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Biomedical subjects

A J Yates

Publications and source records attributed to A J Yates.

At least 55 records · Page 3Linked to original sources
PubMed1998

Survival following intensive chemotherapy with bone marrow reconstitution for children with recurrent intracranial ependymoma--a report of the Children's Cancer Group.

Recurrent intracranial ependymoma is rarely cured by surgery, radiotherapy, and chemotherapy in conventional doses. This study was designed to determine the toxicity, radiographic response rate and outcome following intensive chemotherapy with ThioTEPA, etoposide, carboplatinum and autologous bone marrow rescue (ABMR) for young children with recurrent central nervous system ependymoma. ThioTEPA 300 mg/m2/day (total 900 mg/m2) and etoposide 250 to 500 mg/m2/day (total 750 to 1500 mg/m2) were administered for three consecutive days with or without the addition of carboplatinum 500 mg/m2/day (total 1500 mg/m2) for an additional three consecutive days, and autologous bone marrow was reinfused 72 hours following chemotherapy. Eligibility criteria required adequate renal, hepatic and pulmonary function, and no tumor infiltration of bone marrow. Fifteen children with recurrent intracranial ependymoma, aged 5 months to 12 years (median 22 months), were treated. Five patients died of treatment related toxicities within 62 days of marrow reinfusion. Eight have expired from progressive disease a median of six months post-ABMR, and one has died from unrelated causes. One child remains alive 25 months post-ABMR, following further disease recurrence. No partial or complete responses were observed. This regimen of high-dose ThioTEPA and etoposide with or without additional carboplatinum with ABMR is not an effective strategy for retrieving heavily pre-treated children with recurrent ependymoma.

Antineoplastic Agents↗
PubMed1998

Treatment of high-grade spinal cord astrocytoma of childhood with "8-in-1" chemotherapy and radiotherapy: a pilot study of CCG-945. Children's Cancer Group.

OBJECT: The purpose of this study was to devise an improved method of treating high-grade gliomas of the spinal cord in children who have a dismal prognosis following conventional treatment. METHODS: Eighteen children with newly diagnosed high-grade astrocytomas arising in the spinal cord were enrolled in the Children's Cancer Group (CCG) protocol 945. Following surgery, they were all assigned to receive two cycles of "8-drugs-in-1-day" (8-in-1) chemotherapy prior to radiotherapy and eight additional cycles thereafter. A centralized neuropathology review was used to confirm the diagnosis of high-grade astrocytoma in 13 of the 18 children: anaplastic astrocytoma (eight patients), glioblastoma multiforme (four patients), and mixed malignant glioma (one patient). Diagnoses were discordant in five patients. There were eight boys and five girls in the group with confirmed diagnoses, with a median age of 7 years (range 1-15 years). The extent of resection was confirmed by computerized tomography or magnetic resonance (MR) evaluation in five of 13 patients. There were six gross-total or near-total resections (> 90%), four partial or subtotal resections (10-90%), and three biopsies. Six patients showed evidence of leptomeningeal metastases at diagnosis based on staging MR examinations. Eight of the 13 patients completed at least eight of the prescribed 10 cycles of chemotherapy; five received craniospinal radiotherapy and five spinal radiotherapy. CONCLUSIONS: The 5-year progression-free and total survival rates for the 13 children were 46 +/- 14% and 54 +/- 14%, respectively. Seven patients suffered a relapse at the primary site, four of whom also had leptomeningeal metastases. Seven of the 13 patients (54%) remain alive at the time of this report at a median of 76 months (range 51-93 months) from study entry. Six patients died between 8 and 38 months after diagnosis, all with active disease. Intensification of therapy may further improve outcome in this high-risk population.

Adolescent↗
PubMed1998

Current neurosurgical management and the impact of the extent of resection in the treatment of malignant gliomas of childhood: a report of the Children's Cancer Group trial no. CCG-945.

