The added value of mifepristone to non-surgical treatment regimens for uterine evacuation in case of early pregnancy failure: a systematic review of the literature.

OBJECTIVE(S): Early pregnancy failure (EPF) is a common complication of pregnancy. Surgical intervention carries a risk of complications and, therefore, medical treatment appears to be a safe alternative. Unfortunately, the current medical treatment with misoprostol alone has complete evacuation rates between 53% and 87%. Some reports suggest that sequential treatment with mifepristone and misoprostol leads to higher success rates than misoprostol alone. STUDY DESIGN: To evaluate the added value of mifepristone to current non-surgical treatment regimens in women with EPF we performed a systematic literature search. Electronic databases were searched: PubMed, Cochrane Library, Current Controlled Trials, and ClinicalTrials.gov. Clinical studies, both randomised and non-randomised trials, reporting on the added value of mifepristone to current non-surgical treatment regimens in women with EPF were included. Data of sixteen studies were extracted using a data extraction sheet (based on the Cochrane Consumers and Communication Review Group's data extraction template). The methodological quality was assessed using the Cochrane Collaboration Risk of Bias tool. RESULTS: In five randomised and eleven non-randomised trials, success rates of sequential treatment with mifepristone and misoprostol in case of EPF varied between 52% and 95%. Large heterogeneity existed in treatment regimens and comparators between studies. CONCLUSION(S): The existing evidence is insufficient to draw firm conclusions about the added value of mifepristone to misoprostol alone. A sufficiently powered randomised, double blinded placebo-controlled trial is urgently required to test whether, in EPF, the sequential combination of mifepristone with misoprostol is superior to misoprostol only.

Obesity, weight change, and risk of adenoma recurrence: a prospective trial.

BACKGROUND AND STUDY AIMS: Obesity is a risk factor for colorectal neoplasia. Lifestyle modifications, including weight loss, have been advocated to reduce the risk. However, no prospective study has evaluated whether weight loss actually affects adenoma recurrence. The aim of this study was to examine whether weight change (loss or gain) over 4 years is associated with adenoma recurrence. PATIENTS AND METHODS: A total of 1826 patients with colorectal adenoma in the Polyp Prevention Trial had their height and weight measured at baseline. Adenoma recurrence was determined by end of trial colonoscopy 4 years after study entry when patients' weights were re-measured. Poisson regression models were used to evaluate body mass index (BMI), weight change over 4 years, and the risk of any adenoma and advanced adenoma recurrence. RESULTS: Adenoma recurrence was observed in 723 patients (39.6%), 118 (6.5%) of whom had advanced adenoma recurrence. Among those with baseline BMI < 25 kg/m² (n = 466), BMI 25-29 kg/m² (n = 868), and BMI ≥ 30 kg/m² (n = 492), the recurrence rate was 34.5%, 41.0%, and 41.9%, respectively. Obesity was associated with an increased risk of adenoma recurrence (RR = 1.19; 95%CI 1.01-1.39) and advanced adenoma recurrence (RR = 1.62; 95%CI 1.01-2.57). However, when compared with those with relatively stable weight (weight change < 5 lb) over the 4-year trial, weight gain or loss was not associated with adenoma recurrence. This was consistent, regardless of the baseline BMI. CONCLUSIONS: Weight loss or gain over 4 years does not affect adenoma recurrence. This study does not support weight loss alone as an effective intervention for reducing adenoma recurrence.

Equilibrium lines and barriers to phase transitions: the cubic diamond to beta-tin transition in Si from first principles.

