bluuebunny/crossref_metadata_2025 huggingface dataset:
Redrawing cognitive maps of conflict: Lost spaces and forgetting in the centre of Belfast
Authors: Switzer Catherine , Mcdowell Sara
Published: September 2009

Northern Ireland is currently emerging from three decades of conflict. Belfast, its largest city, experienced some of the worst levels of violence. During these ‘Troubles’ it became a highly segregated city in which its citizens understandings of the urban fabric were mediated through their ethno-religious backgrounds. Yet as the region moves into a post-conflict situation, Belfast has been undergoing rapid physical change. One result of this has been an effort to remove evidence of the conflict from the ‘new’ city centre, despite more than 70 conflict-related deaths having occurred there. The article uses the example of Belfast city centre to explore: (1) how ‘normalization’ strategies employed after conflict seek to reshape cognitive understandings of violent spaces through reconstruction; and (2) how individual memory retains the potential to disrupt these efforts. We argue that the highly regimented spatial patterns of Troubles commemoration in Belfast may influence how the city deals with the challenges of its violent past.
Review: New and developing therapies for celiac disease
Authors: Tennyson Christina A. , Lewis Suzanne K. , Green Peter H. R.
Published: September 2009

The treatment for celiac disease, a removal of gluten in the diet, is safe and effective for the vast majority of patients. There is a large body of evidence that the diagnosis and treatment of those with celiac disease ensures considerable health benefits. Although a gluten-free diet is the principal treatment for celiac disease, it is relatively expensive, inconvenient and difficult to adhere to. For these reasons, there is interest in developing alternative therapies. Emerging research for the treatment of celiac disease has focused on three areas: to decrease gluten exposure, to modify intestinal permeability and to modulate immune activation. Therapies developed thus far consist of enzymes designed to digest gluten and the use of inhibitors of paracellular permeability to decrease the migration of gluten peptides into the lamina propria. Other potential therapeutic maneuvers include the binding of gluten by polymers, the use of tissue transglutaminase (TTG) inhibitors and DQ2 or DQ8 blockers, or modulation of cytokine production. While all represent new and exciting therapies, an ideal therapy should have virtually no side effects similar to a gluten-free diet. A pharmaceutical agent may be used on an intermittent basis, such as following occasional gluten exposure or on a chronic basis to mitigate the effects of potential inadvertent ingestion of gluten.
Protective Athletic Mouthguards: Do They Cause Harm?
Authors: Glass Richard T. , Conrad Robert S. , Wood Charles Rieger , Warren Aric J. , Kohler Gerwald A. , Bullard James W. , Benson Gifty , Gulden Judyth M.
Published: September 2009

Background:

Protective athletic mouthguards (PAMs) have been worn in competitive sports for more than 100 years. Today, participants in contact and noncontact sports wear PAMs.

Hypothesis:

Wearing a PAM produces oral injury.

Study Type:

Case series.

Study Design and Methods:

Sixty-two Division I football players voluntarily participated in the study. Before the beginning of the season, each player underwent a thorough oral examination, and all abnormal oral findings were photographed (hyperkeratosis, erythema, ulceration, and combinations thereof). At midseason, 14 players were given complete oral examinations, with all abnormal oral findings documented. At season end, all remaining players (n = 53) had complete oral examinations and photographs taken of abnormal oral findings.

Results:

The preseason examination of 62 players found a total of 85 lesions (1.4 lesions per player) on the gingiva (n = 17), buccal mucosa (n = 60), and palate (n = 8). The 14 midseason players had 28 lesions (2.0 lesions per player) on gingiva (n = 8), buccal mucosa (n = 16), and tongue (n = 4). At season end, the 53 remaining players had 198 lesions (3.7 per player) on the gingiva (n = 96), buccal mucosa (n = 79), tongue (n = 18), and palate (n = 5). In addition, the lesion intensity scores progressively increased over the season. Because the palate did not come into direct contact with the PAM, it was used as an internal control.

Conclusion:

The wearing of a PAM may increase the number and intensity of oral mucosal injuries, which may cause localized soft tissue reactions such as hyperkeratosis, erythema, and ulceration.

Clinical Relevance:

Because the PAM reduces tooth injury but may cause oral lesions, it should be sanitized daily and changed regularly and replaced whenever it becomes sharp and jagged or when the athlete develops an irritation in the mouth.
Imaging of Cervical Spine Injuries in Athletes
Authors: Bogner Eric A.
Published: September 2009

Trauma of the cervical spine is one of the most harrowing injuries seen in athletics. Although such injuries are not common, their impact can be devastating. Based on a thorough review of the literature, this article explains the identification of cervical spine trauma and the importance of stability therein. Multiple examples are given highlighting these findings and the way that multiple modalities can be used to asses such injuries. The article concludes with a brief review of the current recommendations as they relate to imaging in the initial assessment of cervical spine trauma.
Colony-stimulating factor-1–induced oscillations in phosphatidylinositol-3 kinase/AKT are required for caspase activation in monocytes undergoing differentiation into macrophages
Authors: Jacquel Arnaud , Benikhlef Naïma , Paggetti Jérôme , Lalaoui Najoua , Guery Leslie , Dufour Erick K. , Ciudad Marion , Racoeur Cindy , Micheau Olivier , Delva Laurent , Droin Nathalie , Solary Eric
Published: September 2009

