bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rb Loss and KRAS Mutation Are Predictors of the Response to Platinum-Based Chemotherapy in Pancreatic Neuroendocrine Neoplasm with Grade 3: A Japanese Multicenter Pancreatic NEN-G3 Study
Authors: Hijioka Susumu , Hosoda Waki , Matsuo Keitaro , Ueno Makoto , Furukawa Masayuki , Yoshitomi Hideyuki , Kobayashi Noritoshi , Ikeda Masafumi , Ito Tetsuhide , Nakamori Shoji , Ishii Hiroshi , Kodama Yuzo , Morizane Chigusa , Okusaka Takuji , Yanagimoto Hiroaki , Notohara Kenji , Taguchi Hiroki , Kitano Masayuki , Yane Kei , Maguchi Hiroyuki , Tsuchiya Yoshiaki , Komoto Izumi , Tanaka Hiroki , Tsuji Akihito , Hashigo Syunpei , Kawaguchi Yoshiaki , Mine Tetsuya , Kanno Atsushi , Murohisa Go , Miyabe Katsuyuki , Takagi Tadayuki , Matayoshi Nobutaka , Yoshida Tsukasa , Hara Kazuo , Imamura Masayuki , Furuse Junji , Yatabe Yasushi , Mizuno Nobumasa 
Published: April 2017

Abstract
Purpose: Patients with pancreatic neuroendocrine neoplasm grade-3 (PanNEN-G3) show variable responses to platinum-based chemotherapy. Recent studies indicated that PanNEN-G3 includes well-differentiated neuroendocrine tumor with G3 (NET-G3). Here, we examined the clinicopathologic and molecular features of PanNEN-G3 and assessed the responsiveness to chemotherapy and survival.
Experimental Design: A total of 100 patients with PanNEN-G3 were collected from 31 institutions, and after central review characteristics of each histologic subtype [NET-G3 vs. pancreatic neuroendocrine carcinoma (NEC-G3)] were analyzed, including clinical, radiological, and molecular features. Factors that correlate with response to chemotherapy and survival were assessed.
Results: Seventy patients analyzed included 21 NETs-G3 (30%) and 49 NECs-G3 (70%). NET-G3 showed lower Ki67-labeling index (LI; median 28.5%), no abnormal Rb expression (0%), and no mutated KRAS (0%), whereas NEC-G3 showed higher Ki67-LI (median 80.0%), Rb loss (54.5%), and KRAS mutations (48.7%). Chemotherapy response rate (RR), platinum-based chemotherapy RR, and prognosis differed significantly between NET-G3 and NEC-G3. Chemotherapeutic outcomes were worse in NET-G3 (P &lt; 0.001). When we stratified PanNEN-G3 with Rb and KRAS, PanNENs-G3 with Rb loss and those with mutated KRAS showed significantly higher RRs to platinum-based chemotherapy than those without (Rb loss, 80% vs. normal Rb, 24%, P = 0.006; mutated KRAS, 77% versus wild type, 23%, P = 0.023). Rb was a predictive marker of response to platinum-based chemotherapy even in NEC-G3 (P = 0.035).
Conclusions: NET-G3 and NEC-G3 showed distinct clinicopathologic characteristics. Notably, NET-G3 does not respond to platinum-based chemotherapy. Rb and KRAS are promising predictors of response to platinum-based chemotherapy for PanNEN-G3, and Rb for NEC-G3. Clin Cancer Res; 23(16); 4625–32. ©2017 AACR.
Biomarker Accessible and Chemically Addressable Mechanistic Subtypes of BRAF Melanoma
Authors: Eskiocak Banu , McMillan Elizabeth A. , Mendiratta Saurabh , Kollipara Rahul K. , Zhang Hailei , Humphries Caroline G. , Wang Changguang , Garcia-Rodriguez Jose , Ding Ming , Zaman Aubhishek , Rosales Tracy I. , Eskiocak Ugur , Smith Michael P. , Sudderth Jessica , Komurov Kakajan , Deberardinis Ralph J. , Wellbrock Claudia , Davies Michael A. , Wargo Jennifer A. , Yu Yonghao , De Brabander Jef K. , Williams Noelle S. , Chin Lynda , Rizos Helen , Long Georgina V. , Kittler Ralf , White Michael A. 
Published: April 2017

