A prospective genome-wide study of prostate cancer metastases reveals association of wnt pathway activation and increased cell cycle proliferation with primary resistance to abiraterone acetate-prednisone.

Background: Genomic aberrations have been identified in metastatic castration-resistant prostate cancer (mCRPC), but molecular predictors of resistance to abiraterone acetate/prednisone (AA/P) treatment are not known. Patients and methods: In a prospective clinical trial, mCRPC patients underwent whole-exome sequencing (n = 82) and RNA sequencing (n = 75) of metastatic biopsies before initiating AA/P with the objective of identifying genomic alterations associated with resistance to AA/P. Primary resistance was determined at 12 weeks of treatment using criteria for progression that included serum prostate-specific antigen measurement, bone and computerized tomography imaging and symptom assessments. Acquired resistance was determined using the end point of time to treatment change (TTTC), defined as time from enrollment until change in treatment from progressive disease. Associations of genomic and transcriptomic alterations with primary resistance were determined using logistic regression, Fisher's exact test, single and multivariate analyses. Cox regression models were utilized for determining association of genomic and transcriptomic alterations with TTTC. Results: At 12 weeks, 32 patients in the cohort had progressed (nonresponders). Median study follow-up was 32.1 months by which time 58 patients had switched treatments due to progression. Median TTTC was 10.1 months (interquartile range: 4.4-24.1). Genes in the Wnt/ß-catenin pathway were more frequently mutated and negative regulators of Wnt/ß-catenin signaling were more frequently deleted or displayed reduced mRNA expression in nonresponders. Additionally, mRNA expression of cell cycle regulatory genes was increased in nonresponders. In multivariate models, increased cell cycle proliferation scores (≥ 50) were associated with shorter TTTC (hazard ratio = 2.11, 95% confidence interval: 1.17-3.80; P = 0.01). Conclusions: Wnt/ß-catenin pathway activation and increased cell cycle progression scores can serve as molecular markers for predicting resistance to AA/P therapy.

Season's appreciations.

To follow the tradition set by the late Franz Halberg, highlights of research performed over the last year from his Minnesota Center are summarized. They illustrate the broad international cooperation enjoyed by his center and the diversity of applications of the discipline he founded. The results briefly summarized herein in the form of an annotated bibliography are a testimony that his legacy continues to live on and constitutes a tribute to his memory.

Geographically selective assortment of cycles in pandemics: meta-analysis of data collected by Chizhevsky.

In the incidence patterns of cholera, diphtheria and croup during the past when they were of epidemic proportions, we document a set of cycles (periods), one of which was reported and discussed by A. L. Chizhevsky in the same data with emphasis on the mirroring in human disease of the ~11-year sunspot cycle. The data in this study are based on Chizhevsky's book The Terrestrial Echo of Solar Storms and on records from the World Health Organization. For meta-analysis, we used the extended linear and nonlinear cosinor. We found a geographically selective assortment of various cycles characterizing the epidemiology of infections, which is the documented novel topic of this paper, complementing the earlier finding in the 21st century or shortly before, of a geographically selective assortment of cycles characterizing human sudden cardiac death. Solar effects, if any, interact with geophysical processes in contributing to this assortment.

Measurement, reconstruction, and flow-field computation of the human pharynx with application to sleep apnea.

Repetitive closure of the upper airway characterizes obstructive sleep apnea. It disrupts sleep causing excessive daytime drowsiness and is linked to hypertension and cardiovascular disease. Previous studies simulating the underlying fluid mechanics are based upon geometries, time-averaged over the respiratory cycle, obtained usually via MRI or CT scans. Here, we generate an anatomically correct geometry from data captured in vivo by an endoscopic optical technique. This allows quantitative real-time imaging of the internal cross section with minimal invasiveness. The steady inhalation flow field is computed using a k-ω shear-stress transport (SST) turbulence model. Simulations reveal flow mechanisms that produce low-pressure regions on the sidewalls of the pharynx and on the soft palate within the pharyngeal section of minimum area. Soft-palate displacement and side-wall deformations further reduce the pressures in these regions, thus creating forces that would tend to narrow the airway. These phenomena suggest a mechanism for airway closure in the lateral direction as clinically observed. Correlations between pressure and airway deformation indicate that quantitative prediction of the low-pressure regions for an individual are possible. The present predictions warrant and can guide clinical investigation to confirm the phenomenology and its quantification, while the overall approach represents an advancement toward patient-specific modeling.