The differentiation of human peripheral blood monocytes into resident macrophages is driven by colony-stimulating factor-1 (CSF-1), which upon interaction with CSF-1 receptor (CSF-1R) induces within minutes the phosphorylation of its cytoplasmic tyrosine residues and the activation of multiple signaling complexes. Caspase-8 and -3 are activated at day 2 to 3 and contribute to macrophage differentiation, for example, through cleavage of nucleophosmin. Here, we show that the phosphatidylinositol-3 kinase and the downstream serine/threonine kinase AKT connect CSF-1R activation to caspase-8 cleavage. Most importantly, we demonstrate that successive waves of AKT activation with increasing amplitude and duration are required to provoke the formation of the caspase-8–activating molecular platform. CSF-1 and its receptor are both required for oscillations in AKT activation to occur, and expression of a constitutively active AKT mutant prevents the macrophage differentiation process. The extracellular receptor kinase 1/2 pathway is activated with a coordinated oscillatory kinetics in a CSF-1R–dependent manner but plays an accessory role in caspase activation and nucleophosmin cleavage. Altogether, CSF-1 stimulation activates a molecular clock that involves phosphatidylinositol-3 kinase and AKT to promote caspase activation. This oscillatory signaling pathway, which is coordinated with extracellular receptor kinase 1/2 oscillatory activation, involves CSF-1 and CSF-1R and controls the terminal differentiation of macrophages.
Obesity accelerates thymic aging
Authors: Yang Hyunwon , Youm Yun-Hee , Vandanmagsar Bolormaa , Rood Jennifer , Kumar K. Ganesh , Butler Andrew A. , Dixit Vishwa Deep
Published: September 2009

As the expanding obese population grows older, their successful immunologic aging will be critical to enhancing the health span. Obesity increases risk of infections and cancer, suggesting adverse effects on immune surveillance. Here, we report that obesity compromises the mechanisms regulating T-cell generation by inducing premature thymic involution. Diet-induced obesity reduced thymocyte counts and significantly increased apoptosis of developing T-cell populations. Obesity accelerated the age-related reduction of T-cell receptor (TCR) excision circle bearing peripheral lymphocytes, an index of recently generated T cells from thymus. Consistent with reduced thymopoiesis, dietary obesity led to reduction in peripheral naive T cells with increased frequency of effector-memory cells. Defects in thymopoiesis in obese mice were related with decrease in the lymphoid-primed multipotent progenitor (Lin−Sca1+Kit+ Flt3+) as well as common lymphoid progenitor (Lin−Sca1+CD117loCD127+) pools. The TCR spectratyping analysis showed that obesity compromised V-β TCR repertoire diversity. Furthermore, the obesity induced by melanocortin 4 receptor deficiency also constricted the T-cell repertoire diversity, recapitulating the thymic defects observed with diet-induced obesity. In middle-aged humans, progressive adiposity with or without type 2 diabetes also compromised thymic output. Collectively, these findings establish that obesity constricts T-cell diversity by accelerating age-related thymic involution.
Superagonistic CD28 stimulation of allogeneic T cells protects from acute graft-versus-host disease
Authors: Beyersdorf Niklas , Ding Xin , Hünig Thomas , Kerkau Thomas
Published: September 2009

Acute graft-versus-host disease (aGVHD) often precludes successful immunotherapy of hematologic malignancies with allogeneic T cells. Therefore, we investigated the effect of immunomodulatory superagonistic anti-CD28 monoclonal antibodies (CD28-SA) on the capacity of allogeneic T cells to mediate both aGVHD and the protective graft-versus-tumor (GVT) response. In vivo pretreatment of donor C57BL/6 mice or short-term in vitro culture of donor lymph node cells with a CD28-SA efficiently protected BALB/c recipient mice from aGVHD. This protection strongly relied on the presence of CD28-SA–activated CD4+ CD25+ Foxp3+ regulatory T cells in the donor T-cell inoculum. With respect to the GVT response, CD28-SA–prestimulated T cells were still as potent in clearing lymphoma cells as were T cells without CD28-SA preactivation. Taken together, our data suggest that CD28-SA stimulation of bulk leukocyte cultures in vitro markedly increases the therapeutic window for adoptive immunotherapy with allogeneic T cells in vivo.
"hCG priming" effect in controlled ovarian stimulation through a long protocol
Authors: Beretsos Panagiotis , Partsinevelos George A , Arabatzi Eleni , Drakakis Peter , Mavrogianni Depy , Anagnostou Elli , Stefanidis Kostas , Antsaklis Aris , Loutradis Dimitris
Published: September 2009

Background

Recently, it has been demonstrated that, in patients down-regulated by GnRH analogues (GnRHa), a short-term pre-treatment with recombinant LH (rLH), prior to recombinant FSH (rFSH) administration, increases the number of small antral follicle prior to FSH stimulation and the yield of normally fertilized embryos. However, no data exist in the literature regarding the potential beneficial effect of "hCG priming" in controlled ovarian hyperstimulation (COH) through a long GnRH-a protocol, which binds the same receptor (LH/hCGR), though it is a much more potent compared to LH. The primary aims of this study were to assess the effect of short-term pre-rFSH administration of hCG in women entering an ICSI treatment cycle on follicular development, quality of oocytes and early embryo development. The secondary endpoints were to record the effects on endometrial quality and pregnancy rate.

