bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lamotrigine Use in Pregnancy
Authors: Lilly Carol L , Kaplan-Machlis Barbara 
Published: July 2017

Objective: To review the literature on the proposed mechanisms of teratogenicity of older antiepileptic drugs (AEDs) compared with lamotrigine. Data Sources: Published articles on the use of AEDs during pregnancy were identified from a comprehensive MEDLINE search of the English-language literature (January 1966-January 1998). Additional articles were selected from the references. Search terms included antiepileptic drugs, lamotrigine, and pregnancy. Study Selection: Only human clinical and pharmacokinetic trials and case studies performed in Europe and the US were included. Data Synthesis: Pharmacologic characteristics of the older AEDs that appear to contribute to teratogenicity include antifolate effects, metabolism to oxide metabolites, induction of the hepatic cytochrome P450 system, and a high degree of protein binding. The pharmacokinetics and pharmacodynamics of lamotrigine may offer advantages over other AEDs in terms of teratogenicity because lamotrigine is metabolized by the glucuronidation pathway and is not known to induce the hepatic cytochrome P450 system or to form oxide metabolites. The protein-binding capacity of lamotrigine is considerably lower than that of older AEDs, and antifolate effects have not been observed in humans. Conclusions: Although few data are available, lamotrigine appears to have pharmacokinetic and pharmacodynamic properties that suggest a safer outcome with its use in pregnancy compared with older AEDs.
Depressive and anxious symptoms and the risk of secondary school non-completion
Authors: Brière Frédéric N. , Pascal Sophie , Dupéré Véronique , Castellanos-Ryan Natalie , Allard Francis , Yale-Soulière Gabrielle , Janosz Michel 
Published: July 2017

BackgroundEvidence regarding the association between adolescent internalising symptoms and school non-completion has been limited and inconclusive.AimsTo examine whether depressive and anxious symptoms at secondary school entry predict school non-completion beyond confounders and whether associations differ by baseline academic functioning.MethodWe used logistic regression to examine associations between depressive and anxious symptoms in grade 7 (age 12–14) and school non-completion (age 18–20) in 4962 adolescents.ResultsDepressive symptoms did not predict school non-completion after adjustment, but moderation analyses revealed an association in students with elevated academic functioning. A curvilinear association was found for anxiety: both low and high anxious symptoms predicted school non-completion, although only low anxiety remained predictive after adjustment.ConclusionsAssociations between internalising symptoms and school non-completion are modest. Common school-based interventions targeting internalising symptoms are unlikely to have a major impact on school non-completion, but may prevent non-completion in selected students.
Sleep loss as a trigger of mood episodes in bipolar disorder: Individual differences based on diagnostic subtype and gender
Authors: Lewis Katie Swaden , Gordon-Smith Katherine , Forty Liz , Di Florio Arianna , Craddock Nick , Jones Lisa , Jones Ian 
Published: July 2017

BackgroundSleep loss may trigger mood episodes in people with bipolar disorder but individual differences could influence vulnerability to this trigger.AimsTo determine whether bipolar subtype (bipolar disorder type I (BP-I) or II (BD-II)) and gender were associated with vulnerability to the sleep loss trigger.MethodDuring a semi-structured interview, 3140 individuals (68% women) with bipolar disorder (66% BD-I) reported whether sleep loss had triggered episodes of high or low mood. DSM-IV diagnosis of bipolar subtype was derived from case notes and interview data.ResultsSleep loss triggering episodes of high mood was associated with female gender (odds ratio (OR) = 143, 95% CI 1.17–1.75,P<0.001) and BD-I subtype (OR=2.81, 95% CI 2.26–3.50,P<0.001). Analyses on sleep loss triggering low mood were not significant following adjustment for confounders.ConclusionsGender and bipolar subtype may increase vulnerability to high mood following sleep deprivation. This should be considered in situations where patients encounter sleep disruption, such as shift work and international travel.
Integration of Electronic Patient-Reported Outcomes Into Routine Cancer Care: An Analysis of Factors Affecting Data Completeness
Authors: Wysham Nicholas G. , Wolf Steven P. , Samsa Gregory , Abernethy Amy P. , LeBlanc Thomas W. 
Published: July 2017

Purpose
Routinely collected patient-reported outcomes (PROs) could provide invaluable data to a patient-centered learning health system but are often highly missing in clinical trials. We analyzed our experience with PROs to understand patterns of missing data using electronic collection as part of routine clinical care.

