Changes in the ascertainment of multiple sclerosis.

OBJECTIVE: With diagnostic criteria alterations, increased MRI availability, and awareness of therapies, temporal changes in incidence and prevalence rates may occur, with an increase in the proportion of mildly affected persons diagnosed with multiple sclerosis (MS). The authors assessed temporal trends in the delay from symptom onset to diagnosis (DONDX), and determined whether the degree of disability at diagnosis differs by year of symptom onset (YONSET), using the NARCOMS Registry. METHODS: The authors selected US participants with an age at symptom onset of 10 to 60 years, and YONSET > or = 1980 (n = 16,581). The authors divided YONSET into 5-year groups and compared DONDX between groups using multivariate Cox regression. The authors classified participants enrolled within 2 years of diagnosis (n = 5,548) as having mild, moderate, or severe disability using Patient Determined Disease Steps, and assessed the association of disability with YONSET using polytomous logistic regression. RESULTS: DONDX decreased with later YONSET (r = -0.43, p < 0.0001). This association remained after adjustment for demographic factors in a multivariate Cox model. Later YONSET was associated with increased odds of having mild disability at diagnosis as compared to severe disability (OR = 1.10 per year; 1.09 to 1.11). CONCLUSION: The delay from symptom onset to diagnosis is steadily decreasing in MS. An increasing proportion of patients with MS have mild disability at diagnosis after accounting for confounders. As the effectiveness of therapies is influenced by disease duration, this has implications for comparison of treatment effects in modern clinical trials to earlier study results.

Prevalence and treatment of spasticity reported by multiple sclerosis patients.

The objective of this study was to characterize the population of multiple sclerosis (MS) patients suffering from spasticity and to evaluate treatment patterns, including intrathecal baclofen (ITB) delivery, related to patient quality of life (QOL). We conducted a cross-sectional, two-level study using data from the Patient Registry of the North American Research Committee on MS (NARCOMS). In addition, we surveyed a subgroup of 198 preselected patients who are using ITB (ITBG) and a random sample of 315 oral drug users (ORALG). Among the registrants, 16% reported no spasticity, 31% minimal, 19% mild, 17% moderate (frequently affects activities), 13% severe (daily forced to modify activities) and 4% total (prevents daily activities). Patients experiencing greater severity included by proportion males, and those older and with longer duration of MS. QOL scores decreased inversely with severity. In the focused survey, ITBG reported lower levels of spasticity than ORALG, less stiffness in the legs, less pain and fewer spasms at any time. They scored significantly lower in the SF-36 physical component, yet reported less fatigue on the MFIS scale. Prevalence data reveal that one third of MS patients modify or eliminate daily activities as a result of spasticity. Treatment of spasticity can significantly impact QOL parameters by reducing spasms, pain and fatigue.

Predictors of adherence to Copaxone therapy in individuals with relapsing-remitting multiple sclerosis.

The purpose of this study was to evaluate psychological, biophysical, and sociodemographic variables as predictors of adherence to glatiramer acetate (Copaxone) therapy in individuals with relapsing-remitting multiple sclerosis (MS). Because Copaxone is a daily subcutaneous injection, individuals with MS are challenged by the daily routine of preparation and administration of this medication. Despite the challenges, some individuals with MS adhere to treatment with injectable medications with little or no difficulty, while others struggle to adhere to, and soon abandon, the daily task. It is important to identify predictors of adherence to Copaxone therapy so those at risk can be identified early and provided with individualized support at the onset of therapy. Potential participants were identified from the Consortium of Multiple Sclerosis Centers North American Research Committee on Multiple Sclerosis Patient Registry database (n = 600) and from the Shared Solutions MS patient support database (n = 600). Individuals who had taken or stopped taking Copaxone were specifically selected. Those taking multiple immunomodulating drugs or not able to complete the data collection instruments were excluded. Booklets containing four instruments (MS Self-Efficacy Control and Function Subscales, Rosenberg Self-Esteem Scale, Herth Hope Index [HHI], and Performance Scale) and sociodemographic data sheets were mailed to 1,200 individuals. Of the 594 who completed and returned booklets, 341 individuals had relapsing-remitting MS and met the inclusion criteria. There were 225 individuals in the adherent group and 116 in the nonadherent group. Logistic regression analysis revealed four significant predictors of adherence: self-efficacy (control), hope, perception that the doctor was the most supportive of the individual taking Copaxone, and no previous use of other immunomodulators. The higher the score on the MS Self-Efficacy Control Subscale and HHI, the more likely the individual will adhere to Copaxone therapy. The MS Self-Efficacy Control Subscale and HHI show promise of being useful predictors of adherence. Further testing is recommended. Physician support should be conveyed to all individuals starting and maintaining Copaxone therapy for MS. Greater support needs to be provided to those who have previously taken immunomodulating drugs.

