tbuckley/cabot-search huggingface dataset:
Integrating a paradigm shift in the treatment of metastatic colorectal cancer: Effect of online CME on oncologists' knowledge and competence
Authors: T. Herrmann, D. Cameron, A. Carothers, T. Bekaii-Saab
Journal: Annals of Oncology (2018)

Introduction: The objective of this study was to determine the effect of online continuing medical education on the knowledge and competence of oncologists regarding the management of metastatic renal cell cancer (mCRC) among community oncologists. Methods: The effect of two case-based educational interventions (5000 word interactive text-based and 30-minute video-based) on the treatment of mCRC was analyzed to determine efficacy of online, on-demand, education. The activities launched online in July and December 2017 and data were collected through February 2018. To assess educational effectiveness, participants were asked a set of case-based questions prior to, and again after, exposure to one of the activities. A Chi-square Test of Independence determined statistical significance while Cramer's V was used to estimate the effect of each intervention on oncologists' knowledge and competence. Results: 185 oncologists, 78% of whom saw 10 or fewer patients with mCRC per month indicating that they work in the community, were assessed. Upon completion of either activity, a pre- to post-activity assessment improvement was observed in oncologists': Identification of the most appropriate evidence-based regimen for a patient with mCRC that has progressed on two prior therapies (53% vs 65%, P = 0.10; 58% vs 87%, P < 0.001). Implications of tumor characteristics including BRAF mutational status and presence of right-sided disease on the care of patients with mCRC (65% vs 82%, P < 0.001). Confidence in selecting the most appropriate option for a patient with mCRC whose disease has progressed on therapy (+10% and +17%). Recognition of, and counseling on, common treatment-related adverse events in a patient with mCRC (72% vs 87%, P < 0.001). Conclusion: Use of online, text and video, case-based CME interventions improved the knowledge and competence of participating oncologists, showing that unique educational methodologies and platforms, which are available on-demand can be effective tools for advancing clinical decision making in the rapidly changing environment of mCRC disease management. Additional studies are needed to assess whether improved aptitude translates to improved performance during clinical practice.
EMBR-05. TUMORS OF THE PINEAL REGION CAN BE CLASSIFIED INTO DISTINCT SUBGROUPS BASED ON MOLECULAR CHARACTERISTICS CORRELATING WITH CLINICAL PARAMETERS AND GENETIC ALTERATIONS
Authors: Elke Pfaff, Matija Snuderl, Matthias A Karajannis, Christian Aichmüller, Martin Sill, Brent A Orr, David W Ellison, Stefan M Pfister, David T W Jones
Journal: Neuro-Oncology (2018)

Several different entities with distinct clinical and histopathological features are described within in the group of pineal tumors. Whereas pineocytoma (PC), pineal parenchymal tumors of intermediate differentiation (PPTID) and papillary tumors of the pineal region (PTPR) predominantly affect adults and are associated with a relatively favorable prognosis, pineoblastoma (PB) occurs at young age and constitutes a highly aggressive tumor. Despite multimodal treatment, prognosis is poor (especially for infants and patients with metastatic disease), and therapeutically actionable molecular targets are lacking to date. Most PB arise sporadically, however, DICER1 or RB1 germline mutations are known to predispose to the development of PB, the latter in the context of trilateral retinoblastoma. Genome-wide DNA methylation profiling and copy-number analysis were used to investigate the biological features of 230 pineal tumors of different histologies. Known histopathological entities (PC, PTPR, PPTID) could be clearly separated by unsupervised clustering, as well as further distinct subgroups, including the previously hypothesized PTPR-A and PTPR-B groups. Notably, several biologically discrete subgroups were formed by the tumors initially diagnosed as PB or pineal primitive embryonal tumors/PNETs, which showed distinct clinical associations (e.g. age distribution). Somatic deletions of DROSHA, an endoribonuclease involved in miRNA processing upstream of DICER1, seem to be a recurrent feature of the largest subgroup. Rarer DICER1 and DGCR8 alterations in this group confirm a central role of altered miRNA biogenesis in the development of this subset of PB. Further molecular and functional characterization of novel sub-clusters, including ongoing miRNA-seq, will provide insights into the oncogenesis of PB.
Squamous cell carcinoma of the anal canal and the results of radical treatment with intensity-modulated radiotherapy
Authors: I. Oblak, V. Velenik, F. Anderluh, E. Brecelj, J. But-Hadzic, A. Secerov-Ermenc, A. Jeromen
Journal: Annals of Oncology (2018)