Methods
This is an analysis of a prospectively collected observational database of electronic PROs captured as part of routine clinical care in four different outpatient oncology clinics at an academic referral center.

Results
More than 24,000 clinical encounters from 7,655 unique patients are included. Data were collected via an electronic tablet–based survey instrument (Patient Care Monitor, version 2.0), at the time of clinical care, as part of routine care processes. Missing instruments (ie, no items completed) were submitted for 6.8% of clinical encounters, and 15.8% of encounters had missing items. Nearly 90% of all encounters involved < 10% missing items. In multivariable analyses, younger age, private health insurance, being seen in the breast oncology clinic, less time spent on the instrument, and longitudinal care were significantly associated with less missingness.

Conclusion
Embedding collection of electronic PRO data into routine clinical care yielded low rates of missing data in this real-world, prospectively collected database. In contrast to clinical trial experience, missingness improve with longitudinal care. This approach may be a solution to minimizing missingness of PROs in research or clinical care settings in support of learning health care systems.
Algorithm to Identify Systemic Cancer Therapy Treatment Using Structured Electronic Data
Authors: Carroll Nikki M. , Burniece Kate M. , Holzman Jeff , McQuillan Deanna B. , Plata Angela , Ritzwoller Debra P. 
Published: July 2017

Purpose With the shift in the majority of oncology clinical care in the United States from paper records to electronic health records, researchers need efficient and validated processes to obtain accurate data about the entire treatment history of patients diagnosed with cancer. The objective of this study was to develop and validate an algorithm that is agnostic to the source of data but that can identify specific regimens in the entire course of systemic therapy treatment for patients diagnosed with breast, colorectal, or lung cancer. Methods A cohort of patients with incident breast, colorectal, and lung cancer were randomly distributed into six groups. The algorithm was iteratively modified, and the performance was assessed until no additional modifications could be identified in the first three groups. The performance of the algorithm was confirmed in the three groups that remained. Results The final model produced ranges of sensitivity between 97.2% and 100% for first-course systemic therapy across all cancers, with a false-positive rate of 0%. The algorithm matched the exact number of courses and the exact regimens of systemic therapy agents as captured by infusion, pharmacy, and procedure electronic medical record data for all courses of therapy 88% to 100% of the time. Conclusion Use of our validated algorithm that characterizes entire courses of systemic therapy treatment in patients diagnosed with breast, colorectal, and lung cancer will allow researchers in a variety of settings to conduct comparative effectiveness studies related to the uptake, safety, outcomes, and costs associated with the use of both novel and standard regimens.
Acral Lentiginous Melanoma Harboring a ROS1 Gene Fusion With Clinical Response to Entrectinib
Authors: Couts Kasey L. , McCoach Caroline E. , Murphy Danielle , Christiansen Jason , Turner Jacqueline , Lewis Karl D. , Robinson William A. , Doebele Robert C. 
Published: July 2017

