tbuckley/cabot-search huggingface dataset:
Trends in the Incidence, Prevalence, and Survival Outcomes in Patients With Neuroendocrine Tumors in the United States
Authors: Arvind Dasari, Chan Shen, Daniel Halperin, Bo Zhao, Shouhao Zhou, Ying Xu, Tina Shih, James C. Yao
Journal: JAMA Oncology (2017)

The incidence and prevalence of neuroendocrine tumors (NETs) are thought to be rising, but updated epidemiologic data are lacking.To explore the evolving epidemiology and investigate the effect of therapeutic advances on survival of patients with NETs.A retrospective, population-based study using nationally representative data from the Surveillance, Epidemiology, and End Results (SEER) program was conducted to evaluate 64 971 patients with NETs from 1973 to 2012. Associated population data were used to determine annual age-adjusted incidence, limited-duration prevalence, and 5-year overall survival (OS) rates. Trends in survival from 2000 to 2012 were evaluated for the entire cohort as well as specific subgroups, including distant-stage gastrointestinal NETs and pancreatic NETs. Analyses were conducted between December 2015, and February 2017.Neuroendocrine tumor incidence, prevalence, and OS rates.Of the 64 971 cases of NETs, 34 233 (52.7%) were women. The age-adjusted incidence rate increased 6.4-fold from 1973 (1.09 per 100 000) to 2012 (6.98 per 100 000). This increase occurred across all sites, stages, and grades. In the SEER 18 registry grouping (2000-2012), the highest incidence rates were 1.49 per 100 000 in the lung, 3.56 per 100 000 in gastroenteropancreatic sites, and 0.84 per 100 000 in NETs with an unknown primary site. The estimated 20-year limited-duration prevalence of NETs in the United States on January 1, 2014, was 171 321. On multivariable analyses, the median 5-year OS rate varied significantly by stage, grade, age at diagnosis, primary site, and time period of diagnosis. The OS rate for all NETs improved from the 2000-2004 period to the 2009-2012 period (hazard ratio [HR], 0.79; 95% CI, 0.73-0.85). Even larger increases in OS between these periods were noted in distant-stage gastrointestinal NETs (HR, 0.71; 95% CI, 0.62-0.81) and distant-stage pancreatic NETs (HR, 0.56; 95% CI, 0.44-0.70).The incidence and prevalence of NETs are steadily rising, possibly owing to detection of early-stage disease and stage migration. Survival for all NETs has improved over time, especially for distant-stage gastrointestinal NETs and pancreatic NETs in particular, reflecting improvement in therapies. These data will help to prioritize future research directions.
Impact of physical activity on fatigue and quality of life in people with advanced lung cancer: a randomized controlled trial
Authors: H.M. Dhillon, M.L. Bell, H.P. van der Ploeg, J.D. Turner, M. Kabourakis, L. Spencer, C. Lewis, R. Hui, P. Blinman, S.J. Clarke, M.J. Boyer, J.L. Vardy
Journal: Annals of Oncology (2017)

Physical activity (PA) improves fatigue and quality of life (QOL) in cancer survivors. Our aim was to assess whether a 2-month PA intervention improves fatigue and QOL for people with advanced lung cancer.Participants with advanced lung cancer, Eastern Cooperative Oncology Group performance status (PS) ≤2, >6 months life expectancy, and ability to complete six-min walk test, were stratified (disease stage, PS 0-1 versus 2, centre) and randomized (1:1) in an open-label study to usual care (UC) (nutrition and PA education materials) or experimental intervention (EX): UC plus 2-month supervised weekly PA and behaviour change sessions. Assessments occurred at baseline, 2, 4, and 6 months. The primary endpoint was fatigue [Functional Assessment of Cancer Therapy-Fatigue (FACT-F) questionnaire] at 2 months. The study was designed to detect a difference in mean FACT-F subscale score of 6. Analysis was intention-to-treat using linear mixed models.We recruited 112 patients: 56 (50.4%) were randomized to EX, 55(49.5%) to UC; 1 ineligible. Male 55%; median age 64 years (34-80); 106 (96%) non-small cell lung cancer; 106 (95.5%) stage IV. At 2, 4 and 6 months, 90, 73 and 62 participants were assessed, respectively, with no difference in attrition between groups. There were no significant differences in fatigue between the groups at 2, 4 or 6 months: mean scores at 2 months EX 37.5, UC 36.4 (difference 1.2, 95% CI - 3.5, 5.8, P = 0.62). There were no significant differences in QOL, symptoms, physical or functional status, or survival.Adherence to the intervention was good but the intervention group did not increase their PA enough compared to the control group, and no difference was seen in fatigue or QOL.Australian New Zealand Clinical Trials Registry No. ACTRN12609000971235.
P01.28 Multiplex gene targeting and studying of TSPYL family by CRISPR/Cas mediated gene engineering
Authors: L. PENG, S. Chan
Journal: Neuro-Oncology (2017)

