bluuebunny/crossref_metadata_2025_split huggingface dataset:
Triple-Negative Breast Cancer: An Unmet Medical Need
Authors: Hudis Clifford A. , Gianni Luca 
Published: January 2011

Abstract
Triple-negative breast cancer, characterized by tumors that do not express estrogen receptor (ER), progesterone receptor (PR), or HER-2 genes, represents an important clinical challenge because these cancers do not respond to endocrine therapy or other available targeted agents. The metastatic potential in triple-negative breast cancer is similar to that of other breast cancer subtypes, but these tumors are associated with a shorter median time to relapse and death. One important goal is therefore the identification of prognostic factors and markers to reliably select high and low risk subsets of patients with triple-negative disease for different treatment approaches of subtypes with differential responsiveness to specific agents. However, a reliable prognostic marker has been elusive, and markers have been inconsistently useful. For example, epidermal growth factor receptor (EGFR) has been studied, but there is still a lack of agreement on a standard assay or cutoff for EGFR expression levels with respect to prognosis. Similarly, because triple-negative status is sometimes used as a surrogate for basal-like breast cancer, specific basal markers have been explored. Indeed, trials designed to accrue patients with basal-like breast cancer using ER/PR and HER-2 negativity may provide only an approximation of the triple-negative population and are sometimes reanalyzed using more specific indicators like CK 5/6, EGFR status, and others, again marred by discordances. Chemotherapy remains the mainstay of treatment of triple-negative breast cancer, but important limitations still need to be overcome in the next few years if any significant clinical strides are to be made. Current treatment strategies for triple-negative disease include anthracyclines, taxanes, ixabepilone, platinum agents, and biologic agents. More recently, EGFR inhibition has been proposed as a therapeutic mechanism in triple-negative breast cancer, again with mixed results. Agents that target poly(ADP-ribose) polymerase and androgen receptors have also been proposed in these patients or subsets of them, and ongoing trials should result in definitive guidance with respect to the value of these agents in triple-negative disease.
Triple-negative breast cancer is clearly a distinct clinical subtype, from the perspective of both ER and HER-2 expression, but further subclassification is needed. At present, there is not a clear, proven effective single agent that targets a defining vulnerability in triple-negative breast cancer. This article will review the clinical problem of triple-negative disease, potential prognostic factors, demonstrated efficacy of currently available therapeutic options, and new potential therapies.
Targeting the Phosphoinositide-3 (PI3) Kinase Pathway in Breast Cancer
Authors: Baselga José 
Published: January 2011

AbstractThe phosphoinositide-3 kinase (PI3K) pathway has been identified as an important target in breast cancer research for a number of years, but is new to most clinicians responsible for the daily challenges of breast cancer management. In fact, the PI3K pathway is probably one of the most important pathways in cancer metabolism and growth. Mutations in the PI3K pathway are frequent in breast cancer, causing resistance to human epidermal growth factor receptor 2–targeted agents and, possibly, to hormonal agents as well. Available agents that affect the PI3K pathway include monoclonal antibodies and tyrosine kinase inhibitors, as well as PI3K inhibitors, Akt inhibitors, rapamycin analogs, and mammalian target of rapamycin (mTOR) catalytic inhibitors. Multiple PI3K inhibitors are currently under development, including pure PI3K inhibitors, compounds that block both PI3K and mTOR (dual inhibitors), pure catalytic mTOR inhibitors, and inhibitors that block Akt. It is likely that these agents will have to be given in combination with other signal inhibitors because anti-mTOR agents and PI3K inhibitors may result in the activation of compensatory feedback loops that would in turn result in decreased efficacy. This article reviews current data related to the PI3K pathway, its role in breast cancer, the frequency with which PI3K is aberrant in breast cancer, and the potential clinical implications of using agents that target the PI3K pathway.
Breast Cancer Management: Opportunities and Barriers to an Individualized Approach
Authors: Perez Edith A. 
Published: January 2011

