Multi-protein spatial signatures in ductal carcinoma in situ (DCIS) of breast.

BACKGROUND: There is limited knowledge about DCIS cellular composition and relationship with breast cancer events (BCE). METHODS: Immunofluorescence multiplexing (MxIF) was used to image and quantify 32 cellular biomarkers in FFPE DCIS tissue microarrays. Over 75,000 DCIS cells from 51 patients (median 9 years follow-up for non-BCE cases) were analysed for profiles predictive of BCE. K-means clustering was used to evaluate cellular co-expression of epithelial markers with ER and HER2. RESULTS: Only ER, PR and HER2 significantly correlated with BCE. Cluster analysis identified 6 distinct cell groups with different levels of ER, Her2, cMET and SLC7A5. Clusters 1 and 3 were not significant. Clusters 2 and 4 (high ER/low HER2 and SLC7A5/mixed cMET) significantly correlated with low BCE risk (P = 0.001 and P = 0.034), while cluster 6 (high HER2/low ER, cMET and SLC7A5) correlated with increased risk (P = 0.018). Cluster 5 (similar to cluster 6, except high SLC7A5) trended towards significance (P = 0.072). A continuous expression score (Escore) based on these 4 clusters predicted likelihood of BCE (AUC = 0.79, log-rank test P = 5E-05; LOOCV AUC = 0.74, log-rank test P = 0.006). CONCLUSION: Multiplexed spatial analysis of limited tissue is a novel method for biomarker analysis and predicting BCEs. Further validation of Escore is needed in a larger cohort.

Treatment of chemotherapy-associated cardiomyopathy.

PURPOSE OF REVIEW: The number of cancer survivors is increasing, and cardiovascular events are a significant cause of morbidity and mortality in these patients. Preexisting cardiovascular conditions as well as the development of cancer therapeutics-related cardiac dysfunction (CTRCD), in particular left ventricular dysfunction and heart failure, limit the options for cancer therapies for these patients and contribute to reduced cancer survival. RECENT FINDINGS: Recent guidelines and position statements from various cardiology and oncology societies provide an outline for the practicing physician for the management of CTRCD. However, this is largely based on data extrapolated from the general heart failure population (including patients without cancers) and is not based on strong evidence. There is now emerging evidence for the prevention and treatment of heart failure related to certain established chemotherapeutic drugs, whereas there is lack of trials for specific cardioprotective strategies to reduce cardiotoxicity of newer targeted cancer therapies. SUMMARY: In this article, we discuss the most recent literature for the management of asymptomatic left ventricular dysfunction and heart failure related to chemotherapy, from prevention to the use of goal-directed medical therapies as well as discuss the role for advanced heart failure treatment in this population.

Advanced glycation end products are elevated in estrogen receptor-positive breast cancer patients, alter response to therapy, and can be targeted by lifestyle intervention.

PURPOSE: Lifestyle factors associated with personal behavior can alter tumor-associated biological pathways and thereby increase cancer risk, growth, and disease recurrence. Advanced glycation end products (AGEs) are reactive metabolites produced endogenously as a by-product of normal metabolism. A Western lifestyle also promotes AGE accumulation in the body which is associated with disease phenotypes through modification of the genome, protein crosslinking/dysfunction, and aberrant cell signaling. Given the links between lifestyle, AGEs, and disease, we examined the association between dietary-AGEs and breast cancer. METHODS: We evaluated AGE levels in bio-specimens from estrogen receptor-positive (ER+) and estrogen receptor-negative (ER-) breast cancer patients, examined their role in therapy resistance, and assessed the ability of lifestyle intervention to reduce circulating AGE levels in ER+ breast cancer survivors. RESULTS: An association between ER status and AGE levels was observed in tumor and serum samples. AGE treatment of ER+ breast cancer cells altered ERα phosphorylation and promoted resistance to tamoxifen therapy. In a proof of concept study, physical activity and dietary intervention was shown to be viable options for reducing circulating AGE levels in breast cancer survivors. CONCLUSIONS: There is a potential prognostic and therapeutic role for lifestyle derived AGEs in breast cancer. Given the potential benefits of lifestyle intervention on incidence and mortality, opportunities exist for the development of community health and nutritional programs aimed at reducing AGE exposure in order to improve breast cancer prevention and treatment outcomes.