OBJECT: One hundred seventy-two children with high-grade astrocytomas were treated by members of the Children's Cancer Group in a prospective randomized trial designed to evaluate the role of two chemotherapy regimens. Seventy-six percent of the patients (131 children) in whom a diagnosis of either anaplastic astrocytoma or glioblastoma multiforme was confirmed by central pathological review are the subject of this report. METHODS: Patients were stratified according to the extent of tumor resection (biopsy [< 10%], partial resection [10-50%], subtotal resection [51-90%], near-total resection [> 90%], and total resection) as determined by surgical observation and postoperative computerized tomography scanning. Information on contemporary neurosurgical management was obtained from the patient's operative records and standardized neurosurgical report forms. The vast majority of tumors were supratentorial: 63% (83 tumors) in the superficial cerebral hemisphere, 28% (37 tumors) in the deep or midline cerebrum, and only 8% (11 tumors) in the posterior fossa. A significant association was detected between the primary tumor site and the extent of resection (p < 0.0001). A radical resection (> 90%) was performed in 37% of the children: 49% of the tumors in the superficial hemisphere and 45% of tumors in the posterior fossa compared with 8% of midline tumors. Tumor location could also be used to predict the need for both temporary and permanent cerebrospinal fluid (CSF) diversion. Half of the deep tumors and 8% of the hemispheric astrocytomas ultimately required a permanent CSF shunt. Improvement in preoperative neurological deficits and level of consciousness was seen in 36% and 34% of the children, respectively. New or increased deficits were present in 14% of the children, with 6% experiencing a diminished sensorium after surgery. Postoperative nonneurological complications were rare: infection, hematoma, and CSF fistula each occurred in 1.7% of the children. Univariate and multivariate analyses demonstrated that radical tumor resection (> 90%) was the only therapeutic variable that significantly improved progression-free survival (PFS) rates. For all patients with malignant astrocytomas, the distributions of PFS rates were significantly different (p = 0.006) following radical resection compared with less extensive (< or = 90%) resection. The 5-year PFS rates were 35 +/- 7% and 17 +/- 4%, respectively. The differences in the distribution of PFS rate were significant for the subsets of patients with anaplastic astrocytoma (p = 0.055) and glioblastoma multiforme (p = 0.046). The 5-year PFS rates for anaplastic astrocytoma were 44 +/- 11% and 22 +/- 6% for cases in which the tumor was radically resected and less than radically resected, respectively; whereas the 5-year PFS rates for glioblastoma multiforme were 26 +/- 9% and 4 +/- 3% for cases in which the tumor was radically resected and less than radically resected, respectively. CONCLUSIONS: The demonstration of a survival advantage provided by radical resection should prompt neurosurgeons to treat malignant pediatric astrocytomas with aggressive surgical resection prior to initiation of radiotherapy or adjuvant chemotherapy.

Adolescent↗
PubMed1997

Histomorphometric assessment of the long-term effects of alendronate on bone quality and remodeling in patients with osteoporosis.

Treatment effects on bone quality and remodeling was assessed in postmenopausal women with osteoporosis treated with oral alendronate. One transiliac bone biopsy was obtained from 231 women at either 24 mo (n = 11) or 36 mo (n = 120) from the start of treatment with alendronate at doses of between 5 and 20 mg/d, or placebo. 64 biopsies at 24 mo (31 from the placebo group and 33 alendronate-treated patients) and 95 biopsies at 36 mo (40 from the placebo group and 55 alendronate-treated patients) provided adequate cancellous tissue, and were analyzed by histomorphometry. Mineral apposition rate was unaffected by treatment. At 24 and 36 mo, osteoid thickness, volume, and surface significantly decreased. At each of the doses studied, mineralizing surface and activation frequency significantly decreased at each time point (e.g., -92% and -87%, respectively, for the 10 mg daily dose after 2 yr). These diminutions were of the same magnitude for each dose at 24 mo, and for the two highest doses at 36 mo. A significant increase in wall thickness accompanied by a reduction in erosion depth was detected in biopsies obtained at 24 mo. These findings confirm that mineralization is normal, and trabecular bone turnover markedly decreased in patients receiving long-term dosing with alendronate. The findings also suggest that the observed increases in bone mineral density could result both from a reduction in the remodeling space due to a decreased activation frequency and a possible trend to a positive bone balance. In addition, further studies focused on a possible increase in the degree of mineralization of bone are required.