Abstract
Genomic diversity among melanoma tumors limits durable control with conventional and targeted therapies. Nevertheless, pathologic activation of the ERK1/2 pathway is a linchpin tumorigenic mechanism associated with the majority of primary and recurrent disease. Therefore, we sought to identify therapeutic targets that are selectively required for tumorigenicity in the presence of pathologic ERK1/2 signaling. By integration of multigenome chemical and genetic screens, recurrent architectural variants in melanoma tumor genomes, and patient outcome data, we identified two mechanistic subtypes of BRAFV600 melanoma that inform new cancer cell biology and offer new therapeutic opportunities. Subtype membership defines sensitivity to clinical MEK inhibitors versus TBK1/IKBKϵ inhibitors. Importantly, subtype membership can be predicted using a robust quantitative five-feature genetic biomarker. This biomarker, and the mechanistic relationships linked to it, can identify a cohort of best responders to clinical MEK inhibitors and identify a cohort of TBK1/IKBKϵ inhibitor–sensitive disease among nonresponders to current targeted therapy.
Significance: This study identified two mechanistic subtypes of melanoma: (1) the best responders to clinical BRAF/MEK inhibitors (25%) and (2) nonresponders due to primary resistance mechanisms (9.9%). We identified robust biomarkers that can detect these subtypes in patient samples and predict clinical outcome. TBK1/IKBKϵ inhibitors were selectively toxic to drug-resistant melanoma. Cancer Discov; 7(8); 832–51. ©2017 AACR.
See related commentary by Jenkins and Barbie, p. 799.
This article is highlighted in the In This Issue feature, p. 783
Temporal Trends in Incidence, Prevalence, and Mortality of Atrial Fibrillation in Primary Care
Authors: Lane Deirdre A. , Skjøth Flemming , Lip Gregory Y. H. , Larsen Torben B. , Kotecha Dipak 
Published: April 2017

Background

Incidence and prevalence of atrial fibrillation (
AF
) are expected to increase dramatically; however, we currently lack comprehensive data on temporal trends in unselected clinical populations.

Methods and Results

Analysis of the
UK
Clinical Practice Research Datalink (
CPRD
) from 1998 to 2010 of patients with incident
AF
, excluding major valvular disease, linked to hospital admission data and national statistics. Fifty‐seven thousand eight hundred eighteen adults were identified with mean age 74.2 (
SD
, 11.7) years and 48.3% women. Overall age‐adjusted incidence of
AF
per 1000 person years was 1.11 (95%
CI
, 1.09–1.13) in 1998–2001, 1.33 (1.31–1.34) in 2002–2006, and 1.33 (1.31–1.35) in 2007–2010. Ongoing increases in incidence were noted for patients aged ≥75 years, with similar temporal patterns in women and men. Associated comorbidities varied over time, with a constant prevalence of previous stroke, increases in hypertension and diabetes mellitus, and decreases in ischemic heart disease. Among patients aged 55 to 74 years, there was a significant reduction in mortality over time (
P
<0.001), but mortality rates in patients aged ≥75 years remained static at 14% to 15% per year (
P
=0.84). Projections of
AF
prevalence demonstrated a constant yearly rise, increasing from 700 000 patients in 2010 to between 1.3 and 1.8 million patients with
AF
in the United Kingdom by 2060.

