tbuckley/cabot-search huggingface dataset:
The 21-Gene Recurrence Score Assay for Node-Positive, Early-Stage Breast Cancer and Impact of RxPONDER Trial on Chemotherapy Decision-Making: Have Clinicians Already Decided?
Authors: Jagar Jasem, Christine M. Fisher, Arya Amini, Elena Shagisultanova, Rachel Rabinovitch, Virginia F. Borges, Anthony Elias, Peter Kabos
Journal: Journal of the National Comprehensive Cancer Network (2017)

Background: The 21-gene recurrence score (RS) assay is retrospectively validated for assessing prognosis and benefit from chemotherapy in hormone receptor–positive, early-stage breast cancer (EBC) with low RS. We hypothesized that oncologists have already incorporated the RS assay for decision-making in higher-risk, node-positive disease, despite the lack of prospective data and contrary to NCCN Guideline recommendations. This study provides the first analysis of trends and differences in RS use and therapeutic implications in a population-based data set of patients with node-positive EBC. It also assesses the impact of the RxPONDER trial on clinicians' chemotherapy recommendations. Methods: Node-positive EBC cases diagnosed during 2010 through 2012 and included in the National Cancer Data Base were used. Multivariate logistic regression was used to estimate test use and impact on chemotherapy recommendations. Results: The RS assay was ordered for 16.5% of the 80,405 identified patients. Of all variables, the RS assay had the strongest association with chemotherapy recommendation, with adjusted odds ratios (AORs) of 19 for scores >30. Odds of chemotherapy recommendation were significantly lower for the group who received the test (AOR, 0.21; 95% CI, 0.20–0.22). When divided based on the cutoff point of 25 adopted by the RxPONDER trial, those with an RS of 18 to 25 had significantly lower odds of chemotherapy recommendation compared with those with an RS of 26 to 30 (AOR, 0.32; 95% CI, 0.26–0.40). Test use was lower for blacks, community centers, uninsured/governmentally insured patients, higher tumor grade, larger tumor size, and more nodes involved. Chemotherapy recommendation was higher for patients of younger age, with private insurance, and with higher tumor grade, size, and number of nodes involved. Black patients had significantly higher RS (AOR, 1.37; 95% CI, 1.25–1.79). Conclusions: The RS assay influences clinicians' chemotherapy recommendation in node-positive EBC. Clinicians are using the inclusion criteria of the RxPONDER trial before its final release. Black patients have higher RS, likely representing worse biology. Significant differences exist in test use and clinical implications based on race, insurance, and facility.
P09.49 Prognostic significance of MGMT promoter and mismatch repair system in newly-diagnosed and recurrent malignant gliomas
Authors: K. Saito, K. Kobayashi
Journal: Neuro-Oncology (2017)

Introduction: Malignant glioma, especially glioblastoma (GBM) has a dismal prognosis despite standard treatment with temozolomide (TMZ). Most patients recur as treatment resistance develops and result in fatal outcome. The resistance to TMZ attributes largely to DNA repair enzyme, O6-methylguanine-DNA methyltransferase (MGMT) and mismatch repair (MMR) system. MMR defects are not only caused by TMZ treatment, but also found in primary glioma and are associated with resistance to TMZ and TMZ-induced hypermutator phenotype. However, the association between alteration of MMR system and clinical outcome of both primary and recurrent GBM was yet to be elucidated. Methods: TMZ-treated newly-diagnosed GBMs (135 cases) and gliomas whose initial and recurrent specimens were available (36cases) are eligible for this study. MGMT methylation status, mutations in IDH1/2 and MSH6, and protein expression of MMR genes (MLH1, MSH2, MSH6, and PMS2) were determined by methylation-specific PCR (MSP), Sanger sequencing, and immunoblots/immunohistochemistry staining, respectively. For comprehensive gene mutation analysis, we performed targeted sequencing using Ion Ampliseq Cancer Hotspot Panel. Progression-free and overall survival times according to each molecular status were reviewed. Results: Loss of MMR protein expression (MLH1, MSH2, MSH6, and PMS2) in newly-diagnosed samples was observed in 10.5%, 9.7%, 36.6%, and 11.9%, respectively. In MGMT unmethylated GBM, low expression of MLH 1 or MSH 6 was a significant prognosticator for overall survival (p<0.05), but not for progression-free survival, indicating survival after TMZ treatment failure was significantly shorter in tumors with MMR defects and MGMT unmethylated promoter. In MGMT methylated GBM, MMR protein expression did not correlate with prognosis. After recurrence, there was no correlation between MGMT methylation status and prognosis, whereas patients with reduced MMR protein expression at recurrence tended to have better survival than those with stable MMR expression. The results of mutation analysis of initial and recurrent samples will be reported. Conclusions: Defective MMR may be involved in TMZ resistance in newly-diagnosed GBM with unmethylated MGMT promoter. Further investigation to define optimal treatment for glioma according to MGMT and MMR status is warranted.
Constitutively Active SPAK Causes Hyperkalemia by Activating NCC and Remodeling Distal Tubules
Authors: P. Richard Grimm, Richard Coleman, Eric Delpire, Paul A. Welling
Journal: Journal of the American Society of Nephrology (2017)

