bluuebunny/crossref_metadata_2025 huggingface dataset:
Engineering of chromosomal wax ester synthase integrated Saccharomyces cerevisiae mutants for improved biosynthesis of fatty acid ethyl esters
Authors: Shi Shuobo , Valle‐Rodríguez Juan Octavio , Siewers Verena , Nielsen Jens
Published: April 2014

In recent years, significant advances have been made to engineer robust microbes for overproducing biochemical products from renewable resources. These accomplishments have to a large extend been based on plasmid based methods. However, plasmid maintenance may cause a metabolic burden on the host cell and plasmid‐based overexpression of genes can result in genetically unstable strains, which contributes to loss in productivity. Here, a chromosome engineering method based on delta integration was applied in Saccharomyces cerevisiae for the production of fatty acid ethyl esters (FAEEs), which can be directly used as biodiesel and would be a possible substitute for conventional petroleum‐based diesel. An integration construct was designed and integrated into chromosomal delta sequences by repetitive transformation, which resulted in 1–6 copies of the integration construct per genome. The corresponding FAEE production increased up to 34 mg/L, which is an about sixfold increase compared to the equivalent plasmid‐based producer. The integrated cassette in the yeast genome was stably maintained in nonselective medium after deletion of RAD52 which is essential for efficient homologous recombination. To obtain a further increase of FAEE production, genes encoding endogenous acyl‐CoA binding protein (ACB1) and a bacterial NADP+‐dependent glyceraldehyde‐3‐phosphate dehydrogenase (gapN) were overexpressed in the final integration strain, which resulted in another 40% percent increase in FAEE production. Our integration strategy enables easy engineering of strains with adjustable gene copy numbers integrated into the genome and this allows for an easy evaluation of the effect of the gene copy number on pathway flux. It therefore represents a valuable tool for introducing and expressing a heterologous pathway in yeast. Biotechnol. Bioeng. 2014;111: 1740–1747. © 2014 Wiley Periodicals, Inc.
Biotechnological production of plant‐specific hydroxylated phenylpropanoids
Authors: Lin Yuheng , Yan Yajun
Published: April 2014

Hydroxylated phenylpropanoid compounds (e.g., esculetin, piceatannol, and eriodictyol) have been proved to possess important biological activities and pharmacological properties. These compounds exist at low abundance in nature, which hampers their cost‐effective isolation, and broad application. Meanwhile, regiospecific hydroxylation of complex aromatic compounds is still quite challenging for chemical synthesis. In past decades, biocatalytic hydroxylation of plant phenylpropanoids was achieved due to the identification and engineering of some cytochrome P450 hydroxylases; however, the conversion efficiency was still too low for scale‐up production use. In this work, we identify a non‐P450 monooxygenase (HpaBC) from Escherichia coli, which is able to catalyze the efficient ortho‐hydroxylation towards plant phenylpropanoids umbelliferone and resveratrol; meanwhile it also exhibits activity towards naringenin. On this basis, whole‐cell biocatalysis enables the production of esculetin and piceatannol at high titers (2.7 and 1.2 g/L, respectively, in shake flasks) and high yields (close to 100%). To our knowledge, this work reports the highest titers and yields for biotechnological production of esculetin and piceatannol, representing a promising hydroxylation platform. Biotechnol. Bioeng. 2014;111: 1895–1899. © 2014 Wiley Periodicals, Inc.
Inferring alterations in cell‐to‐cell communication in HER2+ breast cancer using secretome profiling of three cell models
Authors: Klinke David J. , Kulkarni Yogesh M. , Wu Yueting , Byrne‐Hoffman Christina
Published: April 2014

Challenges in demonstrating durable clinical responses to molecular‐targeted therapies have sparked a re‐emergence in viewing cancer as an evolutionary process. In somatic evolution, cellular variants are introduced through a random process of somatic mutation and are selected for improved fitness through a competition for survival. In contrast to Darwinian evolution, cellular variants that are retained may directly alter the fitness competition. If cell‐to‐cell communication is important for selection, the biochemical cues secreted by malignant cells that emerge should be altered to bias this fitness competition. To test this hypothesis, we compared the proteins secreted in vitro by two human HER2+ breast cancer cell lines (BT474 and SKBR3) relative to a normal human mammary epithelial cell line (184A1) using a proteomics workflow that leveraged two‐dimensional gel electrophoresis (2DE) and MALDI‐TOF mass spectrometry. Supported by the 2DE secretome maps and identified proteins, the two breast cancer cell lines exhibited secretome profiles that were similar to each other and, yet, were distinct from the 184A1 secretome. Using protein–protein interaction and pathway inference tools for functional annotation, the results suggest that all three cell lines secrete exosomes, as confirmed by scanning electron microscopy. Interestingly, the HER2+ breast cancer cell line exosomes are enriched in proteins involved in antigen‐processing and presentation and glycolytic metabolism. These pathways are associated with two of the emerging hallmarks of cancer: evasion of tumor immunosurveillance and deregulating cellular energetics. Biotechnol. Bioeng. 2014;111: 1853–1863. © 2014 Wiley Periodicals, Inc.
Physician‐anatomists of Italy in Şānīzāde Mehmed Atāullah Efendi's work Mir'āt al‐Abdān (mirror of bodies)
Authors: Aciduman Ahmet , Arda Berna
Published: April 2014