Introduction: TSPYL (testis-specified Y encoded protein) family proteins belongs to nucleosome assembly protein (NAP) superfamily. There are 6 TSPYL family members in mice: Tspy/Tspy1, Tspyl1, Tspyl2, Tspyl3, Tspyl4 and Tspyl5. Nucleosome assembly protein superfamily members have been demonstrated that play significant roles in gene expression regulation and neuronal functions as histone chaperons. Data analysis from oncogene database highlighted the widespread expression of TSPYL1 and TSPYL2 in most neuronal cell types and their generic function in suppressing growth of most classes of neuroblastic tumor. TSPYL4, TSPYL5 showed lower expression in different brain tumors compared with the normal brain.In addition, the glioblastoma methylome dataset revealed a general increase in methylation status of TSPYL gene loci in glioblastoma samples Previous investigation in our lab found that TSPYL2 played significant role in cell cycle regulation, but the effect is mild. This makes us wonder whether other members of the TSPYL family also participate in cell cycle regulation control and how they involved in biological process like tumorigenesis and neural development. All these preliminary data intricate us to clarify roles of TSPYL family proteins play in neuron tumor. it is meaningful to figure out the functional roles of TSPYL family members. MATERIAL AND METHOD: we mutate Tspyl1, Tspyl2 and Tspyl4 in mouse ES cells using Crispr/Cas-mediated genome engineering, followed by generating the knockout mice through blastocyst injection. We monitor neural differentiation process of embryonic stem cells with Tspy family protein single, double or triple mutation. We did blastocyst injection with these embryonic stem cell to generate Tspyl1, Tspyl2, Tspyl4, single, double or triple gene mutation mice. Immunoprecipitation –mass spectrometric analysis of Tspyl1 and Tspyl4 were carried to figure out their interaction parters. Results: ES cells with Tspyl1,Tspyl4 single or double mutation could go on normally neuronal development. No significant difference of different stage markers in neuronal development like early stem cell marker nestin or mature neuron marker MAP2 and NeurN.In mice injection, the percentage of chimera mice is low. Chimera mice with relative higher percentage are infertility. IP-MS analysis state that Tspyl1 interact with Testis-specific chromodomain protein Y1,neurogenin 2.Tspyl4 interact with chromodomain-helicase-DNA-binding protein1and WAP four-disulfide core domain protein 1. CONCLUSION: Despite single or double knockout of Tspyl1 or Tspyl4 do not influence normal neuronal development. But their function in epigenetic regulation of tumour formation still need to be further clarified. They may play a role chromosome segregation and spermatogenesis.
P08.02 EGFRvIII induced GBM invasion and survival is dependent upon Stat5 activation and Fn14 expression
Authors: R. Alison, M. Sabir, C. Sereduk, S. Tuncali, M. Pineda, N. Millard, H. D. Dhruv, S. Peng, M. E. Berens, J. C. Loftus, J. A. Winkles, N. L. Tran
Journal: Neuro-Oncology (2017)