Abstract
A personalized approach to breast cancer management is increasingly possible with state of the art diagnostics and treatments. However, many challenges still exist in choosing the right therapeutic strategy and the right dosing for a specific patient population. Biomarkers such as estrogen receptor, progesterone receptor, and HER-2 status are used to tailor therapy, but success rates with targeted therapy suggest that appropriate patient populations still require greater definition. The introduction of the genomic era has likewise advanced the ability to offer a tailored approach to breast cancer management, but much work is still needed in this area as well. Microarray-based gene expression profiles have demonstrated initial promise, but we need a better understanding of more complex tumor signaling pathways. Strategies include annotated tumor specimens, next-generation gene sequencing, proteomics, and metabolomics. An individualized approach to breast cancer management has the potential to offer clear clinical benefits and the ability to bring more tailored, cost-effective strategies to the market. The current issues facing the delivery of individualized breast cancer care will be the focus of this discussion.
The Biological Framework: Translational Research from Bench to Clinic
Authors: Yarden Yosef 
Published: January 2011

Abstract
The understanding of cellular signaling pathways in malignant tumors is an important aspect of cancer research and modern targeted therapy strategies. Growth factors and their receptors in particular are critical to modern cancer therapy research, because these factors control all phases of tumor development and metastasis. Most importantly, growth factors are responsible for cell survival under cytotoxic drugs and radiotherapy. These growth factor signaling pathways are composed of complex networks that have adapted to efficiently respond to certain disturbances, such as a single agent that targets one aspect of the pathway. Meanwhile, multiple insults to the pathway, such as combination therapy regimens, are known to be effective in shutting down these pathways and, consequently, killing the tumor cell. Research is currently under way to find new ways to exploit fragile aspects of oncogenic networks, such as uncommon, multiple perturbations that target essential hubs through immunotherapy, combinations of antibodies, heat shock protein inhibitors, or novel drug combinations. Complex growth factor signaling networks and novel methods to shut down these networks are described within a framework of engineering and mathematical concepts.
Chemotherapy: Updates and New Perspectives
Authors: Swain Sandra M. 
Published: January 2011

Abstract
Treatment options for patients with breast cancer have progressively improved over the past 40 years, from an era of no chemotherapy to the introduction of taxanes, hormonal therapy, and biologic therapy. These advances have resulted in substantial, 15%–20% improvements in clinical outcomes. However, progress has yet to be made to improve the prognosis in many breast cancer patients, and research is currently under way to test new tools, or new applications of older tools, to advance breast cancer management. Chemotherapy clearly remains a cornerstone of adjuvant breast cancer treatment, because breast cancer can be very sensitive to the currently available agents. Meanwhile, the era of a one-size-fits-all approach to breast cancer management is over, and the maximum potential of chemotherapy should now be reached by targeting specific populations. Effective biomarkers are therefore needed to optimize chemotherapy, define more selective populations, and clearly tailor treatment. This paper discusses recent data, including new trials that are more fully incorporating current knowledge with respect to molecular markers and the underlying biology of breast cancer.
New Developments in Hormone Receptor–Positive Disease
Authors: Piccart-Gebhart Martine J. 
Published: January 2011

AbstractOf more than one million women diagnosed with breast cancer each year, approximately 700,000 have hormone receptor (HR)+ disease. Although endocrine therapy has revolutionized breast cancer management and substantially improved outcomes in these patients, the optimal management of these patients remains a significant challenge. For instance, the threshold for adding adjuvant chemotherapy is a topic of continuing debate, and the most effective regimens that include endocrine therapy and chemotherapy are still under debate as well. Tumor markers, such as Ki-67, and host markers, such as cytochrome P450 2D6, are being studied as potential tools to offer more tailored adjuvant endocrine therapy. Current research suggests that luminal A and luminal B cancers are two completely different diseases, and work is being performed to better distinguish between these two disease types and deliver more effective therapy to individual patients. This article addresses these important outstanding issues with respect to HR+ disease.
A New Look at Node-Negative Breast Cancer
Authors: Harbeck Nadia , Thomssen Christoph 
Published: January 2011