Associations between smoking and adenocarcinomas and squamous cell carcinomas of the uterine cervix (United States).

OBJECTIVES: Few studies of smoking and cervical carcinoma have addressed the rare cervical adenocarcinomas or used DNA-based tests to control for human papillomavirus (HPV) infection. METHODS: This multicenter case-control study included 124 adenocarcinoma cases, 307 community controls (matched on age, race, and residence to adenocarcinoma cases), and 139 squamous carcinoma cases (matched on age, diagnosis date, clinic, and disease stage to adenocarcinoma cases). Participants completed risk-factor interviews and volunteered cervical samples for PCR-based HPV testing. Polychotomous logistic regression generated adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for both histologic types. RESULTS: Eighteen percent of adenocarcinoma cases, 43% of squamous carcinoma cases, and 22% of controls were current smokers. After control for HPV and other questionnaire data, adenocarcinomas were consistently inversely associated with smoking (e.g. current: OR = 0.6, 95% CI 0.3-1.1; > or = 1 pack per day: OR = 0.7, 95% CI 0.4-1.3), while squamous carcinomas were positively associated with smoking (e.g. current: OR = 1.6, 95% CI 0.9-2.9; > or = 1 pack per day: OR = 1.8, 95% CI 1.0-3.3). Results in analyses restricted to HPV-positive controls were similar. CONCLUSION: Smoking has opposite associations with cervical adenocarcinomas and squamous carcinomas. Although both histologic types are caused by HPV and arise in the cervix, etiologic co-factors for these tumors may differ.

Evaluation of self-collected cervicovaginal cell samples for human papillomavirus testing by polymerase chain reaction.

As human papillomavirus (HPV) becomes accepted as the central cause of cervical cancer, longitudinal studies are shifting focus away from causality to a more detailed investigation of the natural history of HPV infections. These studies commonly require repeated samples for HPV testing over several years, usually collected during a pelvic exam, which is inconvenient to the participants and costly to the study. To alleviate the inconvenience and cost of repeated clinic visits, it has been proposed that women collect cervicovaginal cells themselves, hopefully increasing participation in the natural history studies. We evaluated the technical feasibility of self-collection of cervicovaginal cells using a Dacron swab for HPV DNA detection. We compared the self-collected swab sample and two clinician-administered swab samples (one from the endocervix and another from the ectocervix) from a total of 268 women participating in a case-control study of adenocarcinoma and squamous cell carcinomas of the uterine cervix (111 cases and 157 controls). HPV DNA was detected and genotyped using an L1 consensus PCR assay. The overall agreement between the clinician- and self-collected swabs was excellent [88.1%; kappa = 0.73 (95% confidence interval (CI), 0.61-0.85)]. The correlation was highest between the two clinician-administered swabs [kappa = 0.81 (95% CI, 0.69-0.93)] but was still excellent when comparing either clinician-administered swab to the self-administered sample [kappa = 0.75 (95% CI, 0.63-0.87) and 0.67 (95% CI, 0.55-0.79) for ectocervix and endocervix, respectively]. The type-specific agreement between samples was higher for high-risk, or cancer-associated, HPV genotypes than for low risk, noncancer-associated HPV genotypes when comparing the self-administered swab sample to the clinician-administered swab sample (kappa = 0.78 for high-risk versus 0.66 for low-risk HPV infections, t = -1.45, P = 0.15). The decrease in agreement for low risk types was largely attributable to an increased detection of these types in the self-administered sample (McNemar's chi2 = 6.25, P = 0.01 for clinician- versus self-administered swab comparisons). The agreement did not vary significantly by age, menopausal status, case status, or clinic center. We have demonstrated that a self-collected Dacron swab sample of cervicovaginal cells is a technically feasible alternative to clinician-administered cervical cell collection in natural history studies of HPV and cervical cancer.

