Development of BNBSL: A ß-ν spectra library for spectrometry applications.

While modern nuclear decay data can provide many details of a given nuclides ß-decay modes (branching ratios, decay heating etc.), knowledge of the emitted ß-energy spectrum is often not included. This limitation hampers the use of decay data in some analysis, such as ß-spectrometry of irradiated material, prediction of ß-decay Bremsstrahlung or antineutrino, ν̄, detection. To address this deficiency, and for increased ease of ß-spectrometry studies of complex samples, a library of ß, ν and Bremsstrahlung-spectra, called BNBSL (Beta-Neutrino-Bremsstrahlung spectra library), has been produced. It has been found that the content compares favourably with experimental data and methodologies for its application to complex nuclear inventories have been developed. BNBSL contains spectra for over 1500 nuclides, which is hoped will benefit applied nuclear, radiation and materials science studies.

Phase I-II clinical trial design: a state-of-the-art paradigm for dose finding.

Background: Conventional phase I algorithms for finding a phase-2 recommended dose (P2RD) based on toxicity alone is problematic because the maximum tolerated dose (MTD) is not necessarily the optimal dose with the most desirable risk-benefit trade-off. Moreover, the increasingly common practice of treating an expansion cohort at a chosen MTD has undesirable consequences that may not be obvious. Patients and methods: We review the phase I-II paradigm and the EffTox design, which utilizes both efficacy and toxicity to choose optimal doses for successive patient cohorts and find the optimal P2RD. We conduct a computer simulation study to compare the performance of the EffTox design with the traditional 3 + 3 design and the continuous reassessment method. Results: By accounting for the risk-benefit trade-off, the EffTox phase I-II design overcomes the limitations of conventional toxicity-based phase I designs. Numerical simulations show that the EffTox design has higher probabilities of identifying the optimal dose and treats more patients at the optimal dose. Conclusions: Phase I-II designs, such as the EffTox design, provide a coherent and efficient approach to finding the optimal P2RD by explicitly accounting for risk-benefit trade-offs underlying medical decisions.

A phase II study of bevacizumab and erlotinib after radiation and temozolomide in MGMT unmethylated GBM patients.

Survival for glioblastoma (GBM) patients with an unmethyated MGMT promoter in their tumor is generally worse than methylated MGMT tumors, as temozolomide (TMZ) response is limited. How to better treat patients with unmethylated MGMT is unknown. We performed a trial combining erlotinib and bevacizumab in unmethylated GBM patients after completion of radiation (RT) and TMZ. GBM patients with an unmethylated MGMT promoter were trial eligible. Patient received standard RT (60 Gy) and TMZ (75 mg/m2 × 6 weeks) after surgical resection of their tumor. After completion of RT they started erlotinib 150 mg daily and bevacizumab 10 mg/kg every 2 weeks until progression. Imaging evaluations occurred every 8 weeks. The primary endpoint was overall survival. Of the 48 unmethylated patients enrolled, 46 were evaluable (29 men and 17 women); median age was 55.5 years (29-75) and median KPS was 90 (70-100). All patients completed RT with TMZ. The median number of cycles (1 cycle was 4 weeks) was 8 (2-47). Forty-one patients either progressed or died with a median progression free survival of 9.2 months. At a follow up of 33 months the median overall survival was 13.2 months. There were no unexpected toxicities and most observed toxicities were categorized as CTC grade 1 or 2. The combination of erlotinib and bevacizumab is tolerable but did not meet our primary endpoint of increasing survival. Importantly, more trials are needed to find better therapies for GBM patients with an unmethylated MGMT promoter.

Interatomic potentials for modelling radiation defects and dislocations in tungsten.

We have developed empirical interatomic potentials for studying radiation defects and dislocations in tungsten. The potentials use the embedded atom method formalism and are fitted to a mixed database, containing various experimentally measured properties of tungsten and ab initio formation energies of defects, as well as ab initio interatomic forces computed for random liquid configurations. The availability of data on atomic force fields proves critical for the development of the new potentials. Several point and extended defect configurations were used to test the transferability of the potentials. The trends predicted for the Peierls barrier of the [Formula: see text] screw dislocation are in qualitative agreement with ab initio calculations, enabling quantitative comparison of the predicted kink-pair formation energies with experimental data.

