Evaluation and comparison of covariate balance metrics in studies with time-dependent confounding.

Marginal structural models have been increasingly used by analysts in recent years to account for confounding bias in studies with time-varying treatments. The parameters of these models are often estimated using inverse probability of treatment weighting. To ensure that the estimated weights adequately control confounding, it is possible to check for residual imbalance between treatment groups in the weighted data. Several balance metrics have been developed and compared in the cross-sectional case but have not yet been evaluated and compared in longitudinal studies with time-varying treatment. We have first extended the definition of several balance metrics to the case of a time-varying treatment, with or without censoring. We then compared the performance of these balance metrics in a simulation study by assessing the strength of the association between their estimated level of imbalance and bias. We found that the Mahalanobis balance performed best. Finally, the method was illustrated for estimating the cumulative effect of statins exposure over one year on the risk of cardiovascular disease or death in people aged 65 and over in population-wide administrative data. This illustration confirms the feasibility of employing our proposed metrics in large databases with multiple time-points.

Does socio-economic status influence the effect of multimorbidity on the frequent use of ambulatory care services in a universal healthcare system? A population-based cohort study.

BACKGROUND: Frequent healthcare users place a significant burden on health systems. Factors such as multimorbidity and low socioeconomic status have been associated with high use of ambulatory care services (emergency rooms, general practitioners and specialist physicians). However, the combined effect of these two factors remains poorly understood. Our goal was to determine whether the risk of being a frequent user of ambulatory care is influenced by an interaction between multimorbidity and socioeconomic status, in an entire population covered by a universal health system. METHODS: Using a linkage of administrative databases, we conducted a population-based cohort study of all adults in Quebec, Canada. Multimorbidity (defined as the number of different diseases) was assessed over a two-year period from April 1st 2012 to March 31st 2014 and socioeconomic status was estimated using a validated material deprivation index. Frequents users for a particular category of ambulatory services had a number of visits among the highest 5% in the total population during the 2014-15 fiscal year. We used ajusted logistic regressions to model the association between frequent use of health services and multimorbidity, depending on socioeconomic status. RESULTS: Frequent users (5.1% of the population) were responsible for 25.2% of all ambulatory care visits. The lower the socioeconomic status, the higher the burden of chronic diseases, and the more frequent the visits to emergency departments and general practitioners. Socioeconomic status modified the association between multimorbidity and frequent visits to specialist physicians: those with low socioeconomic status visited specialist physicians less often. The difference in adjusted proportions of frequent use between the most deprived and the least deprived individuals varied from 0.1% for those without any chronic disease to 5.1% for those with four or more chronic diseases. No such differences in proportions were observed for frequent visits to an emergency room or frequent visits to a general practitioner. CONCLUSION: Even in a universal healthcare system, the gap between socioeconomic groups widens as a function of multimorbidity with regard to visits to the specialist physicians. Further studies are needed to better understand the differential use of specialized care by the most deprived individuals.

Combined impacts of multimorbidity and mental disorders on frequent emergency department visits: a retrospective cohort study in Quebec, Canada.

BACKGROUND: Multimorbidity and mental disorders are independently associated with frequent visits to the emergency department (≥ 3 visits/yr), but their interaction has been little studied. We aimed to measure the interaction between mental disorders and physical multimorbidity with respect to frequent visits to the emergency department. METHODS: We conducted a population-based cohort study of adults in Quebec from 2012 to 2016, using the Quebec Integrated Chronic Disease Surveillance System. We assessed multimorbidity as the number of physical illnesses and mental disorders as serious (psychotic or bipolar disorders), common or absent, using data from 2012 to 2014. We counted emergency department visits from 2014 to 2015. We used logistic regression to estimate interaction on frequent visits to the emergency department from 2 perspectives: of public health (additive scale as differences in risk) and of individual patients (multiplicative scale as odds ratios). RESULTS: Each additional physical illness was associated with a greater increase in the absolute risk of frequent visits to the emergency department for people with mental disorders. Between 0 and ≥ 4 physical conditions, the absolute risk increased more for individuals with serious mental disorders (16.2%) than common (15.3%) or no disorders (11.4%). On the relative scale, for people with no mental disorders and ≥ 4 physical conditions, odds of frequent visits to the emergency department were 6.2 (95% confidence interval [CI] 6.08-6.35) times the odds for people with no physical conditions. For individuals with common and serious mental illnesses, corresponding odds ratios were 4.75 (95% CI 4.60-4.90) and 3.7 (95% CI 3.18-3.57), respectively. INTERPRETATION: Mental disorders interact with physical multimorbidity to increase the odds of frequent visits to the emergency department. More research is needed on interventions that promote high-quality care for mental illness, especially in the context of physical multimorbidity.