Use of hormone replacement therapy and adenocarcinomas and squamous cell carcinomas of the uterine cervix.

INTRODUCTION: Exogenous hormones may influence the development of cervical adenocarcinomas. Incidence rates of adenocarcinomas and use of noncontraceptive hormones have increased since the 1970s, but few studies have investigated this potential relationship. METHODS: We conducted a multicenter case-control study of 124 women with adenocarcinomas, 139 women with squamous cell carcinomas matched on age, diagnosis date, clinic, and stage of disease (in situ or invasive) to adenocarcinoma cases, and 307 healthy community controls who were also matched on age, ethnicity, and residence to adenocarcinoma cases. Participants completed in-person interviews regarding exogenous hormone use before diagnosis and other risk factors and volunteered cervical samples for human papillomavirus (HPV) testing via a PCR-based method. Odds ratios (ORs) with 95% confidence intervals (CIs) estimated relative risks. RESULTS: Only 13 adenocarcinoma cases (10.5%), 7 squamous carcinoma cases (5%), and 20 controls (6.5%) had used noncontraceptive hormones for menopausal symptoms, irregular periods, or disease prevention; most use was short-term, former use. Ever-use was associated with adenocarcinomas (OR = 2.1, 95% CI 0.95-4.6) but not squamous carcinomas (OR = 0.85, 95% CI 0.34-2.1). No trends were seen with duration of use or ages at first use, but unopposed estrogens were positively associated with adenocarcinomas (OR = 2.7). Unopposed estrogens remained associated with adenocarcinomas (OR = 2.0) when analyses were restricted to the HPV-positive controls. Menopausal status was not associated with adenocarcinomas or squamous carcinomas and did not modify the other associations. CONCLUSION: Although small numbers warrant tentative conclusions, exogenous estrogens, especially unopposed estrogens, were positively associated with adenocarcinomas. Noncontraceptive hormones were negatively but weakly associated with squamous carcinomas.

Oral contraceptives as risk factors for cervical adenocarcinomas and squamous cell carcinomas.

To assess the hypothesis that oral contraceptives (OCs) increase the risk of cervical adenocarcinomas, we conducted a six-center case-control study of 124 patients with adenocarcinomas, 139 with squamous cell carcinomas, and 307 population controls. Women between the ages of 18 and 69 who were newly diagnosed with cervical adenocarcinomas between 1992 and 1996 were eligible. Healthy female controls and a second case group of incident cervical squamous cell carcinomas were matched to the adenocarcinoma cases. All participants were interviewed regarding OCs, other risk factors for cervical carcinoma, and utilization of cytological screening, and a PCR-based test determined HPV genotype of cervical samples for both case groups and controls. Use of OCs was positively and significantly associated with adenocarcinomas and positively but weakly associated with squamous cell carcinomas. Associations between OCs and invasive adenocarcinomas (n = 91), squamous cell carcinoma in situ (n = 48), and invasive squamous cell carcinomas (n = 91) disappeared after accounting for HPV infection, sexual history, and cytological screening, but a positive association remained between current use of OCs and cervical adenocarcinoma in situ (n = 33). This association persisted after stratification by screening and sexual history and after restriction according to HPV status, but small numbers made it difficult to exclude detection bias, selection bias, or residual confounding by HPV as potential explanations Current OC use was associated with cervical adenocarcinomas in situ, but we saw no other evidence that OCs independently increase the risk of cervical carcinomas.

