Ischemia in the ambulatory setting--the total ischemic burden: relation to exercise testing and investigative and therapeutic implications

To establish the relation between treadmill exercise testing and ambulatory St segment monitoring in the detection of ischemia in patients with coronary artery disease, and to assess whether standard medical therapy affects any such relation, 277 patients with stable angina and angiographically documented coronary artery disease were studied with treadmill exercise testing and 48 h ambulatory ST segment monitoring. One hundred forty-six patients (52%) were studied while receiving no routine antianginal therapy, and 131 (48%) while receiving standard medical therapy. In 187 patients (67%) the exercise test was positive for ischemia. During 11,964 h of ambulatory monitoring, 881 episodes of ischemia (645 [73%] silent) were recorded, of which 809 (92%) occurred in patients with a positive exercise test. The mean heart rate at the onset of ischemic episodes during ambulatory monitoring was significantly less than that at the onset of 1 mm ST segment depression during exercise testing (94.5 versus 105.9 beats/min, p less than 0.0001). However, the frequency of ambulatory ischemic episodes was strongly related to a positive exercise test (p less than 0.001), and this relation was similar for both silent and painful ischemia (p less than 0.0001 for both) and in patients who were and were not receiving therapy (p less than 0.0001 for both). The total duration of ischemia was similarly related to a positive exercise test (p less than 0.0001). Only one patient with a negative exercise test had frequent (greater than 5/day) episodes of ischemia on ambulatory monitoring and had documented coronary artery spasm. Thus, exercise testing identifies the majority of patients likely to have significant ischemia during their daily activities.(ABSTRACT TRUNCATED AT 250 WORDS)     

Adding Pertuzumab to Trastuzumab and Taxanes in HER2 positive breast cancer

Introduction: The monoclonal antibody trastuzumab has improved the median disease free and overall survival of patients with early stage breast cancer that overexpresses the human epidermal growth factor receptor 2 (HER2). Despite this advance, some patients experience cancer relapse and novel approaches are always needed. One such advance is the monoclonal antibody pertuzumab, which prevents dimerisation between members of the HER family of transmembrane glycoprotein receptors.

Areas covered: In this review, the authors analyse recent research which has focused on the development of new HER2 targeting agents for HER2-positive breast cancer, particularly pertuzumab, and its addition to trastuzumab and taxanes.

Expert opinion: Pertuzumab has significantly improved disease control in patients with advanced HER2 positive breast cancer when added to chemotherapy and trastuzumab. Although pertuzumab has also increased response rates in the preoperative setting, this has not yet translated into increased overall survival. The authors believe that future research should focus on improvements in novel biomarkers to select patients for new treatments.     

Racial/Ethnic and Socioeconomic Differences in Short-Term Breast Cancer Survival Among Women in an Integrated Health System

