The Least Mating Pathway: Synthetically Refactoring a Familiar Signaling System for New Applications.

Synthetic refactoring makes naturally occurring regulatory systems more amenable to manipulation by removing or recoding their natural genetic complexity. Shaw et al. apply this technique to the yeast mating response pathway, creating a simplified, highly engineerable signaling module that can be used to construct precisely optimized, application-specific GPCR biosensors.

Association of Patient and Tumor Characteristics With Outcomes in Young Head and Neck Squamous Cell Carcinoma Patients.

INTRODUCTION: We retrospectively studied young patients with head and neck squamous cell carcinoma (HNSCC) to identify factors associated with disease-specific survival (DSS). METHODS: Patient and tumor characteristics of patients aged ≤45 who received treatments for non-metastatic HNSCC were collected to identify factors associated with DSS. Proportional hazards regression was applied separately for surgical and non-surgical patients. RESULTS: 230 patients were included. Surgical and non-surgical patients had similar DSS. Higher pathologic stages, positive margins, perineural invasion (PNI), extranodal extension and negative HPV status were associated with worse DSS for surgical patients and negative HPV status for non-surgical patients. In the multivariate analysis, pathologic stages, positive margins, and PNI were associated with worse DSS in surgical patients. CONCLUSION: Pathologic stages, positive margins, and PNI are independently associated with worse DSS in young surgical HNSCC patients. PNI is a uniquely strong prognostic factor for young patients.

Lifelong Aspirin for All in the Secondary Prevention of Chronic Coronary Syndrome: Still Sacrosanct or Is Reappraisal Warranted?

Four decades have passed since the first trial suggesting the efficacy of aspirin in the secondary prevention of myocardial infarction. Further trials, collectively summarized by the Antithrombotic Trialists' Collaboration, solidified the historical role of aspirin in secondary prevention. Although the benefit of aspirin in the immediate phase after a myocardial infarction remains incontrovertible, a number of emerging lines of evidence, discussed in this narrative review, raise some uncertainty as to the primacy of aspirin for the lifelong management of all patients with chronic coronary syndrome (CCS). For example, data challenging the previously unquestioned role of aspirin in CCS have come from recent trials where aspirin was discontinued in specific clinical scenarios, including early discontinuation of the aspirin component of dual antiplatelet therapy after percutaneous coronary intervention and the withholding of aspirin among patients with both CCS and atrial fibrillation who require anticoagulation. Recent primary prevention trials have also failed to consistently demonstrate net benefit for aspirin in patients treated to optimal contemporary cardiovascular risk factor targets, indicating that the efficacy of aspirin for secondary prevention of CCS may similarly have changed with the addition of more modern secondary prevention therapies. The totality of recent evidence supports further study of the universal need for lifelong aspirin in secondary prevention for all adults with CCS, particularly in stable older patients who are at highest risk for aspirin-induced bleeding.

Characteristics of long-term survivors with multiple myeloma: A National Cancer Data Base analysis.

BACKGROUND: There exist insufficient data characterizing patients with multiple myeloma (MM) who experienced prolonged survival. A population-based analysis of long-term survivors was conducted to investigate the roles of sociodemographic factors and upfront stem cell transplantation (SCT). METHODS: The National Cancer Data Base is a US cancer database of approximately 34 million patients from >1500 cancer centers. Patients with MM were identified using the International Classification of Diseases for Oncology (ICD-O) code 9732 from January 2004 to December 2006 and were divided into 4 groups based on overall survival (OS). Sociodemographic characteristics, treatment facility, and use of SCT were recorded. The univariate and multivariate analyses were performed using multiple logistic regression and Pearson chi-square tests. RESULTS: A total of 26,986 patients with MM were identified. The median OS was 2.74 years. The majority of patients were male (54%), white (77%), insured (93%) and otherwise healthy (78%), lived in a metropolitan area (82%), were of high income (66%) and educational (58%) levels, and received treatment at nonacademic facilities (63%). Upfront SCT was used in 10% of patients. One in 6 patients (16%) were long-term survivors (group 4). When comparing group 4 (OS of ≥8.22 years) with the other groups (OS of <8.22 years), young age, female sex, high income and educational levels, residence in a rural area, insured status, no comorbidity, receipt of upfront SCT, and treatment at high-volume facilities were associated with long-term survival. CONCLUSIONS: Key differences in sociodemographic characteristics, patient volume at treatment facilities, and upfront SCT were associated with long-term survival. Improvements in health care access and health literacy, upfront SCT, and treatment at high-volume facilities might prolong patient survival.