Aberrant activation of with no lysine (WNK) kinases causes familial hyperkalemic hypertension (FHHt). Thiazide diuretics treat the disease, fostering the view that hyperactivation of the thiazide-sensitive sodium-chloride cotransporter (NCC) in the distal convoluted tubule (DCT) is solely responsible. However, aberrant signaling in the aldosterone-sensitive distal nephron (ASDN) and inhibition of the potassium-excretory renal outer medullary potassium (ROMK) channel have also been implicated. To test these ideas, we introduced kinase-activating mutations after Lox-P sites in the mouse Stk39 gene, which encodes the terminal kinase in the WNK signaling pathway, Ste20-related proline-alanine-rich kinase (SPAK). Renal expression of the constitutively active (CA)-SPAK mutant was specifically targeted to the early DCT using a DCT-driven Cre recombinase. CA-SPAK mice displayed thiazide-treatable hypertension and hyperkalemia, concurrent with NCC hyperphosphorylation. However, thiazide-mediated inhibition of NCC and consequent restoration of sodium excretion did not immediately restore urinary potassium excretion in CA-SPAK mice. Notably, CA-SPAK mice exhibited ASDN remodeling, involving a reduction in connecting tubule mass and attenuation of epithelial sodium channel (ENaC) and ROMK expression and apical localization. Blocking hyperactive NCC in the DCT gradually restored ASDN structure and ENaC and ROMK expression, concurrent with the restoration of urinary potassium excretion. These findings verify that NCC hyperactivity underlies FHHt but also reveal that NCC-dependent changes in the driving force for potassium secretion are not sufficient to explain hyperkalemia. Instead, a DCT-ASDN coupling process controls potassium balance in health and becomes aberrantly activated in FHHt.
Biofilm three-dimensional architecture influences in situ pH distribution pattern on the human enamel surface
Authors: Jin Xiao, Anderson T Hara, Dongyeop Kim, Domenick T Zero, Hyun Koo, Geelsu Hwang
Journal: International Journal of Oral Science (2017)

