Hechtia glomerata Zucc: Phytochemistry and Activity of Its Extracts and Major Constituents Against Resistant Bacteria.

Hechtia glomerata Zucc. is used both as a source of food and in ethnomedicine to treat various diseases derived from bacterial infections such as bronchitis, laryngitis, nephritis, whooping cough, urethritis, and sepsis. There are no previous reports about its chemistry and biological activities. Therefore, the aims of this study were to identify components from organic and aqueous extracts of H. glomerata and test the extracts and major isolate compounds against resistant bacteria. Hexane, CHCl3/MeOH, and aqueous extracts were prepared and analyzed by different chromatographic techniques. Structural elucidation was carried out by NMR spectroscopy and X-ray diffraction. The antibacterial activities of extracts, phytochemicals, and semisynthetic derivatives against resistant bacteria were determined by the broth micro-dilution method. From the hexane extract nonacosane (1), hexatriacontanyl stearate (2), hexacosanol (3), oleic acid (4), and ß-sitosterol (5) were isolated and characterized. From the CHCl3/MeOH extract, p-coumaric acid (6), margaric acid (7), caffeic acid (8), daucosterol (9), and potassium chloride (10) were isolated and characterized. A total of 58 volatile compounds were identified by GC-MS from the hexane extract and two solids were isolated from the CHCl3/MeOH extract. The UPLC-QTOF-MS analysis of the aqueous extract allowed the identification of 55 polar compounds. Hexane and aqueous extracts showed antibacterial activity against ESBL Escherichia coli, and three strains of Klebsiella pneumoniae ESBL, NDM-1 +, and OXA-48 with MIC values of 500 µg/mL. The CHCl3/MeOH extract was devoid of activity. The activity of phytocompounds and their semisynthetic derivatives toward resistant bacteria was weak. The most active compound was ß-sitosterol acetate, with a MIC value of 100 µg/mL against carbapenem-resistant A. baumannii. This is the first report of the secondary metabolites of H. glomerata Zucc. and the activity of its extracts and major pure compounds against resistant bacterial strains.

An exploration of low back pain beliefs held by health care professionals in Northern America.

BACKGROUND: Prior research demonstrated that people in the United States and Canada (Northern America) hold predominantly biomedical beliefs about Low back pain (LBP); such beliefs were attributed to healthcare professionals (HCP). Further investigation is needed to understand HCP' LBP beliefs, preferred management strategies, and sources of beliefs. METHODS: Participants were recruited via social media to complete a qualitative cross-sectional online survey. The survey was distributed to assess LBP beliefs in a U.S. and Canadian-based clinician population. Participants answered questions about the cause of LBP, reasons for recurrence or persistence, use of imaging, management strategies, and sources of beliefs. Responses were analysed using an inductive thematic analysis. RESULTS: One hundred and sixty three participants were included, reporting multiple causes for LBP. However, many references were anchored to biological problems. When psychological variables were mentioned, it typically involved patient blaming. Like prior research studies, minimal attention was given to societal and environmental influences. Management strategies often aligned with guideline care except for the recommendation of inappropriate imaging and a reliance on passive interventions. CONCLUSIONS: These findings align with prior research studies on general population beliefs, demonstrating a preference for biological causes of LBP. Further updates are needed for clinical education, while future studies should seek to assess the translation of clinician beliefs into clinical practice and health system constraints.

An exploration of low back pain beliefs in a Northern America based general population.

BACKGROUND: Prior research has demonstrated that people across different populations hold beliefs about low back pain (LBP) that are inconsistent with current evidence. Qualitative research is needed to explore current LBP beliefs in Northern America (NA). OBJECTIVES: We conducted a primarily qualitative cross-sectional online survey to assess LBP beliefs in a NA population (USA and Canada). METHODS: Participants were recruited online using social media advertisements targeting individuals in NA over the age of 18 with English speaking and reading comprehension. Participants answered questions regarding the cause of LBP, reasons for reoccurrence or persistence of LBP, and sources of these beliefs. Responses were analyzed using conventional (inductive) content analysis. RESULTS/FINDINGS: 62 participants were included with a mean age of 47.6 years. Most participants reported multiple causes for LBP as well as its persistence and reoccurrence, however, these were biomedically focused with minimal to no regard for psychological or environmental influences. The primary cited source of participants' beliefs was healthcare professionals. CONCLUSIONS: Our findings align with prior research from other regions, demonstrating a need for updating clinical education and public messaging about the biopsychosocial nature of LBP.

The molecular biology of RU486. Is there a role for antiprogestins in the treatment of breast cancer?

