Boucoiran Bryan T Mayer Elizabeth M Krantz Arnaud Marchant Sunil Pati Suresh Boppana Anna Wald Larry Corey Corey Casper Joshua T Schiffer Soren Gantt

Pediatr Infect Dis J 2018 07;37(7):627-631

Fred Hutchinson Cancer Research Center, Seattle, Washington.

Background: Most infants with congenital Cytomegalovirus (CMV) infection are born to seropositive women as a result of maternal CMV nonprimary infection (reinfection or reactivation). Although infected children are known to transmit CMV to their seronegative mothers, the frequency and magnitude of nonprimary maternal CMV infection after exposure to viral shedding by children in their household have not been characterized.

Methods: A cohort of Ugandan newborns and their mothers were tested weekly for CMV by quantitative polymerase chain reaction of oral swabs. Infant primary infection and maternal nonprimary infection were defined by the onset of persistent high-level oral CMV shedding. Strain-specific antibody testing was used to assess maternal reinfection. Cox regression models with time-dependent covariates were used to evaluate risk factors for nonprimary maternal infection.

Results: Nonprimary CMV infection occurred in 15 of 30 mothers, all after primary infection of their infants by a median of 6 weeks (range: 1-10) in contrast to none of the mothers of uninfected infants. The median duration of maternal oral shedding lasted 18 weeks (range: 4-42) reaching a median maximum viral load of 4.69 log copies/mL (range: 3.22-5.64). Previous-week infant CMV oral quantities strongly predicted maternal nonprimary infection (hazard ratio: 2.32 per log10 DNA copies/swab increase; 95% confidence interval: 1.63-3.31). Maternal nonprimary infections were not associated with changes in strain-specific antibody responses.

Conclusions: Nonprimary CMV infection was common in mothers after primary infection in their infants, consistent with infant-to-mother transmission. Because infants frequently acquire CMV from their mothers, for example, through breast milk, this suggests the possibility of "ping-pong" infections. Additional research is needed to characterize the antigenic and genotypic strains transmitted among children and their mothers.
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http://dx.doi.org/10.1097/INF.0000000000001877DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6016842PMC
July 2018

KSHV oral shedding and plasma viremia result in significant changes in the extracellular tumorigenic miRNA expression profile in individuals infected with the malaria parasite.

Authors:
Minako Ikoma Soren Gantt Corey Casper Yuko Ogata Qing Zhang Ryan Basom Michael R Dyen Timothy M Rose Serge Barcy

PLoS One 2018 9;13(2):e0192659. Epub 2018 Feb 9.

Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, Washington, United States of America.

Kaposi's sarcoma herpesvirus (KSHV) is the etiological agent of Kaposi's sarcoma (KS). Both KSHV and HIV infections are endemic in Uganda, where KS is among the most common cancers in HIV-infected individuals. Recent studies examined the use of small RNAs as biomarkers of disease, including microRNAs (miRNAs), with viral and tumor-derived miRNAs being detected in exosomes from individuals with KSHV-associated malignancies. In the current study, the host and viral extracellular mature miRNA expression profiles were analyzed in blood of KS-negative individuals in Uganda, comparing those with or without KSHV detectable from the oropharynx. We observed increased levels of cellular oncogenic miRNAs and decreased levels of tumor-suppressor miRNAs in plasma of infected individuals exhibiting oral KSHV shedding. These changes in host oncomiRs were exacerbated in people co-infected with HIV, and partially reversed after 2 years of anti-retroviral therapy. We also detected KSHV miRNAs in plasma of KSHV infected individuals and determined that their expression levels correlated with KSHV plasma viremia. Deep sequencing revealed an expected profile of small cellular RNAs in plasma, with miRNAs constituting the major RNA biotype. In contrast, the composition of small RNAs in exosomes was highly atypical with high levels of YRNA and low levels of miRNAs. Mass spectrometry analysis of the exosomes revealed eleven different peptides derived from the malaria parasite, Plasmodium falciparum, and small RNA sequencing confirmed widespread plasmodium co-infections in the Ugandan cohorts. Proteome analysis indicated an exosomal protein profile consistent with erythrocyte and keratinocyte origins for the plasma exosomes. A strong correlation was observed between the abundance of Plasmodium proteins and cellular markers of malaria. As Plasmodium falciparum is an endemic pathogen in Uganda, our study shows that co-infection with other pathogens, such as KSHV, can severely impact the small RNA repertoire, complicating the use of exosome miRNAs as biomarkers of disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0192659PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5806893PMC
April 2018

Whom to treat? Factors associated with chemotherapy recommendations and outcomes among patients with NHL at the Uganda Cancer Institute.

Authors:
Manoj Menon Anna Coghill Innocent Mutyaba Fred Okuku Warren Phipps John Harlan Jackson Orem Corey Casper

PLoS One 2018 1;13(2):e0191967. Epub 2018 Feb 1.

Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America.

Introduction: Cancer treatment options in sub-Saharan Africa are scarce despite an increasing burden of disease. Identification of those cancer patients who would benefit most from the limited resources available would allow broader and more effective therapy.

Methods: We conducted a retrospective analysis of patients over the age of 18 at the time of a pathologic diagnosis of NHL between 2003 and 2010 who were residents of Kyandondo County (Uganda) and presented to the Uganda Cancer Institute for care.

Results: A total of 128 patients were included in this analysis. Chemotherapy was recommended to 117 (91.4%) of the patients; the odds of recommending chemotherapy decreased for each additional month of reported symptoms prior to diagnosis. Of the 117 patients to whom chemotherapy was recommended, 111 (86.7%) patients received at least 1 cycle of chemotherapy; HIV infected patients, as well as those with a lower hemoglobin and advanced disease at the time of diagnosis were significantly less likely to complete therapy. Among the patients who initiated chemotherapy, twenty patients died prior to treatment completion (including nine who died within 30 days). Hemoglobin level at the time of presentation was the only variable associated with early mortality in the adjusted model.

