Survival analysis of carboplatin added to an anthracycline/taxane-based neoadjuvant chemotherapy and HRD score as predictor of response-final results from GeparSixto.

Background: In the neoadjuvant GeparSixto study, adding carboplatin to taxane- and anthracycline-based chemotherapy improved pathological complete response (pCR) rates in patients with triple-negative breast cancer (TNBC). Here, we present survival data and the potential prognostic and predictive role of homologous recombination deficiency (HRD). Patients and methods: Patients were randomized to paclitaxel plus nonpegylated liposomal doxorubicin (Myocet®) (PM) or PM plus carboplatin (PMCb). The secondary study end points disease-free survival (DFS) and overall survival (OS) were analyzed. Median follow-up was 47.3 months. HRD was among the exploratory analyses in GeparSixto and was successfully measured in formalin-fixed, paraffin-embedded tumor samples of 193/315 (61.3%) participants with TNBC. Homologous recombination (HR) deficiency was defined as HRD score ≥42 and/or presence of tumor BRCA mutations (tmBRCA). Results: A significantly better DFS (hazard ratio 0.56, 95% CI 0.34-0.93; P = 0.022) was observed in patients with TNBC when treated with PMCb. The improvement of OS with PMCb was not statistically significant. Additional carboplatin did not improve DFS or OS in patients with HER2-positive tumors. HR deficiency was detected in 136 (70.5%) of 193 triple-negative tumors, of which 82 (60.3%) showed high HRD score without tmBRCA. HR deficiency independently predicted pCR (ypT0 ypN0) [odds ratio (OR) 2.60, 95% CI 1.26-5.37, P = 0.008]. Adding carboplatin to PM significantly increased the pCR rate from 33.9% to 63.5% in HR deficient tumors (P = 0.001), but only marginally in HR nondeficient tumors (from 20.0% to 29.6%, P = 0.540; test for interaction P = 0.327). pCR rates with carboplatin were also higher (63.2%) than without carboplatin (31.7%; OR 3.69, 1.46-9.37, P = 0.005) in patients with high HRD score but no tmBRCA. DFS rates were improved with addition of carboplatin, both in HR nondeficient (hazard ratio 0.44, 0.17-1.17, P = 0.086) and HR deficient tumors (hazard ratio 0.49, 0.23-1.04, P = 0.059). Conclusions: The addition of carboplatin to neoadjuvant PM improved DFS significantly in TNBC. Long-term survival analyses support the neoadjuvant use of carboplatin in TNBC. HR deficiency in TNBC and HRD score in non-tmBRCA TNBC are predictors of response. HRD does not predict for carboplatin benefit.

Prostate cancer outcomes among older men: insurance status comparisons results from CaPSURE database.

With growing number of older adults in the United States and complexity of issues related to Medicare and other insurances more research is needed to evaluate an effectiveness of the different insurance types in prevention, screening and treatment of cancer. With prostate cancer being highly prevalent disease in older men, the importance of appropriate treatment and favorable outcomes is imperative. In this study we examine whether prostate cancer outcomes, such as risk category at diagnosis, treatment and survival differ in relationship to insurance status in older patients in CaPSURE. Data were abstracted from CaPSURE, a longitudinal observational database of 13 124 men with prostate cancer. Men were selected for the study if they were older than 65 years old at diagnosis, newly diagnosed between 1995 and 2005 at entry to CaPSURE with localized disease and received radical prostatectomy (RP), external beam radiation (EBRT), brachytherapy (BT), hormonal therapy or expectant management (EM). Insurance status was summarized by eight categories: Medicare only, Medicare+supplement, Medicare+HMO, Medicare+PPO, Medicare+FFS, health maintenance organization (HMO), preferred provider organization (PPO) and Veteran's Administration (VA). A total of 2983 men met the inclusion criteria. Odds ratios (OR) for the likelihood of receiving each type of therapy compared to RP by insurance status and likelihood of presenting with high-risk classification at diagnosis were derived using multinomial logistic regression, adjusting for clinical and demographic characteristics. Difference in survival between insurance groups was evaluated by Cox's multivariate regression. Multivariate analysis demonstrated a strong association between initial treatment and insurance status. Compared to Medicare patients, men in the CaPSURE database treated at HMO, PPO and VA systems were more likely to receive BT than RP (OR, 1.71-1.92) and less likely to receive this treatment if they were in Medicare+FFS and Medicare+PPO (OR, 0.18-0.38). Hormonal treatment demonstrated similar pattern, however OR did not reached statistical significance for HMO and PPO. Use of EM was much more predominant for patients in VA system (OR, 4.74; 95% CI, 1.94-11.55). Use of EBRT was significantly associated with type of insurance. Men with VA, Medicare+FFS and Medicare+PPO insurance were less likely to receive this treatment compared to RP. Survival and clinical risk at diagnosis was associated with insurance status in univariate analysis but this association diminished after adjusting for possible covariates. This study provides important information on relationship between insurance status and several outcomes in patients with prostate cancer. Even after controlling for important clinical and sociodemographic factors we found marked differences in prostate cancer treatment according to type of insurance. Future explorations of associations between health care delivery system, cancer care and outcomes are needed.