Abstract
Node-negative breast cancer is a prevalent form of the disease worldwide, particularly in regions with rigorous screening and disease awareness efforts. Although there is a common biology between node-negative and node-positive breast tumors, it is still important to specifically address risk assessment and predictive factors in node-negative breast cancer. The relative risks and benefits are more pronounced in these patients, but there is no single prognostic factor available for deciding whether to administer chemotherapy and selecting the best adjuvant chemotherapy regimen. In the absence of universal predictive factors, the trend is to give chemotherapy to all patients to ensure the highest possibility for cure. Tumor grade is important in that it is predictive of risk over time, but lacks standardization. Adjuvant! Online, a web-based algorithm, is also used to guide treatment decisions. Recently, the urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (PAI-1) biomarkers have been used to determine disease risk and, consequently, determine whether or not chemotherapy is needed. However, the assay requires a fresh-frozen tissue sample, which is not always feasible. The oncotype DX® genomic assay has also been used to help prognosis estimation and treatment decisions. It is currently under evaluation in conjunction with the uPA/PAI-1 assay in the Plan B trial. The question that remains in adjuvant chemotherapy today for patients with node-negative disease is proper patient selection. Node-negative breast cancer does not automatically suggest a good prognosis, or the preclusion of chemotherapy benefits, and additional biomarkers are needed to help identify patients who do benefit from chemotherapy.
Molecular Stratification of Triple-Negative Breast Cancers
Authors: Perou Charles M. 
Published: January 2011

Abstract
Research focused on the analysis and classification of breast tumors, primarily using DNA microarrays and patterns of gene expression, has resulted in distinct tumor subtypes. Although no knowledge of patient survival or outcomes was used to derive these gene descriptions, these different classes based upon patterns of gene expression have important prognostic implications. Predictive markers in estrogen receptor–negative and triple-negative disease will be particularly important because in the absence of therapy, these tumor subtypes tend to have a poor prognosis. In addition, the claudin-low subgroup has been found to be common within the triple-negative cancers and may have further prognostic and therapeutic implications. Patients with triple-negative breast cancer do benefit from chemotherapy, but better treatment options are needed that are less toxic, reduce the risk of disease progression, and are more targeted to this patient population. Potential treatments include poly (ADP-ribose) polymerase inhibitors, and therapies that target cancer stem cells could also have an important impact in these patients. This article will focus on the molecular stratification of triple-negative breast cancers and the therapeutic implications of these classifications.
Directed Therapy of Subtypes of Triple-Negative Breast Cancer
Authors: Carey Lisa A. 
Published: January 2011

Abstract
In developed countries, there has been a remarkable improvement in mortality from breast cancer, but almost all of that benefit has occurred in the estrogen receptor (ER)+ and human epidermal growth factor receptor (HER)-2+ subsets. Triple-negative breast cancer, defined as tumors that are negative for ER, progesterone receptor, and HER-2, represent a minority of breast cancers. However, because of the poor prognosis in this particular subtype, triple-negative disease accounts for a disproportionate number of metastatic cases and breast cancer deaths. While chemotherapy is effective in triple-negative disease, research continues to better target therapies and predict prognosis. Recent studies have suggested a link between BRCA mutations and triple-negative disease, but the nature of this link remains opaque. Antiangiogenic agents such as bevacizumab have demonstrated efficacy across subtypes. More recently, poly(ADP-ribose) polymerase inhibitors appear to take advantage of the concept of synthetic lethality, or dual pathway inhibition, in attacking triple-negative and BRCA-associated tumors. These and other studies in triple-negative disease will help us to better identify effective treatment options and improve outcomes in these patients. This article addresses the nature of, and therapeutic strategies for, triple-negative breast cancer.
Coming of Age: Breast Cancer in Seniors
Authors: Muss Hyman B. 
Published: January 2011