The phase transition between the cubic diamond (cd) and beta-tin (ß-Sn) phases of Si under pressure and the region of interaction of the two phases are studied by first-principles total energy calculations. For a non-vibrating crystal we determine the pressure of the thermodynamic phase transition p(t) = 96 kbar, the Gibbs free energy barrier at p(t) of ΔG = 19.6 mRyd/atom that stabilizes the phases against a phase transition and the finite pressure range in which both phases are stable. We show that the phases in that pressure range are completely described by three equilibrium lines of states along which the structure, the total energy E, the hydrostatic pressure p that would stabilize the structure and the values of G all vary. Two equilibrium lines describe the two phases (denoted the ph-eq line, ph is cd or ß-Sn phase); a third line is a line of saddle points of G with respect to structure (denoted the sp-eq line) that forms a barrier of larger G against instability of the metastable ranges of the phase lines. An important conclusion is that the sp-eq line merges with the two ph-eq lines: one end of the sp-eq line merges with the cd-eq line at high pressure, the other end merges with the ß-Sn-eq line at low pressure. The mergers end the barrier protecting the metastable ranges of the two ph-eq lines, hence the lines go unstable beyond the mergers. The mergers thus simplify the phase diagram by providing a natural termination to the stable parts of all metastable ranges of the ph-eq lines. Although 96 kbar is lower than the experimental transition pressure, we note that phonon pressure raises the observed transition pressure.

Structure and stability under pressure of cubic and hexagonal diamond crystals of C, BN and Si from first principles.

Application has been made of first-principles total-energy band-structure theory to find the equilibrium states under constant pressure of the super-hard cubic diamond (cd) and hexagonal diamond (hd) structures of carbon (C), boron nitride (BN) and medium-hard silicon (Si). The absolute stability of the equilibrium state is found by determinations of the breakdown under pressure of several deformations of lattice parameters around the equilibrium state. The calculations show that the hd structures are much stronger than the cd structures. Thus the γ angle of the hd structure of both C and BN is stable for pressures greater than 20 Mbar while the γ angle of the cd structures breaks down at 13 and 11 Mbar respectively. Also the bulk moduli B of the hd structure of C and BN are substantially greater than the B values of the cd structure above 2 Mbar; the B values of hd structures of C and BN are 20% greater than cd structures at p = 20 Mbar. However the cd structures have greater stability relative to the hd structures as shown by a lower Gibbs free energy at pressures up to 20 Mbar. Comparison is made with the pressure dependences of the medium-hard crystals of Si in the same structures, which show notably different behavior.

Elasticity in crystals under pressure.

The elastic behavior and stability of elemental crystals are studied in the neighborhood of a stable equilibrium state, also called a phase, at finite pressure p. It is shown that two kinds of elastic constants are needed to describe elasticity under pressure. One set, designated as c(ij),i,j = 1-6, determines stability or lack of it; another set, designated as c(ij)(p), describes the linear relation between small additional stresses and strains added to the crystal in equilibrium at p. The stress-strain coefficients c(ij)(p) differ from previous formulations of the stress-strain relations by Barron and Klein (1965 Proc. Phys. Soc. 85 523) and Wallace (1972 Thermodynamics of Crystals (New York: Wiley)), who give c(ij) as stress-strain coefficients. Hence we were led to verify the use of the c(ij)(p) using a first-principles numerical calculation example for face centered cubic Al at 1500 kbar. The Gibbs free energy G of the crystal under pressure is shown to provide both a simple definition of equilibrium and an efficient way to calculate all the elastic constants of a general crystal. A computer program finds stable phases by making jumps in structure from an arbitrary initial structure; the jumps converge to minima of G with respect to the structure. In the calculation, 21 elastic constants are evaluated from a special set of G values and the 6 × 6 elastic constant matrix is tested for stability.

Equilibrium lines and crystal phases under pressure.

A crystal phase in equilibrium under changing pressure traces out a line in structure space where each point corresponds to a structure. Along that equilibrium line the structure and all static properties describe the static behavior of the phase, including two sets of elastic constants and the bulk modulus. We discuss and illustrate the calculation of the equilibrium line and the properties from both the Gibbs free energy and the internal energy. We show that the bulk modulus, which gives a stress to strain ratio along the equilibrium line, has a universal relation independent of pressure to that set of elastic constants which control the stability, but not to the set of elastic constants appearing in the stress-strain relations at constant pressure.

Phases of Ca from first principles.

