bluuebunny/crossref_metadata_2025 huggingface dataset:
Renal sodium transporter/channel expression and sodium excretion in P2Y2receptor knockout mice fed a high-NaCl diet with/without aldosterone infusion
Authors: Zhang Yue , Listhrop Raelene , Ecelbarger Carolyn M. , Kishore Bellamkonda K.
Published: December 2010

The P2Y2receptor (P2Y2-R) antagonizes sodium reabsorption in the kidney. Apart from its effect in distal nephron, hypothetically, P2Y2-R may modulate activity/abundances of sodium transporters/channel subunits along the nephron via antagonism of aldosterone or vasopressin or interaction with mediators such as nitric oxide (NO), and prostaglandin E2(PGE2) or oxidative stress (OS). To determine the extent of the regulatory role of P2Y2-R in renal sodium reabsorption, in study 1, we fed P2Y2-R knockout (KO; n = 5) and wild-type (WT; n = 5) mice a high (3.15%)-sodium diet (HSD) for 14 days. Western blotting revealed significantly higher protein abundances for cortical and medullary bumetanide-sensitive Na-K-2Cl cotransporter (NKCC2), medullary α-1-subunit of Na-K-ATPase, and medullary α-subunit of the epithelial sodium channel (ENaC) in KO vs. WT mice. Molecular analysis of urine showed increased excretion of nitrates plus nitrites (NOx), PGE2, and 8-isoprostane in the KO, relative to WT mice, supporting a putative role for these molecules in determining alterations of proteins involved in sodium transport along the nephron. To determine whether genotype differences in response to aldosterone might have played a role in these differences due to HSD, in study 2 aldosterone levels were clamped (by osmotic minipump infusion). Clamping aldosterone (with HSD) led to significantly impaired natriuresis with elevated Na/H exchanger isoform 3 in the cortex, and NKCC2 in the medulla, and modest but significantly lower levels of NKCC2, and α- and β-ENaC in the cortex of KO vs. WT mice. This was associated with significantly reduced urinary NOx in the KO, although PGE2and 8-isoprostane remained significantly elevated vs. WT mice. Taken together, our results suggest that P2Y2-R is an important regulator of sodium transporters along the nephron. Pre- or postreceptor differences in the response to aldosterone, perhaps mediated via prostaglandins or changes in NOS activity or OS, likely play a role.
Misperceptions of speed are accounted for by the responses of neurons in macaque cortical area MT
Authors: Boyraz Pınar , Treue Stefan
Published: December 2010

In humans, the perceived speed of random dot patterns (RDP) moving within small apertures is faster than that of RDPs moving within larger apertures at the same physical speed. To investigate the neural basis of this illusion, we recorded the responses of direction- and speed-selective neurons in the middle temporal area (MT) of macaque monkeys to stimuli varying in size and speed. Our results show that the preferred speed of MT neurons is slower for smaller stimuli. This effect was larger for neurons preferring faster speeds, matching our psychophysical observation in human subjects that the magnitude of the misperception is larger at higher stimulus speeds. Our physiological data indicate that, across a population of speed-tuned neurons in MT, decreasing the size of a stimulus would shift the activity profile to neurons tuned for higher speeds. Modeling a labeled-line readout of this shifted profile, we show an increased apparent speed, in line with the psychophysical observations. This link strengthens the evidence for a causal role of area MT in speed perception. The systematic shift in tuning curves of single neurons with stimulus size might reflect a general mechanism for feature-mismatch illusions in visual perception.
GIRK channel-mediated inhibition of melanin-concentrating hormone neurons by nociceptin/orphanin FQ
Authors: Parsons Matthew P. , Hirasawa Michiru
Published: December 2010

Targeting the melanin-concentrating hormone (MCH) system has been suggested as a potential treatment for obesity, anxiety disorders, as well as addiction. Despite the therapeutic potential of MCH agonists and antagonists, the endogenous factors regulating MCH activity, in particular those implicated in anxiety and reward, are ill-defined. The present study investigated the cellular effects of nociceptin/orphanin FQ (N/OFQ), an endogenous opioid with anxiolytic and antireward properties, on MCH neurons. We found that N/OFQ induced a concentration-dependent reversible outward current in MCH neurons (EC50 = 50.7 nM), an effect that was blocked by the competitive antagonist of the nociceptin opioid peptide (NOP) receptor UFP-101. N/OFQ-induced outward currents persisted in TTX, reversed near the potassium equilibrium potential, and displayed inward rectification, suggesting direct postsynaptic potassium channel activation. Tertiapin-Q completely abolished the N/OFQ effect, whereas glibenclamide did not, implicating protein G-dependent inwardly rectifying potassium (GIRK) and not ATP-sensitive potassium (KATP) channels as the effector ion channel. The N/OFQ-induced outward current desensitized during repeated applications and occluded the inhibitory effect of dynorphin, suggesting that dynorphin and N/OFQ activate the same pathway. N/OFQ also reversibly inhibited voltage-gated calcium currents in MCH neurons. In conclusion, our study indicates N/OFQ as a robust endogenous regulator of MCH neurons, which may play a role in anxiety and drug addiction.
Substrate Effect on the Optical Reflectance and Transmittance of Thin-Film Structures
Authors: Barybin Anatoly , Shapovalov Victor
Published: December 2010