BLOOD PRESSURE, HEART RATE AND MELATONIN CYCLES SYNCHRONIZATION WITH THE SEASON, EARTH MAGNETISM AND SOLAR FLARES.

Three spectral components with periods of about (~) 0.41, ~0.5 and ~1.0 year had been found with serially independent sampling in human circulating melatonin. The time series consisted of around-the-clock samples collected for 24 hours at 4-hour intervals from different patients over several years. Some of these components had been found to be circadian stage-dependent, the daytime measurements following mostly a circannual variation, whereas a half-year characterized the nighttime samples. The latter were incorporated into a circasemiannual map. The relative brevity of the series prevented a check for the coexistence of all three spectral components, even if each component seemed to have a raison d'être. In time series of transdisciplinary data, a 1.00-year synchronized component is interpreted as representing the seasons. The half-year may qualify the circannual waveform, but it is also a signature of geomagnetics. An ~0.41-year (~5-month) component is the signature of solar flares. It has been called a cis-half-year (cis = on this side of a half-year) and may be detected only intermittently. Charles L. Wolff predicted the existence, among others, of ~0.42- and ~0.56-year components as beat periods of rotations at different solar latitudes.The multiple components characterizing circulating melatonin could also be found in a (to our knowledge unique) data set of a clinically healthy scientist (RBS). Herein, we focus on vascular data self-measured by RBS as he aged from ~20 to ~60 years. A multi-component model consisting of cosine curves with periods of 0.41, 0.50 and 1.00 year was fitted to weekly means of systolic (S) and diastolic (D) blood pressure (BP) and heart rate (HR) collected ~5 times a day over 39 years by RBS. All three components can coexist for a while, although all of them are nonstationary in their characteristics and come and go by the criterion of statistical significance.Intermittently, BP and HR are synchronized selectively with one or the other aspect of RBS' physical environment, namely the seasons (at ~1.0 year), earth magnetism (at ~0.5 year) and/or solar flares (at ~0.42 year). Cosmic-biotic transfer of information, albeit hardly of energy (the biospheric amplitudes are very small) may be mediated in this set of frequency windows. As found earlier, RBS' circulation is also frequency-trapped environmentally in multidecadal windows, HR being locked into the transtridecadal Brückner, or rather Brückner-Egeson-Lockyer, BEL sunspot and terrestrial weather cycle, while his BP follows Hale's didecadal cycle in the changing polarity of sunspots.The ~0.41-year HR cycle may be associated with changes in solar flares, the cis-half-year amplitude of HR showing a cross-correlation coefficient of 0.79 with the total solar flare index (from both solar hemispheres) at a lag of ~3.2 years. The superposed time courses of these two variables indicate the presence of a shared Horrebow-Arago-Schwabe sunspot cycle of ~11 years, the cis-half-year in HR being more prominent after the total solar flare index reaches its ~11-year peak. Differences in the time-varying behavior of BP vs. HR are also described.

Managing obstruction of the central airways.

Lung cancer is the most common cause of cancer death in Australia, Europe and the USA. Up to 20-30% of these cancers eventually affect the central airways and result in reduced quality of life, dyspnoea, haemoptysis, post-obstructive pneumonia and ultimately death. Non-malignant processes may also lead to central airway obstruction and can have similar symptoms. With the development of newer technologies, the last 20 years have seen the emergence of the field of interventional pulmonology to deal specifically with the diagnosis and management of thoracic malignancy, including obstruction of the central airways. This review discusses the pathology, pre-procedure work-up and management options for obstructing central airway lesions. Several treatment modalities exist for dealing with endobronchial pathology with local availability and expertise guiding choice of treatment. While the literature lacks large, multicentre, randomized studies defining the optimal management strategy for a given problem, there is growing evidence from numerous case studies of improved physiology, of quality of life and possibly of survival with modern interventional techniques.