Short-course versus long-course antibiotics in prosthetic joint infections: a systematic review and meta-analysis of one randomized controlled trial plus nine observational studies.

BACKGROUND: Prosthetic joint infections (PJIs) often require long-course antibiotic therapy. However, recent studies argue against the current practice and raise concerns such as the development of antibiotic resistance, side effects of medications and medical costs. OBJECTIVES: To review and compare the outcomes of short-course and long-course antibiotics in PJIs. METHODS: We conducted a systemic review and meta-analysis using a predefined search term in PubMed and EMBASE databases. Studies that met the inclusion criteria from inception to June 2018 were included. The quality of the included studies was assessed. RESULTS: A total of 10 articles and 856 patients were analysed, comprising 9 observational studies and 1 randomized controlled trial. Our meta-analysis showed no significant difference between short-course and long-course antibiotics (relative risk = 0.87, 95% CI = 0.62-1.22). Additionally, the older the studied group was, the more short-course antibiotics were favoured. CONCLUSIONS: When treating PJI patients following debridement, antibiotics and implant retention, an 8 week course of antibiotic therapy for total hip arthroplasty and a 75 day course for total knee arthroplasty may be a safe approach. For two-stage exchange, a shorter duration of antibiotic treatment during implant-free periods is also generally safe with the usage of antibiotic-loaded cement spacers.

Public knowledge and understanding of dementia-evidence from a national survey in Ireland.

Background: there is growing consensus around the importance of population level approaches which seek to improve public knowledge and awareness of dementia. Aim: to assess knowledge of the relationship between dementia and ageing, and of the risk and protective factors associated with it, among the general public in Ireland. Design: cross-sectional survey. Participants selected using quota sampling based on Census data. Methods: the final sample of 1,217 respondents provided estimates of dementia knowledge in the Irish population. Logistic regression was used to assess the impact of potential predictor variables on knowledge of dementia. Results: a majority (52%) reported that they knew someone living with dementia. Just 39% were confident that they could tell the difference between the early signs of dementia and normal ageing. Less than half (46%) believed that there were things they could do to reduce their risk of developing dementia, and knowledge of risk and protective factors for dementia was very poor. Although significant differences were seen according to area of residence, social class and experience of dementia, even those groups with 'better' understanding demonstrated substantial knowledge deficits regarding risk and protective factors. Conclusions: the general public in Ireland are confused about the relationship between dementia and ageing, and knowledge of risk and protective factors for dementia is very poor. While not dissimilar to those reported internationally, the findings present a challenge to those tasked with promoting behaviour change and interventions to delay or prevent the onset of dementia.

Hyaluronan Hydrogels for a Biomimetic Spongiosa Layer of Tissue Engineered Heart Valve Scaffolds.

Advanced tissue engineered heart valves must be constructed from multiple materials to better mimic the heterogeneity found in the native valve. The trilayered structure of aortic valves provides the ability to open and close consistently over a full human lifetime, with each layer performing specific mechanical functions. The middle spongiosa layer consists primarily of proteoglycans and glycosaminoglycans, providing lubrication and dampening functions as the valve leaflet flexes open and closed. In this study, hyaluronan hydrogels were tuned to perform the mechanical functions of the spongiosa layer, provide a biomimetic scaffold in which valve cells were encapsulated in 3D for tissue engineering applications, and gain insight into how valve cells maintain hyaluronan homeostasis within heart valves. Expression of the HAS1 isoform of hyaluronan synthase was significantly higher in hyaluronan hydrogels compared to blank-slate poly(ethylene glycol) diacrylate (PEGDA) hydrogels. Hyaluronidase and matrix metalloproteinase enzyme activity was similar between hyaluronan and PEGDA hydrogels, even though these scaffold materials were each specifically susceptible to degradation by different enzyme types. KIAA1199 was expressed by valve cells and may play a role in the regulation of hyaluronan in heart valves. Cross-linked hyaluronan hydrogels maintained healthy phenotype of valve cells in 3D culture and were tuned to approximate the mechanical properties of the valve spongiosa layer. Therefore, hyaluronan can be used as an appropriate material for the spongiosa layer of a proposed laminate tissue engineered heart valve scaffold.

An integrated mechanical degradation model to explore the mechanical response of a bioresorbable polymeric scaffold.

