bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sensitivity and Specificity of Cetuximab-IRDye800CW to Identify Regional Metastatic Disease in Head and Neck Cancer
Authors: Rosenthal Eben L. , Moore Lindsay S. , Tipirneni Kiranya , de Boer Esther , Stevens Todd M. , Hartman Yolanda E. , Carroll William R. , Zinn Kurt R. , Warram Jason M. 
Published: April 2017

Abstract
Purpose: Comprehensive cervical lymphadenectomy can be associated with significant morbidity and poor quality of life. This study evaluated the sensitivity and specificity of cetuximab-IRDye800CW to identify metastatic disease in patients with head and neck cancer.
Experimental Design: Consenting patients scheduled for curative resection were enrolled in a clinical trial to evaluate the safety and specificity of cetuximab-IRDye800CW. Patients (n = 12) received escalating doses of the study drug. Where indicated, cervical lymphadenectomy accompanied primary tumor resection, which occurred 3 to 7 days following intravenous infusion of cetuximab-IRDye800CW. All 471 dissected lymph nodes were imaged with a closed-field, near-infrared imaging device during gross processing of the fresh specimens. Intraoperative imaging of exposed neck levels was performed with an open-field fluorescence imaging device. Blinded assessments of the fluorescence data were compared to histopathology to calculate sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV).
Results: Of the 35 nodes diagnosed pathologically positive, 34 were correctly identified with fluorescence imaging, yielding a sensitivity of 97.2%. Of the 435 pathologically negative nodes, 401 were correctly assessed using fluorescence imaging, yielding a specificity of 92.7%. The NPV was determined to be 99.7%, and the PPV was 50.7%. When 37 fluorescently false-positive nodes were sectioned deeper (1 mm) into their respective blocks, metastatic cancer was found in 8.1% of the recut nodal specimens, which altered staging in two of those cases.
Conclusions: Fluorescence imaging of lymph nodes after systemic cetuximab-IRDye800CW administration demonstrated high sensitivity and was capable of identifying additional positive nodes on deep sectioning. Clin Cancer Res; 23(16); 4744–52. ©2017 AACR.
Feasibility of Ultra-High-Throughput Functional Screening of Melanoma Biopsies for Discovery of Novel Cancer Drug Combinations
Authors: Friedman Adam A. , Xia Yun , Trippa Lorenzo , Le Long Phi , Igras Vivien , Frederick Dennie T. , Wargo Jennifer A. , Tanabe Kenneth K. , Lawrence Donald P. , Neuberg Donna S. , Flaherty Keith T. , Fisher David E. 
Published: April 2017

AbstractPurpose: Successful development of targeted therapy combinations for cancer patients depends on first discovering such combinations in predictive preclinical models. Stable cell lines and mouse xenograft models can have genetic and phenotypic drift and may take too long to generate to be useful as a personalized medicine tool.Experimental Design: To overcome these limitations, we have used a platform of ultra-high-throughput functional screening of primary biopsies preserving both cancer and stroma cell populations from melanoma patients to nominate such novel combinations from a library of thousands of drug combinations in a patient-specific manner within days of biopsy. In parallel, patient-derived xenograft (PDX) mouse models were created and novel combinations tested for their ability to shrink matched PDXs.Results: The screening method identifies specific drug combinations in tumor cells with patterns that are distinct from those obtained from stable cell lines. Screening results were highly specific to individual patients. For patients with matched PDX models, we confirmed that individualized novel targeted therapy combinations could inhibit tumor growth. In particular, a combination of multi-kinase and PI3K/Akt inhibitors was effective in some BRAF–wild-type melanomas, and the addition of cediranib to the BRAF inhibitor PLX4720 was effective in a PDX model with BRAF mutation.Conclusions: This proof-of-concept study demonstrates the feasibility of using primary biopsies directly for combinatorial drug discovery, complementing stable cell lines and xenografts, but with much greater speed and efficiency. This process could potentially be used in a clinical setting to rapidly identify therapeutic strategies for individual patients. Clin Cancer Res; 23(16); 4680–92. ©2017 AACR.
Analytic, Preanalytic, and Clinical Validation of p53 IHC for Detection of TP53 Missense Mutation in Prostate Cancer
Authors: Guedes Liana B. , Almutairi Fawaz , Haffner Michael C. , Rajoria Gaurav , Liu Zach , Klimek Szczepan , Zoino Roberto , Yousefi Kasra , Sharma Rajni , De Marzo Angelo M. , Netto George J. , Isaacs William B. , Ross Ashley E. , Schaeffer Edward M. , Lotan Tamara L. 
Published: April 2017