To investigate how the biofilm three-dimensional (3D) architecture influences in situ pH distribution patterns on the enamel surface. Biofilms were formed on human tooth enamel in the presence of 1% sucrose or 0.5% glucose plus 0.5% fructose. At specific time points, biofilms were exposed to a neutral pH buffer to mimic the buffering of saliva and subsequently pulsed with 1% glucose to induce re-acidification. Simultaneous 3D pH mapping and architecture of intact biofilms was performed using two-photon confocal microscopy. The enamel surface and mineral content characteristics were examined successively via optical profilometry and microradiography analyses. Sucrose-mediated biofilm formation created spatial heterogeneities manifested by complex networks of bacterial clusters (microcolonies). Acidic regions (pH<5.5) were found only in the interior of microcolonies, which impedes rapid neutralization (taking more than 120 min for neutralization). Glucose exposure rapidly re-created the acidic niches, indicating formation of diffusion barriers associated with microcolonies structure. Enamel demineralization (white spots), rougher surface, deeper lesion and more mineral loss appeared to be associated with the localization of these bacterial clusters at the biofilm-enamel interface. Similar 3D architecture was observed in plaque-biofilms formed in vivo in the presence of sucrose. The formation of complex 3D architectures creates spatially heterogeneous acidic microenvironments in close proximity of enamel surface, which might correlate with the localized pattern of the onset of carious lesions (white spot like) on teeth. Acidic microenvironments created by bacterial clusters thriving in a polysaccharide matrix could be behind localized tooth decay. Jin Xiao of the University of Rochester Medical Center and Geelsu Hwang of the University of Pennsylvania with colleagues in the US mapped acidity changes across tooth enamel caused by the microstructure of dental plaque: a film of bacteria and the polysaccharide matrix they secrete. Using fluorescence microscopy, they studied the 3D architecture of plaque that formed on human enamel specimens exposed to sugar solutions. They also measured acidity levels and surface roughness on the enamel. Enamel exposed to sucrose revealed densely packed bacterial clusters surrounded by polysaccharide matrix, creating localized acidic environments and deep lesions on the enamel surface. Biofilms on enamel exposed to glucose or fructose did not form organized bacterial clusters.
A Multicenter Study Evaluating the Safety of Romiplostim at Maximal Dosage for Emergency Bleeding Situations in Immune Thrombocytopenia
Authors: Mathilde Roumier, Louis Terriou, Mohamed Hamidou, Antoine Dossier, Anne Sophie Morin, Virginie Zarrouk, Mickael Ebbo, Guillaume Moulis, Lionel Galicier, Sylvain Audia, Laetitia Languille, Marie Goussef, Solène Poutrel, Marc Michel, Bertrand Godeau, Matthieu Mahévas
Journal: Blood (2016)
P09.27 Effectiveness of antiangiogenic drugs (ADs) in glioblastoma (GBM) patients (PTS): a metanalysis of randomized clinical trials (RCTs)
Authors: G. Lombardi, L. Bellu
Journal: Neuro-Oncology (2017)

Background: GBMs are highly vascularized tumors and various ADs have been investigated in clinical trials showing unclear results. We performed this metanalysis to evaluate the effectiveness of ADs, in terms of progression-free survival (PFS) and overall survival (OS), as first or second-line therapy and their association with chemotherapy in GBM PTS. Methods: the authors searched relevant published and unpublished RCTs analyzing ADs versus chemotherapy in GBM PTS from 2000 to January 2016 in MEDLINE, WEB of SCIENCE, ASCO, ESMO and SNO databases. Results: sixteen RCTs (9 with bevacizumab, 2 cilengitide, 1 enzastaurin, 1 dasatinib, 1 vandetanib, 1 temsirolimus, 1 cediranib) were identified including 4566 PTS. All trials showed no improvement in OS with a pooled HR of 1.02 (95% CI 0.93-1.1; p = 0.7). The use of bevacizumab (BEV) did not improve OS; indeed, the pooled HR for OS for BEV studies (9 studies, 2752 PTS) was 0.98 (95% CI 0.89-1.08; p = 0.7); 6 RCTs (2084 PTS) analyzed BEV as first-line and the pooled HR for OS was 1.02 (95% CI 0.88-1.19; p = 0.8); 3 RCTs studied BEV as second-line therapy and the pooled HR for OS was 0.95 (95% CI 0.77-1.17; p = 0.6). No improvement of OS was shown when BEV was associated with chemotherapy (2588 PTS) with a pooled HR of 0.99 (95% CI 0.88-1.11; p = 0.8). Seven RCTs with a different AD demonstrating no improvement of OS versus standard treatment with a pooled HR of 1.05 (95% CI 0.89-1.23; p = 0.5). 14 RCTs (4349 PTS) were analyzed for PFS and the use of ADs showed a statistically longer PFS with a pooled HR of 0.73 (95% CI 0.62-0.86;p < 0.01); However, among ADs, only bevacizumab (2752 PTS) demonstrated an improvement of PFS; indeed, the pooled HR for PFS for BEV studies was significant at HR = 0.6 (95% CI 0.5-0.7; p < 0.01), both alone (HR = 0.6; CI 95% 0.44-0.82; p < 0.01) or in combination to CT (HR = 0.6; 95% CI 0.4-0.7;p < 0.01), both as first-line treatment (HR = 0.65; 95% CI 0.52-0.83; p < 0.01) or in recurrent disease (HR = 0.51; 95% CI 0.43-0.61; p < 0.01). Conclusions: ADs did not improve OS in GBM PTS, both as first or second-line treatment. Among ADs, only BEV demonstrated a PFS benefit both as single agent or in combination with chemotherapy, both as first or second-line treatment.
Still no “credible plan” to increase GP numbers, say MPs
Authors: Matthew Limb
Journal: BMJ (2017)

