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Roentgenographic review of the first 210 cases of Ewing sarcoma (ES) in the Intergroup Ewing Sarcoma Study revealed that 37.6% of cases had evidence of diffusely increased intraosseous density or diffuse sclerosis (DS). In these cases the sclerosis was usually mixed with various patterns of lysis and/or combined with a periosteal reaction. A radiograph blinded histologic review of selected biopsies showed an 83% incidence of dead bone compared to 23% in those without DS. Ten percent of the cases with DS had appositional new bone formation on dead bone whereas none of the cases without DS showed such reactions. Pathologic explanation of the roentgenographically identified diffuse sclerosis in ES has not been previously well documented in the medical literature. [ABSTRACT FROM AUTHOR]

Florid reactive periostitis is a rare, benign process usually occurring in the small, tubular bones of the hands and feet. Typically the lesion occurs in an adolescent or young adult and presents as a small area of pain and erythema over the affected bone. Although the histologic features may suggest malignancy, there is usually little radiographic evidence to support such a diagnosis. In the following report an unusual example of this entity is described whose large size and relentless local progression led to initial diagnostic uncertainty and eventual aggressive management. This case suggests that a wide spectrum of radiologic and morphologic changes may be seen in this entity and that a seemingly unrelated genetic disease may alter the typical clinical course. [ABSTRACT FROM AUTHOR]

This study sought to determine if weekly X-ray exposure affected breast cancer cell metastasis to bone and to also evaluate the use of bioluminescent imaging (BLI) and microSPECT for detection of metastatic bone lesions. Five week old nude mice were randomly assigned to the CT exposed ( n = 7) and no CT exposure ( n = 6) treatment groups. Mice received an intracardiac injection of MDA-MB-435 human breast cancer cells transduced with luciferase, or a sham injection (saline). The CT exposed group of mice received CT irradiation once a week for 5 weeks. All mice underwent weekly BLI and select mice received Tc-99m-MDP followed by microSPECT imaging after 5 weeks. Pathological evaluation and histomorphometry were used to assess the affect of CT X-rays on bone metastasis and to evaluate BLI. BLI results found no significant difference in metastasis between animals that received CT and those that did not ( P > 0.05); however, histomorphometry of the knee joints revealed a significant increase ( P = 0.029) in tumor area of the leg bones in mice that received CT exposure (60% ± 7%) compared to animals that did not receive CT scans (33% ± 8%). Compared to histological analysis, BLI of the leg and spine was determined to have excellent sensitivity (100%), good specificity (80–90%) and accuracy (90–96%), a positive predictive value of 81–93% and a 100% negative predictive value. Thus, multi-modality imaging techniques can be very useful for monitoring bone metastasis, however microCT X-rays should be used judiciously in order to limit irradiation that may stimulate increased metastasis to specific regions of the skeleton. MicroSPECT imaging did not detect metastatic lesions in the legs of these young nude mice. [ABSTRACT FROM AUTHOR]

Oncolytic viruses represent a novel cancer treatment strategy. Despite their promising preclinical data, however, corresponding clinical trials have disappointed. To aid preclinical analyses, we hypothesized that three-dimensional tumor cell clusters or spheroids might provide an assay system superior to conventional monolayer cell cultures. Spheroids show viral infection, replication and oncolytic patterns distinct from conventional monolayer assays. Therefore, viral tumor penetration and oncolysis measurements may be improved with such three-dimensional models. Also, preclinical analyses of oncolytic viruses frequently measure mitochondrial activity, but more accurate measures of oncolysis might involve quantitation of intracellular protein release. Therefore, we measured luciferase released from luciferase-expressing spheroids and found unique patterns that maintained consistency with various viruses and doses. The relative variations between viruses and doses may represent temporal differences in oncolysis dynamics. Analysis of five recombinant replicative adenoviruses with promise for clinical application showed that Ad5/3-Δ24 produced the most luciferase release 1 week after infection and achieved the earliest and highest peak luciferase release level. Ad5/3-Δ24 also effected the earliest subtotal spheroid cell death. These findings closely parallel monolayer oncolysis assays with these agents. Therefore, the luciferase-expressing tumor spheroid assay represents a promising three-dimensional model for preclinical analysis of replicative oncolytic agents.Cancer Gene Therapy (2007) 14, 421–430. doi:10.1038/sj.cgt.7701028; published online 19 January 2007 [ABSTRACT FROM AUTHOR]

This is the second part of a two-part review presenting an overview of the molecular findings associated with both benign and malignant chondroid neoplasms. The first part presented a brief review of modern methods in molecular pathology, along with a review of the cytogenetic and molecular genetic findings in benign chondroid neoplasms. This second part reviews the cytogenetic and molecular genetic findings in malignant chondroid neoplasms. Clinical aspects of the various lesions are briefly discussed, and each tumor is illustrated with representative radiographic and pathologic images. [ABSTRACT FROM AUTHOR]

