CYP2D6 genotype is not associated with survival in breast cancer patients treated with tamoxifen: results from a population-based study.

PURPOSE: A number of studies have tested the hypothesis that breast cancer patients with low-activity CYP2D6 genotypes achieve inferior benefit from tamoxifen treatment, putatively due to lack of metabolic activation to endoxifen. Studies have provided conflicting data, and meta-analyses suggest a small but significant increase in cancer recurrence, necessitating additional studies to allow for accurate effect assessment. We conducted a retrospective pharmacogenomic analysis of a prospectively collected community-based cohort of patients with estrogen receptor-positive breast cancer to test for associations between low-activity CYP2D6 genotype and disease outcome in 500 patients treated with adjuvant tamoxifen monotherapy and 500 who did not receive any systemic adjuvant therapy. METHODS: Tumor-derived DNA was genotyped for common, functionally consequential CYP2D6 polymorphisms (*2, *3, *4, *6, *10, *41, and copy number variants) and assigned a CYP2D6 activity score (AS) ranging from none (0) to full (2). Patients with poor metabolizer (AS = 0) phenotype were compared to patients with AS > 0 and in secondary analyses AS was analyzed quantitatively. Clinical outcome of interest was recurrence free survival (RFS) and analyses using long-rank test were adjusted for relevant clinical covariates (nodal status, tumor size, etc.). RESULTS: CYP2D6 AS was not associated with RFS in tamoxifen treated patients in univariate analyses (p > 0.2). In adjusted analyses, increasing AS was associated with inferior RFS (Hazard ratio 1.43, 95% confidence interval 1.00-2.04, p = 0.05). In patients that did not receive tamoxifen treatment, increasing CYP2D6 AS, and AS > 0, were associated with superior RFS (each p = 0.0015). CONCLUSIONS: This population-based study does not support the hypothesis that patients with diminished CYP2D6 activity achieve inferior tamoxifen benefit. These contradictory findings suggest that the association between CYP2D6 genotype and tamoxifen treatment efficacy is null or near null, and unlikely to be useful in clinical practice.

Polymorphisms in drug-metabolizing enzymes and steady-state exemestane concentration in postmenopausal patients with breast cancer.

Discovery of clinical and genetic predictors of exemestane pharmacokinetics was attempted in 246 postmenopausal patients with breast cancer enrolled on a prospective clinical study. A sample was collected 2 h after exemestane dosing at a 1- or 3-month study visit to measure drug concentration. The primary hypothesis was that patients carrying the low-activity CYP3A4*22 (rs35599367) single-nucleotide polymorphism (SNP) would have greater exemestane concentration. Additional SNPs in genes relevant to exemestane metabolism (CYP1A1/2, CYP1B1, CYP3A4, CYP4A11, AKR1C3/4, AKR7A2) were screened in secondary analyses and adjusted for clinical covariates. CYP3A4*22 was associated with a 54% greater exemestane concentration (P<0.01). Concentration was greater in patients who reported White race, had elevated aminotransferases, renal insufficiency, lower body mass index and had not received chemotherapy (all P<0.05), and CYP3A4*22 maintained significance after adjustment for covariates (P<0.01). These genetic and clinical predictors of exemestane concentration may be useful for treatment individualization in patients with breast cancer.

CYP2C8*3 increases risk of neuropathy in breast cancer patients treated with paclitaxel.

BACKGROUND: Paclitaxel-induced neuropathy is an adverse event that often leads to therapeutic disruption and patient discomfort. We attempted to replicate a previously reported association between increased neuropathy risk and CYP2C8*3 genotype. PATIENTS AND METHODS: Demographic, treatment, and toxicity data were collected for paclitaxel-treated breast cancer patients who were genotyped for the CYP2C8*3 K399R (rs10509681) variant. A log-rank test was used in the primary analysis of European-American patients. An additional independent replication was then attempted in a cohort of African-American patients, followed by modeling of the entire patient cohort with relevant covariates. RESULTS: In the primary analysis of 209 European patients, there was an increased risk of paclitaxel-induced neuropathy related to CYP2C8*3 status [HR (per allele) = 1.93 (95% CI: 1.05-3.55), overall log-rank P = 0.006]. The association was replicated in direction and magnitude of effect in 107 African-American patients (P = 0.043). In the Cox model using the entire mixed-race cohort (n = 411), each CYP2C8*3 allele approximately doubled the patient's risk of grade 2+ neuropathy (P = 0.004), and non-Europeans were at higher neuropathy risk than Europeans of similar genotype (P = 0.030). CONCLUSIONS: The increased risk of paclitaxel-induced neuropathy in patients who carry the CYP2C8*3 variant was replicated in two racially distinct patient cohorts.

Intravenous glucose suppresses glucose production but not proteolysis in extremely premature newborns.