The government has made “no progress” on increasing the number of GPs in England one year after it committed to recruit 5000 more by 2020, a report by MPs has said.

The Public Accounts Committee issued a progress report on 27 April on its inquiry into access to general practice.2 It said that GP numbers had actually fallen in the past year—from 34 592 full time equivalent doctors in September 2015 to 34 495 in September 2016.1

The committee said that more trainee GPs were being recruited, but the latest recruitment target was missed and the NHS was still having problems retaining existing staff. “Health Education England still lacks a credible plan for ensuring that …
P16.22 Awake-Awake-Awake with dexmedetomidine compared to asleep-awake-asleep craniotomies in glioma surgery - an analysis from 180 glioma patients
Authors: S. Schipmann, E. Suero, I. Müller, J. Wölfer, C. Ewelt, M. Schwake, M. Maas, W. Stummer
Journal: Neuro-Oncology (2017)

Introduction: For over 70 years, awake craniotomies have been part of treatment of gliomas located in so called “eloquent regions”. The patients’ compliance plays an important role in the success of each surgery. Finding the optimal balance between dosage and type of sedative, analgesic and anxiolytic drugs and keeping the patient clinically and neurologically assessable remains challenging. Different techniques are applied in neurooncology centres: “Asleep-awake-asleep” and “awake-awake-awake” are both techniques which have been used at the Department of Neurosurgery, University Hospital of Münster. Since 2013, we performed solely “awake-awake-awake” surgeries using the a2-receptor agonist, dexmedetomidine, as sole anaesthetic drug. The aim of this study was to compare both techniques and evaluate the clinical use of dexmedetomidine in the setting of awake craniotomies for glioma surgery. Material and methods: We retrospectively analysed patients that were operated in the Department of Neurosurgery, University Hospital of Muenster either under “asleep-awake-asleep” using propofol-remifentanil sedation, or under “awake-awake-awake” conditions, using dexmedetomidine infusions. In the,,asleep-awake-asleep”- group patients were intubated with laryngeal mask and extubated for the assessment period. Patients in the fully awake group were sedated with dexmedetomidine beyond the test phase. A scalp block was used in both conditions. We evaluated the electronical medical record and the digitalized anesthetic protocols from each patient. Adverse events, as well as applied drugs with doses and frequency of usage were recorded. Compliance was evaluated according to the surgeons’ perception. Results: Two-hundred twenty-four (n=224) awake surgeries were performed in the period from October 2009 till September 2015. One-hundred eighty (n=180) of these were performed for the resection of gliomas and included into the study. In the “awake-awake-awake”- group (n=75) significantly less opiates (p<0.000), less vasoactive (p<0.000) and antihypertensive (p<0.000) drugs were used in comparison to the “asleep-awake-asleep”- group (n=105). In addition, compliance was much higher rated in the “awake-awake-awake”-group. Furthermore, the overall length of stay (p<0.000) and the surgical time (p<0.000) was significantly lower in the “awake-awake-awake” group. Conclusions: Dexmedetomidine provides excellent setting for fully awake surgeries. Our experience shows that using dexmedetomidine as sole anaesthetic drug during awake craniotomies sedates moderately and acts anxiolytic. Thus, after ceasing infusion it enables quick and reliable clinical neurological assessment of patients. Furthermore, according to our experience, it reduces the length of hospital stay and duration of the whole surgical procedure.
Outbreaks of Escherichia coli O157:H7 Infection Associated With Eating Alfalfa Sprouts—Michigan and Virginia, June-July 1997
Journal: JAMA (1997)

