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Results for “Surrogate variables analysis”

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At least 433 records · Page 24Linked to original sources

PubMed2000

Effect of citicoline on ischemic lesions as measured by diffusion-weighted magnetic resonance imaging. Citicoline 010 Investigators.

We examined the effect of the neuroprotective and neuroreparative agent citicoline on the growth of cerebral ischemic lesions in a double-blind placebo-controlled study involving patients with acute ischemic stroke using diffusion-weighted magnetic resonance imaging (DWI). Patients with acute ischemic stroke symptom onset 24 hours or less before the start of treatment, National Institutes of Health Stroke Scale (NIHSS) scores of 5 or higher, and lesions of 1 to 120 cc in cerebral gray matter by DWI were enrolled. DWI, T2-weighted magnetic resonance imaging (MRI), perfusion-weighted MRI, and magnetic resonance angiography were obtained at baseline, week 1, and week 12. Citicoline (500 mg/day) was administered orally for 6 weeks, and patients were followed for 12 weeks. The primary assessment was progression of ischemic lesion volume from baseline to 12 weeks as measured by MRI. A total of 100 patients entered the study. The primary MRI analysis included 40 placebo-treated patients and 41 citicoline-treated patients with both baseline and week 12 MRI data and failed to demonstrate a significant difference in lesion volume change from baseline to week 12. From baseline to week 12, ischemic lesion volume [all values mean (SE)] expanded by 180% (107) among placebo-treated patients compared with 34% (19) among citicoline-treated patients. In a secondary analysis, lesion volume decreased from week 1 to week 12 by 6.9 cc (2.8) on placebo versus 17.2 cc (2.6) on citicoline. Baseline variables that were predictors of change in lesion size over 12 weeks were the volume of hypoperfusion (strongest association), baseline NIHSS score, lesion volume on DWI, arterial lesion by magnetic resonance angiography, and categorized elapsed time (< or =12 or >12 hours) from stroke onset to first dose. A marked association between lesion volume reduction and improvement of NIHSS score by seven or more points was observed. Significant correlations between lesion volumes and clinical measures were found, replicating values reported in the literature for smaller case series. We observed a reduction in lesion volume growth from baseline to week 12 with citicoline treatment, with a significantly greater reduction in volume from week 1 to week 12 with citicoline. We found a significant inverse relationship between lesion volume change over 12 weeks as measured by MRI and clinical outcome for ischemic stroke. This relationship supports the role of DWI as a surrogate marker of clinically meaningful lesion progression in stroke clinical trials. The hypothesis that citicoline reduces lesion growth and improves clinical outcome will be tested further.

Aged↗

PubMed2000

Lack of clinical evidence for involvement of hepatitis C virus interferon-alpha sensitivity-determining region variability in RNA-dependent protein kinase-mediated cellular antiviral responses.

The hepatitis C virus (HCV) interferon-alpha (IFN-alpha) sensitivity-determining region (ISDR) has been shown to suppress double-stranded RNA-dependent protein kinase (PKR) activity in vitro in a yeast PKR expression system. Since variability of ISDR was shown to correlate with nonresponsiveness to IFN-alpha therapy in chronically HCV-infected patients, it has been suggested that prototype ISDR might be a viral inhibitor of cellular PKR. The present study evaluates the biological significance of ISDR variability in situ, relating it to PKR-mediated cellular antiviral responses within the liver. ISDR variability was determined in patients chronically infected with HCV genotypes 1a, 1b, and 3a by direct sequencing using liver-derived RNA preparations as starting material. As surrogate parameters for PKR-mediated cellular responses, hepatic endogenous IFN-alpha gene expression as well as MxA expression were analysed by a competitive, quantitative reverse transcription-polymerase chain reaction technique. Irrespectively of intra- or intergenotypic ISDR amino acid substitutions, ISDR variability was found not to correlate with endogenous hepatic IFN-alpha or with hepatic MxA gene expression. The data suggest that at least two prominent PKR-mediated cellular responses might be largely unaffected by HCV ISDR variability.

Adolescent↗

PubMed2005

Contributions of bone density and structure to fracture risk assessment in men and women.

