bluuebunny/crossref_metadata_2025_split huggingface dataset:
Plasma Cell-Free DNA Testing of Patients With EGFR Mutant Non–Small-Cell Lung Cancer: Droplet Digital PCR Versus Next-Generation Sequencing Compared With Tissue-Based Results
Authors: Steendam Christi M.J. , Atmodimedjo Peggy , de Jonge Evert , Paats Marthe S. , van der Leest Cor , Oomen-de Hoop Esther , Jansen Maurice P.H.M. , Del Re Marzia , von der Thüsen Jan H. , Dinjens Winand N.M. , van Schaik Ron H.N. , Aerts Joachim G.J.V. , Dubbink Hendrikus Jan ,   on behalf of Erasmus MC Cancer Institute
Published: June 2019

PURPOSE To compare the results of plasma cell-free DNA (cfDNA) droplet digital PCR (ddPCR) and next-generation sequencing (NGS) on detection of epidermal growth factor receptor ( EGFR) primary activating mutations and p.T790M with results of tissue analysis in patients with EGFR mutated non–small-cell lung cancer. METHODS All patients with EGFR mutated non–small cell lung cancer for which a pathology and a plasma specimen were available upon progression between November 2016 and July 2018 were selected. Concordance, Cohen’s κ, and intraclass correlation coefficients were calculated. RESULTS Plasma cfDNA and pathology specimens of 36 patients were analyzed. Agreement between ddPCR and NGS was 86% (κ = 0.63) for the primary activating mutation and 94% (κ = 0.89) for the p.T790M detection. Allele ratios were comparable, with an intraclass correlation coefficient of 0.992 and 0.997, respectively. Discrepancies of some degree were found in 15 patients (41.7%). In six patients (16.7%), no mutations were detected in cfDNA. In three patients (8.3%), p.T790M was detected in plasma but not in the pathology specimen, whereas in three other patients (8.3%), p.T790M was demonstrated in the pathology specimen but not in plasma. Concordance of cfDNA and pathology for the primary activating mutation was 69% for ddPCR and 83% for NGS. For the detection of p.T790M, this was 75% (κ = 0.49) for ddPCR as well as for NGS. CONCLUSION Mutual agreement is high between NGS and ddPCR in cfDNA on the level of a specific mutation, with comparable ratio results. Plasma testing of EGFR primary activating mutations and p.T790M shows high concordance with pathology results, for NGS as well as for ddPCR, depending on the extent of the panel used. In NGS, more genetic aberrations can be investigated at once.
Clinical Utility of Real-Time Targeted Molecular Profiling in the Clinical Management of Ovarian Cancer: The ALLOCATE Study
Authors: Kondrashova Olga , Ho Gwo-Yaw , Au-Yeung George , Leas Leakhena , Boughtwood Tiffany , Alsop Kathryn , Zapparoli Giada , Dobrovic Alexander , Ko Yi-An , Hsu Arthur L. , Love Clare J. , Lunke Sebastian , Wakefield Matthew J. , McNally Orla , Quinn Michael , Ananda Sumitra , Neesham Deborah , Hamilton Anne , Grossi Marisa , Freimund Alison , Kanjanapan Yada , Rischin Danny , Traficante Nadia , Bowtell David , Scott Clare L. , Christie Michael , Taylor Graham R. , Mileshkin Linda , Waring Paul M. ,   on behalf of the Australian Ovarian Cancer Study Group
Published: June 2019

PURPOSE The ALLOCATE study was designed as a pilot to demonstrate the feasibility and clinical utility of real-time targeted molecular profiling of patients with recurrent or advanced ovarian cancer for identification of potential targeted therapies. PATIENTS AND METHODS A total of 113 patients with ovarian cancer of varying histologies were recruited from two tertiary hospitals, with 99 patient cases suitable for prospective analysis. Targeted molecular and methylation profiling of fresh biopsy and archived tumor samples were performed by screening for mutations or copy-number variations in 44 genes and for promoter methylation of BRCA1 and RAD51C. RESULTS Somatic genomic or methylation events were identified in 85% of all patient cases, with potentially actionable events with defined targeted therapies (including four resistance events) detected in 60% of all patient cases. On the basis of these findings, six patients received molecularly guided therapy, three patients had unsuspected germline cancer–associated BRCA1/ 2 mutations and were referred for genetic counseling, and two intermediate differentiated (grade 2) serous ovarian carcinomas were reclassified as low grade, leading to changes in clinical management. Additionally, secondary reversion mutations in BRCA1/ 2 were identified in fresh biopsy samples of two patients, consistent with clinical platinum/poly (ADP-ribose) polymerase inhibitor resistance. Timely reporting of results if molecular testing is done at disease recurrence, as well as early referral for patients with platinum-resistant cancers, were identified as factors that could improve the clinical utility of molecular profiling. CONCLUSION ALLOCATE molecular profiling identified known genomic and methylation alterations of the different ovarian cancer subtypes and was deemed feasible and useful in routine clinical practice. Better patient selection and access to a wider range of targeted therapies or clinical trials will further enhance the clinical utility of molecular profiling.
Evaluating the Low-Dose ACTH Stimulation Test in Children: Ideal Times for Cortisol Measurement
Authors: Gill Harpreet , Barrowman Nick , Webster Richard , Ahmet Alexandra 
Published: June 2019