Methods

Patients with a history of at least one previous unsuccessful ICSI cycle were randomly assigned into two groups to receive treatment with either a long protocol with rFSH (control group) or a long protocol with rFSH and pre-treatment with hCG (hCG group). In particular, in the latter group, a fixed 7 days course of 200 IU/day hCG was administered as soon as pituitary desensitization was confirmed.

Results

The mean number of oocytes retrieved was not significantly different between the two treatment groups, although the percentage of mature oocytes tended to be higher but not significantly different in hCG-treated patients. The percentage of patients with more than one grade 3 embryos was higher in the pre-treatment group, which also showed a higher pregnancy rate.

Conclusion

All the above clinical observations, in conjunction with previous data, suggest a point towards a beneficial "hCG priming" effect in controlled ovarian hyperstimulation through a long GnRH-a down-regulation protocol, particularly in patients with previous ART failures.
Talking to chromatin: post-translational modulation of polycomb group function
Authors: Niessen Hanneke EC , Demmers Jeroen A , Voncken Jan Willem
Published: September 2009

Polycomb Group proteins are important epigenetic regulators of gene expression. Epigenetic control by polycomb Group proteins involves intrinsic as well as associated enzymatic activities. Polycomb target genes change with cellular context, lineage commitment and differentiation status, revealing dynamic regulation of polycomb function. It is currently unclear how this dynamic modulation is controlled and how signaling affects polycomb-mediated epigenetic processes at the molecular level. Experimental evidence on regulation of polycomb function by post-translational mechanisms is steadily emerging: Polycomb Group proteins are targeted for ubiquitylation, sumoylation and phosphorylation. In addition, specific Polycomb Group proteins modify other (chromatin) associated proteins via similar post-translational modifications. Such modifications affect protein function by affecting protein stability, protein-protein interactions and enzymatic activities. Here, we review current insights in covalent modification of Polycomb Group proteins in the context of protein function and present a tentative view of integrated signaling to chromatin in the context of phosphorylation. Clearly, the available literature reveals just the tip of the iceberg, and exact molecular mechanisms in, and the biological relevance of post-translational regulation of polycomb function await further elucidation. Our understanding of causes and consequences of post-translational modification of polycomb proteins will gain significantly from in vivo validation experiments. Impaired polycomb function has important repercussions for stem cell function, development and disease. Ultimately, increased understanding of signaling to chromatin and the mechanisms involved in epigenetic remodeling will contribute to the development of therapeutic interventions in cell fate decisions in development and disease.
The drug-resistance to gefitinib in PTEN low expression cancer cells is reversed by irradiation in vitro
Authors: Zhuang Hong-Qing , Wang Jun , Yuan Zhi-Yong , Zhao Lu-Jun , Wang Ping , Wang Chang-Li
Published: September 2009

Background

Despite of the recent success of EGFR inhibitory agents, the primary drug-resistant becomes a major challenge for EGFR inhibitor therapies. PTEN gene is an important positive regulatory factor for response to EGFR inhibitor therapy. Low-expression of PTEN is clearly one of the important reasons why tumor cells resisted to tyrosine kinase inhibitors.

Methods

To investigate the drug-resistance reversal to gefitinb and the mechanism in PTEN low expression cells which radiated with X-rays in vitro, We demonstrated that H-157 lung cancer cells (low-expression of PTEN but phospho-EGFR overexpressed tumor cells) exposed to X-rays. The PTEN expressions and radiosensitizing effects of tyrosine kinase inhibitor before and after irradiation were observed. The cell-survival rates were evaluated by colony-forming assays. The cell apoptosis was investigated using FCM. The expressions of phospho-EGFR and PTEN were determined by Western blot analysis.

Results

The results showed that the PTEN expressions were significantly enhanced by X-rays. Moreover, the cell growth curve and survival curve were down-regulated in the gefitinib-treated groups after irradiation. Meanwhile, the radiation-induced apoptosis of tumor cells was increased by inhibition of the EGFR through up-regulation of PTEN.

Conclusion

These results suggested that PTEN gene is an important regulator on TKI inhibition, and the resistance to tyrosine kinase inhibitors might be reversed by irradiation in PTEN low expression cancer cells.
Nucleosome deposition and DNA methylation at coding region boundaries
Authors: Choi Jung Kyoon , Bae Jae-Bum , Lyu Jaemyun , Kim Tae-Yoon , Kim Young-Joon
Published: September 2009

Background

Nucleosome deposition downstream of transcription initiation and DNA methylation in the gene body suggest that control of transcription elongation is a key aspect of epigenetic regulation.

Results

Here we report a genome-wide observation of distinct peaks of nucleosomes and methylation at both ends of a protein coding unit. Elongating polymerases tend to pause near both coding ends immediately upstream of the epigenetic peaks, causing a significant reduction in elongation efficiency. Conserved features in underlying protein coding sequences seem to dictate their evolutionary conservation across multiple species. The nucleosomal and methylation marks are commonly associated with high sequence-encoded DNA-bending propensity but differentially with CpG density. As the gene grows longer, the epigenetic codes seem to be shifted from variable inner sequences toward boundary regions, rendering the peaks more prominent in higher organisms.