Structures and properties of many of the phases of Ca under pressure are calculated from first principles by a systematic procedure that minimizes total energy E with respect to structure under the constraint of constant volume V. The minima of E are followed on successive sweeps of lattice parameters for 11 of 14 Bravais symmetries for one-atom-per-cell structures. The structures include the four orthorhombic phases. Also included are the hexagonal close-packed and cubic diamond phases with two atoms per primitive cell. No uniquely orthorhombic phases are found; all one-atom orthorhombic phases over a mega-bar pressure range are identical to higher-symmetry phases. The simple cubic phase is shown to be stable where it is the ground state. The number of distinct one-atom phases reduces to five plus the two two-atom phases. For each of these phases the Gibbs free energy at pressure p, G(p), is calculated for a non-vibrating lattice; the functions G(p) give the ground state at each p, the relative stabilities of all phases and the thermodynamic phase transition pressures for all phase transitions over a several-megabar range.

Phases of vanadium under pressure investigated from first principles.

The existence and stability under pressure of three phases of vanadium are calculated from first principles. The phases are one body-centered cubic (bcc) and two rhombohedral phases (rh(u) and rh(l)), which have greater and lower α values than the primitive bcc rhombohedral cell. The bcc phase is shown in two ways to become unstable at 0.65 Mbar, in agreement with an observed phase transition, but in disagreement with previous higher estimates. The rh phases exist when the bcc phase is unstable, but the bcc phase stabilizes again at 3 Mbar, and the rh phases disappear. At 1.15 Mbar the rh(u) phase becomes and remains unstable and the rh(l) phase becomes the ground state up to 3 Mbar, where the rh(l) phase disappears and the bcc phase takes over. The theory gives four phase transitions among the phases over the pressure range from 0 to 3 Mbar; two of them are bcc to rh(u)-a low pressure (0.3 Mbar) thermodynamic transition found from Gibbs free energies being equal (not observed) and a higher pressure (0.65 Mbar) instability transition when the bcc phase becomes unstable (observed).

Lung cancer screening: an update.

Two prominent and timely issues in lung cancer screening are discussed in this article. First, findings from extended mortality follow-up of participants enrolled as part of the Mayo Lung Project are reviewed. These findings suggest that overdiagnosis-the identification, through screening, of clinically unimportant lung cancer lesions-may occur when screening for lung cancer. Second, the question of whether sufficient evidence exists to advocate mass lung cancer screening with low radiation dose spiral computed tomography (CT) is discussed. Given the absence of lung cancer mortality data for spiral CT, it is concluded that such activities should not be advocated at this point in time. The Lung Screening Study, an ongoing randomized controlled trial of lung cancer screening with spiral CT, also is described.

Lung cancer mortality in the Mayo Lung Project: impact of extended follow-up.

BACKGROUND: The Mayo Lung Project (MLP) was a randomized, controlled clinical trial of lung cancer screening that was conducted in 9211 male smokers between 1971 and 1983. The intervention arm was offered chest x-ray and sputum cytology every 4 months for 6 years; the usual-care arm was advised at trial entry to receive the same tests annually. No lung cancer mortality benefit was evident at the end of the study. We have extended follow-up through 1996. METHODS: A National Death Index-PLUS search was used to assign vital status and date and cause of death for 6523 participants with unknown information. The median survival for lung cancer patients diagnosed before July 1, 1983, was calculated by use of Kaplan-Meier estimates. Survival curves were compared with the log-rank test. RESULTS: The median follow-up time was 20.5 years. Lung cancer mortality was 4.4 (95% confidence interval [CI] = 3.9-4.9) deaths per 1000 person-years in the intervention arm and 3.9 (95% CI = 3.5-4.4) in the usual-care arm (two-sided P: for difference =.09). For participants diagnosed with lung cancer before July 1, 1983, survival was better in the intervention arm (two-sided P: =.0039). The median survival for patients with resected early-stage disease was 16.0 years in the intervention arm versus 5.0 years in the usual-care arm. CONCLUSIONS: Extended follow-up of MLP participants did not reveal a lung cancer mortality reduction for the intervention arm. Similar mortality but better survival for individuals in the intervention arm indicates that some lesions with limited clinical relevance may have been identified in the intervention arm.