N0332 phase 2 trial of weekly irinotecan hydrochloride and docetaxel in refractory metastatic breast cancer: a North Central Cancer Treatment Group (NCCTG) Trial.

BACKGROUND: Because of the single-agent activity of irinotecan hydrochloride, combination of irinotecan and docetaxel treatment against metastatic breast cancer (MBC) should be evaluated. PATIENTS AND METHODS: Single-stage phase 2 study of irinotecan and docetaxel to evaluate tumor response, toxicity, time to progression, and overall survival was carried out. Regimen of docetaxel (25 mg/m(2)) and irinotecan (70 mg/m(2)) was administered on days 1 and 8 of each 3-week cycle. Patients had histologically confirmed breast adenocarcinoma and metastatic cancer measurable with RECIST. RESULTS: Of 70 patients enrolled, 64 were assessable. Prior treatment with an anthracycline and a taxane was required. Eighteen (28%) patients [95% confidence interval (CI) 15% to 31%] had tumor response, plus four patients had stable disease (less than 30% decrease in sum of longest diameter and less than 20% increase) for >6 months. The clinical benefit rate was 34% overall. Median duration of tumor response was 6.7 months (95% CI 4.2-37.7 months); median follow-up was 18.6 months (range 8.5-37.7 months). The most common severe adverse events included fatigue [n = 16 (25%)] and neutropenia [n = 13 (20%)]. CONCLUSIONS: Weekly dosing of combination of irinotecan and docetaxel is active against MBC. However, the response rate to our regimen was not significantly better than single-agent docetaxel. Other schedules of irinotecan plus docetaxel should be considered for future studies.

Measuring airway dimensions during bronchoscopy using anatomical optical coherence tomography.

Airway dimensions are difficult to quantify bronchoscopically because of optical distortion and a limited ability to gauge depth. Anatomical optical coherence tomography (aOCT), a novel imaging technique, may overcome these limitations. This study evaluated the accuracy of aOCT against existing techniques in phantom, excised pig and in vivo human airways. Three comparative studies were performed: 1) micrometer-derived area measurements in 10 plastic tubes were compared with aOCT-derived area; 2) aOCT-derived airway compliance curves from excised pig airways were compared with curves derived using an endoscopic technique; and 3) airway dimensions from the trachea to subsegmental bronchi were measured using aOCT in four anaesthetised patients during bronchoscopy and compared with computed tomography (CT) measurements. Measurements in plastic tubes revealed aOCT to be accurate and reliable. In pig airways, aOCT-derived compliance measurements compared closely with endoscopic data. In human airways, dimensions measured with aOCT and CT correlated closely. Bland-Altman plots showed that aOCT diameter and area measurements were higher than CT measurements by 7.6% and 15.1%, respectively. Airway measurements using aOCT are accurate, reliable and compare favourably with existing imaging techniques. Using aOCT with conventional bronchoscopy allows real-time measurement of airway dimensions and could be useful clinically in settings where knowledge of airway calibre is required.

North Central Cancer Treatment Group (NCCTG) N0432: phase II trial of docetaxel with capecitabine and bevacizumab as first-line chemotherapy for patients with metastatic breast cancer.

