tbuckley/cabot-search huggingface dataset:
P04.09 Low-grade and high-grade glioma patients show different remote effects of the brain tumor on the functional network topology of the contralesional hemisphere
Authors: W. De Baene, G. Rutten, M. M. Sitskoorn
Journal: Neuro-Oncology (2017)

Introduction: Patients with unilateral brain tumors show dramatic alterations in functional brain connectivity. These alterations are not only restricted to the tumor area, but are also thought to occur in remote, even contralateral areas. Functional reshaping is time-dependent, as recruitment of perilesional and remote brain areas is much more efficient in slow growing than acute lesions. Whether the growth-rate of a tumour modulates the functional network topology of the contralesional hemisphere remains, however, unclear. Low-grade glioma (LGG, WHO-grade I-II) and high-grade glioma (HGG, WHO-grade III-IV) patients provide an optimal window to study this. LGG grow more slowly and less aggressively with lower degrees of cell infiltration and proliferation than HGG, permitting a greater plastic reorganization of the functional networks in LGG patients. The goal of this study was therefore to examine the differences between LGG and HGG patients in functional network topology in the contralesional hemisphere. Methods: Resting state fMRI data were acquired in 80 glioma patients with a left hemispheric tumor (40 LGG, 40 HGG patients) before resective brain surgery. A connectivity matrix for the contralesional hemisphere was created. Based on this connectivity matrix, a multivariate pattern classification was used to classify patients as having an LGG or HGG. The following network metrics were computed: global connection strength (provides information on the total degree of connectivity); global efficiency (reflects the integration of network-wide communication); local efficiency (represents the potential for local information transfer); modularity (indicates to what extent the network can be subdivided into separate modules); intra-modular connection weight (reflects the local processing within modules) and inter-modular connection weight (reflects the distributed processing across modules). These metrics were compared between LGG and HGG patients with permutation tests. Results: The multivariate pattern classification based on the contralesional connectivity matrix was successful in classifying LGG and HGG patients (accuracy = 63%; p < .05 above chance). Analyses of the network metrics of the contralesional hemisphere showed a lower local efficiency, a lower intra-modular connection weight and a higher inter-modular connection weight in LGG than in HGG patients (all p's < .05). Conclusions: We were able to correctly classify LGG and HGG patients based on the contralesional connectivity matrix, suggesting differences in the contralesional functional network topology between these two groups. More specifically, LGG patients showed a lower potential for local information transfer and more distributed processing across modules than HGG patients. This suggests that differences in lesion speed can lead to differences in the contralesional functional network topology.
Most drugs paid for by £1.27bn Cancer Drugs Fund had no “meaningful benefit”
Authors: Deborah Cohen
Journal: BMJ (2017)

The Cancer Drugs Fund (CDF) has not “delivered meaningful value” to patients with cancer and may have exposed them to “toxic side effects of drugs,” an analysis has found.1

The CDF was established in 2010 in England to provide “patients with faster access to the most promising new cancer treatments” and to ensure “value for money for taxpayers.” It funded drugs that were not available through the NHS because the drugs had not been appraised, were in the process of being appraised, or had been appraised but not recommended by the National Institute for Health and Care Excellence (NICE). The fund was overhauled last year.

Ajay Aggarwal, academic clinical oncologist at the London School of Hygiene and Tropical Medicine and a lead author of the analysis, said, “From 2010 when it started to 2016 when it closed, the Cancer Drugs Fund cost the UK taxpayer a total of £1.27bn [€1.51bn; $1.64bn], the equivalent of one year’s total spend on all cancer drugs in the NHS.

“The majority of …
Indistinguishable NDM-producing Escherichia coli isolated from recreational waters, sewage, and a clinical specimen in Ireland, 2016 to 2017
Authors: Bláthnaid M Mahon, Carina Brehony, Elaine McGrath, James Killeen, Martin Cormican, Paul Hickey, Shane Keane, Belinda Hanahoe, Ann Dolan, Dearbháile Morris
Journal: Eurosurveillance (2017)

In this study, New Delhi metallo-beta-lactamase (NDM)-producing Enterobacteriaceae were identified in Irish recreational waters and sewage. Indistinguishable NDM-producing Escherichia coli by pulsed-field gel electrophoresis were isolated from sewage, a fresh water stream and a human source. NDM-producing Klebsiella pneumoniae isolated from sewage and seawater in the same area were closely related to each other and to a human isolate. This raises concerns regarding the potential for sewage discharges to contribute to the spread of carbapenemase-producing Enterobacteriaceae.
Comparative Analysis of Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer According to 2007 and 2013 American Society of Clinical Oncology/College of American Pathologists Guideline Recommendations
Authors: Wedad M. Hanna, Elzbieta Slodkowska, Fang-I Lu, Houman Nafisi, Sharon Nofech-Mozes
Journal: Journal of Clinical Oncology (2017)

