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1.  Effect of the Addition of Chemotherapy to Radiotherapy on Cognitive Function in Patients With Low-Grade Glioma: Secondary Analysis of RTOG 98-02 
Journal of Clinical Oncology  2014;32(6):535-541.
Purpose
The addition of PCV (procarbazine, lomustine, and vincristine) chemotherapy to radiotherapy (RT) for patients with WHO grade 2 glioma improves progression-free survival (PFS). The effect of therapy intensification on cognitive function (CF) remains a concern in this population with substantial long-term survival.
Patients and Methods
A total of 251 patients with WHO grade 2 glioma age ≥ 40 years with any extent of resection or age < 40 years with subtotal resection/biopsy were randomly assigned to RT (54 Gy) or RT plus PCV. We observed 111 patients age < 40 years with gross total resection. CF was assessed by Mini–Mental State Examination (MMSE) at baseline and years 1, 2, 3, and 5.
Results
Overall, few patients experienced significant decline in MMSE score. There were no significant differences in the proportion of patients experiencing MMSE score decline between the randomized study arms at any time point. Both study arms experienced a significant gain in average MMSE score longitudinally over time, with no difference between arms.
Conclusion
The MMSE is a relatively insensitive tool, and subtle changes in CF may have been missed. However, the addition of PCV to RT did not result in significantly higher rates of MMSE score decline than RT alone through 5 years of follow-up. Patients in both randomly assigned arms experienced a statistically significant average MMSE score increase over time, with no difference between arms. The addition of PCV chemotherapy to RT improves PFS without excessive CF detriment over RT alone for patients with low-grade glioma.
doi:10.1200/JCO.2013.53.1830
PMCID: PMC3918537  PMID: 24419119
2.  CHOD/BVAM CHEMOTHERAPY AND WHOLE-BRAIN RADIOTHERAPY FOR NEWLY DIAGNOSED PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA 
Purpose
To assess the efficacy and toxicity of chemotherapy consisting of cyclophosphamide, doxorubicin (Adriamycin), vincristine, and dexamethasone (CHOD) plus bis-chloronitrosourea (BCNU), cytosine arabinoside, and methotrexate (BVAM) followed by whole-brain irradiation (WBRT) for patients with primary central nervous system lymphoma (PCNSL).
Methods and Materials
Patients 70 years old and younger with newly diagnosed, biopsy-proven PCNSL received one cycle of CHOD followed by two cycles of BVAM. Patients then received WBRT, 30.6 Gy, if a complete response was evoked, or 50.4 Gy if the response was less than complete; both doses were given in 1.8-Gy daily fractions. The primary efficacy endpoint was 1-year survival.
Results
Thirty-six patients (19 men, 17 women) enrolled between 1995 and 2000. Median age was 60.5 years (range, 34 to 69 years). Thirty (83%) patients had baseline Eastern Cooperative Oncology Group performance scores of 0 to 1. All 36 patients were eligible for survival and response evaluations. Median time to progression was 12.3 months, and median survival was 18.5 months. The percentages of patients alive at 1, 2, and 3 years were 64%, 36%, and 33%, respectively. The best response was complete response in 10 patients and immediate progression in 7 patients. Ten (28%) patients had at least one grade 3 or higher neurologic toxicity.
Conclusions
This regimen did improve the survival of PCNSL patients but also caused substantial toxicity. The improvement in survival is less than that reported with high-dose methotrexate-based therapies.
doi:10.1016/j.ijrobp.2010.06.002
PMCID: PMC4335722  PMID: 20800387
Primary central nervous system lymphoma; Chemotherapy; Whole-brain radiotherapy
3.  Technique, outcomes, and acute toxicities in adults treated with proton beam craniospinal irradiation 
Neuro-Oncology  2013;16(2):303-309.
Background
Proton craniospinal irradiation (p-CSI) has been proposed to reduce side effects associated with CSI. We evaluated acute toxicities and preliminary clinical outcomes in a series of adults treated with p-CSI.
Methods
We reviewed medical records for 50 patients (aged 16–63 y) with malignancies of varying histologies treated consecutively with vertebral body-sparing p-CSI at MD Anderson Cancer Center from 2007 to 2011. Median CSI and total boost doses were 30.6 and 54 Gy. Forty patients received chemotherapy, varying by histology. Median follow-up was 20.1 months (range, 0.3–59).
Results
Median doses to the thyroid gland, pituitary gland, hypothalamus, and cochleae were 0.003 Gy–relative biological effectiveness (RBE; range, 0.001–8.5), 36.1 Gy-RBE (22.5–53.0), 37.1 Gy-RBE (22.3–54.4), and 33.9 Gy-RBE (22.2–52.4), respectively. Median percent weight loss during CSI was 1.6% (range, 10% weight loss to 14% weight gain). Mild nausea/vomiting was common (grade 1 = 46%, grade 2 = 20%); however, only 5 patients experienced grade ≥2 anorexia (weight loss >5% baseline weight). Median percent baseline white blood cells, hemoglobin, and platelets at nadir were 52% (range, 13%–100%), 97% (65%–112%), and 61% (10%–270%), respectively. Four patients developed grade ≥3 cytopenias. Overall and progression-free survival rates were 96% and 82%, respectively, at 2 years and 84% and 68% at 5 years.
Conclusions
This large series of patients treated with p-CSI confirms low rates of acute toxicity, consistent with dosimetric models. Vertebral body-sparing p-CSI is feasible and should be considered as a way to reduce acute gastrointestinal and hematologic toxicity in adults requiring CSI.
doi:10.1093/neuonc/not155
PMCID: PMC3895378  PMID: 24311638
acute toxicity; craniospinal irradiation; proton therapy.