PIP: Considerable animal research and clinical trials demonstrate that progesterone antagonists could treat hormone-dependent breast cancers. Since endogenous progesterone does include mitosis in epithelial cells of the breast, in theory, exogenous progesterone can cause breast cancer. Thus administration of progesterone antagonists could block endogenous progesterone. Yet we do not know the mitosis pattern in breast cancer cells during the menstrual cycle, so research obtaining such data is needed. Ethical problems arise, however, since researchers need multiple breast tumor samples to analyze proliferative activity at various times during the cycle. A possible solution is using an aspirated tumor sample for initial mitotic analysis immediately followed by RU-486 treatment then tumor removal 24 hours later for reanalysis. Ideally well controlled studies using organ-cultured human breast tumors, human breast cancer lines, and human tumors implanted into nude mice are needed to understand the mechanisms of the mitogenic actions of progestins and progestin antagonists. Progestin antagonist may be used to treat locally advanced or metastatic cancers either as an adjuvant endocrine therapy alone or with tamoxifen. An obstacle to longterm use of RU-486 as a treatment for breast cancer is its antiglucocorticoid side effects. But the molecules of newer progesterone antagonists appear to produce maximal antiprogestin activity and minimal antiglucocorticoid activity. In addition, if RU-486 is administered with drugs that prevent adrenal steroidogenesis or peripheral aromatization of adrenal steroids to estrogens, women may take it for longterm treatment. Researchers must have the opportunity to continue basic tumor biological and molecular research to gain an understanding of the exact molecular targets and mechanisms of antagonist action. The current political climate in the US hinders such research, however.^ieng

Effects of low dose oral contraceptives on very low density and low density lipoprotein metabolism.

Oral contraceptives (OC) raise plasma triglyceride and VLDL levels, which may be of concern, since some conditions characterized by elevated triglycerides are associated with atherosclerosis. To identify the responsible mechanism, we studied 11 healthy premenopausal women, 5 of whom were taking OC containing 0.035 mg ethinyl estradiol, and 6 of whom were not. Their rates of VLDL and LDL metabolism were measured by endogenously labeling apoB, the protein component of VLDL and LDL, by an intravenous infusion of deuterated leucine. OC use had the greatest effect on the large, triglyceride-rich VLDL subfraction (Sf 60-400), increasing plasma levels threefold and production rates fivefold (P < 0.05). Among OC users, small VLDL (Sf 20-60) levels were 2.2 times higher, and production rates were 3.4-fold higher (P < 0.05). The fractional catabolic rates of large and small VLDL were similar among OC users and nonusers. LDL levels and metabolic rates were not significantly different between the two groups. Thus, contemporary low dose OC substantially raise VLDL levels by increasing the production rate of large, triglyceride-rich VLDL, and not by slowing VLDL catabolism. Since VLDL catabolism is not impaired, we speculate that the hypertriglyceridemia induced by OC may be less atherogenic than that of hypertriglyceridemia resulting from impaired lipolysis. This may explain why long-term OC use does not appear to promote atherosclerosis.

PIP: At Brigham and Women's Hospital in Boston, Massachusetts, data on 5 women aged 22-24 years using low-dose oral contraceptives (OCs) containing .035 mg ethinyl estradiol were compared with data on 6 women aged 23-27 years not using OCs so researchers could study the metabolism of individual very low density lipoprotein (VLDL) subfractions of low density lipoprotein (LDL) in users of low-dose OCs and nonusers. Specifically, they wanted to determine the mechanisms by which OC use increases plasma VLDL and triglyceride levels. They infused a nonradioactive amino acid tracer (D3-leucine) intravenously into the 11 women to endogenously label the primary protein component of VLDL and of LDL, apoB, allowing them to measure VLDL and LDL synthesis and catabolism. OC users had large triglyceride-rich VLDL subfraction plasma levels 3 times higher than those of nonusers (20.2 nmol/l vs. 6.7 nmol/l; p , .05). OC use increased large, triglyceride-rich VLDL subfraction production rates 5-fold (16.7 nmol/kg/d vs. 3.4 nmol/kg/d; p .005). OC users had 2.2 times higher small VLDL subfraction levels (36.7 nmol/l vs. 16.7 nmol/l; p .05) and 3.4 times higher small VLDL subfraction production rates (22.5 nmol/kg/d vs. 6.7 nmol/kg/d; p .01) than nonusers. The fractional catabolic rates of large and small VLDL were essentially the same for OC users and nonusers (19.4 pool/d vs. 18.2 pool/d and 15.1 pool/d vs. 17 pool/d). Thus, low-dose OC use increases VLDL levels via a rise in the production rate of large VLDL and not by impeding VLDL catabolism. Learning that low-dose OCs do not curb VLDL catabolism, the researchers proposed that the OC-induced hypertriglyceridemia is less likely to be atherogenic than impaired lipolysis induced hypertriglyceridemia. This hypothesis may provide the answer as to why longterm OC use does not apparently foster atherosclerosis.