Purpose To study the effect of the 2013 updates to the 2007 American Society of Clinical Oncology/College of American Pathologists recommendations for human epidermal growth factor receptor 2 (HER2) testing in breast cancer on testing patterns and interpretation in a large regional reference laboratory. Patients and Methods Patient cases with HER2 testing scores for breast biomarker evaluation were selected from our laboratory information system during two 12-month periods (2012 and 2014). The number of tests performed, type of specimens, proportion of HER2-positive and equivocal patient cases, and number of repeat tests on subsequent excisional specimens were examined and compared. Results Although the number of samples tested increased between 2012 and 2014 (2,201 v 2,558 patient cases; 2,278 v 2,659 tumors), HER2 positivity remained constant (15.7% v 15.5%, respectively). The number of repeat tests performed within 6 months more than doubled (122 [5.5%) of 2,201 v 302 [11.8%] of 2,558; P < .001), and the proportion of immunohistochemistry (IHC) 2+ tumors was significantly lower in 2014 than in 2012 (20.3% v 25.3%; P < .001). However, the proportion of patient cases with unresolved HER2 statuses (equivocal by IHC and in situ hybridization) was significantly higher in 2014 (four of 2,278 v 90 of 2,660; P < .001). Conclusion Our findings indicate that the 2013 updates to the American Society of Clinical Oncology/College of American Pathologists recommendations for HER2 testing in breast cancer did not affect the overall HER2-positivity rate or the proportion of patients eligible for HER2-targeted therapy. The proportion of tests and repeat tests performed increased, as did the number of patient cases categorized as ISH equivocal. The benefit of targeted therapy in the equivocal group is not proven, so targeted therapy should not be considered for patients in this category which should be redefined in future iterations of the recommendations.
Abstract 17808: Fasting Levels of High-sensitive Growth Hormone in Males are Associated to Carotid Intima Media Thickness and are Reduced by Treatment With Fluvastatin
Authors: Erik Hallengren, Peter Almgren, Maria Rosvall, Gerd Östling, Margaretha Persson, Andreas Bergmann, Joachim Struck, Gunnar Engström, Bo Hedblad, Olle Melander
Journal: Circulation (2015)

Introduction: Growth hormone (GH) has been linked to cardiovascular disease and lipid metabolism but the exact mechanisms of this association are still unclear. Objectives: We here test if GH is cross-sectionally associated to carotid intima media thickness (IMT) and whether treatment with fluvastatin have any effects on the fasting level of GH in a randomized controlled trial of carotid IMT progression. Methods: We examined the association between GH and IMT in 4425 individuals (aged 46-68 years) included in the baseline examination (1991-1994) of the Malmö Diet and Cancer cardiovascular cohort (MDC-CC). From that cohort we then studied 472 individuals (aged 50-70 years) who also participated (1994-1999) in the β-Blocker Cholesterol-Lowering Asymptomatic Plaque Study (BCAPS), a randomized, double blind, placebo-controlled, single-center clinical trial. Using multivariate linear regression models we related the change in GH-levels at 12 months compared to baseline to treatment with fluvastatin. Results: In MDC-CC fasting values of GH exhibited a positive cross-sectional relation to the IMT at the carotid bifurcation after adjustment for traditional cardiovascular risk factors (p=0.002). In a gender-stratified analysis the association were positive and significant for males (p=0.005), but not for females (p=0.09). In males in BCAPS treated with fluvastatin there tended to be a greater reduction of GH after 12 months when compared to subjects not receiving fluvastatin (p=0.05) (Table). Fasting levels of GH did not interact with the different treatment regimes’ effect on the IMT. Conclusions: We here demonstrate that higher fasting levels of GH are associated to thicker IMT in the carotid bulb and that statin treatment may reduce fasting levels of GH in males. Our results are in line with previous results with GH being associated to cardiovascular disease. The effects of statin treatment on GH are small and need to be confirmed in a larger trial.
P01.01 Detecting alterations in the glioma-related molecular markers using cell free DNA from the cerebrospinal fluid
Authors: J. Adachi, K. Watanabe
Journal: Neuro-Oncology (2017)