Abstract
In the U.S., cancer is a disease of aging. The average 65-year-old patient has an anticipated life expectancy of 20 years, and clinicians should take this into account when making breast cancer management decisions. However, older breast cancer patients can present with wide variations in health status, and treatment in older patients should therefore include a careful evaluation of comorbidities, physical function, polypharmacy, and other issues that could potentially impact a patient's ability to undergo chemotherapy without excessive risk. Evaluation tools are under development, including potential molecular markers, to identify which older patients are the best candidates for chemotherapy, as well as those more susceptible to actually developing cancer. Standard chemotherapy regimens are just as effective in older patients as they are in the younger population, and can substantially prolong life expectancy when used in the right patients. This article discusses breast cancer in seniors, including the epidemiology of breast cancer in these patients, the potential impact of comorbidities, and effective adjuvant therapy in selected older patients.
RIG-I– and MDA5-Initiated Innate Immunity Linked With Adaptive Immunity Accelerates β-Cell Death in Fulminant Type 1 Diabetes
Authors: Aida Kaoru , Nishida Yoriko , Tanaka Shoichiro , Maruyama Taro , Shimada Akira , Awata Takuya , Suzuki Masako , Shimura Hiroki , Takizawa Soichi , Ichijo Masashi , Akiyama Daiichiro , Furuya Fumihiko , Kawaguchi Akio , Kaneshige Masahiro , Itakura Jun , Fujii Hideki , Endo Toyoshi , Kobayashi Tetsuro 
Published: February 2011

OBJECTIVE
The contribution of innate immunity responsible for aggressive β-cell destruction in human fulminant type 1 diabetes is unclear.

RESEARCH DESIGN AND METHODS
Islet cell expression of Toll-like receptors (TLRs), cytoplasmic retinoic acid–inducible gene I (RIG-I)-like receptors, downstream innate immune markers, adaptive immune mediators, and apoptotic markers was studied in three autopsied pancreata obtained 2 to 5 days after onset of fulminant type 1 diabetes.

RESULTS
RIG-I was strongly expressed in β-cells in all three pancreata infected with enterovirus. Melanoma differentiation–associated gene-5 was hyperexpressed in islet cells, including β- and α-cells. TLR3 and TLR4 were expressed in mononuclear cells that infiltrated islets. Interferon (IFN)-α and IFN-β were strongly expressed in islet cells. Major histocompatibility complex (MHC)-class I, IFN-γ, interleukin-18, and CXC motif ligand 10 were expressed and colocalized in affected islets. CD11c+ MHC-class II+ dendritic cells and macrophage subsets infiltrated most islets and showed remarkable features of phagocytosis of islet cell debris. CD4+ forkhead box P3+ regulatory T cells were not observed in and around the affected islets. Mononuclear cells expressed the Fas ligand and infiltrated most Fas-expressing islets. Retinoic acid–receptor responder 3 and activated caspases 8, 9, and 3 were preferentially expressed in β-cells. Serum levels of IFN-γ were markedly increased in patients with fulminant type 1 diabetes.

CONCLUSIONS
These findings demonstrate the presence of specific innate immune responses to enterovirus infection connected with enhanced adoptive immune pathways responsible for aggressive β-cell toxicity in fulminant type 1 diabetes.
Role of Thrombin in Chronic Rhinosinusitis–associated Tissue Remodeling
Authors: Shimizu Shino , Gabazza Esteban C. , Ogawa Takao , Tojima Ichiro , Hoshi Eriko , Kouzaki Hideaki , Shimizu Takeshi 
Published: January 2011