Whereas virotherapy has emerged as a novel and promising approach for neoplastic diseases, appropriate model systems have hampered preclinical evaluation of candidate conditionally replicative adenovirus agents (CRAds) with respect to liver toxicity. This is due to the inability of human viral agents to cross species. We have recently shown the human liver tissue slice model to be a facile means to validate adenoviral replication. On this basis, we sought to determine whether our ex vivo liver tissue slice model could be used to assess CRAd-mediated liver toxicity. We analyzed and compared the toxicity of a conditionally replicative adenovirus (AdΔ24) to that of a replication incompetent adenovirus (Adnull [E1−]) in mouse and human liver tissue slices. To accomplish this, we examined the hepatic apoptosis expression profile by DNA microarray analyses, and compared these results to extracellular release of aminotransferase enzymes, along with direct evidence of apoptosis by caspase-3 immunhistochemical staining and TUNEL assays. Human and mouse liver tissue slices demonstrated a marked increase in extracellular release of aminotransferase enzymes on infection with AdΔ24 compared to Adnull. AdΔ24-mediated liver toxicity was further demonstrated by apoptosis induction, as detected by caspase-3 immunohistochemical staining, TUNEL assay and microarray analysis. In conclusion, concordance of CRAd-mediated apoptosis in both the human and the mouse liver tissue slice models was demonstrated, despite the limited replication ability of CRAds in mouse liver slices. The results of this study, defining the CRAd-mediated apoptosis gene expression profiles in human and mouse liver, may lay a foundation for preclinical liver toxicity analysis of CRAd agents.Cancer Gene Therapy (2006) 13, 606–618. doi:10.1038/sj.cgt.7700934; published online 6 January 2006 [ABSTRACT FROM AUTHOR]

The full realization of conditionally replicative adenoviruses (CRAds) for cancer therapy has been hampered by the limited knowledge of CRAd function in vivo and particularly in an immunocompetent host. To address this issue, we previously proposed a canine adenovirus type 2 (CAV2)-based CRAd for clinical evaluation in canine patients with osteosarcoma (OS). In this study, we evaluated infectivity-enhancement strategies to establish the foundation for designing a potent CAV2 CRAd with effective transduction capacity in dog osteosarcoma cells. The results indicate that the native CAV2 fiber–knob can mediate increased binding, and consequently gene transfer, in both canine osteosarcoma immortalized and primary cell lines relative to previously reported Ad5 infectivity-enhancement strategies. Gene delivery was further enhanced by incorporating a polylysine polypeptide onto the carboxy terminus of the CAV2 knob. This vector demonstrated improved gene delivery in osteosarcoma xenograft tumors. These data provide the rationale for generation of infectivity-enhanced syngeneic CAV2 CRAds for clinical evaluation in a dog osteosarcoma model.Gene Therapy (2006) 13, 389–399. doi:10.1038/sj.gt.3302674; published online 17 November 2005 [ABSTRACT FROM AUTHOR]

Calcium entry into myocytes drives contraction of the embryonic heart. To prepare for the next contraction, myocytes must extrude calcium from intracellular space via the Na+/Ca2+ exchanger (NCX1) or sequester it into the sarcoplasmic reticulum, via the sarcoplasmic reticulum Ca2+-ATPase2 (SERCA2). In mammals, defective calcium extrusion correlates with increased intracellular calcium levels and may be relevant to heart failure and sarcoplasmic dysfunction in adults. We report here that mutation of the cardiac-specific NCX1 (NCX1h) gene causes embryonic lethal cardiac arrhythmia in zebrafish tremblor (tre) embryos. The tre ventricle is nearly silent, whereas the atrium manifests a variety of arrhythmias including fibrillation. Calcium extrusion defects in tre mutants correlate with severe disruptions in sarcomere assembly, whereas mutations in the L-type calcium channel that abort calcium entry do not produce this phenotype. Knockdown of SERCA2 activity by morpholino-mediated translational inhibition or pharmacological inhibition causes embryonic lethality due to defects in cardiac contractility and morphology but, in contrast to tre mutation, does not produce arrhythmia. Analysis of intracellular calcium levels indicates that homozygous tre embryos develop calcium overload, which may contribute to the degeneration of cardiac function in this mutant. Thus, the inhibition of NCX1h versus SERCA2 activity differentially affects the pathophysiology of rhythm in the developing heart and suggests that relative levels of NCX1 and SERCA2 function are essential for normal development. [ABSTRACT FROM AUTHOR]