Epidemiologic evidence showing that human papillomavirus infection causes most cervical intraepithelial neoplasia.

BACKGROUND: Experimental studies have provided strong evidence that human papillomavirus (HPV) is the long-sought venereal cause of cervical neoplasia, but the epidemiologic evidence has been inconsistent. PURPOSE: Given improvements in HPV testing that have revealed a strong link between sexual activity history and cervical HPV infection, we conducted a large case-control study of HPV and cervical intraepithelial neoplasia (CIN) to evaluate whether sexual behavior and the other established risk factors for CIN influence risk primarily via HPV infection. METHODS: We studied 500 women with CIN and 500 control subjects receiving cytologic screening at Kaiser Permanente, a large prepaid health plan, in Portland, Ore. The established epidemiologic risk factors for CIN were assessed by telephone interview. We performed HPV testing of cervicovaginal lavage specimens by gene amplification using polymerase chain reaction with a consensus primer to target the L1 gene region of HPV. Unconditional logistic regression analysis was used to estimate relative risk of CIN and to adjust the epidemiologic associations for HPV test results to demonstrate whether the associations were mediated by HPV. RESULTS: The case subjects demonstrated the typical epidemiologic profile of CIN: They had more sex partners, more cigarette smoking, earlier ages at first sexual intercourse, and lower socioeconomic status. Statistical adjustment for HPV infection substantially reduced the size of each of these case-control differences. Seventy-six percent of cases could be attributed to HPV infection; the results of cytologic review suggested that the true percentage was even higher. Once HPV infection was taken into account, an association of parity with risk of CIN was observed in both HPV-negative and HPV-positive women. CONCLUSION: The data show that the great majority of all grades of CIN can be attributed to HPV infection, particularly with the cancer-associated types of HPV. IMPLICATIONS: In light of this conclusion, the investigation of the natural history of HPV has preventive as well as etiologic importance.

Breast cancer in premenopausal and postmenopausal women.

PIP: In the effort to determine if the risk factors for breast cancer differed between premenopausal and postmenopausal women, a case control study was conducted. The study sample included 95 premenopausal and 278 postmenopausal women with breast cancer admitted to the Ontario Cancer Foundation Clinic in London, Canada during the June 1967 to February 1971 period. The controls were 106 premenopausal and 480 postmenopausal women with benign and malignant diseases of sites other than breast admitted to the same clinic during the same period. The breast cancer risk increased with increasing age at 1st pregnancy among postmenopausal women only. Among the prememopausal women, increased breast cancer was associated with early menarche. Late age at natural menopause was an important risk factor for postmenopausal women. The risk in women experiencing natural menopause over the age of 55 was 2.5 times as great as that of women undergoing menopause before age 40. A longer interval between age at menarche and age at 1st pregnancy increased the risk in both groups. Oral contraceptive use, or duration of use, did not increase the risk of breast cancer. Among oral contraceptive users, there was a trend toward greater risk with increasing age at 1st use of OCs.^ieng

Mortality associated with mode of presentation in the acquired immune deficiency syndrome.

A population-based survival study was done for all cases of the acquired immune deficiency syndrome diagnosed in the city of San Francisco through May 1983. Follow-up was obtained for 165 of 173 diagnosed cases. Median survival among 75 patients presenting with Kaposi's sarcoma (KS) alone was 21 months. Median survival among 90 patients presenting with opportunistic infections, primarily Pneumocystis carinii pneumonia, was 9 months; survival at 21 months was zero. Survival among patients presenting with both KS and opportunistic infections was not statistically different from survival among patients presenting with opportunistic infections only. When cases were divided into those diagnosed before and after May 1982, there was no significant improvement in survival from diagnosis in the more recently diagnosed cohort.

Menopause and breast cancer risk.

PIP: Age at menopause and type of menopause from hospital records of breast cancer patients were compared with similar information reported by a national probability sample of women. The national sample comprised 3581 women who responded to the 1960-1962 National Health Examination Survey. The cancer series consisted of 3887 patients selected from those reported to the Connecticut Cancer Registry between 1950 and 1959. No substantial bias was identified when the validity of the comparison and the effect of the relatively large number of breast cancer patients whose menopause histories were deficient were evaluated. Overall, surgically induced menopause was associated with a reduction in breast cancer risk to about 60% of that experienced by women having natural menopause induced before age 35, but induction up to age 50 was protective. There was little effect in the 10 years following the surgical procedure, but substantial reduction occurred in all subsequent periods. Among women with menopause induced before age 35, breast cancer risk stayed as low as 1/3 that expected 30 and more years later. Relative risk of breast cancer increased with age at natural menopause. Women with natural menopause at age 55 or older had twice the breast cancer risk experienced by those whose menopause occurred before age 45. The relative risk of breast cancer associated with late natural menopause was greatest after age 70.^ieng

Oral contraceptives and breast cancer risk among younger women.