Abstract

Context
Central adrenal insufficiency (AI) can be diagnosed with the low-dose ACTH stimulation test (LDST). Protocols determining timing of cortisol sampling vary, with 30 minutes after stimulation being most common.

Objectives
To determine optimal times to draw cortisol levels and factors predicting timing of peak cortisol levels in children undergoing LDST.

Design
Retrospective chart review of LDSTs between February 2014 and September 2017.

Setting
The Children’s Hospital of Eastern Ontario.

Patients
Patients 3 months to 20 years who underwent LDSTs.

Intervention
LDSTs were performed with cortisol levels at 0, 15, 30, and 60 minutes after 1 μg cosyntropin. Cortisol values <18 μg/dL (500 nmol/L) determined AI.

Main Outcome Measures
The incremental value of testing cortisol at 15 or 60 minutes, in addition to the standard 30-minute sample, was estimated.

Results
A total of 221 patients met inclusion criteria. The mean age was 9.7 years, and 32% were female. Peak cortisol levels were 19%, 67%, and 14% at 15, 30, and 60 minutes, respectively. One false positive LDST result would be prevented for every 24 (95% CI, 13 to 46) or 55 (95% CI, 22 to 141) patients tested at 15 or 60 minutes in addition to the standard 30-minute test. Of the 122 patients who passed the LDST, discontinuing the 15- and 60-minute samples would have misdiagnosed 12 patients (9.8%). Glucocorticoid exposure, age, and body mass index z scores were independent predictors of peak cortisol timing.

Conclusion
Although the majority of patients peak 30 minutes after cosyntropin administration, testing cortisol levels at 15 and 60 minutes reduces the risk of false positive LDSTs.
Haptoglobin Phenotype Modulates Lipoprotein-Associated Risk for Preeclampsia in Women With Type 1 Diabetes
Authors: Kelly Clare B , Yu Jeremy Y , Jenkins Alicia J , Nankervis Alison J , Hanssen Kristian F , Garg Satish K , Scardo James A , Basu Arpita , Hammad Samar M , Aston Christopher E , Lyons Timothy J 
Published: June 2019

AbstractContextThe incidence of preeclampsia (PE) is increased in women with diabetes (∼20% vs ∼5% in the general population), and first trimester lipoprotein profiles are predictive. Haptoglobin (Hp), a protein with functional genetic polymorphisms, has antioxidant, anti-inflammatory, and angiogenic effects. Among people with diabetes, the Hp 2-2 phenotype is associated with cardiorenal disease.ObjectiveTo investigate whether Hp phenotype is associated with PE in type 1 diabetes mellitus (T1DM) and/or modulates lipoprotein-associated risks.Design and SettingMulticenter prospective study of T1DM pregnancy.PatientsPregnant women with T1DM (normal albuminuria, normotensive at enrolment, n = 47) studied at three visits, all preceding PE onset: 12.3 ± 1.9, 21.8 ± 1.5, and 31.5 ± 1.6 weeks’ gestation (mean ± SD).Main Outcome MeasuresHp phenotype and lipoprotein profiles in women with (n = 23) vs without (n = 24) subsequent PE.ResultsHp phenotype did not predict PE, but lipoprotein associations with subsequent PE were confined to women with Hp 2-2, in whom the following associations with PE were observed: increased low-density lipoprotein (LDL) cholesterol, LDL particle concentration, apolipoprotein B (APOB), triacylglycerol/high-density lipoprotein (HDL) cholesterol ratio, and APOB/apolipoprotein AI (APOA1) ratio; decreased HDL cholesterol, APOA1, large HDL particle concentration, and peripheral lipoprotein lipolysis (all P < 0.05). In women with one or two Hp-1 alleles, no such associations were observed.ConclusionsIn women with T1DM, although Hp phenotype did not predict PE risk, lipoprotein-related risks for PE were limited to those with the Hp 2-2 phenotype. Hp phenotype may modulate PE risk in diabetes.
Pasireotide and Pegvisomant Combination Treatment in Acromegaly Resistant to Second-Line Therapies: A Longitudinal Study
Authors: Chiloiro Sabrina , Bima Chiara , Tartaglione Tommaso , Giampietro Antonella , Gessi Marco , Lauretti Liverana , Anile Carmelo , Colosimo Cesare , Rindi Guido , Pontecorvi Alfredo , De Marinis Laura , Bianchi Antonio 
Published: June 2019

