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1.
Ann Oncol ; 28(10): 2588-2594, 2017 Oct 01.
Article in English | MEDLINE | ID: mdl-28961826

ABSTRACT

BACKGROUND: The absence of a survival benefit for whole brain radiotherapy (WBRT) among randomized trials has been attributed to a competing risk of death from extracranial disease. We re-analyzed EORTC 22952 to assess the impact of WBRT on survival for patients with controlled extracranial disease or favorable prognoses. PATIENTS AND METHODS: We utilized Cox regression, landmark analysis, and the Kaplan-Meier method to evaluate the impact of WBRT on survival accounting for (i) extracranial progression as a time-dependent covariate in all patients and (ii) diagnosis-specific graded prognostic assessment (GPA) score in patients with primary non-small-cell lung cancer (NSCLC). RESULTS: A total of 329 patients treated per-protocol were included for analysis with a median follow up of 26 months. One hundred and fifteen (35%) patients had no extracranial progression; 70 (21%) patients had progression <90 days, 65 (20%) between 90 and 180 days, and 79 (24%) patients >180 days from randomization. There was no difference in the model-based risk of death in the WBRT group before [hazard ratio (HR) (95% CI)=0.70 (0.45-1.11), P = 0.133), or after [HR (95% CI)=1.20 (0.89-1.61), P = 0.214] extracranial progression. Among 177 patients with NSCLC, 175 had data available for GPA calculation. There was no significant survival benefit to WBRT among NSCLC patients with favorable GPA scores [HR (95% CI)=1.10 (0.68-1.79)] or unfavorable GPA scores [HR (95% CI)=1.11 (0.71-1.76)]. CONCLUSIONS: Among patients with limited extracranial disease and one to three brain metastases at enrollment, we found no significant survival benefit to WBRT among NSCLC patients with favorable GPA scores or patients with any histology and controlled extracranial disease status. This exploratory analysis of phase III data supports the practice of omitting WBRT for patients with limited brain metastases undergoing SRS and close surveillance. CLINICAL TRIALS NUMBER: NCT00002899.


Subject(s)
Brain Neoplasms/secondary , Brain Neoplasms/therapy , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Non-Small-Cell Lung/therapy , Lung Neoplasms/pathology , Lung Neoplasms/therapy , Brain Neoplasms/radiotherapy , Brain Neoplasms/surgery , Carcinoma, Non-Small-Cell Lung/radiotherapy , Carcinoma, Non-Small-Cell Lung/surgery , Female , Humans , Kaplan-Meier Estimate , Lung Neoplasms/radiotherapy , Lung Neoplasms/surgery , Male , Middle Aged , Prognosis , Radiosurgery , Whole-Body Irradiation
2.
Oncogene ; 36(38): 5421-5431, 2017 09 21.
Article in English | MEDLINE | ID: mdl-28534510

ABSTRACT

Malignant peripheral nerve sheath tumors (MPNSTs) are devastating sarcomas for which no effective medical therapies are available. Over 50% of MPSNTs are associated with mutations in NF1 tumor suppressor gene, resulting in activation of Ras and its effectors, including the Raf/Mek/Erk and PI3K/Akt/mTORC1 signaling cascades, and also the WNT/ß-catenin pathway. As Group I p21-activated kinases (Group I Paks, PAK1/2/3) have been shown to modulate Ras-driven oncogenesis, we asked if these enzymes might regulate signaling in MPNSTs. In this study we found a strong positive correlation between the activity of PAK1/2/3 and the stage of human MPNSTs. We determined that reducing Group I Pak activity diminished MPNST cell proliferation and motility, and that these effects were not accompanied by significant blockade of the Raf/Mek/Erk pathway, but rather by reductions in Akt and ß-catenin activity. Using the small molecule PAK1/2/3 inhibitor Frax1036 and the MEK1/2 inhibitor PD0325901, we showed that the combination of these two agents synergistically inhibited MPNST cell growth in vitro and dramatically decreased local and metastatic MPNST growth in animal models. Taken together, these data provide new insights into MPNST signaling deregulation and suggest that co-targeting of PAK1/2/3 and MEK1/2 may be effective in the treatment of patients with MPNSTs.


Subject(s)
Benzamides/pharmacology , Diphenylamine/analogs & derivatives , Nerve Sheath Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacology , p21-Activated Kinases/antagonists & inhibitors , Animals , Cell Line, Tumor , Diphenylamine/pharmacology , Female , Humans , Mice , Mice, SCID , Molecular Targeted Therapy , Neoplasm Metastasis , Nerve Sheath Neoplasms/enzymology , Nerve Sheath Neoplasms/pathology , Random Allocation , Signal Transduction , Xenograft Model Antitumor Assays , p21-Activated Kinases/metabolism
3.
J Behav Med ; 40(4): 574-582, 2017 Aug.
Article in English | MEDLINE | ID: mdl-28155000

ABSTRACT

The study's purpose was to select/refine measures assessing psychosocial constructs associated with skin cancer risk/protective behaviors. Cognitive interviewing was conducted with twenty participants locally, and a survey was conducted with 965 adults aged 18-25 years at moderate to high risk of developing skin cancer, recruited nationally online. Psychosocial measures assessed variables from the Integrative Model of Behavior Prediction. As a result of expert review and cognitive interviewing, items were removed, added, and/or made simpler, more personal, consistent, and less ambiguous. A factor analysis resulted in 14 scales and adequate model fit. Internal reliability and test-retest reliability was acceptable to good. Correlations among the psychosocial and behavioral variables were generally significant and in expected directions, demonstrating convergent validity. We have refined measures that assess important psychosocial constructs associated with skin cancer-related behaviors, that research participants can understand and complete successfully, and that are reliable and demonstrate evidence for validity.


Subject(s)
Health Behavior , Risk-Taking , Skin Neoplasms/psychology , Adolescent , Adult , Female , Humans , Male , Psychometrics , Reproducibility of Results , Risk , Risk Factors , Skin Neoplasms/prevention & control , Surveys and Questionnaires , Young Adult
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