Adult↗
PubMed1997

Improving diagnostic accuracy and interobserver concordance in the classification and grading of primary gliomas.

BACKGROUND: Accurate histologic diagnosis of gliomas is fundamental to proper patient management and to the interpretation of basic and clinical investigations. Diagnostic accuracy and reproducibility are compromised by the subjective histologic criteria currently used to classify and grade gliomas. METHODS: The histologic features of 4 sets of gliomas (a total of 244 cases) were reviewed independently by 4 neuropathologists to determine interobserver diagnostic concordance rates. Cases wherein diagnostic disagreements arose were reviewed jointly to identify and refine the histologic criteria that were adversely affecting diagnostic reproducibility. Using the criteria developed in the study, a set of 315 gliomas with known survival data was evaluated in order to validate the usefulness of the criteria. RESULTS: There was significant improvement in diagnostic concordance with each session (P = 0.02). For the first session, the concordance rates were as follows: all 4 reviewers, 52%; any 3 reviewers, 60%; 2 reviewers, 70%. For the fourth session, the respective rates were 69%, 75%, and 80%. Although features important in grading, particularly microvascular proliferation, were sometimes problematic, most disagreements related to the classification of tumors. Much of the improvement related to the refinement of criteria distinguishing diffuse astrocytomas from oligodendrogliomas/oligoastrocytomas and pilocytic astrocytomas. It was concluded that the presence of any typical oligodendroglioma was sufficient to remove a tumor from the astrocytoma category. CONCLUSIONS: The authors' data indicate that oligodendroglial tumors comprise up to 25% of gliomas, a significantly higher proportion than was previously recognized. The data also suggest that the wide range of survival times reported for patients with anaplastic astrocytoma may reflect "contamination" resulting from misdiagnosis, particularly of oligodendroglial tumors and pilocytic astrocytomas.

Brain Neoplasms↗
PubMed1997

Gangliosides inhibit growth factor-stimulated neurite outgrowth in SH-SY5Y human neuroblastoma cells.

Exogenously added gangliosides are known to promote neurite outgrowth in a variety of cell types, including some neuroblastoma cell lines. To study neuritogenesis in SH-SY5Y human neuroblastoma we serum starved the cells for 24 hr and exposed them to gangliosides (GM1, GM3, or GT1b), platelet-derived growth factor (PDGF), insulin, nerve growth factor (NGF), insulin-like growth factor I (IGF-I), or combinations of these for 3 days. We measured four parameters of neurite outgrowth using image analysis. PDGF induced neurite outgrowth in SH-SY5Y and GM1 inhibited this. Both phenomena were dose-dependent with neurites/cell and neurite length being below controls with 100 microM GM1, and percent of neurite-bearing cells being below controls with 25, 50, and 100 microM GM1. Similar but more inhibitory results were obtained with GM3 and GT1b. Insulin and IGF-I induced a neuritogenic response that was less potent than that of PDGF and was also inhibited by gangliosides. NGF had no effect on neurite outgrowth but gangliosides were still inhibitory even in cells not treated with growth factors. From this we conclude that gangliosides inhibit spontaneous and trophic factor-induced neurite outgrowth in SH-SY5Y cells. For GM1 and GT1b, but not GM3, this probably involves inhibition of trophic factor receptor function.

Culture Media, Serum-Free↗
PubMed1997

Phalangeal bone density and hip fracture risk.

