Spiritual, religious, and existential concerns of cancer survivors in a secular country with focus on age, gender, and emotional challenges.

PURPOSE: The purpose of this study was to examine the associations between self-reported spiritual/religious concerns and age, gender, and emotional challenges among cancer survivors who have completed a 5-day rehabilitation course at a rehabilitation center in Denmark (the former RehabiliteringsCenter Dallund (RC Dallund)). METHODS: The data stem from the so-called Dallund Scale which was adapted from the NCCN Distress Thermometer and comprised questions to identify problems and concerns of a physical, psychosocial, and spiritual/religious nature. Descriptive statistics were performed using means for continuous variables and frequencies for categorical variables. Odds ratios were calculated by logistic regression. RESULTS: In total, 6640 participants filled in the questionnaire. Among participants, 21% reported one or more spiritual/religious concerns, the most reported concerns related to existence and guilt. Having one or more spiritual/religious concerns was significantly associated with age (OR 0.88), female gender (OR 1.38), and by those reporting emotional problems such as being without hope (OR 2.51), depressed (OR 1.49), and/or anxious (OR 1.95). Among participants, 8% stated they needed help concerning spiritual/religious concerns. CONCLUSIONS: Cancer patients, living in a highly secular country, report a significant frequency of spiritual/religious and existential concerns. Such concerns are mostly reported by the young, female survivors and by those reporting emotional challenges. Spiritual/religious and existential concerns are often times tabooed in secular societies, despite being present in patients. Our results call for an increased systemic attention among health professionals to these concerns, and a particular focus on identifying and meeting the spiritual/religious and existential concerns of women, the young and those challenged by hopelessness, depression, and anxiety.

Effects of elevated CO2, warming and drought episodes on plant carbon uptake in a temperate heath ecosystem are controlled by soil water status.

The impact of elevated CO2, periodic drought and warming on photosynthesis and leaf characteristics of the evergreen dwarf shrub Calluna vulgaris in a temperate heath ecosystem was investigated. Photosynthesis was reduced by drought in midsummer and increased by elevated CO2 throughout the growing season, whereas warming only stimulated photosynthesis early in the year. At the beginning and end of the growing season, a T × CO2 interaction synergistically stimulated plant carbon uptake in the combination of warming and elevated CO2. At peak drought, the D × CO2 interaction antagonistically down-regulated photosynthesis, suggesting a limited ability of elevated CO2 to counteract the negative effect of drought. The response of photosynthesis in the full factorial combination (TDCO2) could be explained by the main effect of experimental treatments (T, D, CO2) and the two-factor interactions (D × CO2, T × CO2). The interactive responses in the experimental treatments including elevated CO2 seemed to be linked to the realized range of treatment variability, for example with negative effects following experimental drought or positive effects following the relatively higher impact of night-time warming during cold periods early and late in the year. Longer-term experiments are needed to evaluate whether photosynthetic down-regulation will dampen the stimulation of photosynthesis under prolonged exposure to elevated CO2.

Interactive effects of elevated CO2, warming, and drought on photosynthesis of Deschampsia flexuosa in a temperate heath ecosystem.