Validation of the Combined Comorbidity Index of Charlson and Elixhauser to Predict 30-Day Mortality Across ICD-9 and ICD-10.

OBJECTIVES: To validate and compare performance of an International Classification of Diseases, tenth revision (ICD-10) version of a combined comorbidity index merging conditions of Charlson and Elixhauser measures against individual measures in the prediction of 30-day mortality. To select a weight derivation method providing optimal performance across ICD-9 and ICD-10 coding systems. RESEARCH DESIGN: Using 2 adult population-based cohorts of patients with hospital admissions in ICD-9 (2005, n=337,367) and ICD-10 (2011, n=348,820), we validated a combined comorbidity index by predicting 30-day mortality with logistic regression. To appreciate performance of the Combined index and both individual measures, factors impacting indices performance such as population characteristics and weight derivation methods were accounted for. We applied 3 scoring methods (Van Walraven, Schneeweiss, and Charlson) and determined which provides best predictive values. RESULTS: Combined index [c-statistics: 0.853 (95% confidence interval: CI, 0.848-0.856)] performed better than original Charlson [0.841 (95% CI, 0.835-0.844)] or Elixhauser [0.841 (95% CI, 0.837-0.844)] measures on ICD-10 cohort. All weight derivation methods provided close high discrimination results for the Combined index (Van Walraven: 0.852, Schneeweiss: 0.851, Charlson: 0.849). Results were consistent across both coding systems. CONCLUSIONS: The Combined index remains valid with both ICD-9 and ICD-10 coding systems and the 3 weight derivation methods evaluated provided consistent high performance across those coding systems.

Involving patient in the early stages of health technology assessment (HTA): a study protocol.

BACKGROUND: Public and patient involvement in the different stages of the health technology assessment (HTA) process is increasingly encouraged. The selection of topics for assessment, which includes identifying and prioritizing HTA questions, is a constant challenge for HTA agencies because the number of technologies requiring an assessment exceeds the resources available. Public and patient involvement in these early stages of HTA could make assessments more relevant and acceptable to them. Involving them in the development of the assessment plan is also crucial to optimize their influence and impact on HTA research. The project objectives are: 1) setting up interventions to promote patient participation in three stages of the HTA process: identification of HTA topics, prioritization, and development of the assessment plan of the topic prioritized; and 2) assessing the impact of patient participation on the relevance of the topics suggested, the prioritization process, and the assessment plan from the point of view of patients and other groups involved in HTA. METHODS: Patients and their representatives living in the catchment area of the HTA Roundtable of Université Laval's Integrated University Health Network (covering six health regions of the Province of Quebec, Canada) will be involved in the following HTA activities: 1) identification of potential HTA topics in the field of cancer; 2) revision of vignettes developed to inform the prioritization of topics; 3) participation in deliberation sessions for prioritizing HTA topics; and 4) development of the assessment plan of the topic prioritized. The research team will coordinate the implementation of these activities and will evaluate the process and outcomes of patient involvement through semi-structured interviews with representatives of the different stakeholder groups, structured observations, and document analysis, mainly involving the comparison of votes and topics suggested by various stakeholder groups. DISCUSSION: This project is designed as an integrated approach to knowledge translation and will be conducted through a close collaboration between researchers and knowledge users at all stages of the project. In response to the needs expressed by HTA producers, the knowledge produced will be directly useful in guiding practices regarding patient involvement in the early phases of HTA.

A comparative analysis of medication counting methods to assess polypharmacy in medico-administrative databases.