Although bone mineral density (BMD) is a strong predictor of fractures, it is only a surrogate for bone strength. Bone structural parameters can now be measured on BMD scans, but it is unclear whether they would be more useful for risk assessment. We measured structural parameters using the Hip Structural Analysis Program and evaluated their association, compared with standard hip BMD, with fracture risk in a population-based sample of 213 postmenopausal women and 200 men > or =50 years of age. Altogether, 38% of the women and 27% of the men had experienced a fracture due to moderate trauma (half involved hip, spine or distal forearm), while 23% and 36%, respectively, had a previous fracture due to severe trauma. In logistic regression analyses adjusted for age, the hip BMD and structural parameters were all associated with moderate trauma fractures generally, and osteoporotic fractures specifically, in women, but the best predictor in a multivariate model was femoral neck BMD (odds ratio [OR], 2.8; 95% confidence interval [CI], 1.9-4.0). BMD and the structural parameters were strongly correlated, however, and could be interchanged with little reduction in predictive power. These variables were less predictive of moderate trauma fractures in men. The best model included age (OR per 10 years, 1.5; 95% CI, 1.1-2.1), femoral neck section modulus (OR, 1.6; 95% CI, 1.1-2.5) and intertrochanteric buckling ratio (OR, 1.6; 95% CI, 1.3-2.0). Correction for body size did not alter these relationships. Fractures due to severe trauma were best predicted by structural parameters: in women, femoral neck buckling ratio (OR, 1.2; 95% CI, 1.04-1.5) and, in men, intertrochanteric buckling ratio (OR, 1.4; 95% CI, 1.2-1.6). These data suggest that selected structural variables as assessed by dual-energy X-ray absorptiometry would be as good as standard BMD measurements for predicting fracture risk. Because of the strong correlations, however, some judgment can be used in selecting the variables easiest to measure.

Absorptiometry, Photon↗

PubMed1995

Community risk indicators for dental caries in school children: an ecologic study.

A statewide survey of NC schoolchildren found wide variation in dental caries prevalence among sampled classrooms. This study examined factors associated with this variation using classrooms as a surrogate for the larger community, in order to identify community risk indicators (CRI). In all, 172 classrooms (3400 students) in Grades K-6 were available for analysis. Initially, 56 sociodemographic, environmental, health system, and clinical factors were evaluated for their association with caries prevalence (K-3: average dfs + DMFS; 4-6: average DMFS) using univariate and bivariate analyses. Of these, 21 factors met our criteria for evaluation using WLS multivariate regression. For Grades K-3 (n = 108), population density, parental education, and coastal residence were negatively associated with caries scores, while age, and medical and dental, Medicaid expenditures were positive. For Grades 4--6 (n = 64), age and fs:dfs ratio were positively associated with caries scores while population density, population:dentist ratio, and years of natural fluoride exposure were negative. CRIs for both models, when compared to individual models, explained a substantial portion of the variation in caries prevalence, 31% for Grades K-3 and 51% for Grades 4-6. Results suggest that a risk assessment model based on community rather than individual variables is feasible and further refinement may reveal factors useful in identifying high risk communities.

Adolescent↗

PubMed2000

Investigation of determinism in heart rate variability.

The article searches for the possible presence of determinism in heart rate variability (HRV) signals by using a new approach based on NARMA (nonlinear autoregressive moving average) modeling and free-run prediction. Thirty-three 256-point HRV time series obtained from Wistar rats submitted to different autonomic blockade protocols are considered, and a collection of surrogate data sets are generated from each one of them. These surrogate sequences are assumed to be nondeterministic and therefore they may not be predictable. The original HRV time series and related surrogates are submitted to NARMA modeling and prediction. Special attention has been paid to the problem of stationarity. The results consistently show that the surrogate data sets cannot be predicted better than the trivial predictor-the mean-while most of the HRV control sequences are predictable to a certain degree. This suggests that the normal HRV signals have a deterministic signature. The HRV time series derived from the autonomic blockade segments of the experimental protocols do not show the same predictability performance, albeit the physiological interpretation is not obvious. These results have important implications to the methodology of HRV analysis, indicating that techniques from nonlinear dynamics and deterministic chaos may be applied to elicit more information about the autonomic modulation of the cardiovascular activity. (c) 2000 American Institute of Physics.

Journal Article↗

PubMed1997

A detailed evaluation of adjustment methods for multiplicative measurement error in linear regression with applications in occupational epidemiology.