A rigorous and consistent approach is demonstrated to develop a model of the 4M structure (the four-media structure of a film on a substrate of finite thickness). The general equations obtained for the reflectance and transmittance spectra of the 4M structure are simplified by employing a procedure of the so-called device averaging to reduce them to a succinct form convenient for processing of experimental spectra for the structures with a thick substrate. The newly derived equations are applied to two special cases: (i) an arbitrary film on highly absorbing substrates and (ii) a slightly absorbing film on transparent substrates. The reflectance and transmittance spectra represented in the simplified (with the device averaging) form have a practical application for determining the film thickness and optical constants from experimental spectra by using the known techniques.
On Multiple Generalizedw‐Genocchi Polynomials and Their Applications
Authors: Jang Lee-Chae
Published: December 2010

We define the multiple generalizedw‐Genocchi polynomials. By using fermionicp‐adic invariant integrals, we derive some identities on these generalizedw‐Genocchi polynomials, for example, fermionicp‐adic integral representation, Witt′s type formula, explicit formula, multiplication formula, and recurrence formula for thesew‐Genocchi polynomials.
The Analysis of Epidemic Network Model with Infectious Force in Latent and Infected Period
Authors: Zhang Juping , Jin Zhen
Published: December 2010

We discuss the epidemic network model with infectious force in latent and infected period. We obtain the basic reproduction number and analyze the globally dynamic behaviors of the disease‐free equilibrium when the basic reproduction number is less than one. The effects of various immunization schemes are studied. Finally, the final sizes relation is derived for the network epidemic model. The derivation depends on an explicit formula for the basic reproduction number of network of disease transmission models.
A Novel Approach to a Piezoelectric Sensing Element
Authors: Martinez M. , Artemev A.
Published: December 2010

Piezoelectric materials have commonly been used in pressure and stress sensors; however, many designs consist of thin plate structures that produce small voltage signals when they are compressed or extended under a pressure field. This study used finite element methods to design a novel piezoelectric pressure sensor with a C-shaped piezoelectric element and determine if the voltage signal obtained during hydrostatic pressure application was enhanced compared to a standard thin plate piezoelectric element. The results of this study demonstrated how small deformations of this C-shaped sensor produced a large electrical signal output. It was also shown that the location of the electrodes for this sensor needs to be carefully chosen and that the electric potential distribution varies depending on the poling of the piezoelectric element. This study indicated that the utilization of piezoelectric materials of different shapes and geometries embedded in a polymer matrix for sensing applications has several advantages over thin plate solid piezoelectric structures.
Cellulose Acetate Sulfate as a Lyotropic Liquid Crystalline Polyelectrolyte: Synthesis, Properties, and Application
Authors: Grinshpan D. D. , Savitskaya T. A. , Tsygankova N. G. , Makarevich S. E. , Tretsiakova S. M. , Nevar T. N.
Published: December 2010

The optimal conditions of cellulose acetate sulfate (CAS) homogeneous synthesis with the yield of 94–98 wt.% have been determined. CAS was confirmed to have an even distribution of functional groups along the polymer chain. The polymer was characterized by an exceptionally high water solubility (up to 70 wt.%). The isothermal diagrams of its solubility in water-alcohol media have been obtained. CAS aqueous solutions stability, electrolytic, thermal, and viscous properties have been defined. The main hydrodynamic characteristics such as intrinsic viscosity, Huggins constant, and crossover concentration have been evaluated. The parameters of polymer chain thermodynamic rigidity have been calculated. The formation of liquid crystalline structures in concentrated CAS solutions has been confirmed. CAS was recommended to be used as a binder for the medicinal forms of activated carbon and carbon sorbent for water treatment, hydrophilic ointment foundation.
Methanogens: Methane Producers of the Rumen and Mitigation Strategies
Authors: Hook Sarah E. , Wright André-Denis G. , McBride Brian W.
Published: December 2010

Methanogens are the only known microorganisms capable of methane production, making them of interest when investigating methane abatement strategies. A number of experiments have been conducted to study the methanogen population in the rumen of cattle and sheep, as well as the relationship that methanogens have with other microorganisms. The rumen methanogen species differ depending on diet and geographical location of the host, as does methanogenesis, which can be reduced by modifying dietary composition, or by supplementation of monensin, lipids, organic acids, or plant compounds within the diet. Other methane abatement strategies that have been investigated are defaunation and vaccines. These mitigation methods target the methanogen population of the rumen directly or indirectly, resulting in varying degrees of efficacy. This paper describes the methanogens identified in the rumens of cattle and sheep, as well as a number of methane mitigation strategies that have been effectivein vivo.
The Discussion Goes on: What Is the Role ofEuryarchaeotain Humans?
Authors: Horz H.-P. , Conrads G.
Published: December 2010

The human body (primarily the intestinal tract, the oral cavity, and the skin) harbours approximately 1,000 different bacterial species. However, the number of archaeal species known to colonize man seems to be confined to a handful of organisms within the classEuryarchaeota(includingMethanobrevibacter smithii,M. oralis, andMethanosphaera stadtmanae). In contrast to this conspicuously low diversity ofArchaeain humans their unique physiology in conjunction with the growing number of reports regarding their occurrence at sites of infection has made this issue an emerging field of study. While previous review articles in recent years have addressed the putative role of particularly methanogenic archaea for human health and disease, this paper compiles novel experimental data that have been reported since then. The aim of this paper is to inspire the scientific community of “Archaeaexperts” for those unique archaeal organisms that have successfully participated in the human-microbe coevolution.
Antiapoptotic and Antioxidant Properties of Orthosiphon stamineus Benth (Cat′s Whiskers): Intervention in the Bcl‐2‐Mediated Apoptotic Pathway
Authors: Abdelwahab Siddig Ibrahim , Mohan Syam , Mohamed Elhassan Manal , Al-Mekhlafi Nabil , Mariod Abdelbasit Adam , Abdul Ahmad Bustamam , Abdulla Mahmood Ameen , Alkharfy Khalid M.
Published: December 2010