Emerging Research on the Implications of Hormone Replacement Therapy on Coronary Heart Disease.

PURPOSE OF REVIEW: Cardiovascular disease (CVD) is known to be an increasing cause of mortality among women, particularly postmenopausal women. Hormone replacement therapy (HRT) is a topic that has been investigated over the past decade for its known impact on the cardiovascular system. This review summarizes the evidence and current opinion on the associations between HRT and CVD, evidence both supporting and against HRT use as a prevention to the development of coronary heart disease (CHD). RECENT FINDINGS: The majority of the new data available suggests the use of HRT has the potential to be more beneficial in the prevention of CVD if started in women at younger ages. Current studies also suggest that while starting HRT in older postmenopausal women may be associated with an initial slight increase in CVD, the overall lifetime occurrence rate is not increased. Several studies have also started to use the "timing hypothesis" to suggest that HRT initiated soon after menopause has the potential of being the greatest cardiovascular benefit to the patient. Overall, the data support the finding that HRT should be used only for symptomatic treatment, not in an attempt to slow progression of CVD. Current evidence does not support the use of HRT for either primary or secondary prevention of CHD. HRT has different implications based on the temporal relationship in which it is initiated in relation to the onset of menopause. Overall, the use of HRT should be an individualized decision with each patient on the basis of the individual's symptoms and overall risk profile.

A semantic interoperability approach to support integration of gene expression and clinical data in breast cancer.

INTRODUCTION: The introduction of omics data and advances in technologies involved in clinical treatment has led to a broad range of approaches to represent clinical information. Within this context, patient stratification across health institutions due to omic profiling presents a complex scenario to carry out multi-center clinical trials. METHODS: This paper presents a standards-based approach to ensure semantic integration required to facilitate the analysis of clinico-genomic clinical trials. To ensure interoperability across different institutions, we have developed a Semantic Interoperability Layer (SIL) to facilitate homogeneous access to clinical and genetic information, based on different well-established biomedical standards and following International Health (IHE) recommendations. RESULTS: The SIL has shown suitability for integrating biomedical knowledge and technologies to match the latest clinical advances in healthcare and the use of genomic information. This genomic data integration in the SIL has been tested with a diagnostic classifier tool that takes advantage of harmonized multi-center clinico-genomic data for training statistical predictive models. CONCLUSIONS: The SIL has been adopted in national and international research initiatives, such as the EURECA-EU research project and the CIMED collaborative Spanish project, where the proposed solution has been applied and evaluated by clinical experts focused on clinico-genomic studies.

Usability on the p-medicine infrastructure: an extended usability concept.

Usability testing methods are nowadays integrated into the design and development of health-care software, and the need for usability in health-care information technology (IT) is widely accepted by clinicians and researchers. Usability assessment starts with the identification of specific objectives that need to be tested and continues with the definition of evaluation criteria and monitoring procedures before usability tests are performed to assess the quality of all services and tasks. Such a process is implemented in the p-medicine environment and gives feedback iteratively to all software developers in the project. GCP (good clinical practice) criteria require additional usability testing of the software. For the p-medicine project (www.p-medicine.eu), an extended usability concept (EUC) was developed. The EUC covers topics like ease of use, likeability, and usefulness, usability in trial centres characterised by a mixed care and research environment and by extreme time constraints, confidentiality, use of source documents, standard operating procedures (SOA), and quality control during data handling to ensure that all data are reliable and have been processed correctly in terms of accuracy, completeness, legibility, consistence, and timeliness. Here, we describe the p-medicine EUC, focusing on two of the many key tools: ObTiMA and the Ontology Annotator (OA).

Systemic sclerosis and the heart.

Heart disease, either clinically apparent or silent, is a frequent complication of systemic sclerosis (SSc, scleroderma) and may affect both patients with diffuse cutaneous and limited cutaneous SSc. The availability of more sensitive modalities has led to an increased awareness of scleroderma heart disease, which often involves the pericardium, myocardium, and cardiac conduction system. This awareness of cardiac involvement requires attention and interventions led by internists, cardiologists, and rheumatologists. Although no specific therapy exists for scleroderma heart disease, early recognition of the presence and type of scleroderma heart disease may lead to more effective management of patients with scleroderma.