Şānīzāde Mehmed Atāullah Efendi was a pioneer in the history of Turkish medical education with his work Ḫamse‐i Şānīzāde (Five Works of Şānīzāde). The first of these works, Mir'āt al‐abdān fī taşrīh‐i a‘ḍāi’l‐insān (Mirror of the Bodies in the Dissection of the Members of the Human Body), concerns anatomy and was written in 1816. Şānīzāde's Mir'āt al‐abdān is an important milestone in the teaching of anatomy in the Ottoman Empire and was also the first book on anatomy both written in a modern manner and printed in the Ottoman Empire. This paper is based on investigation of a printed copy of Mir'āt al‐Abdān in the library of the History of Medicine and Ethics Department, Ankara University Faculty of Medicine. The main text and explanations were transliterated into the contemporary Turkish alphabet. The names of European physicians and their eponyms in the main text and in the explanations of illustrations were identified and evaluated. The names of European masters of anatomy in Şānīzāde are mentioned either in the text or in plate explanations. These names and plates indicate well‐known physicians and masters of anatomy whose works were examined and quoted by Şānīzāde. The references in Şānīzāde's book and presented in this study relate to Italian physician‐anatomists such as Bartolomeo Eustachi, Gabriele Fallopio, Costanzo Varolio and to others, such as Andreas Vesalius and Adriaan van den Spiegel, who were also Padua‐educated but not Italian. Clin. Anat. 27:808–814, 2014. © 2014 Wiley Periodicals, Inc.
Heinrich Obersteiner and his contributions
Authors: Cesmebasi Alper , John Alana , Etienne Denzil , Tubbs R. Shane , Loukas Marios
Published: April 2014

Heinrich Obersteiner (1847–1921) was amongst the most influential neuroscientists in the 19th century. Born into a family of physicians, he gained early exposure to medicine, and as a medical student, he focused much of his research in neuroanatomy, eventually becoming a professor of neuroanatomy at the University of Vienna. Throughout his academic career, he focused greatly on neuropathology, and incorporated much of his research into his textbook, “Introduction to the Study of the Structure of the Central Nervous Organs in Health and Disease,” which was considered the foremost reference text of neurology for many generations of scholars. The culmination of his contributions to the neurological world can be seen as the Neurological Institute of Vienna, which he founded in 1882. Scholars from all over the world sought out his expertize and tutelage. While he was the director of the Institute, over 500 articles were published within the Obersteiner‐Arbeiten. Much of this work helped set the foundation for the eventual development of neurology as a medical discipline. A review of his life will help us better understand the legacy Heinrich Obersteiner left in the field of neurology. Clin. Anat. 28:5–11, 2015. © 2014 Wiley Periodicals, Inc.
Ectopia cordis: A rare congenital anomaly
Authors: Gabriel Abigail , Donnelly Joseph , Kuc Alexander , Good Daniel , Doros Gabriela , Matusz Petru , loukas marios
Published: April 2014

Ectopia cordis (EC) is a rare congenital anomaly associated with the heart positioned outside of the thoracic cavity either partially or completely. The ectopic heart can be found along a spectrum of anatomical locations, including the cervical, thoracic and abdominal regions and in most cases, it protrudes outside the chest through a split sternum. Although the first case of EC was identified during the early 1600s only 91 cases have been reported since then in the literature. This review will discuss the history and prevalence of EC, its etiology, morphology, presentation and symptoms, complications, diagnosis, treatment and management and prognosis. Clin. Anat. 27:1193–1199, 2014. © 2014 Wiley Periodicals, Inc.
Why do some intervertebral discs degenerate, when others (in the same spine) do not?
Authors: Adams Michael A. , Lama Polly , Zehra Uruj , Dolan Patricia
Published: April 2014

This review suggests why some discs degenerate rather than age normally. Intervertebral discs are avascular pads of fibrocartilage that allow movement between vertebral bodies. Human discs have a low cell density and a limited ability to adapt to mechanical demands. With increasing age, the matrix becomes yellowed, fibrous, and brittle, but if disc structure remains intact, there is little impairment in function, and minimal ingrowth of blood vessels or nerves. Approximately half of old lumbar discs degenerate in the sense of becoming physically disrupted. The posterior annulus and lower lumbar discs are most affected, presumably because they are most heavily loaded. Age and genetic inheritance can weaken discs to such an extent that they are physically disrupted during everyday activities. Damage to the endplate or annulus typically decompresses the nucleus, concentrates stress within the annulus, and allows ingrowth of nerves and blood vessels. Matrix disruption progresses by mechanical and biological means. The site of initial damage leads to two disc degeneration “phenotypes”: endplate‐driven degeneration is common in the upper lumbar and thoracic spine, and annulus‐driven degeneration is common at L4‐S1. Discogenic back pain can be initiated by tissue disruption, and amplified by inflammation and infection. Healing is possible in the outer annulus only, where cell density is highest. We conclude that some discs degenerate because they are disrupted by excessive mechanical loading. This can occur without trauma if tissues are weakened by age and genetic inheritance. Moderate mechanical loading, in contrast, strengthens all spinal tissues, including discs. Clin. Anat. 28:195–204, 2015. © 2014 Wiley Periodicals, Inc.
Using and respecting the dead human body: An anatomist's perspective
Authors: Jones D. Gareth
Published: April 2014

In his stimulating article enquiring into what the living owe the dead, Wilkinson (2013, Clin. Anat. DOI: 10.1002/ca.22263) sought to unpack a range of ethical questions of considerable interest to anatomists. In this, he looked closely at the extent to which we are or are not to respect all the prior wishes of the deceased, and the implications of this for the role of the family in providing consent, the use of unclaimed bodies, and the public display of bodies. Some of his conclusions challenge widely encountered views by anatomists. In this response I have re‐visited these topics in an attempt to ground his arguments in the experience of anatomists, by emphasizing the many intimate connections that exist between each of these areas. The following emerge as issues for further debate. I accept that the wishes of the deceased are preeminent, so that authorities should make every effort to abide by these. This reiterates the importance of body bequests over against unclaimed bodies, and provides a context for assessing the role of family consent. This has repercussions for all activities employing dead bodies, from the dissecting room to public plastination exhibitions. In determining the extent to which the wishes of the deceased are followed the input of other interested parties is a relevant consideration. An ethical assessment of the public display of bodies needs to take into account the nature of the plastination process. Clin. Anat. 27:839–843, 2014. © 2014 Wiley Periodicals, Inc.
Anatomical observations of the human acromioclavicular joint
Authors: Emura Kenji , Arakawa Takamitsu , Miki Akinori , Terashima Toshio
Published: April 2014