Antiapoptotic and antioxidant activities of aqueous‐methanolic extract (CAME) of Orthosiphonstamineus Benth(OS), and its hexane (HF), chloroform (CF), n‐butanol (NBF), ethyl acetate (EAF) and water (WF) fractions were investigated. Antioxidant properties were evaluated using the assays of Folin‐Ciocalteu, aluminiumtrichloride, β‐carotene bleaching and DPPH. The role of OS against hydrogen peroxide induced apoptosis on MDA‐M231 epithelial cells was examined using MTT assay, phase contrast microscope, colorimetric assay of caspase‐3, western blot and quantitative real‐time PCR. Results showed that EAF showed the highest total phenolic content followed by CAME, NBF, WF, CF and HF, respectively. Flavonoid content was in the order of the CF > EAF > HF > CAME > NBF > WF. The IC50 values on DPPH assay for different extract/fractions were 126.2 ± 23, 31.25 ± 1.2, 15.25 ± 2.3, 13.56 ± 1.9, 23.0 ± 3.2, and 16.66 ± 1.5 μg/ml for HF, CF, EAF, NBF, WF and CAME, respectively. OSreduced the oxidation of β‐carotene by hydroperoxides. Cell death was dose‐dependently inhibited by pretreatment with OS. Caspase‐3 and distinct morphological features suggest the anti‐apoptotic activities of OS. This plant not only increased the expression of Bcl‐2, but also decreased Bax expression, and ultimately reduced H2O2‐induced apoptosis. The current results showed that phenolics may provide health and nutritional benefits.
Current Evidence on the Use of Antifilarial Agents in the Management of bancroftian Filariasis
Authors: Fernando Sumadhya Deepika , Rodrigo Chaturaka , Rajapakse Senaka
Published: December 2010

Many trials have explored the efficacy of individual drugs and drug combinations to treat bancroftian filariasis. This narrative review summarizes the current evidence for drug management of bancroftian filariasis. Diethylcarbamazine (DEC) remains the prime antifilarial agent with a well-established microfilaricidal and some macrofilaricidal effects. Ivermectin (IVM) is highly microfilaricidal but minimally macrofilaricidal. The role of albendazole (ALB) in treatment regimens is not well established though the drug has a microfilaricidal effect. The combination of DEC+ALB has a better long-term impact than IVM+ALB. Recent trials have shown that doxycycline therapy againstWolbachia, an endosymbiotic bacterium of the parasite, is capable of reducing microfilaria rates and adult worm activity. Followup studies on mass drug administration (MDA) are yet to show a complete interruption of transmission, though the infection rates are reduced to a very low level.
Rodent Models for Metabolic Syndrome Research
Authors: Panchal Sunil K. , Brown Lindsay
Published: December 2010

Rodents are widely used to mimic human diseases to improve understanding of the causes and progression of disease symptoms and to test potential therapeutic interventions. Chronic diseases such as obesity, diabetes and hypertension, together known as the metabolic syndrome, are causing increasing morbidity and mortality. To control these diseases, research in rodent models that closely mimic the changes in humans is essential. This review will examine the adequacy of the many rodent models of metabolic syndrome to mimic the causes and progression of the disease in humans. The primary criterion will be whether a rodent model initiates all of the signs, especially obesity, diabetes, hypertension and dysfunction of the heart, blood vessels, liver and kidney, primarily by diet since these are the diet‐induced signs in humans with metabolic syndrome. We conclude that the model that comes closest to fulfilling this criterion is the high carbohydrate, high fat‐fed male rodent.
Incorporation of Decanethiol-Passivated Gold Nanoparticles into Cross-Linked Poly(Dimethylsiloxane) Films
Authors: Tagaya Motohiro , Nakagawa Masaru
Published: December 2010

Cross-linking degree of a poly(dimethylsiloxane) (PDMS) film was controlled, and the incorporation of hydrophobic decanethiol-passivated gold (Au) nanoparticles into the film was investigated. FT-IR spectra indicated that the hydrosilylation reaction between a vinyl group and a hydrosilyl group occurred with the cross-linking. The swelling degree of the film in toluene changed with a cross-linker concentration, indicating the control of the cross-linking degree of PDMS film. By EDX analysis, the amount of incorporated Au nanoparticles increased with decreasing a cross-linker concentration, indicating the enlarged free volume of the film. The Au nanoparticle-PDMS composite film containing a cross-linker at 6 wt% showed brown color attributed to plasmon resonance of Au nanoparticles, suggesting the Au nanoparticles in the film at monodispersion state. The UV-visible absorbance of the composite film decreased without spectralshift by swelling with toluene, and the changes were reversible. The aggregation among Au nanoparticles in the composite film after calcination also depended on the cross-linking degree. Thus, the control of cross-linking degree of PDMS film successfully leaded to a simple way of fabricating the Au nanoparticle-PDMS composite film at the mono-dispersion state.
The Ontology of Biological Groups: Do Grasshoppers Form Assemblages, Communities, Guilds, Populations, or Something Else?
Authors: Lockwood Jeffrey A.
Published: December 2010