Abstract
Purpose: TP53 missense mutations may help to identify prostate cancer with lethal potential. Here, we preanalytically, analytically, and clinically validated a robust IHC assay to detect subclonal and focal TP53 missense mutations in prostate cancer.
Experimental Design: The p53 IHC assay was performed in a CLIA-accredited laboratory on the Ventana Benchmark immunostaining system. p53 protein nuclear accumulation was defined as any p53 nuclear labeling in &gt;10% of tumor cells. Fifty-four formalin-fixed paraffin embedded (FFPE) cell lines from the NCI-60 panel and 103 FFPE prostate cancer tissues (88 primary adenocarcinomas, 15 metastases) with known TP53 mutation status were studied. DU145 and VCaP xenografts were subjected to varying fixation conditions to investigate the effects of preanalytic variables. Clinical validation was performed in two partially overlapping radical prostatectomy cohorts.
Results: p53 nuclear accumulation by IHC was 100% sensitive for detection of TP53 missense mutations in the NCI-60 panel (25/25 missense mutations correctly identified). Lack of p53 nuclear accumulation was 86% (25/29) specific for absence of TP53 missense mutation. In FFPE prostate tumors, the positive predictive value of p53 nuclear accumulation for underlying missense mutation was 84% (38/45), whereas the negative predictive value was 97% (56/58). In a cohort of men who experienced biochemical recurrence after RP, the multivariable HR for metastasis among cases with p53 nuclear accumulation compared with those without was 2.55 (95% confidence interval, 1.1–5.91).
Conclusions: IHC is widely available method to assess for the presence of deleterious and heterogeneous TP53 missense mutations in clinical prostate cancer specimens. Clin Cancer Res; 23(16); 4693–703. ©2017 AACR.
The Microbiota: A New Variable Impacting Cancer Treatment Outcomes
Authors: Fessler Jessica L. , Gajewski Thomas F. 
Published: April 2017

Abstract
Preclinical evidence has established that the host commensal microbiota can contribute to therapeutic response in cancer models, a finding supported by early clinical data. This connection between the microbiome and clinical outcome in oncology is cause for new consideration in the administration of antibiotics and microbiota-modulating interventions to improve outcomes. Clin Cancer Res; 23(13); 3229–31. ©2017 AACR.
See related article by Galloway-Peña et al., p. 3263
Concordance of Genomic Alterations by Next-Generation Sequencing in Tumor Tissue versus Circulating Tumor DNA in Breast Cancer
Authors: Chae Young Kwang , Davis Andrew A. , Jain Sarika , Santa-Maria Cesar , Flaum Lisa , Beaubier Nike , Platanias Leonidas C. , Gradishar William , Giles Francis J. , Cristofanilli Massimo 
Published: April 2017

Abstract
While identifying genomic alterations in tumor tissue is the current gold-standard technique for molecular profiling, circulating tumor DNA (ctDNA) represents a noninvasive method of assessing genomic alterations using peripheral blood. The concordance of genomic alterations between two commercially available ctDNA and tissue biopsies was compared in 45 patients with breast cancer using paired next-generation sequencing tissue and ctDNA biopsies. Across all genes, concordance between the two platforms was 91.0% to 94.2%. When only considering genomic alterations in either assay (e.g., excluding wild type/wild type genes), concordance was 10.8% to 15.1% with full plus partial concordance of 13.8% to 19.3%. Concordant mutations were associated with significantly higher variant allele frequency. Over half of mutations detected in either technique were not detected using the other biopsy technique. Including variants of unknown significance, the average number of alterations per patient was significantly higher for tissue (4.56) compared with ctDNA (2.16). When eliminating alterations not detectable in the ctDNA assay, mean number of alterations for tissue and ctDNA was similar (2.67 for tissue, 2.16 for ctDNA). Across five representative genes (TP53, PIK3CA, ERBB2, BRCA1, and BRCA2), sensitivity and specificity were 35.7% and 95.0%, respectively. Concordance when genomic alterations was detected in either tissue or ctDNA was low with each technique detecting a significant amount of nonoverlapping mutations. Potential explanations for the lack of concordance include tumor heterogeneity, different sequencing techniques, spatial and temporal factors, and potential germline DNA contamination. The study indicates that both tissue and blood-based NGS may be necessary to describe the complex biology of breast cancer. Mol Cancer Ther; 16(7); 1412–20. ©2017 AACR.
Ref-1/APE1 as a Transcriptional Regulator and Novel Therapeutic Target in Pediatric T-cell Leukemia
Authors: Ding Jixin , Fishel Melissa L. , Reed April M. , McAdams Erin , Czader Magdalena B. , Cardoso Angelo A. , Kelley Mark R. 
Published: April 2017

