Preview of a new trial of extracranial-to-intracranial arterial anastomosis: the carotid occlusion surgery study.

In 1985, the International Study of Extracranial-to-Intracranial Arterial Anastomosis demonstrated no benefit from extracranial-to-intracranial arterial bypass operations in treatment of patients with extensive cerebrovascular disease including those with occlusions of the internal carotid artery. Interest in the potential use of extracranial-to-intracranial arterial bypass operations, however, has been rekindled by evidence that some patients with occlusion of the internal carotid artery have a poor collateral circulation and a high risk for recurrent ischemic events. Other patients with adequate perfusion after occlusion have a low likelihood for recurrent stroke. Restricting surgical treatment to only those patients judged to have a high risk for recurrent stroke might improve the usefulness of the bypass operation. A new clinical trial is proposed, testing the potential usefulness of extracranial-to-intracranial arterial bypass operations for treatment of carefully selected patients with occlusion of the internal carotid artery. Several issues that are being addressed in this new trial are described in this article.

Microcirculation patterns other than loops and networks in choroidal and ciliary body melanomas.

PURPOSE: To provide ophthalmologists and pathologists with expanded criteria for separating patients at high risk of metastatic melanoma from those at low risk on the basis of microcirculation patterns in choroidal and ciliary body melanomas. DESIGN: Tissue culture studies and observational case series. PARTICIPANTS: The pattern-forming ability of four uveal melanoma cell lines of varying degrees of aggressive behavior was studied in vitro. Histologic sections of 234 eyes removed for choroidal or ciliary body melanoma were studied for the presence of microcirculation patterns. METHODS: The study was divided into two phases: the study of histologic sections of eyes removed for choroidal and ciliary body melanomas and observations on the in vitro behavior of cultured melanoma cells of varying degrees of invasive behavior. The presence or absence of each of nine microcirculation patterns was recorded from tissue sections, and interrelationships between different patterns were explored statistically. In vitro reconstitution of patterns and a study of the interrelationships of patterns in histologic sections was carried out. In the in vitro studies, uveal melanoma cell lines of varying degrees of aggressive potential were cultured to observe the development of architectural patterns other than loops and networks. MAIN OUTCOME MEASURES: In histologic studies, the outcome measure was the conditional probability of detecting loops or networks given the presence or absence of other patterns positive for periodic acid-SCHIFF: For tissue culture studies, the outcome measure was either the development or lack of development of patterns of different shapes in vitro. RESULTS: Histologic studies disclosed that given the presence of arcs without or with branching in a tissue section, it is likely that loops or networks will be detected in the same section plane, suggesting that the production of these patterns by aggressive tumor cells reflects a spectrum of architectural potential. In vitro studies confirmed this hypothesis by revealing that highly aggressive and metastatic uveal melanoma cell lines, but not poorly aggressive tumor cell lines, generated parallel channels with and without crosslinking and arcs with and without branching as well as loops and networks. CONCLUSIONS: The criteria for separating patients into low- and high-risk categories for metastasis from uveal melanoma should be expanded to include patterns other than loops or networks. In both the pathology laboratory as well as in a clinical setting, the detection of arcs or arcs with branching and parallel channels should prompt a careful search for loops and networks and for crosslinking parallel channels, respectively.

Residential radon gas exposure and lung cancer: the Iowa Radon Lung Cancer Study.

Exposure to high concentrations of radon progeny (radon) produces lung cancer in both underground miners and experimentally exposed laboratory animals. To determine the risk posed by residential radon exposure, the authors performed a population-based, case-control epidemiologic study in Iowa from 1993 to 1997. Subjects were female Iowa residents who had occupied their current home for at least 20 years. A total of 413 lung cancer cases and 614 age-frequency-matched controls were included in the final analysis. Excess odds were calculated per 11 working-level months for exposures that occurred 5-19 years (WLM(5-19)) prior to diagnosis for cases or prior to time of interview for controls. Eleven WLM(5-19) is approximately equal to an average residential radon exposure of 4 pCl/liter (148 Bq/m3) during this period. After adjustment for age, smoking, and education, the authors found excess odds of 0.50 (95% confidence interval: 0.004, 1.81) and 0.83 (95% percent confidence interval: 0.11, 3.34) using categorical radon exposure estimates for all cases and for live cases, respectively. Slightly lower excess odds of 0.24 (95 percent confidence interval: -0.05, 0.92) and 0.49 (95 percent confidence interval: 0.03, 1.84) per 11 WLM(5-19) were noted for continuous radon exposure estimates for all subjects and live subjects only. The observed risk estimates suggest that cumulative ambient radon exposure presents an important environmental health hazard.