4.  Synergic interplay of the La motif, RRM1 and the interdomain linker of LARP6 in the recognition of collagen mRNA expands the RNA binding repertoire of the La module 
Nucleic Acids Research  2014;43(1):645-660.
The La-related proteins (LARPs) form a diverse group of RNA-binding proteins characterized by the possession of a composite RNA binding unit, the La module. The La module comprises two domains, the La motif (LaM) and the RRM1, which together recognize and bind to a wide array of RNA substrates. Structural information regarding the La module is at present restricted to the prototypic La protein, which acts as an RNA chaperone binding to 3′ UUUOH sequences of nascent RNA polymerase III transcripts. In contrast, LARP6 is implicated in the regulation of collagen synthesis and interacts with a specific stem-loop within the 5′ UTR of the collagen mRNA. Here, we present the structure of the LaM and RRM1 of human LARP6 uncovering in both cases considerable structural variation in comparison to the equivalent domains in La and revealing an unprecedented fold for the RRM1. A mutagenic study guided by the structures revealed that RNA recognition requires synergy between the LaM and RRM1 as well as the participation of the interdomain linker, probably in realizing tandem domain configurations and dynamics required for substrate selectivity. Our study highlights a considerable complexity and plasticity in the architecture of the La module within LARPs.
doi:10.1093/nar/gku1287
PMCID: PMC4288179  PMID: 25488812
5.  Using a discrete choice experiment to inform the design of programs to promote colon cancer screening for vulnerable populations in North Carolina 
Background
Screening for colorectal cancer (CRC) is suboptimal, particularly for vulnerable populations. Effective intervention programs are needed to increase screening rates. We used a discrete choice experiment (DCE) to learn about how vulnerable individuals in North Carolina value different aspects of CRC screening programs.
Methods
We enrolled English-speaking adults ages 50–75 at average risk of CRC from rural North Carolina communities with low rates of CRC screening, targeting those with public or no insurance and low incomes. Participants received basic information about CRC screening and potential program features, then completed a 16 task DCE and survey questions that examined preferences for four attributes of screening programs: testing options available; travel time required; money paid for screening or rewards for completing screening; and the portion of the cost of follow-up care paid out of pocket. We used Hierarchical Bayesian methods to calculate individual-level utilities for the 4 attributes’ levels and individual-level attribute importance scores. For each individual, the attribute with the highest importance score was considered the most important attribute. Individual utilities were then aggregated to produce mean utilities for each attribute. We also compared DCE-based results with those from direct questions in a post-DCE survey.
Results
We enrolled 150 adults. Mean age was 57.8 (range 50–74); 55% were women; 76% White and 19% African-American; 87% annual household income under $30,000; and 51% were uninsured. Individuals preferred shorter travel; rewards or small copayments compared with large copayments; programs that included stool testing as an option; and greater coverage of follow-up costs. Follow-up cost coverage was most frequently found to be the most important attribute from the DCE (47%); followed by test reward/copayment (33%). From the survey, proportion of follow-up costs paid was most frequently cited as most important (42% of participants), followed by testing options (32%). There was moderate agreement (45%) in attribute importance between the DCE and the single question in the post-DCE survey.
Conclusions
Screening test copayments and follow-up care coverage costs are important program characteristics in this vulnerable, rural population.
Electronic supplementary material
The online version of this article (doi:10.1186/s12913-014-0611-4) contains supplementary material, which is available to authorized users.
doi:10.1186/s12913-014-0611-4
PMCID: PMC4267137  PMID: 25433801
Early detection of cancer; Colorectal neoplasms; Vulnerable populations; Rural population; Choice behavior; Decision making; Economics; Behavioral; Questionnaires; Health policy
6.  Comparative Study of Prions in Iatrogenic and Sporadic Creutzfeldt-Jakob Disease 
Differentiating iatrogenic Creutzfeldt-Jakob disease (iCJD) from sporadic CJD (sCJD) would be useful for the identification and prevention of human-to-human prion transmission. Currently, the diagnosis of iCJD depends on identification of a recognized source of contamination to which patients have been exposed, in addition to fulfilling basic requirements for the establishment of diagnosis of CJD. Attempts to identify differences in clinical manifestations, neuropathological changes and pathological prion protein (PrPSc) between iCJD and sCJD have been unsuccessful. In the present study, using a variety of more sophisticated methods including sucrose step gradient sedimentation, conformational stability immunoassay, protein misfolding cyclic amplification (PMCA), fragment-mapping, and transmission study, we show no significant differences in gel profiles, oligomeric state, conformational stability and infectivity of PrPSc between iCJD and sCJD. However, using PMCA, we find that convertibility and amplification efficiency of PrPSc is greater in iCJD than in sCJD in a polymorphism-dependent manner. Moreover, two protease-resistant PrP C-terminal fragments (termed PrP-CTF12/13) were detected in all 9 cases of sCJD but not in 6 of 8 cases of iCJD tested in this study. The use of fragment mapping- and PMCA-based assays thus provides a means to distinguish most cases of iCJD from sCJD.
doi:10.4172/2155-9899.1000240
PMCID: PMC4240320  PMID: 25419482
Human prion diseases; Iatrogenic Creutzfeldt-Jakob disease; Sporadic CJD
7.  Dose-Dense Temozolomide for Newly Diagnosed Glioblastoma: A Randomized Phase III Clinical Trial 
Journal of Clinical Oncology  2013;31(32):4085-4091.
Purpose
Radiotherapy with concomitant and adjuvant temozolomide is the standard of care for newly diagnosed glioblastoma (GBM). O6-methylguanine-DNA methyltransferase (MGMT) methylation status may be an important determinant of treatment response. Dose-dense (DD) temozolomide results in prolonged depletion of MGMT in blood mononuclear cells and possibly in tumor. This trial tested whether DD temozolomide improves overall survival (OS) or progression-free survival (PFS) in patients with newly diagnosed GBM.