Conclusions

In a large general practice population, incident
AF
increased and then plateaued overall, with a continued increase in patients aged ≥75 years. The large projected increase in
AF
prevalence associated with temporal changes in
AF
‐related comorbidities suggests the need for comprehensive implementation of
AF
prevention and management strategies.
Wake-Up Stroke Is Associated With Greater Nocturnal Mean Arterial Pressure Variability
Authors: Lundholm Michelle D. , Rooney Melissa , Maas Matthew B. , Attarian Hrayr , Prabhakaran Shyam 
Published: April 2017

Background and Purpose—
Wake-up strokes (WUS) account for ≈20% to 30% of ischemic strokes. Studies have shown that increased autonomic instability as measured by blood pressure variability (BPV) is greater in stroke patients than nonstroke patients, but no studies have compared BPV in WUS versus non-WUS patients.

Methods—
From a single-center prospective registry, we identified consecutive ischemic stroke patients. BPV was calculated as the coefficient of variation of the mean arterial pressure during the first 24 hours after hospitalization. We assessed 24-hour BPV as a continuous measure and in quartiles in WUS versus non-WUS patients using univariable and multivariable statistics.

Results—

Among 369 patients (64.9±16.5 years; 50.1% male; 64.7% white), 78 were WUS (21.1%). Clinical characteristics and medical history were not different between WUS and non-WUS patients except WUS patients were older (69.0 versus 63.8 years;
P
=0.015) and more frequently had previous ischemic stroke (29.5% versus 17.2%;
P
=0.012). Initial 24-hour BPV (11.77 versus 10.76;
P
=0.098) was similar between groups. However, WUS patients had greater nocturnal BPV (10.50 versus 8.95;
P
=0.030), whereas daytime BPV was similar between groups (10.96 versus 10.47,
P
=0.459). In multivariate analysis, the highest quartile (≥11.48 mm Hg) of nocturnal BPV was independently associated with WUS (adjusted odds ratio, 1.95; confidence interval, 1.13–3.39;
P
=0.017).

Conclusions—
In this single-center study, we observed that greater nocturnal BPV during the first 24 hours after hospitalization occurred in WUS than non-WUS patients. Nocturnal autonomic instability warrants further study as a potential mechanism of WUS.
Early Endarterectomy Carries a Lower Procedural Risk Than Early Stenting in Patients With Symptomatic Stenosis of the Internal Carotid Artery
Authors: Rantner Barbara , Kollerits Barbara , Roubin Gary S. , Ringleb Peter A. , Jansen Olaf , Howard George , Hendrikse Jeroen , Halliday Alison , Gregson John , Eckstein Hans-Henning , Calvet David , Bulbulia Richard , Bonati Leo H. , Becquemin Jean-Pierre , Algra Ale , Brown Martin M. , Mas Jean-Louis , Brott Thomas G. , Fraedrich Gustav 
Published: April 2017

Background and Purpose—
Patients undergoing carotid endarterectomy (CEA) for symptomatic stenosis of the internal carotid artery benefit from early intervention. Heterogeneous data are available on the influence of timing of carotid artery stenting (CAS) on procedural risk.

Methods—
We investigated the association between timing of treatment (0–7 days and >7 days after the qualifying neurological event) and the 30-day risk of stroke or death after CAS or CEA in a pooled analysis of individual patient data from 4 randomized trials by the Carotid Stenosis Trialists’ Collaboration. Analyses were done per protocol. To obtain combined estimates, logistic mixed models were applied.

Results—

Among a total of 4138 patients, a minority received their allocated treatment within 7 days after symptom onset (14% CAS versus 11% CEA). Among patients treated within 1 week of symptoms, those treated by CAS had a higher risk of stroke or death compared with those treated with CEA: 8.3% versus 1.3%, risk ratio, 6.7; 95% confidence interval, 2.1 to 21.9 (adjusted for age at treatment, sex, and type of qualifying event). For interventions after 1 week, CAS was also more hazardous than CEA: 7.1% versus 3.6%, adjusted risk ratio, 2.0; 95% confidence interval, 1.5 to 2.7 (
P
value for interaction with time interval 0.06).