Free energy generalization of the Peierls potential in iron.

In body-centered-cubic (bcc) crystals, 1/2<111> screw dislocations exhibit high intrinsic lattice friction as a consequence of their nonplanar core structure, which results in a periodic energy landscape known as the Peierls potential U(P). The main features determining plastic flow, including its stress and temperature dependences, can be derived directly from this potential, hence its importance. In this Letter, we use thermodynamic integration to provide a full thermodynamic extension of U(P) for bcc Fe. We compute the Peierls free energy path as a function of stress and temperature and show that the critical stress vanishes at 700 K, supplying the qualitative elements that explain plastic behavior in the athermal limit.

Mood disturbance in glioma patients.

Patients diagnosed with primary brain tumors such as glioma experience psychological distress throughout the illness trajectory. Determining which patient characteristics are associated with more severe mood disturbance throughout the illness trajectory can help identify patients at risk and assist in developing targeted interventions based on these factors. Adult glioma patients were eligible for participation. Data collection tools included an investigator completed clinician assessment tool, patient completed demographic form and the Profile of mood states-short form. A multiple regression model was used to describe the relationship between the patient groups and clinical factors. The study enrolled 186 glioma patients of various tumor grades, who were categorized in three groups (newly diagnosed, on-treatment, follow-up) based on disease status at time of visit. Newly diagnosed patients experienced more total mood disturbance than all the other groups. Characteristics associated with more severe mood disturbance varied by patient group: newly diagnosed patients who were not on corticosteroids and were not married were more likely to have higher mood disturbance [R(2) = 0.27, F (2, 29) = 5.31, p < 0.02]. For those on treatment, the use of concomitant medications, having more than 1 recurrence and low income predicted higher mood disturbance [R(2) = 0.417, F (4, 67) = 11.98, p < 0.001]. For those not on active treatment, female sex, anti-depressant use and having a lower income was associated with higher mood disturbance [R(2) = 0.183, F (3, 55) = 4.11, p < 0.02]. Additionally, when compared to other cancer groups, glioma patients reported similar mood disturbance to those with breast cancer. Factors other than disease characteristics are associated with higher mood disturbance and vary according to current disease status. The use of concomitant medications, demographic factors, recurrence and income are associated with mood disturbance and interventions may need to be tailored to these underlying factors.

Assessment of interatomic potentials for atomistic analysis of static and dynamic properties of screw dislocations in W.

Screw dislocations in bcc metals display non-planar cores at zero temperature which result in high lattice friction and thermally-activated strain rate behavior. In bcc W, electronic structure molecular statics calculations reveal a compact, non-degenerate core with an associated Peierls stress between 1.7 and 2.8 GPa. However, a full picture of the dynamic behavior of dislocations can only be gained by using more efficient atomistic simulations based on semiempirical interatomic potentials. In this paper we assess the suitability of five different potentials in terms of static properties relevant to screw dislocations in pure W. Moreover, we perform molecular dynamics simulations of stress-assisted glide using all five potentials to study the dynamic behavior of screw dislocations under shear stress. Dislocations are seen to display thermally-activated motion in most of the applied stress range, with a gradual transition to a viscous damping regime at high stresses. We find that one potential predicts a core transformation from compact to dissociated at finite temperature that affects the energetics of kink-pair production and impacts the mechanism of motion. We conclude that a modified embedded-atom potential achieves the best compromise in terms of static and dynamic screw dislocation properties, although at an expense of about ten-fold compared to central potentials.

Two phase II trials of temozolomide with interferon-alpha2b (pegylated and non-pegylated) in patients with recurrent glioblastoma multiforme.