Conclusions

Recent studies suggest that epigenetic inhibition of transcription elongation facilitates the inclusion of constitutive exons during RNA splicing. The epigenetic marks we identified here seem to secure the first and last coding exons from exon skipping as they are indispensable for accurate translation.
Replacing Lecture with Peer-led Workshops Improves Student Learning
Authors: Preszler Ralph W.
Published: September 2009

Peer-facilitated workshops enhanced interactivity in our introductory biology course, which led to increased student engagement and learning. A majority of students preferred attending two lectures and a workshop each week over attending three weekly lectures. In the workshops, students worked in small cooperative groups as they solved challenging problems, evaluated case studies, and participated in activities designed to improve their general learning skills. Students in the workshop version of the course scored higher on exam questions recycled from preworkshop semesters. Grades were higher over three workshop semesters in comparison with the seven preworkshop semesters. Although males and females benefited from workshops, there was a larger improvement of grades and increased retention by female students; although underrepresented minority (URM) and non-URM students benefited from workshops, there was a larger improvement of grades by URM students. As well as improving student performance and retention, the addition of interactive workshops also improved the quality of student learning: Student scores on exam questions that required higher-level thinking increased from preworkshop to workshop semesters.
Cloning the Professor, an Alternative to Ineffective Teaching in a Large Course
Authors: Nelson Jennifer , Robison Diane F. , Bell John D. , Bradshaw William S.
Published: September 2009

Pedagogical strategies have been experimentally applied in large-enrollment biology courses in an attempt to amplify what teachers do best in effecting deep learning, thus more closely approximating a one-on-one interaction with students. Carefully orchestrated in-class formative assessments were conducted to provide frequent, high-quality feedback that allows students to accurately diagnose the current state of their understanding of fundamental biological concepts and make specific plans to remedy any deficiencies. Teachers can also assume responsibility to guide out-of-class study among classmates by promoting Elaborative Questioning, an inquiry exchange that permits misconceptions to be identified and corrected and that promotes long-lasting metacognitive and analytical thinking skills. Data are presented that demonstrate the positive impact of these innovations on student performance and affect.
Active Learning and Student-centered Pedagogy Improve Student Attitudes and Performance in Introductory Biology
Authors: Armbruster Peter , Patel Maya , Johnson Erika , Weiss Martha
Published: September 2009

We describe the development and implementation of an instructional design that focused on bringing multiple forms of active learning and student-centered pedagogies to a one-semester, undergraduate introductory biology course for both majors and nonmajors. Our course redesign consisted of three major elements: 1) reordering the presentation of the course content in an attempt to teach specific content within the context of broad conceptual themes, 2) incorporating active and problem-based learning into every lecture, and 3) adopting strategies to create a more student-centered learning environment. Assessment of our instructional design consisted of a student survey and comparison of final exam performance across 3 years—1 year before our course redesign was implemented (2006) and during two successive years of implementation (2007 and 2008). The course restructuring led to significant improvement of self-reported student engagement and satisfaction and increased academic performance. We discuss the successes and ongoing challenges of our course restructuring and consider issues relevant to institutional change.
Jo Handelsman
Authors: Mays Hoopes Laura L.
Published: September 2009

Note from the Editor

Educator Highlights for CBE-LSE show how professors at different kinds of institutions educate students in life sciences with inspiration and panache. If you have a particularly creative teaching portfolio yourself, or if you wish to nominate an inspiring colleague to be profiled, please e-mail Laura Hoopes at lhoopes@pomona.edu.
Transform-domain sparsity regularization for inverse problems in geosciences
Authors: Jafarpour Behnam , Goyal Vivek K. , McLaughlin Dennis B. , Freeman William T.
Published: September 2009

We have developed a new regularization approach for estimating unknown spatial fields, such as facies distributions or porosity maps. The proposed approach is especially efficient for fields that have a sparse representation when transformed into a complementary function space (e.g., a Fourier space). Sparse transform representations provide an accurate characterization of the original field with a relatively small number of transformed variables. We use a discrete cosine transform (DCT) to obtain sparse representations of fields with distinct geologic features, such as channels or geologic formations in vertical cross section. Low-frequency DCT basis elements provide an effectively reduced subspace in which the sparse solution is searched. The low-dimensional subspace is not fixed, but rather adapts to the data.The DCT coefficients are estimated from spatial observations with a variant of compressed sensing. The estimation procedure minimizes an [Formula: see text]-norm measurement misfit term while maintaining DCT coefficient sparsity with an [Formula: see text]-norm regularization term. When measurements are noise-dominated, the performance of this procedure might be improved by implementing it in two steps — one that identifies the sparse subset of important transform coefficients and one that adjusts the coefficients to give a best fit to measurements. We have proved the effectiveness of this approach for facies reconstruction from both scattered- point measurements and areal observations, for crosswell traveltime tomography, and for porosity estimation in a typical multiunit oil field. Where we have tested our sparsity regulariza-tion approach, it has performed better than traditional alter-natives.
An exact adjoint operation pair in time extrapolation and its application in least-squares reverse-time migration
Authors: Ji Jun
Published: September 2009

