70 research outputs found
Biomarkers and Mechanisms of FANCD2 Function
Genetic or epigenetic inactivation of the pathway formed by the Fanconi anemia (FA) and BRCA1 proteins occurs in several cancer types, making the affected tumors potentially hypersensitive to DNA cross-linkers and other chemotherapeutic agents. It has been proposed that the inability of FA/BRCA-defective cells to form subnuclear foci of effector proteins, such as FANCD2, can be used as a biomarker to aid individualization of chemotherapy. We show that FANCD2 inactivation not only renders cells sensitive to cross-links, but also oxidative stress, a common effect of cancer therapeutics. Oxidative stress sensitivity does not correlate with FANCD2 or RAD51 foci formation, but associates with increased γH2AX foci levels and apoptosis. Therefore, FANCD2 may protect cells against cross-links and oxidative stress through distinct mechanisms, consistent with the growing notion that the pathway is not linear. Our data emphasize the need for multiple biomarkers, such as γH2AX, FANCD2, and RAD51, to capture all pathway activities
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RTOG 0518: Randomized Phase III Trial to Evaluate Zoledronic Acid for Prevention of Osteoporosis and Associated Fractures in Prostate Cancer Patients
Background: RTOG 0518 evaluated the potential benefit of zoledronic acid therapy in preventing bone fractures for patients with high grade and/or locally advanced, non-metastatic prostate adenocarcinoma receiving luteinizing hormone-releasing hormone (LHRH) agonist and radiotherapy (RT). Methods: Eligible patients with T-scores of the hip ( −2.5 vs. > −1.0) and negative bone scans were prospectively randomized to either zoledronic acid, 4 mg, concurrently with the start of RT and then every six months for a total of 6 infusions (Arm 1) or observation (Arm 2). Vitamin D and calcium supplements were given to all patients. Secondary objectives included quality of life (QOL) and bone mineral density (BMD) changes over a period of three years. Results: Of 109 patients accrued before early closure, 96 were eligible. Median follow-up was 36.3 months for Arm I and 34.8 months for Arm 2. Only two patients experienced a bone fracture (1 in each arm) resulting in no difference in freedom from any bone fracture (p=0.95), nor in QOL. BMD percent changes from baseline to 36 months were statistically improved with the use of zoledronic acid compared to observation for the lumbar spine (6% vs. −5%, p<0.0001), left total hip (1% vs. −8%, p=0.0002), and left femoral neck (3% vs. −8%, p=0.0007). Conclusions: For patients with advanced, non-metastatic prostate cancer receiving LHRH agonist and RT, the use of zoledronic acid was associated with statistically improved BMD percent changes. The small number of accrued patients resulted in decreased statistical power to detect any differences in the incidence of bone fractures or QOL
CogState computerized memory tests in patients with brain metastases: Secondary endpoint results of NRG oncology RTOG 0933
Whole brain radiotherapy (WBRT) is associated with memory dysfunction. As part of NRG Oncology RTOG 0933, a phase II study of WBRT for brain metastases that conformally avoided the hippocampal stem cell compartment (HA-WBRT), memory was assessed pre-and post-HA-WBRT using both traditional and computerized memory tests. We examined whether the computerized tests yielded similar findings and might serve as possible alternatives for assessment of memory in multi-institution clinical trials. Adult patients with brain metastases received HA-WBRT to 30 Gy in ten fractions and completed Hopkins Verbal Learning Test-Revised (HVLT-R), CogState International Shopping List Test (ISLT) and One Card Learning Test (OCLT), at baseline, 2 and 4 months. Tests’ completion rates were 52–53% at 2 months and 34–42% at 4 months. All baseline correlations between HVLT-R and CogState tests were significant (p B 0.003). At baseline, both CogState tests and one component of HVLT-R differentiated those who were alive at 6 months and those who had died (p B 0.01). At 4 months, mean relative decline was 7.0% for HVLT-R Delayed Recall and 18.0% for ISLT Delayed Recall. OCLT showed an 8.0% increase. A reliable change index found no significant changes from baseline to 2 and 4 months for ISLT Delayed Recall (z =-0.40, p = 0.34; z =-0.68, p = 0.25) or OCLT (z = 0.15, p = 0.56; z = 0.41, p = 0.66). Study findings support the possibility that hippocampal avoidance may be associated with preservation of memory test performance, and that these computerized tests also may be useful and valid memory assessments in multi-institution adult brain tumor trials
Association of pretreatment hippocampal volume with neurocognitive function in patients treated with hippocampal avoidance whole brain radiation therapy for brain metastases: Secondary analysis of NRG Oncology/RTOG 0933
PURPOSE: Hippocampal volume (HV) is an established predicting factor for neurocognitive function (NCF) in neurodegenerative disease. Whether the same phenomenon exists with hippocampal-avoidant whole brain radiation therapy is not known; therefore, we assessed the association of baseline HV with NCF among patients enrolled on RTOG 0933.
METHODS AND MATERIALS: Hippocampal volume and total brain volume were calculated from the radiation therapy plan. Hippocampal volume was correlated with baseline and 4-month NCF scores (Hopkins Verbal Learning Test-Revised [HVLT-R] Total Recall [TR], Immediate Recognition, and Delayed Recall [DR]) using Pearson correlation. Deterioration in NCF was defined per the primary endpoint of RTOG 0933(mean 4-month relative decline in HVLT-R DR). Comparisons between patients with deteriorated and nondeteriorated NCF were made using the Wilcoxon test.
RESULTS: Forty-two patients were evaluable. The median age was 56.5 years (range, 28-83 years), and 81% had a class II recursive partitioning analysis. The median total, right, and left HVs were 5.4 cm
CONCLUSIONS: Larger HV was positively associated with improved performance on baseline and 4-month HVLT-R TR and DR scores in patients with brain metastases undergoing hippocampal-avoidant whole brain radiation therapy but was not associated with a change in NCF
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