Prevalence of Chest Pain, Depression, Somatization, Anxiety, Global Distress, and Substance Use among Cardiac and Pulmonary Rehabilitation Patients.

Psychosocial factors of cardiovascular disease receive a preponderance of attention. Little attention is paid to psychosocial factors of pulmonary disease. This paper sought to describe psychosocial characteristics and to identify differences between cardiac and pulmonary patients entering a phase II rehabilitation program. Parametric and nonparametric analyses were conducted to examine scores on the Brief Symptom Inventory-18 (BSI-18) and the CAGE-D, administered at entry as standard clinical care. Participants were 163 cardiac and 63 pulmonary patients. Scores on the BSI-18 "chest pain" item indicated that more cardiac patients report chest pain than pulmonary patients. Among all subjects, chest pain ratings were positively related to anxiety, depression, and global distress. There were equivocal proportions of anxiety and somatization in patient groups. Pulmonary patients were more likely to endorse clinically significant levels of depression and global psychological distress than cardiac patients. Cardiac patients were significantly more likely to screen positively on the CAGE-D than pulmonary patients. Findings show a relationship between symptoms of chest pain and psychological distress. Despite equivalent proportions of anxiety and somatization between groups, a greater proportion of pulmonary patients reported symptoms of depression and global psychological distress, while more cardiac patients reported chest pain. Further research is needed to examine this paradigm.

microRNA-associated progression pathways and potential therapeutic targets identified by integrated mRNA and microRNA expression profiling in breast cancer.

microRNA expression profiling plays an emerging role in cancer classification and identification of therapeutic strategies. In this study, we have evaluated the benefits of a joint microRNA-mRNA analysis in breast cancer. Matched mRNA and microRNA global expression profiling was conducted in a well-annotated cohort of 207 cases with complete 10-year follow-up. Penalized Cox regression including microRNA expression, mRNA expression, and clinical covariates was used to identify microRNAs associated with distant relapse-free survival (DRFS) that provide independent prognostic information, and are not simply surrogates of previously identified prognostic covariates. Penalized regression was chosen to prevent overfitting. Furthermore, microRNA-mRNA relationships were explored by global expression analysis, and exploited to validate results in several published cohorts (n = 592 with DRFS, n = 1,050 with recurrence-free survival). Four microRNAs were independently associated with DRFS in estrogen receptor (ER)-positive (3 novel and 1 known; miR-128a) and 6 in ER-negative (5 novel and 1 known; miR-210) cases. Of the latter, miR-342, -27b, and -150 were prognostic also in triple receptor-negative tumors. Coordinated expression of predicted target genes and prognostic microRNAs strengthened these results, most significantly for miR-210, -128a, and -27b, whose targets were prognostic in meta-analysis of several cohorts. In addition, miR-210 and -128a showed coordinated expression with their cognate pri-microRNAs, which were themselves prognostic in independent cohorts. Our integrated microRNA-mRNA global profiling approach has identified microRNAs independently associated with prognosis in breast cancer. Furthermore, it has validated known and predicted microRNA-target interactions, and elucidated their association with key pathways that could represent novel therapeutic targets.

Automated uro-oncology data collection: the Cancer Research Uro-Oncology Database.

OBJECTIVE: To develop a relational database (Cancer Research Uro-Oncology Database, CRUD) to enable automatic data collection on all urological malignancies within our region, as there is increasing emphasis on good data collection for surgical patients with cancer, and numerous overlapping systems that are amassing data on the same patients. METHODS: Links have been established between pathological databases, multidisciplinary team data-collection systems and patient-survival monitoring facilities, providing accurate pathology, treatment and survival data on all of uro-oncology patients. We are also developing individual modules for the oncological surgeons within our unit that are compatible with the British Association of Urological Surgeons (Section of Oncology), and have plans to connect to the Medical and Clinical Oncology data systems in the future. RESULTS: Pre-existing protocols for fresh tissue, plasma and urine collection have been incorporated within CRUD via a tissue-tracking system, to comply with the Human Tissue Act 2004, and link these samples to accurate clinical, pathological and survival data. Many research and audit projects have already used these data, including the construction of a 274-case tissue microarray for renal cell carcinoma, microRNA hybridization arrays and analysis of 900 nephrectomy cases from the past three decades. CONCLUSIONS: Our work over the past 3 years in Oxford has established numerous links with organizations collecting data on our uro-oncological patients, and we are now able to collect this excellent combined data on all of these patients, in an automated manner.