To ascertain whether the inability to suppress glucose production and increase glucose utilization in response to glucose infusion is an inherent characteristic of immature individuals, we determined glucose rate of appearance (R(a)) in minimally stressed, clinically stable, extremely premature infants (approximately 26-wk gestation) at two glucose infusion rates (6.2 +/- 0.4 and 9.5 +/- 0.5 mg/kg per min). We also assessed whether an increase in glucose delivery suppresses proteolysis by measuring the R(a) of phenylalanine and leucine. Glucose R(a) (and utilization) increased significantly at the higher glucose infusion rate (7.9 +/- 0.5 vs. 9.8 +/- 0.6 mg/kg per min). Glucose production persisted at the lower glucose infusion rate but was suppressed to nearly zero at the higher rate (1.7 +/- 0.5 vs. 0.3 +/- 0.1 mg/kg per min). Proteolysis was unaffected by the higher glucose infusion rate as reflected by no change in the rates of appearance of either phenylalanine (96 +/- 5 vs. 95 +/- 3 mumol/kg per h) or leucine (285 +/- 20 vs. 283 +/- 14 mumol/kg per h). Thus, clinically stable, extremely premature infants suppress glucose production and increase glucose utilization in response to increased glucose infusion, demonstrating no inherent immaturity of these processes. In contrast, increasing the rate of glucose delivery results in no change in whole body proteolysis in these infants. The regulation of proteolysis in this population remains to be defined.

Study of exclusive charmless semileptonic B decays and |Vub|.

We study semileptonic B decay to the exclusive charmless states pi, rho/omega, eta, and eta;{'} using the 16 fb(-1) CLEO Upsilon(4S) data sample. We find B(B0-->pi-l+nu)=(1.37+/-0.15stat+/-0.11sys)x10(-4) and B(B0-->rho-l+nu)=(2.93+/-0.37stat+/-0.37sys)x10(-4) and find evidence for B+-->eta'l+nu, with B(B+-->eta'l+nu)=(2.66+/-0.80stat+/-0.56sys)x10(-4). From our B-->pilnu rate for q2>16 GeV2 and lattice QCD, we find |Vub|=(3.6+/0.4stat+/0.2syst-0.4thy+0.6)x10(-3) [corrected]

Integrated patient and tumor genetic testing for individualized cancer therapy.

Tumor genome analysis is transforming cancer treatment by enabling identification of specific oncogenic drivers and selection of effective targeted agents. Meanwhile, patient genome analysis is being employed across therapeutic areas to inform selection of appropriate drugs and doses for treatment safety. Integration of patient genome analysis concurrent with preemptive tumor genetic testing will enable oncologists to make informed treatment decisions to select the right dose of the right drug for each patient and their tumor.

Insulin binding to erythrocytes of normal infants, children, and adults: variation with age and sex.

The assay of insulin receptors on erythrocytes requires only small amounts of blood and has made it possible to characterize insulin binding in infancy and childhood. To establish normal insulin-binding criteria, we studied 125I binding to insulin receptors on erythrocytes from a large number of normal subjects, including 15 term deliveries, 45 prepubertal children (aged 2 months-12 yr), 15 adult women, and 15 adult men. Insulin binding to cord erythrocytes was significantly higher at tracer and physiological insulin concentrations than binding to cells from any other age group (P less than 0.001). In the prepubertal children after the newborn period, insulin binding was not related to age or sex and did not differ significantly from the binding to cells from adult women. Erythrocytes from adult males, however, bound significantly higher amounts of insulin than did those from adult women or prepubertal children at all insulin concentrations tested (P less than 0.01). Increased binding to cord erythrocytes appeared to be due to an increase in receptor affinity, while the increased binding in adult males was primarily a result of increased receptor concentration. The data confirm previous reports of increased insulin binding to fetal cells and indicate that erythrocyte insulin binding stabilizes at levels similar to those in adult females by the age of 2 months. The increased binding of insulin to erythrocytes from adult males compared to binding to erythrocytes from children or adult females suggests that androgens may increase erythrocyte insulin binding over prepubertal levels.

Infertility and the physician--patient relationship: a biopsychosocial challenge.

Research to date has not been able to dispel controversy over the question of "psychogenicity" of infertility. Increasing numbers of studies suggest that neuroendocrinological factors play a role in what is most likely a multidetermined condition. Whatever the etiology, and whether infertility occurs spontaneously (e.g., anovulation) or by choice (e.g., surgical sterilization), the physician must be alert to the special needs of the patient, to the environmental setting, and to the intricate interplay between infertility and emotional reaction. The physician-patient relationship as a triadic rather than dyadic relationship introduces unique transference and counter-transference considerations which must be an acknowledged part of evaluation and treatment.

Factors influencing the evaluation of psychological and psychosomatic reactions in survivors of the Nazi persecution.