Linked insurance-tumor registry database for health services research.

OBJECTIVE: Breast cancer screening and treatment data are often limited to restricted populations, including women older than 65 years old. The goal of this project was to develop procedures to link tumor registry and insurance claims databases on women younger than 65 years old with breast cancer and to assess the accuracy and validity of the linked dataset. METHODS: Iowa Cancer Registry (ICR) and Wellmark Blue Cross/Blue Shield of Iowa (BC/BS) membership files of women with incident in situ or invasive breast cancer from 1989 to 1996 were linked. An automated deterministic match was followed with visual inspection from three independent reviewers applying a matching protocol. Matched and overall registry data were compared to assess population representativeness. Claims from BC/BS for incident cases during 1994 were examined for coding of a recent breast cancer diagnosis or treatment. RESULTS: The final dataset included 4,397 matched cases of patients aged 21 years and older from 1989 to 1996. The sociodemographic and tumor characteristics of the ICR population younger than 65 years old (n = 7,469) with breast cancer or carcinoma in situ were nearly identical with those of the matched patients younger than 65 years old (n = 3,449). Nearly all (96%) of the 445 matched incident cases in 1994 had claims data (CPT, DRG, or ICD-9 code) indicative of breast cancer. Treatment patterns varied by data source, with agreement ranging from 76% to 82%. CONCLUSIONS: The validity and generalizability of these data demonstrate their potential for further health services research among younger insured women with breast cancer. Additionally, the process outlined may be useful for developing other datasets to study other cancers in the population younger than 65 years old.

Microcirculation architecture of metastases from primary ciliary body and choroidal melanomas.

PURPOSE: To describe the microcirculation architecture of metastatic choroidal and ciliary body melanoma. METHOD: Histologic sections of 35 metastases from 19 primary melanomas were stained to demonstrate microcirculation. RESULT: The appearance of microcirculatory networks in metastases is independent of the target organ but associated with the size of the metastatic deposit (estimated coefficient = 0.5959; SE = 0.3024; P = .0488). CONCLUSION: The microcirculatory patterns of primary uveal melanomas that are associated with metastatic behavior appear in foci of metastasis, regardless of the site of dissemination.

Microbiological factors influencing the outcome of nosocomial bloodstream infections: a 6-year validated, population-based model.

All patients (n = 1,745) with nosocomial bloodstream infection identified between 1986 and 1991 at a single 900-bed tertiary care hospital were studied to identify microbiological factors independently associated with mortality due to the infection. Patients were identified by prospective, case-based surveillance and positive blood cultures. Mortality rates were examined for secular trends. Prognostic factors were determined with use of univariate and multivariate analyses, and both derivation and validation sets were used. A total of 1,745 patients developed nosocomial bloodstream infection. The 28-day crude mortality was 22%, and crude in-hospital mortality was 35%. Factors independently (all P < .05) associated with increased 28-day mortality rates were older age, longer length of hospital stay before bloodstream infection, and a diagnosis of cancer or disease of the digestive system. After adjustment for major confounders, Candida species were the only organisms independently influencing the outcome of nosocomial bloodstream infection (odds ratio [OR] for mortality = 1.84; 95% confidence interval [CI], 1.22-2.76; P = .0035). The two additional microbiological factors independently associated with increased mortality were pneumonia as a source of secondary infection (OR = 2.74; 95% CI, 1.87-4.00; P < .0001) and polymicrobial infection (OR = 1.68; 95% CI, 1.22-2.32; P = .0014). Our data suggest that microbiological factors independently affect the outcome of nosocomial bloodstream infection.

Using Kendall's tau b correlations to improve variable selection methods in case-control studies.