BACKGROUND: Docetaxel (T; Taxotere) with capecitabine (X) is active against metastatic breast cancer (MBC); bevacizumab (BV) has demonstrated efficacy with taxanes in the first-line setting. This study was conducted to assess the safety and efficacy of TX-BV in patients with MBC. PATIENTS AND METHODS: In this single-arm, multicenter phase II study, patients received first-line bevacizumab 15 mg/kg and docetaxel 75 mg/m(2) on day 1 and capecitabine 825 mg/m(2) twice per day on days 1-14 every 21 days. Primary and secondary end points were tumor response rate (RR), overall survival (OS), progression-free survival (PFS), and toxicity. RESULTS: A total of 45 assessable patients received TX-BV for a median of seven cycles. Two complete and 20 partial responses were observed (overall RR 49%); nine patients had stable disease >6 months, for a clinical benefit rate of 69%. Median response duration was 11.8 months. Median OS and PFS were 28.4 and 11.1 months, respectively. Grade 3/4 adverse events included hand-foot syndrome (29%), fatigue (20%), febrile neutropenia (18%), and diarrhea (18%). In cycles 3-10, median dose levels of docetaxel and capecitabine were 60 mg/m(2) and 660 mg/m(2), respectively. CONCLUSION: TX-BV demonstrated significant activity; dose modifications were required to manage drug-related toxic effects.

Quantifying tracheobronchial tree dimensions: methods, limitations and emerging techniques.

The ability to measure airway dimensions is important for clinicians, interventional bronchoscopists and researchers in order to accurately quantify structural abnormalities and track their changes over time or in response to treatment. Most quantitative airway measurements are based on X-ray computed tomography and, more recently, on multidetector computed tomography. Quantitative bronchoscopic techniques have also been developed, although these are less widely employed. Emerging techniques, including magnetic resonance imaging, endoscopic optical coherence tomography, endobronchial ultrasound and confocal endomicroscopy, provide new research tools with potential clinical applications. An understanding of issues related to the acquisition, processing and analysis of images, and how such issues impact on imaging the tracheobronchial tree, is essential in order to assess measurement accuracy and to make effective use of the newer methods. This article contributes to this understanding by providing a comprehensive review of current and emerging techniques for quantifying airway dimensions.

Nocturnal non-invasive nasal ventilation in stable hypercapnic COPD: a randomised controlled trial.

BACKGROUND: Sleep hypoventilation has been proposed as a cause of progressive hypercapnic respiratory failure and death in patients with severe chronic obstructive pulmonary disease (COPD). A study was undertaken to determine the effects of nocturnal non-invasive bi-level pressure support ventilation (NIV) on survival, lung function and quality of life in patients with severe hypercapnic COPD. METHOD: A multicentre, open-label, randomised controlled trial of NIV plus long-term oxygen therapy (LTOT) versus LTOT alone was performed in four Australian University Hospital sleep/respiratory medicine departments in patients with severe stable smoking-related COPD (forced expiratory volume in 1 s (FEV1.0) <1.5 litres or <50% predicted and ratio of FEV1.0 to forced vital capacity (FVC) <60% with awake arterial carbon dioxide tension (PaCO2) >46 mm Hg and on LTOT for at least 3 months) and age <80 years. Patients with sleep apnoea (apnoea-hypopnoea index >20/h) or morbid obesity (body mass index >40) were excluded. Outcome measures were survival, spirometry, arterial blood gases, polysomnography, general and disease-specific quality of life and mood. RESULTS: 144 patients were randomised (72 to NIV + LTOT and 72 to LTOT alone). NIV improved sleep quality and sleep-related hypercapnia acutely, and patients complied well with therapy (mean (SD) nightly use 4.5 (3.2) h). Compared with LTOT alone, NIV (mean follow-up 2.21 years, range 0.01-5.59) showed an improvement in survival with the adjusted but not the unadjusted Cox model (adjusted hazard ratio (HR) 0.63, 95% CI 0.40 to 0.99, p = 0.045; unadjusted HR 0.82, 95% CI 0.53 to 1.25, p = NS). FEV1.0 and PaCO2 measured at 6 and 12 months were not different between groups. Patients assigned to NIV + LTOT had reduced general and mental health and vigour. CONCLUSIONS: Nocturnal NIV in stable oxygen-dependent patients with hypercapnic COPD may improve survival, but this appears to be at the cost of worsening quality of life. TRIAL REGISTRATION NUMBER: ACTRN12605000205639.