Global change factors affect plant carbon uptake in concert. In order to investigate the response directions and potential interactive effects, and to understand the underlying mechanisms, multifactor experiments are needed. The focus of this study was on the photosynthetic response to elevated CO(2) [CO2; free air CO(2) enrichment (FACE)], drought (D; water-excluding curtains), and night-time warming (T; infrared-reflective curtains) in a temperate heath. A/C(i) curves were measured, allowing analysis of light-saturated net photosynthesis (P(n)), light- and CO(2)-saturated net photosynthesis (P(max)), stomatal conductance (g(s)), the maximal rate of Rubisco carboxylation (V(cmax)), and the maximal rate of ribulose bisphosphate (RuBP) regeneration (J(max)) along with leaf δ(13)C, and carbon and nitrogen concentration on a monthly basis in the grass Deschampsia flexuosa. Seasonal drought reduced P(n) via g(s), but severe (experimental) drought decreased P(n) via a reduction in photosynthetic capacity (P(max), J(max), and V(cmax)). The effects were completely reversed by rewetting and stimulated P(n) via photosynthetic capacity stimulation. Warming increased early and late season P(n) via higher P(max) and J(max). Elevated CO(2) did not decrease g(s), but stimulated P(n) via increased C(i). The T×CO2 synergistically increased plant carbon uptake via photosynthetic capacity up-regulation in early season and by better access to water after rewetting. The effects of the combination of drought and elevated CO(2) depended on soil water availability, with additive effects when the soil water content was low and D×CO2 synergistic stimulation of P(n) after rewetting. The photosynthetic responses appeared to be highly influenced by growth pattern. The grass has opportunistic water consumption, and a biphasic growth pattern allowing for leaf dieback at low soil water availability followed by rapid re-growth of active leaves when rewetted and possibly a large resource allocation capability mediated by the rhizome. This growth characteristic allowed for the photosynthetic capacity up-regulations that mediated the T×CO2 and D×CO2 synergistic effects on photosynthesis. These are clearly advantageous characteristics when exposed to climate changes. In conclusion, after 1 year of experimentation, the limitations by low soil water availability and stimulation in early and late season by warming clearly structure and interact with the photosynthetic response to elevated CO(2) in this grassland species.

Defining the landscape of ATP-competitive inhibitor resistance residues in protein kinases.

Kinases are involved in disease development and modulation of their activity can be therapeutically beneficial. Drug-resistant mutant kinases are valuable tools in drug discovery efforts, but the prediction of mutants across the kinome is challenging. Here, we generate deep mutational scanning data to identify mutant mammalian kinases that drive resistance to clinically relevant inhibitors. We aggregate these data with subsaturation mutagenesis data and use it to develop, test and validate a framework to prospectively identify residues that mediate kinase activity and drug resistance across the kinome. We validate predicted resistance mutations in CDK4, CDK6, ERK2, EGFR and HER2. Capitalizing on a highly predictable residue, we generate resistance mutations in TBK1, CSNK2A1 and BRAF. Unexpectedly, we uncover a potentially generalizable activation site that mediates drug resistance and confirm its impact in BRAF, EGFR, HER2 and MEK1. We anticipate that the identification of these residues will enable the broad interrogation of the kinome and its inhibitors.

Efficacy, safety and patterns of response and recurrence in patients with recurrent high-grade gliomas treated with bevacizumab plus irinotecan.

Our objective is to assess treatment efficacy, safety and pattern of response and recurrence in patients with recurrent high-grade glioma treated with bevacizumab and irinotecan. We reviewed retrospectively 51 patients with recurrent high-grade glioma treated with this combination at the Henry Ford Hermelin Brain Tumor Center from 11/15/2005 to 04/01/2008. The 6-month progression-free survival (PFS) for anaplastic gliomas (AGs) was 78.6 and 63.7% for glioblastoma. The median PFS was 13.4 months for AG and 7.6 months for those with glioblastoma. The overall survival rate (OS) at 6 months was 85.7% for AG and 78.0% for glioblastoma. The 12-month OS was 77.9% for AG and 42.6% for glioblastoma. The median OS time for AGs was not reached and was 11.5 months for those with glioblastoma. Thirty-six out of 51 (70.59%) patients demonstrated partial (32/51) or complete (4/51) radiographic response to treatment and 8/51 (15.69%) remained stable. Of the 38 who demonstrated progression on post-gadolinium studies, 23 showed distant progression with or without local recurrence. Seven patients showed progression on FLAIR without concordant findings on post-Gd sequences. Six patients (11.76%) discontinued treatment due to a treatment-emergent adverse event, including one with end-stage renal failure and another with gastric perforation. No symptomatic intracranial hemorrhages were reported. Patients with recurrent high-grade glioma treated with bevacizumab plus irinotecan demonstrate an excellent radiographic response rate and improved clinical outcome when compared to historical data. The high rate of distant tumor progression suggests that tumors may adapt to inhibition of angiogenesis by increased infiltration and vascular co-option.

Intake of vitamin C and E in pregnancy and risk of pre-eclampsia: prospective study among 57 346 women.