BACKGROUND: Several studies have suggested a link between oral contraceptive use and breast cancer in younger women, but it is possible that chance or bias, including selective screening of contraceptive users, contributed to the putative association. PURPOSE: Given that oral contraceptives were first marketed in the United States in the early 1960s, we conducted a population-based case-control study to examine the relationship between use of oral contraceptives and breast cancer among women in a recently assembled cohort, focusing on women younger than 45 years of age who had the opportunity for exposure throughout their entire reproductive years. METHODS: Breast cancer patients and healthy control subjects were identified, the latter group by random-digit dialing, in Atlanta, Ga., Seattle/Puget Sound, Wash., and central New Jersey. In Seattle and New Jersey, the study was confined to women 20 through 44 years of age; in Atlanta the age range was extended through 54 years. Patients included women with in situ or invasive breast cancer newly diagnosed during the period of May 1, 1990, through December 31, 1992. In-person interviews were completed by 2203 (86.4%) of 2551 eligible patients and 2009 (78.1%) of 2571 eligible control subjects. Analyses focused on women younger than 45 years of age (1648 patients and 1505 control subjects) to maximize opportunities for extended exposure. Logistic regression analyses were used to obtain maximum likelihood estimates of relative risks (RRs) and their 95% confidence intervals (CIs). RESULTS: Among women younger than 45 years, oral contraceptive use for 6 months or longer was associated with an RR for breast cancer of 1.3 (95% CI = 1.1-1.5). Risks were enhanced for breast cancers occurring prior to age 35 years (RR = 1.7; 95% CI = 1.2-2.6), with the RR rising to 2.2 (95% CI = 1.2-4.1) for users of 10 or more years. The RR for breast cancer for those whose oral contraceptive use began early (before age 18 years) and continued long-term (> 10 years) was even higher (RR = 3.1; 95% CI = 1.4-6.7). The RRs observed for those who used oral contraceptives within 5 years of cancer diagnosis were higher than for those who had not, with the effect most marked for women younger than age 35 years (RR = 2.0; 95% CI = 1.3-3.1). Oral contraceptive associations were also strongest for cancers diagnosed at advanced stages. Evaluation of screening histories and methods of diagnosis failed to support the speculation that associations could be due to selective screening. Among women 45 years of age and older, no associations of risk with use of oral contraceptives were noted. CONCLUSIONS: The relationship between oral contraceptives and breast cancer in young women appears to have a biologic basis rather than to be an artifact or the result of bias.

PIP: A population-based case control study examined the relationship between use of oral contraceptives and breast cancer among women in a cohort, focusing on women younger than 45 years old who had the opportunity for exposure throughout their entire reproductive years. Breast cancer patients and healthy control subjects were identified, the latter group by random-digit dialing, in Atlanta, Georgia, Seattle/Puget Sound, Washington, and central New Jersey. In Seattle and New Jersey, the study was confined to women 20-44 years old; in Atlanta the age range was extended through 54 years. Patients included women with in situ or invasive breast cancer newly diagnosed during the period of May 1, 1990, through December 31, 1992. In-person interviews were completed by 2203 (86.4%) of 2551 eligible patients and 2009 (78.1%) of 2571 eligible control subjects. Analyses focused on women younger than 45 years old (1648 patients and 1505 control subjects) to maximize opportunities for extended exposure. Logistic regression analyses were used to obtain maximum likelihood estimates of relative risks (RRs). Among women under 45, oral contraceptive use for 6 months or longer was associated with an RR for breast cancer of 1.3. Risks were enhanced for breast cancers occurring prior to age 35 years (RR = 1.7) with the RR rising to 2.2 for users of 10 or more years. The RR for breast cancer for those whose oral contraceptive use began before age 18 years and continued long-term ( 10 years) was even higher (RR = 3.1). The RRs observed for those who used oral contraceptives within 5 years of cancer diagnosis were higher than for those who had not, with the effect most marked for women younger than 35 years (RR = 2.0). Oral contraceptive associations were also strongest for cancers diagnosed at advanced stages. The relationship between oral contraceptives and breast cancer in young women appears to have a biologic basis rather than to be an artifact or the result of bias.

Experts confer on vasectomy and prostate cancer risk.