Background Thrombin, the effector enzyme of the coagulation system, has been reported to promote inflammatory responses in nasal diseases through its protease-activated receptors (PARs). Chronic rhinosinusitis (CRS) is characterized by increased deposition of extracellular matrix proteins, tissue remodeling, and formation of nasal polyps. The role of thrombin in chronic nasal inflammation–associated tissue remodeling still has not been appraised. This study was conducted to elucidate the role of thrombin in the pathogenesis of CRS. Methods Nasal secretion was collected from patients with CRS with nasal polyp (CRSwNP) with asthma (n = 9), CRSwNP without asthma (n = 10), allergic rhinitis (n = 7), and control patients (n = 3). The concentrations of thrombin, thrombin–antithrombin (TAT) complex, and vascular endothelial growth factor (VEGF) were evaluated by enzyme immunoassays. The concentration of thrombin and TAT complex was measured in nasal secretion from each group of patients, and VEGF was measured in culture medium from airway epithelial cells treated with thrombin or thrombin receptor agonist peptide. Results Thrombin and TAT complex were significantly increased in nasal secretion of patients with CRSwNPs with asthma compared with the control group. Thrombin and PAR-1 agonist peptide significantly stimulated VEGF secretion from cultured human airway epithelial cells. Conclusion The results of this study showed that there is increased activation of the coagulation system in the nasal mucosa of CRS patients and that thrombin may play a role in nasal polyp formation by stimulating VEGF production from airway epithelial cells.
Nasal Growth after Pediatric Septoplasty at Long-term Follow-up
Authors: Tasca Ignazio , Compadretti Giacomo Ceroni 
Published: January 2011

Background Septoplasty in children is still a matter of open discussion, because it is thought that a surgical procedure on a developing structure might produce some adverse effects on normal nasal growth. The goal of this retrospective study is to evaluate the effects of pediatric nasal septum surgery in a long-term follow-up by anthropometry. Methods Forty-four Italian patients, 25 male patients and 19 female patients, who had undergone septoplasty during childhood using the endonasal approach, were reassessed after a mean follow-up of 12.2 years. Anthropometric recordings were used to identify any growth retardation due to the operation by a comparison with previously published age-specific normative data of North American white subjects. Nasal measurements consisted of five linear parameters, three angular parameters, and three proportional index. Results There were no significant differences in any of the measures between the sample and controls (p > 0.1) with regard to gender, with the exception of the nasolabial angle measurement. Indeed, the nasolabial angle of the female patients was significantly reduced compared with controls (p = 0.04), whereas that of the male patients was reduced compared with controls (p = 0.08). This measurement seems to be influenced by the type of operation, because it has been noted that the nasolabial angle of patients treated surgically by extracorporeal septoplasty were significantly lower than those of patients treated surgically by conservative septoplasty. Conclusion Pediatric septoplasty may be indicated in selected cases of obstructing nasal septum deformities. The operation, performed via endonasal approach, does not interfere with the normal growing nasal process.
Endoscopically Guided Chitosan Nasal Packing for Intractable Epistaxis
Authors: Shikani Alan H. , Chahine Karim A. , Alqudah Mohannad A. 
Published: January 2011

Background The purpose of this study was to evaluate the effectiveness and safety of endoscopically guided chitosan packing in controlling intractable epistaxis. A prospective case series was performed. Methods This is a prospective clinical study conducted in a tertiary rhinology fellowship training hospital between January 2009 and November 2009. The study population consisted of patients with intractable epistaxis that failed to respond to traditional anterior–posterior nasal packing using either a 10-cm Pope PVA Merocel or a Rapid-Rhino. The bleeding site was identified using a nasal endoscope and controlled using a pack made of a ChitoFlex chitosan dressing wrapped around a polyvinyl acetal nasal sponge. Results The intent-to-treat population consisted of 20 severe epistaxis subjects (8 men and 12 women) who continued to bleed despite traditional anterior–posterior nasal packing. The mean age was 67 years (±19 years). Sixteen subjects were on antiplatelets and/or anticoagulants. Eleven subjects (55%) presented with anterior epistaxis, and 7 subjects (35%) presented with posterior epistaxis. Chitosan nasal packing was performed on an outpatient basis and resulted in effective and immediate hemostasis in 19/20 subjects (95%). One subject had persistent bleeding after the first packing attempt and was successfully repacked within 30 minutes. Time to complete cessation of bleeding was 3.6 ± 2.2 minutes in the 19 subjects; the pack was removed after 48 hours, without any evidence of rebleeding or any serious side effects. Conclusion Endoscopically guided chitosan packing is a safe, effective, and well-tolerated outpatient treatment for the management of intractable epistaxis.