Cigarette smoking, N-acetyltransferase 2 acetylation status, and bladder cancer risk: a case-series meta-analysis of a gene-environment interaction.

Tobacco use is an established cause of bladder cancer. The ability to detoxify aromatic amines, which are present in tobacco and are potent bladder carcinogens, is compromised in persons with the N-acetyltransferase 2 slow acetylation polymorphism. The relationship of cigarette smoking with bladder cancer risk therefore has been hypothesized to be stronger among slow acetylators. The few studies to formally explore such a possibility have produced inconsistent results, however. To assess this potential gene-environment interaction in as many bladder cancer studies as possible and to summarize results, we conducted a meta-analysis using data from 16 bladder cancer studies conducted in the general population (n = 1999 cases), Most had been conducted in European countries. Because control subjects were unavailable for a number of these studies, we used a case-series design, which can be used to assess multiplicative gene-environment interaction without inclusion of control subjects. A case-series interaction odds ratio (OR) > 1.0 indicates that the relationship of cigarette smoking and bladder cancer risk is stronger among slow acetylators as compared with rapid acetylators. We observed an interaction between smoking and N-acetyltransferase 2 slow acetylation (OR, 1.3; 95% confidence interval, 1.0-1.6) that was somewhat stronger when analyses were restricted to studies conducted in Europe (OR, 1.5; confidence interval, 1.1-1.9), a pooling that included nearly 80% of the collected data. Using the predominantly male European study population and assuming a 2.5-fold elevation in bladder cancer risk from smoking, we estimated that the population attributable risk percent was 35% for slow acetylators who had ever smoked and 13% for rapid acetylators who had ever smoked. These results suggest that the relationship of smoking and bladder cancer is stronger among slow acetylators than among rapid acetylators.

The associations of adolescent cigarette smoking, alcoholic beverage consumption, environmental tobacco smoke, and ionizing radiation with subsequent breast cancer risk (United States).

OBJECTIVES: Studies of breast cancer among survivors of the World War II atomic bomb blasts over Japan suggest that the adolescent breast may be particularly sensitive to carcinogenic insult. To further explore that possibility we examined the relationships of cigarette smoking, alcohol consumption, environmental tobacco smoke (ETS) exposure, and medical treatment with ionizing radiation during adolescence with subsequent breast cancer risk. METHODS: Data from the Carolina Breast Cancer Study, a population-based, case-control study of breast cancer in North Carolina women aged 20-74 years (864 cases, 790 controls), were analyzed. RESULTS: A modest increase in breast cancer risk was suggested for women who began to smoke cigarettes between the ages of 10 and 14 years (OR: 1.5, CI: 0.9-2.5), and for women exposed to ionizing radiation between ages 10 and 19 years to treat or monitor a medical condition (OR: 1.6, CI: 0.5-2.5). Neither exposure to ETS at home prior to age 18 years (OR: 1.1, CI: 0.9-1.3) nor initiation of alcoholic beverage consumption between ages 10 and 15 years (OR: 1.1, CI: 0.6-1.8) appeared to increase risk. CONCLUSIONS: Our results are consistent with previous evidence suggesting that some adolescent exposures could influence future breast cancer risk.

NAT2 slow acetylation and bladder cancer risk: a meta-analysis of 22 case-control studies conducted in the general population.