Introduction: Anal canal cancer is predominantly a locoregional disease and distant metastases are found in only 5–10% of the patients. The treatment of choice is radical radiochemotherapy with the sphincter preservation rates of around 80%, even in cases with locally advanced disease. Surgery is a salvage treatment used only in cases of residual or recurrent disease after radiochemotherapy and for complications of radiotherapy. Before 2013, in our institution 3D conformal radiotherapy using a four-field box technique on a 15 MV linear accelerator, was used. Several authors have reported that intensity-modulated radiation therapy (IMRT) for anal cancer can dramatically reduce rates of acute and late adverse effects, while maintaining excellent rates of cure and sphincter preservation. The aim of the study was to retrospectively asses the results of treatment with IMRT and concomitant chemotherapy with fluoropyrimidine derivatives and mitomycin C in patients with squamous cell carcinoma of the anal canal, who were treated at our institution. Methods: Between January 2013 and January 2018, 48 (38 female, 10 male) patients with anal canal cancer were treated with radical intent. Patients were irradiated with IMRT with simultaneous integrated boost technique in 30 fractions to the dose of 45 Gy to the elective volume and 54 Gy or 57 Gy (in cases of bulky disease with tumor diameter of more than 3 cm) to the tumor bed. Actuarial rates of locoregional control (LRC), disease-free survival (DFS), disease-specific survival (DSS), overall survival (OS), colostomy-free survival (CFS) and the rates of acute and chronic side-effects were estimated. Results: Forty-four (93.7%) patients completed treatment according to the protocol. The median follow-up time in 44 (91.7%) survivors was 23 months (range 6-55 months). At 2-years LRC, DFS, DSS, OS and CFS rates were 80.3%, 80.3%, 94.8%, 94.8% and 87.1%, respectively. The most frequent acute side effect of the treatment was radiodermatitis (grade 3 in 79.2% of patients). Dysuria, diarrhoea, infection and hematologic side effects grade 3 were noticed in 4.2%, 6.3%, 10.4% and 8.3% of patients, respectively. Grade 3 late radiation side effects according to the LENT-SOMA scoring system were observed in 5 (10.4%) patients. The most frequent late side effects grade 3 were skin changes and anal sphincter dysfunction with incontinence in 4 (8.3%) and 2 (4.2%) of colostomy-free survivors, respectively. Conclusion: Radiotherapy with IMRT and concurrent chemotherapy with fluoropyrimidines and mitomycin C is feasible and with acceptable toxicity. By comparing our present results of acute toxicity with the results of 3D conformal radiotherapy toxicity published in 2012, we can conclude that treatment with IMRT is less toxic. However, further analysis with longer follow up is needed for the comparison of late side effects.
Metachromatic Leukodystrophy
Authors: Letterio S. Politi, Ettore Salsano, Alessandra Biffi
Journal: JAMA Neurology (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Neurology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Neurology journal
The c-Myc quadruplex-forming sequence inhibits c-Myc expression and leukemic cell proliferation
Authors: Kara Sedoris, Shelia Thomas, Donald Miller
Journal: Cancer Research (2008)