To reduce the migration artifacts arising from incomplete data or inaccurate operators instead of migrating data with the adjoint of the forward-modeling operator, a least-squares migration often is considered. Least-squares migration requires a forward-modeling operator and its adjoint. In a derivation of the mathematically correct adjoint operator to a given forward-time-extrapolation modeling operator, the exact adjoint of the derived operator is obtained by formulating an explicit matrix equation for the forward operation and transposing it. The programs that implement the exact adjoint operator pair are verified by the dot-product test. The derived exact adjoint operator turns out to differ from the conventional reverse-time-migration (RTM) operator, an implementation of wavefield extrapolation backward in time. Examples with synthetic data show that migration using the exact adjoint operator gives similar results for a conventional RTM operator and that least-squares RTM is quite successful in reducing most migration artifacts. The least-squares solution using the exact adjoint pair produces a model that fits the data better than one using a conventional RTM operator pair.
Simultaneous multivintage time-shift estimation
Authors: Zabihi Naeini Ehsan , Hoeber Henning , Poole Gordon , Siahkoohi Hamid R.
Published: September 2009

Time-shift estimation is a key step in seismic time-lapse processing as well as in many other signal-processing applications. We consider the time-shift problem in the setting of multiple repeat surveys that must be aligned consistently. We introduce an optimized least-squares method based on the Taylor expansion for estimating two-vintage time shifts and compare it to crosscorrelation. The superiority of the proposed algorithm is demonstrated with synthetic data and residual time-lapse matching on a U. K. continental shelf data set. We then discuss the shortcomings of cascaded time alignment in multiple repeat monitor surveys and propose an approach to estimate simultaneous multivintage time shifts that uses a constrained least-squares technique combined with elements of network theory. The resulting time shifts are consistent across all vintages in a least-squares sense, improving overall alignment when compared to the classical flow of alignment in a cascaded manner. The method surpasses the cascaded approach, as noted with sample synthetic and three-vintage U. K. continental shelf time-lapse data sets.
Theory and numerical simulation of fluid-pressure diffusion in anisotropic porous media
Authors: Carcione José M. , Gei Davide
Published: September 2009

The physics of fluid diffusion in anisotropic media was studied, based on Biot’s theory of poroelasticity and using wave propagation concepts. Diffusion and elastic strain can be uncoupled fully, being a good approximation in many situations. We have used a correction to the stiffness of the rock under conditions of transverse isotropy and uniaxial strain to model borehole conditions. The concepts of phase, group, and energy velocities were analyzed to describe the location of the diffusion front, and the attenuation and quality factors were obtained to quantify the amplitude decay. We have found that the location of the front is described correctly by the energy velocity. The Green’s function in anisotropic media can be obtained by applying a change of coordinates to the isotropic solution. We have simulated the diffusion in inhomogeneous media using a time-domain spectral explicit scheme and the staggered Fourier pseudospectral method to compute the spatial derivatives. The method is based on a spectral Chebychev expansion of the evolution operator of the system. The scheme allows the solution of linear periodic parabolic equations, having accuracy within the machine precision, in time and in space. The results match the analytic solution obtained from the Green’s function. The performance of the algorithm is confirmed in the case of a pressure field generated by a fluid-injection source in a hydrocarbon reservoir where the properties vary fractally.
Impact of Micrometastases in the Sentinel Node of Patients With Invasive Breast Cancer
Authors: Hansen Nora M. , Grube Baiba , Ye Xing , Turner Roderick R. , Brenner R. James , Sim Myung-Shin , Giuliano Armando E.
Published: September 2009

Purpose

Lymph node metastases are the most significant prognostic indicator for patients with breast cancer. Sentinel node biopsy (SNB) has led to an increase in the detection of micrometastases in the sentinel node (SN). This prospective study was designed to determine the survival impact of micrometastases in SNs of patients with invasive breast cancer. This study is based on the new sixth edition of the American Joint Committee on Cancer (AJCC) staging criteria.

Patients and Methods

Between January 1, 1992 and April 30, 1999, 790 patients entered this prospective study at the John Wayne Cancer Institute. The SN was examined first by hematoxylin and eosin (HE), and if the SN was negative with HE, then immunohistochemical staining was performed. The patients were then divided into four groups based on AJCC nodal staging: pN0(i–), no evidence of tumor (n = 486); pN0(i+), tumor deposit ≤ 0.2 mm (n = 84); pN1mi, tumor deposit more than 0.2 mm but ≤ 2 mm (n = 54), and pN1, tumor deposit more than 2 mm (n = 166). Disease-free survival (DFS) and overall survival (OS) were estimated using the Kaplan-Meier method. The log-rank test was used to determine differences in DFS and OS of patients from different groups.

Results

At a median follow-up of 72.5 months, the size of SN metastases was a significant predictor of DFS and OS.

Conclusion

Patients with micrometastatic tumor deposits, pN0(i+) or pN1mi, do not seem to have a worse 8-year DFS or OS compared with SN-negative patients. As expected, there was a significant decrease in 8-year DFS and OS in patients with pN1 disease in the SN.
Bevacizumab Alone and in Combination With Irinotecan in Recurrent Glioblastoma
Authors: Friedman Henry S. , Prados Michael D. , Wen Patrick Y. , Mikkelsen Tom , Schiff David , Abrey Lauren E. , Yung W.K. Alfred , Paleologos Nina , Nicholas Martin K. , Jensen Randy , Vredenburgh James , Huang Jane , Zheng Maoxia , Cloughesy Timothy
Published: September 2009

Purpose

We evaluated the efficacy of bevacizumab, alone and in combination with irinotecan, in patients with recurrent glioblastoma in a phase II, multicenter, open-label, noncomparative trial.