Total and specific complementary and alternative medicine use in a large cohort of men with prostate cancer.

OBJECTIVES: To assess specific complementary and alternative medicine (CAM) use in the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE), a large, community-based national registry of men with prostate cancer. METHODS: We examined more than 50 types of CAM use in a large, national, community-based registry of men with prostate cancer (CaPSURE). Participants completed biannual surveys within 2 years of diagnosis and treatment. We analyzed associations of CAM use with sociodemographic and clinical features, using chi-square tests and multivariate logistic regression. RESULTS: One third of 2582 respondents reported using CAM. Common practices included vitamin and mineral supplements (26%), herbs (16%), antioxidants (13%), and CAM for prostate health (12%; eg, saw palmetto, selenium, vitamin E, lycopene). In multivariate analyses, users were more likely to have other comorbid conditions, worse cancer grade at diagnosis, higher incomes, more education, and to live in the West. CONCLUSIONS: Complementary and alternative medicine use was associated with sociodemographic and clinical characteristics in this large sample of men with prostate cancer. These results should be considered by health care professionals counseling men with prostate cancer regarding diet and secondary prevention.

The question of declining sperm density revisited: an analysis of 101 studies published 1934-1996.

In 1992 Carlsen et al. reported a significant global decline in sperm density between 1938 and 1990 [Evidence for Decreasing Quality of Semen during Last 50 Years. Br Med J 305:609-613 (1992)]. We subsequently published a reanalysis of the studies included by Carlsen et al. [Swan et al. Have Sperm Densities Declined? A Reanalysis of Global Trend Data. Environ Health Perspect 105:1228-1232 (1997)]. In that analysis we found significant declines in sperm density in the United States and Europe/Australia after controlling for abstinence time, age, percent of men with proven fertility, and specimen collection method. The declines in sperm density in the United States (approximately 1.5%/year) and Europe/Australia (approximately 3%/year) were somewhat greater than the average decline reported by Carlsen et al. (approximately 1%/year). However, we found no decline in sperm density in non-Western countries, for which data were very limited. In the current study, we used similar methods to analyze an expanded set of studies. We added 47 English language studies published in 1934-1996 to those we had analyzed previously. The average decline in sperm count was virtually unchanged from that reported previously by Carlsen et al. (slope = -0.94 vs. -0.93). The slopes in the three geographic groupings were also similar to those we reported earlier. In North America, the slope was somewhat less than the slope we had found for the United States (slope = -0.80; 95% confidence interval (CI), -1.37--0.24). Similarly, the decline in Europe (slope = -2.35; CI, -3.66--1.05) was somewhat less than reported previously. As before, studies from other countries showed no trend (slope = -0.21; CI, -2.30-1.88). These results are consistent with those of Carlsen et al. and our previous results, suggesting that the reported trends are not dependent on the particular studies included by Carlsen et al. and that the observed trends previously reported for 1938-1990 are also seen in data from 1934-1996.

Declining semen quality: can the past inform the present?

By using instrumentation initially designed for counting white blood cells, sperm counts have been utilized by clinicians since 1929, particularly to evaluate cases of suspected infertility. Although this basic biological parameter might be assumed to be stable over time, several studies over the past 20 years have suggested a decline in sperm count or density. The most controversial of these analyses was published in 1992. A flood of criticism followed this analysis of 61 studies that found a 50% decline in sperm density between 1938 and 1990. Critics suggested that historical methods (of counting sperm or conducting studies) were variable and unreliable, differing from modern methods both qualitatively and quantitatively. To address this issue we analyzed these studies for trends in counting methods or their variability. We found neither. Alternative analyses produced some differences in trend estimates, but statistical factors alone could not account for the total decline in sperm density. We reviewed study populations to identify trends in population characteristics, such as abstinence time, that might explain the decline. However, controlling analytically for such factors only increased the rate of decline. We conclude that historical data on sperm density, despite large random error, are surprisingly reliable. Nonetheless, understanding causes of temporal and geographic differences in sperm density must await contemporary data.

