Osteoclast abnormalities in fractured bone during bisphosphonate treatment for osteoporosis: a case report.

Bisphosphonates have been widely used in the treatment of an array of bone disorders. Recent complications have included unusual femoral fractures in patients who have received long term bisphosphonate treatment for osteoporosis. Although it has been shown that bisphosphonates are effective by blunting osteoclast resorption, there has been little morphologic description of the local tissue activity at the site of these unusual fractures. To evaluate for local changes to bone morphology at the fracture site in patients presenting with a bisphosphonate-related femur fracture, a sample of cortical bone was obtained at the site of a bisphosphonate fracture and was processed in a nondecalcified manner. The specimen was evaluated for potential cellular changes consistent with bisphosphonate treatment. Significant osteoclast abnormalities at the fracture site were found in a 69-year-old woman treated for 2 years with Fosamax substantiating that bone remodeling at this site is distinctly abnormal. Addressing the osteoclast dysfunction should be a focus of future therapeutic attention and intervention.

gp130 at the nexus of inflammation, autoimmunity, and cancer.

Glycoprotein 130 (gp130) is a shared receptor utilized by several related cytokines, including IL-6, IL-11, IL-27, Leukemia Inhibitory Factor (LIF), Oncostatin M (OSM), Ciliary Neurotrophic Factor (CNTF), Cardiotrophin 1 (CT-1) and Cardiotrophin-like Cytokine (CLC). Gp130 plays critical roles during development and gp130-deficient mice are embryonically lethal. However, the best characterized facet of this receptor and its associated cytokines is the ability to promote or suppress inflammation. The aim of this review is to discuss the role of gp130 in promoting or preventing the development of autoimmunity and cancer, two processes that are associated with aberrant inflammatory responses.

Thymidine kinase activation of ganciclovir in recurrent malignant gliomas: a gene-marking and neuropathological study.

OBJECT: The gene therapy paradigm of intratumoral activation of ganciclovir (GCV) following transduction of tumor cells by retroviral vectors bearing the thymidine kinase (tk) gene has produced dramatic remissions of malignant gliomas in animal models. In human trials, although the technique has been deemed safe, little antitumor effect has been demonstrated. To evaluate the basis of this inefficacy in human gliomas, the authors conducted a gene-marking trial involving neuropathological and biochemical studies of treated tumor specimens. METHODS: Five patients with malignant recurrent gliomas underwent stereotactic biopsy sampling and intratumoral implantation procedures with three aliquots of 10(6) vector-producing cells (VPCs) in columns. After 5 days, the tumor was resected and the tumor bed reimplanted with VPCs, and a course of GCV was given. Patients received clinical and radiological follow up for 6 months. Tumor specimens were analyzed neuropathologically and for tk gene expression by anti-TK immunohistochemistry and TK enzymatic activity. Four patients tolerated the treatment well but experienced tumor progression. The other developed an abscess after the second operation and died. Increased TK enzymatic activity was demonstrated in the one tumor specimen analyzed. Immunohistochemical evidence of tk gene expression was limited to VPCs. Transduction of tumor cells was not seen. Viable tumor cells were seen near VPCs containing TK. The lymphocytic immune response was mild. CONCLUSIONS: Except for the risk of infection inherent in reoperation, this tk-GCV paradigm was both feasible and safe. Pathological studies indicated that limited dissemination of VPCs and vector from the infusion site and failure to transduce tumor cells with the tk gene are major barriers to efficacy.

Common regions of deletion on chromosome 22q12.3-q13.1 and 22q13.2 in human astrocytomas appear related to malignancy grade.

Approximately 30% of human astrocytomas have been reported to display allelic loss of the long arm of chromosome 22, suggesting the presence of a chromosome 22q astrocytoma suppressor gene. To define the most likely location for this putative tumor suppressor, we performed deletion mapping on 141 tumors using 16 chromosome 22q microsatellite markers. Allelic loss of 22q was observed in 2/12 (17%) of astrocytomas, 9/29 (31%) of anaplastic astrocytomas, and 38/100 (38%) of glioblastomas, consistent with a role for chromosome 22q loss in astrocytoma progression as well as formation. Twenty-two tumors exhibited allelic loss at every informative locus, consistent with loss of the entire arm of 22q. Twenty-seven tumors showed partial deletions, with one common region of deletion at 22q12.3-q13.1 between markers D22S280 and D22S282, and a second candidate region at 22q13.2 near the marker D22S1170. For the proximal candidate region, the incidence of allelic loss was similar between grades; for the distal locus, the incidence increased with grade, raising the possibility that the distal locus is involved in a later stage of astrocytoma tumorigenesis.

Oncolytic virus therapy of multiple tumors in the brain requires suppression of innate and elicited antiviral responses.