Glioblastoma (GB) is among the most genetically heterogeneous, treatment resistant, and lethal of all human cancers. A significant hurdle to effective treatment of GB is the aggressive invasion of tumor cells into surrounding healthy brain tissue that invariably leads to tumor recurrence, brain injury, and patient death. Median survival following recurrence drops to approximately 8 months and overall 2 year survival rates have remained relatively unchanged for more than 25 years. There is presently a limited amount of information available regarding the biological properties of invasive rim cells. As invasion is a universal property of GB, studies focused on this cell population and on the development of therapies that target them are sorely needed in order to significantly improve the survival of GB patients. Comprehensive genomic analyses of GB core specimens and invasive rim components, have helped identify genes and signaling pathways that are frequently altered in GB and brain-invaded regions. Through gene expression analysis on GB patient tumors harboring a wide set of genetic aberrations, we have reported that expression of Fn14, a type I transmembrane receptor of the TNFR super family, is low in normal brain tissue but is highly expressed by infiltrating glioma cells. Increased Fn14 mediated signaling increases GB cell migration/invasion and survival in vitro while knockdown of Fn14 expression increases sensitivity to temozolomide in an intracranial xenograft model, which substantiates its potential as a target to inhibit GB cell invasion and decrease resistance. Amplification and overexpression of the epidermal growth factor (EGFR) is the most common genetic alteration observed in GB. Greater than half of GB tumors with amplification of EGFR also exhibit rearrangements in the EGFR gene resulting in expression of mutated forms of the EGFR, the most common of which is EGFRvIII. EGFR and EGFRvIII cooperate to promote tumor progression and invasion, in part, through activation of the Stat3-signaling pathway; however, the signaling mechanism(s) by which EGFRvIII induces GB invasion and survival differs from EGFR. Preliminary investigation into the mechanistic basis of Fn14 signaling in GB cells revealed that EGFRvIII induces expression of Fn14 and that EGFRvIII mediated GB cell invasion is dependent upon Fn14 expression. EGFRvIII-mediated induction of Fn14 expression is dependent upon Stat5 and requires activation of Src, whereas EGFR regulation of Fn14 is also dependent upon MEK/ERK-Stat3 activation. In addition, Stat5 activation by IL2 is required to induce Fn14 expression, indicating involvement of the microenvironment. Notably, treatment of EGFRvIII expressing GB cells with the Stat5 inhibitor pimozide blocked Stat5 phosphorylation and Fn14 expression positioning Stat5 as a therapeutic target for treatment of invasive GB cells.
P14.01 MTHFR genotype may affect methotrexate toxicity, survival and disease occurrence in patients with central nervous system lymphoma
Authors: A. Ali, D. Aregawi
Journal: Neuro-Oncology (2017)

Introduction: Two common methylenetetrahydrofolate reductase (MTHFR) single nucleotide polymorphisms (SNPs) - C677T and A1298C - have been implicated in MTX toxicity in patients receiving high dose methotrexate (HD-MTX) therapy. Our objective was to explore whether MTHFR polymorphisms are associated with treatment-related toxicity and with tumor-related outcomes. Methods: A retrospective cohort study was conducted which included all patients who received HD-MTX for a central nervous system lymphoma between June 2010 and November 2016. MTHFR genotyping was performed on all patients prior to their first course of HD-MTX as part of our standard management protocol. Patient demographic data, hematologic, hepatic, cutaneous and renal toxicity data, daily MTX levels, and overall survival (OS) and PFS were all recorded. Results: Fifty-one patients were included, and 86.3% [74.3-93.2] had at least one MTHFR SNp. 52.9% [39.5-66.6] of patients were either heterozygous or homozygous for C677T, 58.8% [45.2-71.3] were either heterozygous or homozygous for A1298C, and 25.5% [15.5-38.9] were compound heterozygotes. Peak methotrexate levels were 656.0 [579.6-730.4] in patients with a mutation and 513.43 [376.3-605.5] in non-mutated patients (p=0.11). Serum methotrexate levels >0.05 on day 6 only occurred in patients with a mutation (34.1%, p=0.06). Any grade 2 or greater toxicity occurred in 42.9% of non-mutated and 84.1% of mutated patients (p=0.031). Grade 3 toxicities were only observed in patients with at least one mutation: 14.8% [5.92-32.5] and 23.3% [11.8-40.9] in C677T and A1298C mutations respectively. There was no statistically significant difference between the two mutations (p=0.51). We hypothesized that overall survival might be longer in patients with MTHFR SNPs, but in our cohort that difference was not statistically significant: 730 days in the mutated vs. 284 days in the non-mutated patients (p=0.4). The frequency of MTHFR SNPs was dramatically greater in our lymphoma cohort than in the general population (~33% for C766T and 24-40% for A1298C mutations) raising the possibility that these mutations are themselves associated with CNS lymphomas. Conclusions: MTHFR mutations are associated with an increased frequency of toxicity and prolonged need for leucovorin rescue. Larger patient series may disclose a survival advantage for patients with MTHFR mutations. These mutations may be associated with the occurrence of CNS lymphoma.
Adult low-grade gliomas: The Cleveland Clinic experience.
Authors: Lizbeth Robles Irizarry, Adewale Alade Fawole, Neda Hashemi-Sadraei, Mital Patel, Paul Elson, Tanya M. Tekautz, Erin Sennett Murphy, Violette Recinos, Samuel T. Chao, John H. Suh, David M. Peereboom, Glen Stevens, Robert J. Weil, Michael A. Vogelbaum, Gene H. Barnett, Manmeet Singh Ahluwalia
Journal: Journal of Clinical Oncology (2012)