Cancer in California school employees, 1988-1992.

BACKGROUND: Periodic concerns about excesses of cancer among teachers in California schools prompted our examination of cancer incidence in California school employees. METHODS: Records of school employees between 1987-1992 were linked to the California Cancer Registry of incident cases diagnosed 1988-1992. Sex-, race-, and age-adjusted standardized incidence ratios were calculated for specific cancer sites. Analyses stratified by sex, race/ethnicity, and job assignment were also performed. RESULTS: Melanoma of the skin, thyroid cancer, prostate cancer, and female cancers of the breast, uterus, and ovary all occurred more frequently than expected in these school employees. In contrast, cancers of the respiratory system, oral cavity, digestive system, urinary system, and uterine cervix occurred less frequently. CONCLUSIONS: The incidence of cancers thought to be related to hormones and/or higher socioeconomic status appeared elevated while cancers often linked to smoking and/or alcohol intake occurred less frequently in this large cohort of professional school employees.

Caffeine consumption and menstrual function.

The relation between caffeine intake and menstrual function was examined in 403 healthy premenopausal women who belonged to Kaiser Permanente Medical Care Program in 1990-1991. A telephone interview collected information about caffeinated beverage intake as well as other lifestyle, demographic, occupational, and environmental factors. Subjects collected daily urine samples and completed a daily diary for an average of five menstrual cycles. Metabolites of estrogen and progesterone were measured in the urine, each cycle was characterized as anovulatory or ovulatory, and a probable day of ovulation was selected when appropriate. Logistic regression and repeated measures analyses were performed on menstrual parameters. Women whose caffeine consumption was heavy (>300 mg of caffeine per day) had less than a third of the risk for long menses (> or =8 days) compared with women who did not consume caffeine (adjusted odds ratio = 0.30, 95% confidence interval 0.14-0.66). Those whose caffeine consumption was heavy also had a doubled risk for short cycle length (< or =24 days) (adjusted odds ratio = 2.00, 95% confidence interval 0.98-4.06); this association was also evident in those whose caffeine consumption was heavy who did not smoke (adjusted odds ratio = 2.11, 95% confidence interval 1.03-4.33). Caffeine intake was not strongly related to an increased risk for anovulation, short luteal phase (< or =10 days), long follicular phase (> or =24 days), long cycle (> or =36 days), or measures of within-woman cycle variability.

Cigarette smoking and effects on menstrual function.

OBJECTIVE: To examine the relationship between smoking and menstrual function, using biologic measures rather than self-report of menstrual cycle characteristics. METHODS: In a prospective study, 408 women collected urine daily for one to seven menstrual segments (cycles), maintained daily diaries, and completed detailed interviews. Smoking data from the diaries were averaged over each segment and verified by cotinine assay. Urine samples were analyzed for metabolites of steroid hormones to define the day of ovulation and various menstrual characteristics, including: 1) segment, follicular, luteal phase, and menses length, 2) variability, and 3) anovulation. RESULTS: Heavy smoking (at least 20 cigarettes per day) was associated with nearly four times the risk of short segment (less than 25 days) as was nonsmoking (adjusted odds ratio 3.8, 95% confidence limits 1.1, 12.7). Mean segment length was on average 2.6 days shorter with heavy versus no smoking (95% confidence limits 0.14, 5.0), due almost entirely to shortening of the follicular phase. Women who smoked an average of ten or more cigarettes per day had significantly more variable segment and menses lengths than nonsmokers. Based on small numbers, the data suggested that with greater smoking, there was a possible increased risk of anovulation and short luteal phase. Segments of exsmokers with ten or more pack-years of exposure were more likely to be short and have shorter luteal phases than those of never smokers. CONCLUSION: The effects found in this study of smoking on the menstrual cycle might explain in part associations of smoking with other reproductive endpoints, such as subfecundity and early menopause.

Use of urine biomarkers to evaluate menstrual function in healthy premenopausal women.

