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Much medical research is observational. The reporting of observational studies is often of insufficient quality. Poor reporting hampers the assessment of the strengths and weaknesses of a study and the generalisability of its results. Taking into account empirical evidence and theoretical considerations, a group of methodologists, researchers, and editors developed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) recommendations to improve the quality of reporting of observational studies. The STROBE Statement consists of a checklist of 22 items, which relate to the title, abstract, introduction, methods, results and discussion sections of articles. Eighteen items are common to cohort studies, case-control studies and cross-sectional studies and four are specific to each of the three study designs. The STROBE Statement provides guidance to authors about how to improve the reporting of observational studies and facilitates critical appraisal and interpretation of studies by reviewers, journal editors and readers. This explanatory and elaboration document is intended to enhance the use, understanding, and dissemination of the STROBE Statement. The meaning and rationale for each checklist item are presented. For each item, one or several published examples and, where possible, references to relevant empirical studies and methodological literature are provided. Examples of useful flow diagrams are also included. The STROBE Statement, this document, and the associated Web site (http://www.strobe-statement.org/) should be helpful resources to improve reporting of observational research., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The most effective regimen for acute myeloid leukemia (AML) patients who do not achieve complete remission (CR) after two different courses of front-line chemotherapy has not been established. We therefore evaluated the efficacy, toxicity, and prognostic factors for achieving CR following treatment with fludarabine and cytarabine in 25 newly diagnosed AML patients who did not respond to initial therapy with idarubicin and cytarabine followed by mitoxantrone and etoposide. CR was achieved in 32% of patients; in 55% of patients with intermediate-risk karyotype and in 14% with unfavorable-risk. Eight percent died of infectious complications. Median duration of overall survival was 6.6 months (95% CI 3.4 months to ∞); 3.4 months (95% CI 0.8-8.6 months) for patients with an unfavorable-risk karyotype and 18.1 months (95% CI 5.0 months to ∞) with an intermediate-risk karyotype (p=0.02). Our data suggest that poor-risk karyotype patients are unlikely to benefit from third course treatment with fludarabine-cytarabine, and that this regimen merits further investigation in AML patients with good or intermediate-risk karyotype that have persistent leukemia after two courses of front-line chemotherapy., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Elderly patients with acute myeloid leukemia (AML) are generally unable to withstand the rigors of intensive induction chemotherapy and its attendant complications. Gemtuzumab ozogamicin (GO) is an immunoconjugate that had demonstrated activity in recurrent AML., Methods: The objective of the current study was to determine the prognostic factors for achievement of complete remission (CR) in newly diagnosed elderly AML patients treated with GO as initial induction therapy. A retrospective study was performed of efficacy and toxicity associated with GO therapy, and factors potentially predictive of response were assessed in 49 previously untreated AML patients., Results: CR was achieved in 14% of all treated patients. Among the patients with an intermediate-risk karyotype, the CR rate was 30%, compared with none with an unfavorable karyotype. The median duration of overall survival was 3.7 months (95% confidence interval [95% CI], 1.4-6.9 months), and the median recurrence-free survival in patients who achieved CR was 11.8 months (95% CI, 5.0-ind months)., Conclusions: These data suggest that GO should be considered as a first-line treatment option in older patients with AML with intermediate-risk cytogenetics who cannot tolerate high-dose induction chemotherapy.

The most effective regimen for patients with acute myeloid leukemia (AML) who do not achieve complete remission (CR) after one course of cytarabine and an anthracycline has not been extensively studied. We evaluated retrospectively the efficacy, toxicity, and prognostic factors for the achievement of CR following mitoxantrone and etoposide in 74 patients with newly diagnosed AML who did not respond to one course of therapy with cytarabine and idarubicin. CR was achieved in 39% of patients; 14% died of infectious complications; no grade 3 or 4 hepatic toxicities were observed. Median duration of overall survival was 9.0 months (95% CI 5.8-14.9 months). The median duration of relapse-free survival was 11.0 months (95% CI: 9.0-19.3 months). A lower CR rate was associated with unfavorable risk status at diagnosis and higher percent blasts. Our data suggest that the combination of etoposide and mitoxantrone is an effective second-course therapy in patients with newly diagnosed AML.

Background: There is no standard second-line therapy for advanced pancreatic cancer (APC). We evaluated the epidermal growth factor receptor (EGFR) inhibitor gefitinib and docetaxel in a phase II study following gemcitabine failure., Methods: EGFR overexpression was not required. The initial docetaxel dose was 75 mg/m(2) on day 1 every 21 days. Due to febrile neutropenia in 8 of the first 18 patients, the dose was reduced to 60 mg/m(2). Gefitinib, 250 mg/day orally, was given continuously., Results: Forty-one patients received treatment and were evaluable. Febrile neutropenia was seen in 11 patients (27%), with most events occurring at the docetaxel dose of 75 mg/m(2) (8 of 18 patients). Common treatment-related grade 3/4 toxicities were: fatigue (7%), nausea (7%), diarrhea (5%) and vomiting (2%). There was 1 partial response and stable disease in 19 patients. Time to progression was 1.8 months and median survival was 4.5 months (95% CI 2.9-5.7)., Conclusion: The tolerability and feasibility of second-line therapy for APC was demonstrated. The combination of gefitinib and docetaxel showed evidence of limited efficacy., (Copyright 2009 S. Karger AG, Basel.)