OBJECTIVE: It has been suggested that vitamin C, alone or in combination with vitamin E, may protect against pre-eclampsia, whereas the safety of high-dose vitamin E supplements has been questioned. We investigated dietary intakes of vitamins C and E to see if they correlated with the incidence of pre-eclampsia. DESIGN: Prospective cohort study. SETTING: The Danish National Birth Cohort; a population-based pregnancy cohort; analyses were based on 57 346 pregnancies. METHODS: Vitamin intake was estimated from a food frequency questionnaire completed in gestational week 25, recording intake from diet and supplements during the previous four weeks. Pre-eclampsia diagnoses were obtained from the Danish National Patient Registry; we worked with two entities, 'pre-eclampsia (all types)' and 'severe pre-eclampsia/eclampsia/HELLP'. We adjusted for confounding factors by logistic regression. MAIN OUTCOME MEASURES: A small increase in the incidence of severe disease was also seen in the group of women (64, n = 49 373) with a high intake of vitamin E from supplements and dietary sources. RESULTS: The incidence of 'pre-eclampsia (all types)' did not correlate with dietary vitamin C and E intake. There was a decreasing trend (P = 0.01) in the incidence of 'severe pre-eclampsia/eclampsia/HELLP' with increasing dietary vitamin C intake; with an intake of 130-170 mg/day as reference, odds ratios ranged from 1.21 (95% confidence interval 0.83 to 1.75) for an intake below 70 mg/day to 0.70 (0.40 to 1.23) for an intake exceeding 275 mg/day (total n = 57 346). For vitamin E intake aggregated from diet and supplements (n = 49 373), with an intake of 10.5-13.5 mg/day as reference, the 'severe pre-eclampsia/eclampsia/HELLP' odds ratio was 1.46 (1.02 to 2.09) for an intake exceeding 18 mg/day. CONCLUSIONS: Low dietary intake of vitamin C was associated with a trend towards an increased incidence of either severe pre-eclampsia, eclampsia or HELLP. A small increase in the incidence of severe disease was also seen in the group of women with a high intake of vitamin E from supplements and dietary sources.

Effects of temperature, ultraviolet radiation and pectin methyl esterase on aerobic methane release from plant material.

This study examines the effects of different irradiance types on aerobic methane (CH(4)) efflux rates from terrestrial plant material. Furthermore, the role of the enzyme pectin methyl esterase (PME) on CH(4) efflux potential was also examined. Different types of plant tissue and purified pectin were incubated in glass vials with different combinations of irradiation and/or temperature. Purified dry pectin was incubated in solution, and with or without PME. Before and after incubation, the concentration of CH(4) was measured with a gas chromatograph. Rates of CH(4) emission were found to depend exponentially on temperature and linearly on UV-B irradiance. UV-B had a greater stimulating effect than UV-A, while visible light had no effect on emission rates. PME was found to substantially reduce the potential for aerobic CH(4) emissions upon demethylation of pectin.

Neuropilin-1 promotes human glioma progression through potentiating the activity of the HGF/SF autocrine pathway.

Neuropilin-1 (NRP1) functions as a coreceptor through interaction with plexin A1 or vascular endothelial growth factor (VEGF) receptor during neuronal development and angiogenesis. NRP1 potentiates the signaling pathways stimulated by semaphorin 3A and VEGF-A in neuronal and endothelial cells, respectively. In this study, we investigate the role of tumor cell-expressed NRP1 in glioma progression. Analyses of human glioma specimens (WHO grade I-IV tumors) revealed a significant correlation of NRP1 expression with glioma progression. In tumor xenografts, overexpression of NRP1 by U87MG gliomas strongly promoted tumor growth and angiogenesis. Overexpression of NRP1 by U87MG cells stimulated cell survival through the enhancement of autocrine hepatocyte growth factor/scatter factor (HGF/SF)/c-Met signaling. NRP1 not only potentiated the activity of endogenous HGF/SF on glioma cell survival but also enhanced HGF/SF-promoted cell proliferation. Inhibition of HGF/SF, c-Met and NRP1 abrogated NRP1-potentiated autocrine HGF/SF stimulation. Furthermore, increased phosphorylation of c-Met correlated with glioma progression in human glioma biopsies in which NRP1 is upregulated and in U87MG NRP1-overexpressing tumors. Together, these data suggest that tumor cell-expressed NRP1 promotes glioma progression through potentiating the activity of the HGF/SF autocrine c-Met signaling pathway, in addition to enhancing angiogenesis, suggesting a novel mechanism of NRP1 in promoting human glioma progression.