PIP: In March 1993, physicians attended a US National Institutes of Health (NIH) conference on a possible association between vasectomy and prostate cancer. Participants learned that some studies have found an association while others have not. The strongest evidence of an association is a small association. The inconsistency of the results of various studies and the lack of a convincing biological mechanism satisfied participants that no need exists to recommend changes in clinical and public health practice. 2 recent, well-controlled studies, conducted by researchers at Brigham and Women's Hospital in Boston, Massachusetts, published in the Journal of the American Medical Association found around a 60% increase in risk of developing prostate cancer in men with vasectomies. It found a decreased risk for overall mortality among vasectomized men, however. These studies prompted a call for this NIH conference. Studies prior to these Boston studies had methodological flaws, especially detection bias. Specifically, urologists are more likely to examine men with vasectomies and, therefore, diagnose prostate cancer. A well-controlled, large-scale, case control study in California published in 1991 and its follow-up study did not find an increased risk of prostate cancer in vasectomized men. The follow-up study found a decreased risk for overall mortality among men with vasectomies. The lack of knowledge about the etiology of prostate cancer is the biggest roadblock to understanding the link between vasectomy and prostate cancer. Suggested mechanisms explaining vasectomy's ability to increase prostate cancer risk include changes in hormone levels, immunologic responses, and changes in levels of cancer-promoting growth factors or inhibitors of these factors.^ieng

Vasectomy and prostate cancer: results from a multiethnic case-control study.

BACKGROUND: Vasectomy, a widely used form of contraception, has been associated in some studies with increased prostate cancer risk. PURPOSE: We assessed this association on the basis of data collected in a large multiethnic case-control study of prostate cancer that was conducted in the United States (Los Angeles, San Francisco, and Hawaii) and Canada (Toronto and Vancouver). METHODS: In home interviews conducted with newly diagnosed prostate cancer case patients and population control subjects, we obtained information on the participants' medical history, including a history of vasectomy and the age at which the procedure was performed, as well as other potential risk factors. Blood samples were collected from control subjects only and were assayed for concentration of sex hormones and sex hormone-binding globulin. RESULTS: The present analysis was based on 1642 prostate cancer patients and 1636 control subjects. A history of vasectomy was not significantly associated with prostate cancer risk among all racial/ethnic groups combined (odds ratio [OR] = 1.1; 95% confidence interval [CI] = 0.83-1.3), whites (OR = 0.94; 95% CI = 0.69-1.3), blacks (OR = 1.0; 95% CI = 0.59-1.8), or Chinese-Americans (OR = 0.96; 95% CI = 0.42-2.2). Among Japanese-Americans, the OR was 1.8 (95% CI = 0.97-3.4), but the statistically nonsignificant elevation in risk was limited to more educated men and those with localized cancers. ORs did not vary significantly by age at vasectomy or years since vasectomy. We found a lower serum concentration of sex hormone-binding globulin and a higher ratio of dihydrotestosterone to testosterone among vasectomized control subjects than among nonvasectomized control subjects. CONCLUSIONS: The findings of this study do not support previous reports of increased prostate cancer risk associated with vasectomy. However, the altered endocrine profiles of vasectomized control subjects seen in this cross-sectional comparison warrant further evaluation in longitudinal studies.

PIP: Vasectomy has been associated in some studies with increased prostate cancer risk. This association was assessed on the basis of data collected in a large multiethnic case control study of prostate cancer that was conducted in the United States (Los Angeles, San Francisco, and Hawaii) and Canada (Toronto and Vancouver). In home interviews conducted with newly diagnosed prostate cancer case patients (diagnosed between January 1, 1989 and December 31, 1991 as well as January 1, 1987 and December 31, 1988) and control subjects, information was obtained on the participants' medical history, including a history of vasectomy and the age at which the procedure was performed as well as other potential risk factors. Blood samples were collected from control subjects only and were assayed for concentration of total testosterone, percent of free testosterone, percent of bioavailable testosterone, dihydrotestosterone (DHT), and sex hormone-binding globulin (SHBG) using an automated, polyclonal-monoclonal immunochemiluminometric prostate-specific antigen (PSA) assay. The analysis was based on 1642 prostate cancer patients and 1636 control subjects. The analysis of PSA, androgens, and SHBG by vasectomy status was based on 850 control subjects with normal PSA concentrations. A history of vasectomy was not significantly associated with prostate cancer risk among all racial/ethnic groups combined (odds ratio [OR] = 1.1; Whites OR = 0.94; Blacks OR = 1.0; or Chinese-Americans OR = 0.96). Among Japanese-Americans, the OR was 1.8, but the statistically significant elevation in risk (OR = 4.1) was limited to more educated men with a history of vasectomy and those with localized cancers (OR = 5.3). ORs did not vary significantly by age at vasectomy or years since vasectomy. Lower serum concentration of SHBG and a higher ratio of DHT to testosterone was found among vasectomized control subjects than among nonvasectomized control subjects. The findings do not support previous reports of increased prostate cancer risk associated with vasectomy. However, the altered endocrine profiles of vasectomized control subjects warrant further evaluation in longitudinal studies.

Are dietary fat and vasectomy risk factors for prostate cancer?