The occurrence of multiple tumors in an organ heralds a rapidly fatal course. Although intravascular administration may deliver oncolytic viruses/vectors to each of these tumors, its efficiency is impeded by an antiviral activity present in complement-depleted plasma of rodents and humans. Here, this activity was shown to interact with complement in a calcium-dependent fashion, and antibody neutralization studies indicated preimmune IgM has a contributing role. Short-term exposure to cyclophosphamide (CPA) partially suppressed this activity in rodents and humans. At longer time points, cyclophosphamide also abrogated neutralizing antibody responses. Cyclophosphamide treatment of rats with large single or multiple intracerebral tumors substantially increased viral survival and propagation, leading to neoplastic regression.

Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas.

BACKGROUND/METHODS: Gliomas are common malignant neoplasms of the central nervous system. Among the major subtypes of gliomas, oligodendrogliomas are distinguished by their remarkable sensitivity to chemotherapy, with approximately two thirds of anaplastic (malignant) oligodendrogliomas responding dramatically to combination treatment with procarbazine, lomustine, and vincristine (termed PCV). Unfortunately, no clinical or pathologic feature of these tumors allows accurate prediction of their response to chemotherapy. Anaplastic oligodendrogliomas also are distinguished by a unique constellation of molecular genetic alterations, including coincident loss of chromosomal arms 1p and 19q in 50%-70% of tumors. We have hypothesized that these or other specific genetic changes might predict the response to chemotherapy and prognosis in patients with anaplastic oligodendrogliomas. Therefore, we have analyzed molecular genetic alterations involving chromosomes 1p, 10q, and 19q and the TP53 (on chromosome 17p) and CDKN2A (on chromosome 9p) genes, in addition to clinicopathologic features in 39 patients with anaplastic oligodendrogliomas for whom chemotherapeutic response and survival could be assessed. RESULTS/CONCLUSIONS: Allelic loss (or loss of heterozygosity) of chromosome 1p is a statistically significant predictor of chemosensitivity, and combined loss involving chromosomes 1p and 19q is statistically significantly associated with both chemosensitivity and longer recurrence-free survival after chemotherapy. Moreover, in both univariate and multivariate analyses, losses involving both chromosomes 1p and 19q were strongly associated with longer overall survival, whereas CDKN2A gene deletions and ring enhancement (i.e., contrast enhancement forming a rim around the tumor) on neuroimaging were associated with a significantly worse prognosis. The inverse relationship between CDKN2A gene deletions and losses of chromosomes 1p and 19q further implies that these differential clinical behaviors reflect two independent genetic subtypes of anaplastic oligodendroglioma. These results suggest that molecular genetic analysis may aid therapeutic decisions and predict outcome in patients with anaplastic oligodendrogliomas.

Pre-existing herpes simplex virus 1 (HSV-1) immunity decreases, but does not abolish, gene transfer to experimental brain tumors by a HSV-1 vector.

The influence of pre-existing anti-herpes simplex type 1 (HSV-1) immunity on HSV-1 vector-mediated gene transfer to glioma cells was analyzed in this gene marking study using intracranial D74 gliomas in syngeneic Fischer rats. The HSV-1 mutant virus used, hrR3, is defective in ribonucleotide reductase and bears the marker genes E. coli lacZ and HSV-1 thymidine kinase (HSVtk). Initial marker gene expression in tumors 12 h after direct virus injection was reduced in immunized animals to about 15% of that in nonimmunized animals. Marker gene expression in both sets stayed at initial levels for 2 days after intratumoral injection and declined markedly on day 5. Inflammatory infiltrates in the tumor were more prominent in HSV-1-immunized, as compared with nonimmunized animals, at 12 and 24 h, but appeared similar at 2-5 days after injection. By day 10, the immune reaction had subsided in immunized animals and macrophages remained only in nonimmunized animals. In conclusion, gene transfer to brain tumors using a HSV-1 vector was greatly reduced, but not completely abolished, under pre-immunization conditions. Pre-existing antibodies to HSV-1 may also serve a positive role in providing an increased margin of safety in intracranial application of HSV-1 vectors by limiting spread of the virus within the brain and to other tissues.

Change intolerance to shifts in methadone formulation: a preliminary investigation.

Some patients in methadone maintenance treatment programs have substantial difficulty adjusting to changes in methadone formulation and shifts in other program policies. Clinicians can benefit from the ability to identify individuals who are "at risk" for methadone formulation and other change intolerance. By studying a cohort of 177 patients who were receiving methadone maintenance in a program that changed methadone dispensing formulations, this study revealed significant differences between two underlying patient groups (i.e., change tolerant or intolerant). These patients were distinguished by personal characteristics prior to the formulation change and methadone dose level shifts after the formulation change. Change-intolerant patients experienced formulation-related narcotic withdrawal whereas change-tolerant patients adapted to the new medication format. Gender, treatment history, and methadone abuse were three sociodemographic variables that significantly predicted patients who were intolerant to a methadone formulation change. These findings suggest the need for more research, including plasma and metabolic studies, to clarify the potential biological effects of changes in methadone formulations. In addition, the treatment implications for patients who experience change intolerance are discussed.