Obesity and the lung: 3. Obesity, respiration and intensive care.

Obesity is a major problem from a public health perspective and a difficult practical matter for intensivists. The obesity pandemic has required treating clinicians to develop an appreciation of the substantial pathophysiological effects of obesity on the various organ systems. The important physiological concepts are illustrated by focusing on obstructive sleep apnoea, obesity hypoventilation syndrome, abdominal compartment syndrome and ventilatory management of the obese patient with acute respiratory distress syndrome.

Comparison of incremental and constant load tests of inspiratory muscle endurance in COPD.

The aim of the present study was to determine the relative value of incremental and constant load tests in detecting changes in inspiratory muscle endurance following high-intensity inspiratory muscle training (H-IMT) in chronic obstructive pulmonary disease. In total, 16 subjects (11 males; forced expiratory volume in one second (FEV(1)) 37.4+/-12.5%) underwent H-IMT. In addition, 17 subjects (11 males; FEV(1) 36.5+/-11.5%) underwent sham inspiratory muscle training (S-IMT). Training took place three times a week for 8 weeks. Baseline and post-training measurements were obtained of maximum threshold pressure sustained during an incremental load test (P(th,max)) and time breathing against a constant load (t(lim)). Breathing pattern was unconstrained. H-IMT increased P(th,max) and t(lim) relative to baseline and to any change seen following S-IMT. The effect size for P(th,max) was greater than for t(lim). Post-training tests were accompanied by changes in breathing pattern, including decreased duty cycle, which may have served to decrease inspiratory work and thereby contribute to the increase in P(th,max) and t(lim) in both groups. When assessing inspiratory muscle function in chronic obstructive pulmonary disease via tests in which the pattern of breathing is unconstrained, the current authors recommend incremental load tests be used in preference to constant load tests. However, to attribute changes in these tests to improvements in inspiratory muscle endurance, breathing pattern should be controlled.

High-intensity inspiratory muscle training in COPD.

The aim of the present study was to investigate the effects of an interval-based high-intensity inspiratory muscle training (H-IMT) programme on inspiratory muscle function, exercise capacity, dyspnoea and health-related quality of life (QoL) in subjects with chronic obstructive pulmonary disease. A double-blind randomised controlled trial was performed. Sixteen subjects (11 males, mean forced expiratory volume in one second (FEV(1)) 37.4+/-12.5%) underwent H-IMT performed at the highest tolerable inspiratory threshold load (increasing to 101% of baseline maximum inspiratory pressure). Seventeen subjects (11 males, mean FEV(1 )36.5+/-11.5%) underwent sham inspiratory muscle training (S-IMT) at 10% of maximum inspiratory pressure. Training took place three times a week for 8 weeks and was fully supervised. Pre- and post-training measurements of lung function, maximum inspiratory pressure, maximum threshold pressure, exercise capacity, dyspnoea and QoL (Chronic Respiratory Disease Questionnaire; CRDQ) were obtained. H-IMT increased maximum inspiratory pressure by 29%, maximum threshold pressure by 56%, 6-min walk distance by 27 m, and improved dyspnoea and fatigue (CRDQ) by 1.4 and 0.9 points per item, respectively. These changes were significantly greater than any seen following S-IMT. In conclusion, high-intensity inspiratory muscle training improves inspiratory muscle function in subjects with moderate-to-severe chronic obstructive pulmonary disease, yielding meaningful reductions in dyspnoea and fatigue.

A phase II trial of a combination of pemetrexed and gemcitabine in patients with metastatic breast cancer: an NCCTG study.