Acridologists have used a variety of terms to describe groups of grasshoppers, including assemblage, community, guild, and population. This terminological diversity has raised the question of whether one of these descriptors is the correct one. I take the position that these terms pick out different features of the natural world such that there is no unconditionally or uniquely correct term. By adopting the framework of constrained perspectivism—a form of philosophical pragmatism—it is argued that a term is correct if it accurately reflects the conceptual framework of the investigator and effectively communicates this perspective to others. Such an approach gives rise to terminological pluralism that avoids the problems of relativism (the subjectivist's view that any term can be used) and absolutism (the objectivist's view that there is a single correct term). I describe the contexts in which the most common terms are appropriate.
Approaching Biomarkers of Membranous Nephropathy from a Murine Model to Human Disease
Authors: Wu Chia-Chao , Chen Jin-Shuen , Huang Ching-Feng , Chen Chun-Chi , Lu Kuo-Chen , Chu Pauling , Sytwu Huey-Kang , Lin Yuh-Feng
Published: December 2010

Background. Membranous glomerulonephropathy (MN) is the most prevalent cause of nephrotic syndrome in adult humans. However, the specific biomarkers of MN have not been fully elucidated. We examined the alterations in gene expression associated with the development of MN. Methods. Murine MN was induced by cationic bovine serum albumin (cBSA). After full‐blown MN, cDNA microarray analysis was performed to identify gene expression changes, and highly expressed genes were evaluated as markers both in mice and human kidney samples. Results. MN mice revealed clinical proteinuria and the characteristic diffuse thickening of the glomerular basement membrane. There were 175 genes with significantly different expressions in the MN kidneys compared with the normal kidneys. Four genes, metallothionein‐1 (Mt1), cathepsin D (CtsD), lymphocyte 6 antigen complex (Ly6), and laminin receptor‐1 (Lamr1), were chosen and quantified. Mt1 was detected mainly in tubules, Lamr1 was highly expressed in glomeruli, and CtsD was detected both in tubules and glomeruli. The high expressions of Lamr1 and CtsD were also confirmed in human kidney biopsies. Conclusion. The murine MN model resembled the clinical and pathological features of human MN and may provide a tool for investigating MN. Applying cDNA microarray analysis may help to identify biomarkers for human MN.
Bovine Model of Doxorubicin‐Induced Cardiomyopathy
Authors: Bartoli Carlo R. , Brittian Kenneth R. , Giridharan Guruprasad A. , Koenig Steven C. , Hamid Tariq , Prabhu Sumanth D.
Published: December 2010

Left ventricular assist devices (LVADs) constitute a recent advance in heart failure (HF) therapeutics. As the rigorous experimental assessment of LVADs in HF requires large animal models, our objective was to develop a bovine model of cardiomyopathy. Male calves (n= 8) were used. Four animals received 1.2 mg/kg intravenous doxorubicin weekly for seven weeks and four separate animals were studied as controls. Doxorubicin‐treated animals were followed with weekly echocardiography. Target LV dysfunction was defined as an ejection fraction ≤35%. Sixty days after initiating doxorubicin, a terminal study was performed to determine hemodynamic, histological, biochemical, and molecular parameters. All four doxorubicin‐treated animals exhibited significant (P< 0.05) contractile dysfunction, with target LV dysfunction achieved in three animals. Doxorubicin‐treated hearts exhibited significantly reduced coronary blood flow and interstitial fibrosis and significantly increased apoptosis and myocyte size. Gene expression of atrial natriuretic factor increased more than 3‐fold. Plasma norepinephrine and epinephrine levels were significantly increased early and late during the development of cardiomyopathy, respectively. We conclude that sequential administration of intravenous doxorubicin in calves induces a cardiomyopathy with many phenotypic hallmarks of the failing human heart. This clinically‐relevant model may be useful for testing pathophysiologic responses to LVADs in the context of HF.
Results of the UK NEW START Sentinel Node Biopsy Training Program: A Model for Future Surgical Training.
Authors: Goyal A. , MacNeill F. , Newcombe R. , Townson J. , Keshtgar M. , Mansel R. ,   NEW START Regional Trainers and Steering Group
Published: December 2010