Abstract

Context
The treatment of acromegaly resistant to first- and second-line therapies can be extremely challenging.

Design
We have described six patients who were successfully treated with a combination therapy of pasireotide and pegvisomant and compared them with a control group of patients resistant to conventional somatostatin analogs (SSAs), whose disease was controlled with other treatment, such as pasireotide (as monotherapy) or pegvisomant (as monotherapy or combined with conventional SSAs).

Results
In these six patients, acromegaly was controlled with combined pasireotide and pegvisomant treatment after failure of all other treatments. Compared with the 49 patients in the control group, these six patients had giant and invasive pituitary adenomas (at both the cavernous sinus and other structures). Although not statistically significant, higher growth hormone levels, more elevated Ki-67 expression, greater somatostatin receptor (SSTR) subtype 5 expression, and lower SSTR subtype 2 expression at the diagnosis of acromegaly were detected in patients receiving combination treatment with pasireotide and pegvisomant compared with the control group.

Conclusion
Our data have reinforced the importance of personalized treatment of patients with acromegaly according to the clinical, biochemical, molecular, and morphological disease markers and suggest that combined treatment with pasireotide and pegvisomant can induce disease control in tumors with low SSTR2 expression, resistant to conventional SSAs (alone or combined with pegvisomant) and to new-generation SSAs alone (pasireotide).
Differences in Trabecular Plate and Rod Structure in Premenopausal Women Across the Weight Spectrum
Authors: Schorr Melanie , Fazeli Pouneh K , Bachmann Katherine N , Faje Alexander T , Meenaghan Erinne , Kimball Allison , Singhal Vibha , Ebrahimi Seda , Gleysteen Suzanne , Mickley Diane , Eddy Kamryn T , Misra Madhusmita , Klibanski Anne , Miller Karen K 
Published: June 2019

AbstractContextPremenopausal women with anorexia nervosa (AN) and obesity (OB) have elevated fracture risk. More plate-like and axially aligned trabecular bone, assessed by individual trabeculae segmentation (ITS), is associated with higher estimated bone strength. Trabecular plate and rod structure has not been reported across the weight spectrum.ObjectiveTo investigate trabecular plate and rod structure in premenopausal women.DesignCross-sectional study.SettingClinical research center.ParticipantsA total of 105 women age 21 to 46 years: (i) women with AN (n = 46), (ii) eumenorrheic lean healthy controls (HCs) (n = 29), and (iii) eumenorrheic women with OB (n = 30).MeasuresTrabecular microarchitecture by ITS.ResultsMean age (±SD) was similar (28.9 ± 6.3 years) and body mass index differed (16.7 ± 1.8 vs 22.6 ± 1.4 vs 35.1 ± 3.3 kg/m2; P < 0.0001) across groups. Bone was less plate-like and axially aligned in AN (P ≤ 0.01) and did not differ between OB and HC. After controlling for weight, plate and axial bone volume fraction and plate number density were lower in OB vs HC; some were lower in OB than AN (P < 0.05). The relationship between weight and plate variables was quadratic (R = 0.39 to 0.70; P ≤ 0.0006) (i.e., positive associations were attenuated at high weight). Appendicular lean mass and IGF-1 levels were positively associated with plate variables (R = 0.27 to 0.67; P < 0.05). Amenorrhea was associated with lower radial plate variables than eumenorrhea in AN (P < 0.05).ConclusionsIn women with AN, trabecular bone is less plate-like. In women with OB, trabecular plates do not adapt to high weight. This is relevant because trabecular plates are associated with greater estimated bone strength. Higher muscle mass and IGF-1 levels may mitigate some of the adverse effects of low weight or excess adiposity on bone.
Overcoming Language Barriers Using an Information Video on Spinal Anesthesia for Cesarean Delivery: Implementation and Impact on Maternal Anxiety
Authors: Purcell-Jones Jessica M. A. , Haasbroek Marlis , Van der Westhuizen Justine L. , Dyer Robert A. , Lombard Carl J. , Duys Rowan A. 
Published: June 2019