92   The promoters of several cancer related genes, including the c-myc oncogene, contain sequences capable of forming quadruplex (four- stranded) DNA. The c-myc quadruplex-forming sequence is located upstream of the P1 and P2 promoters of c-myc, which are responsible for up to 95% of total c-myc transcription. This sequence is a 27 bp guanine rich strand (Pu27) forming four loop isomers and appears to play an important role in regulating c-myc expression, although the exact mechanism is unknown. Formation of a quadruplex structure by this sequence appears to negatively regulate c-myc transcription. In order to determine the biological role of Pu27 on cellular proliferation and c-myc expression, U937 leukemia cells were treated with 10 uM of Pu27 or the 27 bp mutant sequence (MutPu27), which lacks strings of two or more guanines. Changes in cell proliferation were measured and compared to c-myc mRNA. Quadruplex formation was confirmed by circular dichroism spectroscopy. Pu27 formed a stable parallel quadruplex structure while the MutPu27 did not form a quadruplex. After 72 h of exposure to Pu27, U937 proliferation was inhibited by more than 90% compared to untreated U937 cells, while MutPu27 treatment had only a minimal effect. Decreased proliferation with Pu27 corresponded with a 90% decrease in c-myc mRNA. In parallel experiments, we tested the effect of Pu27 on cells which had been stably transfected with a vector in which luciferase gene expression was regulated by the c-myc promoter. The luciferase activity in these cells showed marked attenuation in cells treated with Pu27, but not MutPu27. The intracellular stability of Pu27 was determined using fluorescein-labeled Pu27. These studies demonstrated remarkable intracellular stability of Pu27, with a half life of greater than nine days. To characterize the mechanism of action of Pu27, we performed electrophoretic mobility shift assays (EMSA) with an extract from U937 cells. These results demonstrated specific protein binding to the quadruplex sequence. Our results demonstrate striking growth inhibition by the wild type c-myc promoter quadruplex forming sequence, but not by the mutated sequence. They suggest that physiologic G-quadruplex formation in the c-myc promoter region modulates cell proliferation through inhibition of c-myc mRNA. Further, these results suggest that protein binding to Pu27 may play a role in regulating Pu27-mediated inhibition of c-myc mRNA.
Prognostic Value of Methylator Phenotype in Stage III Colon Cancer Treated with Oxaliplatin-based Adjuvant Chemotherapy
Authors: Claire Gallois, Julien Taieb, Delphine Le Corre, Karine Le Malicot, Josep Tabernero, Claire Mulot, Jean-François Seitz, Thomas Aparicio, Gunnar Folprecht, Côme Lepage, Enrico Mini, Jean-Luc Van Laethem, Jean-François Emile, Pierre Laurent-Puig
Journal: Clinical Cancer Research (2018)

Purpose: There are conflicting results concerning the prognostic value of the CpG island methylator phenotype (CIMP) in patients with nonmetastatic colon cancer. We studied this phenotype in stage III colon cancer characterized for mismatch repair (MMR), RAS, and BRAF status, and treated with adjuvant FOLFOX-based regimen.Experimental Design: Tumor samples of 1,907 patients enrolled in the PETACC-8 adjuvant phase III trial were analyzed. The method used was methylation-specific PCR, where CIMP+ status was defined by methylation of at least 3 of 5 following genes: IGF2, CACNA1G, NEUROG1, SOCS1, and RUNX3 Association between CIMP status and overall survival (OS), disease-free survival (DFS), and survival after recurrence (SAR), was assessed by Cox model adjusted for prognostic factors and treatment arm (FOLFOX4 ± cetuximab).Results: CIMP status was successfully determined in 1,867 patients (97.9%): 275 (14.7%) tumors were CIMP+ Compared with CIMP- patients, CIMP+ patients were more frequently older (P = 0.002), females (P = 0.04), with right-sided (P < 0.0001), grade 3-4 (P < 0.0001), pN2 (P = 0.001), dMMR (P < 0.0001), BRAF mutated (P < 0.0001), and RAS wild-type (P < 0.0001) tumors. In multivariate analysis, CIMP+ status was associated with shorter OS [HR, 1.46; 95% confidence interval (CI), 1.02-1.94; P = 0.04] and SAR [HR, 1.76; 95% CI, 1.20-2.56; P < 0.0004]; but not DFS [HR, 1.15; 95% CI, 0.86-1.54; P = 0.34]. A nonsignificant trend of detrimental effect of cetuximab was observed in patients with CIMP+ tumors for OS, DFS, and SAR.Conclusions: In a large cohort of well-defined patients with stage III colon cancer, CIMP+ phenotype is associated with a shorter OS and SAR but not to DFS. Clin Cancer Res; 24(19); 4745-53. ©2018 AACR.
MBRS-28. SINGLE-CELL TRANSCRIPTOME ANALYSIS OF MEDULLOBLASTOMA
Authors: Volker Hovestadt, Mariella G Filbin, Laure Bihannic, McKenzie L Shaw, John M DeWitt, Andrew Groves, Kyle S Smith, Jennifer Hadley, Amar Gajjar, Giles W Robinson, Lisa Mayr, Irene Slavc, Liliana Goumnerova, Keith L Ligon, Mario L Suva, Paul A Northcott, Bradley E Bernstein
Journal: Neuro-Oncology (2018)