Since the termination of World War II, Psychiatry has been challenged with the difficult task of the evaluation of the survivors of the Nazi persecution. The psychiatric sequelae of this era reflect direct connection between the different clinical manifestations and syndromes and the conglomeration of manifold physical and psychological traumas to which the survivors have been exposed, often during a prolonged period of time lasting through several years. The present paper examines the important but somehow neglected, and often intentionally avoided, issue: namely, the review of the problems and reactions which psychiatrists, dealing with the medical examination of survivors for the purpose of reparations' evaluation, may encounter. The confrontation of the different views of psychiatric experts may frequently be complicated by deep-seated emotional issues, related to their identity. The evaluation becomes even more complex when Israeli and German experts review each others' findings. The study summarizes the different psychological mechanisms involved in the process of evaluation. Pitfalls related to inadequate use of mechanisms of defence are pointed out and suggestions for the proper ways of co-operation in the establishment of proper psychiatric and psychosomatic diagnosis are presented.

Initial-impression diagnosis using low-back pain patient pain drawings.

Patient pain drawings were blindly selected from five lumbar spine disorder categories. The drawings were classified by low-back physicians, discriminant analysis, and several computerized artificial neural network configurations. The purpose was to determine the reliability of the patient pain drawing when diagnosing low-back disorders and to delineate the pain mark patterns particular to each disorder by comparing physicians with computerized methods. The physicians averaged 51% accuracy with individual preferences for certain disorder groups. The computerized methods demonstrated comparable accuracy (48%) and more agreement in classification. Associations were found between the predicted pain patterns for each diagnostic group made by an expert and the patterns generated by computerized methods. Variances in these associations are instructive to clinicians for making accurate predictions of diagnosis from pain drawings.

Sepsis in asymptomatic term newborns delivered of antibiotic-treated mothers.

This study was undertaken to assess the incidence of culture-proved sepsis in term infants without symptoms born to mothers receiving intrapartum antibiotics and to determine the usefulness of the immature neutrophil: total neutrophil (I:T) ratio in the initial evaluation of these infants. A retrospective chart review was made of 103 infants born during a 3-year period. There was one positive blood culture and two positive cerebrospinal fluid cultures in three different patients; all three isolates were considered contaminants and all patients remained without symptoms. In spite of the lack of culture-proved sepsis and clinical illness, more than 50% of the initial I:T ratios were greater than the usually accepted upper limit of normal (that is, 0.16). We conclude that the incidence of sepsis in this population is very low and the initial I:T ratio is not useful as a predictive tool in term newborns without symptoms.

Comparison of DNA probe technology and automated continuous-monitoring blood culture systems in the detection of neonatal bacteremia.

OBJECTIVE: The present study assessed the ability of a rapid chemiluminescent DNA probe assay to detect bacterial growth in blood culture specimens before their detection by continuous-monitoring blood culture (CMBC) systems. STUDY DESIGN: Three newborn intensive care units, which are members of the National Institute of Child Health and Human Development Neonatal Research Network, participated in this study. Each center employs an automated CMBC system against which the DNA probe was compared. A total of 1700 blood cultures were analyzed. A 3-ml aliquot of culture medium was removed from each culture during early incubation, processed, and analyzed by the DNA probe. RESULTS: Of 1700 blood cultures, 130 (7.6%) were detected positive by a CMBC system. Coagulase-negative staphylococci (CNS) were present in 90 (69%) of the positive cultures, and 26 (29%) were detected by the DNA probe. Other organisms accounted for the remaining 40 positive cultures, and 31 (78%) of these were detected by the probe assay. Seventy-six percent of all positive cultures were detected by a CMBC system within 24 hours. Ninety-eight percent of all positive cultures were detected by a CMBC system within 48 hours. Of the two organisms that grew in a CMBC system beyond 48 hours, both were CNS and one of these was considered a contaminant. Therefore, 99% of clinically significant organisms were detected by a CMBC system within 48 hours. CONCLUSION: This DNA probe is not sufficiently sensitive to be clinically useful; however, automated CMBC systems are sufficiently sensitive to aid in clinical decision-making regarding the continuance or discontinuance of antibiotic therapy following 48 hours of culture incubation.

Bio-psycho-social consequences of migration stress: a multidimensional approach.

This paper emphasizes the complexity of contemporary migration research. It presents the different choices for investigation, namely the biological, psychological and social aspects. Different clinical findings are presented that are found in migrant groups, individuals and families ranging from temporary crisis situations to adjustment difficulties, leading eventually to maladjustment.

Trauma and nostalgia: new aspects on the coping of aging Holocaust survivors.

This paper examines the coping mechanism of aging survivors of the Holocaust with the extreme traumatic stressors they experienced in the past. Differences in the role of memories, reminiscences and nostalgic longings are presented. The potential role of sensory stimuli in the development of reminiscences and nostalgic feelings is emphasized. The comparison of the genesis of reminiscences and nostalgic phenomena may offer additional parameters for the understanding of the symptom formation in the elderly.