Patients and Methods

One hundred sixty-seven patients were randomly assigned to receive bevacizumab 10 mg/kg alone or in combination with irinotecan 340 mg/m2 or 125 mg/m2 (with or without concomitant enzyme-inducing antiepileptic drugs, respectively) once every 2 weeks. Primary end points were 6-month progression-free survival and objective response rate, as determined by independent radiology review. Secondary end points included safety and overall survival.

Results

In the bevacizumab-alone and the bevacizumab-plus-irinotecan groups, estimated 6-month progression-free survival rates were 42.6% and 50.3%, respectively; objective response rates were 28.2% and 37.8%, respectively; and median overall survival times were 9.2 months and 8.7 months, respectively. There was a trend for patients who were taking corticosteroids at baseline to take stable or decreasing doses over time. Of the patients treated with bevacizumab alone or bevacizumab plus irinotecan, 46.4% and 65.8%, respectively, experienced grade ≥ 3 adverse events, the most common of which were hypertension (8.3%) and convulsion (6.0%) in the bevacizumab-alone group and convulsion (13.9%), neutropenia (8.9%), and fatigue (8.9%) in the bevacizumab-plus-irinotecan group. Intracranial hemorrhage was noted in two patients (2.4%) in the bevacizumab-alone group (grade 1) and in three patients (3.8%) patients in the bevacizumab-plus-irinotecan group (grades 1, 2, and 4, respectively).

Conclusion

Bevacizumab, alone or in combination with irinotecan, was well tolerated and active in recurrent glioblastoma.
Centralization of Cancer Surgery: Implications for Patient Access to Optimal Care
Authors: Stitzenberg Karyn B. , Sigurdson Elin R. , Egleston Brian L. , Starkey Russell B. , Meropol Neal J.
Published: September 2009

Purpose

The volume-outcomes relationship has led many to advocate centralization of cancer procedures at high volume hospitals (HVH). We hypothesized that in response cancer surgery has become increasingly centralized and that this centralization has resulted in increased travel burden for patients.

Patients and Methods

Using 1996 to 2006 discharge data from NY, NJ, PA, all patients ≥ 18 years old treated with extirpative surgery for colorectal, esophageal, or pancreatic cancer were examined. Patients and hospitals were geocoded. Annual hospital procedure volume for each tumor site was examined, and multiple quantile and logistic regressions were used to compare changes in centralization and distance traveled.

Results

Five thousand two hundred seventy-three esophageal, 13,472 pancreatic, 202,879 colon, and 51,262 rectal procedures were included. A shift to HVH occurred to varying degrees for all tumor types. The odds of surgery at a low volume hospital decreased for esophagus, pancreas and colon: per year odds ratios (ORs) were 0.87 (95% CI, 0.85 to 0.90), 0.85 (95% CI, 0.84 to 0.87), and 0.97 (95% CI, 0.97 to 0.98). Median travel distance increased for all sites: esophagus 72%, pancreas 40%, colon 17%, and rectum 28% (P < .0001). Travel distance was proportional to procedure volume (P < .0001). The majority of the increase in distance was attributable to centralization.

Conclusion

There has been extensive centralization of complex cancer surgery over the past decade. While this process should result in population-level improvements in cancer outcomes, centralization is increasing patient travel. For some subsets of the population, increasing travel requirements may pose a significant barrier to access to quality cancer care.
Concurrent Trastuzumab and HER2/neu-Specific Vaccination in Patients With Metastatic Breast Cancer
Authors: Disis Mary L. , Wallace Danelle R. , Gooley Theodore A. , Dang Yushe , Slota Meredith , Lu Hailing , Coveler Andrew L. , Childs Jennifer S. , Higgins Doreen M. , Fintak Patricia A. , dela Rosa Corazon , Tietje Kathleen , Link John , Waisman James , Salazar Lupe G.
Published: September 2009

Purpose

The primary objectives of this phase I/II study were to evaluate the safety and immunogenicity of combination therapy consisting of concurrent trastuzumab and human epidermal growth factor receptor 2 (HER2)/neu-specific vaccination in patients with HER2/neu-overexpressing metastatic breast cancer.

Patients and Methods

Twenty-two patients with stage IV HER2/neu-positive breast cancer receiving trastuzumab therapy were vaccinated with an HER2/neu T-helper peptide-based vaccine. Toxicity was graded according to National Cancer Institute criteria, and antigen specific T-cell immunity was assessed by interferon gamma enzyme-linked immunosorbent spot assay. Data on progression-free and overall survival were collected.

Results

Concurrent trastuzumab and HER2/neu vaccinations were well tolerated, with 15% of patients experiencing an asymptomatic decline in left ventricular ejection fraction below the normal range during combination therapy. Although many patients had pre-existing immunity specific for HER2/neu and other breast cancer antigens while treated with trastuzumab alone, that immunity could be significantly boosted and maintained with vaccination. Epitope spreading within HER2/neu and to additional tumor-related proteins was stimulated by immunization, and the magnitude of the T-cell response generated was significantly inversely correlated with serum transforming growth factor beta levels. At a median follow-up of 36 months from the first vaccine, the median overall survival in the study population has not been reached.