Human cancers are composed of cells with heterogeneous genetic and epigenetic states, resulting in substantial phenotypic diversity. Medulloblastoma (MB), a clinically challenging, malignant childhood brain tumor, is no exception. A better understanding of its cellular heterogeneity is urgently needed in order to develop more efficacious therapeutic strategies that eliminate all tumor subclones underlying MB initiation, maintenance, progression, and relapse. We used single-cell RNA sequencing to assess intratumoral heterogeneity in 20 MB samples representing all four molecular subgroups. Fresh surgical biopsies were dissociated and flow sorted into single cells prior to full-length transcriptome sequencing using the Smart-seq2 protocol. Computational analyses conducted on >6,000 single cells identified cellular hierarchies ranging from proliferative, undifferentiated cell types to more differentiated neural- and astrocyte-like progeny. Transcriptional differences in undifferentiated cell populations between MB subgroups suggested distinct cellular origins, and informed oncogenic pathways believed to promote MB pathogenesis. Identification of transcriptional programs active in single cells aided the deconvolution of published bulk RNA-seq profiles, providing a deeper understanding of the heterogeneity characteristic of Group 3/4 subtypes. Lastly, inference of copy-number variations and probable driver-gene mutations from the single-cell data provided evidence for genetic subclones in a subset of patients. Overlaying transcriptional profiles on MB genetic subclones unveiled how oncogenic programs adapted during tumor evolution. These interim results provide unparalleled insights into the cellular heterogeneity of MB subgroups. Analyses aimed at further resolving molecular substructure in Group 3/4, verifying the developmental origins of MB subgroups, and implicating defined cell populations driving tumorigenesis are ongoing.
Development of Paper-Based Analytical Devices for Minimizing the Viscosity Effect in Human Saliva
Authors: Julaluk Noiphung, Michael P. Nguyen, Chamindie Punyadeera, Yunxia Wan, Wanida Laiwattanapaisal, Charles S. Henry
Journal: Theranostics (2018)

Rationale: Saliva as a sample matrix is rapidly gaining interest for disease diagnosis and point-of-care assays because it is easy to collect (non-invasive) and contains many health-related biomarkers.However, saliva poses particular problems relative to more common urine and blood matrices, which includes low analyte concentrations, lack of understanding of biomolecule transportation and inherent viscosity variability in human samples.While several studies have sought to improve assay sensitivity, few have addressed sample viscosity specifically.The goal of this study is to minimize the effect of sample viscosity on paper-based analytical devices (PADs) for the measurement of pH and nitrite in human saliva.Methods: PADs were used to measure salivary pH from 5.0 to 10.0 with a universal indicator consisting of chlorophenol red, phenol red and phenolphthalein.Nitrite determination was performed using the Griess reaction.Artificial saliva with viscosity values between 1.54 and 5.10 mPa•s was tested on the proposed PAD.To ensure the proposed PADs can be tailored for use in-field analysis, the devices were shipped to Australia and tested with human specimens.Results: Initial experiments showed that viscosity had a significant impact on the calibration curve for nitrite; however, a more consistent curve could be generated when buffer was added after the sample, irrespective of sample viscosity.The linear range for nitrite detection was 0.1 to 2.4 mg/dL using the improved method.The nitrite measurement in artificial saliva also showed a good correlation with the standard spectrophotometry method (p=0.8484,paired sample t-test, n=20).Measured pH values from samples with varying viscosities correlated well with the results from our pH meter.Conclusions: The inherent variation of salivary viscosity that impacts nitrite and pH results can be addressed using a simple washing step on the PAD without the need for complex procedures.
Urgent primary care services work well but are under-resourced, says CQC
Authors: Adrian O’Dowd
Journal: BMJ (2018)

The vast majority of urgent primary care services in England work well and provide a good, cost effective service, but their worth is underestimated with poor resourcing, the main NHS regulator has said.1

The Care Quality Commission (CQC) collected results and ratings from its inspections of 147 providers of urgent primary care: 64 urgent care and walk-in centres, 20 NHS 111 services, and 63 GP out-of-hours services.

Results showed that most (87%) of these providers were rated as either good (118) or outstanding (10), while 13% were either described as requiring improvement (16) or rated as inadequate (3).

The authors emphasised that …
MBRS-07. BCOR LOSS IMPACTS SHH MEDULLOBLASTOMA FORMATION VIA TRANSCRIPTIONAL UP-REGULATION OF Igf2
Authors: Daisuke Kawauchi, Jessica Clark, Konstantin Okonechnikov, Nadja Batora, Mikaella Vouri, Sjoerd van Rijn, Micah Gearhart, Brent Orr, Andrey Korshunov, Marcel Kool, Vivian Bardwell, Stefan Pfister, Paul Northcott
Journal: Neuro-Oncology (2018)

