Search

Objective: The aim of the study was to describe longitudinal changes in serum lipids among HIV-infected men receiving highly active antiretroviral therapy (HAART) with long-term follow-up., Methods: A total of 304 HIV-infected men who initiated HAART and who had serum lipid measurements prior to and for up to 7 years after HAART initiation were identified from the Multicenter AIDS Cohort Study (MACS). Mean levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) were examined at biannual time-points., Results: Significant lipid changes were seen within 0.5 years of HAART initiation but increases in TC (+1.09 mmol/L), LDL-C (+0.57 mmol/L), HDL-C (+0.16 mmol/L) and non-HDL-C (+0.91 mmol/L) reached peak levels 2-3 years after HAART initiation. Declines in serum TC, LDL-C and non-HDL-C in subsequent years occurred concurrently with a substantial increase in use of lipid-lowering medications (from 1% usage pre-HAART to 43% 6-7 years after HAART initiation) but the proportion of men who either were treated with cholesterol-lowering medication or had elevated cholesterol levels (>5.18 mmol/L) did not change during the 2-7-year interval after HAART. Mean HDL-C also decreased after 2-3 years and was low (<1.04 mmol/L) in 55% of HIV-infected men 6-7 years after HAART initiation., Conclusions: Atherogenic serum lipids increased early after the initiation of HAART, peaked at 2-3 years and remained high or required treatment thereafter. Low HDL-C levels persisted in the majority of men. The long-term effects of lipid abnormalities on cardiovascular risk and the effectiveness and toxicity of prolonged use of lipid-lowering medications in combination with HAART are not known.

Background: The histological diagnosis of early lesions of mycosis fungoides (MF) is often difficult for dermatopathologists and prior studies have shown a low agreement rate among pathologists. An important reason for such difficulty may be the lack of specific histological criteria., Methods: We tested a new method to interpret and report biopsies suspicious for MF. The method is based on a grading system reflecting the pathologist's degree of diagnostic certainty. A panel of four pathologists independently assessed a set of 50 biopsies suspicious for MF first without (Phase I) and subsequently with specific histological criteria (Phase II). A third Phase was carried out after a training session, using a new set of cases with corresponding immunophenotyping and gene rearrangement analysis. Weighted and unweighted kappa statistics were used to assess inter- and intra-pathologist variation., Results: The consensus rate among pathologists improved from 48% in Phase I to 76% in Phase III. Overall precision weighted kappas increased from 0.630 in Phase I to 0.854 in Phase III, indicating excellent inter-pathologist agreement by Phase III. There was a significant association between the presence of an abnormal phenotype and/or T-cell clonality and a higher diagnostic score., Conclusions: The use of uniform criteria and training sessions can substantially improve the consensus rate among pathologists in the diagnosis of MF.

Longitudinal studies of health effects often relate individuals' biomarker levels to disease progression. Repeated measurements also provide an opportunity to assess within-individual biomarker variability, and it is reasonable to postulate that this measure might provide additional information about a particular outcome variable. Given the existing precedent for application of adjustment methods to account for measurement error in subject-specific average levels of a covariate, this concept motivates the application of such methods to incorporate variability as well. In this paper, we investigate the nature of the relationship between the decline of CD4 cell count induced by infection with human immunodeficiency virus, and CD4 level and variability prior to infection. We first describe the distribution of repeated CD4 measurements prior to infection using a model that accounts both for random average levels and random subject-specific variance components. Based on this model, we define true unobservable random variables that correspond to prior level and stability. We perform a linear regression analysis, using these latent variables as covariates, by means of a full maximum likelihood approach. We compare the resulting parameter estimates with those based on regressions employing sample-based estimates of pre-infection levels and variances, and empirical Bayes estimates of these quantities. Although the final inferences are similar to those based on the unadjusted analysis, we find that the magnitude of association with prior level decreases, while that with prior stability increases. Stratified analyses indicate that smoking status affects the relationship between prior CD4 level and initial CD4 decline. We point out advantages associated with the maximum likelihood approach in this particular application.

Researchers commonly express scepticism about using observational data to estimate the effect of a treatment on an outcome the treatment is intended to affect. In this paper, we consider using data from the Multicenter AIDS Cohort Study (MACS) to determine whether zidovudine prevents the development of Kaposi's sarcoma among HIV-positive gay men. Several methodologic issues common to observational data characterized the study: information on potentially important confounders was missing at some study visits; investigators did not always know the time of changes in treatment level, nor the value of confounders at that time, and the censoring process depended strongly on time-varying covariates related to outcome. We describe application to our data of Robins' paradigm for defining, modelling and estimating the effect of a time-varying treatment and show how to modify his approach to deal with the methodologic issues we have mentioned. Further, we demonstrate that relative risk regression is less well equipped to deal with these issues. We compare our results to the findings from randomized trials, and conclude that observational studies may sometimes be useful in evaluating the effect of treatment on an intended outcome.