BACKGROUND: The variety of methods for counting medications may lead to confusion when attempting to compare the extent of polypharmacy across different populations. OBJECTIVE: To compare the prevalence estimates of polypharmacy derived from medico-administrative databases, using different methods for counting medications. METHODS: Data were drawn from the Québec Integrated Chronic Disease Surveillance System. A random sample of 110,000 individuals aged >65 was selected, including only those who were alive and covered by the public drug plan during the one-year follow-up. We used six methods to count medications: #1-cumulative one-year count, #2-average of four quarters' cumulative counts, #3-count on a single day, #4-count of medications used in first and fourth quarters, #5-count weighted by duration of exposure, and #6-count of uninterrupted medication use. Polypharmacy was defined as ≥5 medications. Cohen's Kappa was calculated to assess the level of agreement between the methods. RESULTS: A total of 93,516 (85 %) individuals were included. The prevalence of polypharmacy varied across methods. The highest prevalence was observed with cumulative methods (#1:74.1 %; #2:61.4 %). Single day count (#3:47.6 %), first and fourth quarters count (#4:49.5 %), and weighted count (#5:46.6 %) yielded similar results. The uninterrupted use count yielded the lowest estimate (#6:35.4 %). The weighted method (#5) showed strong agreement with the first and fourth quarters count (#4). Cumulative methods identified higher proportions of younger, less multimorbid individuals compared to other methods. CONCLUSION: Counting methods significantly affect polypharmacy prevalence estimates, necessitating their consideration when comparing and interpretating results.

Effect of statin use for the primary prevention of cardiovascular disease among older adults: a cautionary tale concerning target trials emulation.

OBJECTIVES: Evidence concerning the effect of statins in primary prevention of cardiovascular disease (CVD) among older adults is lacking. Using Quebec population-wide administrative data, we emulated a hypothetical randomized trial including older adults >65 years on April 1, 2013, with no CVD history and no statin use in the previous year. STUDY DESIGN AND SETTING: We included individuals who initiated statins and classified them as exposed if they were using statin at least 3 months after initiation and nonexposed otherwise. We followed them until March 31, 2018. The primary outcome was the composite endpoint of coronary events (myocardial infarction, coronary bypass, and percutaneous coronary intervention), stroke, and all-cause mortality. The intention-to-treat (ITT) effect was estimated with adjusted Cox models and per-protocol effect with inverse probability of censoring weighting. RESULTS: A total of 65,096 individuals were included (mean age = 71.0 ± 5.5, female = 55.0%) and 93.7% were exposed. Whereas we observed a reduction in the composite outcome (ITT-hazard ratio (HR) = 0.75; 95% CI: 0.68-0.83) and mortality (ITT-HR = 0.69; 95% CI: 0.61-0.77) among exposed, coronary events increased (ITT-HR = 1.46; 95% CI: 1.09-1.94). All multibias E-values were low indicating that the results were not robust to unmeasured confounding, selection, and misclassification biases simultaneously. CONCLUSION: We cannot conclude on the effectiveness of statins in primary prevention of CVD among older adults. We caution that an in-depth reflection on sources of biases and careful interpretation of results are always required in observational studies.

Marginal structural models with latent class growth analysis of treatment trajectories: Statins for primary prevention among older adults.

Latent class growth analysis is increasingly proposed as a solution to summarize the observed longitudinal treatment into a few distinct groups. When latent class growth analysis is combined with standard approaches like Cox proportional hazards models, confounding bias is not properly addressed because of time-varying covariates that have a double role of confounders and mediators. We propose to use latent class growth analysis to classify individuals into a few latent classes based on their medication adherence pattern, then choose a working marginal structural model that relates the outcome to these groups. The parameter of interest is defined as a projection of the true marginal structural model onto the chosen working model. Simulation studies are used to illustrate our approach and compare it with unadjusted, baseline covariates adjusted, time-varying covariates adjusted, and inverse probability of trajectory groups weighted adjusted models. Our proposed approach yielded estimators with little or no bias and appropriate coverage of confidence intervals in these simulations. We applied our latent class growth analysis and marginal structural model approach to a database comprising information on 52,790 individuals from the province of Quebec, Canada, aged more than 65 and who were statin initiators to estimate the effect of statin-usage trajectories on a first cardiovascular event.

Gonadotropin-releasing hormone agonists in the treatment of prostate cancer.

