Epstein‐Barr virus (EBV) serology for predicting distant metastases in a white juvenile patient with nasopharyngeal carcinoma and no clinical response to EBV lytic induction therapy

Stevens, Servi J.C.; Zwaan, C. Michel; Verkuijlen, Sandra A.W.M.; Middeldorp, Jaap M.

doi:10.1002/hed.20466

Cited by 14 publications

(13 citation statements)

References 16 publications

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“…All 3 patients showed a biological response to CLVA therapy indicated by an increase in viral DNA load in the blood, as observed in a previous case study (14). This increase reflects fragmented EBV DNA derived from apoptotic tumor cells (29).…”

Section: Discussionsupporting

confidence: 75%

“…Besides tumor cell apoptosis induced by GCb, it could reactivate EBV within the tumor cells. The potential for EBV lytic induction by GCb in EBV-positive NPC cell lines was shown to be higher than by 5-FU, which was used in a previous juvenile NPC case study (14,25,26). Activation of highly methylated DNA of latent EBV can be enhanced by epigenetic chromatin remodeling of the EBV genome induced by HDAC inhibitors and DNA-demethylating agents (7)(8)(9)(10)(11).…”

Section: Discussionmentioning

confidence: 99%

“…After 5 days, the patient received antiviral treatment with valganciclovir (GCV). This treatment resulted in an increase of viral DNA in the circulation, reflecting shedding of apoptotic fragments from the tumor, which was not observed before treatment (14).…”

Section: Introductionmentioning

confidence: 87%

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Cytolytic Virus Activation Therapy for Epstein-Barr Virus–Driven Tumors

Wildeman

Novalić

Verkuijlen

et al. 2012

Clinical Cancer Research

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115

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Purpose: Nasopharyngeal carcinoma (NPC) is causally linked to Epstein-Barr virus (EBV) infection. Because all tumor cells carry EBV, the virus itself is a potential target for therapy. In these tumor cells, EBV hides in a latent state and expresses only a few non-immunogenic proteins for EBV maintenance and contributes to tumor growth. We developed a cytolytic virus activation (CLVA) therapy for NPC treatment, reactivating latent EBV, triggering immune recognition, and inducing susceptibility to antiviral therapy.Experimental Design: CLVA therapy combines gemcitabine (GCb) and valproic acid (VPA) for virus activation and tumor clearance with (val)ganciclovir (GCV) as the antiviral drug to block virus replication and kill proliferating virus-infected cells. CLVA treatment was optimized and validated in NPC cell lines and subsequently tested in 3 Dutch patients with NPC that was refractory to conventional treatment.Results: In NPC cell lines, both GCb and VPA can induce the lytic cycle of EBV. Their combination resulted in a strong synergistic effect. The addition of GCV resulted in higher cytotoxicity compared with chemotherapy alone, which was not observed in EBV-negative cells. CLVA therapy was analyzed in 3 patients with end-stage NPC. Patients developed increased levels of viral DNA in the circulation originating from apoptotic tumor cells, had disease stabilization, and experienced improved quality of life.Conclusions: Our results in the initial CLVA-treated patients indicate that the therapy had a biological effect and was well tolerated with only moderate transient toxicity. This new virus-specific therapy could open a generic approach for treatment of multiple EBV-associated malignancies.

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Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

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Cytolytic Virus Activation Therapy for Epstein-Barr Virus–Driven Tumors

Wildeman

Novalić

Verkuijlen

et al. 2012

Clinical Cancer Research

Self Cite

115

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“…Because immunoblot studies revealed a diagnostic value of multiple EBV proteins, in particular certain EBV-EA markers, we recently developed a separate IgA EA ELISA using native EA proteins (22). In addition to their role in primary diagnosis, anti-EBV IgA responses, in particular the IgA EA response, also have a distinct role for posttreatment follow-up monitoring, as declining responses correlate with a good prognosis and increasing responses are related to persistence of relapsing tumor (6,16,24). The availability of two distinct and biochemically well-defined EBV IgA ELISA systems addressing responses to different EBV antigens for NPCspecific serology may add to further standardization.…”

mentioning

confidence: 99%

Two-Step Epstein-Barr Virus Immunoglobulin A Enzyme-Linked Immunosorbent Assay System for Serological Screening and Confirmation of Nasopharyngeal Carcinoma