Objectives. We examined the combined influence of race/ethnicity and neighborhood socioeconomic status (SES) on short-term survival among women with uniform access to health care and treatment.Methods. Using electronic medical records data from Kaiser Permanente Northern California linked to data from the California Cancer Registry, we included 6262 women newly diagnosed with invasive breast cancer. We analyzed survival using multivariable Cox proportional hazards regression with follow-up through 2010.Results. After consideration of tumor stage, subtype, comorbidity, and type of treatment received, non-Hispanic White women living in low-SES neighborhoods (hazard ratio [HR] = 1.28; 95% confidence interval [CI] = 1.07, 1.52) and African Americans regardless of neighborhood SES (high SES: HR = 1.44; 95% CI = 1.01, 2.07; low SES: HR = 1.88; 95% CI = 1.42, 2.50) had worse overall survival than did non-Hispanic White women living in high-SES neighborhoods. Results were similar for breast cancer–specific survival, except that African Americans and non-Hispanic Whites living in high-SES neighborhoods had similar survival.Conclusions. Strategies to address the underlying factors that may influence treatment intensity and adherence, such as comorbidities and logistical barriers, should be targeted at low-SES non-Hispanic White and all African American patients.Breast cancer is the most common cancer among women in the United States, and it is the second leading cause of cancer death.1 Despite significant improvements in breast cancer survival from 1992 to 2009,1,2 racial/ethnic and socioeconomic survival disparities have persisted.3,4 African American women have consistently been found to have worse survival after breast cancer,3,5–11 Hispanic women have worse or similar survival,3,9,11,12 and Asian women as an aggregated group have better or similar survival3,9,11,12 than do non-Hispanic White women. Underlying factors thought to contribute to these racial/ethnic disparities include differences in stage at diagnosis,8,12,13 distributions of breast cancer subtypes,14–16 comorbidities,12,13,17 access to and utilization of quality care,13,18 and treatment.12,13Numerous studies also have found poorer survival after breast cancer diagnosis among women residing in neighborhoods of lower socioeconomic status (SES).6,9,19,20 Research has shown that inadequate use of cancer screening services, and consequent late stage diagnosis and decreased survival, contribute to the SES disparities.21,22 Similar to racial/ethnic disparities, SES disparities have been attributed to inadequate treatment and follow-up care and comorbidities.18 Previous population-based studies have continued to observe racial/ethnic survival disparities after adjusting for neighborhood SES, but these studies have not considered the combined influence of neighborhood SES and race/ethnicity.3,9,11,12,23 These disparities may remain because information on individual-level SES, health insurance coverage, comorbidities, quality of care, and detailed treatment regimens have typically not been available.3,8,9,11,13 Even among studies using national Surveillance Epidemiology and End Results–Medicare linked data, in which more detailed information on treatment and comorbidities are available among some patients aged 65 years and older, survival disparities have remained.12,23,24 However, not all data on medical conditions and health care services are captured in Medicare claims, including data on Medicare beneficiaries enrolled in HMOs (health maintenance organizations).25,26Using electronic medical records data from Kaiser Permanente Northern California (KPNC) linked to data from the population-based California Cancer Registry (CCR), we recently reported that chemotherapy use followed practice guidelines but varied by race/ethnicity and neighborhood SES in this integrated health system.27 Therefore, to overcome the limitations of previous studies and address simultaneously the multiple social28 and clinical factors affecting survival after breast cancer diagnosis, we used the linked KPNC–CCR database to determine whether racial/ethnic and socioeconomic differences in short-term overall and breast cancer–specific survival persist in women in a membership-based health system. Our study is the first, to our knowledge, to consider the combined influence of neighborhood SES and race/ethnicity and numerous prognostic factors, including breast cancer subtypes and comorbidities, thought to underlie these long-standing survival disparities among women with uniform access to health care and treatment.     

Practical non-pharmacological intervention approaches for sleep problems among older adults

Poor sleep is common among older adults, often caused by multiple underlying factors such as chronic stress. Poor sleep is subsequently associated with negative health outcomes including higher morbidity and mortality. Our primary purpose is to explore practical non-pharmacological intervention approaches integrating stress management to improve sleep quality among older adults. In doing so, we highlight approaches that appear to hold promise in real-world settings with older individuals. We conducted a tailored literature review specifically on approaches to improve sleep quality among older adults, with emphasis on those integrating stress management. Online search engines were reviewed to identify research in these areas. Various non-pharmacological intervention approaches, such as mindfulness and cognitive behavioral therapy, have shown promise in improving sleep quality and health outcomes within this population. Those integrating chronic stress management appear to be particularly successful. Thus further development of multidimensional sleep interventions integrating stress management with seniors is warranted.     

Educating and Training a Workforce for Nutrition in a Post-2015 World

Nearly all countries in the world today are burdened with malnutrition, manifesting as undernutrition, micronutrient deficiencies, and/or overweight and obesity. Despite some progress, efforts to alleviate malnutrition are hampered by a shortage in number, skills, and geographic coverage, of a workforce for nutrition. Here, we report the findings of the Castel Gandolfo workshop, a convening of experts from diverse fields in March 2014 to consider how to develop the capacity of a global cadre of nutrition professionals for the post-2015 development era. Workshop participants identified several requirements for developing a workforce for nutrition, including an ability to work as part of a multisectoral team; communication, advocacy, and leadership skills to engage decision makers; and a set of technical skills to address future challenges for nutrition. Other opportunities were highlighted that could immediately contribute to capacity development, including the creation of a consortium to link global North and South universities, online training modules for middle managers, and practical, hands-on experiences for frontline nutrition workers. Institutional and organizational support is needed to enable workshop recommendations on education and training to be effectively implemented and sustained. The findings from the Castel Gandolfo workshop can contribute to the delivery of successful nutrition-relevant actions in the face of mounting external pressures and informing and attaining the forthcoming Sustainable Development Goals.     