In this manuscript we evaluate the performance of a variable selection procedure that could be used in case-control studies. This method is based on selection statistics computed from a matrix of Kendall tau b correlation coefficients. A simulation study was performed to compare the performance of this method to logistic regression, discriminant analysis, and the rank-transformed versions of these methods. For most of the situations studied the method based on Kendall tau b correlation coefficients correctly selected the variables that were related to case-control status more often than any of the other methods. We discuss the implications of the results of this study for epidemiologic research.

Relation between the microcirculation architecture and the aggressive behavior of ciliary body melanomas.

PURPOSE: To study the relation between vascular patterns and the biologically aggressive behavior of ciliary body melanomas. METHODS: The authors compared the frequency distribution of vascular patterns by location for 234 uveal melanomas (54 tumors involving the ciliary body, and 180 without ciliary body involvement). Stepwise Cox regressions (for the endpoint of time-to-death due to melanoma), performed separately for melanomas with and without ciliary body involvement, included the following variables: size, vascular patterns, cell type, mean of the largest nucleoli, mitoses, tumor infiltrating lymphocytes, age, and sex. A separate Cox regression procedure included the variable of tumor location. Kaplan-Meier survival curves were generated for time to melanoma death with ciliary body involvement and melanomas without ciliary body involvement for tumors containing or lacking vascular networks. RESULTS: These vascular patterns appear more often in the ciliary body than in the choroid: parallel vessels (P = 0.022), arcs (P = 0.003), and parallel with cross-linking, arcs with branching, and loops and networks (all P = 0.0001). Stepwise regression for tumors confined to the choroid indicated that the presence of networks was the most significant variable (P = 0.0001); stepwise regression for tumors with ciliary body involvement suggested that only one variable, networks, was significant (P = 0.0066). Kaplan-Meier survival estimates indicated that the survival of patients with tumors containing networks in the ciliary body was comparable to those containing networks in the choroid. CONCLUSION: Regardless of location, ciliary body or choroid, the presence of vascular networks shortens survival. The tumor location does not enter a stepwise Cox regression model when vascular patterns are included as variables. Therefore, the aggressive behavior of ciliary body melanomas appears to be related to the tendency for vascular networks to develop in this location.

Mean of the ten largest nucleoli, microcirculation architecture, and prognosis of ciliochoroidal melanomas.

BACKGROUND: Cytomorphometric measurements and the architecture of the microcirculation in tissue sections of eyes removed for ciliary body or choroidal melanomas have been identified independently as prognostically significant factors for survival. The relative significance of these two histologic features is addressed in this study. METHODS: The same 234 cases used to assess the prognostic significance of the microcirculatory patterns of choroidal and ciliary body melanomas were examined by two independent observers who measured the largest diameter of melanoma cell nucleoli from digitized images at a high magnification (x 3000) using the laser scanning confocal microscope. The mean of the ten largest nucleoli was calculated for each tumor according to previously published methods. Intraobserver and interobserver reproducibility was assessed for these measurements. Several Cox multiple regression models were constructed which included this cytomorphometric variable with and without the inclusion of the microcirculatory patterns. RESULTS: There is a high degree of intraobserver reproducibility but only a weak degree of interobserver reproducibility in measuring the mean of the ten largest nucleoli. Using multiple Cox regression models, the mean of the ten largest nucleoli from each observer failed to exert any effect on outcome after enucleation, regardless of whether the presence of networks of closed vascular loops was considered in the statistical formulation. The presence of networks of closed vascular loops was found to be the most statistically dominant histologic prognostic characteristic. CONCLUSION: The authors have not been able to confirm the use of the mean of the ten largest nucleoli as a significant prognostic factor in the outcome of patients whose eyes have been removed for ciliary body or choroidal melanomas. Further investigation of this cytomorphometric technique by other laboratories is warranted.

Microcirculation architecture of melanocytic nevi and malignant melanomas of the ciliary body and choroid. A comparative histopathologic and ultrastructural study.

