Nicole P. Sandhu

Evaluation and management of patients with heart disease and cancer: cardio-oncology.

The care for patients with cancer has advanced greatly over the past decades. A combination of earlier cancer diagnosis and greater use of traditional and new systemic treatments has decreased cancer-related mortality. Effective cancer therapies, however, can result in short- and long-term comorbidities that can decrease the net clinical gain by affecting quality of life and survival. In particular, cardiovascular complications of cancer treatments can have a profound effect on the health of patients with cancer and are more common among those with recognized or unrecognized underlying cardiovascular diseases. A new discipline termed cardio-oncology has thus evolved to address the cardiovascular needs of patients with cancer and optimize their care in a multidisciplinary approach. This review provides a brief introduction and background on this emerging field and then focuses on its practical aspects including cardiovascular risk assessment and prevention before cancer treatment, cardiovascular surveillance and therapy during cancer treatment, and cardiovascular monitoring and management after cancer therapy. The content of this review is based on a literature search of PubMed between January 1, 1960, and February 1, 2014, using the search terms cancer, cardiomyopathy, cardiotoxicity, cardio-oncology, chemotherapy, heart failure, and radiation.

Magnetic Forces Enable Rapid Endothelialization of Synthetic Vascular Grafts

Background— Synthetic vascular grafts cannot be used in small vessels because of graft failure caused by thrombosis and neointima formation. Rapid endothelialization may overcome this limitation. We hypothesized that a magnetic graft would be able to capture and retain endothelial cells labeled with paramagnetic particles. Methods and Results— Porcine blood derived endothelial cells were allowed to endocytose superparamagnetic iron oxide microspheres. Cell survival was assessed by trypan blue exclusion and demonstrated a dose-dependent cell survival of 75% to 95%. A flexible magnetic sheet was annealed to the external surface of a knitted Dacron graft. Labeled cells (106/mL) were placed within the graft for 5 minutes. Confocal and electron microscopy confirmed uniform cell capture at the magnetized surface. The effect of shear forces on the adherent cells was evaluated in a flow chamber. The cells remained attached at rates up to 300 mL/min, with cell loss commencing at 400 mL/min. Prototype magnetic grafts were implanted in porcine carotid arteries. Labeled cells were placed within the graft for 10 minutes at the time of implantation. The grafts were evaluated after one day and uniform cell coverage was noted on the magnetized surface. In comparison, relatively few labeled cells were seen attached to a nonmagnetized surface. Conclusions— Magnetic forces can be used to rapidly cover a vascular graft with paramagnetically labeled cells. This biophysical interaction is sufficient to retain cells in the presence of blood flow. Applications of this technique may include rapid endothelialization of synthetic vascular grafts and dialysis fistulas.

Osteoporosis prevention, screening, and treatment: a review.

Osteoporosis, defined as low bone mass leading to increased fracture risk, is a major health problem that affects approximately 10 million Americans. The aging U.S. population is predicted to contribute to as much as a 50% increase in prevalence by 2025. Although common, osteoporosis can be clinically silent, and without prevention and screening, the costs of osteoporotic fracture-related morbidity and mortality will burden the U.S. healthcare system. This is a particularly relevant concern in the context of diminishing health care resources. Dual-energy X-ray absorptiometry is the most widely used, validated technique for measuring bone mineral density (BMD) and diagnosing osteoporosis. Cost-effectiveness analyses support early detection and treatment of high-risk patients with antiresorptive medications such as bisphosphonates. Moreover, optimization of bone health throughout life can help prevent osteoporosis. Current guidelines recommend screening women by age 65 years, but because no guidelines for screening intervals exist, decisions are made on the basis of clinical judgment alone. Although the recent literature provides some guidance, this review further explores current recommendations in light of newer evidence to provide more clarity on prevention, screening, and management strategies for patients with osteoporosis in the primary care setting.

Urine Biomarkers of Risk in the Molecular Etiology of Breast Cancer

Endogenous estrogens can be bio-activated to endogenous carcinogens via formation of estrogen quinones. Estrogen-3,4-quinones react with DNA to form mutagenic depurinating estrogen-DNA adducts. The carcinogenicity of endogenous estrogens is related to unbalanced estrogen metabolism leading to excess estrogen quinones and formation of depurinating DNA adducts. The present studies were initiated to confirm that relatively high levels of depurinating estrogen-DNA adducts are present in women at high risk for breast cancer or diagnosed with the disease. These adducts may be biomarkers for early detection of breast cancer risk. The estrogen metabolites, conjugates and depurinating DNA adducts were identified and quantified by using ultraperformance liquid chromatography/tandem mass spectrometry to analyze urine samples from 40 healthy control women, 40 high-risk women and 40 women with newly diagnosed breast cancer. Estrogen metabolism was shifted from protective methoxylation and conjugation pathways in healthy control women towards activating pathways leading to formation of depurinating DNA adducts in women at high risk or with breast cancer. These results support the hypothesis that breast cancer is initiated by mutations derived from depurination of estrogen-DNA adducts. Therefore, relative levels of depurinating estrogen-DNA adducts could become biomarkers for early detection of breast cancer risk and aid in determining preventive strategies.