Conclusions—
In randomized trials comparing stenting with CEA for symptomatic carotid artery stenosis, CAS was associated with a substantially higher periprocedural risk during the first 7 days after the onset of symptoms. Early surgery is safer than stenting for preventing future stroke.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00190398; URL:
http://www.controlled-trials.com
. Unique identifier: ISRCTN57874028; Unique identifier: ISRCTN25337470; URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00004732.
Long-Term Exposure to Ambient Air Pollution and Subclinical Cerebrovascular Disease in NOMAS (the Northern Manhattan Study)
Authors: Kulick Erin R. , Wellenius Gregory A. , Kaufman Joel D. , DeRosa Janet T. , Kinney Patrick L. , Cheung Ying Kuen , Wright Clinton B. , Sacco Ralph L. , Elkind Mitchell S. 
Published: April 2017

Background and Purpose—
Long-term exposure to ambient air pollution is associated with higher risk of cardiovascular disease and stroke. We hypothesized that long-term exposure to air pollution would be associated with magnetic resonance imaging markers of subclinical cerebrovascular disease.

Methods—
Participants were 1075 stroke-free individuals aged ≥50 years drawn from the magnetic resonance imaging subcohort of the Northern Manhattan Study who had lived at the same residence for at least 2 years before magnetic resonance imaging. Cross-sectional associations between ambient air pollution and subclinical cerebrovascular disease were analyzed.

Results—
We found an association between distance to roadway, a proxy for residential exposure to traffic pollution, and white matter hyperintensity volume; however, after adjusting for risk factors, this relationship was no longer present. All other associations between pollutant measures and white matter hyperintensity volume were null. There was no clear association between exposure to air pollutants and subclinical brain infarcts or total cerebral brain volume.

Conclusions—
We found no evidence that long-term exposure to ambient air pollution is independently associated with subclinical cerebrovascular disease in an urban population-based cohort.
Classification of Bleeding Events
Authors: Neuberger Ulf , Möhlenbruch Markus Alfred , Herweh Christian , Ulfert Christian , Bendszus Martin , Pfaff Johannes 
Published: April 2017

Background and Purpose—
Intracranial hemorrhage (ICH) after acute ischemic stroke treatments represents a feared complication with possible prognostic implications. In recent years, ICHs were commonly classified according to the ECASS (European Cooperative Acute Stroke Study). To improve the clinical applicability and relevance, the new Heidelberg Bleeding Classification (HBC) has been proposed in 2015. Here, we compared the ECASS and HBC classification with regard to observed events and prognostic relevance.

Methods—
A retrospective analysis of a prospectively compiled database of patients with acute ischemic stroke in the anterior circulation who received mechanical thrombectomy between February 2011 and March 2016 was performed. Presence of ICH after mechanical thrombectomy was evaluated on postinterventional computed tomographic imaging. ICHs were specified according to both ECASS III and HBC classification and analyzed with regard to their symptoms and outcome.

Results—
ICHs were observed in 156 of 768 patients (20.3%). Using ECASS III classification, 101 ICHs could be unambiguously assigned, of which 28 (27.7%; 3.6% of all treated patients) were symptomatic ICHs. Using HBC, 55 additional ICHs could be categorized. Of these total 156 ICHs, 29 (18.6%; 3.8% of all treated patients) were classified as symptomatic according to HBC.

Conclusions—
Classification of ICH by ECASS III and HBC criteria show distinct differences. These differences warrant special attention during interpretation and comparison of scientific publications.
Acupuncture Therapy and Incidence of Depression After Stroke
Authors: Lu Chung-Yen , Huang Hsin-Chia , Chang Hen-Hong , Yang Tsung-Hsien , Chang Chee-Jen , Chang Su-Wei , Chen Pei-Chun 
Published: April 2017

Background and Purpose—
We investigated whether use of acupuncture within a 3-month poststroke period after hospital discharge is associated with reduced risk of depression.