Major dietary patterns in pregnancy and fetal growth.

OBJECTIVES: To investigate possible associations between maternal diet during pregnancy and fetal growth. METHOD: Factor analysis was used to explore dietary patterns among pregnant women. The association between maternal dietary patterns and fetal growth (in terms of small for gestational age, SGA) was investigated by logistic regression. Prospective cohort study, including information on 44 612 women in Denmark. RESULTS: Two major dietary patterns were defined: the first pattern was characterized by red and processed meat, high-fat dairy, and the second pattern was characterized by intake of vegetables, fruits, poultry and fish. Women were classified into three classes according to their diet: the first class had high intake of foods of the first dietary pattern, and was classified as 'the Western diet', the second class preferred foods of the second pattern and was classified as the 'Health Conscious'; and the third one had eaten foods of both patterns, and was classified as the 'Intermediate'. The odds ratio of having a small for gestational-age infant (with a birth weight below the 2.5th percentile for gestational age and gender) was 0.74 (95% CI 0.64-0.86) for women in the Health Conscious class compared with women in the Western Diet class. The analyses were adjusted for parity, maternal smoking, age, height, pre-pregnancy weight and father's height. CONCLUSIONS: Our results indicated that a diet in pregnancy, based on red and processed meat and high-fat diary, was associated with increased risk for SGA. Further studies are warranted to identify specific macro-, or micronutrients that may be underlying these associations.

Estimation of health hazards resulting from a radiological terrorist attack in a city.

In recent years, the concern for protection of urban populations against terror attacks involving radiological, biological or chemical substances has attracted increasing attention. It sets new demands to decision support and consequence assessment tools, where the focus has traditionally been on accidental exposure. The aim of the present study was to illustrate issues that need to be considered in evaluating the radiological consequences of a 'dirty bomb' explosion. This is done through a worked example of simplified calculations of relative dose contributions for a specific 'dirty bomb' scenario leading to atmospheric dispersion of 90Sr contamination over a city area. Also, the requirements of atmospheric dispersion models for such scenarios are discussed.

Role of perfusion CT in glioma grading and comparison with conventional MR imaging features.

BACKGROUND AND PURPOSE: Perfusion imaging using CT can provide additional information about tumor vascularity and angiogenesis for characterizing gliomas. The purpose of our study was to demonstrate the usefulness of various perfusion CT (PCT) parameters in assessing the grade of treatment-naïve gliomas and also to compare it with conventional MR imaging features. MATERIALS AND METHODS: PCT was performed in 19 patients with glioma (14 high-grade gliomas and 5 low-grade gliomas). Normalized ratios of the PCT parameters (normalized cerebral blood volume [nCBV], normalized cerebral blood flow [nCBF], normalized mean transit time [nMTT]) were used for final analysis. Conventional MR imaging features of these tumors were assessed separately and compared with PCT parameters. Low- and high-grade gliomas were compared by using the nonparametric Wilcoxon 2-sample tests. RESULTS: Mean nCBV in the high- and low-grade gliomas was 3.06 +/- 1.35 and 1.44 +/- 0.42, respectively, with a statistically significant difference between the 2 groups (P = .005). Mean nCBF for the high- and low-grade gliomas was 3.03 +/- 2.16 and 1.16 +/- 0.36, respectively, with a statistically significant difference between the 2 groups (P = .045). Cut points of >1.92 for nCBV (85.7% sensitivity and 100% specificity), >1.48 for nCBF (71.4% sensitivity and 100% specificity), and <1.94 for nMTT (92.9% sensitivity and 40% specificity) were found to identify the high-grade gliomas. nCBV was the single best parameter; however, using either nCBV of >1.92 or nCBF of >1.48 improved the sensitivity and specificity to 92.9% and 100%, respectively. The sensitivity and specificity for diagnosing a high-grade glioma with conventional MR imaging were 85.7% and 60%, respectively. CONCLUSIONS: PCT can be used for preoperative grading of gliomas and can provide valuable complementary information about tumor hemodynamics, not available with conventional imaging techniques. nCBV was the single best parameter correlating with glioma grades, though using nCBF when nCBV was <1.92 improved the sensitivity. An nCBV threshold of >1.92 was found to identify the high-grade gliomas.