A total of 403 healthy, premenopausal women, residing near Santa Clara, California, were recruited from a large health care plan in California for a study of menstrual function. After a telephone interview, participants collected daily urine samples and recorded bleeding and other information in diaries. Data were collected during 1990-1991. Urine samples were analyzed for creatinine and for estradiol and progesterone metabolites by enzyme-linked immunoassay. Computer algorithms were developed to derive menstrual segment length, ovulatory status, day of ovulation, and other parameters from the urine and diary data. (We use "segment" rather than "cycle" to avoid implying that normal cycling occurred.) The average length of participation was 141 (standard deviation, 45) days. The mean segment length was 28.8 (standard deviation, 4.4) days; follicular phase length, 16.0 (standard deviation, 4.4) days; and luteal phase length, 12.9 (standard deviation, 1.7) days; 19 (4.7%) women experienced anovulatory episodes. In exploratory multivariate analyses, important associations included the following: age of > or = 35 years with decreased segment and follicular phase lengths; heavier weight (upper quartile) with anovulation and increased follicular phase and decreased luteal phase lengths; Hispanic ethnicity with anovulation and increased segment length; and past difficulty in achieving pregnancy with anovulation and increased length and variability of segments and follicular phases. Urine biomarkers can be used successfully to evaluate menstrual function in epidemiologic studies.

Health state preferences of persons with anxiety.

We compared patient ratings of the desirability of anxiety health states with measures of psychological distress and functional status and investigated how these ratings predicted treatment by primary care and mental health clinicians. As expected, associations between desirability ratings and psychological and physical health status were low to moderate. Persons who rated their current anxiety health state as more desirable received fewer mental health referrals and were statistically more likely to receive a prescription for psychotropic medication. Simple ratings of health state desirability may help clinicians evaluate patients' views of their health status and discuss potential treatment options.

Can preference scores for discrete states be used to derive preference scores for an entire path of events? An application to prenatal diagnosis.

The authors conducted a study exploring whether preferences for sequences of events can be approximated by preferences for component discrete states. Visual-analog-scale (VAS) and standard-gamble (SG) scores for a subset of the possible sequences of events (path states) and component temporary and chronic outcomes (discrete states) that can follow prenatal diagnostic decisions were elicited from 121 pregnant women facing a choice between chorionic villus sampling and amniocentesis. For individuals, preference scores for path states could not be predicted easily from discrete-state scores. Mean path-state VAS scores, however, were predicted reasonably accurately by multiple regression models (R2 = 0.85 and 0.82 for two different anchoring schemes), with most measured scores lying within the 95% confidence intervals of the derived scores. It is concluded that, for individual patient decision making, preferences for path states should be elicited. When mean preference values for a population are sought, however, it may be reasonable to derive regression weights from a subset of respondents and then to apply those weights to preferences for discrete states elicited from a larger group.

Have sperm densities declined? A reanalysis of global trend data.

In 1992 a worldwide decline in sperm density was reported; this was quickly followed by numerous critiques and editorials. Because of the public health importance of this finding, a detailed reanalysis of data from 61 studies was warranted to resolve these issues. Multiple linear regression models (controlling for abstinence time, age, percent proven fertility, specimen collection method, study goal and location) were used to examine regional differences and the interaction between region (United States, Europe, and non-Western countries) and year. Nonlinear models and residual confounding were also examined in these data. Using a linear model (adjusted R2 = 0. 80), means and slopes differed significantly across regions (p = 0. 02). Mean sperm densities were highest in Europe and lowest in non-Western countries. A decline in sperm density was seen in the United States (studies from 1938-1988; slope = -1.50; 95% confidence interval (CI), -1.90--1.10) and Europe (1971-1990; slope = -3.13; CI, -4.96- -1.30), but not in non-Western countries (1978-1989; slope = 1.56; CI, -1.00-4.12). Results from nonlinear models (quadratic and spline) were similar. Thus, further analysis of these studies supports a significant decline in sperm density in the United States and Europe. Confounding and selection bias are unlikely to account for these results. However, some intraregional differences were as large as mean decline in sperm density between 1938 and 1990, and recent reports from Europe and the United States further support large interarea differences in sperm density. Identifying the cause(s) of these regional and temporal differences, whether environmental or other, is clearly warranted.

Health-related quality of life of patients with acute erosive reflux esophagitis.

One thousand one hundred forty-five patients with acute erosive reflux esophagitis participating in an eight-week double-blind, multicenter study of lansoprazole 15 mg daily, lansoprazole 30 mg daily, omeprazole 20 mg daily, and placebo responded to a health-related quality of life (HRQoL) questionnaire at baseline and at two, four, and eight weeks. At baseline, there were no HRQoL differences among the four study groups. However, all three active treatment groups improved statistically significantly more than placebo on most HRQoL scales at each follow-up. There were no statistically significant differences among the three active treatment groups at week 2, although in most instances lansoprazole 30 mg showed slightly more improvement. After week 2, benefits in all the study groups leveled off and remained constant. Greater acid suppression appeared to result in greater improvement in terms of HRQoL.

Predicting Mycobacterium avium complex bacteremia in patients infected with human immunodeficiency virus: a prospectively validated model.