It is often appropriately assumed, based on both theoretical and empirical considerations, that airborne exposures in the workplace are lognormally distributed, and that a worker's mean exposure over a reference time period is a key predictor of subsequent adverse health effects for that worker. Unfortunately, it is generally impossible to accurately measure a worker's true mean exposure. We begin by introducing a familiar model for exposure that views this true mean, as well as logical surrogates for it, as lognormal random variables. In a more general context, we then consider the linear regression of a continuous health outcome on a lognormal predictor measured with multiplicative error. We discuss several candidate methods of adjusting for the measurement error to obtain consistent estimators of the true regression parameters. These methods include a simple correction of the ordinary least squares estimator based on the surrogate regression, the regression of the outcome on the covariates and on the conditional expectation of the true predictor given the observed surrogate, and a quasi-likelihood approach. By means of a simulation study, we compare the various methods for practical sample sizes and discuss important issues relevant to both estimation and inference. Finally, we illustrate promising adjustment strategies using actual lung function and dust exposure data on workers in the Dutch animal feed industry.

Analysis of Variance↗

PubMed2004

The peak bone mass concept: is it still relevant?

The peak bone mass concept implies that optimal skeletal development during childhood and adolescence will prevent fractures in late adulthood. This concept is based on the observation that areal bone density increases with growth during childhood, is highest around 20 years of age and declines thereafter. However, it is now clear that strong bones in the youngster do not necessarily lead to a fracture-free old age. In the recent bone densitometric literature, the terms bone mass and bone density are typically used synonymously. In physics, density has been defined as the mass of a body divided by its volume. In clinical practice and science, "bone density" usually has a different meaning-the degree to which a radiation beam is attenuated by a bone, as judged from a two-dimensional projection image (areal bone density). The attenuation of a radiation beam does not only depend on physical density, but also on bone size. A small bone therefore has a lower areal bone density than a larger bone, even if the physical density is the same. Consequently, a low areal bone density value can simply reflect the small size of an otherwise normal bone. At present, bone mass analysis is very useful for epidemiological studies on factors that may have an impact on bone development. There is an ongoing discussion about whether the World Health Organization (WHO) definition of osteoporosis is over-simplistic and requires upgrading to include indices representing the distribution of bone and mineral (bone strength indices). The following suggestions and recommendations outline a new concept: bone mass should not be related to age. There is now more and more evidence that bone mass should be related to bone size or muscle function. Thus analyzed, there is no such entity as a "peak bone mass". Many studies are currently under way to evaluate whether these novel approaches increase sensitivity and specificity of fracture prediction in an individual. Furthermore, the focus of many bone researchers is shifting away from bone mass to bone geometry or bone strength. Bone mass is one surrogate marker of bone strength. Widely available techniques for measurement of bone mass, such as dual-energy X-ray absorptiometry, radiogrammetry, and computed tomography, can also be used to measure variables of bone geometry such as cortical thickness, cortical area, and moment of inertia.

Adolescent↗

PubMed2005

Predictive regression equations and clinical uses of peripheral pulse timing characteristics in children.

Studies have shown that increased arterial stiffening can be an indication of cardiovascular diseases like hypertension. In clinical practice, this can be detected by measuring the blood pressure (BP) using a sphygmomanometer but it cannot be used for prolonged monitoring. It has been established that pulse wave velocity (PWV) is a direct measure of arterial stiffening but its usefulness is hampered by the absence of non-invasive techniques to estimate it. Pulse transit time (PTT) is a simple and non-invasive method derived from PWV. However, limited knowledge of PTT in children is found in the present literature. The aims of this study are to identify independent variables that confound PTT measure and describe PTT regression equations for healthy children. Therefore, PTT reference values are formulated for future pathological studies. Fifty-five Caucasian children (39 male) aged 8.4 +/- 2.3 yr (range 5-12 yr) were recruited. Predictive equations for PTT were obtained by multiple regressions with age, vascular path length, BP indexes and heart rate. These derived equations were compared in their PWV equivalent against two previously reported equations and significant agreement was obtained (p < 0.05). Findings herein also suggested that PTT can be useful as a continuous surrogate BP monitor in children.

Anthropometry↗

PubMed2004

Characterization of an urban-rural CO2/temperature gradient and associated changes in initial plant productivity during secondary succession.