Purpose ROS1 gene fusions demonstrate oncogenic activity, and patients with non–small-cell lung cancer (NSCLC) harboring a ROS1 fusion benefit from the use of a ROS1 inhibitor; however, clinical response to ROS1 inhibitors remains largely uncharacterized outside of NSCLC. ROS1 fusions have been identified in multiple tumor types but have not been reported in cutaneous melanoma. Patients and Methods Tumors from 22 patients with acral lentiginous melanoma (ALM) were analyzed with targeted RNA sequencing to detect fusions in ROS1, NTRK1, NTRK2, NTRK3, and ALK genes. A patient harboring a ROS1 fusion was enrolled in a phase I basket trial of a ROS1/TRK/ALK inhibitor (entrectinib). An additional 78 tumors with different subtypes of melanoma were screened by ROS1 immunohistochemistry. Results Targeted sequencing identified a GOPC- ROS1 fusion in a patient with ALM. The patient underwent a dramatic and durable response to entrectinib, with a RECIST (version 1.1) partial response of −38% at 3 months and −55% at 11 months. The response is ongoing, and the patient has not developed any new lesions. No additional ROS1 fusions were identified by immunohistochemistry, resulting in a frequency of 3.0% in ALM and 1.3% in all melanomas. Conclusion ROS1 fusions occur and can respond to targeted therapy in cutaneous melanoma; however, they may be specific to ALM subtype. This report expands knowledge of ROS1 inhibitor response outside of NSCLC and identifies new therapeutic options for a subset of patients with ALM.
Unexpected CDH1 Mutations Identified on Multigene Panels Pose Clinical Management Challenges
Authors: Lowstuter Katrina , Espenschied Carin R. , Sturgeon Duveen , Ricker Charité , Karam Rachid , LaDuca Holly , Culver Julie O. , Dolinsky Jill S. , Chao Elizabeth , Sturgeon Julia , Speare Virginia , Ma Yanling , Kingham Kerry , Melas Marilena , Idos Gregory E. , McDonnell Kevin J. , Gruber Stephen B. 
Published: July 2017

Purpose Mutations in the CDH1 gene confer up to an 80% lifetime risk of diffuse gastric cancer and up to a 60% lifetime risk of lobular breast cancer. Testing for CDH1 mutations is recommended for individuals who meet the International Gastric Cancer Linkage Consortium (IGCLC) guidelines. However, the interpretation of unexpected CDH1 mutations identified in patients who do not meet IGCLC criteria or do not have phenotypes suggestive of hereditary diffuse gastric cancer is clinically challenging. This study aims to describe phenotypes of CDH1 mutation carriers identified through multigene panel testing (MGPT) and to offer informed recommendations for medical management. Patients and Methods This cross-sectional prevalence study included all patients who underwent MGPT between March 2012 and September 2014 from a commercial laboratory (n = 26,936) and an academic medical center cancer genetics clinic (n = 318) to estimate CDH1 mutation prevalence and associated clinical phenotypes. CDH1 mutation carriers were classified as IGCLC positive (met criteria), IGCLC partial phenotype, and IGCLC negative. Results In the laboratory cohort, 16 (0.06%) of 26,936 patients were identified as having a pathogenic CDH1 mutation. In the clinic cohort, four (1.26%) of 318 had a pathogenic CDH1 mutation. Overall, 65% of mutation carriers did not meet the revised testing criteria published in 2015. All three CDH1 mutation carriers who had risk-reducing gastrectomy had pathologic evidence of diffuse gastric cancer despite not having met IGCLC criteria. Conclusion The majority of CDH1 mutations identified on MGPT are unexpected and found in individuals who do not fit the accepted diagnostic testing criteria. These test results alter the medical management of CDH1-positive patients and families and provide opportunities for early detection and risk reduction.
Next-Generation Rapid Autopsies Enable Tumor Evolution Tracking and Generation of Preclinical Models
Authors: Pisapia David J. , Salvatore Steven , Pauli Chantal , Hissong Erika , Eng Ken , Prandi Davide , Sailer Verena-Wilbeth , Robinson Brian D. , Park Kyung , Cyrta Joanna , Tagawa Scott T. , Kossai Myriam , Fontugne Jacqueline , Kim Robert , Sigaras Alexandros , Rao Rema , Pancirer Danielle , Faltas Bishoy , Bareja Rohan , Molina Ana M. , Nanus David M. , Rajappa Prajwal , Souweidane Mark M. , Greenfield Jeffrey , Emde Anne-Katrin , Robine Nicolas , Elemento Olivier , Sboner Andrea , Demichelis Francesca , Beltran Himisha , Rubin Mark A. , Mosquera Juan Miguel 
Published: July 2017

