Limits...
Is CMV a target in pediatric glioblastoma? Expression of CMV proteins, pp65 and IE1-72 and CMV nucleic acids in a cohort of pediatric glioblastoma patients.

Wakefield A, Pignata A, Ghazi A, Ashoori A, Hegde M, Landi D, Gray T, Scheurer ME, Chintagumpala M, Adesina A, Gottschalk S, Hicks J, Powell SZ, Ahmed N - J. Neurooncol. (2015)

Bottom Line: While the 5-year overall survival is better in pediatric than in adult patients diagnosed with glioblastoma (GBM), outcomes in children remain very poor.ISH positive samples showed high concordance with being pp65 or IE1-72 positive.These findings, paired with the association of CMV expression with poor prognosis and overall survival, indicate the need to further investigate how these antigens are promoting tumor growth and preventing cell death.

View Article: PubMed Central - PubMed

Affiliation: Texas Children's Hospital, Houston Methodist Hospital, Center for Cell and Gene Therapy, Baylor College of Medicine, 1102 Bates Street MC 3-3320, Houston, TX, 77030, USA.

ABSTRACT
While the 5-year overall survival is better in pediatric than in adult patients diagnosed with glioblastoma (GBM), outcomes in children remain very poor. Understanding the mechanisms of tumorigenesis and tumor propagation can identify therapeutic targets to improve these outcomes. Human cytomegalovirus (CMV) proteins and nucleic acids are present in the majority of adult GBM. Indeed, CMV is emerging as a potential glioma-associated target for anti-CMV agents and cellular therapeutics. Furthermore, CMV appears to contribute to GBM's malignant phenotype, although its role in tumorigenesis is less certain. In this cohort of 25 serially diagnosed pediatric GBMs, the largest described cohort to date, we used immunohistochemical staining and in situ hybridization to show the presence of CMV antigens pp65 and IE1-72 as well as CMV nucleic acids, respectively. Our cohort indicated either CMV antigen pp65 or IE1-72 was present in approximately 67 % of pediatric GBM samples. The majority of samples stained positive for either CMV antigen showing a cytoplasmic pattern in 25-50 % of cells within the sample at a moderate intensity, while a few samples showed nuclear staining and higher grade/intensity. Of 16 samples where in situ hybridization was performed, 13 (81 %) showed specific staining using a CMV genome specific probe cocktail. ISH positive samples showed high concordance with being pp65 or IE1-72 positive. These findings, paired with the association of CMV expression with poor prognosis and overall survival, indicate the need to further investigate how these antigens are promoting tumor growth and preventing cell death. Also, the expression of these antigens in a majority of tumor tissues should be considered for immunotherapeutic targets in cases of pediatric GBM.

No MeSH data available.


Related in: MedlinePlus

IHC staining showing representative grade and intensity scoring. a Sample with 0 % positive staining. b Sample staining positive at Grade: 1 (0–25 %) with Intensity: 2+. c Sample staining positive at Grade: 2 (26–50 %) with Intensity: 1+. d Sample staining positive at Grade: 3 (51–75 %) with Intensity: 2+. e Sample staining positive at Grade: 4 (76–100 %) with Intensity: 3+. Grade and intensity were measured by three independent pathologist for all tested patients. Magnification ×100
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4612329&req=5

Fig1: IHC staining showing representative grade and intensity scoring. a Sample with 0 % positive staining. b Sample staining positive at Grade: 1 (0–25 %) with Intensity: 2+. c Sample staining positive at Grade: 2 (26–50 %) with Intensity: 1+. d Sample staining positive at Grade: 3 (51–75 %) with Intensity: 2+. e Sample staining positive at Grade: 4 (76–100 %) with Intensity: 3+. Grade and intensity were measured by three independent pathologist for all tested patients. Magnification ×100

Mentions: All IHC stains were given a grade (based on percent positivity) and an additional score for intensity of the stain using a pre-determined scheme (Fig. 1). All slides were reviewed for by 3 independent pathologists and the grading system was established by all pathologists and verified by independent sample review. Staining grade ranged from 1 to 4 with grade 1 indicating a positive stain visible in 1–25 % of cells, grade 2 in 26–50 % of cells, grade 3 in 51–75 % of cells, and grade 4 in 76–100 % of cells. Intensity ranged from 1+ to 3+ based on the positivity observed on control slides. Representatives for each grade and intensity are shown (Fig. 1) including a negative control (Fig. 1a). Grade distribution is shown increasing from grade 1 (Fig. 1b), grade 2 (Fig. 1c), grade 3 (Fig. 1d), and grade 4 (Fig. 1e). Intensity increases from 1+ (Fig. 1c), 2+ (Fig. 1d), and 3+ (Fig. 1e). There was no correlation between that staining grade or intensity and any particular pathological features.Fig. 1


Is CMV a target in pediatric glioblastoma? Expression of CMV proteins, pp65 and IE1-72 and CMV nucleic acids in a cohort of pediatric glioblastoma patients.