Immunogenicity of kappa-casein and glycomacropeptide.

Glycomacropeptide (GMP), arising from the cleavage of kappa-casein by chymosin or pepsin, has been correlated with a wide variety of biological activities including immunosuppression capacity, inhibition of pathogen invasion, and induction of satiety. Due to the interest in exploiting such potential of GMP, we aimed at characterizing the immunogenic properties of GMP as an indication of its potential allergenicity. Immunogenicity of kappa-casein and GMP were investigated using 2 animal models based on different routes of immunization: 1) mice immunized intraperitoneally or subcutaneously with either kappa-casein, polymerized GMP, GMP coupled to the immunogenic carrier ovalbumin, or GMP alone; 2) mice coadministered kappa-casein or GMP and cholera toxin. The specific antibody response to GMP was evaluated as well as the antigen-specific T-cell response. The results demonstrated that immunization or feeding with kappa-casein induced GMP-specific antibodies, whereas GMP per se lacked immunogenicity independently of the mode of presentation. The size of the presented form of GMP did not influence its immunogenicity. Because the results showed that GMP did not induce a specific T-cell response, we postulate that GMP lacks the ability to stimulate antigen-specific T cells.

Increasing incidence of primary malignant brain tumors: influence of diagnostic methods.

BACKGROUND: The incidence of brain cancer has increased dramatically over the last decades in most developed countries. Whether these trends can be attributed to improved diagnosis is not clear. PURPOSE: To determine the effect of new imaging technology on increased rates of brain cancer, we assessed the level of detection for neurological disorders when computed tomography (CT) and magnetic resonance imaging (MRI) results were not available. METHODS: A neurologist performed a blind review of hospital charts from 356 randomly selected patients, hospitalized between 1985 and 1989 for neurological disorders, including brain cancer. All prediagnosis information except CT and MRI results was used as a basis for diagnostic re-evaluation. Also, a random sample of 151 brain cancer patients diagnosed between 1960 and 1965 was selected for a description of diagnostic methods used during that period. RESULTS: A comparison between the original diagnoses and the re-evaluations for patients in the 1985-1989 sample indicated that there was, among the diseases selected, a 24% misclassification when CT scans and MRI were not available. In particular, 20% of brain tumors were undetected (95% confidence interval = 15%-25%), and 10% of non-tumor disorders were inaccurately labeled as brain tumors in the absence of these tests. The repeatability of the re-evaluations was 86%. CONCLUSIONS: Among elderly North Americans, at least twofold increases in brain cancer incidence were observed over the last two decades. Since our findings show that CT scans and MRI are responsible for the detection of about 20% of brain tumors, we conclude that other factors also are responsible for the observed trends.

Cathepsin B expression and localization in glioma progression and invasion.

The poor prognosis of human malignant gliomas is due to their invasion and recurrence, the molecular mechanisms of which remain poorly characterized. We have accumulated substantial evidence implicating the cysteine protease cathepsin B in human glioma malignancy. Increases in cathepsin B expression were observed throughout progression. In primary brain tumor tissue, transcript abundance (Northern blot analysis) increased in low-grade astrocytoma to high-grade glioblastoma from 3- to 6-fold, respectively, above normal brain levels. This increase correlated with increases in protein abundance (from + to ) as measured by immunohistochemistry. Furthermore, in glioblastoma cell lines increases in transcript abundance (ranging from 3- to 12-fold) were accompanied by increases in enzyme activity (44-133 nmol/min x mg protein). Altered subcellular localization was observed both immunohistochemically and by indirect immunofluorescence confocal microscopy and was found to correlate with increased grade. In addition, this increase in cathepsin B expression and altered subcellular localization correlated with histomorphological invasion and clinical evidence of invasion as detected by magnetic resonance imaging. These data support the hypothesis that cathepsin B plays a role in human glioma progression and invasion.