BACKGROUND:
It is unknown whether the implementation of an information video on spinal anesthesia for cesarean delivery, narrated in a patient’s first language, reduces anxiety, increases satisfaction, and improves doctor–patient communication if there is a language barrier. In South Africa, most doctors speak English, and patients speak Xhosa, with educational and cultural disparities existing in many doctor–patient interactions.

METHODS:
One hundred seventy-five Xhosa patients scheduled for elective cesarean delivery were enrolled in the study. The first 92 patients received “usual care” verbal explanations of the spinal anesthesia procedure (control group); the next 83 patients watched a spinal anesthesia information video (intervention group), narrated in Xhosa. Videos were displayed using smartphones. Maternal anxiety was assessed before and after spinal explanation, using a Numerical Visual Analog Anxiety Scale (NVAAS). A difference in postexplanation NVAAS score of 1.5 points between intervention and control groups was regarded as clinically significant. Patient satisfaction was assessed using the Maternal Satisfaction Scale for Cesarean Section (MSSCS).

RESULTS:
The mean (standard deviation [SD]) age (31.5 years [5.2 years] and 32.1 years [5.4 years]) and preexplanation NVAAS score (4.2 [3.2] and 4.0 [3.0]) of the intervention and control groups, respectively, showed no difference at baseline. The mean (SD) postexplanation decrease in NVAAS score was greater in the intervention than in the control group (1.6 [3.5] vs 0.7 [2.3]; P = .046; unadjusted mean difference, 0.9 points [95% confidence interval {CI}, 0.02–1.8]). A linear regression model for the postexplanation NVAAS score showed that the intervention effect was significantly associated with the preexplanation score (P = .002), adjusted for age and English fluency. Patients with preexplanation NVAAS scores ≥5 showed a statistically significant intervention effect. There was no significant difference in patient satisfaction between the intervention and control groups. The smartphone was an accessible and convenient display medium for the video. Ninety-nine percent of patients exposed to the intervention would recommend watching the video before the procedure.

CONCLUSIONS:
In this pilot study, lower NVAAS scores were observed in anxious patients, when a Xhosa information video was used to ameliorate challenges posed by a doctor–patient language barrier. It is easily implemented and demonstrates a novel use of mobile health technology. The study provides baseline data to inform sample size calculations for future studies. A high level of patient recommendation for the video suggests that this is an agreeable practice.
Anesthesia Type Is Not Associated With Postoperative Complications in the Care of Patients With Lower Extremity Traumatic Fractures
Authors: Brovman Ethan Y. , Wallace Frances C. , Weaver Michael J. , Beutler Sasha S. , Urman Richard D. 
Published: June 2019

BACKGROUND:
Lower extremity fracture fixation is commonplace and represents the majority of orthopedic trauma surgical volume. Despite this, few studies have examined the use of regional anesthesia or neuraxial anesthesia (RA/NA) versus general anesthesia (GA) in this surgical population. We aimed to determine the overall rates of RA/NA use and whether RA/NA was associated with lower mortality and morbidity versus GA for patients with lower extremity orthopedic trauma.

METHODS:
We conducted a propensity-matched, retrospective cohort study of hospitalized patients. We used the American College of Surgeons National Surgical Quality Improvement Project (ACS-NSQIP) dataset to identify patients undergoing surgical correction of low velocity orthopedic lower extremity traumas between 2011 and 2016. Patients were separated into 2 groups based on anesthesia type (RA/NA versus GA). The primary outcome was 30-day mortality. Secondary outcomes included return to the operating room, failure to wean from the ventilator, intubation, pneumonia, acute kidney injury, myocardial infarction, transfusion, venous thromboembolism (VTE), urinary tract infection, sepsis, length of stay, days from operation to discharge, number of complications, and unplanned readmission.