Abstract
The increasing characterization of childhood acute lymphoblastic leukemia (ALL) has led to the identification of multiple molecular targets but has yet to translate into more effective targeted therapies, particularly for high-risk, relapsed T-cell ALL. Searching for master regulators controlling multiple signaling pathways in T-ALL, we investigated the multifunctional protein redox factor-1 (Ref-1/APE1), which acts as a signaling “node” by exerting redox regulatory control of transcription factors important in leukemia. Leukemia patients' transcriptome databases showed increased expression in T-ALL of Ref-1 and other genes of the Ref-1/SET interactome. Validation studies demonstrated that Ref-1 is expressed in high-risk leukemia T cells, including in patient biopsies. Ref-1 redox function is active in leukemia T cells, regulating the Ref-1 target NF-κB, and inhibited by the redox-selective Ref-1 inhibitor E3330. Ref-1 expression is not regulated by Notch signaling, but is upregulated by glucocorticoid treatment. E3330 disrupted Ref-1 redox activity in functional studies and resulted in marked inhibition of leukemia cell viability, including T-ALL lines representing different genotypes and risk groups. Potent leukemia cell inhibition was seen in primary cells from ALL patients, relapsed and glucocorticoid-resistant T-ALL cells, and cells from a murine model of Notch-induced leukemia. Ref-1 redox inhibition triggered leukemia cell apoptosis and downregulation of survival genes regulated by Ref-1 targets. For the first time, this work identifies Ref-1 as a novel molecular effector in T-ALL and demonstrates that Ref-1 redox inhibition results in potent inhibition of leukemia T cells, including relapsed T-ALL. These data also support E3330 as a specific Ref-1 small-molecule inhibitor for leukemia. Mol Cancer Ther; 16(7); 1401–11. ©2017 AACR.
Cotargeting mTORC and EGFR Signaling as a Therapeutic Strategy in HNSCC
Authors: Swick Adam D. , Prabakaran Prashanth J. , Miller Margot C. , Javaid Amal M. , Fisher Michael M. , Sampene Emmanuel , Ong Irene M. , Hu Rong , Iida Mari , Nickel Kwangok P. , Bruce Justine Y. , Wheeler Deric L. , Kimple Randall J. 
Published: April 2017

Abstract
Head and neck squamous cell carcinomas (HNSCC) are frequently altered along the PI3K/AKT/mTORC signaling axis. Despite excellent preclinical data, the use of compounds targeting this pathway as monotherapy has been underwhelming in initial clinical trials, and identification of predictive biomarkers remains challenging. To investigate mTORC-specific inhibition, we tested catalytic mTORC (AZD8055) and PI3K/mTORC (NVP-BEZ-235) inhibitors ± cetuximab in a panel of HNSCC cell lines and patient-derived xenografts (PDX). Cell lines were assayed for response to all agents and siRNA knockdown of targets by multiple approaches. All cell lines showed similar response to both drug and siRNA inhibition of both PI3K and mTORC pathways, with anti-EGFR combination producing modest additive effect. Five PDX models that presented PIK3CA mutation or intrinsic cetuximab resistance were treated with a combination of cetuximab and AZD8055. In vivo single-agent mTORC inhibition inhibited growth of one PIK3CA-mutant cancer, but had little effect on any PIK3CAWT or a second PIK3CA-mutant model. In all models, the combination therapy showed greater growth delay than monotherapy. The uniform ability of PI3K and mTORC inhibition to suppress the growth of HNSCC cells highlights the pathway's role in driving proliferation. Although single-agent therapy was largely ineffective in vivo, improved response of combination treatment in an array of PDXs suggests the potential for adding a catalytic mTORC inhibitor to cetuximab therapy. Overall, these results add to a growing body of evidence, suggesting that approaches that attempt to match biomarkers to the optimal therapy in HNSCC remain complex and challenging. Mol Cancer Ther; 16(7); 1257–68. ©2017 AACR.
Endogenous developmental endothelial locus-1 limits ischaemia- related angiogenesis by blocking inflammation
Authors: Klotzsche - von Ameln Anne , Cremer Sebastian , Hoffmann Jedrzej , Schuster Peggy , Khedr Sherif , Korovina Irina , Troullinaki Maria , Neuwirth Ales , Sprott David , Chatzigeorgiou Antonios , Economopoulou Matina , Orlandi Alessia , Hain Andreas , Zeiher Andreas M. , Deussen Andreas , Hajishengallis George , Dimmeler Stefanie , Chavakis Triantafyllos , Chavakis Emmanouil 
Published: April 2017