Purpose Patients with cancer who graciously consent for autopsy represent an invaluable resource for the study of cancer biology. To advance the study of tumor evolution, metastases, and resistance to treatment, we developed a next-generation rapid autopsy program integrated within a broader precision medicine clinical trial that interrogates pre- and postmortem tissue samples for patients of all ages and cancer types. Materials and Methods One hundred twenty-three (22%) of 554 patients who consented to the clinical trial also consented for rapid autopsy. This report comprises the first 15 autopsies, including patients with metastatic carcinoma (n = 10), melanoma (n = 1), and glioma (n = 4). Whole-exome sequencing (WES) was performed on frozen autopsy tumor samples from multiple anatomic sites and on non-neoplastic tissue. RNA sequencing (RNA-Seq) was performed on a subset of frozen samples. Tissue was also used for the development of preclinical models, including tumor organoids and patient-derived xenografts. Results Three hundred forty-six frozen samples were procured in total. WES was performed on 113 samples and RNA-Seq on 72 samples. Successful cell strain, tumor organoid, and/or patient-derived xenograft development was achieved in four samples, including an inoperable pediatric glioma. WES data were used to assess clonal evolution and molecular heterogeneity of tumors in individual patients. Mutational profiles of primary tumors and metastases yielded candidate mediators of metastatic spread and organotropism including CUL9 and PIGM in metastatic ependymoma and ANKRD52 in metastatic melanoma to the lung. RNA-Seq data identified novel gene fusion candidates. Conclusion A next-generation sequencing–based autopsy program in conjunction with a premortem precision medicine pipeline for diverse tumors affords a valuable window into clonal evolution, metastasis, and alterations underlying treatment. Moreover, such an autopsy program yields robust preclinical models of disease.
PTEN Loss-of-Function Alterations Are Associated With Intrinsic Resistance to BRAF Inhibitors in Metastatic Melanoma
Authors: Catalanotti Federica , Cheng Donavan T. , Shoushtari Alexander N. , Johnson Douglas B. , Panageas Katherine S. , Momtaz Parisa , Higham Catherine , Won Helen H. , Harding James J. , Merghoub Taha , Rosen Neal , Sosman Jeffrey A. , Berger Michael F. , Chapman Paul B. , Solit David B. 
Published: July 2017

Purpose The clinical use of BRAF inhibitors in patients with melanoma is limited by intrinsic and acquired resistance. We asked whether next-generation sequencing of pretreatment tumors could identify coaltered genes that predict for intrinsic resistance to BRAF inhibitor therapy in patients with melanoma as a prelude to rational combination strategies. Patients and Methods We analyzed 66 tumors from patients with metastatic BRAF-mutant melanoma collected before treatment with BRAF inhibitors. Tumors were analyzed for > 250 cancer-associated genes using a capture-based next-generation sequencing platform. Antitumor responses were correlated with clinical features and genomic profiles with the goal of identifying a molecular signature predictive of intrinsic resistance to RAF pathway inhibition. Results Among the 66 patients analyzed, 11 received a combination of BRAF and MEK inhibitors for the treatment of melanoma. Among the 55 patients treated with BRAF inhibitor monotherapy, objective responses, as assessed by Response Evaluation Criteria in Solid Tumors (RECIST), were observed in 30 patients (55%), with five (9%) achieving a complete response. We identified a significant association between alterations in PTEN that would be predicted to result in loss of function and reduced progression-free survival, overall survival, and response grade, a metric that combines tumor regression and duration of treatment response. Patients with melanoma who achieved an excellent response grade were more likely to have an elevated BRAF-mutant allele fraction. Conclusion These results provide a rationale for cotargeting BRAF and the PI3K/AKT pathway in patients with BRAF-mutant melanoma when tumors have concurrent loss-of-function mutations in PTEN. Future studies should explore whether gain of the mutant BRAF allele and/or loss of the wild-type allele is a predictive marker of BRAFi sensitivity.
Breast and Ovarian Cancer Penetrance Estimates Derived From Germline Multiple-Gene Sequencing Results in Women
Authors: Kurian Allison W. , Hughes Elisha , Handorf Elizabeth A. , Gutin Alexander , Allen Brian , Hartman Anne-Renee , Hall Michael J. 
Published: July 2017