PURPOSE: This study was designed to (1) describe the vascular patterns of ciliary body and choroidal nevi by light microscopy, (2) compare the vascular ultrastructure of nevi with vessels of the normal uvea and uveal melanomas, and (3) compare the behavior of ciliochoroidal melanomas with and without a nevus-like vascular architecture. METHODS: After delineating the vascular patterns of 23 choroidal and ciliary body nevi by light microscopy, the authors identified 49 melanomas that had the same vascular patterns as nevi from a previously published series of 234 uveal melanomas. The survival of these 49 patients who had melanomas with a nevus-like vascular architecture was compared with the 185 patients who had melanomas that lacked this vascular profile. RESULTS: By light microscopy, the only vascular patterns identified in nevi are "normal" vessels, zones of avascularity ("silent" pattern), straight, and parallel vessels; closed vascular loops and networks were not detected in nevi. By transmission electron microscopy, the vascular basement membrane of malignant melanomas was multilaminar, fragmented, and significantly thicker than in normal eyes or nevi. None of the patients with nevi died of metastatic disease. Fourteen percent of patients whose melanomas had the same vascular profile as nevi died of metastatic disease, whereas 32% of patients whose melanomas had vascular patterns other than those seen in nevi died of metastatic melanoma (P = 0.012). CONCLUSIONS: The microcirculation architecture marks tumor progression in uveal melanocytic lesions by light and electron microscopy. In the spectrum of these lesions, nevi are benign, melanomas that have the same vascular profile as nevi have an intermediate biologic behavior, and melanomas with vascular networks are strongly associated with death due to metastatic disease.

Residential radon exposure and lung cancer: evidence of an urban factor in Iowa.

An ecological study of lung cancer, cigarette smoking, and radon exposure was conducted in 20 Iowa counties. County-based lung cancer incidence data for white female residents of Iowa were stratified according to radon level and smoking status. Cancer incidence data for the period 1973-1990 were obtained from the State Health Registry of Iowa. Smoking level was determined from a randomly mailed survey. Radon level was determined according to an EPA supported charcoal canister survey. Within low smoking counties, rates for all lung cancer and small cell carcinoma were significantly lower (p < 0.05) in the high radon counties relative to the medium and low radon counties. However, within high smoking counties, rates for all lung cancer, adenocarcinoma, and small cell carcinoma were significantly higher (p < 0.05) in the high radon counties relative to the low radon counties. Variations in socioeconomic data for these counties, available through the 1980 and 1990 census, did not explain these results. Lung cancer rates also were significantly increased in urban counties even after holding smoking status constant. Multivariate analyses revealed significant interactions between smoking, urbanization, radon levels, and lung cancer. The results of this hypothesis generating study will be tested in a case/control study now ongoing in Iowa. Analysis will need to include separate evaluations by smoking status, radon level, and residence in urban or rural areas for the major morphologic types of lung cancer.

The prognostic value of tumor blood vessel morphology in primary uveal melanoma.

BACKGROUND: It is possible to identify at least nine vascular patterns in melanomas of the ciliary body and choroid from histologic sections. An association between the presence of at least one closed vascular loop and death from metastases was shown in a matched-pair, case-control study of 40 patients whose eyes were removed for ciliary body or choroidal melanomas. METHODS: Two independent observers who were masked to the follow-up of patients examined histologic preparations of 234 eyes removed for ciliary body or choroidal melanomas for the presence of each of the tumor vascular patterns. Statistical analyses included tests for interobserver reliability, Kaplan-Meier survival curves, and the fitting of Cox regression models. RESULTS: The detection of each of the nine vascular patterns is highly reproducible. The Cox model indicates that the presence of vascular networks, defined as at least three back-to-back closed vascular loops, is the feature most strongly associated with death from metastatic melanoma. Other significant factors in the Cox model include (in descending order of importance) largest tumor dimension, mitoses, the parallel with cross-linking vascular pattern, age, the presence of tumor-infiltrating lymphocytes, and male gender. CONCLUSIONS: The presence of vascular networks provides the most significant association with death from metastatic melanoma of all variables tested. The presence of this pattern should be recorded on pathology reports. If it becomes possible to detect this vascular pattern clinically using a noninvasive imaging technique, then ophthalmologists may be able to determine the likely biologic behavior of a melanoma before resorting to the removal of tissue.

The morphologic characteristics of tumor blood vessels as a marker of tumor progression in primary human uveal melanoma: a matched case-control study.