Patients and Methods
This phase III trial enrolled patients older than age 18 years with a Karnofsky performance score of ≥ 60 with adequate tissue. Stratification included clinical factors and tumor MGMT methylation status. Patients were randomly assigned to standard temozolomide (arm 1) or DD temozolomide (arm 2) for 6 to 12 cycles. The primary end point was OS. Secondary analyses evaluated the impact of MGMT status.
Results
A total of 833 patients were randomly assigned to either arm 1 or arm 2 (1,173 registered). No statistically significant difference was observed between arms for median OS (16.6 v 14.9 months, respectively; hazard ratio [HR], 1.03; P = .63) or median PFS (5.5 v 6.7 months; HR, 0.87; P = .06). Efficacy did not differ by methylation status. MGMT methylation was associated with improved OS (21.2 v 14 months; HR, 1.74; P < .001), PFS (8.7 v 5.7 months; HR, 1.63; P < .001), and response (P = .012). There was increased grade ≥ 3 toxicity in arm 2 (34% v 53%; P < .001), mostly lymphopenia and fatigue.
Conclusion
This study did not demonstrate improved efficacy for DD temozolomide for newly diagnosed GBM, regardless of methylation status. However, it did confirm the prognostic significance of MGMT methylation. Feasibility of large-scale accrual, prospective tumor collection, and molecular stratification was demonstrated.
doi:10.1200/JCO.2013.49.6968
PMCID: PMC3816958  PMID: 24101040
8.  New validated prognostic models and prognostic calculators in patients with low-grade gliomas diagnosed by central pathology review: a pooled analysis of EORTC/RTOG/NCCTG phase III clinical trials 
Neuro-Oncology  2013;15(11):1568-1579.
Background
In a previous study, the European Organisation for Research and Treatment of Cancer (EORTC) reported a scoring system to predict survival of patients with low-grade gliomas (LGGs). A major issue in the diagnosis of brain tumors is the lack of agreement among pathologists. New models in patients with LGGs diagnosed by central pathology review are needed.
Methods
Data from 339 EORTC patients with LGGs diagnosed by central pathology review were used to develop new prognostic models for progression-free survival (PFS) and overall survival (OS). Data from 450 patients with centrally diagnosed LGGs recruited into 2 large studies conducted by North American cooperative groups were used to validate the models.
Results
Both PFS and OS were negatively influenced by the presence of baseline neurological deficits, a shorter time since first symptoms (<30 wk), an astrocytic tumor type, and tumors larger than 5 cm in diameter. Early irradiation improved PFS but not OS. Three risk groups have been identified (low, intermediate, and high) and validated.
Conclusions
We have developed new prognostic models in a more homogeneous LGG population diagnosed by central pathology review. This population better fits with modern practice, where patients are enrolled in clinical trials based on central or panel pathology review. We could validate the models in a large, external, and independent dataset. The models can divide LGG patients into 3 risk groups and provide reliable individual survival predictions. Inclusion of other clinical and molecular factors might still improve models’ predictions.
doi:10.1093/neuonc/not117
PMCID: PMC3813419  PMID: 24049111
low-grade glioma; predictive accuracy; prognostic factors
9.  Visualized effect of oxidation on magnetic recording fidelity in pseudo-single-domain magnetite particles 
Nature Communications  2014;5:5154.
Magnetite (Fe3O4) is an important magnetic mineral to Earth scientists, as it carries the dominant magnetic signature in rocks, and the understanding of its magnetic recording fidelity provides a critical tool in the field of palaeomagnetism. However, reliable interpretation of the recording fidelity of Fe3O4 particles is greatly diminished over time by progressive oxidation to less magnetic iron oxides, such as maghemite (γ-Fe2O3), with consequent alteration of remanent magnetization potentially having important geological significance. Here we use the complementary techniques of environmental transmission electron microscopy and off-axis electron holography to induce and visualize the effects of oxidation on the magnetization of individual nanoscale Fe3O4 particles as they transform towards γ-Fe2O3. Magnetic induction maps demonstrate a change in both strength and direction of remanent magnetization within Fe3O4 particles in the size range dominant in rocks, confirming that oxidation can modify the original stored magnetic information.
Magnetite provides a valuable record of the Earth's geomagnetic history. Here, Almeida et al. combine electron microscopy and energy-loss spectroscopy to study the effects of in situ oxidation on the magnetization fidelity and crystalline phase of pseudo-single domain magnetite grains.
doi:10.1038/ncomms6154
PMCID: PMC4214405  PMID: 25300366
10.  A Randomized Trial of Bevacizumab for Newly Diagnosed Glioblastoma 
The New England journal of medicine  2014;370(8):699-708.
BACKGROUND
Concurrent treatment with temozolomide and radiotherapy followed by maintenance temozolomide is the standard of care for patients with newly diagnosed glioblastoma. Bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor A, is currently approved for recurrent glioblastoma. Whether the addition of bevacizumab would improve survival among patients with newly diagnosed glioblastoma is not known.
METHODS
In this randomized, double-blind, placebo-controlled trial, we treated adults who had centrally confirmed glioblastoma with radiotherapy (60 Gy) and daily temozolomide. Treatment with bevacizumab or placebo began during week 4 of radiotherapy and was continued for up to 12 cycles of maintenance chemotherapy. At disease progression, the assigned treatment was revealed, and bevacizumab therapy could be initiated or continued. The trial was designed to detect a 25% reduction in the risk of death and a 30% reduction in the risk of progression or death, the two coprimary end points, with the addition of bevacizumab.