The condition of the acromioclavicular joint (ACJ) is considered to be one factor in the etiology of shoulder impingement syndrome, but there are few supporting morphological data. Fifty‐two sides of 35 cadavers were investigated macroscopically and histologically using Safranin O, Fast green, and Weigert's iron hematoxylin staining. The ACJs were classified into three major types depending on the presence or absence of the articular disk. In type 1, the articular disk divided the articular cavity completely (n = 2; 3.8%). In type 2, the articular disk was incomplete and divided the joint cavity incompletely (n = 13; 25%). Type 2 was further divided into subtypes 2a and 2b depending on the configurations of the articular facets. In type 3, no articular disk was found in the joint cavity (n = 37; 71.2%). Type 3 was further divided into subtypes 3a, 3b, and 3c depending on the configurations of the articular surfaces. Fewer than half of the ACJ specimens (22/52 or 42.3%) demonstrated an ellipsoid character in which axial rotation was limited. Histological observation revealed that the upper part of the articular disk of the ACJ comprised fibrocartilage while the lower part comprised dense connective tissue. In cases where the ACJ appears to be an ellipsoid joint, its limited axial rotation restricts posterior tilting of the scapula during arm elevation, which could contribute to shoulder impingement syndrome. Clin. Anat. 27:1046–1052, 2014. © 2014 Wiley Periodicals, Inc.
Transcatheter closure of sinus venosus atrial septal defect with anomalous drainage of right upper pulmonary vein into superior vena cava—An innovative technique
Authors: Garg Gaurav , Tyagi Himanshu , Radha Anil Sivadasan
Published: April 2014

Sinus venosus atrial septal defect (SVASD) is located high in the atrial septum where the right superior vena cava (RSVC) enters the right atrium, and is commonly associated with partial anomalous pulmonary venous return of right upper pulmonary vein (RUPV) into RSVC. Transcatheter closure of such defects has not been described in the literature. We have developed an innovative technique to close this defect by transcatheter means. We present here a 35‐year old patient with SVASD and anomalous drainage of RUPV in RSVC in whom we closed the defect along with rerouting of RUPV to left atrium (LA) using a 12 mm × 61 mm adventa V12 covered stent in the RSVC with good outcome. © 2014 Wiley Periodicals, Inc.
Clinical outcome of patients with implantation of second‐generation drug‐eluting stents in the right coronary ostium: Insights from 2‐year follow‐up of the TWENTE trial
Authors: Lam Ming Kai , Sen Hanim , Tandjung Kenneth , Löwik Marije M. , Basalus Mounir W.Z. , Mewes Janne C. , Stoel Martin G. , van Houwelingen K. Gert , Linssen Gerard C.M. , Ijzerman Maarten J. , Doggen Carine J.M. , von Birgelen Clemens
Published: April 2014

Objectives

The aim of the present study was to assess the impact on clinical outcome of right coronary artery (RCA) ostial coverage with second‐generation drug‐eluting stents (DES).

Background

Treatment of the aorta‐ostial (AO) region of the RCA with bare metal stents and first‐generation DES has been associated with a higher risk of target‐lesion revascularization (TLR).

Methods

Of the 1,391 patients of the prospective TWENTE trial, we identified 321 (23%) with single‐vessel RCA treatment, who were categorized into stenting with AO stent coverage (AOC) versus stenting without AOC. The AO region was defined as 3 mm from the aortic orifice.

Results

The 67 (20.9%) patients with AOC showed more severe lesion calcifications than the 254 patients without AOC (31.3% vs. 12.6%; P < 0.01). In the AOC group, there was a higher prevalence of hypercholesterolemia and family history of coronary disease (75.4% vs. 61.6%, and 68.7% vs. 53.5%, respectively; P = 0.03). During 2‐year follow‐up, patients in the AOC group had a higher incidence of TLR (7.5% vs. 1.6%; P = 0.02). Following adjustment for confounders, AOC independently predicted TLR with an adjusted hazard ratio of 4.1 (95% CI: 1.17–14.39; P = 0.03).

Conclusion

AO treatment of the RCA with second‐generation DES is feasible, but our data suggest that stent coverage of the right AO segment remains a predictor of TLR. © 2014 Wiley Periodicals, Inc.
Angiographic characteristics of definite stent thrombosis: Role of thrombus grade, collaterals, epicardial coronary flow, and myocardial perfusion
Authors: Reeves Ryan R. , Patel Mitul , Armstrong Ehrin J. , Sab Shiv , Waldo Stephen W. , Yeo Khung‐Keong , Shunk Kendrick A. , Low Reginald I. , Rogers Jason H. , Mahmud Ehtisham
Published: April 2014

Objectives

To characterize the prevalence of thrombus burden, collateral vessels to the infarct‐related artery, epicardial coronary artery flow, and myocardial perfusion in patients with angiographically confirmed definite stent thrombosis (ST), and to define their relationship with associated treatments and outcomes.

Background

Angiographic characteristics of ST are not well defined.

Methods

All cases of angiographically determined ST at five academic hospitals from 2005 to 2012 were reviewed. Demographic, procedural, and angiographic characteristics were recorded. In‐hospital and 1‐year follow‐up data were obtained.