Risk factors for rapid-onset cervical cancer.

OBJECTIVES: The current study was designed to elucidate risk factors associated with the development of cervical cancer during the course of routine Papanicolaou smear screening (rapid-onset cervical cancer). STUDY DESIGN: Four hundred eighty-three women diagnosed with invasive cervical cancer, representing 73% of all such tumors diagnosed in Connecticut between 1985 and 1990, were studied. Papanicolaou smear screening and risk factor information was obtained by questionnaire and physician record review. Results from human papillomavirus deoxyribonucleic acid testing by polymerase chain reaction of tumor samples were available for 278 study participants. Prediagnostic Papanicolaou smear slides were reviewed for 67% of cases with a screening history. Screening history information, slide review, and questionnaire data were used to classify women as having rapid-onset cervical cancer (n = 43), possible rapid-onset cervical cancer (n = 111), or normal-onset cervical cancer (n = 329). RESULTS: Compared with normal-onset cases, rapid-onset cases tended to be younger (P =.001) and were more likely to be white (P =.002), diagnosed with adenocarcinomas or adenosquamous carcinomas (P =.001), and diagnosed with early-stage disease (P =.001). Cases diagnosed as possible rapid-onset disease tended to have a profile that was intermediate to that observed for rapid-onset and normal-onset cases. Human papillomavirus deoxyribonucleic acid was detected in 75.2% of cases tested. Compared with women who tested positive for human papillomavirus type 16 or other, those positive for human papillomavirus type 18 had a relative risk for rapid-onset disease of 1.6 (95% confidence interval 0.52-4.9). No significant association was observed between type 18 and possible rapid-onset disease when possible rapid-onset cases were compared with women diagnosed with normal-onset cervical cancer (relative risk 0.67, 95% confidence interval 0.29-1.6). Oral contraceptive use, cigarette smoking, number of pregnancies, and a maternal history of cervical cancer were not significantly associated with rapid-onset disease. CONCLUSIONS: Results from this study suggest that the risk factors associated with the development of rapid-onset cervical cancer are similar to those for normal-onset disease.

Rapidly progressive cervical cancer: the Connecticut experience.

A review is presented of 15 years of clinical experience working with women who developed cervical cancer within a short interval after the last reported negative Papanicolaou smear. Our initial report concerned isolated cases in which women were diagnosed with invasive cervical cancer within 1 year of a reported normal Papanicolaou smear. Our second report focused on a 10-year review of the Yale-New Haven Hospital experience, during which 40 of 555 women had rapidly progressive invasive disease; 35 cases (87.5%) occurred in women younger than 40 years old and almost all of the 40 diagnosed because of persistent symptoms despite a recent normal Papanicolaou smear. Our final experience is a population-based study of all women in Connecticut who developed cervical cancer between 1985 and 1990. A total of 118 of 481 (24.5%) participants were diagnosed with cervical cancer within 3 years of their last true-negative Papanicolaou smear. Adenocarcinomas occurred in 38 cases (32.2%). These data suggest that rapidly occurring cervical cancer may be a manifestation of endocervical carcinomas that have been inadequately screened.

The screening histories of women with invasive cervical cancer, Connecticut.

OBJECTIVES: Each case of a continuous series of invasive cervical cancer cases was studied with a structured review procedure conducted by an expert panel to assess the reason that it was not detected before it became invasive. METHODS: All cases of invasive cervical cancer diagnosed in a 5-year period among Connecticut residents were identified; a screening history and screening outcome were obtained for 72% (481 of 664). RESULTS: Two hundred fifty women (51.9%) had suboptimal screening. One hundred thirty-seven women (28.5%) had never had a screening test, and their mean age was greater than that of the rest of the study population (64.5 years vs 46.5 years). Of the 344 women who had ever had a Pap test, 113 (32.8%) had their last Pap test 5 or more years before their diagnosis of invasive cancer; 52 (15.1%) were not followed up properly; 33 (9.6%) had their last smear misread as normal; and 118 (34.3%) developed cervical cancer within 3 years of their last Pap test. CONCLUSIONS: Physicians, nurses, and other care providers need to ensure that woman have timely and accurate screening with proper follow-up, make increased efforts to reach older women, and improve quality control of Pap smear readings.