PURPOSE: This phase II study was undertaken to define the efficacy and toxicity of pemetrexed in combination with gemcitabine in patients with metastatic breast cancer. PATIENTS AND METHODS: Patients with measurable metastatic breast cancer who had previously received an anthracycline and a taxane in either the adjuvant or metastatic setting were treated with gemcitabine 1250 mg/m2 (intravenous; days 1 and 8) and pemetrexed 500 mg/m2 (intravenous; day 8) every 21 days. RESULTS: Fifty-nine patients received a median of five cycles (range one to 22) of treatment and were followed until death or for a median of 28 months (range 19.4-36.6) among living patients. Fourteen partial responses for an overall response rate of 24% [95% confidence interval (CI) 16% to 39%] were documented. Nine (15%; CI 5% to 32%) patients had stable disease for >6 months. The median survival time was 10.3 months (95% CI 8.3-18.9) and the 1 year survival rate was 49% (95% CI 38% to 64%). The median time to progression was estimated to be 3.7 months (95% CI 2.3-5.3). The most common grade 3 or 4 toxicities were neutropenia and thrombocytopenia in 83% and 27% of patients, respectively. Fourteen percent of patients experienced febrile neutropenia. Other common grade 3 or 4 non-hematological toxicities included fatigue (17%), dyspnea (15%), rash (7%) and anorexia (5%). CONCLUSIONS: The combination of pemetrexed and gemcitabine is clinically active, with an overall response rate of 24% in patients with metastatic breast cancer who have previously been treated with an anthracycline and a taxane. Myelosuppression (66% grade 4 neutropenia and 14% febrile neutropenia) was the major treatment-related toxicity observed for this combination.

The effect of interstate travel on sleep patterns of elite Australian Rules footballers.

The purpose of the current study was to examine the effect of interstate air travel on the quality and quantity of sleep in elite Australian Rules football players. Ten elite male athletes, who were members of a Western Australian-based Australian Football League (AFL) team, participated in the study. Sleep pattern was assessed by measuring sleep duration (SLD), sleep efficiency (SE), number of wakings (NW) and total wake time after sleep onset (WT) using a wrist-worn actigraph. Subjective sleep quality (SQ) was assessed using a scale of sleep rating. Throughout the 2002 AFL season, measurements were obtained on the night before (N1), the night of (N2) and the night after (N3) home and away games. Baseline measurements were obtained from five consecutive non-game nights. Compared to baseline, SLD on N1 was increased when home and away (by 51 and 105 mins respectively, p<0.05), while all other measures of sleep pattern were unchanged. On N2, SLD was decreased to a similar degree whether home or away (by 68 and 64 mins respectively, p<0.05), while all other measures of sleep pattern were unchanged. By N3 all measures of sleep pattern had returned to baseline values. Relative to baseline, perception of SQ was worst on N2 of a home game. This study has shown that interstate travel by elite AFL players has no adverse effects on sleep pattern on the night before a game.

The upper airway during anaesthesia.

Upper airway obstruction is common during both anaesthesia and sleep. Obstruction is caused by loss of muscle tone present in the awake state. The velopharynx, a particularly narrow segment, is especially predisposed to obstruction in both states. Patients with a tendency to upper airway obstruction during sleep are vulnerable during anaesthesia and sedation. Loss of wakefulness is compounded by depression of airway muscle activity by the agents, and depression of the ability to arouse, so they cannot respond adequately to asphyxia. Identifying the patient at risk is vital. Previous anaesthetic history and investigations of the upper airway are helpful, and a history of upper airway compromise during sleep (snoring, obstructive apnoeas) should be sought. Beyond these, risk identification is essentially a search for factors that narrow the airway. These include obesity, maxillary hypoplasia, mandibular retrusion, bulbar muscle weakness and specific obstructive lesions such as nasal obstruction or adenotonsillar hypertrophy. Such abnormalities not only increase vulnerability to upper airway obstruction during sleep or anaesthesia, but also make intubation difficult. While problems with airway maintenance may be obviated during anaesthesia by the use of aids such as the laryngeal mask airway (LMA( dagger )), identification of risk and caution are keys to management, and the airway should be secured before anaesthesia where doubt exists. If tracheal intubation is needed, spontaneous breathing until intubation is an important principle. Every anaesthetist should have in mind a plan for failed intubation or, worse, failed ventilation.