PIP: Prostate cancer is the most commonly diagnosed malignancy among US males. Its incidence, however, varies markedly from 2 per 100,000 per year in Shanghai, China, to 62 and 82, respectively, for US Whites and Blacks. Mortality due to prostate cancer is twice as high among US Blacks than among US Whites. A familial component is important in determining prostate cancer risk, but does not appear to explain the variation in rates between US Blacks and Whites. Dietary fat, the consumption of which varies on a national basis in parallel with prostate cancer rates, may be a major risk factor for the disease. A study by Whittemore et al. involved more than 1500 cases and controls including Whites, Blacks, Chinese-Americans, and Japanese-Americans in five cities in the US and Canada. On the basis of detailed dietary interviews, Whittemore shows that prostate cancer risk increases with higher intake of saturated fat. The effect holds true for both younger and older men. The risk was significantly elevated for Asian-Americans, and less pronounced for Blacks and Whites, yet nonetheless consistent with an overall excess. Risk was unrelated to the intake of other macronutrients, intake of vitamin A, intake of fruits and vegetables, body mass, or physical activity. Among Asian-Americans, long-term residents in the US were at greatest risk of prostate cancer independent of dietary fat intake. A study by John et al. has found vasectomy to not be related to the development of prostate cancer. Reasons why the finding of this study is opposite from the general body of evidence supporting an increased risk of prostate cancer following vasectomy are not apparent.^ieng

Cutaneous melanoma in relation to exogenous hormones and reproductive factors.

Eighty-seven women of ages 37-74, who resided in King County, Wash., and who had been diagnosed between July 1976 and November 1979 as having cutaneous malignant melanoma, were interviewed regarding prior use of estrogen-containing preparations and reproductive history. The responses were compared with those of a random sample of 863 women from the same county. Among the 61 women with superficial spreading melanoma (SSM), use of oral contraceptives for 5 years or more was more common than among controls. The estimated relative risks for users of 5-9 and 10 years or more were 2.4 and 3.6, respectively. No differences between cases and controls were noted for oral contraceptive use of 4 years or less. Giving birth to a first child after age 30 was also associated with an increased relative risk of SSM. Although the positive findings regarding oral contraceptive use and age at birth of first child must be interpreted cautiously pending results of other studies, they suggest that hormonal factors can play a role in the etiology of SSM.

PIP: 87 women ages 37-74 who resided in King County, Washington, and who had been diagnosed between July 1976-November 1979 as having cutaneous malignant melanoma, were interviewed regarding prior use of estrogen-containing preparations and reproductive history. The responses were compared with those of a random sample of 863 women from the same county. Among the 61 women with superficial spreading melanoma (SSM), use of oral contraceptives (OCs) for 5 years or more was more common than among controls. The estimated relative risks for users of 5-9 and 10 years or more were 2.4 and 3.6, respectively. No differences between cases and controls were noted for OC use of 4 or fewer years. Giving birth to a 1st child after age 30 was also associated with an increased relative risk of SSM. Although the positive findings regarding OC use and age at birth of 1st child must be interpreted cautiously pending results of other studies, they suggest that hormonal factors can play a role in SSM etiology.

Breast cancer risk factors among screening program participants.

PIP: Data were obtained by mailed questionnaire from 405 breast cancer patients identified during the first 2 years of operation of the Breast Cancer detection Demonstration Project in the U.S. and from a sample of 1156 normal screenees (response rate = 88%) in an attempt to examine whetHer the usual risk indicators for breast cancer apply to individuals participating in screening programs. No substantial differences were found between the respondents and the nonrespondents for the variables on which information had been obtained at the time of the initial screening. Nearly all of t(e recognized risk factors were seen in this population. The relative risk (FF) of breast cancer was 3.9 among women whose mothers were also affected; this finding was statistically significant. Relative risk was increased for women reporting early menarche, late menopause, nulliparity, late age when 1st child was born, and excessive weight. The relative risk was not elevated in women with a prior breast biopsy but was excessive for those with more than 1 biopsy. No association with thyroid medications or menopausal hormones was found. Among women having undergone a natural menopause, a nonstatistically significant elevation in the relative risk was noted for long term oral contraceptive users; this excess relative risk was restricted to those using OCs in the presence of breast cancer risk indicators. The results indicate the need for further study of women with extended periods of OC use, particularly when accompanied by other known risk indicators.^ieng

Risk of breast cancer among young women: relationship to induced abortion.