SummaryWe have recently identified endothelial cell-secreted developmental endothelial locus-1 (Del-1) as an endogenous inhibitor of β2-integrin–dependent leukocyte infiltration. Del-1 was previously also implicated in angiogenesis. Here, we addressed the role of endogenously produced Del-1 in ischaemia-related angiogenesis. Intriguingly, Del-1–deficient mice displayed increased neovascularisation in two independent ischaemic models (retinopathy of prematurity and hind-limb ischaemia), as compared to Del-1–proficient mice. On the contrary, angiogenic sprouting in vitro or ex vivo (aortic ring assay) and physiological developmental retina angiogenesis were not affected by Del-1 deficiency. Mechanistically, the enhanced ischaemic neovascularisation in Del-1-deficiency was linked to higher infiltration of the ischaemic tissue by CD45+ haematopoietic and immune cells. Moreover, Del-1-deficiency promoted β2-integrin–dependent adhesion of haematopoietic cells to endothelial cells in vitro, and the homing of hematopoietic progenitor cells and of immune cell populations to ischaemic muscles in vivo. Consistently, the increased hind limb ischaemia-related angiogenesis in Del-1 deficiency was completely reversed in mice lacking both Del-1 and the β2-integrin LFA-1. Additionally, enhanced retinopathy-associated neovascularisation in Del-1-deficient mice was reversed by LFA-1 blockade. Our data reveal a hitherto unrecognised function of endogenous Del-1 as a local inhibitor of ischaemia-induced angiogenesis by restraining LFA-1–dependent homing of pro-angiogenic haematopoietic cells to ischaemic tissues. Our findings are relevant for the optimisation of therapeutic approaches in the context of ischaemic diseases.Supplementary Material to this article is available online at www.thrombosis-online.com.
F7 gene variants modulate protein levels in a large cohort of patients with factor VII deficiency
Authors: Quintavalle Gabriele , Riccardi Federica , Rivolta Gianna , Martorana Davide , Di Perna Caterina , Percesepe Antonio , Tagliaferri Annarita ,   on behalf of the Ad-Hoc Study Group
Published: April 2017

SummaryCongenital factor VII (FVII) deficiency is a rare bleeding disorder caused by mutations in F7 gene with autosomal recessive inheritance. A clinical heterogeneity with poor correlation with FVII:C levels has been described. It was the objective of this study to identify genetic defects and to evaluate their relationships with phenotype in a large cohort of patients with FVII:C<50%. One hundred twenty-three probands were genotyped for F7 mutations and three polymorphic variants and classified according to recently published clinical scores. Forty out of 123 patients (33?%) were symptomatic (43 bleedings). A severe bleeding tendency was observed only in patients with FVII:C<0.10%. Epistaxis (11%) and menorrhagia (32% of females in fertile age) were the most frequent bleedings. Molecular analysis detected 48 mutations, 20 not reported in the F7 international databases. Most mutations (62%) were missense, large deletions were 6.2%. Compound heterozygotes/homozygotes for mutations presented lower FVII:C levels compared to the other classes (Chi2=43.709, p<0,001). The polymorphisms distribution was significantly different among the three F7 genotypic groups (Chi2=72.289, p<0,001). The presence of truncating mutations was associated with lowest FVII:C levels (Chi2=21.351, p=0.002). This study confirms the clinical and molecular variability of the disease and the type of symptoms. It shows a good correlation between the type of F7 mutation and/or polymorphisms and FVII:C levels, without a direct link between FVII:C and bleeding tendency. The results suggest that large deletions are underestimated and that they represent a common mechanism of F7 gene inactivation which should always be investigated in the diagnostic testing for FVII deficiency.
Effects of the Mean Amplitude of Glycemic Excursions and Vascular Endothelial Dysfunction on Cardiovascular Events in Nondiabetic Patients With Coronary Artery Disease
Authors: Akasaka Tomonori , Sueta Daisuke , Tabata Noriaki , Takashio Seiji , Yamamoto Eiichiro , Izumiya Yasuhiro , Tsujita Kenichi , Kojima Sunao , Kaikita Koichi , Matsui Kunihiko , Hokimoto Seiji 
Published: April 2017

Background

Mean amplitude of glycemic excursion (
MAGE
) is commonly used to gauge the degree of glucose level fluctuations.
MAGE
plays a significant role in vascular endothelial dysfunction and cardiovascular events in patients with diabetes mellitus (
DM
), but its significance is not clear in non‐
DM
patients. Thus, we examined the impact of
MAGE
and vascular endothelial dysfunction on clinical outcomes in non‐
DM
patients with coronary artery disease.