Background: NEW START the world's largest structured, multi-professional and validated surgical training programme was established to allow rapid transfer of appropriate knowledge and technical skills to ensure safe and competent sentinel node biopsy (SNB) in the UK. The number of training cases is larger than the number of cases in the NSABP-32 randomised trial.Methods: A sentinel node (SN) localisation protocol was standardised using the combined technique of isotope (0.05-0.1ml 99mTc-albumin colloid - Nanocoll®) and blue dye (Patent Blue V) injected into the tumour quadrant peri-areolar tissue. Isotope was injected intra-dermally and static scintigraphic images obtained, blue dye was injected sub-dermally after anaesthetic induction.Multi-professional teams attended a theory/skills-lab day at a regional center. All surgeons then performed 30 consecutive SNB's (minimum 10 node positive) either followed immediately by standard axillary staging - mentorship model - or as a stand-alone procedure - apprenticeship model. An accredited NEW START trainer supervised the first 5 cases, or all 30 cases if stand-alone apprenticeship, in the participant's hospital.Validation standards were based on published literature with a localization rate of >90% and false-negative rate of <10%. Participants continued in validation until the standards were achieved.Results: From October 2004 to December 2008, SNB was performed on 6685 patients, in 103 centres by 210 SNB naive surgeons. SNB was followed by immediate axillary staging (mentorship model) in 87% (5849/6685), axillary nodal metastases were found in 31% (2098/6685) of whom 1821 had SNB followed by immediate axillary staging.Scintigraphy identified axillary lymph node drainage in 85% (5564/6511) with a total SN localisation rate of 99% (6610/6685, 95% CI 0.9% to 1.4%). There were 163 false negatives, resulting in a false negative rate (FNR) of 8.9% (163/1821, 95% CI 7.7% to 10.4%). The median SN yield was 2.0 (range 1-11).Localization and FNR's improved with surgeon caseload but no significant learning curve was identified. The FNR decreased to <10% after 20 cases.Failed localisation rate and false-negative rate by surgeon case number Surgeon Case Number 1 to 1011 to 2021 to 3031 to 4041 to 75Failed localisation rate (%)1.21.11.11.20.9False-negative rate (%)9.410.28.57.76.4 Conclusion: NEW START is a unique training programme that establishes a benchmark for future surgical training. It demonstrates that carefully planned multi-professional training can translate specialist performance standards across a national service and abolish learning curves so ensuring patient safety during training.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1001.
Do We Need Axillary Staging for All Breast Cancers? A Cohort Study from Sweden. The Natural Course of Small Breast Cancer.
Authors: Sveinsdottir H.
Published: December 2010

Introduction: Screening mammography, starting in the late eighties in Sweden, has improved the prognosis of breast cancer by detection of small breast cancer at an early stage.Thus, relatively fewer women have lymph node metastases at time of diagnosis. Data from a previous registry study from two Swedish regions showed that screening detected cancers <10mm and Elston Grade 1-2 had a low rate of pN1 (7%). This prospective study investigates if axillary surgery safely can be omitted in such a predefined low risk group of breast cancer.Methods: A prospective cohort study was designed, including patients from 5 out of 6 regions in Sweden. From 1997-2002 1584 patients, with invasive breast cancer ≤10mm, Nottingham Histological Grade (NHG) I or II, were included in the cohort. These included patients did not have any axillary surgery at all. They were clinically followed for 5 years.As a complement to the study registry all patients being alive 10 years after study start received a questionnaire on recurrence, latest cancer control and adjuvant therapy in 2007-2009.Cause of death was collected from the Swedish Death Registry.Of the 1584 patients, 12 were excluded from the cohort due to re-evaluated size and grade.Results: Median age at inclusion was 61 years (31-87) and tumor size 8mm (range 1-10 mm). 94% underwent breast conserving surgery and 2/3 of them had postoperative radiotherapy to the breast, according to local Regional Guidelines.160 of the included patients have died, only 18 (1,1%) in breast cancer. 1412 pat received the questionnaire and 96% of them answered. Of patients alive, 109 patients (7,7%) were diagnosed with a recurrence or a contralateral breast cancer.Type of first recurrences were: 22 (1,5%) in ipsilateral lymph nodes; 9 (0.6%) as single event and 13 breast + axillary relapses), 55 in the breast only (3,9% of total) and 23 (1,6%) had contralateral breast cancer. 9 patients had distant metastases as first event.31 patients have so far been diagnosed with distant metastases, but 13 are still alive. 10 year over all survival is 88,7%, and breast cancer specific survival 97,4%.Conclusion: After a median follow-up time of 8,8 years only 0,6% had metastases in the axilla as first event and 0,7% showed relaps in breast together with the axilla. 6,6% of the patients were diagnosed with a recurrence of the breast cancer, 1,5% with contralateral breast cancer and 1,1% had died from breast cancer. Promising results with low rate of events in the axilla still give us a responsibility of meticulous control of this cohort for many years to provide us with important information on the natural course of early breast cancer and the significance of excluded axillary surgical staging for small tumours, even in the era of sentinel lymph node biopsy.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1009.
SPIO Enhanced MR Imaging for the Detection of Metastases in Sentinel Nodes Localized by CT Lymphography in Patients with Breast Cancer.
Authors: Motomura K. , Ishitobi M. , Komoike Y. , Koyama H. , Inaji H. , Horinouchi T. , Nakanishi K.
Published: December 2010