Purpose Multiple-gene, next-generation sequencing panels are increasingly used to assess hereditary cancer risks of patients with diverse personal and family cancer histories. The magnitude of breast and ovarian cancer risk associated with many clinically tested genes, and independent of family cancer history, remains to be quantified. Methods We queried a commercial laboratory database of 95,561 women tested clinically for hereditary cancer risk with a 25-gene ( APC, ATM, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDK4, CHEK2, MLH2, MSH2, MSH6, MUTYH, NBN, P14ARF, P16, PALB2, PMS2, PTEN, RAD51C, RAD51D, SMAD4, STK11, and TP53) next-generation sequencing panel. Multivariable logistic regression models accounting for family history were used to examine the association between pathogenic mutations and breast or ovarian cancer. As a confirmatory approach, a matched case-control analysis was conducted, defining cases as patients with breast or ovarian cancer and controls as women without cancer. Results One or more pathogenic mutations were detected in 6,775 (7%) of 95,561 women. Eight genes ( ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, PTEN, and TP53) were associated with breast cancer, with odds ratios (ORs) ranging from two-fold ( ATM: OR, 1.74; 95% CI, 1.46 to 2.07) to six-fold ( BRCA1: OR, 5.91; 95% CI, 5.25 to 6.67). Eleven genes ( ATM, BRCA1, BRCA2, BRIP1, MLH1, MSH2, MSH6, NBN, STK11, RAD51C, and RAD51D) were associated with ovarian cancer, with OR ranging from two-fold ( ATM: OR, 1.69; 95% CI, 1.19 to 2.40) to 40-fold ( STK11: OR, 41.9; 95% CI, 5.55 to 315). Multivariable models and matched case-control analyses yielded similar results. Conclusion Among nearly 100,000 clinically tested women, 7% carried a pathogenic mutation in one or more cancer-associated genes. Associated breast and ovarian cancer risks ranged from two- to 40-fold after controlling for family history. These results may inform cancer risk counseling.
Molecular and Clinical Characterization of a Claudin-Low Subtype of Gastric Cancer
Authors: Nishijima Tomohiro F. , Kardos Jordan , Chai Shengjie , Smith Christof C. , Bortone Dante S. , Selitsky Sara R. , Parker Joel S. , Sanoff Hanna K. , Lee Michael S. , Vincent Benjamin G. 
Published: July 2017

Purpose Claudin-low molecular subtypes have been identified in breast and bladder cancers and are characterized by low expression of claudins, enrichment for epithelial-to-mesenchymal transition (EMT), and tumor-initiating cell (TIC) features. We evaluated whether the claudin-low subtype also exists in gastric cancer. Materials and Methods Four hundred fifteen tumors from The Cancer Genome Atlas (TCGA) gastric cancer mRNA data set were clustered on the claudin, EMT, and TIC gene sets to identify claudin-low tumors. We derived a 24-gene predictor that classifies gastric cancer into claudin-low and non–claudin-low subtypes. This predictor was validated with the Asian Cancer Research Group (ACRG) data set. We characterized molecular and clinical features of claudin-low tumors. Results We identified 46 tumors that had consensus enrichment for claudin-low features in TCGA data set. Claudin-low tumors were most commonly diffuse histologic type (82%) and originally classified as TCGA genomically stable (GS) subtype (78%). Compared with GS subtype, claudin-low subtype had significant activation in Rho family of GTPases signaling, which appears to play a key role in its EMT and TIC properties. In the ACRG data set, 28 of 300 samples were classified as claudin-low tumors by the 24-gene predictor and were phenotypically similar to the initially derived claudin-low tumors. Clinically, claudin-low subtype had the worst overall survival. Of note, the hazard ratios that compared claudin-low versus GS subtype were 2.10 (95% CI, 1.07 to 4.11) in TCGA and 2.32 (95% CI, 1.18 to 4.55) in the ACRG cohorts, with adjustment for age and pathologic stage. Conclusion We identified a gastric claudin-low subtype that carries a poor prognosis likely related to therapeutic resistance as a result of its EMT and TIC phenotypes.
Έμφυλες αναπαραστάσεις στα σχολικά εγχειρίδια θετικής κατεύθυνσης των δύο τελευταίων τάξεων του Δημοτικού σχολείου
Authors: Πλιόγκου Βασιλική , Κανταρτζή Ευαγγελία , Τριανταφύλλου Μαίρη 
Published: July 2017