Leukemia, lymphoma, and multiple myeloma after pelvic radiotherapy for benign disease.

The relationship between exposure to sparsely ionizing radiation and mortality due to cancers of hematopoietic and lymphopoietic tissues was studied among 12,955 women treated for benign gynecological disorders at any of 17 hospitals in New England or New York State and followed for an average of 25 years; 9770 women were treated by radiation (intracavitary 226Ra, external-beam X rays), while 3185 were treated by other methods, including curettage, surgery, and hormones. The average age at treatment was 46.5 years, and the mean dose to active bone marrow among irradiated women was 119 cGy. Forty deaths due to acute, myelocytic, or monocytic leukemia were observed among irradiated women. This number was 70% higher than expected based on U.S. mortality rates [standardized mortality ratio (SMR) = 1.7; 90% confidence interval (CI) 1.3-2.3]. A deficit was recorded among nonirradiated women, based on three observed deaths (SMR = 0.5; 90% CI 0.1-1.2). A well-defined gradient in the SMR with dose among exposed women was not detected. The SMR was highest within 5 years after irradiation but remained elevated even after 30 years. The temporal pattern differed by subtype of leukemia: excess mortality due to chronic myelocytic leukemia occurred almost exclusively within the first 15 years, whereas the SMR for acute leukemia, though also elevated, varied little over time. Cancers of lymphoreticular tissue occurred more often than expected based on U.S. mortality rates, but not appreciably differently for irradiated and nonirradiated women. There was little or no evidence of effects attributable to radiotherapy for chronic lymphocytic leukemia [relative risk (RR) = 1.1; 90% CI 0.5-3.0], Hodgkin's disease (RR = 0.9; 90% CI 0.3-3.2), non-Hodgkin's lymphoma (RR = 0.9; 90% CI 0.6-1.6), or multiple myeloma (RR = 0.6; 90% CI 0.3-1.4). These results corroborate previous findings indicating that acute and myelocytic leukemias are the most prominent malignancies after exposure to sparsely ionizing radiation, occurring in excess shortly after irradiation, and that lymphomas are either not caused by radiation or are induced only rarely.

The mortality of US nuclear submariners, 1969-1982.

A mortality study of 76,160 men who served on US nuclear submarines is reported. Indirect standardization was used to compare mortality rates to those of the US male population. Multiplicative models were developed to explore patterns of mortality within the cohort. Mortality rates for leukemia, acute myocardial infarction, and for motor vehicle accidents were equivalent to those of US males; rates for other causes were lower, generally consistent with the "healthy worker effect." Motor vehicle accident mortality dropped during the study period, perhaps reflecting efforts to control the problem. Suicide rates were depressed during the period of active duty. There was a suggestion that cancer mortality was associated with submarine type; however, the age distribution casts doubt that the excess was occupationally induced.

Histologic and clinical characteristics associated with rapidly progressive invasive cervical cancer: a preliminary report from the Yale Cancer Control Research Unit.