Background: Mutation in the IDH1 gene is a genetic defect exclusively found in glioma as a mutation in solid tumors, and has been established as a prognostic factor for WHO Grade 2–4 glioma. Therefore, detecting this mutation is clinically important. In this study, we report the results of analyzing defects in the IDH1 gene by detecting circulating cell free (ccf) DNA in the CSF derived from the tumor tissue of glioma patients. Moreover, MGMT promoter methylation was evaluated for the same samples in a subset of patients. Methods: Lumbar puncture was performed to obtain CSF from 7 patients with glioma. ccfDNA was extracted from 1 ml of CSF using the Maxwell rapid sample concentrator system. Subsequently, the presence of point mutation of the IDH1 gene at codon 132 was screened by real-time PCR/high-resolution melting (HRM) curve analysis, and the mutation was confirmed on the basis of DNA sequencing results. Status in the IDH1 gene was also analyzed using the same assay technique for the DNA extracted from the excised fresh tumor tissue, to compare the results with that of CSF-derived ccfDNA. In addition, ccfDNA was also extracted from the plasma in 3 patients to additionally examine the presence of the IDH1 gene mutation. For MGMT promoter methylation, a quantitative analysis was performed using the methylation-specific HRM method. Results: CSF-derived ccfDNA was successfully extracted from all patients and analyzed using real-time PCR/high-resolution melting curve analysis. IDH1 gene mutation was detected in 3 of the 7 glioma patients. The results of the IDH1 gene analysis of CSF-derived ccfDNA and that of the DNA extracted from the surgically excised tumor tissue were consisted in all patients. However, IDH1 gene mutation was not detected all in plasma-derived ccfDNA. MGMT methylation was evaluated in two cases. Conclusion: Gene analysis of ccfDNA from the CSF, not from the plasma, enabled the evaluation of IDH1 gene defect in glioma patients less invasively, without directly obtaining any tumor tissue. Moreover, this technique can be applied to analyze MGMT gene promotor methylation.
P08.27 Isolation of tumor mesenchymal stem-like cells from high grade gliomas according to the weight of fresh specimens
Authors: E. Kim, S. Kong, J. Lee, S. Moon, J. Oh, K. Sung, S. Kim, S. Park, J. Shim, S. Yoon, J. Moon, J. Park, S. Kim, S. Lee, Y. Huh, J. Chang, S. Kang
Journal: Neuro-Oncology (2017)

It is known that tumor mesenchymal stem-like cells (tMSLCs) can be isolated from high-grade gliomas and also play a role in glioma progression. Moreover, it has been reported that the success of tMSLCs isolation is a critical indicator of the overall survival of World Health Organization grade IV glioma patients. Despite these reports, attempts to isolate tMSLCs from surgical specimen are not always successful. Given that weights of surgical specimens from high-grade gliomas vary, we presumed that weightier surgical specimens would be better for tMSLC isolation. To test this, we assessed 51 fresh, high-grade glioma specimens and divided them into two groups according to success or failure of tMSLCs isolation. We found no significant difference in the weights of specimens in the two groups. We further found no significant differences between the two groups in terms of patient age, sex, pathological diagnosis, tumor type, or molecular markers. We did, however, determine that the estimated optimal weight of samples for tMSLC isolation was 180 mg. Collectively, our findings indicate that, contrary to our expectations, the efficiency of tMSLCs isolation was not related to the weight of surgical specimens.This study was supported by grants from the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI14C0042, HI14C1324), and the “Dongwha” Faculty Research Assistance Program of Yonsei University College of Medicine (6-2015-0171).
Can the FIGO 2000 scoring system for gestational trophoblastic neoplasia be simplified? A new retrospective analysis from a nationwide dataset
Authors: Y.K. Eysbouts, P.B. Ottevanger, L.F.A.G. Massuger, J. IntHout, D. Short, R. Harvey, B. Kaur, N.J. Sebire, N. Sarwar, F.C.G.J. Sweep, M.J. Seckl
Journal: Annals of Oncology (2017)