Much medical research is observational. The reporting of observational studies is often of insufficient quality. Poor reporting hampers the assessment of the strengths and weaknesses of a study and the generalizability of its results. Taking into account empirical evidence and theoretical considerations, a group of methodologists, researchers, and editors developed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) recommendations to improve the quality of reporting of observational studies. The STROBE Statement consists of a checklist of 22 items, which relate to the title, abstract, introduction, methods, results and discussion sections of articles. Eighteen items are common to cohort studies, case-control studies and cross-sectional studies and four are specific to each of the three study designs. The STROBE Statement provides guidance to authors about how to improve the reporting of observational studies and facilitates critical appraisal and interpretation of studies by reviewers, journal editors and readers.This explanatory and elaboration document is intended to enhance the use, understanding, and dissemination of the STROBE Statement. The meaning and rationale for each checklist item are presented. For each item, one or several published examples and, where possible, references to relevant empirical studies and methodological literature are provided. Examples of useful flow diagrams are also included. The STROBE Statement, this document, and the associated web site (http://www.strobe-statement.org) should be helpful resources to improve reporting of observational research.

Two influential case-control studies that clearly implicated cigarette smoking as a cause of lung cancer are reviewed in terms of their respective strengths and weaknesses. The findings from a U.S. study reported in 1950 by Wynder and Graham were strikingly similar to those arising from a U.K. study reported later that year by Doll and Hill. The methodological rigor of these investigations effectively ruled out alternatives to smoking as plausible explanations for the increased risk, although additional investigations in animals and man were needed to buttress the original results. The exceptionally high relative risk of lung cancer that was found has had far-reaching medical, social, and economic consequences.

Two-stage designs are used widely in Phase II oncology clinical trials to reduce the number of patients placed on ineffective experimental therapies. They provide clear-cut rules for stopping early in the event that treatment is not succeeding as hoped and are relatively simple to implement. Such designs, however, can lead to situations in which patient accrual is continued in the face of a clearly inferior treatment. In situations where patients' response can be determined for many or most subjects before additional patients are enrolled, analyses using Bayesian methodology can lead to earlier termination of studies of ineffective treatments and better align the statistical assessment of treatment effect with the therapeutic objectives of study. These points are discussed in context of the role of Phase II clinical trials in the development of new treatments for cancer.

Inactivation of tumor suppressor genes by promoter methylation is an important mechanism of tumorigenesis. Increased expression of DNA methyltransferases has been commonly observed in cancer. A C/T polymorphism in the DNA methyltransferase 3b (DNMT3b) promoter region results in increased activity and has recently been identified as a risk factor for lung cancer. In this study, we examined the C/T polymorphism of the DNMT3b gene in specimens from 81 patients with prostate cancer and 42 controls selected from patients with benign prostatic hypertrophy (BPH). Genomic DNA was isolated from archived formaldehyde-fixed and paraffin-embedded tissue blocks. DNMT3b genotypes were determined by restriction-fragment-length-polymorphism polymerase chain reaction. The DNMT3b polymorphism frequencies in the prostate cancer and BPH specimens were, respectively, 20 and 26% for CC, 42 and 52% for CT, and 38 and 21% for TT. Although such differences fall within the realm of chance variation (P>0.05), the data suggest that the TT genotype may be associated with an increased risk of prostate cancer: the age-adjusted odds ratio (aOR) was 2.6 [95% confidence interval: 0.8-8.0]; the increase in odds ratio was seen in both blacks and whites (aOR=4.3 in blacks, and 2.0 in whites). The samples used in this study have previously been examined for methylation index (MI) based on the number of genes methylated, the range being 0 to 5. A trend toward an increase in MI was detected for the DNMT3b polymorphisms in prostate cancer patients but not for BPH subjects (mean MI 2.6, 2.9, 3.1 for CC, CT, and TT genotype in prostate cancer; 0.8, 0.8, 0.7 for CC, CT, and TT genotype in BPH subjects). These findings suggest that the DNMT3b polymorphisms may be associated with an increase in promoter methylation of tumor-suppressor genes related to the development of prostate cancer, and may thereby increase the risk of this disease.

Methylenetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolate, which is involved in the methylation of homocysteine to methionine. Genetic polymorphisms that decrease MTHFR activity result in an altered cancer risk depending on folic acid intake. In this study we examined the C677T and A1298C polymorphisms of the MTHFR gene in specimens from 81 patients with prostate cancer and 42 controls selected from patients with benign prostatic hypertrophy (BPH). Genomic DNA was isolated from archived formaldehyde-fixed and paraffin-embedded tissue blocks. MTHFR genotypes were determined by restriction-fragment-length-polymorphism polymerase chain reaction. The MTHFR polymorphism frequencies in the prostate-cancer and BPH specimens were, respectively, 60% and 48% for 677CC, 31% and 48% for 677CT, 9% and 5% for 677TT, 36% and 43% for 1298AA, 53% and 40% for 1298AC, and 11% and 17% for 1298CC. Although such differences fall within the realm of chance variation (P>0.05), the data suggest that the 677CT genotype may be associated with a reduced risk of prostate cancer: the age-adjusted odds ratio (aOR) was 0.6 [95% confidence interval (CI): 0.3-1.4]; the odds-ratio reduction was similar in both blacks and whites (aOR=0.4 in blacks, and 0.6 in whites); and when polymorphisms at the 677 and 1298 loci were analyzed in conjunction, a lower frequency of the 677CT-1298AA genotype was observed in the patients with prostate cancer (aOR=0.3, 95% CI: 0.1-1.1). This particular genotype, moreover, was associated with lower Gleason score tumors (aOR=0.1 for Gleason-score 7 versus 6 tumors, 95% CI: 0.0-0.7) and earlier stage disease (aOR=0.3 for stage III versus II, 95% CI: 0.3-2.6). These findings suggest that polymorphisms of the MTHFR gene may alter the risk of developing prostate cancer.