Role of transesophageal echocardiography among patients with atrial fibrillation undergoing electrophysiology testing.

External or internal shocks administered to terminate ventricular arrhythmias as a part of electrophysiology or implantable cardioverter-defibrillator testing, can inadvertently cardiovert atrial fibrillation (AF). Moreover, anticoagulation therapy is often withheld in these patients in anticipation of an invasive procedure. The risk of embolic events during these procedures has not been well described. Accordingly, the present study was a prospective evaluation of the incidence of left atrial (LA) thrombus and AF cardioversion among patients undergoing ventricular arrhythmia assessment. Transesophageal echocardiography was routinely performed on 44 consecutive patients in AF with subtherapeutic anticoagulation undergoing electrophysiology or implantable cardioverter-defibrillator testing. Arrhythmia induction was not performed when LA thrombus was present. The incidence and clinical predictors of thrombus, the inadvertent cardioversion of AF, and adverse events related to the procedure were assessed during the subsequent 4 to 6 weeks. Left atrial thrombus was observed in 12 patients (27%). Sinus rhythm was restored in 29 patients (91%), at least transiently, who underwent testing with a shock delivered. No adverse neurologic or hemorrhagic complications were observed. Univariate analysis identified no predictors of LA thrombus or cardioversion to sinus rhythm. In conclusion, LA thrombus and cardioversion to sinus rhythm are common among patients with AF undergoing an evaluation of ventricular arrhythmias. Transesophageal echocardiography performed before the procedure in patients with subtherapeutic anticoagulation is warranted to minimize embolic complications. This strategy appears to be a safe method to guide diagnostic testing in this patient population.

Ethnic disparities among patients with pulmonary hypertension associated with systemic sclerosis.

OBJECTIVE: To examine a cohort of patients with systemic sclerosis (SSc) and pulmonary hypertension (PH) for ethnic disparities in clinical presentation, disease detection, or management. METHODS: Encounters of patients with SSc seen at the Medical University of South Carolina were recorded in a computerized database from November 1997 through January 2004. Patients were evaluated for discrepancy in disease manifestation and treatment. Evaluation criteria included patient ethnicity (by self report), age, disease duration from onset of first non-Raynaud's symptom, presence or absence of PH, incidence of diastolic dysfunction and left ventricular hypertrophy among patients with PH, severity of interstitial lung disease, and treatment course. RESULTS: African Americans were more likely than Caucasians to have diffuse cutaneous SSc (dcSSc) (69.9% vs 42.9%, p < 0.001) and they presented with PH (defined as right ventricular systolic pressure > 40 mm Hg by echocardiogram or mean pulmonary artery pressure > 25 mm Hg by right heart catheterization (RHC) at a younger age (60.9 yrs vs 49.0 yrs, p < 0.001). There were no ethnic disparities in time from onset of the first non-Raynaud's symptom to detection of PH, method of PH detection, or treatment modalities. Patients with PH were more likely to have diastolic dysfunction than those without PH (52.3% vs 35.9%, p = 0.011). CONCLUSION: In this cohort of patients, African Americans were more likely to have dcSSc. Among patients with PH, African Americans presented at a younger age than their Caucasian counterparts. Incidence of diastolic dysfunction was higher in the PH population. There were no significant ethnic disparities in time of progression to PH or in treatment modalities employed in our cohort.

Rhabdomyolysis with concurrent atorvastatin and diltiazem.