OBJECTIVE: To assess the long-term predictive usefulness of radiographic absorptiometry measurements of phalangeal bone density for hip fracture risk. METHODS: Participants were members of the First National Health and Nutrition Examination Survey Epidemiologic Follow Up Study cohort. Subjects were followed up for a maximum of 16 years. The First National Health and Nutrition Examination Survey data were obtained from a nationally representative sample of non-institutionalized civilians. A cohort of 3481 white and black subjects (1559 white women) aged 45 through 74 years at baseline (1971-1975) were observed through 1987. Ninety-eight percent of the original cohort completed the study. Hospital records and death certificates were used to identify a total of 72 hip fracture cases. Phalangeal bone density at baseline was measured using photodensitometry (PD), and later reanalyzed by radiographic absorptiometry (RA), a newer, more sophisticated technique. RESULTS: Results were evaluated to determine the relative risk for hip fracture per 1-SD decrease in bone density, after controlling for age at baseline, race, gender, weight, and previous fractures. Both RA and PD measurements showed a significant inverse relationship to hip fracture risk, with RA density measurements showing a slightly higher adjusted relative risk per 1-SD density decrease than PD measurements. For RA bone density, the relative risk for all subjects was 1.81 (95% confidence interval, 1.34-2.44) compared with 1.57 (95% confidence interval, 1.19-2.07) for PD bone density after adjusting for age at baseline, race, gender, weight, and previous fractures. Results for white women were essentially the same as those for all subjects for RA bone density and PD bone density. CONCLUSIONS: Phalangeal bone density determined from standard hand x-ray films is a significant predictor of future hip fracture risk. Availability of a valid method to assess fracture risk using conventional radiographs will expand the ability to identify individuals with osteoporosis.

Absorptiometry, Photon↗
PubMed1997

An information system to support collaborative brain-tumor research.

We have developed and are currently maintaining a Neuro-Oncology Information System (NOIS) to support brain-tumor research. The system has been adopted for use by a group of researchers at several centers in the U.S.A. who are collaborating to input, store, and retrieve information concerning tissue specimens, corresponding clinical and diagnostic information, and eventual research results. The information system consists of a database and user-interface components. The database has clinical, diagnostic and tissue-inventory subsystems, the user interfaces allow for input and query functions on the database.

Biomedical Research↗
PubMed1997

Ganglioside GM1 enhances induction by nerve growth factor of a putative dimer of TrkA.

GM1 enhances nerve growth factor (NGF)-stimulated neuritogenesis and prevents apoptotic death of PC12 cells; both may be due to enhancement of TrkA dimerization. In this study, we examined the effect of GM1 on NGF-induced TrkA dimerization in Trk-PC12 (6-24) cells. NGF increased tyrosine phosphorylation of the 140-kDa protein (TrkA monomer), and preincubation with GM1 potentiated this effect. Adding the protein cross-linker bis(sulfosuccinimidyl) suberate with NGF resulted in the appearance of two major bands (220 and 330 kDa) when probed with antibodies against TrkA or phosphotyrosine, and GM1 also enhanced this effect. We interpret the 330-kDa band as being a homodimer of TrkA. The identity of the 220-kDa band is still not certain but may consist of a posttranslationally modified form of TrkA. Our results suggest that GM1 is augmenting the effects of NGF on PC12 cells by enhancing the dimerization and activation of the TrkA receptor.

Animals↗
PubMed1997

Ganglioside GM1 activates the mitogen-activated protein kinase Erk2 and p70 S6 kinase in U-1242 MG human glioma cells.

Gangliosides are implicated in the regulation of cellular proliferation as evidenced by differences in ganglioside composition associated with malignant transformation and density of cells in culture, as well as their inhibitory effects when added to cells growing in culture. Exogenously added gangliosides have a bimodal effect on proliferation in U-1242 MG glioma cells, inhibiting DNA synthesis in growing cells and stimulating it in quiescent cells. We investigated the mechanisms involved in stimulation of DNA synthesis using [3H]thymidine incorporation and immune complex kinase assays to identify responsible signal transduction pathways. Treatment of quiescent U-1242 MG cells with GM1 caused activation of the mitogen-activated protein (MAP) kinase isoform Erk2. Pretreatment with the specific MAP kinase kinase inhibitor PD98059 prevented the GM1-stimulated Erk2 activation and GM1-stimulated DNA synthesis. GM1 treatment stimulated another distinct signaling pathway leading to activation of p70 S6 kinase (p70s6k), and this was prevented by pretreatment with rapamycin. Rapamycin also inhibited GM1-stimulated DNA synthesis. Activation of both pathways and stimulation of DNA synthesis were inhibited by forskolin treatment; however, GM1 had no effect on cyclic AMP levels. Platelet-derived growth factor also activated both Erk2 and p70s6k but did not cause DNA synthesis, suggesting that GM1 may stimulate additional cascades, which also contribute to GM1-mediated DNA synthesis.