RESULTS
A total of 978 patients were registered, and 637 underwent randomization. There was no significant difference in the duration of overall survival between the bevacizumab group and the placebo group (median, 15.7 and 16.1 months, respectively; hazard ratio for death in the bevacizumab group, 1.13). Progression-free survival was longer in the bevacizumab group (10.7 months vs. 7.3 months; hazard ratio for progression or death, 0.79). There were modest increases in rates of hypertension, thromboembolic events, intestinal perforation, and neutropenia in the bevacizumab group. Over time, an increased symptom burden, a worse quality of life, and a decline in neurocognitive function were more frequent in the bevacizumab group.
CONCLUSIONS
First-line use of bevacizumab did not improve overall survival in patients with newly diagnosed glioblastoma. Progression-free survival was prolonged but did not reach the prespecified improvement target.
doi:10.1056/NEJMoa1308573
PMCID: PMC4201043  PMID: 24552317
11.  Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trial 
Neuro-Oncology  2013;15(10):1429-1437.
Background
To determine the protective effects of memantine on cognitive function in patients receiving whole-brain radiotherapy (WBRT).
Methods
Adult patients with brain metastases received WBRT and were randomized to receive placebo or memantine (20 mg/d), within 3 days of initiating radiotherapy for 24 weeks. Serial standardized tests of cognitive function were performed.
Results
Of 554 patients who were accrued, 508 were eligible. Grade 3 or 4 toxicities and study compliance were similar in the 2 arms. There was less decline in delayed recall in the memantine arm at 24 weeks (P = .059), but the difference was not statistically significant, possibly because there were only 149 analyzable patients at 24 weeks, resulting in only 35% statistical power. The memantine arm had significantly longer time to cognitive decline (hazard ratio 0.78, 95% confidence interval 0.62–0.99, P = .01); the probability of cognitive function failure at 24 weeks was 53.8% in the memantine arm and 64.9% in the placebo arm. Superior results were seen in the memantine arm for executive function at 8 (P = .008) and 16 weeks (P = .0041) and for processing speed (P = .0137) and delayed recognition (P = .0149) at 24 weeks.
Conclusions
Memantine was well tolerated and had a toxicity profile very similar to placebo. Although there was less decline in the primary endpoint of delayed recall at 24 weeks, this lacked statistical significance possibly due to significant patient loss. Overall, patients treated with memantine had better cognitive function over time; specifically, memantine delayed time to cognitive decline and reduced the rate of decline in memory, executive function, and processing speed in patients receiving WBRT.
RTOG 0614, ClinicalTrials.gov number CT00566852.
doi:10.1093/neuonc/not114
PMCID: PMC3779047  PMID: 23956241
radiotherapy; brain metastases; cognition; memantine; neuroprotective agents
12.  Leptospirosis and malaria as causes of febrile illness during a dengue epidemic in Jamaica 
Pathogens and Global Health  2013;107(6):329-334.
Background:
Epidemics of febrile illnesses are often associated with rainy seasons in the tropics. During 2007–2008 an epidemic of dengue was identified in Jamaica based on serological testing of sera.
Methods:
A subset of 3165 of 5400 sera submitted for dengue analysis was tested for Leptospira IgM and malaria IgG using ELISA to determine their role in causing epidemic fever.
Findings:
Seropositivity for dengue, leptospirosis, and malaria were 38.4 and 6.0 and 6.5%, respectively, indicative of three concurrent epidemics. Mixed exposure to all three diseases was rare (0.1%), as were mixed dengue/malaria (2.4%); dengue/leptospirosis (1.6%), and leptospirosis/malaria (0.03%) exposure. Exposure to dengue and malaria appeared to occur most frequently among children while leptospirosis was more common among adults.
Conclusion:
While serological diagnosis definitively established that dengue was the main cause of the epidemic febrile illness, the data suggested that there may be other causes of fever, which may occur simultaneously. Consequently, leptospirosis and malaria should be considered as causes of fever during epidemics of dengue in endemic areas.
doi:10.1179/2047773213Y.0000000112
PMCID: PMC4001614  PMID: 24188242
Epidemic; Seropositive; Febrile illness; Diagnosis; Geographic distribution
13.  Changes in presentation, treatment, and outcomes of adult low-grade gliomas over the past fifty years 
Neuro-Oncology  2013;15(8):1102-1110.
Background
To identify changes in patient presentation, treatment, and outcomes of low-grade gliomas (LGGs) over the past 50 years.
Methods
Records of 852 adults who received a diagnosis at Mayo Clinic from 1960 through 2011 with World Health Organization grade II LGGs were reviewed and grouped by those who received a diagnosis before (group I: 1960–1989) and after (group II: 1990–2011) the routine use of postoperative MRI.
Results
Median follow-up was 23.3 and 8.7 years for groups I and II, respectively. Patients in group I more often presented with seizures, headaches, sensory/motor impairment, and astrocytoma histology. Over time, more gross total resections (GTRs) were achieved, fewer patients received postoperative radiotherapy (PORT), and more received chemotherapy.
Median progression-free survival (PFS) and overall survival (OS) were 4.4 and 8.0 years, respectively. Although PFS was similar, 10-year OS was better in group II (47%) than in group I (33%; P < .0001). Improved PFS in multivariate analysis was associated with group I patients, nonastrocytoma histology, small tumor size, successful GTR, or radical subtotal resection (rSTR), PORT, and postoperative chemotherapy. Factors associated with improved OS in multivariate analysis were younger age, nonastrocytoma histology, small tumor size, and GTR/rSTR.
Conclusions
OS for LGG has improved over the past 50 years, despite similar rates of progression. In the modern cohort, more patients are receiving a diagnosis of oligodendroglioma and are undergoing extensive resections, both of which are associated with improvements in OS. Because of risk factor stratification by clinicians, the use of PORT has decreased and is primarily being used to treat high-risk tumors in modern patients.
doi:10.1093/neuonc/not080
PMCID: PMC3714159  PMID: 23814262
central nervous system tumors; external-beam radiotherapy; low-grade glioma; neurosurgery; oligodendroglioma
14.  Molecular Comparisons of Full Length Metapneumovirus (MPV) Genomes, Including Newly Determined French AMPV-C and –D Isolates, Further Supports Possible Subclassification within the MPV Genus 
PLoS ONE  2014;9(7):e102740.