Simulation of bioresorbable medical devices is hindered by the limitations of current material models. Useful simulations require that both the short- and long-term response must be considered; existing models are not physically-based and provide limited insight to guide performance improvements. This study presents an integrated degradation framework which couples a physically-based degradation model, which predicts changes in both crystallinity (Xc) and molecular weight (Mn), with the results of a micromechanical model, which predicts the effective properties of the semicrystalline polymer. This degradation framework is used to simulate the deployment of a bioresorbable PLLA (Poly (L-lactide) stent into a mock vessel and the subsequent mechanical response during degradation under different diffusion boundary conditions representing neointimal growth. A workflow is established in a commercial finite element code that couples both the immediate and long-term responses. Clinically relevant lumen loss is reported and used to compare different responses and the effect of neo-intimal tissue regrowth post-implantation on degradation and on the mechanical response is assessed. In addition, the effects of possible changes in Xc, which could occur during processing and stent deployment, are explored.

Experimental and computational investigation of the role of stress fiber contractility in the resistance of osteoblasts to compression.

The mechanical behavior of the actin cytoskeleton has previously been investigated using both experimental and computational techniques. However, these investigations have not elucidated the role the cytoskeleton plays in the compression resistance of cells. The present study combines experimental compression techniques with active modeling of the cell's actin cytoskeleton. A modified atomic force microscope is used to perform whole cell compression of osteoblasts. Compression tests are also performed on cells following the inhibition of the cell actin cytoskeleton using cytochalasin-D. An active bio-chemo-mechanical model is employed to predict the active remodeling of the actin cytoskeleton. The model incorporates the myosin driven contractility of stress fibers via a muscle-like constitutive law. The passive mechanical properties, in parallel with active stress fiber contractility parameters, are determined for osteoblasts. Simulations reveal that the computational framework is capable of predicting changes in cell morphology and increased resistance to cell compression due to the contractility of the actin cytoskeleton. It is demonstrated that osteoblasts are highly contractile and that significant changes to the cell and nucleus geometries occur when stress fiber contractility is removed.

The effect of opioids on the efficacy of immunotherapy in recurrent/metastatic squamous cell carcinoma of the head and neck.

OBJECTIVES: Head and neck squamous cell carcinoma (HNSCC) causes severe pain and opioids, the mainstay of pain management, may have immunomodulatory effects. We evaluated the effect of opioids on immunotherapy efficacy in recurrent/metastatic (R/M) HNSCC patients. MATERIALS AND METHODS: In a retrospective study of 66 R/M HNSCC patients from 2015 to 2020, opioid dosage, calculated as mean morphine milligram equivalent per day, was assessed on the day of anti-PD-1 monoclonal antibody (mAb) treatment and most recent prior visit. Intratumoral T cells were evaluated by single cell RNAseq and immunohistochemistry prior to treatment. Univariable and multivariable Cox proportional hazards and logistic regression models were used to estimate the association between opioid usage, progression-free survival (PFS), overall survival (OS), disease control rate. RESULTS: Patients were 79% male, 35% oropharynx, 35% oral cavity, 40% locoregional recurrence, and 56% platinum failure. Higher opioid dosage by continuous variable was significantly associated with lower PFS (p = 0.016) and OS (p < 0.001). In multivariable analysis, including platinum failure status and PD-L1, higher opioids were associated with lower OS. Opioid usage by categorical variable was associated with significantly lower intratumoral CD8+ T cells. Opioid receptor, OPRM1, expression was identified in intratumoral and circulating T cells. CONCLUSIONS: In our study cohort of anti-PD-1 mAb treatment in R/M HNSCC patients, higher opioids were associated with significantly lower PFS and OS and lower CD8+ T cells in the tumor microenvironment. To our knowledge, this is the first analysis in R/M HNSCC patients and further research into the clinical and biologic effect of opioids is warranted.

Ultra-high throughput mapping of genetic design space.