Background: The American College of Surgeons conducted a national patient care and evaluation study of invasive cervical carcinoma in pregnant patients., Methods: Invasive cervical carcinoma was diagnosed in 161 patients who were pregnant at the time of diagnosis. A long term study of 78 patients diagnosed in 1984 was compared with a short term study of 83 patients diagnosed in 1990., Results: The mean age of the patients was 31.8 years. Clinical stages were: IA (29%); IB (54%); IIA (6%); IIB (4%); IIIA (0%); IIIB (3%); IV (1%; AND IVB 3%). Thirty-one percent of patient were diagnosed in the first trimester, 34% in the second, and 35% in the third. A tumor size of 4 cm or larger in diameter was found in 36% of the patients diagnosed in the first trimester, 40% of the patients diagnosed in the second, and 38% of the patients diagnosed in the third. Patients were treated with surgery alone (86), radiotherapy alone (30), or with combination therapy (45). The overall 5-year survival rate for patients diagnosed in 1984 was 82%. In this group, the 5-year survival rate for patients diagnosed in the first trimester was 94.6%, in the second, 76.9%, and in the third, 68.9%. Comparing the two time periods, surgical therapy was performed more often by gynecologic oncologists in 1990 (69% vs. 42%), and a greater percentage of patients were diagnosed with a tumor size of 4 cm or larger in diameter (43% vs. 26%) as well as with stage IIB-IVB disease (15% vs. 6.7%)., Conclusions: The prognosis of pregnant patients with invasive cervical carcinoma is similar to that for nonpregnant patients. The significant number of patients diagnosed in the second and third trimesters and the frequent finding of large tumors in all trimesters emphasize the need for patient education and early prenatal evaluation, including cervical cytology and biopsy of any clinically abnormal cervix.

Background: The authors' aim was to assess whether there is a difference in biologic behavior and survival in comparing adenocarcinoma (AdCA), squamous cell carcinoma (SCC), and adenosquamous carcinoma (Ad/SC) of the cervix., Methods: Cancer registrars at 703 hospitals submitted anonymous data on 11,157 patients with cervical cancer diagnosed and/or treated in 1984 and 1990 for a Patient Care Evaluation Study of the American College of Surgeons. Among these patients, 9351 (83.8%) had SCC; 1405 (12.6%), AdCA; and 401 (3.6%), Ad/SC cancers. There were no significant changes in percentages of the different histologic types between the study years 1984 and 1990, nor was the patient distribution different regarding age, race/ethnicity, and socioeconomic background for each histologic group. Furthermore, the distribution of patients who had had a hysterectomy did not change between 1984 and 1990., Results: A larger percent of patients with SCC (63.8%) than those with Ad/SC (59.8%) or AdCA (50.2%) had tumors larger than 3 cm at greatest dimension. Early stage patients (IA, IB, IIA) often were treated by hysterectomy alone (45.5%) or combined with radiation (21.1%). The remaining patients (21.9%) received radiation alone. Of the patients with clinical stage I disease, 7.6% of Ad/CA patients, 15.5% of Ad/SC patients and 12.6% of SCC patients had positive nodes. Although patients with SCC had higher survival rates for all four clinical stages (I-IV), the differences were only significant for Stage II patients. Patients with clinical stage IB SCC and AdCA treated by surgery alone were found to have significantly better survival rates (93.1% and 94.6% at 5 years, respectively) than women treated by either radiation alone or a combination of surgery and radiation (P < 0.001, both histologic comparisons). For women with Ad/SC tumors, however, the 5-year survival rate was 87.3% for those receiving combined treatment compared with those receiving surgery alone (69.2%) or radiation alone (79.2%). However, these survival curves were not significantly different (P = 0.496). One hundred six patients with positive nodes were available for analysis. The 5-year survival rate of patients with SCC and positive nodes was 76.1%. Surprisingly, patients with Ad/SC and positive nodes had the highest 5-year survival rate (85.7%), whereas, women with AdCA and positive nodes had a sharply reduced 5-year survival rate (33.3%). The curves were significantly different (P < 0.01). For patients with clinical stage I, the risk factors for age, tumor size, nodal status, histologic features, and treatment were analyzed with Cox's multivariate regression. In this analysis, subset IB, greater tumor size, age 80 or older, and positive nodal status were each independently significant for poorer survival. Patients who were treated by surgery alone had a significantly better survival than patients who had other types of treatment or no treatment. Histologic characteristics had no significant effect on survival. In the analysis of patients with pathologic stage I disease, those with SCC had significantly poorer survival and those with Ad/SC had significantly better survival than patients with Ad/CA. Positive nodes had no significant independent effect on survival. In another analysis, tissue type was not found to be an important factor in recurrence time., Conclusions: 1. Ad/CA and Ad/SC tumors were found to represent 12.6% and 3.6%, respectively, of a large series (N = 11,157) of cervical cancers diagnosed in 1984 and 1990 and reported to the Commission on Cancer of the American College of Surgeons. 2. Two thirds of women with early clinical stage disease (IA, IB, IIA) had hysterectomy as all or part of their primary therapy. 3. No significant differences were found in 5-year survival among the three tissue types in any clinical stage except American Joint Committee on Cancer stage II.