Promoter methylation plays an important role in the inactivation of tumor suppressor genes during tumorigenesis. We examined the methylation status of glutathione s-transferase Pi1 (GSTP1), retinoic acid receptor beta (RARB), CD44, E-cadherin (ECAD), RAS association domain family protein 1A (RASSF1A) and endothelin B receptor (EDNRB) genes in 81 prostate cancer and 42 benign prostatic hyperpasia specimens. Genomic DNA was isolated from archived formaldehyde-fixed and paraffin-embedded tissue blocks. Methylation-specific PCR (MSP) was carried out after bisulfite treatment of genomic DNA. Methylation frequencies in prostate cancer and benign prostatic hyperplasia were 72% and 5% for GSTP1, 40% and 0% for RARB, 72% and 38% for CD44, 61% and 14% for ECAD, 49% and 19% for RASSF1A and 72% and 62% for EDNRB, respectively. Methylation of GSTP1, RARB, CD44, ECAD and RASSF1A, but not of EDNRB was detected at a statistically higher frequency in prostate cancer than in the benign prostatic hypertrophy specimens. Methylation of RARB occurred more frequently in early onset (age <55 years) as compared to late onset disease (age >70 years) (odds ratio, 8.6; 95% CI, 1.4-51.4; P=0.02). Methylation of RARB also occurred more frequently in stage III as compared to stage II disease (odds ratio, 3.2; 95% CI, 1.1-8.8; P=0.03). A methylation index (MI) was calculated as the total number of genes methylated, excluding EDNRB. A trend toward higher MI was noted in stage III as compared to stage II disease, and in Gleason score 7 as compared to Gleason score 6 tumors. Our results suggest that the methylation of selected genes in prostate cancers correlates with clinicopathological features of poor prognosis.

Purpose: To determine the safety, immunogenicity, and clinical response to an allogeneic tumor vaccine for non-small-cell lung cancer, we conducted a phase I trial in patients with advanced metastatic disease., Patients and Methods: We treated 19 patients with a vaccine based on an adenocarcinoma line (AD100) transfected with B7.1 (CD80) and HLA A1 or A2. Patients were vaccinated intradermally with 5 x 10(7) cells once every 2 weeks. Three vaccinations represented one course of treatment. If patients had complete response, partial response, or stable disease, they continued with the vaccinations for up to three courses (nine vaccinations). Immune response was assessed by a change between pre-study and postvaccination enzyme-linked immunospot frequency of purified CD8 T-cells secreting interferon-gamma in response to in vitro challenge with AD100., Results: Four patients experienced serious adverse events that were unrelated to vaccine. Another four patients experienced only minimal skin erythema. All but one patient had a measurable CD8 response after three immunizations. The immune response of six surviving, clinically responding patients shows that CD8 titers continue to be elevated up to 150 weeks, even after cessation of vaccination. Overall, one patient had a partial response, and five had stable disease. Median survival for all patients is 18 months (90% CI, 7 to 23 months), with corresponding estimates of 1-year, 2-year, and 3-year survival of 52%, 30%, and 30%, respectively. HLA matching of vaccine, age, sex, race, and pathology did not bear a significant relation to response., Conclusion: Minimal toxicity and good survival in this small population suggest clinical benefit from vaccination.

Since the introduction of hormonal contraceptives in the 1960s, there have been a variety of both health benefits and safety concerns attributed to their use. In most instances, the noncontraceptive benefits of oral contraceptives (OCs) outweigh the potential cardiovascular risks. In fact, the probability of a patient experiencing a cardiovascular event while taking a low-dose OC is very low. However, smoking, hypertension, obesity, and diabetes are risk factors that must be taken into account when prescribing OCs. The neoplastic effects of hormonal contraceptives have been extensively studied, and recent meta-analyses indicate that there is a reduction in the risk of endometrial and ovarian cancer, a possible small increase in the risk for breast and cervical cancer, and an increased risk of liver cancer. Finally, many women will experience noncontraceptive health benefits with OCs that expand far beyond pregnancy prevention. Some of these benefits include reduction in menstrual-related symptoms, fewer ectopic pregnancies, a possible increase in bone density, and possible protection against pelvic inflammatory disease.

Large tumor burdens in advanced non-small-cell lung carcinoma (NSCLC) are thought to be immunosuppressive. To determine whether CD8-mediated immune responses could be elicited in stage IIIB/IV NSCLC patients, 14 subjects were immunized several times with allogeneic NSCLC cells transfected with CD80 (B7.1) and HLA-A1 or A2. Patients enrolled were matched or unmatched at the HLA A1 or A2 locus and their immune response compared. Immunization significantly increased the frequencies of interferon-gamma secreting CD8 T cells in all but one patient in response to ex vivo challenge with NSCLC cells. The CD8 response of matched and unmatched patients was not statistically different. NSCLC reactive CD8 cells did not react to K562. Clinically, five of 14 patients responded to immunization with stable disease or partial tumor regression. The study demonstrates that CD8 Ifn-gamma responses against nonimmunogenic or immunosuppressive tumors can be evoked by cellular vaccines even at advanced stages of disease. The positive clinical outcome suggests that nonimmunogenic tumors may be highly susceptible to immune effector cells generated by immunization.