Four avian metapneumovirus (AMPV) subgroups (A–D) have been reported previously based on genetic and antigenic differences. However, until now full length sequences of the only known isolates of European subgroup C and subgroup D viruses (duck and turkey origin, respectively) have been unavailable. These full length sequences were determined and compared with other full length AMPV and human metapneumoviruses (HMPV) sequences reported previously, using phylogenetics, comparisons of nucleic and amino acid sequences and study of codon usage bias. Results confirmed that subgroup C viruses were more closely related to HMPV than they were to the other AMPV subgroups in the study. This was consistent with previous findings using partial genome sequences. Closer relationships between AMPV-A, B and D were also evident throughout the majority of results. Three metapneumovirus “clusters” HMPV, AMPV-C and AMPV-A, B and D were further supported by codon bias and phylogenetics. The data presented here together with those of previous studies describing antigenic relationships also between AMPV-A, B and D and between AMPV-C and HMPV may call for a subclassification of metapneumoviruses similar to that used for avian paramyxoviruses, grouping AMPV-A, B and D as type I metapneumoviruses and AMPV-C and HMPV as type II.
doi:10.1371/journal.pone.0102740
PMCID: PMC4103871  PMID: 25036224
15.  Proton Beam Craniospinal Irradiation Reduces Acute Toxicity for Adults with Medulloblastoma 
PURPOSE
Efficacy and acute toxicity of proton craniospinal irradiation (p-CSI) were compared with conventional photon CSI (x-CSI) for adults with medulloblastoma.
METHODS AND MATERIALS
Forty adult medulloblastoma patients treated with x-CSI (n=21) or p-CSI (n=19) at XXXXX from 2003–2011 were retrospectively reviewed. Median CSI and total doses were 30.6 and 54 Gy, respectively. The median follow-up was 57 months (range 4–103) for x-CSI patients and 26 months (range 11–63) for p-CSI.
RESULTS
p-CSI patients lost less weight than x-CSI patients (1.2%, versus 5.8%; p=0.004), and less p-CSI patients had greater than 5% weight loss compared to x-CSI (16% versus 64%; p=0.004). p-CSI patients experienced less grade 2 nausea and vomiting compared to x-CSI (26% versus 71%; p=0.004). Patients treated with x-CSI were more likely to have medical management of esophagitis than p-CSI patients (57% vs 5%, p=<0.001).
p-CSI patients had a smaller reduction in peripheral white blood cells (WBC), hemoglobin and platelets compared to x-CSI (WBC 46% versus 55%, p=0.04; hemoglobin 88% versus 97%, p=0.009; platelets 48% versus 65%, p=0.05). Mean vertebral doses were significantly associated with reductions in blood counts.
CONCLUSIONS
This report is the first analysis of clinical outcomes for adult medulloblastoma patients treated with p-CSI. Patients treated with p-CSI experienced less treatment-related morbidity including less acute gastrointestinal and hematologic toxicities.
doi:10.1016/j.ijrobp.2013.01.014
PMCID: PMC3954470  PMID: 23433794
16.  Treatment, prognostic factors, and outcomes in spinal cord astrocytomas 
Neuro-Oncology  2013;15(4):406-412.
Background
Spinal astrocytomas are rare intramedullary CNS tumors for which there is limited consensus on treatment; the importance of the extent of resection (EOR), postoperative radiotherapy, and chemotherapy remains poorly understood. We report on outcomes associated with surgery, postoperative radiotherapy, and chemotherapy in a series of patients treated at M. D. Anderson Cancer Center (MDACC) with the aim of elucidating the role of these treatments in spinal astrocytomas.
Methods
We retrospectively reviewed charts from a series of 83 patients with histologically confirmed spinal astrocytoma treated at MDACC during 1990–2011. Data collected included patient demographic characteristics, prognostic indicators, and treatment modality at diagnosis. We analyzed overall survival (OS) and progression-free survival (PFS) for pilocytic (World Health Organization [WHO] grade I) and infiltrative (WHO grades II, III, and IV) astrocytomas, separately. Multivariate analysis was performed for the infiltrative patients but not the pilocytic patients because of a limited number of cases.
Results
Higher WHO grade among all patients was associated with worse OS (P < .0001) and PFS (P = .0003). Among patients with infiltrative tumors, neither EOR nor radiotherapy was associated with a difference in outcomes in multivariate analysis; however, among patients with infiltrative astrocytomas, chemotherapy was significantly associated with improved PFS (hazard ratio = .22, P = .0075) but not OS (hazard ratio = .89, P = .83) in multivariate analysis.
Conclusion
WHO grade was the strongest prognostic indicator in patients with spinal cord astrocytomas. Our results also show that chemotherapy improved PFS in infiltrative astrocytomas in multivariate analysis, but neither EOR nor radiation therapy influenced outcomes in this group.
doi:10.1093/neuonc/nos309
PMCID: PMC3607259  PMID: 23322747
chemotherapy; glioma; intramedullary; management prognosis
17.  CDER Risk Assessment Exercise to Evaluate Potential Risks from the Use of Nanomaterials in Drug Products 
The AAPS Journal  2013;15(3):623-628.