Background: Ultrasonography, magnetic resonance (MR) imaging, and computed tomography (CT) may detect nodal metastases in patients with breast cancer, but there is not sufficient accuracy with the conventional methods. Recently, superparamagnetic nanoparticles-enhanced MR imaging has been reported to be a promising improvement for diagnostic imaging of lymph node metastases from various tumors. Moreover, sentinel nodes have been reported to be well-identified using CT lymphography in patients with breast cancer. This study evaluated MR imaging with superparamagnetic iron oxide (SPIO) enhancement for the detection of metastases in sentinel nodes localized by CT lymphography in patients with breast cancer, with histopathologic findings as the reference standard.Methods: This study included 102 patients with breast cancer with clinically negative nodes. Each contrast agent was injected intradermally into the skin overlying the breast tumor and in the subareolar region. Sentinel nodes were identified by CT lymphography, and SPIO-enhanced MR imaging of the axilla was performed to detect metastases in the sentinel nodes. A node was considered non-metastatic if it showed a homogenous low signal intensity and metastatic if the entire node or a focal area did not show a low signal intensity on MR imaging. Sentinel node biopsy was performed using a combination of dye and radiocolloid. Imaging results were correlated with histopathologic findings.Results: The mean number of sentinel nodes identified by CT lymphography was 1.1 (range 1–3). Twenty-one of 25 patients with positive sentinel nodes definitively diagnosed by pathology demonstrated metastases on SPIO-enhanced MR imaging. Seventy of 77 patients with negative sentinel nodes definitively diagnosed by pathology were non-metastatic on imaging studies. The sensitivity, specificity, and overall accuracy of MR imaging for the diagnosis of sentinel node metastases were 84%, 91%, and 89%, respectively. In four of 10 patients with micrometastases, the metastases were not detected, but all 15 patients with macrometastases were successfully demonstrated. There were no adverse events associated with either CT or MR imaging.Conclusions: SPIO-enhanced MR imaging is a useful method of detecting metastases in sentinel nodes localized by CT lymphography in patients with breast cancer. Patients with clinically negative nodes may be spared sentinel node biopsy when the sentinel node is diagnosed as disease-free using SPIO-enhanced MR imaging.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1010.
Clinicopathological Factors and Nomograms Predicting Non Sentinel Lymph Nodes Metastases after Neoadjuvant Chemotherapy in Breast Cancer Patients.
Authors: Gimbergues P. , Abrial C. , Abrial C. , Durando X. , Durando X. , Le Bouëdec G. , Cachin F. , Cachin F. , Penault-Llorca F. , Mouret-Reynier M. , Mouret-Reynier M. , Kwiatkowski F. , Maublant J. , Maublant J. , Maublant J. , Tchirkov A. , Tchirkov A. , Dauplat J. , Chollet P. , Chollet P. , Chollet P.
Published: December 2010

Background : Studies have demonstrated the feasibility and accuracy of sentinel lymph node (SLN) biopsy after neoadjuvant chemotherapy (NAC) in breast cancer. Some SLN-positive patients have low risk of non-sentinel lymph node (non-SLN) involvement. The aim of the present study performed on this group of SLN-positive patients after NAC was to determine clinicopathological factors associated with non-SLN involvement and to test scoring systems predicting the risk of additional nodal metastases currently available for SLN-positive patients not treated with NAC.Patients and methods : Patients with infiltrating breast carcinoma (n= 132) were studied prospectively. All patients received NAC. At surgery, SLN biopsy followed by axillary lymph node dissection was performed. Lymphatic mapping was done using the isotope method. Fifty-one patients were SLN positive.Results : In univariate analysis, tumor size more than 26 mm (P= 0.016) and the size of SLN metastases more than 2 mm (P= 0.0055) were significantly correlated with the presence of non-SLN metastases. In multivariate analysis, SLN macrometastases conferred a 10.2-fold greater risk of non-SLN positivity than SLN micrometastases (P= 0.047, 95%-confidence interval, 1.15-90.2). The Memorial Sloan-Kettering Cancer Center nomogram was not reliably predictive for non-SLN metastases (AUC, area under the receiver operating characteristic curve, of 0.542), whereas the MD Anderson (AUC= 0.716) and Tenon scoring systems (AUC= 0.778) were validated.Conclusion: Our results suggest that clinicopathological factors predicting non-SLN involvement in SLN-positive patients with and without NAC are essentially the same. The risk of involvement may be assessed using existing nomograms, but additional large prospective studies are needed to determine their accuracy in patients after NAC.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1011.
Sentinel Lymph Node Navigation Surgery with Indocyanine Green Fluorescence in Early Breast Cancer.
Authors: Sugie T. , Kassim K. , Tsuji W. , Takeuchi M. , Yamashiro M. , Ueno T. , Toi M.
Published: December 2010

Background: Sentinel lymph node (SLN) biopsy is a minimally invasive and effective method for assessing axillary lymph node status in breast cancer. Currently dye techniques, radioisotope techniques or combined techniques are used for SLN detection and recently, near infrared fluorescence imaging has been applied clinically in a breast cancer patient to identify SLN. The concept of this technique is to detect the subcutaneous lymphatic flow from the areola toward the axilla in real time and identify SLN as florescence spot. Our aim in this study is evaluate the feasibility of SLNB by using the ICG technique and the effect of Body Mass Index (BMI) on the number of SLN identify. Methods: The study involved one hundred patients with clinically node negative early breast cancer who were assigned to SLNB, bilateral SLNB were performed on seven of them. A combination of indocyanine green as a fluorescence emitting source and patent blue dyes were injected in the periareolar area and a charge coupled device camera equipped with a cut filter was used, first to trace the subcutaneous lymphatic channels then to identify the florescence image of SLN after meticulous dissection. Both of them were seen in real time on a TV monitor. According to their florescence imaging and the blue color, the LNs were classified as SLN which is either double positive (ICG+/ Dye+) or single positive (ICG+/Dye- or ICG-/ Dye+) and para SLN which is double negative (ICG-/Dye -). Results: The subcutaneous lymphatic channels were detected precisely in all cases. The identification rate of SLN was 100%, (107/107) with a mean number of 3.7 nodes (rang-1 - 12), double positive nodes were found in 83.2% (89/107) with a mean number of 1.5 (range 0-6). The single positive SLNs, i.e. ICG+/ Dye- or ICG-/ Dye+ were found in (87/107) and (4/107) respectively. In twenty six cases (24.3%), the SLNs were involved and all of them were ICG positive. BMI is negatively correlated with number of double positive SLN identified (r= -0.19, P = .02). Conclusion: The ICG and patent blue dye technique gives high sensitivity and provides a comparable result to the dye and radioactive technique. Obesity may reduce the number of double positive SLNs identified.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1017.
Combining Genomic Profiling (70 Gene-Mammaprint) with Nodal Status Allows To Classify Patients with Primary Breast Cancer and Positive Lymph Nodes (1-9) into Very Distinct Prognostic Subgroups That Could Help Tailor Treatment Strategies.
Authors: Saghatchian M. , Mook S. , Pruneri G. , Viale G. , Glas A. , Eekhout I. , Delaloge S. , van 't Veer L.
Published: December 2010