Methods—
This cohort study included 16 046 patients aged ≥18 years with an initial hospitalization for stroke during 2000 and 2012 in the claims database of a universal health insurance program. Patients who had received acupuncture therapies within 3 months of discharge were defined as acupuncture users (n=1714). All patients were followed up for incidence of depression until the end of 2013. We assessed the association between use of acupuncture and incidence of depression using Cox proportional hazards models in all subjects and in propensity score–matched samples consisting of 1714 pairs of users and nonusers.

Results—
During the follow-up period, the incidence of depression per 1000 person-years was 11.1 and 9.7 in users and nonusers, respectively. Neither multivariable-adjusted Cox models (hazard ratio, 1.04; 95% confidence interval, 0.84–1.29) nor the propensity score-matching model (hazard ratio, 1.06; 95% confidence interval, 0.79–1.42) revealed an association between use of acupuncture and incidence of depression.

Conclusions—
In patients admitted to hospital for stroke, acupuncture therapy within 3 months after discharge was not associated with subsequent incidence of depression.
Region-specific disruption of the blood-brain barrier following repeated inflammatory dural stimulation in a rat model of chronic trigeminal allodynia
Authors: Fried Nathan T , Maxwell Christina R , Elliott Melanie B , Oshinsky Michael L 
Published: April 2017

Background The blood-brain barrier (BBB) has been hypothesized to play a role in migraine since the late 1970s. Despite this, limited investigation of the BBB in migraine has been conducted. We used the inflammatory soup rat model of trigeminal allodynia, which closely mimics chronic migraine, to determine the impact of repeated dural inflammatory stimulation on BBB permeability. Methods The sodium fluorescein BBB permeability assay was used in multiple brain regions (trigeminal nucleus caudalis (TNC), periaqueductal grey, frontal cortex, sub-cortex, and cortex directly below the area of dural activation) during the episodic and chronic stages of repeated inflammatory dural stimulation. Glial activation was assessed in the TNC via GFAP and OX42 immunoreactivity. Minocycline was tested for its ability to prevent BBB disruption and trigeminal sensitivity. Results No astrocyte or microglial activation was found during the episodic stage, but BBB permeability and trigeminal sensitivity were increased. Astrocyte and microglial activation, BBB permeability, and trigeminal sensitivity were increased during the chronic stage. These changes were only found in the TNC. Minocycline treatment prevented BBB permeability modulation and trigeminal sensitivity during the episodic and chronic stages. Discussion Modulation of BBB permeability occurs centrally within the TNC following repeated dural inflammatory stimulation and may play a role in migraine.
Optimization of the French cystic fibrosis newborn screening programme by a centralized tracking process
Authors: Munck Anne , Delmas Dominique , Audrézet Marie-Pierre , Lemonnier Lydie , Cheillan David , Roussey Michel 
Published: April 2017

Objectives To evaluate the French cystic fibrosis newborn screening algorithm, based on data tracked by a centralized monitoring process, from 2002 to 2014. The programme aimed to attain European Standards in terms of positive predictive value, sensitivity, the ratio of screen positive patients diagnosed with cystic fibrosis to infants who screen positive but with inconclusive diagnosis (CFSPID), and time to diagnosis. Methods Retrospective analysis of programme performance, compliance with the algorithm, and changes in screening strategy. Results Modifications in the flow chart protocol improved the positive predictive value to 0.31 while maintaining the sensitivity at 0.95. Among infants diagnosed with cystic fibrosis, or identified as CFSPID, sweat test results were obtained for 94%, and two mutations were identified after exhaustive screening for the gene, when applicable, in 99.6%. The rate of pending diagnosis was very low (0.5%). The ratio of infants with cystic fibrosis:CFSPID was 6.3:1. Age at initial visit at the CF centre was ≤ 35 days, respectively, in 53%/26%. Conclusion Performances were in agreement with European standards, but timeliness of initial visit needed improvement. Our data complement an accumulating body of evidence demonstrating that attention must be paid to such ethical considerations as limiting carrier detection and inconclusive diagnosis. Newborn screening programmes should have a rigorous centralized monitoring process to warrant adjustments for improving performance to attain consensus guidelines.
Arthroscopic Correlates of Subtle Syndesmotic Injury
Authors: Guyton Gregory P. , DeFontes Kenneth , Barr Cameron R. , Parks Brent G. , Camire Lyn M. 
Published: April 2017