Calcium-Calmodulin-Dependent Protein Kinases↗
PubMed1997

Bisphosphonate effects and the bone remodeling transient.

Published randomized clinical trial data for alendronate, given at a dose of 10 mg/day, were fitted by a computer algorithm to the currently accepted model of the bone remodeling process. The purpose was to determine how much of the reported improvement in lumbar spine bone density could be attributed to the inevitable remodeling transient and how much might represent positive bone balance. Very good fits to the clinical data were easily obtained, indicating the general validity of current syntheses of bone remodeling biology. The best fit was provided by simulations produced by combinations of 36-38% suppression of remodeling activation and positive remodeling balance ranging from 1.1 to 1.4% per year. Whole body bone biomarker changes would have suggested both a slightly greater degree of suppression and a higher baseline level of remodeling than could be provided by any of the simulations if they were to fit the clinical data. Either regional skeletal heterogeneity or lack of a one-to-one quantitative relationship between remodeling changes and biomarker changes may explain the discrepancies between the two approaches.

Alendronate↗
PubMed1996

Glycolipids and myelin proteins in human oligodendrogliomas.

We studied myelin proteins and glycolipids in 24 human oligodendrogliomas (16 pure, eight mixed), including two grade I, 13 grade II, five grade III, and four grade IV. Tumours with a 1b ganglioside content (GD1b, GT1b and GQ1b) over 30% of total gangliosides occur more frequently in the WHO grade I and II (47%) and grade III (40%) than in the grade IV (25%) group; there was no difference in the amounts of total ganglioside or individual gangliosides between pure and mixed oligodendrogliomas. The presence of 6'-LM1 correlated with higher grades of tumours (chi 2 P approximately 0.02); however, 3'-LM1 and total neolacto-series gangliosides did not correlated with grade. Immunohistochemical studies of oligodendrocyte and myelin markers (GalCer, sulfatide, 2',3' -cyclic nucleotide phosphodiesterase, myelin basic protein and proteolipid protein) using specific antibodies showed only a very small proportion of tumour cells staining. These data do not support the hypothesis that tumours classified as oligodendrogliomas are derived from mature oligodendrocytes.

Brain Neoplasms↗
PubMed1996

Body size accounts for most differences in bone density between Asian and Caucasian women. The EPIC (Early Postmenopausal Interventional Cohort) Study Group.

We compared bone mineral density (BMD) of the whole body (and subregions: arm, leg, and pelvis), hip, spine, lateral spine, wrist, and forearm among Caucasian and Asian women at four geographic centers (Honolulu, HI; Nottingham, UK; Portland, OR; Copenhagen, Denmark). Data were derived from the baseline examination of 1367 Caucasian and 162 Asian women enrolled in the 1609-subject Early Postmenopausal Interventional Cohort (EPIC) study. After adjusting for age, study site, years postmenopause, and years of estrogen use, BMD was approximately 4-6% lower (P < 0.05) among Asian women at most skeletal sites, but there was no significant difference for wrist or forearm BMD. Adding height, lean body mass, fat mass, and/or quadriceps muscle strength to the regression models reduced the racial differences at most skeletal sites; after these additional adjustments, Asian women had significantly lower BMD only for the lateral spine (-4.4%; P < 0.005), arm (-2.20%; P < 0.05) and leg (-1.65%; P < 0.05), whereas the wrist was significantly greater (4.64%; P < 0.005) for Asian women. Further research is needed to determine why racial differences in BMD persist at certain skeletal sites, but not others, after adjusting for body size.