Radiographic (ILO) readings predict arterial oxygen desaturation during exercise in subjects with asbestosis.

BACKGROUND: Exercise impairment is common in subjects with asbestosis. Arterial oxygen desaturation during exercise is an important contributor to exercise limitation. The International Labour Office (ILO) classification of plain chest radiographs correlates with resting pulmonary function, but its value in predicting abnormal ventilatory responses to exercise, including desaturation, has not been explored. AIMS: To determine in subjects with asbestosis (1) if radiographic profusion scores and the extent of small irregular shadows on plain chest radiographs correlate with resting lung function and abnormal ventilatory responses to exercise; and (2) if radiographic scores add value to resting lung function tests in predicting abnormal ventilatory responses to exercise. METHODS: Thirty eight male subjects with asbestosis were included. Plain chest radiographs were read according to the ILO classification independently by three observers. All subjects underwent assessment of lung function and an incremental exercise test. RESULTS: Profusion scores and number of affected zones correlated significantly with the percentage predicted values of single breath diffusing capacity (DLCO), forced vital capacity (FVC), and total lung capacity (TLC). Arterial oxygen desaturation occurred in 29% of the subjects. The severity of desaturation correlated significantly with profusion and the number of affected zones. The combined use of number of affected zones, FEV(1)/FVC ratio and DLCO predicted desaturation during exercise with an explained variance of 41%. VO(2)max was significantly related only to DLCO but was not predicted by the ILO score. CONCLUSION: Arterial oxygen desaturation correlated with the profusion and extent of parenchymal abnormality on chest radiographs. The addition of morphological indices to physiological measurements is valuable for predicting oxygen desaturation during exercise but not for VO(2)max. Refinement of the radiographic scoring system and the addition of more sophisticated imaging techniques may further improve the predictive power.

A preliminary study of serum concentrations of soluble epidermal growth factor receptor (sErbB1), gonadotropins, and steroid hormones in healthy men and women.

Soluble ErbB (sErbB) growth factor receptors are being investigated as cancer biomarkers. Gonadotropic and steroid hormones have been shown to modulate the expression of ERBB family members in vivo. Accordingly, the range of sErbB1 values and their relationship to gonadotropic and steroid hormones need to be established in healthy subjects to provide a baseline for future clinical studies. We assayed sera from healthy men and women to determine p110 sErbB1 concentrations by acridinium-linked immunosorbent assay (ALISA). Follicle-stimulating hormone (FSH), estradiol, and testosterone concentrations were measured using the ACS:180 Immunoassay Analyzer. Luteinizing hormone (LH) and progesterone concentrations were quantified using the Access Immunoassay System. Unadjusted for age, p110 sErbB1 concentrations in healthy men and women do not differ significantly. However, sErbB1 concentrations show a strong age-gender interaction, increasing with age in men but decreasing with age in women. Consequently, sErbB1 concentrations are significantly higher in premenopausal women compared with either postmenopausal women or age-matched men and in age-matched men compared with postmenopausal women. Serum sErbB1 concentrations show significant negative associations with both FSH and LH concentrations in healthy women and a significant positive association with FSH concentrations in healthy men. Univariate linear regression models show that these respective gonadotropic hormones and age are independent predictors of sErbB1 concentrations in men and women. Multivariate models show that when age and FSH and LH concentrations are mutually adjusted for each other, they account for 22% of the variability observed in sErbB1 concentrations in healthy women. These data support the hypothesis that gonadotropic and steroid hormones may modulate ERBB1 expression in vivo and suggest that age- and gonadotropin-adjusted sErbB1 concentrations may be of clinical utility. Furthermore, these data demonstrate that gender, age, menstrual cycle phase, menopausal status, and exogenous hormone use must be considered when using serum p110 sErbB1 concentrations as cancer biomarkers.