Results

Among 205 cases of angiographic definite ST (60 ± 8 years; 87% male), the majority presented with late/very late ST (69%) and STEMI (66%). High‐risk angiographic findings at presentation included thrombus grade 4–5 (87%), absence of collateral vessels (76%), and reduced initial TIMI 3 flow (90%). Final TIMI 3 flow was achieved in 90% of patients and was associated with greater use of aspiration thrombectomy (60% vs. 25%; P = 0.003), glycoprotein IIb/IIIa inhibitors (80% vs. 30%, P < 0.001), and repeat stenting (67% vs. 10%, P < 0.001). A final myocardial perfusion grade of 2–3 was achieved in 79% of patients and was associated with greater use of aspiration thrombectomy (61% vs. 36%, P = 0.003). After multivariable logistic regression, aspiration thrombectomy (AOR 2.6, 95% CI 1.3–5.2) and implantation of a new stent (AOR 2.1, 95% CI 1.1–4.3) were associated with optimal combined epicardial flow and myocardial perfusion. At 1‐year follow‐up, significantly lower risk of repeat ST (HR 0.1; 95% CI 0.1,0.2; P < 0.001) among patients with initial TIMI 3 flow at index ST was observed.

Conclusions

The majority of ST patients present with late/very late ST with high thrombus burden and STEMI. Presence of collateral vessels and low thrombus burden is cardioprotective, while reduced initial TIMI flow is associated with larger infarct size and recurrent ST. Aspiration thrombectomy and repeat stenting are associated with improved epicardial coronary artery flow and myocardial perfusion among patients treated for ST. © 2014 Wiley Periodicals, Inc.
Shorter (≤6 months) versus longer (≥12 months) duration dual antiplatelet therapy after drug eluting stents: A meta‐analysis of randomized clinical trials
Authors: Pandit Anil , Giri Smith , Hakim Fayaz Ahmad , Fortuin F. David
Published: April 2014

Objective

Optimal duration of dual antiplatelet therapy (DAPT), defined as use of both aspirin and a P2Y12 receptor inhibitor, after implantation of drug eluting stents (DES) is still subject of ongoing debate. We systematically review efficacy and safety of ≤6 months versus ≥12 months DAPT after implantation of DES.

Methods

PubMed, Scopus, Cochrane, and clinicaltrials.gov databases were searched for studies published until 30th November 2013. The studies were limited to randomized clinical trials. Independent observers abstracted the data on outcomes, characteristics, and qualities of studies included. Random effect model was employed for meta‐analysis. Heterogeneity of studies included was analyzed using I2 statistics.

Results

In four randomized clinical trials published involving 8,163 patients with DES, 4,081 patients were randomized to shorter and 4,082 patients to longer duration DAPT. The P2Y12 receptor inhibitor used in all four studies was clopidogrel. Longer duration of DAPT did not reduce risk of all cause mortality (pooled OR 0.89, 95% CI 0.67–1.17, P = 0.4, I2 = 0%), myocardial infarction (pooled OR 1.16, 95% CI 0.85–1.57, P = 0.35, I2 = 0%) cardiac death (pooled OR 0.88, 95% CI 0.61–1.25, P = 0.47, I2 = 0%), stent thrombosis (pooled OR 1.29, 95% CI 0.76–2.21, P = 0.35, I2 = 0%) or cerebrovascular accidents (pooled OR 0.73, 95% CI 0.41–1.27, P = 0.26, I2 = 0%). Longer duration of DAPT was associated with increased risk of TIMI major bleeding (pooled OR 0.51, 95% CI 0.29–0.89, P = 0.02, I2 = 0%).

Conclusion

There was no difference in efficacy outcomes between ≤6 months of DAPT and ≥12 months of DAPT in patients with coronary artery disease and DES implantation. Moreover, longer duration of DAPT is associated with increased risk of bleeding complications. © 2014 Wiley Periodicals, Inc.
Taguchi's methodology for determining optimum operating conditions in hydrothermal pretreatments applied to canola seeds
Authors: Fernández María B. , Burnet Margarita A. , Perez Ethel E. , Crapiste Guillermo H. , Nolasco Susana M.
Published: April 2014

The aim of the present work was to determine the optimum operating conditions in hydrothermal pretreatments applied to canola seeds. The effect of these pretreatments on the canola oil extraction yield and quality was evaluated. Samples were characterized by proximate analysis. Acidity and peroxide value were studied as parameters for the determination of oil quality. Seeds were exposed to direct steam contact in an autoclave. Pretreatments were carried out using different temperatures (100, 120 and 130 °C), exposition times (5, 15 and 30 min) and seed granulometry (ground seeds, with a particle size in a range from 0.420 to 1.000 mm; broken seeds, with a particle size ranging from 1.000 to 1.410 mm, and entire seeds). After each hydrothermal pretreatment, oil extraction was carried out by the Soxhlet method (hexane). The Taguchi method was followed in order to explore the optimum operating conditions by using an L9 experimental design, and select the most favourable levels of each variable. Initial oil content was 44.2% dry basis (db). The selected optimum experiment, using a temperature of 120 °C, a time of 5 min and broken seeds, generated an oil yield increase of 20% compared with non‐hydrothermally treated seeds, whereas quality parameters remained within the accepted values for trade standards.
Magnetic resonance imaging in patients with newly diagnosed breast cancer: A review of the literature
Authors: Pilewskie Melissa , King Tari A.
Published: April 2014