Anthropometry↗
PubMed1996

Oral alendronate induces progressive increases in bone mass of the spine, hip, and total body over 3 years in postmenopausal women with osteoporosis.

To determine the effects of long-term daily oral alendronate sodium (ALN) on bone mass in postmenopausal women with osteoporosis, 19 centers enrolled 516 postmenopausal women aged 45-80 years with spine bone mineral density (BMD) at least 2.5 SD below the mean for young premenopausal women in a 3-year, double-blind, placebo-controlled study. Subjects were randomly allocated to one of four treatment groups: placebo; alendronate, 5 or 10 mg/day for 3 years; or alendronate, 20 mg/day for 2 years followed by 5 mg/day for the 3rd year. All patients received 500 mg/day of supplemental calcium to ensure adequate calcium intake. BMD was measured by dual-energy X-ray absorptiometry at several skeletal sites. Nonsignificant mean decreases in BMD of the spine, femoral neck, and trochanter of 0.6, 0.7, and 0.4%, respectively, occurred in the placebo group at 3 years. Relative to placebo-treated patients, spine BMD increased by 5.4%, 7.4%, and 8.4% in the 5, 10, and 20/5 mg ALN groups, respectively. Increases at the femoral neck were 3.5%, 5.5%, and 4.3%, and those at the trochanter were 5.1%, 7.2%, and 7.2%, respectively. Thus, efficacy of 10 and 20/5 mg ALN was similar, whereas the 5 mg dose was less effective. BMD continued to increase over the entire 3-year study duration in the ALN-treated groups and, compared with the other dosage groups, 10 mg ALN produced the largest gains in BMD during the 3rd year. Changes in biochemical markers of bone turnover and mineral homeostasis confirmed the effect of ALN to decrease bone turnover to a new steady-state level. The safety and tolerability of ALN were comparable with those of placebo. In summary, 10 mg daily oral ALN given for 3 years significantly and progressively increases bone mass and is a generally well-tolerated treatment for osteoporosis in postmenopausal women.

Administration, Oral↗
PubMed1996

Biochemical and radiologic improvement in Paget's disease of bone treated with alendronate: a randomized, placebo-controlled trial.

PURPOSE: The potent bisphosphonates offer great promise in the management of Paget's disease of bone, but are currently available only as parenteral preparations in most countries. There is a need for a well-tolerated, oral therapy. Furthermore, none of the currently available therapies have been rigorously demonstrated to heal the lytic bone lesions characteristic of this condition. Alendronate is a potent new oral aminobisphosphonate that has shown promising effects on Paget's disease in preliminary studies. METHODS: We report a double-blind, randomized comparison of oral alendronate 40 mg/day and placebo over 6 months in 55 patients with Paget's disease. Efficacy was determined from measurements of biochemical indices of bone turnover (serum alkaline phosphatase and urine N-telopeptide) and blinded radiologic assessment of lytic bone lesions. RESULTS: N-telopeptide excretion declined by 86% and serum alkaline phosphatase by 73% in patients receiving alendronate, but remained stable in patients receiving placebo (P < 0.001 between groups for both indices). Responses were similar whether or not patients had previously received bisphosphonate treatment. Alendronate treatment normalized alkaline phosphatase in 48% of patients. Forty-eight percent of alendronate-treated patients showed radiologic improvement in osteolysis whereas in the placebo group only 4% improved (P = 0.02 for between-groups comparison). No patient in either group showed worsening of osteolysis. Bone histomorphometry indicated that alendronate tended to normalize turnover indices. There was no evidence of abnormal mineralization in bone biopsies taken from 12 alendronate-treated subjects. The treatment was well tolerated. CONCLUSION: Oral alendronate appears to be a safe and effective therapy for Paget's disease and results in healing of lytic bone lesions.

Administration, Oral↗