Deterioration in performance in obtaining bone marrow trephine biopsy cores from children. European Neuroblastoma Study Group

AIM: To complete an audit of bone marrow trephine biopsy adequacy in children MATERIAL: 605 specimens from children with neuroblastoma submitted by 25 centres were reviewed centrally. This reassessment ran between January 1995 and August 1998. RESULTS: 25% of specimens (95% confidence interval (CI) 21% to 29%) were inadequate compared with 17% (95% CI 14% to 20%) in a previous study. Variation between individual centres' performance remains high (5-54% of specimens inadequate). Had five centres performed as well as previously, the inadequate biopsy rate would have been unchanged from that found in the previous study. There was no important improvement in any centre's performance. Earlier suggestions about change in practice have had no discernible impact on centres' ability to obtain adequate bone marrow trephine biopsies from children. CONCLUSIONS: The responsibility for improving the rate of adequate biopsies lies with individual centres. Reporting pathologists might help by making even more positive attempts to influence operators within their own centres.     

Antiviral properties of new arylsulfone derivatives with activity against human betaherpesviruses

Based on our previous experience with arylsulfone derivatives displaying antiherpetic activity, we synthesized several analogues in which the sulfonyl group is part of a bicyclic structure. The benzene-fused derivative 2H-3-(4-chlorophenyl)-3,4-dihydro-1,4-benzo-thiazine-2-carbonitrile 1,1-dioxide and its thiophene-fused analogue were shown to have favorable activity and selectivity against the betaherpesviruses human cytomegalovirus (HCMV) and human herpesvirus 6 (HHV-6) and 7 (HHV-7). The benzene-fused derivative retained its anti-HCMV activity when evaluated against virus strains resistant to foscarnet, ganciclovir, and/or cidofovir. The compound conferred >or=95% inhibition of viral DNA synthesis in HHV-6-infected cells. RT-PCR analysis of immediate-early, early and late gene products revealed that this arylsulfone compound acts at a step preceding late gene expression, and coinciding with the inhibition exerted by foscarnet. No inhibitory effect was seen in an enzyme assay for DNA elongation catalyzed by the HCMV or HHV-6 DNA polymerase catalytic subunit. The arylsulfone derivatives had no effect on the functional interaction between the catalytic subunit of HCMV DNA polymerase and its accessory protein, nor did they disrupt the physical interaction between the two proteins. We conclude that these arylsulfone derivatives represent new betaherpesvirus inhibitors with a novel mode of action that results in indirect inhibition of viral DNA synthesis.     

Extracellular cAMP-dependent protein kinase (ECPKA) in melanoma

Melanoma is one of the fastest rising malignancies in the United States. When detected early, primary melanomas are curable through surgery. However, despite significant improvements in diagnosis and surgical, local and systemic therapy, mortality rate in metastatic melanoma remains high. Furthermore, genetic alterations associated with the development and stepwise progression of melanoma, are still unclear. Previous reports show that the catalytic kinase subunit of the cAMP-dependent protein kinase is secreted by tumor cells and can be detected in the serum of cancer patients. We examine in this report the clinical significance of this secreted C subunit kinase termed extracellular protein kinase (ECPKA) in melanoma patients. Our results showed the presence of ECPKA activity in the serum of melanoma patients and correlate with the appearance and size of the tumor. Most importantly, surgical removal of melanoma causes a precipitous decrease in ECPKA activity in the sera of patients, suggesting that ECPKA may be a novel predictive marker in melanoma.     

In vitro assessment of mutagenicity and clastogenicity of BDE-99, a pentabrominated diphenyl ether flame retardant

Polybrominated diphenyl ethers (PBDEs), which are widely used as flame retardants, are considered persistent organic pollutants. To date, the available toxicological data on PBDEs are limited and were primarily obtained by studying technical blends. The present study was undertaken to investigate the genotoxicity of the pure congener 2,2',4,4',5-brominated diphenyl ether (BDE-99), one of the major isomers present in penta-commercial products. Bacterial reverse mutation assays in Salmonella typhimurium strains TA98 and TA100 and in Escherichia coli WP2 uvrA, and the Allium cepa chromosome aberration test were carried out to evaluate mutagenicity and clastogenicity. The experimental design also involved testing a well-known polychlorinated biphenyl (PCB) mixture, Aroclor(R) 1254, which is structurally related to PBDEs. BDE-99 was negative in the bacterial mutagenicity assays, with and without S9 mix. Also, the frequency of structural chromosome aberrations was not significantly higher than the control and no signs of cytotoxicity were observed in BDE-99-treated A. cepa. Aroclor(R) 1254 was not mutagenic, but it induced a significant increase in chromosomal aberrations in A. cepa. In conclusion, BDE-99 was not mutagenic in S. typhimurium or E. coli, or clastogenic in A. cepa; however, the possibility that PBDEs might act through an epigenetic mechanism cannot be excluded.     