Background: The American College of Surgeons conducted a national patient care and evaluation study of invasive cervical cancer to measure any changes in patterns of care for the years 1984 and 1990., Methods: Hospitals with cancer programs were invited to submit data on up to 25 consecutive patients with newly diagnosed invasive cervical cancer for each of the two study years. Data were obtained from 684 hospitals on 5904 patients diagnosed in 1984 and from 700 hospitals on 5817 patients diagnosed in 1990. A long term study of patients diagnosed in 1984 was compared with a short term study of patients diagnosed in 1990. Survival data were described only for patients diagnosed in 1984., Results: Of a total of 11,721 patients, 59.4% were diagnosed and treated at the reporting institution in 1984 and 54.8% in 1990. The remaining patients were referred for treatment after diagnosis elsewhere. The diagnosis was established by cervical biopsy for 69.8% of patients, by conization alone for 9.3%, and by both procedures for 11.8%. The histopathologic diagnoses were squamous cell carcinoma (79.8%), adenocarcinoma (15.8%), and other (4.4%). The stage distributions were as follows: IA, 15.9%; IB, 36.8%; IIA, 8.2%; IIB, 15.5%; IIIA, 2.5%; IIIB, 13.3%; IVA, 2.6%; and IVB, 5.2%. The stage was listed as unknown for 20.3% of patients. Patients were treated with surgery alone (29.2%), radiation alone (40.7%), chemotherapy alone (0.7%), or combination therapy (21.5%), and 7.9% received no treatment at the reporting institution. The overall survival for patients diagnosed in 1984 was 68.3%. Survival by stage in this group was as follows: IA, 93.7%; IB, 80.0%; IIA, 67.2%; IIB, 64.7%; III, 37.9%; and IV, 11.3%., Conclusions: These data indicate that invasive cervical cancer is highly curable when diagnosed early. During the 5-year period, stage distributions were similar, the use of extended hysterectomy increased, and gynecologic oncologists were more often the primary surgeons. The use of radiation alone decreased.

Methods are developed to estimate and test for the impact of intervention use on a population's survival function (time to AIDS). Each participant's history is divided into J + 1 components: omega 0 occurring before the intervention is available and omega 1 to omega J occurring later, as the intervention becomes successively more available. Distribution free truncated Kaplan-Meier models based on time since exposure fit separately to the risk sets/outcomes in omega 0 to omega J directly show the changing patterns of survival. Multivariate proportional hazards models can be used to adjust for covariates. Application of these methods indicates that availability of proven anti-AIDS interventions may have delayed time to AIDS by 8 months in an educated HIV-1 infected homosexual cohort with good access to medical care.

Background: The Commission on Cancer of the American College of Surgeons recently finished a national survey of patients with ovarian cancer patients. The goal was to compare the patterns of care over a 5-year period., Methods: Data were collected from 25 consecutive patients whose disease was diagnosed first at 904 hospitals with cancer programs in 1983 and 1988., Results: There was a total of 12,316 patients, of whom 80% were 45-85 years old. Contrary to popular belief, only 8.2% of patients were nulliparous; 85% of patients had one to five children. Of significance, 18.2% of patients with ovarian cancer had undergone a previous hysterectomy with ovarian preservation. Primary surgical treatment was used in 94.9% of patients and consisted of: oophorectomy, 81.9%; hysterectomy, 55.1%; and omentectomy, 59.0%. However, only 12-25% of patients had biopsies of the diaphragm, paracolic gutters, colon, small bowel, pelvic and paraaortic lymph nodes, and cul-de-sac to permit adequate surgical staging. The primary surgeons were: gynecologic oncologists, 21%; obstetrician-gynecologists, 45%; general surgeons, 21%; and others, 13%., Conclusions: These data indicate that additional resources are needed to improve the care of patients with ovarian cancer.