Wakefield A, Pignata A, Ghazi A, Ashoori A, Hegde M, Landi D, Gray T, Scheurer ME, Chintagumpala M, Adesina A, Gottschalk S, Hicks J, Powell SZ, Ahmed N - J. Neurooncol. (2015)

IHC staining showing representative grade and intensity scoring. a Sample with 0 % positive staining. b Sample staining positive at Grade: 1 (0–25 %) with Intensity: 2+. c Sample staining positive at Grade: 2 (26–50 %) with Intensity: 1+. d Sample staining positive at Grade: 3 (51–75 %) with Intensity: 2+. e Sample staining positive at Grade: 4 (76–100 %) with Intensity: 3+. Grade and intensity were measured by three independent pathologist for all tested patients. Magnification ×100
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4612329&req=5

Fig1: IHC staining showing representative grade and intensity scoring. a Sample with 0 % positive staining. b Sample staining positive at Grade: 1 (0–25 %) with Intensity: 2+. c Sample staining positive at Grade: 2 (26–50 %) with Intensity: 1+. d Sample staining positive at Grade: 3 (51–75 %) with Intensity: 2+. e Sample staining positive at Grade: 4 (76–100 %) with Intensity: 3+. Grade and intensity were measured by three independent pathologist for all tested patients. Magnification ×100
Mentions: All IHC stains were given a grade (based on percent positivity) and an additional score for intensity of the stain using a pre-determined scheme (Fig. 1). All slides were reviewed for by 3 independent pathologists and the grading system was established by all pathologists and verified by independent sample review. Staining grade ranged from 1 to 4 with grade 1 indicating a positive stain visible in 1–25 % of cells, grade 2 in 26–50 % of cells, grade 3 in 51–75 % of cells, and grade 4 in 76–100 % of cells. Intensity ranged from 1+ to 3+ based on the positivity observed on control slides. Representatives for each grade and intensity are shown (Fig. 1) including a negative control (Fig. 1a). Grade distribution is shown increasing from grade 1 (Fig. 1b), grade 2 (Fig. 1c), grade 3 (Fig. 1d), and grade 4 (Fig. 1e). Intensity increases from 1+ (Fig. 1c), 2+ (Fig. 1d), and 3+ (Fig. 1e). There was no correlation between that staining grade or intensity and any particular pathological features.Fig. 1

Bottom Line: While the 5-year overall survival is better in pediatric than in adult patients diagnosed with glioblastoma (GBM), outcomes in children remain very poor.ISH positive samples showed high concordance with being pp65 or IE1-72 positive.These findings, paired with the association of CMV expression with poor prognosis and overall survival, indicate the need to further investigate how these antigens are promoting tumor growth and preventing cell death.

View Article: PubMed Central - PubMed

Affiliation: Texas Children's Hospital, Houston Methodist Hospital, Center for Cell and Gene Therapy, Baylor College of Medicine, 1102 Bates Street MC 3-3320, Houston, TX, 77030, USA.

ABSTRACT
While the 5-year overall survival is better in pediatric than in adult patients diagnosed with glioblastoma (GBM), outcomes in children remain very poor. Understanding the mechanisms of tumorigenesis and tumor propagation can identify therapeutic targets to improve these outcomes. Human cytomegalovirus (CMV) proteins and nucleic acids are present in the majority of adult GBM. Indeed, CMV is emerging as a potential glioma-associated target for anti-CMV agents and cellular therapeutics. Furthermore, CMV appears to contribute to GBM's malignant phenotype, although its role in tumorigenesis is less certain. In this cohort of 25 serially diagnosed pediatric GBMs, the largest described cohort to date, we used immunohistochemical staining and in situ hybridization to show the presence of CMV antigens pp65 and IE1-72 as well as CMV nucleic acids, respectively. Our cohort indicated either CMV antigen pp65 or IE1-72 was present in approximately 67 % of pediatric GBM samples. The majority of samples stained positive for either CMV antigen showing a cytoplasmic pattern in 25-50 % of cells within the sample at a moderate intensity, while a few samples showed nuclear staining and higher grade/intensity. Of 16 samples where in situ hybridization was performed, 13 (81 %) showed specific staining using a CMV genome specific probe cocktail. ISH positive samples showed high concordance with being pp65 or IE1-72 positive. These findings, paired with the association of CMV expression with poor prognosis and overall survival, indicate the need to further investigate how these antigens are promoting tumor growth and preventing cell death. Also, the expression of these antigens in a majority of tumor tissues should be considered for immunotherapeutic targets in cases of pediatric GBM.

No MeSH data available.


Related in: MedlinePlus