In 1979, the first prostate cancer patient was treated with a GnRH agonist at the Laval University Medical Center in Quebec City, Canada, thus rapidly leading to the worldwide replacement of surgical castration and high doses of estrogens. The discovery of medical castration with GnRH agonists was soon followed by fundamental changes in the endocrine therapy of prostate cancer. Most importantly, the excellent tolerance accompanying the treatment with GnRH agonists has been a key factor that permitted a series of studies demonstrating a major reduction in the death rate from prostate cancer ranging from 31 to 87% at 5 yr of follow-up in patients with localized or locally advanced prostate cancer. In fact, a one third reduction in prostate cancer deaths has been calculated in the metaanalysis of all available studies. The general acceptance of this discovery by patients and physicians is illustrated by world sales above 3.0 billion U.S. dollars in 2003. Although extremely efficient in achieving complete medical castration and well tolerated, with no other side effects than the expected hypoandrogenicity, GnRH agonists should not be administered alone. In fact, shortly after discovery of the castration effects of GnRH agonists, we observed that approximately 50% of androgens remain in the prostate after castration, thus leading to the recognition of the role of adrenal dehydroepiandrosterone as an important source of the androgens synthesized locally in the prostate and in many peripheral target tissues. We therefore developed combined androgen blockade (CAB), whereby the androgens of both testicular and adrenal origins are blocked simultaneously at start of treatment with the combination of a GnRH agonist to block the testis and a pure antiandrogen to block the action of the androgens produced locally. CAB, first used in advanced metastatic disease, has been the first treatment shown to prolong life in prostate cancer. Most interestingly, in 2002, we made the observation that CAB alone given continuously for 6.5 yr or more leads to cure of the disease in at least 90% of cases, thus suggesting that androgen blockade combining a GnRH agonist and a pure antiandrogen could well be the most efficient treatment of localized prostate cancer, and thus offering the possibility of practically eliminating death from prostate cancer.

Metabolism of DHEA in postmenopausal women following percutaneous administration.

The marked decline in serum dehydroepiandrosterone (DHEA) with age is believed to play a role in health problems associated with aging, these health issues being potentially preventable or reversible by the exogenous administration of DHEA. In the present study, liquid chromatography/mass spectrometry/mass spectrometry (LC/MS/MS) and gas chromatrography/mass spectrometry (GC/MS) were used to measure the serum levels of DHEA and 11 of its metabolites in seventy-five 60-65-year-old Caucasian women who received 3g of 0.1%, 0.3%, 1.0% or 2.0% DHEA cream or placebo applied twice daily on the face, upper chest, arms and legs. The serum levels of DHEA increased 574% over control at the 2.0% DHEA dose while the sum of the androgen metabolites androsterone glucuronide (ADT-G), 3alpha-androstenediol-3G (3alpha-diol-3G) and 3alpha-diol-17G increased by only 231%. On the other hand, serum testosterone and dihydrosterone were increased by 192% and 275%, respectively, above basal levels compared to 139% and 158% for estrone and estradiol. Such data show that the transformation of exogenous DHEA in postmenopausal women is preferentially into androgens rather than into estrogens. On the other hand, the present data indicate that serum DHEA measurements following DHEA supplementation in postmenopausal women are an overestimate of the formation of active androgens and estrogens and suggest a decreased efficiency of transformation of DHEA into androgens and estrogens with aging.

Androgen glucuronides, instead of testosterone, as the new markers of androgenic activity in women.

Despite the long series of cohort studies performed during the last 20 years, the correlation between serum testosterone and any clinical situation believed to be under androgen control in women has remained elusive. This is likely related to the recent finding that the androgens made locally in large amounts in peripheral tissues from the precursor dehydroepiandrosterone (DHEA) act in the same cells where synthesis takes place and are not released in significant amounts in the circulation, thus making unreliable the measurement of serum testosterone as marker of total androgenic activity. The objective is to determine if serum androgen glucuronides can be replaced by testosterone or another steroid as measure of androgenic activity. Since the glucuronide derivatives of androgens are the obligatory route of elimination of all androgens, these metabolites were measured by liquid chromatography tandem mass spectrometry under basal conditions in 377 healthy postmenopausal women aged 55-65 years as well as in 47 premenopausal women aged 30-35 years while testosterone was assayed by gas chromatography mass spectrometry. No correlation was found between the serum concentration of testosterone and that of androsterone glucuronide (ADT-G) or androstenediol glucuronide (3alpha-diol-G), the androgen metabolites which account for the total pool of androgens. The present data show that measurement of the total pool of androgens reflected by the serum levels of ADT-G and 3alpha-diol-G cannot be replaced by serum testosterone or any other steroid, including DHEA or DHEA sulphate. These findings may have implications for women with androgen deficiency involving osteoporosis, obesity, type 2 diabetes, sexual dysfunction, loss of muscular strength and a series of other clinical situations affecting women's health. Measuring ADT-G and 3alpha-diol-G might identify cases of true androgen deficiency and provide an opportunity to offer appropriate androgen therapy.