The NAT2 gene is involved in phase II detoxification of aromatic monoamines, a class of known bladder carcinogens. Certain allelic combinations result in the slow acetylation phenotype, which is thought to increase bladder cancer risk. We conducted a meta-analysis of all identifiable published case-control studies conducted in the general population that had examined the relationship of acetylation status and bladder cancer risk (22 studies, 2496 cases, 3340 controls). Using meta-analysis techniques that employed weighting based on individual-study variation, slow acetylators had an approximately 40% increase in risk compared with rapid acetylators [odds ratio (OR) 1.4, 95% confidence interval (CI) 1.2-1.6]. Statistical tests indicated, however, that pooling of all studies, or of studies conducted in Caucasian populations, hid potentially important heterogeneity in the individual study results, and suggested that the relationship of NAT2 slow acetylation and bladder cancer risk might differ by geographical region. Studies conducted in Asia generated a summary OR of 2.1 (CI 1.2-3.8), in Europe, a summary OR of 1.4 (CI 1.2-1.6), and in the USA, a summary OR of 0.9 (CI 0.7-1.3). Among European studies, the relationship between NAT2 slow acetylation and bladder cancer risk did not differ by method used to assess acetylation status (older drug-based phenotyping methods: 10 studies, OR 1.5, CI 1.2-1.8; more recent NAT2 genotyping methods: four studies, OR 1.4, CI 1.1-1.7). Our results suggest that in most populations studied to date, NAT2 slow acetylation status is associated with a modest increase in bladder cancer risk.

Physical activity at age 12 and adult breast cancer risk (United States).

OBJECTIVES: Some epidemiologic studies suggest that adolescent physical activity reduces subsequent breast cancer risk. To examine this question further, we analyzed data on physical activity at age 12 that had been collected as part of the Carolina Breast Cancer Study (CBCS). METHODS: The CBCS is a population-based, case-control study of 527 white and 337 African-American cases and 790 controls, frequency-matched on age and race. Respondents were asked whether, and to what extent, they engaged in four specific activities at age 12 (walking to school, biking to school, competitive training, performing vigorous household chores). RESULTS: Women who reported participation in any of the four activities had a modest reduction in breast cancer risk (odds ratio (OR): 0.8, 95% confidence interval (CI): 0.6-1.0). Using an index measuring approximate number of activity episodes per week, analyses revealed modest inverse relationships for nearly all levels of activity relative to no reported activity; a weighting of the index by metabolic equivalent scores produced similar results. CONCLUSIONS: Our findings support the hypothesis that adolescent physical activity may protect against adult breast cancer, even at moderate levels.

Adolescent reproductive events and subsequent breast cancer risk.

OBJECTIVES: This study investigated the relationship between reproductive events during adolescence and subsequent breast cancer risk. METHODS: Logistic regression models used self-reported data from 862 case patients and 790 controls in the Carolina Breast Cancer Study. RESULTS: Miscarriage, induced abortion, and full-term pregnancy before 20 years of age were not associated with breast cancer. Among premenopausal women, breast-feeding before 20 years of age was inversely associated with disease. Oral contraceptive use before 18 years of age was positively associated with disease risk among African American women only. CONCLUSIONS: Pregnancy during adolescence does not appear to influence breast cancer risk, but breast-feeding may. A possible increased breast cancer risk among African American women who used oral contraceptives as adolescents warrants further study.

Reanalysis of the Mayo Lung Project data: the impact of confounding and effect modification.

OBJECTIVES: To examine whether age at entry, history of cigarette smoking, exposure to non-tobacco lung carcinogens, or previous pulmonary illnesses were confounders or effect modifiers of the relation between screening and lung cancer mortality in the Mayo Lung Project. SETTING: The Mayo Lung Project was a randomised, controlled, clinical trial conducted between 1971 and 1986 in 9211 male smokers over the age of 45 in Minnesota (USA). The group screened received chest x ray examination and sputum cytology every four months for six years. The unscreened group were recommended to obtain usual care (annual chest x ray examination and sputum cytology). After follow up, lung cancer mortality was similar in both groups. METHODS: Proportional hazard models were used to analyse data. A variable was considered a confounder if its inclusion in a model changed the rate ratio for screening by more than 15%; a variable was considered an effect modifier if its stratum-specific rate ratio for screening differed by a factor of two. RESULTS: None of the four aforementioned variables changed the rate ratio associated with screening (1.07) by more than 2%. The effect of screening may have differed by years smoked (rate ratio for smoking fewer than 30 years 2.4; rate ratio for smoking 30 or more years 1.0), though we suspect that this result occurred by chance. CONCLUSION: Adjustment for or stratification by four established lung cancer risk factors did not alter the original findings of the Mayo Lung Project.

The association of calcium and vitamin D, and colon and rectal cancer in Wisconsin women.