High preoperative serum carcinoembryonic antigen predicts metastatic recurrence in potentially curative colonic cancer: Results of a five-year study

INTRODUCTION: Serum carcinoembryonic antigen is used mainly for tumor follow-up to detect recurrence of colonic cancer. However, raised preoperative carcinoembryonic antigen levels may be helpful for the identification of understaged cases and of patients meriting more intensive preoperative and postoperative diagnostic workup. METHODS: From a prospectively collected database, the data on 261 patients who had curative colonic carcinoma with a minimal follow-up of five years and who had preoperative carcinoembryonic antigen levels assessed were retrieved and analyzed. Outcome parameters were local and/or distant recurrence and time to recurrence. These parameters were correlated with Dukes staging and preoperative carcinoembryonic antigen levels. RESULTS: The cumulative diseasefree survival of patients with a preoperative carcinoembryonic antigen level within the normal range was significantly better than that of those whose carcinoembryonic antigen was 5 ng/ml or more (P=0.001). No patient with carcinoembryonic antigen levels less than 1 ng/ml developed metastatic recurrence. Twenty-three percent of all patients with a raised carcinoembryonic antigen above 5 ng/ml compared with 2.1 percent of patients with carcinoembryonic antigen below 5 ng/ml developed a metastasis at two years. At five years, these figures were 37.2 percent and 7.5 percent, respectively. Dukes staging and carcinoembryonic antigen levels were found to be directly correlated (P<0.001) when all patients were included. Carcinoembryonic antigen of more of 15 ng/ml was found to be a significant adverse prognostic indicator for disease-free survival irrespective of Dukes staging (P<0.02). Raised carcinoembryonic antigen levels predicted distant metastatic recurrence (P<0.001) but did not predict local recurrence (P=0.72). CONCLUSIONS: High preoperative carcinoembryonic antigen levels above 15 ng/ml predicted an increased risk of metastatic recurrence in potentially curative colonic cancer and may indicate undetectable disseminated disease. Preoperative carcinoembryonic antigen levels predict understaging and the possibility of distant recurrence. Such patients may therefore be selected for adjuvant therapy where indicated. Therefore, carcinoembryonic antigen is complementary to conventional Dukes staging for the prediction of recurrence and survival.     

Isolation of an additional member of the fibroblast growth factor receptor family, FGFR-3.

The fibroblast growth factors are a family of polypeptide growth factors involved in a variety of activities including mitogenesis, angiogenesis, and wound healing. Fibroblast growth factor receptors (FGFRs) have previously been identified in chicken, mouse, and human and have been shown to contain an extracellular domain with either two or three immunoglobulin-like domains, a transmembrane domain, and a cytoplasmic tyrosine kinase domain. We have isolated a human cDNA for another tyrosine kinase receptor that is highly homologous to the previously described FGFR. Expression of this receptor cDNA in COS cells directs the expression of a 125-kDa glycoprotein. We demonstrate that this cDNA encodes a biologically active receptor by showing that human acidic and basic fibroblast growth factors activate this receptor as measured by 45Ca2+ efflux assays. These data establish the existence of an additional member of the FGFR family that we have named FGFR-3.     

Pharmacodynamic studies in suicidal digoxin poisoning (author's transl)

In two patients with suicidal digoxin poisoning the correlations between serum digoxin concentration and changes in the duration of QTc and the flattening of the T-waves were studied. The digoxin serum half-life following suicidal digoxin poisoning was in the first patient (10 mg beta-acetyl derivative of digoxin) 77 h, prolonged cause of renal insufficiency, and in the second patient 39.6 h. (20 mg beta-acetyl derivative of digoxin). In both patients the digoxin induced flattening of the T-wave reached a plateau of maximum efficacy at a serum level of 2-3 ng/ml with no further change up to a serum level of 13.2 ng/ml and 9.6 ng/ml respectively. A linear correlation, however, was found between the digoxin serum concentration and the digoxin induced shortening of QTc, r = 0.88 and r = 0.92 respectively. A plateau maximum efficacy was not found. The regression equations were y = -12.0 chi + 430.8 and y = -8.0 chi + 391.9 respectively. The shortening of QTc is therefore an important parameter for the diagnosis of digoxin poisoning. It can be determined very quick with no methodical problems.