Systematic review and meta-analysis procedures make use of explicit methods to methodically search and critically appraise and synthesize the medical care research literature. The methods involve refining a clinical question, designing a search procedure to find eligible studies, and determining the validity of the eligible studies. Independent data extraction by two or more reviewers is preferred. Agreement between the reviewers with respect to relevance and validity should be measured. Meta-analysis procedures estimate an overall average effect from the individual study effects and determine whether these effects appear to measure the same relationship (that is, the studies are not heterogeneous). In the inverse variance method, which is most frequently applied, the overall effect is a weighted average of the individual study effects, where each weight is the inverse of the study variance. To evaluate a systematic review, first determine whether it addresses a question that is relevant to the patients, treatments, and outcomes that are usual in your clinical practice. Then assess the validity of the systematic review, which is reflected by quality of the individual studies, the rigor with which the systematic methods were applied, and the extent of heterogeneity. If the results of the systematic review are valid, then is the effect important enough to make a difference in your clinical practice? Applying the results to an individual patient involves the absolute treatment effect or the number needed to treat, and an awareness of the patient's specific level of risk and personal preferences.

The effect of reproductive hormone use in the form of oral contraception or HRT on endometrial cancer incidence is not caused by simply bias: the epidemiologic studies are consistent; the effect of ERT is large; the biologic rationale cited is a plausible mechanism; and the response to progestin in oral contraception or combined HRT tends to confirm the biologic mechanism. In contrast, it remains unclear whether changes in breast cancer incidence following use of oral contraception and HRT are caused by hormone exposure or to other factors: the results of epidemiologic studies are not entirely consistent, and the smaller relative effect on risk of breast cancer is susceptible to bias and other sources of error. Although the exact nature of the association between repro ductive hormone use and breast cancer incidence is not yet clear, breast cancer is a common neoplasm in older women. Prescribers and users should take this into account in weighing benefits to ensure that unnecessary risks are avoided.

Purpose: To assess the effect of nerve-sparing (NS) radical retropubic prostatectomy (RRP) on surgical margins and biochemical recurrence., Patients and Methods: Location and incidence of positive surgical margins, recurrence, and time to recurrence were assessed in a consecutive series of 734 men who underwent RRP for localized prostate cancer from 1992 through February 2000. NS procedures were used in 33% (n = 240) of 734 patients studied., Results: Surgical margins were positive for 24% (n = 58) and 31% (n = 152) of NS and non-NS patients, respectively (P =.06). No significant difference between the groups was found in location of positive margins (P =.92). Prostate-specific antigen level greater than 10 ng/mL, extraprostatic extension, tumor volume more than 20%, capsular penetration, Gleason score > or = 7, positive margins, and seminal vesicle invasion were associated with significantly increased risk of recurrence. However, NS patients were not at increased risk of recurrence compared with non-NS patients (hazard ratio, 0.96; 95% confidence interval, 0.53 to 1.72). The cumulative risk of recurrence within 3 and 5 years of surgery in NS patients was 9.7% and 14.4%, respectively, as compared with 17.1% and 21.1% for non-NS patients., Conclusion: In patients with localized prostate cancer, neither margin status nor biochemical-free survival within 5 years of surgery were altered by the nerve preservation technique. Given our experience, we recommend preservation of neurovascular bundles in these patients whenever the procedure is technically feasible.

Objective: The purpose of this study was to determine whether women with a family history of ovarian cancer are at reduced risk of ovarian cancer from the use of oral contraceptives and to compare their risk with that of women with no family history of ovarian cancer., Study Design: A population-based case-controlled study was conducted from May 1994 through July 1998 in which 767 women aged 20 to 69 years with a diagnosis of epithelial ovarian cancer were ascertained from 39 hospitals in 3 northeastern states. Personal interviews with the women and 1367 control subjects provided data that allowed us to estimate the relative risk of ovarian cancer in relation to a family history of cancer and total duration of oral contraception., Results: Among the 33 case patients and 24 control subjects with a first-degree family history of ovarian cancer, risk of ovarian cancer declined with increasing duration of oral contraception (P =.01). Risk reduction from short-term use of oral contraceptives (< or = 48 months) did not differ significantly by family history (combined estimate of odds ratio, 0.72; 90% CI, 0.59%-0.87%). Risk reduction from long-term use of oral contraceptives (>48 months) was greater in women with a positive family history of ovarian cancer (odds ratio, 0.12) than in women with a negative family history of ovarian cancer (odds ratio, 0.51; test of interaction, P =.04; 692 case patients, 1279 control subjects)., Conclusion: Four to 8 years of oral contraception may substantially reduce the risk of ovarian cancer by age 70 years in women with a family history of the disease, from approximately 4 women per 100 women who did not use oral contraceptives to only 2 women per 100 women who did use oral contraceptives.

Although past studies have shown that oral contraceptives with 50 microg or more of estrogen reduce the risk of ovarian cancer, it is not clear whether newer, lower-dose formulations do as well. We conducted a population-based, case-control study in the Delaware Valley to assess the impact of dose of oral contraception on risk of ovarian cancer. Cases aged 20-69 years with a diagnosis of epithelial ovarian cancer ascertained between May 1994 and July 1999 (n = 767) were compared with community controls (n = 1,367). Compared with never users, the adjusted risk of ovarian cancer was reduced by 40% for oral contraceptive users overall, with longer duration of use affording greater protection. The ovarian cancer risk reduction was similar for women who initiated oral contraception before 1972, when high-dose pills dominated the market; between 1972 and 1980; and after 1980, when newer, lower-dose pills dominated. Oral contraceptive estrogen and progestin content were compared for cases and controls after adjustment for current age, number of pregnancies, race, and family history of ovarian cancer. Use of low-estrogen/low-progestin pills afforded an estimated risk reduction (odds ratio = 0.5, 95% confidence interval: 0.3, 0.6) that was identical to that for high-estrogen/high-progestin pills (odds ratio = 0.5, 95% confidence interval: 0.3, 0.7).