BackgroundWorldwide introduction of the International Fedaration of Gynaecology and Obstetrics (FIGO) 2000 scoring system has provided an effective means to stratify patients with gestational trophoblastic neoplasia to single- or multi-agent chemotherapy. However, the system is quite elaborate with an extensive set of risk factors. In this study, we re-evaluate all prognostic risk factors involved in the FIGO 2000 scoring system and examine if simplification is feasible.Patients and methodsBetween January 2003 and December 2012, 813 patients diagnosed with gestational trophoblastic neoplasia were identified at the Trophoblastic Disease Centre in London and scored using the FIGO 2000. Multivariable analysis and stepwise logistic regression were carried out to evaluate whether the FIGO 2000 scoring system could be simplified.ResultsOf the eight FIGO risk factors only pre-treatment serum human chorionic gonadotropin (hCG) levels exceeding 10 000 IU/l (OR = 5.0; 95% CI 2.5–10.4) and 100 000 IU/l (OR = 14.3; 95% CI 4.7–44.1), interval exceeding 7 months since antecedent pregnancy (OR = 4.1; 95% CI 1.0–16.2), and tumor size of over 5 cm (OR = 2.2; 95% CI 1.3–3.6) were identified as independently predictive for single-agent resistance. In addition, increased risk was apparent for antecedent term pregnancy (OR = 3.4; 95% CI 0.9–12.7) and the presence of five or more metastases (OR = 3.5; 95% CI 0.4–30.4), but patient numbers in these categories were relatively small. Stepwise logistic regression identified a simplified risk scoring model comprising age, pretreatment serum hCG, number of metastases, antecedent pregnancy, and interval but omitting tumor size, previous failed chemotherapy, and site of metastases. With this model only 1 out 725 patients was classified different from the FIGO 2000 system.ConclusionOur simplified alternative using only five of the FIGO prognostic factors appears to be an accurate system for discriminating patients requiring single as opposed to multi-agent chemotherapy. Further work is urgently needed to validate these findings.
Transient CDK4/6 inhibition protects hematopoietic stem cells from chemotherapy-induced exhaustion
Authors: Shenghui He, Patrick J. Roberts, Jessica A. Sorrentino, John E. Bisi, Hannah Storrie-White, Renger G. Tiessen, Karenann M. Makhuli, William A. Wargin, Henko Tadema, Ewoud-Jan van Hoogdalem, Jay C. Strum, Rajesh Malik, Norman E. Sharpless
Journal: Science Translational Medicine (2017)

The concomitant use of CDK4/6 inhibitors with cytotoxic agents may prevent chemotherapy-induced bone marrow exhaustion in cancer patients.
A 3D-printed cap with sideoptics for colonoscopy: a randomized ex vivo study
Authors: Benjamin Walter, Alexander Hann, Rena Frank, Alexander Meining
Journal: Endoscopy (2017)

Abstract Background Adequate polyp detection is crucial to colonoscopy; however, detection can be impaired. In particular, flat polyps located behind folds or near the colonic flexures appear to be a problem. We present a cheap and easily adjustable 3D-printed tool to enhance the view of a standard colonoscope using additional commercially available sideoptics. Materials and methods A cap adjustable to a standard endoscope was printed by a 3 D printer and had two microcameras fixed to offer two additional views. Fourteen endoscopists performed one standard and one sideoptic-enhanced colonoscopy in a randomized order. Flat lesions were simulated in an endoscopy training model. Time for withdrawal was measured, along with the number of flat lesions detected. Results Withdrawal time did not differ significantly between standard and sideoptic-enhanced colonoscopy (329 vs. 389 seconds). The median number of detected flat lesions per endoscopic examination was significantly higher using the sideoptic tool (8 vs. 6.5; P = 0.001). Conclusions A 3D-printed sideoptic-enhanced cap including two microcameras may be a cheap, easy, and feasible add-on to improve adenoma detection rates in routine colonoscopy.
P11.09 Radiation DNA damage repair inhibition by GSK-J4 induced chromatin compaction in DIPG
Authors: N. Louis, X. He, A. Plunti, A. Saratsis, R. Lulla, C. Horbinski, S. Goldman, C. D. James, A. Shilatifard, R. Hashizume
Journal: Neuro-Oncology (2017)