Massively parallel genetic screens have been used to map sequence-to-function relationships for a variety of genetic elements. However, because these approaches only interrogate short sequences, it remains challenging to perform high throughput (HT) assays on constructs containing combinations of sequence elements arranged across multi-kb length scales. Overcoming this barrier could accelerate synthetic biology; by screening diverse gene circuit designs, "composition-to-function" mappings could be created that reveal genetic part composability rules and enable rapid identification of behavior-optimized variants. Here, we introduce CLASSIC, a generalizable genetic screening platform that combines long- and short-read next-generation sequencing (NGS) modalities to quantitatively assess pooled libraries of DNA constructs of arbitrary length. We show that CLASSIC can measure expression profiles of >10 5 drug-inducible gene circuit designs (ranging from 6-9 kb) in a single experiment in human cells. Using statistical inference and machine learning (ML) approaches, we demonstrate that data obtained with CLASSIC enables predictive modeling of an entire circuit design landscape, offering critical insight into underlying design principles. Our work shows that by expanding the throughput and understanding gained with each design-build-test-learn (DBTL) cycle, CLASSIC dramatically augments the pace and scale of synthetic biology and establishes an experimental basis for data-driven design of complex genetic systems.

Locoregional recurrence after breast cancer surgery: a systematic review by receptor phenotype.

Molecular subtyping confirms that breast cancer comprises at least four genetically distinct entities based on the expression of specific genes including estrogen receptor (ER), progesterone receptor (PR), and HER2/neu receptor. The quantitative influence of subtype on ipsilateral locoregional recurrence (LRR) is unknown. The aim of this study was to systematically appraise the influence of breast cancer subtype on LRR following breast conserving therapy (BCT) and mastectomy. A comprehensive search for studies examining outcomes after BCT and/or mastectomy according to breast cancer subtype was performed using Medline and cross-referencing available data. Reviews of each study were conducted and data extracted to perform meta-analysis. Primary outcome was LRR related to breast cancer subtype. A total of 12,592 breast cancer patients who underwent either BCT (n = 7,174) or mastectomy (n = 5,418) were identified from 15 studies. Patients with luminal subtype tumors (ER/PR +ve) had a lower risk of LRR than both triple-negative (RR 0.38; 95% CI 0.23-0.61); and HER2/neu-overexpressing (RR 0.34; 95% CI 0.26-0.45) tumors following BCT. Luminal tumors were also less likely to develop LRR than HER2/neu-overexpressing (OR 0.69; 95% CI 0.54-0.89) or triple-negative tumors (OR 0.61; 95% CI 0.46-0.79) after mastectomy. HER2/neu-overexpressing tumors have increased risk of LRR compared to triple-negative tumors (RR 1.44; 95% CI 1.06-1.95) following BCT but there was no difference in LRR between HER2/neu-overexpressing and triple-negative tumors following mastectomy (RR 0.91; 95% CI 0.68-1.22). Luminal tumors exhibit the lowest rates of LRR. Patients with triple-negative and HER2/neu-overexpressing breast tumors are at increased risk of developing LRR following BCT or mastectomy. Breast cancer subtype should be taken into account when considering local control and identifies those at increased risk of LRR, who may benefit from more aggressive local treatment.

TOP2A amplification in the absence of that of HER-2/neu: toward individualization of chemotherapeutic practice in breast cancer.

PRIMARY OBJECTIVE: To investigate the relationship between human epidermal growth factor receptor (HER)-2/neu and the gene encoding topoisomerase IIα (TOP2A) in breast cancer, while elucidating their association with clinicopathological variables. METHODS: Real-time quantitative polymerase chain reaction (RQ-PCR) was performed on a 96-patient study group to assess gene amplification, and levels were determined using the comparative cycle threshold approach and Taqman assays. An immunohistochemistry (IHC) microarray (n = 76) was then employed to check for correlation between gene amplification and protein expression levels. RESULTS: Amplification levels of TOP2A did not differ significantly according to HER-2/neu status by either RQ-PCR or IHC microarray. Of the HER-2/neu(-) patients, 29.1% demonstrated levels of TOP2A above the third quartile, whereas 22.9% of the HER-2/neu(+) patients had values in the first quartile (log TOP2A <0.62), thereby indicating low-level amplification. Of the 60 patients characterized as HER-2/neu(-) using IHC and fluorescence in situ hybridization (FISH), 22.9% were classified as TOP2A(+) on the IHC microarray. Of the 14 patients deemed HER-2/neu(+) using IHC and FISH, meanwhile, the majority (n = 10) were classified as TOP2A(+). CONCLUSIONS: Our results indicate that amplification of TOP2A in breast cancer is not confined to those who are concomitantly HER-2/neu(+), and suggest that a significant proportion of HER-2/neu(-) patients exhibit high levels of TOP2A.

The effect of breast cancer awareness month on internet search activity--a comparison with awareness campaigns for lung and prostate cancer.