Revision of the International Neuroblastoma Pathology Classification: confirmation of favorable and unfavorable prognostic subsets in ganglioneuroblastoma, nodular

BACKGROUND: Ganglioneuroblastoma, nodular (GNBn) comprises one of the categories of peripheral neuroblastic tumors. All tumors in this category, according to the original International Neuroblastoma Pathology Classification, are classified into an unfavorable histology group. Subsequently, it has been reported that GNBn can be divided into two prognostic subsets, a favorable subset (FS) and an unfavorable subset (US). METHODS: Histology slides from 70 patients who were enrolled in Children's Cancer Group studies 3881 and 3891 and who had a diagnosis of GNBn were reviewed jointly by the members of International Neuroblastoma Pathology Committee (INPC): 1) to confirm the diagnosis of GNBn, 2) to identify the FS and US by applying the same age-linked criteria that were used to distinguish the favorable histology group and unfavorable histology group in conventional neuroblastoma tumors from the neuroblastomatous component of GNBn tumors, and 3) to verify the significant prognostic difference between these two subsets. The patients had been used in a previous study, and survival data for the patients were updated since the time of their last report. RESULTS: The review clarified and illustrated morphologic characteristics of classical GNBn and it variants. The diagnosis of GNBn was confirmed in 67 of 70 patients. There were 22 patients with GNBn in the FS and 45 patients with GNBn in the US. The estimated survival differences between the FS and US patients with GNBn were statistically significant (8-year event free survival rate: 86.1% vs. 32.2%; P = 0.0003; overall survival rate: 90.5% vs. 33.2%; P = 0.0003). CONCLUSIONS: This study confirmed the recently defined prognostic subsets of GNBn. The INPC proposes to modify the International Neuroblastoma Pathology Classification by distinguishing the FS and the US among patients with GNBn tumors.     

Terminology and morphologic criteria of neuroblastic tumors: recommendations by the International Neuroblastoma Pathology Committee.

BACKGROUND: As part of the international cooperative effort to develop a complete set of International Neuroblastoma Risk Groups, the International Neuroblastoma Pathology Committee (INPC) initiated activities in 1994 to devise a morphologic classification of neuroblastic tumors (NTs; neuroblastoma, ganglioneuroblastoma, and ganglioneuroma). METHODS: Six member pathologists (H.S., I.M.A., L.P.D., J.H., V.V.J., and B.R.) discussed and defined morphologically based classifications (Shimada classification; risk group and modified risk group proposed by Joshi et al.) on the basis of a review of 227 cases, using various pathologic characteristics of the NTs. The classification-grading system was evaluated for prognostic significance and biologic relevance. RESULTS. The INPC has adopted a prognostic system modeled on one proposed by Shimada et al. It is an age-linked classification dependent on the differentiation grade of the neuroblasts, their cellular turnover index, and the presence or absence of Schwannian stromal development. Based on morphologic criteria defined in this article, NTs were classified into four categories and their subtypes: 1) neuroblastoma (Schwannian stroma-poor), undifferentiated, poorly differentiated, and differentiating; 2) ganglioneuroblastoma, intermixed (Schwannian stroma-rich); 3) ganglioneuroma (Schwannian stroma-dominant), maturing and mature; and 4) ganglioneuroblastoma, nodular (composite Schwannian stroma-richlstroma-dominant and stroma-poor). Specific features, such as the mitosis-karyorrhexis index, the mitotic rate, and calcification, were also included to allow the prognostic significance of the classification to be tested. Recommendations are made regarding the surgical materials to use for an optimal pathobiologic assessment and the practical handling of samples. CONCLUSIONS. The current article covers the essentials and important points regarding the histopathologic evaluation of NTs. Using the morphologic criteria described herein, the INPC is proposing the International Neuroblastoma Pathology Classification. It is reported in a companion article in this issue (Cancer 1999;86:363-71).     

Bone marrow trephine biopsy in infants

Accepted 23 April 1997
Central review of bone marrow trephine biopsies obtained between January 1990 and July 1996 from 282 children with neuroblastoma showed that 18% of cores from older children and an unacceptably high 36% from infants were inadequate (p = 0.0002). Centres should choose their operators for this invasive investigation of infants with more care in order to reduce the failure rate.