Sarcomas infrequently develop in osseous sites of fibrous dysplasia. We report a patient with Mazabraud's syndrome (polyostotic fibrous dysplasia and soft tissue myxomas) complicated by the development of osteogenic sarcoma in a bone affected by fibrous dysplasia. This is the third case of osteosarcoma within the small population of reported patients with Mazabraud's syndrome. There may be an increased incidence of malignant transformation in these individuals' dysplastic bones above that associated with patients suffering from fibrous dysplasia alone. [ABSTRACT FROM AUTHOR]

The lesion we described is an osteoid producing mitotically active spindle cell soft tissue neoplasm, which has light and ultrastructural features of an osteosarcoma. By immunohistochemistry it marks with p30/32MIC2-directed antibodies but fails to react with antibodies associated with other soft tissue neoplasms. The precise histogenesis of the lesion is unknown, but failure to elicit a periosteal reaction makes the periosteum less likely to be the primary tissue of origin. The failure to demonstrate any radiologic or histologic evidence of involvement of the underlying bone leaves the soft tissue as the most reasonable site of origin, although the parosteal region cannot be completely excluded. [ABSTRACT FROM AUTHOR]

We previously demonstrated that delivery of a gene encoding an anti-erbB-2 intracellular single-chain antibody (sFv) resulted in down-regulation of cell surface erbB-2 levels and induction of apoptosis in erbB-2 overexpressing ovarian cancer cells. Based upon these findings, we hypothesized that human breast carcinomas overexpressing erbB-2 would be similarly affected by this genetic intervention. We evaluated the phenotypic effects resulting from intracellular expression of the anti-erbB-2 sFv on the human breast cancer cell lines MDA-MB-361, SK-BR-3, BT-474, MCF-7 and MDA-MB-231. Recombinant adenoviruses encoding either a reporter gene (AdCMVLacZ) or the endoplasmic reticulum (ER) directed anti-erbB-2 sFv (Ad21) were delivered to various breast cancer cell lines. Cell viability was determined by a proliferation assay and fluorescent microscopy allowed visualization of apoptotic cells. An erbB-2 ELISA quantified the endogenous erbB-2 levels of each cell line. The anti-erbB-2 sFv-encoding-adenovirus, Ad21, but not the β-galactosidase encoding adenovirus, AdCMVLacZ, was cytotoxic to >95% of the tumor cells in the MDA-MB-361 and SK-BR-3 lines, and >60% of the tumor cells in the BT-474 line. In marked contrast, the MCF-7 and MDA-MB-231 cell lines showed no change in the rate of cell proliferation following this treatment. The cytotoxic effects generated in the first three lines were a consequence of the induction of apoptosis by the anti-erbB-2 sFv. An ELISA specific for erbB-2 showed that the breast cancer cell lines most susceptible to the anti-erbB-2 sFv, MDA-MB-361, SK-BR-3 and BT-474, overexpressed the erbB-2 protein while the cell lines demonstrating no response to the anti-erbB-2 sFv, MCF-7 and MDA-MB-231, expressed the lowest levels of erbB-2. These results demonstrate that targeted killing of erbB-2 overexpressing cells via intracellular knockout can be accomplished in the context of breast carcinoma. Furthermore, erbB-2 levels in breast tumor cells... [ABSTRACT FROM AUTHOR]

The herpes simplex virus thymidine kinase gene is the most widely utilized toxin for selective killing of carcinoma cells. Expression of the viral thymidine kinase gene renders cells sensitive to the toxic effects of nucleoside analogs such as ganciclovir. An advantage of this system is the 'bystander effect' whereby thymidine kinase transduced tumor cells elicit a toxic effect on surrounding nontransduced tumor cells. Ovarian carcinoma appears to be an ideal candidate for gene therapy as the majority of women present with advanced stage disease, have poor prognosis for long-term survival and have the disease confined within the peritoneal cavity. Therefore the utility of an adenoviral vector to elicit an in vitro by-stander effect in ovarian carcinoma cells and the therapeutic efficacy of such a system in vivo was undertaken. Immunocompetent animals were utilized to determine the maximum dose of adenovirus that could be administered without any undesirable side effects and that preimmunization had no effects on subsequent challenge. SCID mice were orthotopically transplanted with human ovarian carcinoma cells and, after establishment of tumor, given a recombinant adenovirus expressing either the herpes simplex virus thymidine kinase or the Escherichia coli β-galactosidase gene. Half the animals from each viral group were treated with either a ganciclovir regiment (50 mg/kg daily for 14 days) or an equal volume of serum-free media. A subset of mice were killed following drug treatment and analyzed for tumor reduction. The remaining animals were followed daily for survival. The animals treated with the recombinant adenovirus expressing the herpes simplex virus thymidine kinase gene and ganciclovir had significant reduction in overall tumor burden and demonstrated statistically significant prolongation in overall survival. [ABSTRACT FROM AUTHOR]