BACKGROUND: This work aimed to assess the effects of the annual breast cancer awareness campaign on internet search activity, and to compare these effects with those of similar campaigns in prostate and lung cancer. We further aimed to assess overall levels of online activity relating to all three neoplasms between 2004 and 2009. METHODS: Google Insights for Search was employed to examine search trends for the term "breast cancer", across all Google domains between January 2004 and December 2009 (6 years). Search trends for both "prostate cancer" and "lung cancer" across all domains were also analysed for the same period, and these trends were compared with those for "breast cancer". Repeated measures ANOVA and Tukey post-hoc analyses were performed to assess for significant differences in activity. RESULTS: Increased levels of online activity relating to breast cancer are consistently generated each October. There is a significantly higher level of background activity in breast cancer compared with that in lung or prostate cancer (p < 0.001), and the October campaign stimulates online activity more effectively than equivalent campaigns for these other malignancies (p < 0.001). CONCLUSIONS: The annual breast cancer awareness campaign is proving effective in stimulating online activity and may hold useful lessons for other cancer awareness initiatives.

Younger age as a prognostic indicator in breast cancer: a cohort study.

BACKGROUND: The debate continues as to whether younger women who present with breast cancer have a more aggressive form of disease and a worse prognosis. The objectives of this study were to determine the incidence of breast cancer in women under 40 years old and to analyse the clinicopathological characteristics and outcome compared to an older patient cohort. METHODS: Data was acquired from a review of charts and the prospectively reviewed GUH Department of Surgery database. Included in the study were 276 women diagnosed with breast cancer under the age of forty and 2869 women over forty. For survival analysis each women less than 40 was matched with two women over forty for both disease stage and grade. RESULTS: The proportion of women diagnosed with breast cancer under the age of forty in our cohort was 8.8%. In comparison to their older counterparts, those under forty had a higher tumour grade (p = 0.044) and stage (p = 0.046), a lower incidence of lobular tumours (p < 0.001), higher estrogen receptor negativity (p < 0.001) and higher HER2 over-expression (p = 0.002); there was no statistical difference as regards tumour size (p = 0.477). There was no significant difference in overall survival (OS) for both groups; and factors like tumour size (p = 0.026), invasion (p = 0.026) and histological type (p = 0.027), PR (p = 0.031) and HER2 (p = 0.002) status and treatment received were independent predictors of OS CONCLUSION: Breast cancer in younger women has distinct histopathological characteristics; however, this does not result in a reduced survival in this population.

Interns' attitudes to IV cannulation: a KAP study.

UNLABELLED: One of the most common procedures for junior medical doctors is peripheral intravenous cannulation (PIVC). Considering this, an understanding of the peripheral intravenous cannulation procedure is paramount. AIM: The objective of this study was to identify the level of understanding of interns regarding intravenous cannulation. METHOD: An anonymized structured questionnaire using a knowledge attitude and practices (KAP) format was distributed to 60 interns affiliated to a university college hospital in Ireland. FINDINGS: This study suggests that interns are poorly prepared for one of the most common clinical skills they will perform. They showed poor understanding of whether peripheral cannulation is a clean or aseptic technique, and lacked knowledge of the potential side effects of peripheral cannulation and IV therapy. RECOMMENDATIONS: A structured learning module on peripheral intravenous cannulation is required. A rigid, evidence-based, Objective Structured Clinical Examination (OSCE) on peripheral cannulation is recommended. The reduction of junior doctors' weekly working hours to 48 under the European Working Time Directive offers the potential for nurses to take ownership of IV cannulation. This will allow junior doctors to focus on other clinical skills and assessments, which can only be to the advantage of the patient.

Immunotherapy in Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck.

Head and neck cancer is the 6th most common cancer worldwide with the most common histology being squamous cell carcinoma (HNSCC). While the majority of patients present at a stage where curative intent therapy is possible, when patients recur and/or develop metastatic disease, outcomes are generally poor, especially with systemic therapy alone, and they lag behind other solid tumors. Over the last decade immunotherapy has revolutionized the field of oncology, and anti-PD-1-based therapy has changed the standard of care in recurrent/metastatic (R/M) HNSCC as well. With these gains have come new questions to continue to move the field forward. In this review, we discuss the tumor immune microenvironment and predictive biomarkers and current status and future directions for immunotherapy in recurrent/metastatic head and neck cancer.

A hepatitis C elimination model in healthcare for the homeless organization: A novel reflexive laboratory algorithm and equity assessment.

