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1.  Transmission of scrapie prions to primate after an extended silent incubation period 
Scientific Reports  2015;5:11573.
Classical bovine spongiform encephalopathy (c-BSE) is the only animal prion disease reputed to be zoonotic, causing variant Creutzfeldt-Jakob disease (vCJD) in humans and having guided protective measures for animal and human health against animal prion diseases. Recently, partial transmissions to humanized mice showed that the zoonotic potential of scrapie might be similar to c-BSE. We here report the direct transmission of a natural classical scrapie isolate to cynomolgus macaque, a highly relevant model for human prion diseases, after a 10-year silent incubation period, with features similar to those reported for human cases of sporadic CJD. Scrapie is thus actually transmissible to primates with incubation periods compatible with their life expectancy, although fourfold longer than BSE. Long-term experimental transmission studies are necessary to better assess the zoonotic potential of other prion diseases with high prevalence, notably Chronic Wasting Disease of deer and elk and atypical/Nor98 scrapie.
doi:10.1038/srep11573
PMCID: PMC4485159  PMID: 26123044
2.  CD36/SR-B2-TLR2 Dependent Pathways Enhance Porphyromonas gingivalis Mediated Atherosclerosis in the Ldlr KO Mouse Model 
PLoS ONE  2015;10(5):e0125126.
There is strong epidemiological association between periodontal disease and cardiovascular disease but underlying mechanisms remain ill-defined. Because the human periodontal disease pathogen, Porphyromonas gingivalis (Pg), interacts with innate immune receptors Toll-like Receptor (TLR) 2 and CD36/scavenger receptor-B2 (SR-B2), we studied how CD36/SR-B2 and TLR pathways promote Pg-mediated atherosclerosis. Western diet fed low density lipoprotein receptor knockout (Ldlr°) mice infected orally with Pg had a significant increase in lesion burden compared with uninfected controls. This increase was entirely CD36/SR-B2-dependent, as there was no significant change in lesion burden between infected and uninfected Ldlr° mice. Western diet feeding promoted enhanced CD36/SR-B2-dependent IL1β generation and foam cell formation as a result of Pg lipopolysaccharide (PgLPS) exposure. CD36/SR-B2 and TLR2 were necessary for inflammasome activation and optimal IL1ß generation, but also resulted in LPS induced lethality (pyroptosis). Modified forms of LDL inhibited Pg-mediated IL1ß generation in a CD36/SR-B2-dependent manner and prevented pyroptosis, but promoted foam cell formation. Our data show that Pg infection in the oral cavity can lead to significant TLR2-CD36/SR-B2 dependent IL1ß release. In the vessel wall, macrophages encountering systemic release of IL1ß, PgLPS and modified LDL have increased lipid uptake, foam cell formation, and release of IL1ß, but because pyroptosis is inhibited, this enables macrophage survival and promotes increased plaque development. These studies may explain increased lesion burden as a result of periodontal disease, and suggest strategies for development of therapeutics.
doi:10.1371/journal.pone.0125126
PMCID: PMC4418723  PMID: 25938460
3.  Randomized Controlled Trial of Maintaining Quality of Life During Radiation Therapy for Advanced Cancer 
Cancer  2012;119(4):880-887.
BACKGROUND
Often psychosocial interventions address only one domain of quality of life (QOL), are offered to early stage cancer patients, do not include the caregiver, and are delivered after cancer treatment has been completed.
METHODS
In this randomized controlled trial, 131 radiation therapy patients with advanced cancer and their caregivers were randomly assigned to either a six-session structured multidisciplinary intervention arm or a standard care arm. Average age of the patients was 58 years, most were male (63%), and tumor types varied: gastrointestinal (37%), brain (22%), head and neck (16%), lung (13%), and other (12%). The six 90-minute sessions addressed the five domains of QOL: cognitive, physical, emotional, social, and spiritual. The in-person intervention was followed by ten brief telephone counseling sessions over the next six months.