Introduction: Diffuse intrinsic pontine glioma (DIPG) is among the most devastating childhood cancers, and virtually all patients die within two years after diagnosis. Since these tumors occur in the brainstem, there are no surgical options for providing relief to patients. The only therapeutic modality routinely used in the treatment of DIPG is radiation. Radiation often provides transient relief from DIPG symptoms, as cancer recurrence and patient demise are inevitable. Therefore, identifying efficacious therapeutics to enhance radiation effect is desperately needed. We have recently shown that inhibition of the histone H3K27 demethylase JMJD3 acts to restore H3K27 methylation in DIPG harboring H3K27M mutation, while demonstrating potent anti-tumor activity, both in vitro and in vivo. Our gene expression profiling of K27M DIPG treated with GSK-J4, a JMJD3 demethylase inhibitor, revealed several decreases in the genes encoding proteins involved in DNA double-strand break (DSB) repair. Our aim is to investigate the hypothesis that GSK-J4 may inhibit radiation-induced DNA repair by chromatin modification, in association with analysis of therapeutic combination of GSK-J4 and radiation. METHODS: We evaluated DNA damage repair via quantitative-PCR, immunocytochemistry of DSB markers γH2AX and 53BP1, western blotting and DNA repair assay. MNase digestion and FAIRE-seq was used to analyze nucleosome assembly and transcriptional activity in cellular chromatin. Assessment of DIPG response to radiation therapy (RT) in combination with GSK-J4 was performed using clonogenic survival assays. In vivo response to radiation monotherapy and combination of RT + GSK-J4 were measured by bioluminescence imaging and animal survival studies. RESULTS: qPCR results showed that GSK-J4 significantly reduces DNA DSB repair genes such as PARP1, PARP2, SMARCB1 and BRCA1, in irradiated DIPG cells. Immunocytochemistry results support that GSK-J4 sustains high levels of γH2AX and 53BP1 in irradiated DIPG cells, thereby inhibiting DNA DSB repair. Mnase assay indicated that GSK-J4 causes chromatin compaction which prevents DNA DSB repair. We are currently conducting clonogenic assays to assess long term effect of GSK-J4 on radiated cells as well as western blotting, FAIRE-seq and in vivo studies, the results of which will be reported at the meeting. GRANTS AND FELLOWSHIPS: This work was supported by the US National Institutes of Health RO1NS093079, the Bear Necessities Pediatric Cancer Foundation and Rally Foundation.
Abstract 285: Cardiac Inflammation and Fibrosis Induced by Heart Failure Are Reversed by Short-Duration Estrogen Therapy
Authors: Andrea Iorga, Rangarajan Nadadur, Salil Sharma, Jingyuan Li, Mansoureh Eghbali
Journal: Circulation Research (2012)

Heart failure is generally characterized by increased fibrosis and inflammation, which leads to functional and contractile defects. We have previously shown that short-term estrogen (E2) treatment can rescue pressure overload-induced decompensated heart failure (HF) in mice. Here, we investigate the anti-inflammatory and anti-fibrotic effects of E2 on reversing the adverse remodeling of the left ventricle which occurs during the progression to heart failure. Trans-aortic constriction procedure was used to induce HF. Once the ejection fraction reached ∼30%, one group of mice was sacrificed and the other group was treated with E2 (30 αg/kg/day) for 10 days. In vitro, co-cultured neonatal rat ventricular myocytes and fibroblasts were treated with Angiotensin II (AngII) to simulate cardiac stress, both in the presence or absence of E2. In vivo RT-PCR showed that the transcript levels of the pro-fibrotic markers Collagen I, TGFβ, Fibrosin 1 (FBRS) and Lysil Oxidase (LOX) were significantly upregulated in HF (from 1.00±0.16 to 1.83±0.11 for Collagen 1, 1±0.86 to 4.33±0.59 for TGFβ, 1±0.52 to 3.61±0.22 for FBRS and 1.00±0.33 to 2.88±0.32 for LOX) and were reduced with E2 treatment to levels similar to CTRL. E2 also restored in vitro AngII-induced upregulation of LOX, TGFβ and Collagen 1 (LOX:1±0.23 in CTRL, 6.87±0.26 in AngII and 2.80±1.5 in AngII+E2; TGFβ: 1±0.08 in CTRL, 3.30±0.25 in AngII and 1.59±0.21 in AngII+E2; Collagen 1: 1±0.05 in CTRL.2±0.01 in AngII and 0.65±0.02 (p&lt;0.05, values normalized to CTRL)). Furthermore, the pro-inflammatory interleukins IL-1β and IL-6 were upregulated from 1±0.19 to 1.90±0.09 and 1±0.30 to 5.29±0.77 in the in vivo model of HF, respectively, and reversed to CTRL levels with E2 therapy. In vitro, IL-1β was also significantly increased ∼ 4 fold from 1±0.63 in CTRL to 3.86±0.14 with AngII treatment and restored to 1.29±0.77 with Ang+E2 treatment. Lastly, the anti-inflammatory interleukin IL-10 was downregulated from 1.00±0.17 to 0.49±0.03 in HF and reversed to 0.67±0.09 in vivo with E2 therapy (all values normalized to CTRL). This data strongly suggests that one of the mechanisms for the beneficial action of estrogen on left ventricular heart failure is through reversal of inflammation and fibrosis.