BACKGROUND: Because of the poor outcomes for patients with recurrent glioblastoma multiforme (GBM), and some laboratory and clinical evidence of efficacy using interferon in GBM, we assessed the toxicity and efficacy of temozolomide (TMZ) combined with either short-acting (IFN) or long-acting (pegylated) interferon alpha2b (PEG) in two single-arm phase II studies, and compared the results to 6-month progression-free survival (PFS-6) data from historical controls. METHODS: Two single-arm phase II studies were carried out in adults with GBM. Patients were treated with the standard regimen of TMZ (150-200 mg m(-2) per day x 5 days every month) combined with either 4 million units per m(2) subcutaneously (SQ) three times weekly of IFN or 0.5 microg kg(-1) SQ weekly of PEG. Physical exams and imaging evaluations were carried out every 8 weeks. RESULTS: On the IFN study, 34 adults (74% men) were enrolled, and 29 adults (55% men) on the PEG study; median Karnofsky performance status was 80 and 90 for the IFN and PEG studies, respectively. Grade 3 or 4 toxicities were common, leucopoenia and thrombocytopoenia occurring in 35-38% and 18-21% of patients, respectively. Grade 3 or 4 fatigue occurred in 18% of patients on both studies. Lymphopoenia was infrequent. PFS-6 was 31% for 29 evaluable patients in the IFN study and 38% for 26 evaluable patients in the PEG study. CONCLUSION: In recurrent GBM patients, both studies of standard dose TMZ with either IFN or PEG showed improved efficacy when compared to historical controls, or reports using TMZ alone. Even though the TMZ+PEG study met criteria for further study, the results of both of these studies must be considered in light of the standard of care (TMZ plus radiotherapy) for newly diagnosed GBM, which has evolved since the inception of these studies. Despite the results of the current studies being eclipsed by the new GBM standard of care, these results can still inform the development of newer approaches for GBM, either in an earlier, upfront setting, or by extrapolation of the results and consideration of the use of PEG or IFN in conjunction with other antiglioma strategies.

Phase II study of carboplatin and erlotinib (Tarceva, OSI-774) in patients with recurrent glioblastoma.

Targeting the epidermal growth factor receptor (EGFR) may be effective in a subset of glioblastoma patients. This phase II study assessed the clinical activity of erlotinib plus carboplatin and to determine molecular predictors of response. The primary endpoint was progression free survival (PFS). Patients with recurrent glioblastoma with no more than two prior relapses received carboplatin intravenously on day 1 of every 28-day cycle (target AUC of 6 mg x ml/min). Daily erlotinib at 150 mg/day was dose escalated to 200 mg/day, as tolerated. Clinical and MRI assessments were made every 4 and 8 weeks, respectively. Tumor tissue was evaluated for EGFR, AKT and phosphatase and tensin homolog (PTEN) status. One partial response (PR) was observed out of 43 assessable patients. Twenty patients (47%) had stable disease (SD) for an average of 12 weeks. Median PFS was 9 weeks. The 6-month PFS rate was 14%. Median overall survival (OS) was 30 weeks. This regimen was well tolerated with grade 3/4 toxicities of fatigue, leukopenia, thrombocytopenia and rash requiring dose reductions. A recursive partitioning analysis (RPA) predicted that patients with KPS >or=90 treated with more than 1 prior regimen had the highest OS. No correlation was observed between EGFR, Akt or PTEN expression and either PFS or OS. Carboplatin plus erlotinib is well tolerated but has modest activity in unselected patients. Future trials should be stratified based on optimal molecular or clinical characteristics.

Antiepileptic drugs for preventing seizures in people with brain tumors.