To examine the impact of climate change on vegetative productivity, we exposed fallow agricultural soil to an in situ temperature and CO2 gradient between urban, suburban and rural areas in 2002. Along the gradient, average daytime CO2 concentration increased by 21% and maximum (daytime) and minimum (nighttime) daily temperatures increased by 1.6 and 3.3 degrees C, respectively in an urban relative to a rural location. Consistent location differences in soil temperature were also ascertained. No other consistent differences in meteorological variables (e.g. wind speed, humidity, PAR, tropospheric ozone) as a function of urbanization were documented. The urban-induced environmental changes that were observed were consistent with most short-term (approximately 50 year) global change scenarios regarding CO2 concentration and air temperature. Productivity, determined as final above-ground biomass, and maximum plant height were positively affected by daytime and soil temperatures as well as enhanced [CO2], increasing 60 and 115% for the suburban and urban sites, respectively, relative to the rural site. While long-term data are needed, these initial results suggest that urban environments may act as a reasonable surrogate for investigating future climatic change in vegetative communities.

Atmosphere↗

PubMed2004

Quality of life as a survival predictor for esophageal squamous cell carcinoma treated with radiotherapy.

PURPOSE: Accumulating reports suggest that quality of life (QOL) may predict survival in cancer patients. In this study, we longitudinally investigated whether the QOL data assessed before, during, and after treatment are prognostic for the survival of patients with esophageal squamous cell carcinoma treated with primary radiotherapy (RT). METHODS AND MATERIALS: A total of 110 consecutive new esophageal squamous cell carcinoma patients treated with primary RT were studied. The European Organization for the Research and Treatment of Cancer questionnaire QLQ-C30 (in the Taiwan Chinese version) plus the scales concerning dysphagia and odynophagia were completed before, during, and 2 months after RT. Cox proportional hazards models were used to analyze the impact of clinical and QOL variables on survival. RESULTS: A clinical model that included clinical and sociodemographic variables to predict survival using multivariate analysis revealed weight loss, American Joint Committee on Cancer stage, and radiation dose to be statistically significant survival predictors. For QOL scores before RT, physical functioning was the most significant survival predictor. The 2-year survival rate was 30% for patients with a physical functioning score of > or =80.0 compared with a survival rate of 20% for those with a score of <80.0. The QOL scores during RT did not significantly correlate with survival. Of the QOL scores 2 months after RT, the dysphagia symptom scale was the most significant survival predictor. Improvement in dysphagia was observed in 43.0% of patients during RT and in 48.4% of patients 2 months after RT. A dysphagia-free status was found in 35.5% of patients 2 months after RT. The 2-year survival rate was 54.5% for patients without dysphagia 2 months after RT compared with 14.3% for those with dysphagia (p <0.001). CONCLUSION: The data provide evidence to support the correlation of patient-reported QOL scores with survival. Pretreatment physical functioning might be a surrogate marker of an unrecognized biologic prognostic factor. The poor survival outcome for patients with persistent dysphagia after treatment implies that local control remains the main issue to overcome in treating esophageal cancer with RT.

Aged↗

PubMed2003

Prediction of unconfined compressive strength of cement paste containing industrial wastes.

Neural network analysis was used to construct models of unconfined compressive strength (UCS) as a function of mix composition using existing data from literature studies of Portland cement containing real industrial wastes. The models were able to represent the known non-linear dependency of UCS on curing time and water content, and generalised from the literature data to find relationships between UCS and quantities of five waste types. Substantial decreases in UCS were caused by all wastes; except for EAF dust, the effect was nonlinear with the greatest decrease caused initially by approx. 12% plating sludge, 40% foundry dust, 58% other ash, and 72% MSWI fly ash by mass of dry product. It appears that the maximum waste additions used in modelling may approximate the practical limits of waste additions used in modelling may approximate the practical limits of waste addition to Portland cement, i.e., 50% plating sludge or EAF dust, 64% foundry dust, 92% other ash, and 85% MSWI fly ash by mass of dry product. The laboratory was found to be a key predictive variable and acted as a surrogate for laboratory-specific variables related to cement composition, strength and hardening class, product mixing and preparation details, laboratory conditions, and testing details. While the neural network modelling approach has been shown to be feasible, development of better models would require larger data sets with more complete information regarding laboratory-specific variables and waste composition.

Compressive Strength↗

PubMed1990

A clinical-severity staging system for patients with lung cancer.