Understanding cancer networks better to implement them more effectively: a mixed methods multi-case study.

BACKGROUND: Managed cancer networks are widely promoted in national cancer control programs as an organizational form that enables integrated care as well as enhanced patient outcomes. While national programs are set by policy-makers, the detailed implementation of networks is delegated at the service delivery and institutional levels. It is likely that the capacity to ensure more integrated cancer services requires multi-level governance processes responsive to the strengths and limitations of the contexts and capable of supporting network-based working. Based on an empirical case, this study aims to analyze the implementation of a mandated cancer network, focusing on governance and health services integration as core concepts in the study. METHODS/DESIGN: This nested multi-case study uses mixed methods to explore the implementation of a mandated cancer network in Quebec, a province of Canada. The case is the National Cancer Network (NCN) subdivided into three micro-cases, each defined by the geographic territory of a health and social services region. For each region, two local health services centers (LHSCs) are selected based on their differences with respect to determining characteristics. Qualitative data will be collected from various sources using three strategies: review of documents, focus groups, and semi-directed interviews with stakeholders. The qualitative data will be supplemented with a survey that will measure the degree of integration as a proxy for implementation of the NCN. A score will be constructed, and then triangulated with the qualitative data, which will have been subjected to content analysis. Qualitative, quantitative, and mixed methods data will be interpreted within and across cases in order to identify governance patterns similarities and differences and degree of integration in contexts. DISCUSSION: This study is designed to inform decision-making to develop more effective network implementation strategies by thoroughly describing multi-level governance processes of a sample of settings that provide cancer services. Although the study focuses on the implementation of a cancer network in Quebec, the rich descriptions of multiple nested cases will generate data with a degree of generalizability for health-care systems in developed countries.

Barriers and facilitators to implementing continuous quality improvement programs in colonoscopy services: a mixed methods systematic review.

BACKGROUND AND AIM: Continuous quality improvement (CQI) programs may result in quality of care and outcome improvement. However, the implementation of such programs has proven to be very challenging. This mixed methods systematic review identifies barriers and facilitators pertaining to the implementation of CQI programs in colonoscopy services and how they relate to endoscopists, nurses, managers, and patients. METHODS: We developed a search strategy adapted to 15 databases. Studies had to report on the implementation of a CQI intervention and identified barriers or facilitators relating to any of the four groups of actors directly concerned by the provision of colonoscopies. The quality of the selected studies was assessed and findings were extracted, categorized, and synthesized using a generic extraction grid customized through an iterative process. RESULTS: We extracted 99 findings from the 15 selected publications. Although involving all actors is the most cited factor, the literature mainly focuses on the facilitators and barriers associated with the endoscopists' perspective. The most reported facilitators to CQI implementation are perception of feasibility, adoption of a formative approach, training and education, confidentiality, and assessing a limited number of quality indicators. Receptive attitudes, a sense of ownership and perceptions of positive impacts also facilitate the implementation. Finally, an organizational environment conducive to quality improvement has to be inclusive of all user groups, explicitly supportive, and provide appropriate resources. CONCLUSION: Our findings corroborate the current models of adoption of innovations. However, a significant knowledge gap remains with respect to barriers and facilitators pertaining to nurses, patients, and managers.

Activity and safety of the antiestrogen EM-800, the orally active precursor of acolbifene, in tamoxifen-resistant breast cancer.