BACKGROUND: Reaching World Health Organization hepatitis C (HCV) elimination targets requires diagnosis and treatment of people who use drugs (PWUD) with direct acting antivirals (DAAs). PWUD experience challenges engaging in HCV treatment, including needing multiple provider and laboratory appointments. Women, minoritized racial communities, and homeless individuals are less likely to complete treatment. METHODS: We implemented a streamlined opt-out HCV screening and linkage-to-care program in two healthcare for the homeless clinics and a medically supported withdrawal center. Front-line staff initiated a single-order reflex laboratory bundle combining screening, confirmation, and pre-treatment laboratory evaluation from a single blood draw. Multinomial logistic regression models identified characteristics influencing movement through each stage of the HCV treatment cascade. Multiple logistic regression models identified patient characteristics associated with HCV care cascade progression and Cox proportional hazards models assessed time to initiation of DAAs. RESULTS: Of 11,035 clients engaged in services between May 2017 and March 2020, 3,607 (32.7%) were screened. Of those screened, 1,020 (28.3%) were HCV PCR positive. Of those with detectable RNA, 712 (69.8%) initiated treatment and 670 (94.1%) completed treatment. Of those initiating treatment, 407 (57.2%) achieved SVR12. There were eight treatment failures and six reinfections. In the unadjusted model, the bundle intervention was associated with increased care cascade progression, and in the survival analysis, decreased time to initiation; these differences were attenuated in the adjusted model. Women were less likely to complete treatment and SVR12 labs than men. Homelessness increased likelihood of screening and diagnosis but was negatively associated with completing SVR12 labs. Presence of opioid and stimulant use disorder diagnoses predicted increased care cascade progression. CONCLUSIONS: The laboratory bundle and referral pathways improved treatment initiation, time to initiation, and movement across the cascade. Despite overall population improvements, women and homeless individuals experienced important gaps across the HCV care cascade.

Breast cancer research output, 1945-2008: a bibliometric and density-equalizing analysis.

NTRODUCTION: Breast cancer is the most common form of cancer among women, with an estimated 194,280 new cases diagnosed in the United States in 2009 alone. The primary aim of this work was to provide an in-depth evaluation of research yield in breast cancer from 1945 to 2008, using large-scale data analysis, the employment of bibliometric indicators of production and quality, and density-equalizing mapping. METHODS: Data were retrieved from the Web of Science (WOS) Science Citation Expanded database; this was searched using the Boolean operator, 'OR', with different terms related to breast cancer, including "breast cancer", "mammary ductal carcinoma" and "breast tumour". Data were then extracted from each file, transferred to Excel charts and visualised as diagrams. Mapping was performed as described by Groneberg-Kloft et al. in 2008. RESULTS: A total of 180,126 breast cancer-associated items were produced over the study period; these had been cited 4,136,224 times. The United States returned the greatest level of output (n = 77,101), followed by the UK (n = 18,357) and Germany (n = 12,529). International cooperation peaked in 2008, with 3,127 entries produced as a result; relationships between the United States and other countries formed the basis for the 10 most common forms of bilateral cooperation. Publications from nations with high levels of international cooperation were associated with greater average citation rates. A total of 4,096 journals published at least one item on breast cancer, although the top 50 most prolific titles together accounted for over 43% (77,517/180,126) of the total output. CONCLUSIONS: Breast cancer-associated research output continues to increase annually. In an era when bibliometric indicators are increasingly being employed in performance assessment, these findings should provide useful information for those tasked with improving that performance.

Topoisomerase 2 alpha and the case for individualized breast cancer therapy.

BACKGROUND: Many patients with breast cancer receive no benefit from their treatment. This has led to a search for novel therapeutic targets whose identification may facilitate a more tailored approach, thereby avoiding unnecessary toxicity. Of these, topoisomerase 2 alpha (TOP2A), located at the HER2/neu amplicon on chromosome 17, has generated particular interest because its expression has been shown to correlate with response to anthracycline-based therapies. METHODS: We evaluated the relationship between TOP2A and its collocated gene, HER2/neu, and summarized the evidence for and against confining anthracycline-based therapies to those patients who demonstrate increased expression or amplification of these targets. RESULTS: The emerging consensus supports the restriction of anthracyclines to those patients who are HER2/neu positive, with the evidence suggesting that alterations in the status of TOP2A are almost completely restricted to this group of patients. CONCLUSIONS: It seems increasingly likely that response to anthracyclines is predicated on these alterations.