The use of magnetic resonance imaging (MRI) in patients with newly diagnosed breast cancer remains controversial. Here we review the current use of breast MRI and the impact of MRI on short‐term surgical outcomes and rates of local recurrence. In addition, we address the use of MRI in specific patient populations, such as those with ductal carcinoma in situ, invasive lobular carcinoma, and occult primary breast cancer, and discuss the potential role of MRI for assessing response to neoadjuvant chemotherapy. Although MRI has improved sensitivity compared with conventional imaging, this has not translated into improved short‐term surgical outcomes or long‐term patient benefit, such as improved local control or survival, in any patient population. MRI is an important diagnostic test in the evaluation of patients presenting with occult primary breast cancer and has shown promise in monitoring response to neoadjuvant chemotherapy; however, the data do not support the routine use of perioperative MRI in patients with newly diagnosed breast cancer. Cancer 2014;120:120:2080–2089. © 2014 American Cancer Society.
Cancer rehabilitation and prehabilitation may reduce disability and early retirement
Authors: Silver Julie K.
Published: April 2014

Prehabilitation and rehabilitation are essential components of high‐quality cancer care. Screening followed by evidence‐based, interdisciplinary rehabilitation interventions improves physical and psychological health outcomes and will likely reduce work‐related disability and the risk of early retirement in survivors.
A phase 2 cooperative group adjuvant trial using a biomarker‐based decision algorithm in patients with stage I non‐small cell lung cancer (SWOG‐0720, NCT00792701)
Authors: Bepler Gerold , Zinner Ralph G. , Moon James , Calhoun Royce , Kernstine Kemp , Williams Charles C. , Mack Philip C. , Oliveira Vasco , Zheng Zhong , Stella Philip J. , Redman Mary W. , Gandara David R.
Published: April 2014

BACKGROUND

This cooperative group adjuvant phase 2 trial in patients with completely resected stage I non‐small cell lung cancer with tumor diameters measuring ≥ 2 cm was designed to assess the feasibility and preliminary efficacy of assigning patients to therapy or observation using a molecularly based decision algorithm.

METHODS

At least a lobectomy and sampling of recommended mediastinal lymph node stations, good Zubrod performance status, adequate organ function, and a formalin‐fixed and paraffin‐embedded tumor specimen were required. Excision repair cross‐complementing group 1 (ERCC1) and ribonucleotide reductase M1 (RRM1) were analyzed using immunofluorescence‐based in situ automated quantitative image analysis and categorized as high or low using prespecified cutoff values. Patients with high ERCC1 and RRM1 were assigned to observation and all others to 4 cycles of cisplatin and gemcitabine. Feasibility was defined as treatment assignment within 84 days from surgery in > 85% of patients. Secondary objectives were to estimate the 2‐year survival.

RESULTS

Treatment assignment met the feasibility criteria in 88% of eligible patients (71 of 81 patients). The collective 2‐year disease‐free and overall survival rates were 80% and 96%, respectively. Protein levels for RRM1 fell within the previously established range, ERCC1 levels were slightly lower than expected, and they were significantly correlated (correlation coefficient, 0.4). The rates of assignment of patients to observation (22%) and chemotherapy (78%) were as expected.

CONCLUSIONS

Gene expression analysis for treatment assignment is feasible. Survival results are encouraging and require future validation. Real‐time performance of quantitative in situ ERCC1 and RRM1 analysis requires further development. Cancer 2014;120:2343–2351. © 2014 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.
Early retirement in cancer patients with or without comorbid mental health conditions: A prospective cohort study
Authors: Singer Susanne , Meyer Alexandra , Wienholz Sabine , Briest Susanne , Brown Anna , Dietz Andreas , Binder Harald , Jonas Sven , Papsdorf Kirsten , Stolzenburg Jens‐Uwe , Köhler Uwe , Raßler Jörg , Zwerenz Rüdiger , Schröter Katharina , Mehnert Anja , Löbner Margrit , König Hans‐Helmut , Riedel‐Heller Steffi G.
Published: April 2014

BACKGROUND

The authors investigated whether cancer patients who have comorbid mental health disorders (MD) are at greater risk of early retirement compared with those who do not have MD.

METHODS

Individuals ages 18 to 55 years from a consecutive sample of patients who were admitted for inpatient oncologic treatment were interviewed using structured clinical interviews to ascertain MD. The patients were followed for 15 months, and the date of early retirement was documented. Rates of early retirement per 100 person‐years (py) in patients with and without MD were compared using multivariate Poisson regression models.

RESULTS

At baseline, 491 patients were interviewed, and 150 of those patients (30.6%) were diagnosed with MD. Forty‐one patients began full early retirement during follow‐up. In patients with MD, the incidence of early retirement was 9.3 per 100 py compared with 6.1 per 100 py in mentally healthy patients. The crude rate ratio (RR) was 1.5 (95% confidence interval [CI], 0.8‐2.8). The effect of MD on early retirement was modified in part by income: in patients with low income, the adjusted RR was 11.7, whereas no effect was observed in higher income groups. Patients with depression were at greater risk of retirement when they had higher income (RR, 3.4; P = .05). The effects of anxiety (RR, 2.4; P = .05), adjustment disorders (RR, 1.7; P = .21), and alcohol dependence (RR, 1.8; P = .40) on early retirement were equal across income groups.

CONCLUSIONS

Mental health conditions are risk factors for early retirement in cancer patients, although this effect differs according to the type of disorder and the patient's income level. Cancer 2014;120:2199–2206. © 2014 American Cancer Society.
Everolimus in combination with octreotide long‐acting repeatable in a first‐line setting for patients with neuroendocrine tumors: An ITMO group study
Authors: Bajetta Emilio , Catena Laura , Fazio Nicola , Pusceddu Sara , Biondani Pamela , Blanco Giusi , Ricci Sergio , Aieta Michele , Pucci Francesca , Valente Monica , Bianco Nadia , Mauri Chiara Maria , Spada Francesca
Published: April 2014

BACKGROUND

Preclinical and clinical studies suggest synergistic activity between somatostatin analogues and mammalian target of rapamycin inhibitors. The activity and safety of everolimus was assessed in combination with octreotide long‐acting repeatable (LAR) in patients with neuroendocrine tumors (NETs) of gastroenteropancreatic and lung origin.