OBJECTIVESThe axillary lymph node (LN) status is considered to be one of the most important factors for chemotherapy decision-making of operable breast cancer patients (pts). It is commonly agreed that combination therapies with taxane-containing regimens should be recommended for these pts, whereas high-dose regimens have failed to provide further improvement for pts clinically considered at high-risk.It has previously been shown that the 70-gene profile (MammaPrint®TM), which was developed in node-negative patients is excellent in predicting disease outcome in pts with 1-3 positive nodes and similarly in pts with 4-9 positive-nodes. Further analysis based on adjuvant treatment received and pooled analysis of the 2 LN positive series was performed in order to assess the prognostic added-value of genomic profiling in LN positive pts.METHODS Frozen tumor samples from breast cancer pts with positive LN coming from 2 hospitals were selected in consecutive series (1-3 LN, 4-9 LN; all female, diagnosed between 1984 and 1995, primary invasive breast carcinoma, unilateral T1, T2 or operable T3, mastectomy or breast-conserving therapy, no prior malignancies, fresh frozen tumor material available). Samples were evaluated by gene expression profiling for the 70-gene profile and were classified as genomic high risk (poor prognosis) or genomic low risk (good prognosis).RESULTS A total of 519 pts have been analyzed: 346 with 1-3 positive LN (PN1) and 173 with 4-9 positive LN (PN2). Among them, 212 (41%) had the 70-gene good prognosis-profile and 307 (59%) had the 70-gene poor prognosis-profile (strictly equal proportions among the 2 LN groups). Median follow-up was 10.3 years: distant metastases occurred in 141 patients (116 as first event) and 103 (20 %) died of their disease. Distance metastases as first event and breast cancer specific survival according to LN group (PN) and genomic profile (MP) are shown in Figures 1 and 2.CONCLUSION Our data show that the 70-gene profile is a strong prognostic marker of distant recurrence and breast specific death in breast cancer patients with positive LN. Combining nodal status (1-3 nodes vs. 4-9 nodes) and 70-gene profile (good vs. poor) allows stratifying patients among subgroups for whom tailored treatment strategies should be designed and assessed based on their very different outcome. Pts with elevated number of lymph nodes and high genomic risk have a very poor prognosis and might need to be considered for stronger treatment strategies.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 102.
China Validation Study of GeneSearchTM Breast Lymph Node Assay for the Diagnosis of Sentinel Lymph Nodes of Breast Cancer – CBCSG-001a Interim Results.
Authors: Wang Y. , Ouyang T. , Liu Y. , Wu J. , Yang X. , Su F. , Liao N.
Published: December 2010

Background: The use of sentinel lymph node (SLN) biopsy is becoming the standard of care in China. With the adoption of this technique there is an increasing need for rapid and accurate detection of metastases in the SLNs. Histological intra-operative techniques such as touch imprint and frozen section offer limited sensitivity, increasing the risk of intra-operatively missing relevant SLN metastases (>0.2 mm). Post-operative histology (H&E) also risks missing metastases due to tissue sampling limitations and being partially dependent on pathologist expertise. A real-time RT-PCR assay, GeneSearchÔ Breast Lymph Node (BLN) Assay, may offer a standardized intra-operative way to evaluate larger portions of the SLN. CBCSG-001a is a prospective multicenter trial to validate the GeneSearchÔ BLN Assay in China.Methods: Started from February 2009, CBCSG-001a is being conducted at 6 centers with a total enrollment of 540 cases by the end of June 2009. SLNs are cut into alternating ∼2mm sections. One half of the sections are sampled for H&E. The other half is fully tested with the BLN assay. The assay detects the presence of cytokeratin-19 and mammaglobin to assess if metastases are in SLNS. Predetermined cutoffs are calibrated so only metastases >0.2 mm are detected. Each assay run has internal and external controls to confirm a valid result.About 40% cases would receive axillary lymph node dissection (ALND) in spite of the status of SLN in 3 of the 6 centers. Intraoperative frozen section for SLN diagnosis was conducted in 4 of the 6 centers, and intraoperative touch imprint cytological diagnosis for all sections was conduced in 2 of the 6 centers.Results: Interim results are based on 20% (114/540) of the planned breast cancer patients for the study. Current histology positive rate is 30%. The BLN assay shows high performance as compared to H&E. The results are also very similar to those seen in the larger US clinical validation trial.Discussion: Interim results indicate that the BLN assay has high performance as compared to H&E, and allows same surgery ALND avoiding the need to wait for a second surgery. In addition the performance is equivalent to the results seen in the larger US clinical validation trial, indicating the assay performance is fairly robust. So there is clinical potential of using the assay for performance similar to H&E with the advantage of being an intra-operative, objective and standardized test that examines a larger portion on the nodal tissue. The final results of 550 cases will be updated at the SABCS.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1023.
Limited Clinical Utility of Prognostic Gene Expression Profiles in Grade 3 Node-Negative Early Stage Breast Cancer.
Authors: Bedard P. , Ignatiadis M. , Haibe-Kains B. , Haibe-Kains B. , Loi S. , Criscitiello C. , Desmedt C. , Bontempi G. , Piccart M. , Piccart M. , Sotiriou C. , Sotiriou C.
Published: December 2010