BACKGROUND: Calcium and vitamin D have been hypothesized to reduce colorectal cancer risk. Epidemiological evidence, however, is mixed. METHODS: To explore those relationships, data were collected as part of a population-based, case-control study of colorectal cancer in Wisconsin women (678 controls, 348 colon and 164 rectal cancer cases). A semi-quantitative food frequency questionnaire was used to ascertain food and dietary supplement intake 2 years prior to interview. Logistic regression models were used to calculate odds ratios (OR). RESULTS: Higher levels of calcium intake were associated with reduced colon and rectal cancer risk. The following adjusted OR and 95% confidence intervals (CI) were observed, comparing the fifth quintile (based on control intake) with the first: colon cancer: OR = 0.6, 95% CI: 0.4-1.0, P-trend: 0.03; rectal cancer: OR = 0.6, 95% CI: 0.3-1.1, P-trend: 0.07. Similar relationships were observed for vitamin D intake, although OR were closer to the null value and did not always behave in a step-wise fashion (fifth quintile versus the first--colon cancer: OR = 0.7, 95% CI: 0.4-1.1, P-trend: 0.05; rectal cancer: OR = 0.8, 95% CI: 0.5-1.5, P-trend: 0.42). CONCLUSION: These data support a protective association of calcium on colon and rectal cancer risk.

Female breast cancer and trihalomethane levels in drinking water in North Carolina.

Some studies indicate that chlorination by-products in drinking water may contribute slightly to breast cancer risk. This ecologic study describes the association between total trihalomethane levels in publicly supplied water and the incidence of female invasive breast cancer. We included 71 North Carolina water suppliers serving at least 10,000 customers in the summer of 1995 as the units of analysis. We estimated incidence rates using 6,462 cases who were either white or black and between 35 and 84 years old and were linked by zip codes to the water supplier. We treated ecologic measurements of age, income, education, urban status, and race as potential confounders. Total trihalomethane levels were not associated materially with breast cancer risk, adjusting for potential confounders. The rate ratio for 80.0 parts per billion (ppb) or more vs less than 40.0 ppb total trihalomethanes was 1.1 [95% confidence interval (CI) = 0.9-1.2]. When stratified by race, the observed association for the aforementioned total trihalomethane category was not very different in black women (rate ratio = 1.2; 95% CI = 0.8-1.8) than in white women (rate ratio = 1.1; 95% CI = 0.9-1.3). These ecologic data are compatible with trihalomethanes in drinking water being either unrelated or weakly related to breast cancer risk.

Body mass and breast cancer. Relationship between method of detection and stage of disease.

BACKGROUND: Obesity is associated with advanced stage breast cancer at diagnosis and a poorer prognosis. Stage of breast cancer at diagnosis is also strongly influenced by the method of cancer detection. The objective of this study was to determine the relationship between body mass index (BMI) and breast cancer disease stage, taking into account the method of cancer detection (i.e., self-detection, screening mammography, and clinical breast examination [CBE]). METHODS: From 1988 to 1990, 2863 patients with invasive breast cancer were identified through a statewide, population-based, cancer reporting system and were interviewed as part of a larger study of breast cancer etiology. Stage of disease was classified as either localized or nonlocalized (regional and distant disease combined). The relation between BMI and disease stage was examined by using multiple logistic regression adjusting for age, education, race, year of diagnosis, and prior mammography use. RESULTS: Thirty-eight percent (1092 of 2863) of the women had nonlocalized breast cancer. A strong dose-response relationship was observed between increased BMI and the likelihood of nonlocalized disease (P < 0.001). However, this association was present only among the 55% of women (1585 of 2863) who self-detected their tumors. The odds ratios for nonlocalized cancer increased from 1.0 for the lowest quintile of BMI to 1.3, 1.6, 1.7, and 1.8 for the second through fifth quintiles, respectively, for this group. CONCLUSIONS: Greater body mass was associated with nonlocalized breast cancer; however, this association was restricted to women who detected their own cancer. No association was found between BMI and stage of disease among cases detected by either mammography or CBE.