METHODS

This was a phase 2, multicenter trial using a Simon's 2‐stage minimax design. Treatment‐naive patients with advanced well‐differentiated NETs of gastroenteropancreatic tract and lung origin received everolimus 10 mg daily, in combination with octreotide LAR 30 mg every 28 days. The primary endpoint was objective response rate (ORR).

RESULTS

A total of 50 patients (median age, 60.5 years) were enrolled. Primary tumor sites were: pancreas (14 patients), lung (11 patients), ileum (9 patients), jejunum and duodenum (2 patients), and unknown (14 patients). Thirteen patients (26%) had carcinoid syndrome. Treatment‐related adverse events (AEs) were mostly grade 1 or 2; the only grade 4 AE was mucositis in 1 patient, whereas grade 3 AEs included skin rash in 1 case (2%), stomatitis in 4 cases (8%), and diarrhea in 11 cases (22%). The ORR was 18%; 2% of patients had a complete response (CR), 16% a partial response (PR) and 74% achieved stable disease (SD). All CRs and all PRs as well as 92% of SDs had a duration ≥6 months. The clinical benefit (CR+PR+SD) was 92%. At a median follow‐up of 277 days, median time to progression and overall survival were not reached.

CONCLUSIONS

The everolimus‐octreotide LAR combination was active and well tolerated in these previously treated patients with advanced NETs, suggesting a possible role as first‐line treatment in patients with NET. Cancer 2014;120:2457–2463. © 2014 American Cancer Society.
Contemporary cost‐effectiveness analysis comparing sequential bacillus Calmette‐Guerin and electromotive mitomycin versus bacillus Calmette‐Guerin alone for patients with high‐risk non–muscle‐invasive bladder cancer
Authors: Bachir Bassel G. , Dragomir Alice , Aprikian Armen G. , Tanguay Simon , Fairey Adrian , Kulkarni Girish S. , Breau Rodney H. , Black Peter C. , Kassouf Wassim
Published: April 2014

BACKGROUND

Sequential bacillus Calmette‐Guerin (BCG) and electromotive mitomycin (sequential therapy) have been shown in a randomized prospective trial to be superior to therapy with BCG alone in patients with high‐risk non–muscle‐invasive bladder cancer. The objective of the current study was to compare the costs and benefits of these 2 treatment strategies by performing a 5‐year and 10‐year cost‐effectiveness study.

METHODS

A Markov model was developed to estimate the incremental cost‐effectiveness ratio over a 5‐year and 10‐year period. Estimates of disease progression, death, and treatment efficacy were obtained from what to the authors' knowledge is the only randomized trial comparing the 2 therapies. Costs included: 1) medical costs (physician fees); 2) drug costs (preparation and instillation); and 3) hospital costs (procedure fees, admission fees, and tests and procedures done during surveillance). Patients were allowed a second course of induction therapy.

RESULTS

Sequential therapy was found to be associated with a higher initial material cost for induction and maintenance. The average effectiveness for the patients treated with therapy with BCG alone was 4.39 years with a mean cost of $9236 (95% confidence interval, $9118‐$9345) per patient. The sequential group resulted in an average effectiveness of 4.65 years, with a mean cost of $16,468 (95% confidence interval, $16,371‐$16,527). The 5‐year incremental cost‐effectiveness ratio of sequential versus BCG‐alone therapy was $27,815 per life‐year gained. The corresponding figure over a 10‐year period was $8618 per life‐year gained.

CONCLUSIONS

The results of the current study suggest that sequential therapy is a cost‐effective treatment for patients with high‐risk non–muscle‐invasive bladder cancer.Cancer2014;120:2424–2431.©2014 American Cancer Society.
Long‐term cause‐specific mortality in survivors of adolescent and young adult bone and soft tissue sarcoma: A population‐based study of 28,844 patients
Authors: Youn Paul , Milano Michael T. , Constine Louis S. , Travis Lois B.
Published: April 2014

BACKGROUND

Despite improved cure rates for bone and soft tissue sarcomas, to the authors' knowledge, no large population‐based study to date has evaluated long‐term cause‐specific mortality in patients diagnosed in the adolescent and young adult (AYA) age range (15 years‐39 years).

METHODS

A total of 28,844 survivors of AYA bone and soft tissue sarcoma, who accrued 113,206 person‐years of follow‐up, were identified in the population‐based Surveillance, Epidemiology, and End Results program. Standardized mortality ratios (SMR) and absolute excess risks (AER) (per 10,000 person‐years) were calculated to evaluate associations with histology (chemotherapy‐sensitive subtypes: Ewing sarcoma, osteosarcoma, and rhabdomyosarcoma vs all other subtypes), age, and initial therapy.

RESULTS

All‐cause mortality in survivors of AYA sarcoma was found to be significantly increased compared with that of the general population (SMR, 1.76; 95% confidence interval [95% CI], 1.60‐1.92 [AER of 19]), and persisted for > 20 years (SMR, 1.39; 95% CI, 1.04‐1.82 [AER of 20]). Significant excess mortality was observed for both second malignant neoplasms (SMR, 2.05; 95% CI, 1.71‐2.43 [AER of 7]) and noncancer causes (SMR, 1.66; 95% CI, 1.49‐1.85 [AER of 19]). Significant excess deaths occurred among patients with chemotherapy‐sensitive (SMR, 2.76; 95% CI, 2.20‐3.41 [AER of 32]) and nonchemosensitive (SMR, 1.63; 95% CI, 1.47‐1.80 [AER of 17]) subtypes. Significantly elevated noncancer mortality in the former group included cardiovascular disease (SMR, 2.33) and infections (SMR, 15.6), whereas significant excess deaths in the latter group included diabetes (SMR, 2.40) and infections (SMR, 2.77).