Approximately 25% of patients with stage I (node negative) breast cancer relapse at a rate similar to those with stage II disease. Inadvertent pathologic "understaging" of lymph node status is one plausible explanation for this phenomenon. While many studies have shown that additional sectioning +/- immunohistochemical staining for epithelial markers increases the rate of detection of small deposits of metastatic carcinoma, few have had sufficient statistical power to examine the impact of "occult" metastasis on clinical outcome. This provocative update by the International Ludwig Breast Cancer Study Group provides support for considering going "the extra mile" to detect lymph node metastasis in postmenopausal patients and those with the lobular subtype of invasive breast cancer.

Previous epidemiologic observations consistently suggest that suppression of ovulation, tubal ligation, and hysterectomy reduce the risk of ovarian cancer and that perineal talc use increases the risk. We examined these and other risk factors in the context of a new hypothesis: that inflammation may play a role in ovarian cancer risk. Ovulation entails ovarian epithelial inflammation; talc, endometriosis, cysts, and hyperthyroidism may be associated with inflammatory responses of the ovarian epithelium; gynecologic surgery may preclude irritants from reaching the ovaries via ascension from the lower genital tract. We evaluated these risk factors in a population-based case-control study. Cases 20-69 years of age with a recent diagnosis of epithelial ovarian cancer (767) were compared with community controls (1,367). We found that a number of reproductive and contraceptive factors that suppress ovulation, including gravidity, breast feeding, and oral contraception, reduced the risk of ovarian cancer. Environmental factors and medical conditions that increased risk included talc use, endometriosis, ovarian cysts, and hyperthyroidism. Gynecologic surgery including hysterectomy and tubal ligation were protective. Tubal ligation afforded a risk reduction even 20 or more years after the surgery. The spectrum of associations provides support for the hypothesis that inflammation may mediate ovarian cancer risk.

The most frequent major adverse effect of hormonal contraception is an increased risk of cardiovascular disease. The effect on the risk of venous thromboembolism (VTE), ischemic and hemorrhagic stroke, and myocardial infarction (MI) differs and is strongly influenced by smoking and the presence of other cardiovascular risks factors, such as hypertension and diabetes mellitus. The incidence of each disease rises with age and there are differences in risk among hormonal contraceptive preparations. This article provides a framework within which to assess the balance of risks among types of hormonal contraceptives according to individual circumstances. Data on cardiovascular disease mortality rates in women of reproductive age in different countries of the world were compiled from nationally reported statistics and supplemented where possible with reported disease incidence rates. Risks associated with current use of hormonal contraception were compiled from the most recent publications on the cardiovascular effects of steroid hormone contraception. These were combined to estimate the total cardiovascular incidence and mortality according to baseline cardiovascular risk and individual characteristics. Mortality rates for cardiovascular diseases are very low in women of reproductive age. Myocardial infarction mortality rates rise from < 0.4 per 100,000 woman-years at age 15-24 years to the range 2 to 7 per 100,000 woman-years at age 35-44 years. Stroke mortality rates similarly rise steeply with age and are between 3 and 5 times higher than those for MI. VTE mortality rates rise less steeply with age and are approximately one-tenth the MI mortality rates at age 35-44 years. The adverse effect of oral contraceptives (OC) on the risk of VTE is the most important contributor to the total number of cardiovascular cases attributable to OC use. The increased risk of stroke and MI dominate the patterns of mortality in OC users and smokers. The additional risks attributable to smoking are greater than the additional risks attributable to OC use. The risk attributable to OC use in women < 35 years of age is small, even if they smoke, but there are substantially increased risks in older women who both smoke and use OC. The additional mortality attributable to OC use can be reduced by screening users, as this results in lower relative risks of ischemic stroke and MI. Differences between OC types in the relative risk of VTE contribute little to the total cardiovascular mortality associated with OC use, even though the total number of cardiovascular events is increased. A potential reduction in the risk of MI with desogestrel and gestodene compared with levonorgestrel-containing OC would have little difference on overall mortality rates in women in their 20s and 30s, but may result in a net reduction in OC-attributable mortality in women aged 40-44 years who smoke. An overall quantification of the risks for different types of oral contraceptive users is necessary for an informed choice of contraceptive method, and any assessment of the balance of cardiovascular risks is complex. The model provides a tool to assess, at the level of the individual, the risks associated with use of different OC according to personal circumstances. It is important to consider the user's age and smoking status when determining OC attributable risks.

Objective: To understand physician concerns about litigation and beliefs regarding vaccine safety., Design: A stratified random sample of family physicians, pediatricians, and general practitioners younger than 65 years who were in office-based practices across the United States was selected from the American Medical Association list that includes nonmembers. A standardized telephone survey was conducted by trained interviewers in 1995., Participants: Physicians seeing 5 or more patients per week younger than 6 years and having 50% or more primary care patients were eligible for the study., Results: Of the 1236 physicians who were surveyed, 32% and 13% overestimated the risk for serious adverse effects related to pertussis and measles vaccines, respectively. Among physicians who thought that serious adverse effects from diphtheria and tetanus toxoids and pertussis vaccine (DTP) were unlikely, 15% were highly concerned about litigation; however, among those with higher ratings of the likelihood of serious adverse effects, 38% were highly concerned about vaccine litigation (P < .01). Of those aware of the Vaccine Injury Compensation Program, only 41% believed that it afforded a high level of liability protection; 22% believed that it gives little protection, and 37% gave an intermediate answer. Among physicians highly concerned about vaccine litigation, 22% were unlikely to recommend the third dose of DTP for a child with a fever of 39.4 degrees C and no other symptoms after the second dose of DTP, whereas among those expressing little concern about litigation, only 12% were unlikely to vaccinate (P < .05). Although some physicians were concerned about litigation, most (86%) encouraged vaccination even if a parent was argumentative about possible adverse effects., Conclusion: Physicians' perceptions about the risk for adverse effects and protection afforded by the Vaccine Injury Compensation Program influence their concern about litigation and, to a lesser extent, their reported likelihood to administer immunizations.