Prophylactic and therapeutic mastectomy in BRCA mutation carriers: can the nipple be preserved?

BackgroundUse of nipple-sparing mastectomy (NSM) is increasing. We sought to look at the role of NSM in BRCA mutation carriers.MethodsTissue from women with a BRCA1 or BRCA2 mutation who underwent mastectomy between March 1987 and June 2009 at a single institution was reviewed. The entire nipple–areolar complex (NAC) was excised and histologically evaluated. The presence of terminal duct lobular units (TDLUs) and premalignant or malignant lesions in the NAC was noted.ResultsSixty-two NACs from 33 women (25 BRCA1, 8 BRCA2) were studied. TDLUs were present in 15 (24%) NAC specimens. No evidence of atypical hyperplasia, carcinoma in situ, or invasive carcinoma was found in any of the 33 prophylactic mastectomy specimens. Among the 29 breasts with cancer and available tissue, 2 (7%) had malignant findings and 1 (3%) had atypia in the NAC. One woman who underwent bilateral mastectomy for bilateral invasive carcinoma had one nipple with tumor within lymphatics, and her contralateral nipple had atypical lobular hyperplasia. A second woman had ductal carcinoma in situ involving a single major lactiferous duct.ConclusionsThe probability of nipple involvement by premalignant or malignant lesions in the NAC of BRCA mutation carriers is low at time of prophylactic mastectomy, but higher (10%) in women undergoing therapeutic mastectomy. NSM may be appropriate and oncologically safe for selected women with BRCA mutations. However, 24% of NACs contained TDLUs, with only 8% found in the nipple papilla; the significance of this for long-term risk is unknown.

Diagnosis and Management of Benign, Atypical, and Indeterminate Breast Lesions Detected on Core Needle Biopsy

Imaging abnormalities detected by mammographic screening often lead to diagnostic evaluations, with suspicious abnormalities subjected to image-guided core needle biopsy (CNB) to exclude malignancy. Most CNBs reveal benign pathological alterations, termed benign breast disease (BBD). Adoption of CNB presents challenges with pathologic classification of breast abnormalities and management of patients with benign or atypical histological findings. Patient management and counseling after CNB diagnosis of BBD depends on postbiopsy determination of radiologic-pathologic concordancy. Communication between radiologists and pathologists is crucial in patient management. Management is dependent on the histological type of BBD. Patients with concordant pathologic imaging results can be reassured of benign biopsy findings and advised about the future risk of developing breast cancer. Surgical consultation is advised for patients with discordant findings, symptomatic patients, and high-risk lesions. This review highlights benign breast lesions that are encountered on CNB and summarizes management strategies. For this review, we conducted a search of PubMed, with no date limitations, and used the following search terms (or a combination of terms): atypical ductal hyperplasia, atypical hyperplasia, atypical lobular hyperplasia, benign breast disease, cellular fibroepithelial lesions, columnar cell lesions, complex sclerosing lesion, core needle biopsy, fibroadenomas, flat epithelial atypia, lobular carcinoma in situ, lobular neoplasia, mucocele-like lesions, phyllodes tumor, pseudoangiomatous stromal hyperplasia, radial scar, and vascular lesions. The selection of references included in this review was based on study relevance and quality. We used additional articles culled from the bibliographies of retrieved articles to examine the published evidence for risk factors of BBD.

Systems biology approaches to adverse drug effects: the example of cardio-oncology

Increased awareness of the cardiovascular toxic effects of chemotherapy has led to the emergence of cardio-oncology (or onco-cardiology), which focuses on screening, monitoring and treatment of patients with cardiovascular dysfunctions resulting from chemotherapy. Anthracyclines, such as doxorubicin, and HER2 inhibitors, such as trastuzumab, both have cardiotoxic effects. The biological rationale, mechanisms of action and cardiotoxicity profiles of these two classes of drugs, however, are completely different, suggesting that cardiotoxic effects can occur in a range of different ways. Advances in genomics and proteomics have implicated several genomic variants and biological pathways that can influence the susceptibility to cardiotoxicity from these, and other drugs. Established pathways include multidrug resistance proteins, energy utilization pathways, oxidative stress, cytoskeletal regulation and apoptosis. Gene-expression profiles that have revealed perturbed pathways have vastly increased our knowledge of the complex processes involved in crosstalk between tumours and cardiac function. Utilization of mathematical and computational modelling can complement pharmacogenomics and improve individual patient outcomes. Such endeavours should enable identification of variations in cardiotoxicity, particularly in those patients who are at risk of not recovering, even with the institution of cardioprotective therapy. The application of systems biology holds substantial potential to advance our understanding of chemotherapy-induced cardiotoxicity.