CONCLUSIONS

Survivors of AYA bone and soft tissue sarcoma experience significant long‐term mortality due to second malignant neoplasms and noncancer causes. Further research is needed to develop preventive and surveillance guidelines in this understudied population to prevent and reduce long‐term excess mortality. Cancer 2014;120:2334–2342. © 2014 American Cancer Society.
Risk stratification in follicular neoplasm: A cytological assessment using the modified bethesda classification
Authors: Ustun Berrin , Chhieng David , Van Dyke Alison , Carling Tobias , Holt Elizabeth , Udelsman Robert , Adeniran Adebowale J.
Published: April 2014

BACKGROUND

The 2007 Bethesda classification for thyroid cytology defines follicular neoplasm as a category of cases with cellular specimens demonstrating abundant follicular cells arranged in a microfollicular pattern with little or no colloid. The current recommendation for the management of these cases is diagnostic lobectomy. There has been great difficulty and variability in triaging and reporting follicular neoplasm. To increase diagnostic accuracy, at the study institution, this category is subclassified further into 3 categories: 1) microfollicular‐patterned neoplasm (MN); 2) Hürthle cell neoplasm (HN); and 3) follicular lesion with some features suggestive of but not diagnostic of the follicular variant of papillary thyroid carcinoma (FL). The authors reviewed the cases of follicular neoplasm observed over a period of 5 years to document the follow‐up trend using this modified classification.

METHODS

A search of the cytology records was performed for the period between January 2008 and December 2012. All thyroid fine‐needle aspiration cases were reviewed and those with a diagnosis of follicular neoplasm (including Hürthle cell neoplasm) were identified. Correlating follow‐up surgical pathology reports were reviewed.

RESULTS

A total of 399 cases of follicular neoplasm with surgical follow‐up were identified. Malignancy was identified in 32% of all cases of follicular neoplasm and was found to be disproportionately higher in the FL category (73%). A cytological diagnosis of FL is more likely to be called malignant (73%) than benign neoplastic (9%) or benign nonneoplastic (18%). A cytological diagnosis of MN or HN is more likely to be benign neoplastic (46% and 46%, respectively) than malignant (29% and 26%, respectively) or benign nonneoplastic (25% and 28%, respectively). Of the cytological features examined, 2 (nuclear enlargement and nuclear grooves) were significantly associated with the follicular variant of papillary thyroid carcinoma.

CONCLUSIONS

The results of the current study clearly indicate that follicular lesions with even subtle nuclear atypia have a high positive predictive value for malignancy and therefore should be distinguished from other follicular lesions because these cases require more aggressive surgical management. The current study also raises an important issue concerning the current thyroid classification based on the 2007 Bethesda classification for thyroid cytology. Future thyroid fine‐needle aspiration classification schemes should consider subclassifying follicular neoplasms for the purpose of risk stratification. Cancer (Cancer Cytopathol) 2014;122:536–545. © 2014 American Cancer Society.
Evaluation of intraoperative cytological assessment of bone resection margins in patients with oral squamous cell carcinoma
Authors: Nieberler Markus , Häusler Patrick , Drecoll Enken , Stoeckelhuber Mechthild , Deppe Herbert , Hölzle Frank , Kolk Andreas , Wolff Klaus‐Dietrich , Kesting Marco Rainer , Weirich Gregor
Published: April 2014

BACKGROUND

Frozen sections are routinely applied to control for adequate resection margins. In cases in which carcinoma infiltrates bone, the intraoperative microscopic assessment of bone margins remains challenging due to technical difficulties to section native bone. The objective of the current study was to evaluate an intraoperative cytological approach to control bone resection margins in patients with bone‐infiltrating oral squamous cell carcinomas.

METHODS

A total of 174 cytological preparations obtained from bone margins of bone‐infiltrating oral squamous cell carcinomas (28 patients) were assessed intraoperatively and compared with the corresponding histological findings. In a validation cohort (45 patients) the intraoperative cytological assessment of bone resection margins (ICAB) (104 margins) was evaluated as a diagnostic tool for routine clinical application.

RESULTS

In the first patient cohort, the ICAB revealed 95.3% sensitivity and 96% specificity. The results provided an accuracy of 95.7% with a significant correlation noted between cytological and histological results (κ, 0.91; P < .001), and a positive predictive value and negative predictive value of 93.8% and 96.9%, respectively. In the validation cohort, ICAB revealed 80% sensitivity and 98.9% specificity with 98% accuracy. There was a significant correlation found between cytological and histological results (κ, 0.91; P < .001), providing a positive predictive value and negative predictive value of 80% and 98%, respectively. ICAB could predict final resection status at bone margins with 80% sensitivity and 97.5% specificity. A significant correlation was found between the cytological and histological resection status at bone margins (κ, 0,75; P < .001).

CONCLUSIONS

ICAB could supplement intraoperative frozen sections of soft tissue margins as a standard procedure to control for adequate resection at bone margins. Cancer (Cancer Cytopathol) 2014;122:646–656. © 2014 American Cancer Society.
Targeted multiprobe fluorescence in situ hybridization analysis for elucidation of inconclusive pancreatobiliary cytology
Authors: Vlajnic Tatjana , Somaini Gina , Savic Spasenija , Barascud Audrey , Grilli Bruno , Herzog Michelle , Obermann Ellen C. , Holmes Brittany J. , Ali Syed Z. , Degen Lukas , Bubendorf Lukas
Published: April 2014

BACKGROUND

Endoscopic fine‐needle aspiration (FNA) and brush cytology are standard methods for the diagnosis of pancreatobiliary malignancies. Although the majority of cytological diagnoses are straightforward, there remains a difficult category of inconclusive cytology. This study explored the utility of fluorescence in situ hybridization (FISH) to improve the diagnostic stratification between reactive and malignant cells in cases of inconclusive cytology.