The Nanotechnology Risk Assessment Working Group in the Center for Drug Evaluation and Research (CDER) within the United States Food and Drug Administration was established to assess the possible impact of nanotechnology on drug products. The group is in the process of performing risk assessment and management exercises. The task of the working group is to identify areas where CDER may need to optimize its review practices and to develop standards to ensure review consistency for drug applications that may involve the application of nanotechnology. The working group already performed risk management exercises evaluating the potential risks from administering nanomaterial active pharmaceutical ingredients (API) or nanomaterial excipients by various routes of administration. This publication outlines the risk assessment and management process used by the working group, using nanomaterial API by the oral route of administration as an example.
doi:10.1208/s12248-013-9466-6
PMCID: PMC3691428  PMID: 23512727
CDER; nanomaterial; nanotechnology; risk assessment; risk management
18.  Phase II Trial of Erlotinib Plus Concurrent Whole-Brain Radiation Therapy for Patients With Brain Metastases From Non–Small-Cell Lung Cancer 
Journal of Clinical Oncology  2013;31(7):895-902.
Purpose
Brain metastasis (BM) is a leading cause of death from non–small-cell lung cancer (NSCLC). Reasoning that activation of the epidermal growth factor receptor (EGFR) contributes to radiation resistance, we undertook a phase II trial of the EGFR inhibitor erlotinib with whole-brain radiation therapy (WBRT) in an attempt to extend survival time for patients with BM from NSCLC. Additional end points were radiologic response and safety.
Patients and Methods
Eligible patients had BM from NSCLC, regardless of EGFR status. Erlotinib was given at 150 mg orally once per day for 1 week, then concurrently with WBRT (2.5 Gy per day 5 days per week, to 35 Gy), followed by maintenance. EGFR mutation status was tested by DNA sequencing at an accredited core facility.
Results
Forty patients were enrolled and completed erlotinib plus WBRT (median age, 59 years; median diagnosis-specific graded prognostic assessment score, 1.5). The overall response rate was 86% (n = 36). No increase in neurotoxicity was detected, and no patient experienced grade ≥ 4 toxicity, but three patients required dose reduction for grade 3 rash. At a median follow-up of 28.5 months (for living patients), median survival time was 11.8 months (95% CI, 7.4 to 19.1 months). Of 17 patients with known EGFR status, median survival time was 9.3 months for those with wild-type EGFR and 19.1 months for those with EGFR mutations.
Conclusion
Erlotinib was well tolerated in combination with WBRT, with a favorable objective response rate. The higher-than-expected rate of EGFR mutations in these unselected patients raises the possibility that EGFR-mutated tumors are prone to brain dissemination.
doi:10.1200/JCO.2011.40.1174
PMCID: PMC3577951  PMID: 23341526
19.  Validation of Recursive Partitioning Analysis and Diagnosis-Specific Graded Prognostic Assessment in patients treated initially with radiosurgery alone 
Journal of neurosurgery  2012;117(0):38-44.
Object
Brain metastases present a therapeutic challenge because patients with metastatic cancers live longer now than in the recent past due to systemic therapies that, while effective, may not penetrate the blood-brain barrier. In the present study the authors sought to validate the Diagnosis-Specific Graded Prognostic Assessment (DS-GPA), a new prognostic index that takes into account the histological characteristics of the primary tumor, and the Radiation Therapy Ontology Group Recursive Partitioning Analysis (RPA) system by using a single-institution database of patients who were treated initially with stereotactic radiosurgery (SRS) alone for brain metastases.
Methods
Investigators retrospectively identified adult patients who had undergone SRS at a single institution, MD Anderson Cancer Center, for initial treatment of brain metastases between 2003 and 2010 but excluded those who had undergone craniotomy and/or whole-brain radiation therapy at an earlier time; the final number was 251. The Leksell Gamma Knife was used to treat 223 patients, and a linear accelerator was used to treat 28 patients. The patient population was grouped according to DS-GPA scores as follows: 0–0.5 (7 patients), 1 (33 patients), 1.5 (25 patients), 2 (63 patients), 2.5 (14 patients), 3 (68 patients), and 3.5–4 (41 patients). The same patients were also grouped according to RPA classes: 1 (24 patients), 2 (216 patients), and 3 (11 patients). The most common histological diagnoses were non–small cell lung cancer (34%), melanoma (29%), and breast carcinoma (16%). The median number of lesions was 2 (range 1–9) and the median total tumor volume was 0.9 cm3 (range 0.3–22.9 cm3). The median radiation dose was 20 Gy (range 14–24 Gy). Stereotactic radiosurgery was performed as the sole treatment (62% of patients) or combined with a salvage treatment consisting of SRS (22%), whole-brain radiation therapy (12%), or resection (4%). The median duration of follow-up was 9.4 months.
Results
In this patient group the median overall survival was 11.1 months. The DS-GPA prognostic index divided patients into prognostically significant groups. Median survival times were 2.8 months for DS-GPA Scores 0–0.5, 3.9 months for Score 1, 6.6 months for Score 1.5, 12.9 months for Score 2, 11.9 months for Score 2.5, 12.2 months for Score 3, and 31.4 months for Scores 3.5–4 (p < 0.0001). In the RPA groups, the median overall survival times were 38.8 months for Class 1, 9.4 months for Class 2, and 2.8 months for Class 3 (p < 0.0001). Neither the RPA class nor the DS-GPA score was prognostic for local tumor control or new lesion–free survival. A multivariate analysis revealed that patient age > 60 years, Karnofsky Performance Scale score ≤ 80%, and total lesion volume > 2 cm3 were significant adverse prognostic factors for overall survival.
Conclusions
Application of the DS-GPA to a database of patients with brain metastases who were treated with SRS appears to be valid and offers additional prognostic refinement over that provided by the RPA. The DS-GPA may also allow for improved selection of patients to undergo initial SRS alone and should be studied further.
doi:10.3171/2012.3.GKS1289
PMCID: PMC3910154  PMID: 23205787
stereotactic radiosurgery; Gamma Knife surgery; brain metastasis; prognostic factor; Diagnosis-Specific Graded Prognostic Assessment; Recursive Partitioning Analysis
20.  Safety and Tolerability of SBRT after High-Dose External Beam Radiation to the Lung 
Frontiers in Oncology  2015;4:376.