Inhibition of angiogenesis in human glioblastomas by chromosome 10 induction of thrombospondin-1.

Glioblastoma multiforme is distinguished from its less malignant astrocytoma precursors by intense angiogenesis and frequent loss of tumor suppressor genes on chromosome 10. Here we link these traits by showing that when a wild-type chromosome 10 was returned to any of three human glioblastoma cell lines U251, U87, or LG11, they lost their ability to form tumors in nude mice and switched to an antiangiogenic phenotype, as measured by the inhibition of capillary endothelial cell migration and of corneal neovascularization. This change in angiogenesis was directly due to the increased secretion of a potent inhibitor of angiogenesis, thrombospondin-1, because: (a) neutralizing thrombospondin completely relieved the inhibition; (b) the inhibitory activity of thrombospondin was not dependent on transforming growth factor beta; and (c) chromosome 10 introduction did not alter secreted inducing activity. The inducing activity was dependent on vascular endothelial cell growth factor and had an ED50 of 10 microg/ml in media conditioned by parental cells and 9-13 microg/ml in media conditioned by chromosome 10 revertants. Normal human astrocytes were also antiangiogenic due to secreted thrombospondin. The effect of chromosome 10 on thrombospondin production in vitro was reflected in patient material. Normal brain and lower grade astrocytomas known to retain chromosome 10 stained strongly for thrombospondin, but 12 of 13 glioblastomas, the majority of which lose chromosome 10, did not. These data indicate that the loss of tumor suppressors on chromosome 10 contributes to the aggressive malignancy of glioblastomas in part by releasing constraints on angiogenesis that are maintained by thrombospondin in lower grade tumors.

Carboxyamido-triazole induces apoptosis in bovine aortic endothelial and human glioma cells.

Carboxyamido-triazole (CAI), an inhibitor of non-voltage-gated calcium channels, has been studied in Phase I/II clinical trials following the identification of its inhibitory effects on tumor cell invasion and motility. It has also been reported to inhibit human endothelial cell proliferation, migration, and adhesion to the basement membrane. In glioma, biological assays have shown CAI to be active in inhibiting the phenotypes of invasion and angiogenesis. The exact mechanism of action is not clearly understood, although it appears to work via inhibition of calcium influx in several signal transduction pathways that inhibit cell cycle progression. Recent evidence implicates apoptosis as a contributing mechanism of chemotherapy-induced tumor cytotoxicity. Therefore, we studied the effects of CAI on apoptosis in bovine aortic endothelial cells and a human glioma cell line (U251N) using a variety of methods, including: (a) cell morphology; (b) terminal deoxynucleotidyl transferase-mediated nick end labeling analysis of in situ DNA strand breaks; (c) agarose gel electrophoresis to visualize DNA fragmentation; and (d) flow cytometry. Here we report that the kinetics of CAI-induced apoptosis in bovine aortic endothelial cells and glioma cells was determined to be both dose and time dependent in micromolar concentrations achievable in brain tissue in vivo.

Caseinomacropeptide self-association is dependent on whether the peptide is free or restricted in kappa-casein.

There is a general agreement that the experimentally determined molecular weight (MW) of caseinomacropeptide (CMP) is greater than the theoretical MW. Some studies suggest that this is due to a pH-dependent aggregation of monomeric CMP. How this aggregation is influenced by pH is not understood. This study was carried out to study the nature of CMP aggregates and to clarify which conditions affect aggregation of CMP. The apparent MW of CMP at different pH values was determined using size-exclusion chromatography. Caseinomacropeptide was further characterized by immunochemical analysis, sodium dodecyl sulfate-PAGE, N-terminal sequencing, and mass spectrometry. The hydrophobicity of CMP was studied by means of 1-anilino-naphthalene-8-sulfonic acid binding experiments. Four CMP products prepared by different methods were studied: CMP produced by enzymatic (chymosin or pepsin) hydrolysis of kappa-casein (CN), and 2 commercial CMP products. Both commercial products and CMP resulting from chymosin-hydrolysis of kappa-CN (at pH 6.6) had elution volumes with a MW corresponding to 35 kDA at pH 8.0 and 3.4. Caseinomacropeptide prepared from pepsin-hydrolysis of kappa-CN (at pH 2.5) eluted as multiple peaks with apparent MW of 35, 18, and 9 kDa, again independently of pH. Hydrolysis of kappa-CN with chymosin or pepsin at different pH values (pH 2.5, 3.4, and 6.6) produced differently sized aggregates of CMP, largely depending on the pH of the hydrolysis. These results indicate that, whereas CMP molecules are irreversibly associated, CMP in kappa-CN may associate reversibly in a pH-dependent manner. We suggest that interactions between para-kappa-CN parts of the kappa-CN molecules may be a requisite for the pH-dependent dissociation/association.