BACKGROUND: Seizures can present at any time before or after diagnosis of a brain tumor. The risk of seizures varies by tumor type and its location in the brain. For a long time we believed that preventing seizures with antiepileptic drugs (seizure prophylaxis) was effective and necessary, but the supporting evidence was little and mixed. Such evidence was the basis for previous reviews to conclude that seizure prophylaxis was ineffective in people with brain tumors. OBJECTIVES: To estimate the effectiveness of seizure prophylaxis in people with brain tumors, and to estimate the adverse event rates in the identified clinical trials. SEARCH STRATEGY: A search strategy that included free-text and MeSH terms in LILACS, EMBASE, PubMed, CENTRAL, and The Cochrane Library (1966 to 2007). SELECTION CRITERIA: Controlled clinical trials with random allocation, blinded or unblinded, and placebo or observation in the control groups. DATA COLLECTION AND ANALYSIS: We screened the articles, extracted the data, and rated the validity of each trial to assess the risk of bias. Our primary outcome was the occurrence of a first seizure. The secondary outcome was adverse events. We pooled the aggregate data for each outcome into a random-effects model meta-analysis using the relative risk (RR). For adverse events, we also included the number needed to harm (NNH) using the absolute risk increase to compute the NNH. MAIN RESULTS: There was no difference between the treatment interventions and the control groups in preventing a first seizure in participants with brain tumors. The risk of an adverse event was higher for those on antiepileptic drugs than for participants not on antiepileptic drugs (NNH 3; RR 6.10, 95% CI 1.10 to 34.63; P = 0.046). AUTHORS' CONCLUSIONS: The evidence is neutral, neither for nor against seizure prophylaxis, in people with brain tumors. These conclusions apply only for the antiepileptic drugs phenytoin, phenobarbital, and divalproex sodium. The decision to start an antiepileptic drug for seizure prophylaxis is ultimately guided by assessment of individual risk factors and careful discussion with patients.

Validation of the M.D. Anderson Symptom Inventory Brain Tumor Module (MDASI-BT).

BACKGROUND: Symptom occurrence has been shown to predict treatment course and survival in patients with solid tumors. Primary brain tumor (PBT) patients are unique in the occurrence of neurologic symptoms. Currently, no instrument exists that measures both neurologic and cancer-related symptoms. METHODS: Patients diagnosed with PBT participated in this study. Data was collected at one point in time and included demographic and clinical factors, and the M.D. Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT). The study evaluated the reliability and validity of the MDASI-BT in primary brain tumor patients. RESULTS: Two hundred and one patients participated in this study. Mean symptom severity of items as well as cluster analysis was used to reduce the number of total items to 22 (13 core, 9 brain tumor items). Regression analysis showed more than half (56%) of the variability in symptom severity was explained by brain module items. The MDASI-BT measures six underlying constructs including affective, cognitive, focal neurologic deficit, constitutional, generalized symptom, and a gastrointestinal related factor. The internal consistency (reliability) of the instrument was 0.91. The MDASI-BT was sensitive to disease severity based on performance status (P<0.001), tumor recurrence (P<0.01), and mean symptom interference (P<0.001). CONCLUSIONS: The 22 item MDASI-BT demonstrated validity and reliability in patients with PBT. This instrument can be used to identify symptom occurrence throughout the disease trajectory and to evaluate interventions designed for symptom management.

Brain metastases: still an 'orphan' disease?

The diagnosis of brain metastases from systemic cancer has been associated with a poor prognosis. In fact, most chemotherapy clinical trials exclude patients with metastatic disease. In the past, clinical and basic research activity in this area has been only moderate. Recent developments in clinical trial design, as evidenced by recursive partitioning analysis and complemented by new treatment strategies in neurosurgery and radiotherapy, suggest a change in attitude and approach to the management of brain metastases. The role of chemotherapy will require more focused investigation, but recent advances in our understanding of the biology of brain metastases suggest that the next generation of chemotherapy treatments will involve targeting specific pathways of metastatic disease.

Application of advances in molecular biology to the treatment of brain tumors.

Recent advances in molecular biology have substantially improved our understanding of the molecular genetics of primary brain neoplasms. Soon each histopathologic category of glioma will be further divided into subgroups according to similar genetic background, gene expression profile, and similarity of biologic responses to radiotherapy or chemotherapy. Identification of key molecules that are specifically altered in neoplastic cells will provide candidate molecular targets for tumor treatment. Novel therapeutic tools for targeting tumor cells, such as viral vectors for gene therapy, have been created. In the near future, the accumulation of new knowledge in brain tumor biology and genetics, combined with rational drug design, will revolutionize the treatment of malignant gliomas, which are among the most lethal human cancers.

Metastatic brain tumors: diagnosis, treatment, and nursing interventions.