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Saturated fat does not clog the arteries: coronary heart disease is a chronic inflammatory condition, the risk of which can be effectively reduced from healthy lifestyle interventions
Authors: Aseem Malhotra, Rita F Redberg, Pascal Meier
Journal: British Journal of Sports Medicine (2017)

Coronary artery disease pathogenesis and treatment urgently requires a paradigm shift. Despite popular belief among doctors and the public, the conceptual model of dietary saturated fat clogging a pipe is just plain wrong. A landmark systematic review and meta-analysis of observational studies showed no association between saturated fat consumption and (1) all-cause mortality, (2) coronary heart disease (CHD), (3) CHD mortality, (4) ischaemic stroke or (5) type 2 diabetes in healthy adults.1 Similarly in the secondary prevention of CHD there is no benefit from reduced fat, including saturated fat, on myocardial infarction, cardiovascular or all-cause mortality.2 It is instructive to note that in an angiographic study of postmenopausal women with CHD, greater intake of saturated fat was associated with less progression of atherosclerosis whereas carbohydrate and polyunsaturated fat intake were associated with greater progression.3 

The inflammatory processes that contribute to cholesterol deposition within the artery wall and subsequent plaque formation (atherosclerosis), more closely resembles a ‘pimple’ (figure 1). Most cardiac events occur at sites with <70% coronary artery obstruction and these do not …
P10.07 Prognostic factors of gliosarcoma - a single institution study
Authors: H. Kim, S. Kim, J. Chang, C. Suh, J. Cho
Journal: Neuro-Oncology (2017)

Purpose: Gliosarcoma is an extremely rare disease, which is a variant of glioblastoma exhibiting a biphasic histologic characteristic of both glial and mesenchymal components. We investigated to identify prognostic or therapeutic factors impacting on survival outcomes in patients with gliosarcoma treated in a single institution. Materials and Methods: Patients who had been treated with a pathology-confirmed diagnosis of gliosarcoma at Yonsei University Medical Center between 1991 and 2015 were retrospectively analyzed. Patients who were <20 years old at diagnosis or have not been followed up after treatment were excluded. Primary gliosarcoma (PGS) was defined as a tumor developed de novo, whereas those diagnosed subsequent to glioblastoma that have been treated with surgery and adjuvant radiotherapy were termed secondary gliosarcoma (SGS). Molecular analysis performed on eight patients including IDH1, TP53, Ki-67 and EGFR. Results: A total of 19 patients were identified, including 17 PGS and 2 SGS patients. All patients received surgery followed by adjuvant radiotherapy with a median dose of 60 Gy. Gross total resection was performed in 6 patients, while subtotal resection was performed in 13 patients. The concurrent chemotherapy with temozolomide was performed in 10 patients. The Median overall survival (OS) for all patients was 12.9 months from the diagnosis of gliosarcoma, with a progression free survival (PFS) of 5.5 months. The median OSs were 12.9 and 5.2 months for PGS and SGS, respectively (P = 0.035) and the median PFSs were 6.1 and 0.8 months (P = 0.048). In the two cases of SGS, SGS developed 10 and 18 months after the diagnosis of GBM for each. The univariate analysis revealed that good performance status (KPS ≥ 80), PGS and salvage treatment after recurrence were significant prognostic factors related to better OS. All these factors were also remained as independent prognostic factors for OS in the multivariate analysis. Molecular analysis revealed a high incidence of TP53 mutations and, rarely, EGFR and IDH1 mutations. Conclusion: Primary and secondary gliosarcoma had an even poorer survival, compared with primary and recurrent glioblastoma, respectively, in patients treated during the same period in our institution. Further molecular marker study should be done to explain the dismal prognosis of gliosarcoma. And multi-institutional collaborative study is needed to characterize prognostic factors and design optimal treatment.