PURPOSE: To determine the efficacy and safety of EM-800 (SCH-57050), the precursor of acolbifene, a new, highly potent, orally active, pure antiestrogen in the mammary gland and endometrium, for the treatment of tamoxifen-resistant breast cancer. PATIENTS AND METHODS: Forty-three post menopausal/ovariectomized women with breast cancer who had received tamoxifen, either for metastatic disease or as adjuvant to surgery for > or = 1 year, and had relapsed were treated in a prospective, multicenter, phase II study with EM-800 (20 mg/d [n = 21] or 40 mg/d [n = 22] orally). Results Thirty-seven patients had estrogen receptor (ER)-positive tumors (>10 fmol/mg; mean, 146 fmol/mg cytosolic protein), three patients had ER-negative/progesterone receptor-positive tumors, and three patients had undetermined ER status. The objective response rate to EM-800 was 12%, with one complete response and four partial responses. Ten patients (23%) had stable disease for > or = 3 months, and 7 patients (16%) had stable disease for > or = 6 months. With a median follow-up of 29 months, median duration of response was 8 months (range, 7 to 71+ months). Treatment with EM-800 was well tolerated. No significant adverse events related to the study drug were observed clinically or biochemically. CONCLUSION: EM-800 produced responses in a significant proportion of patients with tamoxifen-resistant breast cancer, thus showing that this highly potent, selective estrogen receptor modulator, which lacks estrogenic activity in the mammary gland and endometrium, has incomplete cross-resistance with tamoxifen, thus suggesting additional benefits in the treatment of breast cancer.

The combination of a novel selective estrogen receptor modulator with an estrogen protects the mammary gland and uterus in a rodent model: the future of postmenopausal women's health?

The Women's Health Initiative Study and other reports have created major uncertainty among postmenopausal women and physicians concerning hormone replacement therapy. We have thus investigated the possibility of replacing the progestin in hormone replacement therapy by a novel selective estrogen receptor (ER) modulator having potent and pure antiestrogenic activity in the mammary gland and uterus. As measured by changes in histology and Cdc47 labeling in the rat model, the present study shows that the stimulatory effect of estradiol in the mammary gland and uterus is efficiently blocked by simultaneous administration of the novel selective ER modulator EM-652, but bone mineral density is preserved and serum cholesterol is decreased. After the administration of 14C-labeled EM-652, we observed that there is no detectable radioactivity in the brain. Moreover, ER alpha immunoreactivity remained constant in the hypothalamus after EM-652 treatment, whereas ER alpha became almost undetectable in the mammary gland and uterus. The present data show the poor or absent access of EM-652 to the brain, whereas the effects of estrogens are efficiently neutralized in the mammary gland and uterus. Such data support the exciting possibility of a novel approach that could meet most of the needs of women's health at menopause, namely control of hot flushes and prevention of breast, uterine, and ovarian cancer as well as osteoporosis and potentially helping brain function and preventing Alzheimer's disease with no identifiable risk or negative effect.

Bioavailability and pharmacokinetics of dehydroepiandrosterone in the cynomolgus monkey.

We have studied the pharmacokinetics of dehydroepiandrosterone (DHEA) administered orally (PO), i.v., and during a continuous i.v. infusion in ovariectomized cynomolgus monkeys under suppression of adrenal DHEA secretion with dexamethasone. The glucocorticoid induced a rapid suppression of serum cortisol, DHEA, and DHEA-sulfate (DHEA-S) as well as their metabolites, thus permitting to use this model to study the pharmacokinetic parameters of DHEA and its metabolites without significant interference by endogenous steroid levels. After a single 10 mg i.v. dose of DHEA, the metabolic clearance rate and terminal half-life of DHEA were 99.9 +/- 9.1 liter/d and 4.5 +/- 0.3 h, respectively. Following a 50-mg DHEA PO dose, systemic availability was only 3.1 +/- 0.4%. As shown by their high conversion ratios, the major circulating metabolites of DHEA are DHEA-S, androsterone glucuronide, and androstane-3 alpha,17 beta-diol-glucuronide. The conversion ratios of androst-5-ene-3 beta,17 beta-diol, testosterone, dihydrotestosterone, and androstenedione are, in comparison, small. No transformation to estrogens could be detected in the circulation after either i.v. or PO DHEA administration. The present data indicate that DHEA is transformed predominantly into androgens in peripheral tissues in ovariectomized cynomolgus monkeys with minimal (androgens) or no (estrogens) release of the bioactive steroids in the circulation. Furthermore, the present study supports the importance of measuring circulating androgen glucuronide derivatives to assess hormonal exposure of peripheral tissues to androgens after DHEA administration.

Pharmacokinetics of oral dehydroepiandrosterone (DHEA) in the ovariectomised cynomolgus monkey.