Histologic and clinical characteristics associated with rapidly progressive invasive cervical cancer are presented in this preliminary report from a population-based study involving all patients in Connecticut diagnosed with cervical cancer from March 1, 1985. Rapidly progressive invasive cervical cancer, i.e., invasive cancer diagnosed within three years of a true negative Pap smear, is more likely to occur in younger women with high annual incomes (61 percent greater than $40,000) who report a greater frequency of benign gynecologic conditions (uterine leiomyomata, vaginitis) compared to a control cervical cancer group. These preliminary data suggest that as many as 35 percent of the rapidly progressive cervical cancers are likely to be adenocarcinomas. Because they are mostly endocervical in origin, they may not be detected cytologically if scrapers or cotton swabs are used to sample the endocervical canal. New cytologic screening techniques using brushes may identify these lesions earlier and should routinely be employed in cytologic screening for cervical neoplasia. The difficulty in early detection of this form of the disease requires that physicians rapidly assess patients with unexplained pelvic and lower abdominal pain, vaginal discharge, or abnormal vaginal bleeding since early recognition is the only chance for cure. Further analyses of this population of women will be made to identify additional risk factors when the study data are complete.

Abortion before first livebirth and risk of breast cancer.

The present study examined the association between abortion prior to a first livebirth and breast cancer risk among a cohort of 3,315 women who had been delivered of liveborn children between 1946 and 1965 in a group of private gynaecology practices in Connecticut and followed through 1980 for the incidence of cancer. Among women with one livebirth at the time of cohort identification, a spontaneous abortion before this livebirth was associated with a 3.5-fold increase in the risk of breast cancer. The elevation in risk was independent of some of the major risk factors of breast cancer and became more pronounced as the number of years since the abortion increased.

Cancer risk among women exposed to exogenous estrogens during pregnancy.

A cohort of 3,139 obstetric patients, who delivered children between 1946 and 1965, was followed retrospectively to assess the relationship between exposure to diethylstilbestrol [(DES) CAS: 56-53-1; alpha, alpha'-diethyl-4,4'-stilbenediol] or other estrogenic substances during pregnancy and subsequent cancer incidence. Among the 1,531 women exposed to DES, the relative risk (RR) for all cancers was 1.46 [95% confidence interval (CI), 1.07-2.00]. The RR for cancers of the breast, cervix, and ovary were 1.37 (adjusted), 1.40, and 2.83, respectively, but none of these estimates was statistically significant. For breast cancer an RR in excess of 2.28 can be excluded, with 95% CI for doses averaging 2,100 mg. Within the exposed group there was no evidence for a dose-response relationship.

Mortality and cancer incidence experience of employees in a nuclear fuels fabrication plant.

The mortality and cancer incidence experience of 4,106 employees in a nuclear fuels fabrication plant was evaluated in this retrospective cohort study. Standardized mortality (SMR) and incidence ratios were calculated for groups of employees holding different jobs in the company associated with various types of industrial exposures and with low levels of radiation. Connecticut population mortality rates and Connecticut Tumor Registry incidence rates, specific for age-sex, calendar year and cause of death or cancer site, were used for the calculation of expected rates. Results showed the SMR for all male employees to be significantly lower than expected for all causes and what would be expected for all cancer deaths. More deaths were observed than expected from diseases of the central and peripheral nervous system and from obstructive pulmonary disease. The overall cancer incidence experience of the male employees was significantly lower than expected; cancer of the brain was found to be significantly higher than expected among the industrial employees. These was no risk associated with any particular job exposure group. Log linear models analysis showed no significant effect from industrial and radiation exposures or from their combined influence.

Evaluation of an occupational respiratory exposure to a zirconium-containing dust.

A group of handfinishers of zirconium metal reactor components questioned whether the dust to which they were exposed would cause chronic lung disease or cancer, or both. To investigate this possibility, the work environment was surveyed, and 32 male employees who had worked as handfinishers from one to seventeen years, were compared to a group of controls in reference to a respiratory questionnaire, chest x-ray findings, and expiratory lung function tests. The controls were matched to the handfinishers for age, sex, payroll status and smoking history. No significant differences were found between the exposed and the control groups. Results of earlier animal respiratory studies vary from no effect to definite pathology. Previous employee exposure studies are short-term and have methodological shortcomings. It would appear that lifetime animal respiratory studies and systematic epidemiological studies of employee populations with long-term inhalation exposure are needed to demonstrate unequivocally whether zirconium and zirconium compounds are harmful.