Methods and Results

We followed non‐
DM
patients (n=65) for 12 months who underwent percutaneous coronary intervention and assessed the relationship among
MAGE
, reactive hyperemia index (
RHI
) measured by reactive hyperemia peripheral arterial tonometry as endothelial function, and cardiovascular events. Cardiovascular events analyzed were cardiovascular death, myocardial infarction, unstable angina, and revascularizations. Compared with patients with
MAGE
<65 mg/dL (normal glycemic excursions), the group with
MAGE ≥
65 mg/dL (high glycemic excursions) had significantly higher high‐sensitivity C‐reactive protein (0.10±0.11 mg/dL versus 0.18±0.13 mg/dL,
P
=0.006) and lower
RHI
(0.64±0.21 versus 0.51±0.22,
P
=0.035). The multivariable analysis identified high
MAGE
and low
RHI
(≤0.56) as risk factors associated with cardiovascular events (hazard ratio, 5.6; 95%
RI,
1.72–18.4 [
P
=0.004] versus hazard ratio, 4.5; 95%
RI,
1.37–14.9 [
P
=0.013]). When the prognosis was classified by combination with
MAGE
and
RHI
, the incidence of cardiovascular events was 46.7% (high
MAGE
+low
RHI
), 26.7% (high
MAGE
+high
RHI
), 20.0% (low
MAGE
+low
RHI
), and 6.6% (low
MAGE
+high
RHI
) in descending order (
P
=0.014). Receiver operating characteristic curve analysis revealed that
MAGE
,
RHI
, and
MAGE
+
RHI
were each associated with cardiovascular events (area under the curve 0.780, 0.727, and 0.796, respectively).

Conclusions

MAGE
was associated with cardiovascular events in non‐
DM
patients with coronary artery disease. Furthermore, the combination with
MAGE
and
RHI
was useful for further subdivision of the risk of cardiovascular events.
Use of Noncontrast Computed Tomography and Computed Tomographic Perfusion in Predicting Intracerebral Hemorrhage After Intravenous Alteplase Therapy
Authors: Batchelor Connor , Pordeli Pooneh , d’Esterre Christopher D. , Najm Mohamed , Al-Ajlan Fahad S. , Boesen Mari E. , McDougall Connor , Hur Lisa , Fainardi Enrico , Shankar Jai Jai Shiva , Rubiera Marta , Khaw Alexander V. , Hill Michael D. , Demchuk Andrew M. , Sajobi Tolulope T. , Goyal Mayank , Lee Ting-Yim , Aviv Richard I. , Menon Bijoy K. 
Published: April 2017

Background and Purpose—
Intracerebral hemorrhage is a feared complication of intravenous alteplase therapy in patients with acute ischemic stroke. We explore the use of multimodal computed tomography in predicting this complication.

Methods—

All patients were administered intravenous alteplase with/without intra-arterial therapy. An age- and sex-matched case–control design with classic and conditional logistic regression techniques was chosen for analyses. Outcome was parenchymal hemorrhage on 24- to 48-hour imaging. Exposure variables were imaging (noncontrast computed tomography hypoattenuation degree, relative volume of very low cerebral blood volume, relative volume of cerebral blood flow ≤7 mL/min·per 100 g, relative volume of T
max
≥16 s with all volumes standardized to
z
axis coverage, mean permeability surface area product values within T
max
≥8 s volume, and mean permeability surface area product values within ipsilesional hemisphere) and clinical variables (NIHSS [National Institutes of Health Stroke Scale], onset to imaging time, baseline systolic blood pressure, blood glucose, serum creatinine, treatment type, and reperfusion status).

Results—

One-hundred eighteen subjects (22 patients with parenchymal hemorrhage versus 96 without, median baseline NIHSS score of 15) were included in the final analysis. In multivariable regression, noncontrast computed tomography hypoattenuation grade (
P
<0.006) and computerized tomography perfusion white matter relative volume of very low cerebral blood volume (
P
=0.04) were the only significant variables associated with parenchymal hemorrhage on follow-up imaging (area under the curve, 0.73; 95% confidence interval, 0.63–0.83). Interrater reliability for noncontrast computed tomography hypoattenuation grade was moderate (κ=0.6).

Conclusions—
Baseline hypoattenuation on noncontrast computed tomography and very low cerebral blood volume on computerized tomography perfusion are associated with development of parenchymal hemorrhage in patients with acute ischemic stroke receiving intravenous alteplase.