Objective: To determine the causes of low childhood immunization rates based on physicians' knowledge, attitudes, and self-reported practices concerning childhood immunization., Design: A standardized telephone survey conducted by trained interviewers., Setting: Primary care physicians across the United States., Participants: A stratified random sample of office-based family physicians, pediatricians, and general practitioners younger than 65 years was selected from the American Medical Association master file list that includes nonmembers. Physicians seeing 5 or more patients per week younger than 6 years and having 50% or more primary care patients were eligible for study. Of 1769 eligible physicians who spoke directly with the interviewers, 70% (N = 1241) completed the questionnaire., Interventions: The interview was designed to determine physicians' likelihood of recommending vaccination in common clinical scenarios and to probe reasons behind these decisions., Results: Only 4% of physicians who thought the risk for side effects was increased by upper respiratory tract infection (URI) were likely to vaccinate a child with URI vs 55% of physicians who thought there would be no increased risk (P < .001). Eighty-three percent of those who thought the efficacy of measles, mumps, and rubella vaccine would not be affected by a URI recommended vaccination vs only 8% of physicians who thought efficacy would decrease (P < .001). Some respondents (11%) would not administer 3 injectable vaccines simultaneously based on beliefs about side effects, parental objections, and vaccine efficacy. Physicians' likelihood of vaccination also varied by type of visit: 47% were less likely to vaccinate a child with a URI in an acute care as opposed to a well-child setting., Conclusion: Physicians' beliefs and practice policies materially influence their likelihood of recommending vaccinations.

Objective: To estimate by meta-analysis the risk of developing cancer of the breast, uterine cervix, endometrium, ovary, and liver from age 20-54 years in the United States in women using oral contraceptives (OCs) for 4, 8, or 12 years., Data Sources: Using pairs of terms (such as oral contraception and breast neoplasms), I searched for English-language literature on OC use and cancer published since 1980 and cited through July 1994 in the MEDLINE data base., Methods of Study Selection: I analyzed all epidemiologic studies reporting estimates of relative risk (RR) by duration and recency of OC use (79 independent studies in total)., Data Extraction and Synthesis: Reported duration-specific and recency-specific estimates of RR, with the corresponding numbers of cases and controls or person-time at risk for cohort studies, were abstracted from each article. Relative risk of cancer as a function of both duration and recency of OC use was then estimated by weighted regression and applied, using life-table methods, to United States population-based data on age-specific mortality and cancer incidence., Conclusions: For every 100,000 women in the United States who never use OCs, the number developing cancer from age 20-54 years is estimated to be 2782 (breast), 425 (cervix), 438 (endometrium), 369 (ovary), and 20 (liver). For women using OCs for 8 years, the estimated number of additional or fewer cases per 100,000 users is +151 (breast), +125 (cervix), -197 (endometrium), -193 (ovary), and +41 (liver). Therefore, from a population perspective, there are only small cancer-related risks and benefits associated with OC use and, on balance, the net effect is negligible.

Objective: To determine the effect of oral contraceptive (OC) use on the cumulative incidence of epithelial ovarian cancer from ages 20-40, 20-50, and 20-55 years among four groups of women: positive family history, negative family history, parous, and nulliparous., Methods: Cancer and Steroid Hormone Study data were combined with data from the Surveillance, Epidemiology, and End Results Network to provide estimates of the age-specific incidence rates of epithelial ovarian cancer among never-users of OCs in the four specified groups of women. These rates provided the basis for calculating cumulative incidences. The rates in women using OCs were estimated from meta-analyses of the epidemiologic literature, using regression equations expressing the log-relative rate of epithelial ovarian cancer as a function of duration of use and recency., Results: In all four groups, the cumulative number of epithelial ovarian cancer cases estimated to occur per 100,000 OC users, compared to never-users, decreased with increasing duration of OC use. Our results suggest that 5 years of OC use by nulliparous women can reduce their ovarian cancer risk to the level seen in parous women who never use OCs, and that 10 years of OC use by women with a positive family history can reduce their risk to a level below that for women whose family history is negative and who never use OCs., Conclusion: These data represent the first published estimates of the effect of OC use on the cumulative incidence of epithelial ovarian cancer by family history and by parity. The demonstrated substantial noncontraceptive benefit from OCs justifies their judicious use as a potentially powerful resource for primary prevention in women at high risk of ovarian cancer.

Short-term use (less than 1 year) or oral contraceptives has been associated with increased to slightly decreased risks of epithelial ovarian cancer in several studies. To determine what might account for a statistically significant 40% reduction in risk associated with as little as 3 to 6 months of use, a finding previously reported from the Cancer and Steroid Hormone Study, and to consider the implications for mechanisms of pathogenesis, the authors compared numerous characteristics of short-term users of oral contraceptives (41 cases, 412 controls) with those of never users (242 cases, 1,517 controls). The reduced risk among short-term users was consistently restricted to women who stopped using oral contraceptives for medical reasons, which were essentially side effects; there was little evidence of a protective effect among women who stopped for nonmedical reasons. Factors such as age, parity, family history of ovarian cancer, estrogen dose, history of sterilization, and latency (interval from first use) could not account for the finding. These analyses suggest that short-term use of oral contraceptives has little to no effect per se on reducing the risk of epithelial ovarian cancer and that side effects resulting in cessation of oral contraceptive use shortly after it was begun may be indicative of factors that are protective against the disease.