Σκοπός της παρούσας μελέτης είναι η ανίχνευση των στοιχείων που συνθέτουν την παρουσία του φύλου στα σχολικά εγχειρίδια θετικής κατεύθυνσης του Δημοτικού σχολείου. Συγκεκριμένα, εξετάζονται τα σχολικά εγχειρίδια -Βιβλία και Τετράδια Εργασιών- των Μαθηματικών, της Φυσικής και της Γεωγραφίας των δύο τελευταίων τάξεων του Δημοτικού. Τα σχολικά εγχειρίδια επιτελούν έναν διττό ρόλο. Από τη μια, αποτελούν ένα εργαλείο που βοηθάει στην πρόσβαση στη γνώση και από την άλλη, συμβάλλουν στην υιοθέτηση αντιλήψεων και ιδεολογιών από τους/τις μαθητές/τριες. Για αυτόν τον λόγο θεωρείται σκόπιμο να μελετηθεί ο τρόπος που απεικονίζονται τα φύλα στα σχολικά εγχειρίδια του Δημοτικού. Αρχικά, γίνεται μια σύντομη επισκόπηση των ερευνών που έλαβαν χώρα σε Ελλάδα και εξωτερικό και διερεύνησαν τον τρόπο με τον οποίο προσεγγίζεται το φύλο στο σχολείο, στην ευρύτερη εκπαιδευτική κοινότητα και απεικονίζεται στα σχολικά εγχειρίδια. Τα αποτελέσματα των ερευνών αναδεικνύουν την ανισότητα που υπάρχει στην παρουσίαση αγοριών και κοριτσιών, κυρίως, στα σχολικά εγχειρίδια θετικής κατεύθυνσης, αλλά και στην απόκλιση που παρατηρείται μεταξύ των φύλων στην επίδοση στα παραπάνω μαθήματα. Ως μέθοδος επεξεργασίας και διερεύνησης των εγχειριδίων χρησιμοποιήθηκε η μέθοδος ανάλυσης περιεχομένου. Μετά την εμβριθή μελέτη των εγχειριδίων, εντοπίστηκαν και ορίστηκαν οι τέσσερις προς διερεύνηση κατηγορίες. Τα ευρήματα της μελέτης έδειξαν ότι τα σχολικά εγχειρίδια θετικής κατεύθυνσης του Δημοτικού σχολείου παρουσιάζουν, ακόμη και σήμερα, στερεότυπες αντιλήψεις γύρω από το φύλο. Από τα αποτελέσματα διαφαίνεται ότι οι άντρες εμφανίζονται περισσότερο, αναλαμβάνουν πρωταγωνιστικούς ρόλους και ηγετικές θέσεις και απασχολούνται σε όλων των ειδών τα επαγγέλματα. Εν αντιθέσει, οι γυναίκες εμφανίζονται πιο περιορισμένα, ασχολούνται με πιο παραδοσιακές εργασίες και παρουσιάζονται πιο ευάλωτες και αδύναμες. Παρ’ όλο που τα σημερινά σχολικά εγχειρίδια, συγκριτικά με τα παλαιότερα, επιχειρούν μια πιο δίκαιη παρουσίαση του γυναικείου φύλου και μεγαλύτερη συμμετοχή της γυναίκας στον επαγγελματικό και κοινωνικό στίβο, η προσπάθεια αυτή παραμένει περιορισμένη και αποσπασματική. Τα στερεότυπα μεταξύ των φύλων παραμένουν και η ολιστική αποδόμηση των έμφυλων ταυτοτήτων δεν έχει επιτευχθεί. Ζητούμενο, ωστόσο, αποτελεί και ο τρόπος διαχείρισης των εγχειριδίων από τον/την εκπαιδευτικό, του/της οποίου/ας η στάση οφείλει να προωθεί την ισότητα αγοριών και κοριτσιών εντός και εκτός τάξης. Τέλος, παρουσιάζονται δράσεις που στοχεύουν στην ευαισθητοποίηση των εκπαιδευτικών απέναντι σε ζητήματα φύλου.