OBJECTIVE: To report a case of rhabdomyolysis and acute hepatitis associated with the coadministration of atorvastatin and diltiazem. CASE SUMMARY: A 60-year-old African American man with a significant past medical history presented to the emergency department with acute renal failure secondary to rhabdomyolysis. In addition, liver enzymes were elevated to greater than 3 times normal. The only change in medication was the initiation of diltiazem 3 weeks earlier for atrial fibrillation to a complicated medication regimen that included atorvastatin. DISCUSSION: Rhabdomyolysis has been reported in patients receiving hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors when coadministered with agents that may inhibit their metabolism. Atorvastatin is the most potent of this class of agents currently available and is commonly used in the treatment of hyperlipidemia. Rhabdomyolysis resulting from the drug interaction between diltiazem and other HMG-CoA reductase inhibitors has been described in the literature. However, no report has specifically associated this adverse event with atorvastatin and diltiazem. We describe a patient with a complex medication regimen who was admitted for rhabdomyolysis and accompanying acute renal failure, along with acute hepatitis, thought to be secondary to a drug interaction between atorvastatin and diltiazem. CONCLUSIONS: While optimizing the patient's lipid profile should be the primary factor in choosing one statin over another, the potential for drug interactions requires close attention. All patients beginning HMG-CoA reductase inhibitor therapy should be counseled regarding the signs and symptoms of muscle injury; particular attention should be paid to those patients who are taking medications that may interact.

Relation of hypoxia-inducible factor-2 alpha (HIF-2 alpha) expression in tumor-infiltrative macrophages to tumor angiogenesis and the oxidative thymidine phosphorylase pathway in Human breast cancer.

Tumor-associated macrophages (TAMs) produce angiogenic factors and in breast cancer are associated with high vascular grade and poor survival. TAMs preferentially migrate to hypoxic areas within tumors and strongly express hypoxia-inducible factor (HIF)-2 alpha. This study examined whether HIF-2 alpha was involved in TAM angiogenic activation by correlating its expression with tumor microvessel density as a marker of angiogenesis, and other tumor variables, in a series of human primary invasive breast carcinomas. A correlation was found between high TAM HIF-2 alpha and high tumor vascularity (P < 0.0001), as well as high tumor grade (P = 0.007). The relation of HIF-2 alpha expression to a recently described oxygen-dependent pathway of angiogenesis was also studied, and an inverse relationship was found between TAM HIF-2 alpha and tumor thymidine phosphorylase expression (P = 0.02). These results suggest that TAM HIF-2 signaling may be a useful target for future antiangiogenic strategies but show that tumors use both oxygen-dependent and oxygen deficiency-regulated pathways for angiogenesis. Thus, combined blockade of pathways and careful assessment of these pathways in trials are necessary.

Ulnar artery involvement in systemic sclerosis (scleroderma).

OBJECTIVE: Microvascular disease is one of the hallmarks of systemic sclerosis (SSc, scleroderma), but macrovascular involvement also exists in some patients. Patients with SSc may have severe Raynaud's phenomenon (RP) characterized by refractory digital ulcerations. We investigated if large artery involvement, that is, ulnar artery occlusion, has a role in the development of refractory digital ulcerations, and if both screening for this involvement and revascularization of the ulnar artery occlusive disease may improve digital ulcer healing. METHODS: A retrospective chart review was performed of 15 patients with SSc, all of whom had severe RP and digital ulceration, together with a positive Allen test and ulnar artery occlusive disease documented by angiography. RESULTS: Women outnumbered men 2:1, with limited disease predominating (7), 5 patients having diffuse cutaneous disease and 3 overlap syndromes. All patients had positive antinuclear antibody and capillary microscopy findings consistent with SSc. Antiphospholipid antibodies were present in 4 of 6 patients tested. Tobacco use was seen in 5 patients, only 2 of whom were current smokers. All patients failed conventional medical therapy (nitrates, calcium channel blockers, antiplatelet agents) for RP and digital ulceration. Only 1/8 patients improved with stellate ganglion block, and one patient had no improvement following digital sympathectomy. Eight patients underwent ulnar artery revascularization combined with digital sympathectomy, and 8 experienced dramatic improvement in RP and healing of digital ulcers. CONCLUSION: An Allen test should be performed routinely on all SSc patients with severe RP and refractory digital ulceration to investigate the possibility of ulnar artery occlusive disease. If suspected ulnar artery occlusion is confirmed by angiography or ultrasonography, ulnar artery revascularization with or without digital sympathectomy should be considered in patients who fail conventional medical therapy.