Purpose: Stereotactic body radiotherapy (SBRT) is commonly used to treat unresectable lung nodules. Given its relative safety and effective local control, SBRT has also been used to treat recurrent lung nodules after high-dose external beam radiation (EBRT) to the lung. The toxicity of such treatment is unknown.
Methods and Materials: Between 2006 and 2012, 18 subjects at the Mayo Clinic with 27 recurrent lung nodules were treated with SBRT after receiving EBRT to the lung. Median local control, overall survival, and progression-free survival (PFS) were described. Acute toxicity and late toxicity (defined as toxicity ≥ and >90 days, respectively) were reported and graded as per standardized CTCAE 4.0 criteria.
Results: The median age of patients treated was 68 years. Fifteen patients had recurrent lung cancer as their primary histology. Twelve patients received ≥60 Gy of conventional EBRT prior to SBRT. SBRT dose and fractionation varied; the most common prescriptions were 48 Gy/4, 54 Gy/3, and 50 Gy/5 fractions. Only four patients had SBRT planning target volumes (PTVs) that overlapped more than 50% of their prior EBRT PTV. Two patients developed local recurrence following SBRT. With a median follow up of 21.2 months, median SBRT-specific overall survival and PFS were 21.7 and 12.3 months, respectively. No grade ≥3 acute or late toxicities were noted.
Conclusion: Stereotactic body radiotherapy may be a good salvage option for select patients with recurrent lung nodules following definitive EBRT to the chest. Toxicity is minimal and local control is excellent.
doi:10.3389/fonc.2014.00376
PMCID: PMC4294121  PMID: 25642416
stereotactic body radiotherapy; reirradiation; external beam radiotherapy; lung cancer; toxicity tests; acute; late toxicity
21.  Recurrence following neurosurgeon-determined gross-total resection of adult supratentorial low-grade glioma: results of a prospective clinical trial 
Journal of neurosurgery  2008;109(5):10.3171/JNS/2008/109/11/0835.
Object
In 1998, the Radiation Therapy Oncology Group initiated a Phase II study of observation for adults < 40 years old with cerebral low-grade glioma who underwent a neurosurgeon-determined gross-total resection (GTR).
Methods
Patient eligibility criteria included the presence of a World Health Organization Grade II astrocytoma, oligodendroglioma, or mixed oligoastrocytoma confirmed histologically; age 18–39 years; Karnofsky Performance Scale score ≥ 60; Neurologic Function Scale score ≤ 3; supratentorial tumor location; neurosurgeon-determined GTR; and pre- and postoperative MR imaging with contrast enhancement available for central review by the principal investigator. Patients were observed following GTR and underwent MR imaging every 6 months. Prognostic factors analyzed for their contribution to patient overall survival, progression-free survival (PFS), and tumor recurrence included age, sex, Karnofsky Performance Scale score, Neurologic Function Scale score, histological type, contrast enhancement on preoperative MR imaging, preoperative tumor diameter, residual disease based on postoperative MR imaging, and baseline Mini-Mental State Examination score.
Results
Between 1998 and 2002, 111 eligible patients were entered into the study. In these 111 patients, the overall survival rates at 2 and 5 years were 99 and 93%, respectively. The PFS rates in these 111 patients at 2 and 5 years were 82 and 48%, respectively. Three prognostic factors predicted significantly poorer PFS in univariate and multivariate analyses: 1) preoperative tumor diameter ≥ 4 cm; 2) astrocytoma/oligoastrocytoma histological type; and 3) residual tumor ≥ 1 cm according to MR imaging. Review of the postoperative MR imaging results revealed that 59% of patients had < 1 cm residual disease (with a subsequent 26% recurrence rate), 32% had 1–2 cm residual disease (with a subsequent 68% recurrence rate), and 9% had > 2 cm residual disease (with a subsequent 89% recurrence rate).
Conclusions
These data suggest that young adult patients with low-grade glioma who undergo a neurosurgeon-determined GTR have a > 50% risk of tumor progression 5-years postoperatively, warranting close follow-up and consideration for adjuvant treatment.
doi:10.3171/JNS/2008/109/11/0835
PMCID: PMC3833272  PMID: 18976072
gross-total resection; low-grade glioma; progression-free survival; surgery
22.  Phase I/II Trial of Single Session Stereotactic Body Radiotherapy for Previously Un-irradiated Spinal Metastases 
Cancer  2012;118(20):5069-5077.
Background
This Phase I/II study tests the hypothesis that single-fraction SBRT for previously un-irradiated spinal metastases is a safe, feasible, and efficacious treatment approach.
Methods
All patients were evaluated by a multidisciplinary team. Spinal MRI was performed before treatment and at regular intervals to both define target volume and response to treatment. SBRT was delivered to a peripheral dose of 16–24 Gy in 1 fraction while limiting dose to the spinal cord. Higher doses were used for renal cell histology. The NCI Common Toxicity Criteria 2.0 and McCormick neurological function score were used as toxicity assessment tools.
Results
A total of 61 patients harboring 63 tumors of the non-cervical spine were enrolled and treated with SBRT between 2005 and 2010 on a prospective Phase I/II trial at the University of Texas M. D. Anderson Cancer Center. Mean follow-up was 20 months. Actuarial 18-month imaging local control for all patients was 88%. Actuarial 18-month overall survival for all patients was 64%. Median survival for all patients was 30 months. No significant differences in outcomes were noted with respect to tumor histology and SBRT dose. Two patients experienced radiation adverse events (Grade 3 or higher). Actuarial 18-month freedom from neurologic deterioration from any cause as was 82%.