Paramita

Fachiroh

Haryana

et al. 2009

Clin Vaccine Immunol

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Undifferentiated nasopharyngeal carcinoma (NPC; WHO type III) is 100% associated with Epstein-Barr virus (EBV) infection and the fourth most prevalent cancer in Indonesian males. Therapy failure is high, since most patients come to the hospital at an advanced stage of disease. Screening for early-stage NPC is needed. Here, a simple and economical two-step enzyme-linked immunosorbent assay (ELISA) system is proposed for diagnosing NPC in high-risk populations, employing the peptide-based immunoglobulin A (IgA) EBNA1 plus viral capsid antigen p18 ELISA as an initial screening test and the IgA early antigen (EA) ELISA using a different set of EBV antigens as a confirmation test. A total of 151 NPC patients and 199 regional healthy EBV carriers were used to evaluate the two-step ELISA approach. Routinely, EBV IgG immunoblotting is used as a standard confirmation test. The sensitivity and specificity for diagnosing NPC by the two-step ELISA approach increased from 85.4% to 96.7% and 90.1% to 98%, respectively, with positive predictive values and negative predictive values increasing from 78.7 and 93.9% to 97.3 and 97.5%, respectively, relative to the immunoblotting confirmation system. On discrepant samples, additional testing was done by EBV DNA load quantification in blood. Results showed that 5/11 discrepant NPC samples with an elevated IgA EA ELISA also had elevated an EBV DNA load in the circulation (range, 3,200 to 25,820 copies/ml). Therefore, the IgA EA ELISA is proposed as a confirmation test in first-line NPC serological screening studies. This two-step EBV ELISA system provides a standardized approach for NPC screening and may be used in combination with dried blood sampling in future field studies for identification of early-stage NPC in high-risk regions.

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“…NPC is characterized by aberrant immunoglobulin G (IgG) and particularly IgA responses directed against various latent and lytic EBV antigens (13). These aberrant responses have diagnostic relevance in screening for early-stage and posttreatment monitoring (7,22,23,43). The diagnosis and screening of NPC are done mostly by indirect antibody detection using cell spot slide tests, one of the earliest serology methods developed, which to date is still used as a "gold standard" (8,35).…”

mentioning

confidence: 99%

Dried-Blood Sampling for Epstein-Barr Virus Immunoglobulin G (IgG) and IgA Serology in Nasopharyngeal Carcinoma Screening

et al. 2008

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Dried-blood (DB) samples on filter paper are considered clinical specimens for diagnostic use because of the ease of collection, storage, and transport. We recently developed a synthetic-peptide-based immunoglobulin A (IgA) (EBNA1 plus viral capsid antigen [VCA]-p18) enzyme-linked immunosorbent assay (ELISA) for nasopharyngeal carcinoma (NPC) screening. Here, we evaluate the use of two filter papers for DB sampling, i.e., Schleicher & Schuell (S&S) no. 903 and Whatman no. 3; the DB samples were either taken directly from a finger prick or spotted from a Vacutainer blood collector. The elution of DB samples on filter paper was optimized and tested for IgG and IgA reactivity by ELISA (EBNA1 plus VCA-p18) and compared to simultaneously collected plasma samples. The results showed that both types of filter paper can be used for sample collection in NPC diagnosis by using either finger prick or blood spot sampling. Both DB sampling methods produced comparable ELISA (EBNA1 plus VCA-p18) results for IgG and IgA reactivity in 1:100-diluted plasma samples. DB samples of whole blood or finger prick blood show correlation coefficients (r 2 ) of 0.825 to 0.954 for IgA on S&S no. 903 filter paper, 0.9133 to 0.946 for IgA on Whatman no. 3 filter paper, 0.807 to 0.886 for IgG on S&S no. 903 filter paper, and 0.819 to 0.934 for IgG on Whatman no. 3 filter paper. Using plasma IgA as a reference, DB sampling showed sensitivities and specificities of 75.0 to 96.0% and 93.5 to 100%, respectively. DB samples could be stored at 37°C for 1 to 4 weeks on S&S no. 903 filter paper and 1 to 6 weeks on Whatman no. 3 filter paper without a significant loss of reactivity, with provision of transport options for tropical conditions. IgA proved to be more stable than IgG. Whatman no. 3 filter paper is a more economical yet diagnostically comparable alternative to S&S no. 903 filter paper. Finger prick DB sampling is proposed for NPC diagnosis, particularly for remote hospitals and field screening studies.

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Epstein‐Barr virus (EBV) serology for predicting distant metastases in a white juvenile patient with nasopharyngeal carcinoma and no clinical response to EBV lytic induction therapy

Abstract: In contrast to EBV DNA load, EBV serology was useful in predicting distant NPC metastasis after initial complete remission in this patient.

Cited by 14 publications

References 16 publications

Cytolytic Virus Activation Therapy for Epstein-Barr Virus–Driven Tumors

Cytolytic Virus Activation Therapy for Epstein-Barr Virus–Driven Tumors

Two-Step Epstein-Barr Virus Immunoglobulin A Enzyme-Linked Immunosorbent Assay System for Serological Screening and Confirmation of Nasopharyngeal Carcinoma

Dried-Blood Sampling for Epstein-Barr Virus Immunoglobulin G (IgG) and IgA Serology in Nasopharyngeal Carcinoma Screening

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