RESULTS
Of the 117 study completers, overall QOL (assessed by FACT-G) at week 4 was significantly higher (75.2) in the intervention group (n = 54) compared with the standard arm (n = 63) control group (68.7; p=0.02). The ten brief telephone contacts did not impact QOL as at week 27 the groups had identical QOL (means of 77.6 and 77.7). There was no effect of the intervention on caregiver QOL.
CONCLUSIONS
Participating in a six-session multidisciplinary intervention was effective in maintaining the QOL of patients with advanced cancer who were actively receiving radiation therapy. The QOL and symptom burden of this population is striking, making it important to identify effective QOL strategies to implement in conjunction with cancer care.
doi:10.1002/cncr.27776
PMCID: PMC4405146  PMID: 22930253
Quality of Life; Radiation Therapy; Caregivers; Support Groups; Advanced Cancer
4.  Cancer Caregiver Fatigue: A High Level of Symptom Burden 
Fatigue is the problematic symptom identified by cancer patients. However, fatigue has not been widely examined for caregivers of cancer patients. In this project, 131 caregivers of patients diagnosed with advanced stage cancer and actively receiving radiotherapy reported experiencing the most difficulties with fatigue (mean 46.9; on a 0 to 100 scale, with a 10-point difference having clinical meaning) at baseline and at a six-month follow-up (mean 48.3). This is in sharp contrast to other domains of quality of life and functioning being rated in the 60s, 70s and 80s by the cancer caregivers. Given the level of fatigue reported by the cancer caregivers, if confirmed by other investigators in larger and more diverse samples, interventions targeting caregiver fatigue should be explored.
doi:10.1177/1049909113479153
PMCID: PMC4392763  PMID: 23434836
fatigue; cancer; caregivers; quality of life; symptom burden; burnout
5.  Outcomes and toxicities of stereotactic body radiation therapy for non-spine bone oligometastases 
Practical radiation oncology  2013;4(2):e143-e149.
Purpose
Stereotactic body radiation therapy (SBRT) is being applied more widely for oligometastatic disease. This technique is now being used for non-spine bony metastases in addition to liver, spine, and lung. However, there are few studies examining the toxicity and outcomes of SBRT for non-spine bone metastases.
Methods and Materials
Between 2008 and 2012, 74 subjects with oligometastatic non-spine bony metastases of varying histologies were treated at the Mayo Clinic with SBRT. A total of 85 non-spine bony sites were treated. Median local control, overall survival, and progression-free survival were described. Acute toxicity (defined as toxicity <90 days) and late toxicity (defined as toxicity ≥90 days) were reported and graded as per standardized Common Toxicity Criteria for Adverse Events 4.0 criteria.
Results
The median age of patients treated was 60 years. The most common histology was prostate cancer (31%) and most patients had fewer than 3 sites of disease at the time of simulation (64%). Most of the non-spine bony sites lay within the pelvis (65%). Dose and fractionation varied but the most common prescription was 24 Gy/1 fraction. Local recurrence occurred in 7 patients with a median time to failure of 2.8 months. Local control was 91.8% at 1 year. With a median follow-up of 7.6 months, median SBRT specific overall survival and progression-free survival were 9.3 months and 9.7 months, respectively. Eighteen patients developed acute toxicity (mostly grade 1 and 2 fatigue and acute pain flare); 9 patients developed grade 1–2 late toxicities. Two patients developed pathologic fractures but both were asymptomatic. There were no late grade 3 or 4 toxicities.
Conclusions
Stereotactic body radiation therapy is a feasible and tolerable treatment for non-spine bony metastases. Longer follow-up will be needed to accurately determine late effects.
doi:10.1016/j.prro.2013.05.006
PMCID: PMC4364394  PMID: 24890360
6.  Adult Low-grade Glioma 19-year Experience at a Single Institution 
Objectives
To determine prognostic factors and optimal timing of postoperative radiation therapy (RT) in adult low-grade gliomas.
Methods
Records from 554 adults diagnosed with nonpilocytic low-grade gliomas at Mayo Clinic between 1992 and 2011 were retrospectively reviewed.