BACKGROUND: Certain events of reproductive life, especially completed pregnancies, have been found to influence a woman's risk of breast cancer. Prior studies of the relationship between breast cancer and a history of incomplete pregnancies have provided inconsistent results. Most of these studies included women beyond the early part of their reproductive years at the time induced abortion became legal in the United States. PURPOSE: We conducted a case-control study of breast cancer in young women born recently enough so that some or most of their reproductive years were after the legalization of induced abortion to determine if certain aspects of a woman's experience with abortion might be associated with risk of breast cancer. METHODS: Female residents of three counties in western Washington State, who were diagnosed with breast cancer (n = 845) from January 1983 through April 1990, and who were born after 1944, were interviewed in detail about their reproductive histories, including the occurrence of induced abortion. Case patients were obtained through our population-based tumor registry (part of the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute). Similar information was obtained from 961 control women identified through random digit dialing within these same counties. Logistic regression analysis was used to estimate odds ratios and confidence intervals (CIs). RESULTS: Among women who had been pregnant at least once, the risk of breast cancer in those who had experienced an induced abortion was 50% higher than among other women (95% CI = 1.2-1.9). While this increased risk did not vary by the number of induced abortions or by the history of a completed pregnancy, it did vary according to the age at which the abortion occurred and the duration of that pregnancy. Highest risks were observed when the abortion was done at ages younger than 18 years--particularly if it took place after 8 weeks' gestation--or at 30 years of age or older. No increased risk of breast cancer was associated with a spontaneous abortion (RR = 0.9; 95% CI = 0.7-1.2). CONCLUSION: Our data support the hypothesis that an induced abortion can adversely influence a woman's subsequent risk of breast cancer. However, the results across all epidemiologic studies of this premise are inconsistent--both overall and within specific subgroups. The risk of breast cancer should be reexamined in future studies of women who have had legal abortion available to them throughout the majority of their reproductive years, with particular attention to the potential influence of induced abortion early in life.

PIP: Epidemiologists compared data on 845 white women who were diagnosed with breast cancer between January 1983 and April 1990, were born after 1944, and lived in King, Pierce, or Snohomish counties in Washington State with data on 961 white women with no breast cancer from the same counties. They wanted to determine whether induced abortion increases the risk of breast cancer. Restricting cases to women born after 1944 allowed the researchers to focus only on legal induced abortions. When the researchers limited the analysis only to women who had been pregnant at least once, the risk of developing breast cancer in women who had had at least 1 induced abortion was 50% greater than those who had not had an induced abortion. This risk differed depending on the age at which the women underwent the induced abortion and the duration of that pregnancy. A gestational age (at the time of the first aborted pregnancy) of 9-12 weeks carried the highest risk of breast cancer (RR = 1.9 vs. 1.4 for =or 8 weeks and =or 13 weeks). Further, the breast cancer risk was greatest among women who underwent the induced abortion when they were less than 18 years old (relative risk [RR] = 2.5). It was especially high for women who were less than 18 years old and who had the abortion between 9 and 24 weeks of gestation (RR = 9). It was also high for those who were at least 30 years old at the time of the abortion (RR = 2.1). Spontaneous abortion was not associated with an increased risk (RR = 0.9). Neither the number of induced abortions nor the history of a completed pregnancy were associated with an increased risk of breast cancer. These findings suggest that an induced abortion during the last month of the first trimester increases the risk of breast cancer and that women who were at a very young age at the time of the first induced abortion face an increased risk of breast cancer.

Oral contraceptive use and risk of gestational trophoblastic tumors.

BACKGROUND: Gestational trophoblastic disease refers to a spectrum of rare benign and malignant gynecologic disorders whose pathogenesis is not well understood. Recent studies from China and the United States have raised the hypothesis that long-term use of oral contraceptives before conception may increase the risk of gestational trophoblastic tumors. A multicenter case-control study of gestational trophoblastic tumors was undertaken to test this hypothesis. METHODS: Telephone interviews were conducted with 235 case patients, including 50 with gestational choriocarcinoma, and 413 control subjects matched on recentness of pregnancy, age at pregnancy, and area of residence. Relative risks (odds ratios) were computed by conditional logistic regression. Reported P values are two-sided. RESULTS: The relative risk estimate for ever having used oral contraceptives before the index pregnancy was 1.9 (95% confidence interval [CI] = 1.2-3.0), and the risk increased with duration of use (P for trend = .05). The estimate was highest for women who used oral contraceptives during the cycle in which they became pregnant (relative risk = 4.0; 95% CI=1.6-10), but there was no consistent pattern according to the time interval since last use. Separate analyses of choriocarcinoma and persistent mole yielded similar results, i.e., the relative risk estimates for oral contraceptive use were 2.2 (95% CI=0.8-6.4) and 1.8 (95% CI=1.0-3.0), respectively. Control for the number of sexual partners, which was independently associated with risk (P for trend = .05), did not materially change the results. CONCLUSIONS: This study, the largest to date, indicates that long duration of oral contraceptive use before conception increases the risk of gestational trophoblastic tumors. These findings may provide clues to the pathogenesis of this rare disease. Changes in use of oral contraceptives are not warranted, however, because the incidence attributable to oral contraceptive use is very low.