Metastatic tumors are by far the most common cause of brain cancer, with an incidence rate higher than all other types of primary brain tumors combined. Cancer cells can spread to the brain from other sites via the blood supply, lymphatic system, or direct extension. Neurologic symptoms, which are dependent on tumor location, often include headache, weakness, or cognitive deficits. Although the standard of care is evolving, treatment often includes some combination of surgery and radiation therapy. Newer treatments, including radiosurgery and novel chemotherapy approaches, currently are being investigated. These treatment advances have markedly altered the prognosis for patients with brain metastases. Consequently, the status of the systemic components of the malignancy often may be the determinant of outcome.

Chemotherapy of astrocytomas: an overview.

OBJECTIVES: To provide an overview of the use of chemotherapy in the treatment of malignant brain tumors, with an emphasis on malignant gliomas. DATA SOURCES: Published articles, research studies, and reference books. CONCLUSIONS: Chemotherapy has primarily been used in a adjuvant setting after radiation therapy for primary brain tumors. This focus has not had a significant effect on survival. In an effort to more effectively treat the tumor, innovative chemotherapy treatments have been developed. These include the use of neoadjuvant chemotherapy, changes in timing of administration, new classes of chemotherapeutic agents, new routes of delivery, and augmentation of the body's own immune system to treat the tumor. IMPLICATIONS FOR NURSING PRACTICE: It is the challenge of the oncology nurse caring for the patient with a malignant brain tumor to gain knowledge of the disease process, side effect management, and the most up-to-date treatment regimens.

Phase II study of paclitaxel in patients with recurrent malignant glioma.

PURPOSE: To assess the efficacy and toxicity of paclitaxel administered as a 3-hour infusion to patients with recurrent malignant glioma. PATIENTS AND METHODS: Adult patients with recurrent malignant glioma following radiation therapy, who had received no more than one prior chemotherapy regimen and who had a Karnofsky performance status (KPS) > or = 60, were treated with a 3-hour infusion of paclitaxel every 3 weeks. The initial dose was 210 mg/m2; dose escalation to 240 mg/m2 was allowed. Tumor response was assessed at 6-week intervals using radiographic and clinical criteria. Treatment was continued until documented tumor progression or a total of 12 paclitaxel infusions. RESULTS: Of 41 eligible patients, all were assessable for treatment toxicity and 40 (98%) were assessable for response. The response rate (disease stabilization or better) was 35%. Twenty-nine patients (71%) underwent dose escalation to 240 mg/m2 without the use of growth factors. Toxicities included alopecia (98%), nausea (22%), arthralgias (32%), CNS toxicity (24%), peripheral neuropathy (15%), cardiac toxicity (7%), and myelosuppression (10% grade 3 or 4 hematologic toxicity). No patient developed febrile neutropenia. There was one allergic reaction (2%). CONCLUSION: Paclitaxel is well tolerated at this dose schedule in patients with recurrent malignant glioma, and affords a modest response rate. Because minimal myelotoxicity was encountered in our patients, a dose-escalating phase I/II study of paclitaxel is planned to determine the maximal-tolerated dose (MTD).

Glial neoplasms: classification, treatment, and pathways for the future.

PURPOSE/OBJECTIVES: To provide a review of glial neoplasms including histologic classification, signs and symptoms, diagnostic evaluation, treatment options, and nursing care. DATA SOURCES: Articles, books, proceedings of national meetings. DATA SYNTHESIS: Glial neoplasms vary according to prognosis and treatment options based on histologic classifications. Prediction of deficits and potential complications of disease and treatment can prepare the patient and healthcare provider in management. Treatment options include surgery, radiation therapy, and chemotherapy or combinations of these options. New treatment regimes currently are being investigated. CONCLUSIONS: Despite advances in the diagnosis and treatment of malignant gliomas, the outlook remains poor. As new combination treatment regimens become available, nursing care will significantly affect outcome and quality of life. IMPLICATIONS FOR NURSING PRACTICE: Goals of nursing care include prevention and education related to tumor- and treatment-related side effects, providing support and coordinating referrals to appropriate services during the disease process, and helping the patient and family cope with this devastating disease.