Results
Median follow-up was 5.2 years. Histology revealed astrocytoma in 22%, oligoastrocytoma in 34%, and oligodendroglioma in 45%. Initial surgery achieved gross total resection in 31%, radical subtotal resection in 10%, subtotal resection (STR) in 21%, and biopsy only in 39%. Median overall survival (OS) and progression-free survival (PFS) were 11.4 and 4.1 years, respectively. On multivariate analysis, factors associated with lower OS included astrocytomas and use of postoperative RT. Adverse prognostic factors for PFS on multivariate analysis included tumor size, astrocytomas, STR/biopsy only and not receiving RT. Patients undergoing gross total resection/radical subtotal resection had the best OS and PFS. Comparing survival with the log-rank test demonstrated no association between RT and PFS (P = 0.24), but RT was associated with lower OS (P < 0.0001). In patients undergoing STR/biopsy only, RT was associated with improved PFS (P < 0.0001) but lower OS (P = 0.03). Postoperative RT was associated with adverse prognostic factors including age > 40 years, deep tumors, size ≥ 5 cm, astrocytomas and STR/biopsy only. Patients delaying RT until recurrence experienced 10-year OS (71%) similar to patients never needing RT (74%; P = 0.34).
Conclusions
This study supports the association between aggressive surgical resection and better OS and PFS, and between postoperative RT and improved PFS in patients receiving STR/biopsy only. In addition, our findings suggest that delaying RT until progression is safe in patients who are eligible.
doi:10.1097/COC.0b013e31825d580a
PMCID: PMC4361933  PMID: 22892428
low-grade glioma; clinical outcomes; radiotherapy; prognosis
7.  Clinical and prognostic features of adult patients with gangliogliomas 
Neuro-Oncology  2013;16(3):409-413.
Background
Gangliogliomas (GGs) represent <1% of primary brain tumors in adults. Little is known regarding prognostic features, clinical characteristics, or the impact of treatment on patient outcomes.
Methods
Our neuro-oncology longitudinal database was screened for patients with GG from 1992 to 2012. Sixty-seven patients (age >18 y) were identified.
Results
Sixty-two patients presented with low-grade GG and 5 with anaplastic GG. The median age at diagnosis was 29 years. With a median follow-up of 4.7 years after the initial diagnosis, 23 patients had progressive disease. Range of time to progression was 0.2–20 years. Nine patients with low-grade GG progressed to a malignant tumor. The median overall survival (OS) for all patients was not reached. The 2-, 5-, and 10-year OS for patients with low-grade GG were 100%, 88% (95% confidence interval [CI]: 73%, 95%), and 84% (95% CI: 67%, 93%), respectively.
Factors identified by univariate analysis that were significantly associated with OS were age, KPS, extent of resection (EOR), and grade. Factors on univariate analysis that were significantly associated with progression-free survival were grade and EOR. On multicovariate Cox regression, lower tumor grade and younger age were significant factors for longer OS. EOR is a significant factor for progression-free survival.
Conclusions
While GG has excellent prognosis, malignant histologic grade, older age, and diagnosis with biopsy could indicate worse prognosis. The late nature and high rate of progression emphasize the importance of long-term follow-up. The role of chemotherapy and radiation therapy for incompletely resected low-grade GG remains unclear.
doi:10.1093/neuonc/not169
PMCID: PMC3922509  PMID: 24305706
adults; ganglioglioma; malignant transformation; progression; treatment
8.  The incidence of cerebrovascular accidents and second brain tumors in patients with pituitary adenoma: a population-based study 
Neuro-Oncology Practice  2014;1(1):22-28.
Background
To assess the risk of cerebrovascular accidents (CVAs) and second brain tumors (SBTs) in patients with pituitary adenoma after surgery or radiotherapy.
Methods
A cohort of 143 people from Olmsted County, who were diagnosed with pituitary adenoma between 1933 and 2000, was studied. Only patients from Olmsted County were included because of the unique nature of medical care in Olmsted County, which allows the ascertainment of virtually all cases of pituitary adenoma for this community's residents and comparisons to the general population in the county. Surgical resection was performed in 76 patients, 29 patients underwent radiotherapy (with 21 undergoing both surgery and radiotherapy), 5 patients were reirradiated, and 59 patients were managed conservatively and observed.