Conclusion: In resource-poor areas, it is essential to align health care expenditures with interventions likely to provide benefit to affected populations. Targeting cancer therapy to those with a favorable chance of responding will not only save limited resources, but will also prevent harm in those patients unlikely to realize an effect of cancer-directed therapy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0191967PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5794100PMC
March 2018

Omega-3 decreases IL-6 levels in HIV and human herpesvirus-8 coinfected patients in Uganda.

Authors:
Anna E Coghill Jeannette M Schenk Zeina Mahkoul Jackson Orem Warren Phipps Corey Casper

AIDS 2018 02;32(4):505-512

Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

Objective: Kaposi sarcoma is a HIV-associated malignancy caused by human herpesvirus-8 (HHV-8) that occurs at highest incidence in sub-Saharan Africa. Kaposi sarcoma patients often present with inflammatory symptoms associated with higher mortality.

Design: We conducted a double-blind, randomized, placebo-controlled study in Uganda to test whether omega-3 supplementation could reduce inflammation in HIV and HHV-8 coinfected adults. Patients with acute illness, AIDS, or advanced Kaposi sarcoma were ineligible, as were pregnant women. Participant IDs were pre-randomized, blocked by Kaposi sarcoma status, to either the omega-3 or placebo arm.

Methods: Omega-3 participants received a 3-g pill dose daily for 12 weeks (1.8-g eicosapentaenoic acid, 1.2-mg docosapentaenoic acid); placebo participants received 44.8 mg of high oleic safflower oil that appeared indistinguishable from the active supplement. Intervention effects were evaluated as the baseline-adjusted mean difference after 12 weeks between omega-3 and placebo participants in concentrations of fatty acids, inflammatory cytokines, and immune cells.

Results: The final study population included 56 Kaposi sarcoma patients and 11 Kaposi sarcoma-negative, HIV and HHV-8-positive participants randomized to receive either omega-3 (N = 33) or placebo (N = 34). Inflammatory cytokine IL-6 concentrations decreased in omega-3 participants (-0.78 pg/ml) but increased in placebo participants (+3.2 pg/ml; P = 0.04). We observed a trend toward decreased IL-6 after omega-3 supplementation specific to Kaposi sarcoma patients (P = 0.08). CD8 T-cell counts tended to increase in the omega-3 arm Kaposi sarcoma patients (+60 cells/μl), in contrast to decreases (-47 cells/μl) among placebo (P = 0.11).

Conclusion: Omega-3 supplementation decreased IL-6 concentrations among HIV and HHV-8 coinfected Ugandans, which may have clinical benefit for Kaposi sarcoma patients.
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http://dx.doi.org/10.1097/QAD.0000000000001722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5872837PMC
February 2018

High-throughput sequencing of the B-cell receptor in African Burkitt lymphoma reveals clues to pathogenesis.

Authors:
Katharine A Lombardo David G Coffey Alicia J Morales Christopher S Carlson Andrea M H Towlerton Sarah E Gerdts Francis K Nkrumah Janet Neequaye Robert J Biggar Jackson Orem Corey Casper Sam M Mbulaiteye Kishor G Bhatia Edus H Warren

Blood Adv 2017 Mar 21;1(9):535-544. Epub 2017 Mar 21.

Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA.

Burkitt lymphoma (BL), the most common pediatric cancer in sub-Saharan Africa, is a malignancy of antigen-experienced B lymphocytes. High-throughput sequencing (HTS) of the immunoglobulin heavy () and light chain (/) loci was performed on genomic DNA from 51 primary BL tumors: 19 from Uganda and 32 from Ghana. Reverse transcription polymerase chain reaction analysis and tumor RNA sequencing (RNAseq) was performed on the Ugandan tumors to confirm and extend the findings from the HTS of tumor DNA. Clonal and / rearrangements were identified in 41 and 46 tumors, respectively. Evidence for rearrangement of the second allele was observed in only 6 of 41 tumor samples with a clonal rearrangement, suggesting that the normal process of biallelic to diversity-joining (DJ) rearrangement is often disrupted in BL progenitor cells. Most tumors, including those with a sole dominant, nonexpressed DJ rearrangement, contained many and / sequences that differed from the dominant rearrangement by < 10 nucleotides, suggesting that the target of ongoing mutagenesis of these loci in BL tumor cells is not limited to expressed alleles. usage in both BL tumor cohorts revealed enrichment for genes that are infrequently used in memory B cells from healthy subjects. Analysis of publicly available DNA sequencing and RNAseq data revealed that these same genes were overrepresented in dominant tumor-associated rearrangements in several independent BL tumor cohorts. These data suggest that BL derives from an abnormal B-cell progenitor and that aberrant mutational processes are active on the immunoglobulin loci in BL cells.
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http://dx.doi.org/10.1182/bloodadvances.2016000794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5728594PMC
March 2017

High-throughput sequencing reveals novel features of immunoglobulin gene rearrangements in Burkitt lymphoma.

Authors:
Katharine A Lombardo David G Coffey Alicia J Morales Christopher S Carlson Andrea M H Towlerton Sarah E Gerdts Francis K Nkrumah Janet Neequaye Robert J Biggar Jackson Orem Corey Casper Sam M Mbulaiteye Kishor G Bhatia Edus H Warren

Blood Adv 2017 Jul 3;1(16):1261-1262. Epub 2017 Jul 3.

Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA.

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http://dx.doi.org/10.1182/bloodadvances.2017008060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5728551PMC
July 2017