Conclusion

Combination therapy with trastuzumab and a HER2/neu vaccine is associated with minimal toxicity and results in prolonged, robust, antigen-specific immune responses in treated patients.
Phase III Prospective Randomized Double-Blind Placebo-Controlled Trial of Plerixafor Plus Granulocyte Colony-Stimulating Factor Compared With Placebo Plus Granulocyte Colony-Stimulating Factor for Autologous Stem-Cell Mobilization and Transplantation for Patients With Non-Hodgkin's Lymphoma
Authors: DiPersio John F. , Micallef Ivana N. , Stiff Patrick J. , Bolwell Brian J. , Maziarz Richard T. , Jacobsen Eric , Nademanee Auayporn , McCarty John , Bridger Gary , Calandra Gary
Published: September 2009

Purpose

This study evaluates the safety and efficacy of plerixafor (AMD3100), a CXCR4 antagonist, in mobilizing hematopoietic stem cells for autologous stem-cell transplantation in non-Hodgkin's lymphoma (NHL) patients.

Patients and Methods

This is a phase III, multicenter, randomized (1:1), double-blind, placebo-controlled study. Patients with non-Hodgkin's lymphoma requiring an autologous hematopoietic stem-cell transplantation in first or second complete or partial remission were eligible. Patients received granulocyte colony-stimulating factor (G-CSF; 10 μg/kg) subcutaneously daily for up to 8 days. Beginning on evening of day 4 and continuing daily for up to 4 days, patients received either plerixafor (240 μg/kg) or placebo subcutaneously. Starting on day 5, patients began daily apheresis for up to 4 days or until ≥ 5 × 106 CD34+ cells/kg were collected. The primary end point was the percentage of patients who collected ≥ 5 × 106 CD34+ cells/kg in 4 or fewer apheresis days.

Results

This report presents all data for all patients (n = 298) through 12 months follow-up. Eighty-nine (59%) of 150 patients in the plerixafor group and 29 (20%) of 148 patients in the placebo group met the primary end point (P < .001). One hundred thirty-five patients (90%) in plerixafor group and 82 patients (55%) in placebo group underwent transplantation after initial mobilization. Median time to engraftment was similar in both groups. The most common plerixafor-associated adverse events were GI disorders and injection site reactions.

Conclusion

Plerixafor and G-CSF were well tolerated and resulted in a significantly higher proportion of patients with non-Hodgkin's lymphoma achieving the optimal CD34+ cell target for transplantation in fewer apheresis days, compared with G-CSF alone.
Occult Nipple Involvement in Breast Cancer: Clinicopathologic Findings in 316 Consecutive Mastectomy Specimens
Authors: Brachtel Elena F. , Rusby Jennifer E. , Michaelson James S. , Chen L. Leon , Muzikansky Alona , Smith Barbara L. , Koerner Frederick C.
Published: September 2009

Purpose

Although breast-conserving surgery is a standard approach for patients with breast cancer, mastectomy often becomes necessary. Surgical options now include nipple-sparing mastectomy but its oncological safety is still controversial. This study evaluates frequency and patterns of occult nipple involvement in a large contemporary cohort of patients with the retroareolar margin as possible indicator of nipple involvement.

Patients and Methods

Three hundred sixteen consecutive mastectomy specimens (232 therapeutic, 84 prophylactic) with grossly unremarkable nipples were evaluated by coronal sections through the entire nipple and subareolar tissue. Extent and location of nipple involvement by carcinoma was assessed with the tissue deep to the skin as potential retroareolar en-face resection margin.

Results

Seventy-one percent of nipples from therapeutic mastectomies showed no pathologic abnormality, 21% had ductal carcinoma in situ (DCIS), invasive carcinoma (IC), or lymphovascular invasion (LVI), and 8% lobular neoplasia (lobular carcinoma in situ). Human epidermal growth factor receptor 2 amplification, tumor size, and tumor-nipple distance were associated with nipple involvement by multivariate analysis (P = .0047, .0126, and .0176); histologic grade of both DCIS (P = .002) and IC (P = .03), LVI (P = .03), and lymph node involvement (P = .02) by univariate analysis. Nipple involvement by IC or DCIS was identified in the retroareolar margin with a sensitivity of 0.8 and a negative predictive value of 0.96. None of the 84 prophylactic mastectomies showed nipple involvement by IC or DCIS.

Conclusion

Nipple-sparing mastectomy may be suitable for selected cases of breast carcinoma with low probability of nipple involvement by carcinoma and prophylactic procedures. A retroareolar en-face margin may be used to test for occult involvement in patients undergoing nipple-sparing mastectomy.
Health-Related Quality of Life Among Long-Term Rectal Cancer Survivors With an Ostomy: Manifestations by Sex
Authors: Krouse Robert S. , Herrinton Lisa J. , Grant Marcia , Wendel Christopher S. , Green Sylvan B. , Mohler M. Jane , Baldwin Carol M. , McMullen Carmit K. , Rawl Susan M. , Matayoshi Eric , Coons Stephen Joel , Hornbrook Mark C.
Published: September 2009

Purpose

Intestinal stomas can pose significant challenges for long-term (≥ 5 years) rectal cancer (RC) survivors. Specifying common challenges and sociodemographic or clinical differences will further the development of tailored interventions to improve health-related quality of life (HRQOL).

Patients and Methods

This was a matched cross-sectional study of long-term RC survivors conducted in three Kaiser Permanente regions. The mailed questionnaire included the modified City of Hope Quality of Life-Ostomy (mCOH-QOL-Ostomy) and Medical Outcomes Study 36-Item Short-Form Health Survey, version 2 (SF-36v2). Groups surveyed were permanent ostomates (cases) and those who did not require an ostomy (controls). RC survivors were matched on sex, age, and time since diagnosis. Comparisons between groups used regression analysis with adjustment for age, comorbidity score, history of radiation therapy, income, and work status.