Results
Median follow-up was 15.5 years. There was no difference in CVA-free survival between treatment groups. On univariate analysis age > 60 years (hazard ratio [HR], 11.93; 95% CI, 6.26–23.03; P < .001); male sex (HR, 3.67; 95% CI, 2.03–6.84; P < .001), and reirradiation (HR, 3.41; 95% CI, 1.05–9.68; P = .04) were associated with worse CVA-free survival. In multivariate analysis, only age > 60 years was associated with worse CVA-free survival. Compared with the general population, there was a 4-fold increase in the rate of CVAs in pituitary adenoma patients (HR, 4.2; 95% CI, 2.8–6.1). Two patients developed SBT (an irradiated patient and a surgically managed patient).
Conclusion
CVA is a significant risk for patients with pituitary tumors, but treatment does not seem to impact the risk. Even with long-term follow-up, SBTs are a rare event regardless of treatment modality.
doi:10.1093/nop/npt001
PMCID: PMC4369699  PMID: 26034611
pituitary adenoma; radiotherapy; secondary malignancy; stroke; surgery
9.  Central Nervous System Cancers, Version 2.2014 
The NCCN Guidelines for Central Nervous System Cancers provide multidisciplinary recommendations for the clinical management of patients with cancers of the central nervous system. These NCCN Guidelines Insights highlight recent updates regarding the management of metastatic brain tumors using radiation therapy. Use of stereotactic radiosurgery (SRS) is no longer limited to patients with 3 or fewer lesions, because data suggest that total disease burden, rather than number of lesions, is predictive of survival benefits associated with the technique. SRS is increasingly becoming an integral part of management of patients with controlled, low-volume brain metastases.
PMCID: PMC4337873  PMID: 25361798
10.  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
11.  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
12.  Outcomes of Stereotactic Body Radiotherapy (SBRT) treatment of multiple synchronous and recurrent lung nodules 
Background
Stereotactic body radiotherapy (SBRT) is evolving into a standard of care for unresectable lung nodules. Local control has been shown to be in excess of 90% at 3 years. However, some patients present with synchronous lung nodules in the ipsilateral or contralateral lobe or metasynchronous disease. In these cases, patients may receive multiple courses of lung SBRT or a single course for synchronous nodules. The toxicity of such treatment is currently unknown.
Methods
Between 2006 and 2012, 63 subjects with 128 metasynchronous and synchronous lung nodules were treated at the Mayo Clinic with SBRT. Demographic patient data and dosimetric data regarding SBRT treatments were collected. Acute toxicity (defined as toxicity < 90 days) and late toxicity (defined as toxicity > = 90 days) were reported and graded as per standardized CTCAE 4.0 criteria. Local control, progression free survival and overall survival were also described.
Results
The median age of patients treated was 73 years. Sixty five percent were primary or recurrent lung cancers with the remainder metastatic lung nodules of varying histologies. Of 63 patients, 18 had prior high dose external beam radiation to the mediastinum or chest. Dose and fractionation varied but the most common prescriptions were 48 Gy/4 fractions, 54 Gy/3 fractions, and 50 Gy/5 fractions. Only 6 patients demonstrated local recurrence. With a median follow up of 12.6 months, median SBRT specific overall survival and progression free survival were 35.7 months and 10.7 months respectively. Fifty one percent (32/63 patients) experienced acute toxicity, predominantly grade 1 and 2 fatigue. One patient developed acute grade 3 radiation pneumonitis at 75 days. Forty six percent (29/63 patients) developed late effects. Most were grade 1 dyspnea. There was one patient with grade 5 pneumonitis.
Conclusion
Multiple courses of SBRT and SBRT delivery after external beam radiotherapy appear to be feasible and safe. Most toxicity was grade 1 and 2 but the risk was approximately 50% for both acute and late effects.
doi:10.1186/s13014-015-0340-9
PMCID: PMC4341868  PMID: 25889747
13.  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.
14.  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
15.  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
16.  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
17.  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
18.  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
19.  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
20.  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
21.  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
22.  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
23.  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
24.  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
25.  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

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