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.     

Do I really want to be going on a bloody diet? Gendered narratives in older men with painful knee osteoarthritis

Purpose: Small reductions in body weight can decrease osteoarthritic knee pain. Intuitively this should provide a strong incentive for weight-loss. However many people undergoing knee joint replacement (KJR) are categorised as obese. Gender theories can help us to understand differential responses to illness and therefore make an important contribution to rehabilitation. We aimed to explore barriers to weight loss in a group of older men with osteoarthritis.

Materials and methods: We conducted 12 in-depth interviews, before and 1 year after surgery, with six obese men listed for KJR. Analysis was influenced by constructivist grounded theory. We abstracted conceptual themes from the data through constant comparison.

Results: We identified the following themes: (1) I am big and healthy and don’t need to lose weight; (2) being this size isn’t good for me; (3) men don’t have to worry about that sort of thing; (4) I am not as active as I used to be; (5) I have worked hard all my life; (6) what is the point in trying anyway?

Conclusions: Gendered narratives can make it challenging for men to lose weight. Healthcare professionals cannot ignore the influence of gender on rehabilitation and should consider gender specific strategies.

• Implications for rehabilitation

• Men may not associate being overweight with being unhealthy.

• Men may take pride in being in good shape and may respond better to weight loss strategies that focus on fitness not body size.

• Men may link weight gain with decrease in activity levels rather than overeating.

• Health care professionals should challenge the assumption that weight loss will follow surgery.

• Health care professionals cannot ignore the influence of gender on the success of rehabilitation.

     

Surgical intervention for drug-resistant ventricular tachycardia

Endocardial resection was required in 26 patients with sustained drug-resistant ventricular tachycardia. The early mortality rate (within 30 days after operation) was 12%. Two deaths were the result of low cardiac output, and the third death was related to recurrent ventricular septal defect after septal endocardial resection. The survivors of endocardial resection were followed up from 6 to 92 months (mean 43). There were no recurrences of ventricular arrhythmias, and patients did not require antiarrhythmic drug therapy. The late mortality rate after endocardial resection was 19%. There were two late cardiac-related deaths (unrelated to arrhythmias) and three late deaths from noncardiac causes. Complete endocardial resection successfully ablates drug-resistant ventricular tachycardia, but is associated with an increased perioperative mortality rate in those patients who have severely depressed left ventricular function without a well defined left ventricular aneurysm.     

Strengthening the fellowship training experience: findings from a national survey of fellowship trained geriatricians 1990-1998

Geriatric fellowship training has significantly advanced in the past 2 decades in number, organization, and accreditation of formal fellowship programs. A recent survey examined career decision-making, fellowship training, and current professional activities of fellowship trained geriatricians. This paper focuses upon further desired fellowship training identified by these individuals. The responses reflect skills relevant to four aspects of professional performance: administration, management, clinical geriatrics, research, and education. More than half of the respondents documented the need for increased training in administration, including long-term care medical directorship and Medicare/managed care. Regarding clinical training, 66% recommended additional subspecialty training, particularly in psychiatry, neurology, rehabilitation, and hospice/palliative care. Seventeen percent identified a need for training in research methodology, grant writing, and mentorship. Some 6% indicated a need for further training in education, citing teaching skills and program/faculty development. This article provides examples of opportunities to strengthen each of the four defined areas, including formal training in medical administration by the American Medical Director's Association, model strategies for incorporating subspecialties, hospice/palliative care, programs to pursue graduate level training in research at many universities, and faculty development programs such as those offered by Harvard and Stanford. Accredited geriatric fellowship programs as well as fellows should recognize potential gaps in training, and make available opportunities to strengthen these areas critical to preparing for future careers in geriatric medicine.     

Fetal growth and impaired glucose tolerance in men and women

Summary A follow-up study was carried out to determine whether reduced fetal growth is associated with the development of impaired glucose tolerance in men and women aged 50 years. Standard oral glucose tolerance tests were carried out on 140 men and 126 women born in Preston (Lancashire, UK) between 1935 and 1943, whose size at birth had been measured in detail. Those subjects found to have impaired glucose tolerance or non-insulin-dependent diabetes mellitus had lower birthweight, a smaller head circumference and were thinner at birth. They also had a higher ratio of placental weight to birthweight. The prevalence of impaired glucose tolerance or diabetes fell from 27% in subjects who weighed 2.50 kg (5.5 pounds) or less at birth to 6% in those who weighed more than 3.41 kg (7.5 pounds) (p < 0.002 after adjusting for body mass index). Plasma glucose concentrations taken at 2-h in the glucose tolerance test fell progressively as birthweight increased (p < 0.004), as did 2-h plasma insulin concentrations (p < 0.001). The trends with birthweight were independent of duration of gestation and must therefore be related to reduced rates of fetal growth. These findings confirm the association between impaired glucose tolerance in adult life and low birthweight previously reported in Hertfordshire (UK), and demonstrate it in women as well as men. It is suggested that the association reflects the long-term effects of reduced growth of the endocrine pancreas and other tissues in utero. This may be a consequence of maternal undernutrition.     