2076 Background: Low-grade gliomas account for 10-20% of all primary brain tumors. There is limited data on specific prognostic factors for patients with low-grade gliomas. Methods: After obtaining IRB approval, the Cleveland Clinic Brain Tumor and Neuro-Oncology Center’s database was used to identify patients with histologically confirmed grade 2 glioma at the time of diagnosis. Multivariable analysis was conducted with use of a Cox proportional hazards model and a stepwise selection algorithm that used p&lt;0.10 as the criteria for entry and p&lt;0.05 as retention in the model to identify independent predictors of survival. Results: Chart records of 478 patients (54% of whom were men) diagnosed between 1991 and 2010 were included for analysis. The median age at presentation was 41 years (range, 18-83 years). 42% of patients had biopsy only, 27% had gross total resection, 6% had near total resection, and 25% had subtotal resection. 22% of patients were initially treated with radiation, 30% with adjuvant chemotherapy, and 7% with concurrent chemotherapy. Median progression free survival and median overall survival (OS) were 5.1 years and 12.8 years, respectively. On multivariate analysis, independent of additional therapy, five factors were identified as independent predictors of OS: age at diagnosis (p=0.002), Karnofsky performance status (KPS, p&lt;0.0001), histology (astrocytoma vs. other, p=0.001), hemispheric location (left or bilateral involvement vs. right, p=0.02) and gender (male vs. female, p=0.0003). Conclusions: Older age, male gender, poor performance status, astrocytic histology, and left hemispheric or bilateral involvement are associated with higher mortality. [Table: see text]
Abstract P122: Characterization of Ventricular Assist Device Mediated Sensitization in the Bridge to Heart Transplant Patient
Authors: Murray H Kwon, Jennifer Q Zhang, Ani Abrahamyan, Zilu K Zhang, David W Gjertson, Abbas Ardehali, Jon Kobashigawa, Richard J Shemin, Elaine F Reed
Journal: Circulation Research (2011)

Purpose: To clarify patterns of anti-HLA antibody expression (sensitization) occurring in patients bridged to transplantation (BTT) with ventricular assist devices (VADs). Methods: The study is a retrospective review of 68 patients undergoing BTT with either Heartmate II (HMII) axial flow LVAD or paracorporal BIVAD from January 2007 to July 2010 at UCLA Medical Center. Results: Five of 15 (33.3%) HMII pts became sensitized during treatment compared to 29 of 53 (54.7%) BIVAD patients, p=0.24. Table 1 shows common etiologies for patient sensitization of which only PRBC transfusion was statistically significant. [ table 1 ] Multiple variable analysis comparing BIVAD vs. HMII while controlling for previous cardiac surgery, pregnancy, and PRBC transfusion demonstrated an Odds Ratio of 5.20, p=0.029 (robust variance estimator). Of sensitized patients, all 5 (100%) of the HMII patients had pre-existing antibodies prior to VAD placement compared to 11 of 29 (62.1%) BIVAD patients, p=0.016. Maximum cumulative MFIs for BIVAD were 46,259 ± 66,349 vs. 42540 ± 12840 for HMII, p=0.90. Time to maximum antibody expression was shorter for the HMII group (34 ± 28 days vs. 5.8 ± 9 days, p=0.04). Table 1. Sensitization Risk Factors Antibodies + Antibodies − p-value Previous Cardiac Surgery 23.5% 8.8% 0.19 Pregnancy 20.6% 2.9% 0.05 PRBC 52.1±34.7 35.9±22.3 0.04 FFP 29.4±14.4 23.6±15.2 0.15 Platelets 9.8±9.7 6.8±6.7 0.20 Cryoprecipitate 3.2±2.6 3.1±2.6 0.74 Blood products expressed as mean units ± std dev Conclusion: BIVADs were associated with a five fold increased risk for sensitization when accounting for other risk factors. HMII patients required pre-sensitization to express antibodies during their treatment interval whereas BIVAD patients developed de novo antibodies. Although the peak cumulative MFIs were similar for both VAD types, the days to reach this peak were significantly less in the HMII group. These data suggest that sensitization in HMII patients may not be due to antigenic stimulation from the device itself.
The MHC locus and genetic susceptibility to autoimmune and infectious diseases
Authors: Vasiliki Matzaraki, Vinod Kumar, Cisca Wijmenga, Alexandra Zhernakova
Journal: Genome biology (2017)