Results

Response rate was 54% (491 of 909). Cases and controls had similar demographic characteristics. On the basis of the mCOH-QOL-Ostomy, both male and female cases had significantly worse social well-being compared with controls, while only female cases reported significantly worse overall HRQOL and psychological well-being. For younger females (< age 75 years), ostomy had a greater impact on physical well-being compared with older females. Based on the SF-36v2, statistically significant and meaningful differences between female cases and controls were observed for seven of the eight scales and on the physical and mental component summary scores.

Conclusion

Men and women report a different profile of challenges, suggesting the need for targeted or sex-specific interventions to improve HRQOL in this population. This may include focus on physical HRQOL for female ostomy survivors younger than age 75.
Frequent Pathologic Complete Responses in Aggressive Stages II to III Breast Cancers With Every-4-Week Carboplatin and Weekly Paclitaxel With or Without Trastuzumab: A Brown University Oncology Group Study
Authors: Sikov William M. , Dizon Don S. , Strenger Rochelle , Legare Robert D. , Theall Kathy P. , Graves Theresa A. , Gass Jennifer S. , Kennedy Teresa A. , Fenton Mary Anne
Published: September 2009

Purpose

To evaluate the efficacy and safety of neoadjuvant carboplatin and weekly paclitaxel ± weekly trastuzumab in resectable and locally advanced breast cancer.

Patients and Methods

Women with stages IIA to IIIB disease received carboplatin dosed by six times the area under the curve every 4 weeks and paclitaxel 80 mg/m2 weekly for 16 weeks, and weekly trastuzumab was added for human epidermal growth factor receptor 2 (HER2) –positive status. The primary end point was the pathologic complete response (pCR) rate, defined as the absence of invasive disease in the breast and axillary nodes. Postoperative therapies were at the discretion of the treating physicians.

Results

Fifty-five patients were enrolled, and of these 43 had resectable disease. The median age was 54 years (range, 31 to 74 years). Treatment was well tolerated; there were no episodes of febrile neutropenia or grade 4 thrombocytopenia, and there were only two instances of grade 3 peripheral neuropathy. Overall, the pCR rate was 45%. The pCR rate was 43% (95% CI, 28% to 58%) in patients with resectable disease. Higher pCR rates occurred in patients with HER2-positive tumors (76% v 31% for HER2-negative tumors; P = .003), with estrogen receptor (ER) –negative tumors (75% v 27% for ER-positive tumors; P = .001), or with triple-negative tumors (67% v 12% ER-positive and HER2-negative tumors; P = .002). At a median of 28 months postoperation, recurrence-free survival (RFS) was 88.7%. If patients with ER-positive and HER2-negative tumors are excluded from analysis, patients who achieved a pCR were less likely to experience disease recurrence (RFS, 86%) than those who did not achieve a pCR (RFS, 75%).

Conclusion

Neoadjuvant carboplatin and weekly paclitaxel ± trastuzumab achieve high pCR rates in patients with HER2-positive and triple-negative disease without exposure to an anthracycline. Preliminary RFS results are encouraging but are likely influenced by adjuvant therapy received. Additional study of this regimen in high-risk patients is warranted.
Impact of Pathological Characteristics on Local Relapse After Breast-Conserving Therapy: A Subgroup Analysis of the EORTC Boost Versus No Boost Trial
Authors: Jones Heather A. , Antonini Ninja , Hart Augustinus A.M. , Peterse Johannes L. , Horiot Jean-Claude , Collin Françoise , Poortmans Philip M. , Oei S. Bing , Collette Laurence , Struikmans Henk , Van den Bogaert Walter F. , Fourquet Alain , Jager Jos J. , Schinagl Dominic A.X. , Wárlám-Rodenhuis Carla C. , Bartelink Harry
Published: September 2009

Purpose

To investigate the long-term impact of pathologic characteristics and an extra boost dose of 16 Gy on local relapse, for stage I and II invasive breast cancer patients treated with breast conserving therapy (BCT).

Patients and Methods

In the European Organisation for Research and Treatment of Cancer boost versus no boost trial, after whole breast irradiation, patients with microscopically complete excision of invasive tumor, were randomly assigned to receive or not an extra boost dose of 16 Gy. For a subset of 1,616 patients central pathology review was performed.

Results

The 10-year cumulative risk of local breast cancer relapse as a first event was not significantly influenced if the margin was scored negative, close or positive for invasive tumor or ductal carcinoma in situ according to central pathology review (log-rank P = .45 and P = .57, respectively). In multivariate analysis, high-grade invasive ductal carcinoma was associated with an increased risk of local relapse (P = .026; hazard ratio [HR], 1.67), as was age younger than 50 years (P < .0001; HR, 2.38). The boost dose of 16 Gy significantly reduced the local relapse rate (P = .0006; HR, 0.47). For patients younger than 50 years old and in patients with high grade invasive ductal carcinoma, the boost dose reduced the local relapse from 19.4% to 11.4% (P = .0046; HR, 0.51) and from 18.9% to 8.6% (P = .01; HR, 0.42), respectively.

Conclusion

Young age and high-grade invasive ductal cancer were the most important risk factors for local relapse, while margin status had no significant influence. A boost dose of 16 Gy significantly reduced the negative effects of both young age and high-grade invasive cancer.