The prognostic staging of cancer in general, and lung cancer in particular, has customarily depended mainly on morphologic distinctions. The gross anatomic extensiveness of cancers is cited with TNM stages that describe the primary tumor (T), spread to regional lymph nodes (N), and metastatic dissemination (M) to distant sites. Microscopic characteristics are cited according to the cancer's cell type (e.g., adenocarcinoma, epidermoid carcinoma) and/or grade of differentiation (e.g., well differentiated, poorly differentiated, anaplastic). Although the clinical manifestations, functional effects, and associated co-morbidity of a cancer are universally recognized as having major prognostic importance, they have not been classified with a standard system of taxonomy. When considered at all, clinical phenomena have been cited with a surrogate index of "performance status" that ignores the underlying clinical dysfunctions while being greatly affected by non-clinical phenomena, such as the patient's psychic status, economic motivations, and system of social support. The current research was done to develop a standard system of taxonomy (or "staging") for the prognostic impact of clinical distinctions in patients with primary lung cancer. Appropriate data were obtained, computer-coded, and analyzed from medical records for the complete clinical course of an inception cohort of 1266 patients who were first treated at either the Yale-New Haven Hospital or the West Haven Veterans Administration Hospital during the interval January 1, 1953-December 31, 1964. The information under analysis included clinical phenomena as well as anatomic extensiveness (TNM stage), microscopic histology, the chronometric duration of the interval from the first symptom of lung cancer to zero time, the iatrotropic reason why the patient sought medical attention, the presence of anemia, the amount of customary cigarette use, and the conventional demographic data for age and gender. The main clinical phenomena were expressed in variables for symptom pattern severity, and co-morbidity. Symptom pattern referred to the existence of specific pulmonic symptoms (e.g., hemoptysis), systemic symptoms (e.g., complaint of weight loss), and metastatic symptoms that might be mediastinal (e.g., superior vena cava syndrome), regional (e.g., the Horner syndrome), or distantly metastatic (e.g., central nervous system). The symptom severity variable included the amount of weight loss, and the existence of severe dyspnea or particularly severe tumor effects (such as mental obtundation, rather than hemiparesis in patients with CNS metastasis). Prognostic co-morbidity was cited for coexisting diseases, such as recurrent myocardial infarctions, that might be more lethal than the lung cancer itself.(ABSTRACT TRUNCATED AT 400 WORDS)

Humans↗

PubMed1999

Antepartum fetal and maternal carboxyhemoglobin and cotinine levels among cigarette smokers.

The objective of this study was to examine the association of carboxyhemoglobin (COHb) and plasma cotinine levels among pregnant women who smoke cigarettes and their fetuses. Fifteen pregnant women who smoked and their fetuses undergoing cordocentesis had blood samples analysed simultaneously for COHb and cotinine. Linear regression was used to test for associations among study variables. Significant maternal-fetal associations were observed both with COHb (r = 0.72, p = 0.003) and with cotinine (r = 0.96, p = 0.003). Maternal cotinine levels were correlated with maternal and fetal COHb levels (r = 0.96, p = 0.003; r = 0.99, p = 0.0003, respectively). Fetal cotinine levels were correlated with COHb in maternal and in fetal blood (r = 0.81, p = 0.0003; r = 0.88, p<0.0001, respectively). The strong direct associations of maternal and fetal levels of COHb and cotinine indicate that maternal COHb and cotinine measurements may be interpreted as surrogates of fetal COHb levels. However, the specificity, ex vivo stability and ease of measurement of cotinine offer advantages over using COHb in quantifying fetal CO exposure following maternal cigarette smoking.

Adult↗

PubMedDate not supplied

Correlation among Poincaré plot indexes and time and frequency domain measures of heart rate variability.

PRIMARY OBJECTIVE: In order to corroborate the rported performance advantage of Poincaré plot indexes as autonomic activity markers, the correlation among these indexes and those computed from the time and frequency domains were obtained. METHODS AND PROCEDURES: Starting from the RR series derived from the ECG of 21 healthy volunteers during five manoeuvres, longitudinal (L), transverse (T) axis, and autocorrelation (r) from Poincaré plots, rMSSD and standard deviation (SD) in the temporal domain, and frequency domain indexes were computed. MAIN OUTCOMES AND RESULTS: Poincaré plot indexes were correlated in a better way with the time indexes, rather than the spectral measures. A strong correlation (0.997) between L and SD was observed, while an underlying mathematical relationship was established for T vs rMSSD. CONCLUSIONS: Poincaré plot indexes may be considered as equivalent or surrogates of the temporal ones, and they do not have a better performance as autonomic markers.