Nine morphologic patterns of tumor vessels were identified in eyes removed for ciliary body or choroidal melanoma by the examination of tissue sections stained with fluorescein-conjugated Ulex europaeus I using laser scanning confocal microscopy. This technique also highlights intravascular tumor invasion. Each of these nine morphologic patterns of tumor vessels also may be demonstrated by a modification of the periodic acid-Schiff reaction, viewed with a green narrow band pass filter, but this modified histochemical technique does not accurately identify intravascular tumor invasion. Most tumors have a heterogeneous distribution of vascular patterns. Melanomas in two groups of 20 tumors each were matched by tumor size and location (one group of tumors from patients who survived at least 15 years free of metastatic melanoma after enucleation and one group of tumors from patients who died of metastatic melanoma). A matched case-control analysis indicates that the presence of at least one closed vascular loop in a uveal melanoma is the most significant vascular pattern associated with death from metastatic melanoma after enucleation. Closed loops are associated with other histologic features that are predictive of an unfavorable outcome after enucleation: epithelioid cells and mitotic figures. In this preliminary study the formation of closed vascular loops is a marker of tumor progression in ciliary body and choroidal melanomas.

Dietary habits, prepregnancy weight, and weight gain during pregnancy. Risk of pre term rupture of amniotic sac membranes.

BACKGROUND: Premature rupture of amniotic sac membranes (PROM) is associated with perinatal morbidity and mortality. A matched case-control study was undertaken to determine whether dietary habits, prepregnancy weight, and weight gain during pregnancy were associated with increased risks for PROM. METHODS: Three study groups were defined, consisting of women delivering pre term with PROM (PP), full term with PROM (FP), and pre term without PROM (PWP). Cases were singly matched by race, age, and parity with women having full term deliveries without PROM. Data were collected by face-to-face structured interviews with eligible subjects and by medical records abstraction. RESULTS: Conditional multiple logistic regression indicated that during pregnancy, PP cases were significantly more likely to have gained less than 21 pounds (9.5 kg) (OR = 2.7, CI = 1.14-6.36) and were only half as likely as controls to have improved their diet (OR = 0.43, CI = 0.18-0.99) while controlling for cigarette smoking, urinary tract infection, chorioamnionitis, chlamydia, and a history of previous PROM. FP cases were significantly less likely than controls to have gained 31-40 pounds (14-18 kg) while pregnant (OR = 0.56, CI = 0.33-0.94) and were significantly more likely than controls to have a somewhat inadequate pregnancy diet (OR = 2.05, CI = 1.11-3.77) while controlling for a history of previous PROM. PWP cases were significantly less likely to have gained 31-40 pounds (14-18 kg) (OR = 0.42, CI = 0.21-0.84) or greater than 40 pounds (18 kg) (OR = 0.37, CI = 0.17-0.80) while pregnant or to have had adequate dairy products intake (OR = 0.60, CI = 0.36-0.99) while controlling for cigarette usage. CONCLUSION: Maternal dietary habits, weight gain during pregnancy, and supplement intake are associated with the occurrence of both pre term and full term PROM and pre term delivery without PROM.

Variability in expression of common fragile sites: in search of a new criterion.

Fragile sites are nonrandom, heritable sites on chromosomes that can be induced to form gaps, breaks, and rearrangements under specific conditions. There is currently no established criterion to define a common fragile site. We applied seven published criteria to our data from three groups of subjects: (1) three pairs of like-sexed twins, (2) four unaffected von Hippel-Lindau (VHL) family members, and (3) six patients affected with VHL disease. Substantial differences were present in the numbers of sites considered positive by these criteria. While some of this variability can be attributed to technical factors, our data illustrate the problems in comparing results from different studies to assess the significance of fragile sites. A recently published criterion is based upon the Poisson distribution. We found this criterion to be flawed in its presentation, and furthermore, the Poisson distribution did not provide an adequate approximation to our data. We propose here an alternative approach based upon the negative binomial distribution.

Chlorinated drinking water and bladder cancer: effect of misclassification on risk estimates.