RESULTS:
We identified 18,467 patients undergoing surgical repair of lower extremity fractures. Approximately 9.58% had RA/NA and 89.9% had GA as their primary anesthetic. After 1:1 propensity matching, the final cohort had 3254 patients. Our analysis did not find a difference in 30-day mortality between the 2 groups. There were also no significant differences in secondary outcomes.

CONCLUSIONS:
Despite the potential advantages of RA/NA, utilization for lower extremity trauma was low in our analysis; only 9.58% of patients were in the RA/NA group, with the majority receiving spinal anesthesia. This may be due to surgeon preference to allow for postoperative monitoring for neurologic injury and compartment syndrome or logistical factors given the urgent nature of these trauma cases. No significant differences in 30-day mortality and postoperative complications were found between RA/NA and GA for patients with lower extremity orthopedic fractures. The choice of anesthesia is multifactorial and may be driven by patient and provider preferences in these operations.
Development of mouse models of angiosarcoma driven by p53
Authors: Salter Donald M. , Griffin Meredyth , Muir Morwenna , Teo Katy , Culley Jayne , Smith James R. , Gomez-Cuadrado Laura , Matchett Kylie , Sims Andrew H. , Hayward Larry , Henderson Neil C. , Brunton Valerie G. 
Published: June 2019

ABSTRACT
Angiosarcomas are a rare group of tumours which have poor prognosis and limited treatment options. The development of new therapies has been hampered by a lack of good preclinical models. Here, we describe the development of an autochthonous mouse model of angiosarcoma driven by loss of p53 in VE-cadherin-expressing endothelial cells. Using Cdh5-Cre to drive recombination in adult endothelial cells, mice developed angiosarcomas with 100% penetrance upon homozygous deletion of Trp53 with a median lifespan of 325 days. In contrast, expression of the R172H mutant p53 resulted in formation of thymic lymphomas with a more rapid onset (median lifespan 151 days). We also used Pdgfrb-Cre-expressing mice, allowing us to target predominantly pericytes, as these have been reported as the cell of origin for a number of soft tissue sarcomas. Pdgfrb-Cre also results in low levels of recombination in venous blood endothelial cells in multiple tissues during development. Upon deletion of Trp53 in Pdgfrb-Cre-expressing mice (Pdgfrb-Cre, Trp53fl/fl mice), 65% developed lymphomas and 21% developed pleomorphic undifferentiated soft tissue sarcomas. None developed angiosarcomas. In contrast, 75% of Pdgfrb-Cre, Trp53R172H/R172H mice developed angiosarcomas, with 60% of these mice also developing lymphomas. The median lifespan of the Pdgfrb-Cre, Trp53R172H/R172H mice was 151 days. Re-implantation of angiosarcoma tumour fragments from Cdh5-Cre, Trp53fl/fl mice provided a more consistent and rapid model of angiosarcoma than the two spontaneous models. The ability to passage tumour fragments through the mouse provides a novel model which is amenable to preclinical studies and will help the development of potential new therapies for angiosarcoma.
The exocyst complex and Rab5 are required for abscission by localizing ESCRT III subunits to the cytokinetic bridge
Authors: Kumar Harsh , Pushpa Kumari , Kumari Amrita , Verma Kuldeep , Pergu Rajaiah , Mylavarapu Sivaram V. S. 
Published: June 2019

ABSTRACT
Cytokinesis is the final step of cell division following chromosome segregation that generates two daughter cells. The conserved exocyst complex is required for scission of the intercellular cytokinetic bridge, although the molecular mechanisms it employs in this process are unclear. We identify and validate the early endocytic GTPase Rab5 as interacting with the exocyst complex in mammalian cells. Rab5 localizes in the cytokinetic bridge and on the midbody ring in a manner similar to the exocyst complex. Depletion of Rab5 led to delayed abscission. Caenorhabditis elegans orthologs of both exocyst complex subunits and Rab5 localize along the cleavage furrow and are required for cytokinesis in early embryos. Cytokinetic cells depleted of either Rab5 or the exocyst subunits Exoc3 and Exoc4 showed impaired deposition of the endosomal sorting complexes required for transport (ESCRT) III subunits CHMP2B and/or CHMP4B near the midbody ring. The study reveals an evolutionarily conserved role for the early endocytic marker Rab5 in cytokinetic abscission. In addition, it uncovers a key requirement of the exocyst and Rab5 for the delivery of components of the membrane-severing ESCRT III machinery to complete cytokinesis.