METHODS

The multiprobe FISH assay UroVysion was used for copy number assessment of chromosomes 3, 7, 17, and the 9p21 locus on Papanicolaou‐stained specimens with a diagnosis of inconclusive cytology (n = 50), adenocarcinoma (n = 31) and no evidence of malignancy (n = 9). The target cells were photographed and their coordinates saved on an automated stage prior to hybridization. A positive test was defined as increased copy number (> 2) of at least 2 chromosomes (3, 7, or 17) in at least 4 atypical cells, or loss of 9p21 in at least 12 cells.

RESULTS

FISH confirmed all 31 cytological diagnoses of pancreatobiliary adenocarcinomas, and was negative in the 9 patients with negative cytology. Among the 50 cases with inconclusive cytology, FISH detected 19 of 31 cases with a final diagnosis of adenocarcinoma, and was negative in all 19 cases with no final evidence of malignancy (sensitivity of 61.3%, specificity of 100%, positive predictive value of 100%, negative predictive value of 61.3%). Loss of 9p21 was found in 43 (86%) of all 50 FISH‐positive cases.

CONCLUSIONS

Multiprobe FISH combined with automated relocation of atypical cells is a powerful technique to clarify inconclusive cytology of the pancreatobiliary tract, allowing for a better distinction between reactive atypia and malignancy. Cancer (Cancer Cytopathol) 2014;122:627–634. © 2014 American Cancer Society.
Systematic comparison of adeno‐associated virus and biotinylated dextran amine reveals equivalent sensitivity between tracers and novel projection targets in the mouse brain
Authors: Wang Quanxin , Henry Alex M. , Harris Julie A. , Oh Seung Wook , Joines Kevin M. , Nyhus Julie , Hirokawa Karla E. , Dee Nick , Mortrud Marty , Parry Sheana , Ouellette Benjamin , Caldejon Shiella , Bernard Amy , Jones Allan R. , Zeng Hongkui , Hohmann John G.
Published: April 2014

As an anterograde neuronal tracer, recombinant adeno‐associated virus (AAV) has distinct advantages over the widely used biotinylated dextran amine (BDA). However, the sensitivity and selectivity of AAV remain uncharacterized for many brain regions and species. To validate this tracing method further, AAV (serotype 1) was systematically compared with BDA as an anterograde tracer by injecting both tracers into three cortical and 15 subcortical regions in C57BL/6J mice. Identical parameters were used for our sequential iontophoretic injections, producing injections of AAV that were more robust in size and in density of neurons infected compared with those of BDA. However, these differences did not preclude further comparison between the tracers, because the pairs of injections were suitably colocalized and contained some percentage of double‐labeled neurons. A qualitative analysis of projection patterns showed that the two tracers behave very similarly when injection sites are well matched. Additionally, a quantitative analysis of relative projection intensity for cases targeting primary motor cortex (MOp), primary somatosensory cortex (SSp), and caudoputamen (CP) showed strong agreement in the ranked order of projection intensities between the two tracers. A detailed analysis of the projections of two brain regions (SSp and MOp) revealed many targets that have not previously been described in the mouse or rat. Minor retrograde labeling of neurons was observed in all cases examined, for both AAV and BDA. Our results show that AAV has actions equivalent to those of BDA as an anterograde tracer and is suitable for analysis of neural circuitry throughout the mouse brain. J. Comp. Neurol. 522:1989–2012, 2014. © 2014 Wiley Periodicals, Inc.
Central projections of intrinsically photosensitive retinal ganglion cells in the macaque monkey
Authors: Hannibal J. , Kankipati L. , Strang C.E. , Peterson B.B. , Dacey D. , Gamlin P.D.
Published: April 2014

Circadian rhythms generated by the suprachiasmatic nucleus (SCN) are entrained to the environmental light/dark cycle via intrinsically photosensitive retinal ganglion cells (ipRGCs) expressing the photopigment melanopsin and the neuropeptide pituitary adenylate cyclase‐activating polypeptide (PACAP). The ipRGCs regulate other nonimage‐forming visual functions such as the pupillary light reflex, masking behavior, and light‐induced melatonin suppression. To evaluate whether PACAP‐immunoreactive retinal projections are useful as a marker for central projection of ipRGCs in the monkey brain, we characterized the occurrence of PACAP in melanopsin‐expressing ipRGCs and in the retinal target areas in the brain visualized by the anterograde tracer cholera toxin subunit B (CtB) in combination with PACAP staining. In the retina, PACAP and melanopsin were found to be costored in 99% of melanopsin‐expressing cells characterized as inner and outer stratifying melanopsin RGCs. Two macaque monkeys were anesthetized and received a unilateral intravitreal injection of CtB. Bilateral retinal projections containing colocalized CtB and PACAP immunostaining were identified in the SCN, the lateral geniculate complex including the pregeniculate nucleus, the pretectal olivary nucleus, the nucleus of the optic tract, the brachium of the superior colliculus, and the superior colliculus. In conclusion, PACAP‐immunoreactive projections with colocalized CtB represent retinal projections of ipRGCs in the macaque monkey, supporting previous retrograde tracer studies demonstrating that melanopsin‐containing retinal projections reach areas in the primate brain involved in both image‐ and nonimage‐forming visual processing. J. Comp. Neurol. 522:2231–2248, 2014. © 2014 Wiley Periodicals, Inc.