Adult↗

PubMed2002

Survival of breast cancer patients in Connecticut in relation to socioeconomic and health care access indicators.

The purpose of this study of 16,931 black and white Connecticut women diagnosed with invasive breast cancer in 1988-1995 was to examine survival in relation to surrogate or proxy indicators of both socioeconomic status (SES) and access to primary care. Patients were followed through 1998, and the risk of death was elevated for the lowest (vs. highest) SES category independent of stage at diagnosis and other characteristics, especially among patients diagnosed before age 65 years. The health care access indicator was not associated with risk of death when other patient characteristics (including the SES variable and stage at diagnosis) were taken into account. Unexplained elevations, relative to the rest of the state, in risk of death were found for patients diagnosed while living in two of the state's four largest cities.

Adult↗

PubMed2006

Alternative clinical end points in rectal cancer--are we getting closer?

BACKGROUND: In rectal cancer a high risk of local recurrence has been reported for patients treated by surgery alone. It is also recognised that 20%-40% of rectal cancer patients continue to develop distant metastases and die, even when a very low risk of local recurrence has been achieved with the use of preoperative radiotherapy and total mesorectal excision (TME). Hence, the current design of randomised trials in rectal cancer continues to use the standard end points of local control and survival. This strategy is time-consuming. The recently published EORTC 22921 trial, which compared radiotherapy with chemoradiotherapy and tested the role of postoperative adjuvant chemotherapy, has taken 14 years from planning to results. The aim of this review was to use the evidence from both phase II and phase III trials to provide a comprehensive survey of alternative clinical trial end points in rectal cancer, where preoperative chemoradiation has now become the standard treatment. We describe their strengths and weaknesses. Some are clearly defined, easy to assess and can be obtained early, because surgical resection usually takes place within 6-8 weeks of the completion of treatment. Some pathological response end points reflect biological activity, although their effect on survival has yet to be validated in randomised controlled trials. We will propose measurement and analytical techniques for minimising bias and intra- and inter-observer variability of the non-validated end points in the hope of basing these judgements on as firm a ground as possible. METHODS: A literature search identified both randomised and non-randomised trials of preoperative radiation therapy (RT) and chemoradiation therapy (CRT) in rectal cancer from 1993 to 2005. The aim was to find those studies that documented potential alternative end points. RESULTS: Pathological parameters have been used as early end points to compare studies of preoperative radiotherapy or chemoradiation. In the light of the German CAO/ARO/AIO-94 study, which demonstrated an improved therapeutic ratio for preoperative treatment, enthusiasm for preoperative chemoradiation in the management of rectal cancer is increasing. Current evidence cannot indicate whether the degree of response to chemoradiation (e.g. complete pathological response; downsizing the primary tumour; sterilizing the regional nodes; tumour regression grades or residual cell density) or the achievement of a curative resection (CRM/R0 resection) is the best early clinical end point. Problems with these end points include lack of structured measurement and analysis techniques to control for intra- and inter-observer variation and lack of validation as surrogates for long-term clinical end points such as local control and survival. However, retrospective studies in rectal cancer have confirmed a strong association between the presence of microscopic tumour cells within 1 mm of the CRM and increased risks of both local recurrence and distant metastases. Further end points of current clinical relevance for which adequate methodologies for assessment are lacking include sphincter sparing end points, and assessment of long-term toxicities, ano-rectal function and their specific impact on quality of life. Recommendations are made as to the most appropriate information, which should be documented in future trials. CONCLUSIONS: Pathological complete response following preoperative chemoradiation does not reliably predict late outcome. There are other events not mediated through this end point and there are also unintended effects (often an excess of non-cancer related deaths). Disease-free survival currently remains the best (because it is relatively quick) primary end point in designing randomised phase III studies of preoperative chemoradiation in rectal cancer, although it is necessary to control for postoperative adjuvant chemotherapy. However, the CRM status can substantially account for effects on disease-free and overall survival after chemoradiation, radiation or surgery alone. Hopefully, randomised controlled trials, which utilise these alternative clinical end points, will in future determine the precise percentages of the effect of different chemoradiation schedules on disease-free and overall survival.