Analyses of tumor size and breast cancer stage were used to determine whether biased detection of breast cancer could have materially influenced estimates of risk associated with use of oral contraceptives. In a population-based case-control study conducted from 1980-1982, surveillance for breast cancer by breast exams, but not mammography, was found to be strongly linked to use of oral contraceptives. Tumors were slightly smaller and less likely to be late-stage (TNM stage III or IV) in patients who had used oral contraceptives. The net effect of any diagnostic bias on advancing the date of cancer diagnosis, whether from breast exams or other sources, was estimated to be less than 8 weeks. This corresponds to spuriously increasing the risk of early-occurring breast cancer in oral contraceptive users by at most 2.4% (relative risk = 1.024).

Effects of oral contraception on neoplasia of the uterine corpus are reviewed on the basis of epidemiologic studies reported to date. A duration-related protective effect against endometrial cancer occurs from use of combined oral contraceptives, those in which each active pill contains both estrogen and progestogen. The risk before age 60 years is reduced by about 38% with two years of use; use of combined OCs for 4, 8, and 12 years, respectively, confers an estimated 51%, 64%, and 70% reduction in endometrial cancer risk. The protective effect appears not to be diminished by discontinued use, even 15 or more years after stopping. Whether protection continues throughout the entire postmenopausal period, even in the presence of long-term hormone replacement therapy, remains to be seen. Use of combined OCs may protect against uterine leiomyomas ("fibroids"), but the evidence is not conclusive. The few findings about effects of oral contraception on the risk of adenomatous hyperplasia are of uncertain validity. Only one study, with few patients, has considered oral contraception in relation to uterine sarcomas.

Among women in general the risk of breast cancer through 59 years of age does not appear to be affected appreciably by the use of oral contraceptives. Nonetheless, concern continues to be expressed about the effects of early age at first use, long-term duration of use, formulation, and a variety of other factors thought to influence breast cancer risk in the presence of oral contraception. A number of recent studies restricted to young women suggest that long-term use may increase the risk of disease occurring very early, but the present lack of consistent findings in well-conducted epidemiologic studies prevents any certain conclusion with regard to cause-and-effect. However, if an increased risk were indeed present, the most plausible interpretation is that long-term oral contraception promotes earlier clinical manifestation of breast cancer in some women while having no net impact on their lifetime risk of the disease.

Consistency and plausibility are fundamental criteria for judging cause and effect from observational studies. They are applied here to the interpretation of data from a population-based case-control study of oral contraceptives and breast cancer. A preliminary analysis of oral contraceptive use in young nulliparous women, who had no family history of either breast cancer or benign breast disease, showed a statistically significant dose-response, with long-term users (49 months or more) having an apparent 4-fold elevation in risk of early breast cancer. Further analyses, however, revealed striking inconsistencies which were biologically implausible. These effectively undermine cause and effect as an explanation for the initial finding.

In case-control studies, exposure to a risk factor often occurs at several levels, so the attributable risk at each level is of interest. In this paper, estimation for the 2 X 2 table (case-control status versus dichotomous exposure) and the 2 X k table (case-control status versus exposure at several levels) are reviewed along with an example. A method for finding confidence intervals for attributable risk in the 2 X k table is proposed, and its application to estimates adjusted across strata (the 2 X k X s case) is indicated. The results of a Monte Carlo study of the procedure demonstrate that the nominal and actual coverage probabilities agree satisfactorily for practical applications.

A financial review of five case-control studies concerning the relationship of birth control methods to the occurrence of disease was conducted. The review had two major objectives: first, to identify costs associated with the planning, conduct and analysis of case-control studies; second, to assess whether sample size determination based on optimal allocation would have resulted in a significant reduction in cost. The data collection phase represented about 75% of the total cost of a study, whereas the costs of planning and analysis were roughly 10% and 15% of total cost, respectively. The typical cost in mid-1970s dollars was from +100-+200 per subject. Evaluation of an optimal allocation procedure based on the relative cost of cases and controls demonstrated that such a method was likely to reduce total study cost by at most 2 per cent.

Effects of oral contraception on cancers of the female breast and reproductive tract are critically reviewed from human studies reported since 1980. The cumulative risk of breast cancer through 59 years of age appears to bear no relationship to oral contraceptive (OC) use whatsoever. Studies restricted to women under age 45, however, raise concern about a possible adverse effect from OC use before a first-term pregnancy. A duration-related protective effect against endometrial cancer occurs from use of combined OCs. The risk is reduced by about 40% with 2 years of use, and by about 60% with 4 or more years of oral contraception. Oral contraception in excess of 3 years protects against ovarian cancer. Four years of use confers a 50% reduction in risk and 7 or more years of use confers a 60%-80% reduction in ovarian cancer risk. Studies of cervical dysplasia and carcinoma in situ suggest elevated risks with 2 or more years of OC use, although results are difficult to interpret in view of numerous factors that might distort the findings. The risk of invasive cervical cancer appear to be unaffected by up to 5 years of oral contraception. Beyond this, there is evidence suggesting an elevated risk which approaches a 2-fold increase at 10 years of use. Cancers of the vagina and fallopian tube are extremely rare. Their risks have yet to be characterized in relation to oral contraception.