Background: There are a variety of commercially available prognostic gene expression profiles (GEPs) for early stage breast cancer. These have been shown to be highly concordant in their risk classification, as their prognostic performance is largely driven by an improved quantification of cellular proliferation in the ER+/HER2- (luminal) subtype. We hypothesized that the clinical utility of prognostic GEPs would be limited to the subset of tumors with an indeterminate assessment of proliferation by histological grading (grade 2).Methods: We computed five gene-expression signatures – genomic grade index (GGI), 70-gene signature (GENE70), 76-gene signature (GENE76), 21-gene recurrence score, and wound response signature – in 999 lymph node negative, untreated breast tumors (median follow-up of 7.8 years) from six publicly available datasets. We compared their performance against traditional clinicopathological risk classification using Adjuvant!Online (AOL) for each histological grading category.Results: All five GEPs demonstrated superior prognostication of 10-year distant metastasis free survival (DMFS) in grade 1 (range of area under the ROC curves (AUC)=0.63-0.75) and grade 2 (AUC=0.64-0.71) tumors than in grade 3 (AUC=0.48-0.53) tumors. For the GGI, GENE70, and GENE76 profiles, discordant risk classification with AOL was more frequent in grade 2 (53%) than grade 1 (38%) and grade 3 (26%) tumors (p<.001). In the event of discordant risk classification, GEP identified a low risk subgroup that might be spared chemotherapy in grade 2 (10-yr DFMS: 80% vs 66% (GGI); 81% vs 65% (GENE70); 80% vs 67% (GENE76)) and grade 1 (10-yr DFMS: 92% vs 69% (GGI); 84% vs 79% (GENE70); and 87% vs 70% (GENE76)) but not grade 3 (10-yr DFMS: 67% vs 47% (GGI); 75% vs 47% (GENE70); and 71% vs 52% (GENE76)). Even within the subset of all small (T<2cm), ER-positive, node-negative grade 3 tumors, low genomic risk patients did not experience a sufficiently favorable long-term outcome (10-yr DMFS: 60% (GGI), 69% (GENE70) and 64% (GENE76)) to justify the omission of adjuvant chemotherapy.Conclusion: There is limited clinical utility of prognostic GEPs in grade 3 early breast cancer. Histological grading should guide decision-making for assessment of genomic risk.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 103.
Comparison of Prognostic Signatures in Node-Negative Tamoxifen-Treated Breast Cancer Patients.
Authors: Müller V. , Schmidt M. , Rody A. , Milde-Langosch K. , Kaufmann M. , Kölbl H. , Jänicke F. , Weber K. , Gehrmann M.
Published: December 2010

Background: A number of molecular signatures have been published to aid breast cancer prognosis and therapy response prediction. A 76-gene signature has been developed in a node-negative patient cohort that did not receive systemic therapy.1 Another prognostic 97-gene signature measures predominantly proliferation-associated genes.2 Finally, a 21-gene signature has been developed for node-negative and estrogen receptor–positive breast cancer patients treated with tamoxifen in the adjuvant setting.3 Here we compare the prognostic performance of all three published algorithms in a cohort of 189 node-negative breast cancer patients treated with tamoxifen.Materials and Methods: Fresh-frozen tumors from node-negative patients were profiled on HG-U133a arrays. In addition, HG-U133a datasets with clinical annotation were downloaded from GEO (http://www.ncbi.nlm.nih.gov/geo/). All patients received tamoxifen only as adjuvant treatment after surgery. We determined the molecular subclass on the basis of ESR1 and ERBB2 mRNA expression; only ESR1-positive and ERBB2-negative tumors were considered for further analysis, leaving 141 in-house and 48 public datasets. After mapping of the gene signatures to the HG-U133a platform, we performed Cox regression and ROC curve analysis with distant metastasis as endpoint.Results: Cox regression analysis yielded a significant outcome association for all three gene signatures (76-gene signature: P = 0.0018; 97-gene signature: P = 0.0294; 21-gene signature: P = 0.0025) in the whole ESR1+/ERBB2– cohort. However, the 97-gene signature did not yield a significant result by ROC analysis for distant metastasis at 5 years (76-gene signature: AUC = 0.645, CI = 0.505–0.785; 97-gene signature: AUC = 0.608, CI = 0.462–0.754; 21-gene signature: AUC = 0.744, CI = 0.633–0.854). In addition, when the analysis was restricted to grade 2 tumors (n = 114), only the 21-gene signature remained prognostic by Cox regression (76-gene signature: P = 0.2405; 97-gene signature: P = 0.9001; 21-gene signature: P = 0.047) as well as by ROC curve analysis at 5 years (76-gene signature: AUC = 0.575, CI = 0.398–0.751; 97-gene signature: AUC = 0.532, CI = 0.347–0.717; 21-gene signature: AUC = 0.699, CI = 0.549–0.849).Discussion: While all three gene signatures reveal a significant outcome association in our whole patient cohort by Cox regression analysis, only the 21-gene signature remains significant in a subset analysis of grade 2 tumors. Since this group is clinically particularly challenging, further comparison between prognostic gene signatures in homogeneously treated patient cohorts is needed.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 104.