Conclusions
This Phase I/II data support an expanded indication for SBRT as first-line treatment of selected spinal metastases patients. Additional studies that can prospectively identify predictive factors for spinal cord toxicity after SBRT are warranted to minimize the incidence of this serious yet rare complication.
doi:10.1002/cncr.27530
PMCID: PMC3635840  PMID: 22511344
radiation; stereotactic body radiotherapy; radiosurgery; spinal metastases
23.  Randomized Trial of Radiation Therapy Plus Procarbazine, Lomustine, and Vincristine Chemotherapy for Supratentorial Adult Low-Grade Glioma: Initial Results of RTOG 9802 
Journal of Clinical Oncology  2012;30(25):3065-3070.
Purpose
A prior Radiation Therapy Oncology Group (RTOG) clinical trial in anaplastic oligodendroglioma suggested a progression-free survival benefit for procarbazine, lomustine, and vincristine (PCV) chemotherapy in addition to radiation therapy (RT), as have smaller trials in low-grade glioma (LGG).
Patients and Methods
Eligibility criteria included supratentorial WHO grade 2 LGG, age 18 to 39 years with subtotal resection/biopsy, or age ≥ 40 years with any extent resection. Patients were randomly assigned to RT alone or RT followed by six cycles of PCV. Survival was compared by using the modified Wilcoxon and log-rank tests.
Results
In all, 251 patients were accrued from 1998 to 2002. Median overall survival (OS) time and 5-year OS rates for RT versus RT + PCV were 7.5 years versus not reached and 63% versus 72%, respectively (hazard ratio [HR]; 0.72; 95% CI, 0.47 to 1.10; P = .33; log-rank P = .13). Median progression-free survival (PFS) time and 5-year PFS rates for RT versus RT + PCV were 4.4 years versus not reached and 46% versus 63%, respectively (HR, 0.6; 95% CI, 0.41 to 0.86; P = .06; log-rank P = .005). OS and PFS were similar for all patients between years 0 and 2. After 2 years, OS and PFS curves separated significantly, favoring RT + PCV. For 2-year survivors (n = 211), the probability of OS for an additional 5 years was 74% with RT + PCV versus 59% with RT alone (HR, 0.52; 95% CI, 0.30 to 0.90; log-rank P = .02).
Conclusion
PFS but not OS was improved for adult patients with LGG receiving RT + PCV versus RT alone. On post hoc analysis, for 2-year survivors, the addition of PCV to RT conferred a survival advantage, suggesting a delayed benefit for chemotherapy.
doi:10.1200/JCO.2011.35.8598
PMCID: PMC3732006  PMID: 22851558
24.  Evaluation of the Zoonotic Potential of Transmissible Mink Encephalopathy 
Pathogens  2013;2(3):520-532.
Successful transmission of Transmissible Mink Encephalopathy (TME) to cattle supports the bovine hypothesis for the still controversial origin of TME outbreaks. Human and primate susceptibility to classical Bovine Spongiform Encephalopathy (c-BSE) and the transmissibility of L-type BSE to macaques indicate a low cattle-to-primate species barrier. We therefore evaluated the zoonotic potential of cattle-adapted TME. In less than two years, this strain induced in cynomolgus macaques a neurological disease similar to L-BSE but distinct from c-BSE. TME derived from another donor species (raccoon) induced a similar disease with even shorter incubation periods. L-BSE and cattle-adapted TME were also transmissible to transgenic mice expressing human prion protein (PrP). Secondary transmissions to transgenic mice expressing bovine PrP maintained the features of the three tested bovine strains (cattle TME, c-BSE and L-BSE) regardless of intermediate host. Thus, TME is the third animal prion strain transmissible to both macaques and humanized transgenic mice, suggesting zoonotic potentials that should be considered in the risk analysis of animal prion diseases for human health. Moreover, the similarities between TME and L-BSE are highly suggestive of a link between these strains, and therefore the possible presence of L-BSE for many decades prior to its identification in USA and Europe.
doi:10.3390/pathogens2030520
PMCID: PMC4235697  PMID: 25437205
primate; prion; transgenic mice; TME; cattle; raccoon; zoonotic potential
25.  Adverse Clinical Events During Intrahospital Transport by a Specialized Team: A Preliminary Report 
Background
Caring for patients during intrahospital transport is a high-risk activity. Few data exist on the use of specialized transport teams similar to the teams used for out-of-hospital transport.
Objective
To describe the experience with a dedicated, intrahospital transport program, to report the rate of clinically significant adverse events, and to examine types of adverse events, interventions provided, and outcomes.
Methods
Patient transports within an academic quaternary-care hospital from November 2007 through April 2008 were retrospectively reviewed. Adverse events were defined as extubation, code team activation, death, sustained arrhythmia, hypoxia exceeding 5 minutes, hypotension exceeding 20% of baseline systolic or diastolic blood pressure and requiring intervention, use of physical restraints, or acute change in mental status.
Results
A total of 3383 charts were reviewed (91.8% of all completed transports).The overall rate of adverse events was 1.7% (59 events). Most events were related to hypoxia (25/59) and blood pressure changes (25/59). One extubation and one code team activation occurred. Most interventions involved adjustments to oxygen therapy (22/59) and vasopressor management (18/59). Only 12 (20.3%) of the transports with adverse events were aborted, more often during magnetic resonance imaging (χ2 = 6.86, df= 1, P= .01) and in older patients (mean [SD], 70.8 [14.2] vs 58.7 [14.9] years; P = .02).
Conclusions
The rate of clinically significant adverse events during patient transport by a specialized team is relatively low. Further studies are needed to compare effectiveness and mortality benefits between intrahospital transport teams and traditional transport teams.
doi:10.4037/ajcc2011478
PMCID: PMC3715047  PMID: 21362719

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