Biomarkers, Tumor↗

PubMed1992

Use of human data in quantitative risk assessment of carcinogens: impact on epidemiologic practice and the regulatory process.

Epidemiologic data are increasingly being used to assess cancer risk from chemicals as their value is recognized and as more and better studies become available. Weight-of-evidence approaches are now available for classifying the experimental and epidemiological evidence regarding human carcinogenicity. When the human data are extensive and of good quality, they should be given substantial weight in assessing risk. Both the positive and the negative epidemiologic data should be used in a quantitative risk assessment (QRA), because only then can an unbiased risk assessment be derived. Good-quality epidemiological studies are those with sound methodology, lack of bias, long enough follow-up times to observe a carcinogenic response, adequate exposure information, and dose-response information. Before a lack of carcinogenicity can be inferred, it is essential that the exposures be of substantial duration and intensity, and that the number of exposed persons be reasonably large. Epidemiologists need to give more attention to exposure assessment, because lack of quantitative exposure information is often the limiting factor that prevents the use of epidemiologic data in QRA. Development of methods to estimate historical workplace exposure intensities from surrogate industrial hygiene variables should receive high research priority, since they have the potential to increase the usefulness in QRA of many epidemiologic studies that have limited exposure information. Several frequently used surrogates for exposure measurements have limitations or pitfalls in their use. In particular, the use of "ever/never" exposed has a large potential to produce falsely negative results by means of a "dilution" effect, especially in the common case where the exposure distribution is skewed. Duration of exposure (rather than duration x intensity) may also give misleading results. There is little information to suggest that synergistic exposures to multiple toxicants in an industrial environment are likely to invalidate QRAs, probably because few studies have identified a group of workers with major workplace exposures to multiple carcinogens that cause the same type of cancer. Most of the interactive effects which have been identified to date are between smoking and some occupational carcinogen, so this possibility needs careful evaluation for smoking-related diseases. It is important to evaluate dose-response gradients in a QRA to obtain maximum precision and accuracy in the resulting risk coefficient. The analysis should take into account an appropriate cancer induction period. Various methods to account for cancer induction times are compared; those that incorporate a lag period or model the induction-time distribution are superior to other methods.(ABSTRACT TRUNCATED AT 400 WORDS)

Carcinogens↗

PubMed1995

Evaluation of prostate-specific antigen as a surrogate marker for response of hormone-refractory prostate cancer to suramin therapy.

PURPOSE: We evaluated the surrogate role of serum prostate-specific antigen (PSA) using prospectively collected information from patients with hormone-refractory prostate cancer (HRPC) treated with suramin. MATERIALS AND METHODS: Data from 103 patients were analyzed using survival analysis, exploratory analysis, and regression analysis. RESULTS: There was a significant survival difference between groups of patients with a PSA decrease of < or = 0% or greater than 0% (P = .018). There were no significant overall survival differences between groups of patients with PSA decreases less than 50% or > or = 50% and less than 75% or > or = 75%. Tree-based modeling did not define a specific threshold percentage PSA change as a response criterion. For a response of 1-year survival, sensitivity increased (0.91 v 0.69), but specificity decreased (0.37 v 0.62), with a 75% versus 50% PSA decrease used as classification criterion. Differences between the area under the receiver-operating curves (ROCs) with 50% and 75% PSA decreases as threshold values were small. For a response of 1-year survival, attributable proportions were 0.38 and 0.68, respectively, with 50% and 75% PSA decreases as threshold values. When pretreatment variables were assessed by Cox proportional hazards model, hemoglobin level was the most significant predictor of survival. When percentage PSA change was included in the model, hemoglobin level remained the most significant factor, but percentage PSA change was also a weak, but statistically significant, factor. PSA was a weak, but statistically significant, predictor of survival in Cox proportional hazards model with PSA as a time-variant covariate. CONCLUSION: Reduction in PSA level has weak prognostic significance with respect to survival in HRPC patients, but, currently, PSA reduction cannot be used as a reliable response criterion to evaluate treatment efficacy in individual patients. Prospective, randomized studies, including prospective measurement of other indices related to symptomatic clinical benefits, are required.

Adult↗