Background: Arthroscopic criteria for identifying syndesmotic disruption have been variable and subjective. We aimed to quantify syndesmotic disruption arthroscopically using a standardized measurement device. Methods: Ten cadaveric lower extremity specimens were tested in intact state and after serial sectioning of the syndesmotic structures (anterior inferior tibiofibular ligament [AiTFL], interosseous ligament [IOL], posterior inferior tibiofibular ligament [PiTFL], deltoid). Diagnostic ankle arthroscopy was performed after each sectioning. Manual external rotational stress was applied across the tibiofibular joint. Custom-manufactured spherical balls of increasing diameter mounted on the end of an arthroscopic probe were inserted into the tibiofibular space to determine the degree of diastasis of the tibiofibular joint under each condition. Results: A ball 3 mm in diameter reliably indicated a high likelihood of combined disruption of the AiTFL and IOL. Disruption of the AiTFL alone could not be reliably distinguished from the intact state. Conclusion: Use of a spherical probe placed into the tibiofibular space during manual external rotation of the ankle provided an objective measure of syndesmotic instability. Passage of a 2.5-mm probe indicated some disruption of the syndesmosis, but the test had poor negative predictive value. Passage of a 3.0-mm spherical probe indicated very high likelihood of disruption of both the AiTFL and the IOL. Clinical Relevance: The findings challenge the previously used but unsupported standard of a 2-mm diastasis of the tibiofibular articulation for diagnosis of subtle syndesmotic instability.
Effect of Negative Pressure Wound Therapy on Cellular Fibronectin and Transforming Growth Factor-β1 Expression in Diabetic Foot Wounds
Authors: Yang Shao Ling , Zhu Lv Yun , Han Rui , Sun Lei Lei , Dou Jing Tao 
Published: April 2017

Background: Chronic diabetic foot wounds are a leading cause of amputation, morbidity, and hospitalization for patients with diabetes. Negative-pressure wound therapy (NPWT) can putatively facilitate wound healing, but the underlying mechanisms remain unclear. Cellular fibronectin (cFN) and transforming growth factor-β1 (TGF-β1) play an important role in wound healing. This prospective randomized controlled trial evaluated the effects of NPWT on the production of cFN and the expression of TGF-β1 in diabetic foot wounds of patients. Methods: From January 2012 to January 2015, 40 patients with diabetic foot wounds were randomly and equally apportioned to receive either NPWT or advanced moist wound therapy (control) for 7 days. Granulation tissue was harvested before and after treatment. Immunohistochemistry and Western blot were performed to evaluate protein levels of cFN and TGF-β1, and real-time polymerase chain reaction (PCR) to measure corresponding mRNA expressions. Results: NPWT facilitated the expression of cFN and TGF-β1 in diabetic foot wounds. Immunohistochemical analysis revealed higher levels of cFN and TGF-β1 in the NPWT group than in the control group. Western blot and real-time PCR analysis further showed that protein and mRNA levels of cFN or TGF-β1 were higher in the NPWT group than that in the control group ( P < .01, both). Conclusion: Our results showed that NPWT facilitated the production of cFN and the expression of TGF-β1 in granulation tissue in diabetic foot ulcers. Level of Evidence: Level I, randomized controlled study.