Background: Primary renal sarcomas in adults are rare and unusual neoplasms. This study was performed to better define the natural history and current management of these sarcomas in a typical medical setting in the United States., Methods: The hospital records of 4018 adult patients with renal neoplasms treated in the state of Illinois from 1975 to 1985 were examined by American Cancer Society professional volunteers., Results: A primary renal sarcoma occurred in 34 patients (0.8% incidence). Eleven adult patients had Wilms tumor, 21 had primary renal sarcoma (47% leiomyosarcoma), and 2 were not found to have sarcoma on review. The median age of the patients with Wilms tumor was 30 years, whereas that of the patients with non-Wilms sarcoma was 65 years. Four of the patients with Wilms tumor (36%) are long-term survivors and all received adjuvant chemotherapy after radical nephrectomy. Six of the patients with non-Wilms sarcoma (29%) are long-term survivors after radical nephrectomy alone., Conclusions: Primary renal sarcomas, when treated with radical nephrectomy and, in the case of Wilms tumor, adjuvant chemotherapy, appear to be curable in 29-36% of cases. Histologic review of patients younger than 40 years of age with renal neoplasia is recommended.

We have formulated the problem of determining whether there has been an upturn in HIV-1 seroconversion incidence over the first five years of follow-up in the Multicenter AIDS Cohort Study (MACS) as that of locating the minimum of a quadratic regression or examination of two-knot piecewise spline models. Under a quadratic model, we propose a method to obtain a direct estimate and a bootstrap estimate for the location of the temporal turning point (local minimum) for HIV-1 seroconversion incidence and three methods to estimate confidence intervals for the location of the turning point for HIV seroconversion incidence: (1) Wald confidence interval estimate with or without log transformation assuming the asymptotic normality and applying the Delta method; (2) asymmetric confidence intervals using Fieller's Theorem and its modification; and (3) bootstrapping confidence intervals. Inferences for the temporal turning point based on Wald tests for a single regression term in a non-linear regression model were not reliable compared to inferences based on confidence intervals placed on calendar time. We present results using these different methods applied to the MACS data and we obtain power estimates to illustrate the performances of different methods.

In natural history studies of human immunodeficiency virus type 1 (HIV-1) infection a substantial proportion of participants are seropositive at time of enrollment in the study. These participants form a prevalent subcohort. Estimation of the unknown times since exposure to HIV-1 in the prevalent subcohort is of primary importance for estimation of the incubation time of AIDS. The subset of the cohort that tested negative for antibody to HIV-1 at study entry and was observed to seroconvert forms the incident subcohort that provides longitudinal data on markers of maturity (that is, duration) of infection. We use parametric life table regression models incorporating truncation to describe the conditional distribution (imputing model) of the times since seroconversion given a vector of the markers of maturity. Using the fitted model and the values of the markers of maturity of infection provided by the seroprevalent subcohort at entry into the study, we can impute the unknown times since seroconversion for the prevalent subcohort. We implement multiple imputation based on a model-robust estimate of the covariance matrix of parameters of the imputing model to provide confidence intervals for the geometric mean of the time since seroconversion in the prevalent subcohort, and to compare maturity of infection of cohorts recruited in different cities. The accuracy of imputation is further validated by comparisons of imputation-based estimates of AIDS incubation distribution in the seroprevalent subcohort with more direct estimates obtained from the seroincident subcohort.

Recruitment of disease-free subjects into cohort studies and measurement of their time from exposure/infection to disease selectively excludes individuals (the unseen sample) who had earlier exposure and who have shorter times to disease. The unseen and observed samples may differ in other characteristics in addition to incubation period and exposure/infection time. For data with known truncation times, we develop non-parametric maximum likelihood estimates of the size, exposure/infection dates and distribution of incubation time in the unseen sample. We provide procedures to estimate and compensate for the biasing effects due to exclusion of the unseen sample in descriptive and survival analysis. We give consistency properties of these estimates and assess variability using bootstrap methods. One can use imputation to derive the above estimates from data with unknown truncation times that have been estimated parametrically. Application is made to an AIDS cohort study of over 5000 homosexual men. Important estimates obtained from this application are the annual seroconversion rates from 1978 to 1983, not otherwise obtainable in this study population.

Multiple imputation is a model based technique for handling missing data problems. In this application we use the technique to estimate the distribution of times from HIV seroconversion to AIDS diagnosis with data from a cohort study of 4954 homosexual men with 4 years of follow-up. In this example the missing data are the dates of diagnosis with AIDS. The imputation procedure is performed in two stages. In the first stage, we estimate the residual AIDS-free time distribution as a function of covariates measured on the study participants with data provided by the participants who were seropositive at study entry. Specifically, we assume the residual AIDS-free times follow a log-normal regression model that depends on the covariates measured at enrolment on the seropositive participants. In the second stage we impute the date of AIDS diagnosis for the participants who seroconverted during the course of the study and are AIDS-free with use of the log-normal distribution estimated in the first stage and the covariates from each seroconverter's latest visit. The estimated proportions developing AIDS within 4 and within 7 years of seroconversion are 15 and 36 per cent respectively, with associated 95 per cent confidence intervals of (10, 21) and (26, 47) per cent. We discuss the Bayesian foundations of the multiple imputation technique and the statistical and scientific assumptions.