Comparison of the effect of the metabolic syndrome and multiple traditional cardiovascular risk factors on vascular function.

OBJECTIVE To assess the effect of the metabolic syndrome (MetS) on endothelial function and compare these findings to those in individuals with a similar burden of traditional cardiovascular (CV) risk factors (≥ 3) without MetS. PATIENTS AND METHODS Both MetS and multiple CV risk factors were identified from 1103 individuals who underwent the evaluation of endothelial function at the Mayo Clinic, in Rochester, Minnesota, from July 1, 2000, through July 31, 2011. Endothelial function was measured using digital arterial tonometry by assessing reactive hyperemia-induced vasodilation in one arm and adjusting for changes in the contralateral arm (reactive hyperemia index [RHI]). RESULTS A total of 316 individuals with MetS and 210 with multiple risk factors were assessed. Endothelial dysfunction was more pronounced in the MetS group compared with the multiple risk factor group (mean ± SD natural logarithmic RHI, 0.61 ± 0.25 and 0.68 ± 0.28, respectively; P=.006). Leukocyte count (7.00 ± 1.89 × 10(9)/L vs 6.41 ± 1.76 × 10(9)/L, respectively; P=.001) and high-sensitivity C-reactive protein level (1.78 ± 1.53 mg/L vs 1.48 ± 1.42 mg/L, respectively; P=.01) were higher in the MetS group compared with the multiple risk factor group. After adjustment for covariates and 6 traditional CV risk factors in a multivariate regression model, MetS had a significant and independent influence on natural logarithmic RHI (β=-.11; P=.01). CONCLUSION The current study found that individuals with MetS have a higher degree of endothelial dysfunction and inflammation compared with individuals with multiple CV risk factors and may therefore have an increased CV risk beyond the contributions of multiple traditional risk factors.

Factors Associated with Surgical Decision Making in Women with Early-Stage Breast Cancer: A Literature Review

BACKGROUND Current recommendations for surgical management of early-stage breast cancer include breast-conserving surgery with postoperative irradiation. However, studies show that mastectomy is still being used by women with early-stage breast cancer. METHODS Review of the medical literature published between 2000 and 2010 to determine the factors associated with the decision of patients for surgical treatment in early-stage breast cancer. RESULTS The following patient characteristics affect the surgical decision-making process in early-stage breast cancer: age, socioeconomic factors, geographic area in which the patient lives, proximity to a radiation therapy center, testing for BRCA gene, breast imaging, and decision aids. CONCLUSIONS Of increasing importance in the decision making about treatment of women with early-stage breast cancer are the womans perception of having a surgical choice and the influence of that choice on postoperative quality of life.

Evaluation of serum estrogen-DNA adducts as potential biomarkers for breast cancer risk.

This study was conducted to determine whether the ratio of estrogen-DNA adducts to their respective metabolites and conjugates in serum differed between women with early-onset breast cancer and those with average or high risk of developing breast cancer. Serum samples from women at average risk (n=63) or high risk (n=80) for breast cancer (using Gail model) and women newly diagnosed with early breast cancer (n=79) were analyzed using UPLC-MS/MS. Adduct ratios were statistically compared among the three groups, and the Area Under the Receiver Operating Characteristic Curve (AUC) was used to identify a diagnostic cut-off point. The median adduct ratio in the average-risk group was significantly lower than that of both the high-risk group and the breast cancer group (p values<0.0001), and provided good discrimination between those at average versus high risk of breast cancer (AUC=0.84, 95% CI 0.77-0.90). Sensitivity and specificity were maximized at an adduct ratio of 77. For women in the same age and BMI group, the odds of being at high risk for breast cancer was 8.03 (95% CI 3.46-18.7) times higher for those with a ratio of at least 77 compared to those with a ratio less than 77. The likelihood of being at high risk for breast cancer was significantly increased for those with a high adduct ratio relative to those with a low adduct ratio. These findings suggest that estrogen-DNA adducts deserve further study as potential biomarkers for risk of developing breast cancer.