Sonic hedgehog (SHH) medulloblastoma (MBSHH) accounts for approximately 25% of all MB diagnoses and is the predominant disease subgroup in infants and adults. In addition to obligatory constitutive activation of SHH signaling, previous studies have indicated the requirement of secondary genetic hits for transformation of cerebellar granule cell progenitors (GNPs) to MBSHH. Recent MB genomic studies have identified subgroup-specific recurrent mutations of chromatin modifiers. However, functional evidence substantiating a role for these mutations in MBSHH progression is currently lacking. Here, we report the first evidence that BCOR, a subunit of the PRC1.1 complex targeted by deleterious mutations in ~10% of MBSHH patients, functions as an inhibitor of MBSHH progression. Given that BCOR mutants in human MBSHH commonly lack the PUFD domain, we utilized Bcor-knockout mice that recapitulate loss of this functional domain. Conditional genetic ablation of Bcor in GNPs strongly accelerated tumor formation in Ptch1+/- mice. Transcriptional analyses revealed ~100-fold upregulation of Igf2 in Bcor-deficient Ptch1+/- MBs versus controls. Igf2 upregulation was only observed in neoplastic lesions but not in developing granule cells, indicating potential epigenetic regulation of Igf2 during tumorigenesis. Forced expression of Igf2 in Ptch1+/- GNPs generated tumors with 100% penetrance. In human MBSHH, we observed a striking association between deleterious BCOR mutations and high IGF2 expression, substantiating the results observed in transgenic mice. Thus, Bcor attenuates Igf2 expression in transforming GNPs, loss of which cooperates with aberrant SHH signaling to promote Igf2-dependent tumor growth. Ongoing work involves studying the molecular mechanisms underlying Bcor-dependent Igf2 regulation.
PTH-070 The prevalence of anaemia in ibd, and the demand for intra-venous iron therapy: a 7 year retrospective review
Authors: A Gould, LB Johnson, K Lithgo, GD Sakthivel, MW Johnson
Journal: Gut (2017)

Introduction  The current prevalence of IBD in UK is said to be 400/100,000 (0.4%). Anaemia is a common problem in IBD, contributing to tiredness and lethargy, and has multifactorial causes. Current ECCO guidelines recommend that all patients with IBD should be assessed for iron deficiency anaemia (IDA) and that iron supplementation be given as indicated in their European Consensus Guidelines [2].  Objective  To assess the prevalence of Iron deficiency anaemia (IDA) in our IBD cohort,. The frequency these patients presented with IDA was also reviewed, along with the appropriate provision of intravenous (IV) iron, where needed.  Method  The Luton and Dunstable (L and D) University Hospital serves a catchment of 3 30 000 and has a database of 3014 IBD patients (0.9%). This is made up of 186 Proctitis, 1447 UC, 1037 Crohn’s, 71 Microscopic colitis, 273 Indeterminate colitis patients. A 7 year retrospective database was also created, documenting each occasion a patient to the hospital with blood tests confirming iron deficiency anaemia (IDA). For the purposes of this study we defined iron deficiency anaemia as a haemoglobin level of   Results  The prevalence of IBD is high in the local area (almost 1%). Over the 7 year review period, 633 (21%) of our local IBD patients were found to have IDA, with an median Hb level of 118 (130-47) g/L and ferritin count of 16.9 (49.8–2.4) ng/ml (median for men and women for Hb was 114 and 119 respectively, and for ferritin was 18.3 and 15.2 g/L, respectively). Of these, just 71 (11.3%) with a median Hb level of of 109 (130-35) g/L and ferritin count of 12.7 (40–1) ng/ml, received IV iron infusion. These 71 patients had presented 764 times (average 10.7 times) over 7 years with IDA that had not been appropriately corrected before they received an iron infusion.  Conclusion  Iron deficiency anaemia was common (21%) in our local IBD cohort. Iron replacement therapy was mostly administered in the oral form. Current practice in our trust does not comply with ECCO guidelines. Just 11.3% were considered for IV iron therapy, despite these patients repeatedly presenting with IDA (on average 10.7 times over 7y), and ferritin counts below 30 ng/ml. Closer adherence to ECCO guidelines is needed, in order to improve the general well being of our patients and prevention of recurrent attendances.  References  . Loftus EV. Clinical epidemiology of inflammatory bowel disease: Incidence, prevalence, and environmental influences.  Gastroenterology  2004;126:1504–1517.  . Dignass AU  et al .  Journal of Crohn’s and Colitis  2015;1:1–12.  Disclosure of Interest  None Declared