Outcome of Adult Brain Tumor Consortium (ABTC) prospective dose-finding trials of I-125 balloon brachytherapy in high-grade gliomas: challenges in clinical trial design and technology development when MRI treatment effect and recurrence appear similar.

OBJECTIVES: The aim of this study is to define the maximal safe radiation dose to guide further study of the GliaSite balloon brachytherapy (GSBT) system in untreated newly diagnosed glioblastoma (NEW-GBM) and recurrent high-grade glioma (REC-HGG). GBST is a balloon placed in the resection cavity and later filled through a subcutaneous port with liquid I-125 Iotrex, providing radiation doses that diminish uniformly with distance from the balloon surface. METHODS: The Adult Brain Tumor Consortium initiated prospective dose-finding studies to determine maximum tolerated dose in NEW-GBM treated before standard RT or after surgery for REC-HGG. Patients were inevaluable if there was progression before the 90-day posttreatment toxicity evaluation point. RESULTS: Ten NEW-GBM patients had the balloon placed, and 2/10 reached the 90 day timepoint. Five REC-HGG enrolled and two were assessable at the 90-day evaluation endpoint. Imaging progression occurred before 90-day evaluation in 7/12 treated patients. The trials were closed as too few patients were assessable to allow dose escalation, although no dose-limiting toxicities (DLTs) were observed. Median survival from treatment was 15.3 months (95 % CI 7.1-23.6) for NEW-GBM and 12.8 months (95 % CI 4.2-20.9) for REC-HGG. CONCLUSION: These trials failed to determine a maximum tolerated dose (MTD) for further testing as early imaging changes, presumed to be progression, were common and interfered with the assessment of treatment-related toxicity. The survival outcomes in these and other related studies, although based on small populations, suggest that GSBT may be worthy of further study using clinical and survival endpoints, rather than standard imaging results. The implications for local therapy development are discussed.

SPARC: a signal of astrocytic neoplastic transformation and reactive response in human primary and xenograft gliomas.

In an attempt to identify genetic alterations occurring early in astrocytoma progression, we performed subtractive hybridization between astrocytoma and glioblastoma cDNA libraries. We identified secreted protein acidic and rich in cysteine (SPARC), a protein implicated in cell-matrix interactions, as a gene overexpressed early in progression. Northern blot and immunohistochemical analyses indicated that transcript and protein were both elevated in all tumor specimens (grades II-IV) examined when compared with levels in normal brain. The level of SPARC expression was found to be tumor-dependent rather than grade-related. Immunohistochemically, SPARC protein was found to be overexpressed in 1) cells in the less cellularly dense regions within the tumor mass, 2) histomorphologically neoplastic-looking cells in adjacent normal brain at the tumor/brain interface, 3) neovessel endothelial cells in both the tumor and adjacent normal brain, and 4) reactive astrocytes in normal brain adjacent to tumor. Using a combination of DNA in situ hybridization and protein immunohistochemical analyses of the human/rat xenograft, SPARC expression was observed in the human glioma cells within the tumor mass, and in cells that invaded along vascular basement membranes and individually into the rat brain parenchyma, suggesting it may be an invasion-related gene. While it remains to be determined whether SPARC functionally contributes to tumor cell invasion, these data suggest that the early onset of increased SPARC expression, though complex, may serve as a signal indicative of neoplastic astrocytic transformation and reactive response to tumor-induced stress.