Effects of 1,25-dihydroxyvitamin D3 and cortisol on bovine and human parathyroid cells

Incubation of bovine parathyroid cells with 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) decreased both preproparathyroid mRNA levels and parathyroid hormone (PTH) secretion. There was a fall to 56.6 +/- 13.7% (mean +/- S.E.M.) and 65.1 +/- 9.3% in mRNA levels and PTH secretion respectively at 1 nmol 1,25-(OH)2D3/l, and 41.1 +/- 13.6% and 42.0 +/- 12.1% at 10 nmol 1,25-(OH)2D3/l after 24 h. After 48 h in 0.1 nmol 1,25-(OH)2D3/l, mRNA levels had fallen to 35.3 +/- 12.6% and PTH secretion to 32.1 +/- 5.0%. In human adenomatous cells, however, incubation with 1,25-(OH)2D3 (10 nmol/l) had no effect on either mRNA levels or PTH secretion even after 48 h. This lack of sensitivity of adenomatous cells to 1,25-(OH)2D3 was not due to an absence of receptors (3847 +/- 39 receptors/ng cytosolic protein in adenomatous cells compared with 4068 +/- 371 in bovine cells) or receptors being of low affinity. Cortisol (1 mumol/l) caused a reduction in the number of receptors for 1,25-(OH)2D3 in bovine parathyroid cells of approximately 20% within 24 h of incubation, but no change in affinity. This decrease was accompanied by abolition of the response to 1,25-(OH)2D3 and was reversible, in that withdrawal of cortisol for the final 24 h of incubation was sufficient for the response to return, the number of receptors having returned to control values. These results suggest that only a small percentage of receptors for 1,25-(OH)2D3 in bovine parathyroid cells may be functional at any one time.(ABSTRACT TRUNCATED AT 250 WORDS)     

Human dihydrofolate reductase gene is located in chromosome 5 and is unlinked to the related pseudogenes.

The chromosomal location of the human dihydrofolate reductase (DHFR; EC 1.5.1.3) gene that is amplified in a methotrexate-resistant human cell line has been investigated by screening a large number of human-mouse cell hybrids containing overlapping subsets of human chromosomes. A correlation of genomic blotting data with the chromosome constitution of the individual cell hybrids has allowed the assignment of the human DHFR gene to chromosome 5. This chromosome assignment has been confirmed by the observation of a concomitant loss of the human DHFR gene and of sensitivity to diphtheria toxin, a marker associated with chromosome 5, in two human-mouse cell hybrids selected for resistance to the toxin. Six EcoRI fragments of human DNA containing DHFR pseudogenes or other DHFR-related sequences have been assigned to chromosomes other than chromosome 5.     

Fetal programming of coronary heart disease.

People who develop coronary heart disease grow differently from other people both in utero and during childhood. Slow growth during fetal life and infancy is followed by accelerated weight gain in childhood. Two disorders that predispose to coronary heart disease, type 2 diabetes and hypertension, are preceded by similar paths of growth. Mechanisms underlying this are thought to include the development of insulin resistance in utero, reduced numbers of nephrons associated with small body size at birth and altered programming of the micro-architecture and function of the liver. Slow fetal growth might also heighten the body's stress responses and increase vulnerability to poor living conditions in later life. Coronary heart disease appears to be a developmental disorder that originates through two widespread biological phenomena, developmental plasticity and compensatory growth.     

Multilocus mapping of the X-linked hypophosphatemic rickets gene.

X-linked hypophosphatemic rickets (HYP), the most common form of familial hypophosphatemic (vitamin D-resistant) rickets, is an X-linked dominant disorder characterized by decreased renal tubular phosphate reabsorption and consequent hypophosphatemia. Despite the application of a wide variety of biochemical and cell biology techniques, controversy exists regarding whether a primary renal abnormality underlies the abnormal phosphate transport or if this defect is secondary to the effects of a hormonal/metabolic factor. Thus localization of the HYP gene and its ultimate cloning may be necessary to elucidate the pathophysiology of the disorder. In order to map the human HYP gene we investigated several new polymorphic probes for linkage to HYP and constructed a map of markers around the gene. The database used to ascertain linkage and perform mapping included 5 large HYP kindreds, 40 Centre d'Etudie Polymorphisms Humain reference pedigrees, and 19 kindreds which had been obtained for other disease linkage studies. Two point LOD scores (odds of linkage, log10) indicate that the probes DXS365, DXS257, DXS451, and DXS41 are tightly linked to the HYP locus. Indeed, there were no cross-overs between DXS365 and HYP with a peak LOD score of 13.98 [recombination fraction (theta) = 0.00]. Moreover, multipoint analysis reveals a probable locus order of: Xtel-DXS315-DXS43-DXS257-HYP-DXS41-DXS4 51-Xcen. The likelihood of HYP occurring between DXS257 and DXS41 is 407:1 over the next most likely position. DXS365 is located between DXS41 and DXS43 but could not be located with respect to HYP and DXS257. Regardless, we have located the HYP gene between the flanking markers DXS257 (telomeric) and DXS41 (centromeric) which are 3.5 centiMorgans apart. Thus, the results of this study will facilitate attempts to further localize and eventually clone the gene.