Characteristics of women with potential for modifying the relationship between use of oral contraceptives (OCs) and the risk of premenopausal breast cancer were investigated using data from the Cancer and Steroid Hormone study, a population-based, case-control study conducted in eight geographic areas of the United States. Cases consisted of 2945 women who were premenopausal and 20-54 years of age when breast cancer was diagnosed between December 1, 1980, and December 31, 1982; controls consisted of 2646 women with no history of breast cancer who were also premenopausal and 20-54 years of age when selected during the same period. Results are presented with the cases and controls divided into eight groups on the basis of age at diagnosis on selection (20-44, 45-54), parity (0, greater than or equal to 1), and age at menarche (less than 13, greater than or equal to 13). Among nulliparous women who experienced menarche before age 13, the relative risk of developing breast cancer in the age interval 20-44 years is estimated to be 1.0 for never-users of OCs (reference), 1.3 for greater than 0-3 years of use (95% confidence intervals 0.7-2.4), 1.3 for 4-7 years (95% CI 0.7-2.6), 2.7 for 8-11 years (95% CI 1.2-6.3), and 11.8 for 12 years or longer (95% CI 1.4-95.7). OC use is not significantly related to the risk of breast cancer among women in any of the other seven groups. These findings suggest that prolonged OC use may accelerate the onset of breast cancer for a small group of susceptible women while having no appreciable impact on overall risk. The findings should be regarded as tentative, however, since they are based upon numerous comparisons and because age of menarche was stratified at 13 years to highlight the concentration of breast cancer risk apparent in our data.

Five study centers enrolled 1,311 women seeking postcoital contraception methods. Ethinyl estradiol was administered at 5 mg/day and conjugated estrogens at 30 mg/day for five consecutive days starting within 72 hours of unprotected coitus. Eleven pregnancies occurred in the 976 women who had a single unprotected coitus at midcycle. Based on published information, 69 pregnancies would have been expected if no contraceptives were used. Although both treatments were effective in preventing pregnancy, ethinyl estradiol seemed to be more effective. At the two centers alternately prescribing both drugs, none of 137 women treated with ethinyl estradiol became pregnant, while six of the 132 given conjugated estrogens became pregnant. Women whose treatment commenced on the first postcoital day seemed to have lower pregnancy rates than those whose medication was delayed to the second or third postcoital day regardless of which drug was used. Side effects were mainly limited to nausea that occurred in 70% and vomiting that was experienced by 33% of all women treated.

To evaluate the effect of oral contraceptive use on the risk of breast cancer from 20-54 years of age in women with a family history of the disease, we analyzed data from the Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development. For 2 years, beginning December 1980, the study enrolled from eight geographical areas in the United States 4730 women with breast cancer and 4646 controls who were breast cancer-free. For women with a first-degree family history of breast cancer, 554 cases and 280 controls, there was no evidence that use of oral contraceptives, even long-term, contributed to their risk of the disease. Neither total duration of use nor duration of use before first term pregnancy bore any relationship with breast cancer risk. Analyses designed to reveal a potential latent effect also showed no evidence of an adverse effect. For women with a second-degree family history of breast cancer, 777 cases and 595 controls, some isolated elevations in risk were observed for selected subgroups of oral contraceptive users. Detailed analyses of oral contraceptive formulation, the characteristics of the women involved, and the patterns of risk observed by latent period and duration of use suggest that these results, most within the limits of chance variation, are not likely to be a consequence of oral contraception.

The consequences of a factory closure on future employment, disability and death were investigated in a 10-year prospective follow-up study in a general practice setting. The study population consisted of 85 persons who lost their jobs when a brisling sardine factory close to Bergen in Norway was shut down in 1975. The employees of a nearby "sister factory" within the same company were chosen as a control population, consisting of 87 persons. After the factory closure, the annual employment rate of the study group showed a steady rise to a maximum level of 44% within 6 years, but even after 10 years never matched the employment rate of the controls. The cumulative rates of disability pension, granted for medical conditions only, was more than three times higher in the study group than among controls from the second through the fourth year of follow-up. This excess of disabilities then stayed relatively constant at approximately 17 per 100 persons from 5 to 10 years after the shut-down. Given present days' unemployment, the results of this investigation point to the importance of acknowledging a long-term effect of job-loss on health and social readjustment.

A long-term effect of oral contraceptives (OCs) on breast cancer risk has been suggested as an explanation for some studies' failure to detect an association between OCs and breast cancer. To address this latency hypothesis, we analyzed data on 4714 case subjects and 4540 control subjects from the population-based Cancer and Steroid Hormone Study. No support was evident for a latent effect of OCs on breast cancer risk through age 54 years: among parous women who had cumulated more than six years of OC use before their first term pregnancy, the risk of breast cancer, relative to nonusers before first term pregnancy, was 0.6 at zero to four years after first term pregnancy (95% confidence interval [Cl], 0.2 to 1.8), 0.7 at five to nine years (95% Cl, 0.3 to 1.7), and 1.1 at ten to 14 years (95% Cl, 0.3 to 3.9). Among nulliparous women with more than six years of OC use in total, the relative risk of breast cancer, by interval from last use of OCs, was 1.3 at zero to four years (95% Cl, 0.8 to 2.0), 1.1 at five to nine years (95% Cl, 0.5 to 2.0), and 0.6 at ten to 14 years (95% Cl, 0.1 to 3.7).

The procedure of in vitro fertilization, including ova collection and embryo culture and transfer, raises concern about the risk of abnormalities arising from the technique. In vitro versus in vivo comparison might be made in the study of preimplantation embryos and spontaneous abortions, the results of amniocentesis, and the findings among fetal deaths and live births. In vivo, 40% to 50% of implantation blastocysts are estimated to have a chromosomal abnormality, over 99% of which are estimated to be eliminated during the course of pregnancy. In principle, the use of early spontaneous abortions can be more efficient than amniocentesis for detecting an increased risk of chromosomal abnormalities at birth. Unless in vitro fertilization in humans strongly contradicts the experience in domestic animal reproduction, which suggests no increased risk of abnormalities at birth, a large number of births would be required to provide a definitive assessment of risk.