In the past 50 years, variants in the major histocompatibility complex (MHC) locus, also known as the human leukocyte antigen (HLA), have been reported as major risk factors for complex diseases. Recent advances, including large genetic screens, imputation, and analyses of non-additive and epistatic effects, have contributed to a better understanding of the shared and specific roles of MHC variants in different diseases. We review these advances and discuss the relationships between MHC variants involved in autoimmune and infectious diseases. Further work in this area will help to distinguish between alternative hypotheses for the role of pathogens in autoimmune disease development.
P08.62 Extracellular signal-regulated kinase 1 (ERK1) mediates the autocrine positive feedback loop of TGF-β and furin in glioblastoma stem cells
Authors: E. Ventura, M. Weller, I. Burghardt
Journal: Neuro-Oncology (2017)

Glioblastoma is the most common and aggressive intrinsic brain tumor in adults. Self-renewing, highly tumorigenic glioblastoma stem cells/glioma-initiating cells (GIC) have been linked to glioma invasive properties, immunomodulation and increased angiogenesis leading to resistance to therapy. TGF-β signaling has been associated to the tumorigenic activity of GIC. TGF-β is synthesized as a precursor molecule and proteolytically processed to the mature form by members of the family of the proprotein convertases subtilisin/kexin (PCSK). Here we report that furin is unique among the PCSK in being highly expressed in human GIC. Furin cleaves and promotes activation of pro-TGF-β1/2, and TGF-β2 in turn increases furin levels. Notably, TGF-β2 controls furin activity in a ALK-5-dependent manner involving members of the ERK/MAPK pathway. Specifically, these results uncover a role of ERK1 in the regulation of furin activity by supporting a self-sustaining loop for high TGF-β activity in GIC.
Do guidelines for treating chest disease in children use Cochrane Reviews effectively? A systematic review
Authors: Andrew P Prayle, Tessy Cox, Sherie J Smith, Joanne Rycroft-Malone, Kim S Thomas, Dyfrig A Hughes, Alan R Smyth
Journal: Thorax (2017)

Cochrane Reviews summarise best evidence and should inform guidelines. We assessed the use of Cochrane Reviews in the UK guidelines for paediatric respiratory disease. We found 21 guidelines which made 1025 recommendations, of which 96 could be informed by a Cochrane Review. In 38/96 recommendations (40%), some or all of the relevant Cochrane Reviews were not cited. We linked recommendations to 140 Cochrane Reviews. In 37/140 (26%) cases, the guideline recommendation did not fully agree with the Cochrane Review. Guideline developers may fail to use Cochrane Reviews or may make recommendations which are not in line with best evidence.
Birth decade affects the sensitization pattern and asthma risk in Finnish adult population
Authors: S. Toppila‐Salmi, A. Luukkainen, R. Lemmetyinen, J. Karjalainen, H. Huhtala, R. Renkonen, D. Y. Wang, M. J. Mäkelä, J. Pekkanen
Journal: Allergy (2017)

Abstract We have previously shown that sensitizations to several types of allergens distinguish subjects with and without adult‐onset asthma in Finland. The aim was to analyze how age affects sensitization and asthma risk. We used previous population‐based case‐control data (N=456) from Finnish adult asthma patients with one or two matched controls. Asthma was diagnosed based on a typical history of asthmatic symptoms and lung function tests. Allergic sensitization was determined by skin prick test ( SPT ) to 17 aeroallergens. Information on demographics was obtained by a questionnaire. Sensitization to more than one allergen type and the number of positive SPT reactions associated with younger age and asthma. Atopic subjects aged 65 and above were characterized by sensitization to only one to two allergens, with very few animal danders and without an association with asthma. Multiple sensitizations and animal dander sensitization are more common among Finnish asthmatic adults aged under 56 than among older asthmatics. Cohort studies are needed to understand timing of host‐environmental interactions behind this.