Humans and primates are unique in having adrenals that secrete large amounts of DHEA and DHEA-S in the circulation. These steroids act as precursors of active androgens and estrogen's in a long series of peripheral target intracrine tissues. The marked decline of serum DHEA and DHEA-S concentrations with age in men and women has been incriminated in the development of various pathologies. This study provides detailed information on the effect of a single 50mg oral dose of DHEA on circulating estrogen's as well as androgens and their metabolites over 10h in adult ovariectomised (OVX) Cynomolgus monkeys. Serum DHEA, DHEA-S, testosterone (Testo) and androstenedione (4-dione) concentrations increased rapidly with a maximal value at approximately 1h after DHEA administration followed by a 60-80% decrease during the next 2-6h. An important sulfatation of DHEA occurs through first hepatic pass, thus, leading to a marked increase in serum DHEA-S. Serum androst-5-ene-3beta,17beta-diol and androsterone glucuronide (ADT-G) levels remained elevated on a plateau for 6h. Androstan-3alpha,17beta-diol-glucuronide, estradiol and estrone levels remained unchanged. The present data indicate the predominant transformation of the adrenal precursor DHEA into active androgens in peripheral tissues and support the importance of measurement of circulating glucuronide derivatives as index of peripheral or intracrine androgen formation and action.

Major impact of hormonal therapy in localized prostate cancer--death can already be an exception.

For about 50 years, androgen blockade in prostate cancer has been limited to monotherapy (surgical castration) or high doses of estrogens in patients with advanced disease and bone metastases. The discovery of medical castration with LHRH agonists has led to fundamental changes in the endocrine therapy of prostate cancer. In 1979, the first prostate cancer patient treated with an LHRH agonist received such treatment at the Laval University Medical Center. A long series of studies have clearly demonstrated that medical castration with an LHRH agonist has inhibitory effects on prostate cancer equivalent to those of surgical castration. The much higher acceptability of LHRH agonists has been essential to permit a series of studies in localized disease. Based upon the finding that the testicles and adrenals contribute approximately equal amounts of androgens in the human prostate, the combination of medical (LHRH agonist) or surgical castration associated with a pure antiandrogen (flutamide, nilutamide or bicalutamide) has led to the first demonstration of a prolongation of life in prostate cancer, namely a 10-20% decreased risk of death according to the various metaanalyses of all the studies performed in advanced disease. In analogy with the other types of advanced cancers, the success of combined androgen blockade in metastatic disease is limited by the development of resistance to treatment. To avoid the problem of resistance to treatment while taking advantage of the relative ease of diagnosis of prostate cancer at an "early" stage, the much higher acceptability of LHRH agonists has permitted a series of studies which have demonstrated a major reduction in deaths from prostate cancer ranging from 31% to 87% at 5 years of follow-up in patients with localized or locally advanced prostate cancer. Most importantly, recent data show that the addition of a pure antiandrogen to an LHRH agonist in order to block the androgens made locally in the prostate leads to a 90% long-term control or probable cure of prostate cancer.

[From the gene to the clinic: prostate cancer death can now be an exception?]. / De la biologie à la clinique : le décès dû au cancer de la prostate peut-il maintenant être une exception ?

The most significant discovery of the second half of the XXth century in the field of prostate cancer therapy is probably the observation that the human prostate, as well as many other peripheral human tissues, synthesize locally an important amount of androgens from the inactive steroid precursors dehydroepiandrosterone (DHEA) and its sulfate DHEA-S. In parallel with these observations, two important discoveries also made by our group are applied in the clinic worldwide, namely the use of LHRH (luteininizing hormone-releasing hormone) agonists to completely block testicular androgens, while, simultaneously, the androgens made locally in the prostate from DHEA are blocked in their access to the androgen receptor by a pure antiandrogen of the class of flutamide. This treatment, called combined androgen blockade, has been the first treatment demonstrated to prolong life in prostate cancer. While the first studies were performed in patients with advanced and metastatic disease, our recent data indicate a remarkable level of efficacy of the same treatment applied to localized prostate cancer, namely a 90% possibility of cure. However, in order to be able to treat localized prostate cancer, early diagnosis must be achieved. In the first large-scale randomized study of prostate cancer screening, we have demonstrated that 99% of prostate cancers can be diagnosed at the localized or potentially curable stage, using simple annual measurement of PSA (prostatic specific antigen). Today's data show that with the simple application of the available diagnostic and therapeutic tools, death from prostate cancer should be an exception.