Data are presented from the Iowa portion of the National Bladder Cancer Case-Control Study demonstrating the effect of misclassification on depressing odds ratio estimates for years of exposure to chlorinated drinking water and bladder cancer. Four methods (METHODS 1 through 4) of quantifying chlorination exposure with sequentially decreasing degrees of misclassification are presented for the 268 bladder cancer cases and 658 population-based controls fulfilling criteria for inclusion in this study. Twenty-eight other risk factors for bladder cancer were considered along with chlorinated drinking water exposure estimated by METHOD 4. Stepwise regression models included as significant factors cigarette smoking (p less than .001), chlorination exposure (p = .038), and irradiation to the pelvic area (p = .040). Replacement of chlorinated drinking water exposure estimated by METHOD 4 with any of the remaining three methods resulted in models that included cigarette smoking and irradiation to the pelvic area, but not chlorination exposure. Thus, misclassification of chlorination exposure signified the difference between observing and not observing an association with bladder cancer.

Hospital-acquired pneumonia. Attributable mortality and morbidity.

A total of 1,001 consecutive episodes of nosocomial pneumonia in 901 patients was identified by routine surveillance at the University of Virginia Medical Center between 1979 and 1983 (8.6 episodes/1,000 admissions). When only initial episodes were examined, 890 patients comprised the study sample. The overall case fatality rate was 30%. Stepwise logistic regression indicated that time from admission to pneumonia (p = 0.0006), age (p less than 0.0001), prior use of mechanical ventilation (p = 0.0032), and neoplastic disease (p = 0.0062) were associated with mortality. Multiple regression analysis indicated that the factors associated with increased length of hospitalization included posttracheostomy status (p = 0.0001), prior mechanical ventilation (p = 0.0001), immunosuppressive or leukopenic status (p = 0.0009), nasogastric intubation (p = 0.0003), and prior bacteremia (p = 0.0127). A sampled, individually matched cohort study (n = 74 pairs) was conducted to determine the proportion of mortality in cases that was attributable to infections (33%) and to determine excess hospital stay (seven days) among the patients with nosocomial pneumonia. Excess stay was statistically significant (p less than 0.0001), but proportional mortality was only marginally significant (p = 0.0892). Our findings suggest that nosocomial pneumonia accounts for approximately 33% of the crude mortality and contributes significantly to the economic burden associated with prolonged hospitalization.

A Monte Carlo investigation of homogeneity tests of the odds ratio under various sample size configurations.

Epidemiologic data for case-control studies are often summarized into K 2 x 2 tables. Given a fixed number of cases and controls, the degree of sparseness in the data depends on the number of strata, K. The effect of increasing stratification on size and power of seven tests of homogeneity of the odds ratio is studied using Monte Carlo methods. In all the designs considered here, the numbers of cases and controls per stratum are the same. Considering both size and power in non-sparse-data settings, we recommend the Breslow-Day statistic (1980, Statistical Methods in Cancer Research, 1. The Analysis of Case-Control Studies, p. 142; Lyon: International Agency for Research on Cancer) for general use. In sparse-data settings the T4 statistic of Liang and Self (1985, Biometrika 72, 353-358) performs the best when all tables, regardless of sample size, have odds ratios generated from the same distribution. In sparse-data settings characterized by a large table with an odds ratio of 1 and many small tables with odds ratios greater than 1, the T5 statistic of Liang and Self (1985) performs the best. One of the most important results of this study is the generally low power for all homogeneity tests especially when the data are sparse.

Sample size for case-control studies using Cochran's statistic.

Sample size determination for case-control studies of chronic disease are often based on the simple 2 X 2 tabular cross-classification of exposure and disease, thereby ignoring stratification which may be considered in the analysis. One consequence of this approach is that the sample size may be inadequate to attain a specified power and size when performing a statistical analysis on J 2 X 2 tables using Cochran's (1954, Biometrics 10, 417-451) statistic or the Mantel-Haenszel (1959, Journal of the National Cancer Institute 22, 719-748) statistic. A sample size formula is derived from Cochran's statistic and it is compared with the corresponding one derived when the data are treated as unstratified, and also with two other formulas proposed for stratified data analysis. The formula developed yields values slightly higher than one recently proposed by Muñoz and Rosner (1984, Biometrics 40, 995-1004), which assumes that both margins of each 2 X 2 table are fixed, while the present study considers only the case-control margin to be fixed.