In cases of advanced infection with human immunodeficiency virus, mycobacterial blood cultures are frequently used to diagnose disseminated infection with the Mycobacterium avium complex (MAC). However, no prospectively validated guidelines exist for the use of such cultures. In this study, a two-part model for predicting MAC bacteremia was developed and then validated prospectively. First, a CD4+ cell count of < or = 50/microL was used to predict bacteremia. Then, among patients with < or = 50 CD4+ cells/microL, the documentation of fever on more than 30 days during the preceding 3 months, a hematocrit of < 30%, or a serum albumin concentration of < 3.0 g/dL was used to predict bacteremia. This model had a sensitivity of 89% and positive and negative predictive values of 30% and 98%, respectively, for the identification of patients with bacteremia. Had the model been applied to patients in this study, the number of blood cultures performed would have decreased by 61%, but 11% of the positive cultures would have been missed. In short, this model can predict MAC bacteremia and can potentially guide the use of mycobacterial blood cultures.

Environmental risk factors for acquisition of Mycobacterium avium complex in persons with human immunodeficiency virus infection.

A case-control study was done to determine risk factors for Mycobacterium avium complex (MAC) disease in persons infected with human immunodeficiency virus (HIV) with < 50 CD4+ cells/mm3. In univariate analysis, cases (n = 83) had lower CD4+ cell counts than controls (n = 177) (median, 10 vs. 17/mm3; P < .001) and were more likely to have consumed hard cheese (odds ratio [OR], 5.44; 95% confidence interval [CI], 1.61-18.4) but were less likely to have taken daily showers (OR, 0.55; 95% CI, 0.33-0.94). In multivariate analysis, CD4+ cell count < 25/mm3 (OR, 3.58; 95% CI, 1.71-7.49) and consumption of hard cheese (OR, 5.63; 95% CI, 1.58-20.1) remained associated with disease, while daily showering (OR, 0.58; 95% CI, 0.28-0.88) remained protective. Increased risk for MAC disease in persons with HIV infection and low CD4+ cell counts is not associated with exposure to water or a variety of other environmental sources but may be associated with consumption of hard cheese.

A preliminary study of reproductive outcomes of female maquiladora workers in Tijuana, Mexico.

Maquiladoras are plants on the Mexican side of the United States-Mexico border which are used largely by U.S. manufacturers to assemble premanufactured parts. We examined reproductive outcomes of women employed in electronics (N = 120) and garment (N = 121) maquiladora work compared to women employed in the service sector (N = 119) in Tijuana, Mexico. Women recruited by community health workers were interviewed about their reproductive history, sociodemographic characteristics, health behaviors, and characteristics of their current job. Length of regular menstrual cycle in the past year as well as time of conception and rates of fetal loss in the most recent pregnancy were similar across occupational groups. However, infants of garment maquiladora workers were 653 g lighter (95% confidence interval [CI]: -1,041 g, -265 g) and infants of electronic maquiladora workers were 337 g lighter (95% CI: -682 g, 9 g) than infants of service workers after adjusting for potential confounders. The cause of these differences remains unclear.

Fetal growth retardation in infants of multiparous and nulliparous women with preeclampsia.

OBJECTIVE: Infants of women with preeclampsia are considered at high risk of fetal growth retardation. The purpose of our study was to determine whether the risk differed by parity. STUDY DESIGN: We compared the outcomes of 133 case patients with preeclampsia (101 nulliparous women and 32 multiparous women) and 132 normotensive control patients (52 nulliparous women and 80 multiparous women) who delivered at Northern California Kaiser Permanente hospitals between 1984 and 1985. RESULTS: Women with preeclampsia were more likely than control patients to deliver a small-for-gestational-age infant (adjusted odds ratio 7.0, 95% confidence interval 2.8 to 18.1). After we controlled for smoking status, age, Quetelet index, and race, multiparous women with preeclampsia were at greater risk of having a small-for-gestational-age infant (adjusted odds ratio 29.4, 95% confidence interval 5.2 to 167.5) than were nulliparous women (adjusted odds ratio 4.1, 95% confidence interval 1.2 to 14.1) when compared with normotensive control patients of similar parity. Although multiparous women with preeclampsia had higher mean arterial pressures and somewhat earlier onsets of elevated mean arterial pressure than nulliparous women with preeclampsia, neither of these variables predicted whether the infants would be small for gestational age. CONCLUSION: Multiparous women with preeclampsia are at higher risk of having an infant with fetal growth retardation than are nulliparous women with preeclampsia.