PIP: Recent studies in the US and China have suggested that long-term use of oral contraceptives (OCs) before conception increases the risk of gestational trophoblastic tumors. This association was investigated further in a study conducted at 8 US medical centers that specialize in the treatment of this gynecologic disorder. 235 cases, including 50 women with gestational choriocarcinoma, were matched with 413 controls on recentness of pregnancy, age at pregnancy, and area of residence. The relative risk estimate for ever-use of OCs before the index pregnancy was 1.9 (95% confidence interval [CI], 1.2-3.0) and the risk increased with duration of OC use. The relative risk was highest (4.0; 95% CI, 1.6-10.0) for women who used OCs during the cycle in which they became pregnant, but there was no consistent pattern according to the time interval since last OC use. The relative risks for choriocarcinoma and persistent mole associated with OC use were 2.2 (95% CI, 0.8-6.4) and 1.8 (95% CI, 1.0-3.0), respectively. This study, the largest to date, suggests that a long duration of OC use before conception does, indeed, increase the risk of gestational trophoblastic tumors.

Cancer mortality among nuns: role of marital status in etiology of neoplastic disease in women.

PIP: To clarify the role of marital status in human carcinogenesis, a 1968 Cancer Institute study analyzed the cancer mortality experience of 31,658 white Catholic nuns from 41 religious orders in the U.S. from 1900-1954. The national white female population was used for cause-specific comparison and both groups were assigned cohorts depending upon the year of birth. When examined by 10-year age groups, rates for cancer at all sites was generally lower for nuns than for controls aged 59 or 69 but were substantially higher at older ages. Postmenopausal nuns (aged 69 and over) displayed a higher rate (38.6%) of cancer of the large intestine than did controls (22.6%) but had a lower proportion of deaths from cancer of the biliary passages and liver (13.0% vs. 22.6%). Nuns displayed a striking excess in breast cancer mortality over the age span of 40-74 years and had consistently higher rates than controls for each age group above 39 years. Lower cervical cancer rates for nuns (10.8%) than for controls (56.6%) seemed related to coital factors. Cancer of the uterus accounted for 63% of the genital cancer deaths among sisters. Overall, the genital cancer mortality rates for nuns were consistent with high mortality rates for the single, white female population of the U.S. The increased risk of breast cancer and cancers of the corpus uteri and ovary would seem to reflect an established link with infertility. Combination of these factors with the excess incidence of cancer of the large intestine among postmenopausal nuns suggests a common pathogenic mechanism of a hormonal nature operating in some women.^ieng

Changes in mammographic densities induced by a hormonal contraceptive designed to reduce breast cancer risk.

BACKGROUND: It has been known for some time that oral contraceptives substantially reduce the risk of endometrial and ovarian cancer, but they do not reduce the risk of breast cancer. A hormonal contraceptive regimen has been developed which uses a gonadotropin-releasing hormone against (GnRHA) to suppress ovarian function, and this regimen includes the administration of very low doses of both estrogen and progestogen. This hormonal contraceptive regimen attempts to minimize exposure of the breast epithelium to these steroids and to preserve the maximum beneficial effects of estrogen, while still preventing endometrial hyperplasia. PURPOSE: Our purpose was to determine whether changes occurred in mammographic densities between baseline and 1 year for women on this hormonal contraceptive regimen with reduced estrogen and progestogen levels compared with women in a control group. METHODS: Twenty-one women were randomly assigned in a 2:1 ratio to the GnRHA-based contraceptive group (14 women) or to a control group (seven women). The contraceptive group received the following: 7.5 mg leuprolide acetate depot by intramuscular injection every 28 days; 0.625 mg conjugated estrogen by mouth for 6 days out of 7 every week; and 10 mg medroxyprogesterone acetate orally for 13 days every fourth 28-day cycle. The control group received no medication. Baseline and 1-year follow-up mammograms of contraceptive and control subjects were reviewed in a blinded fashion by two radiologists. RESULTS: Comparison of the changes between the baseline and 1-year mammograms in the two groups of women showed significant (P = .039) reduction in mammographic densities at 1 year for women on the contraceptive regimen. Assessing the reduction in mammographic densities by noting the fineness of fibrous septae showed a highly significant (P = .0048) difference in the contraceptive regimen group. One of the women on the contraceptive regimen was withdrawn from the study because of poor compliance. CONCLUSION: The reduced estrogen and progestogen exposures to the breast that were achieved by the hormonal contraceptive regimen resulted in substantial reductions in follow-up mammographic densities at 1 year compared with baseline. Although there is no direct evidence that such a reduction in densities will lead to a reduced risk of breast cancer, indirect evidence for a protective effect of this regimen is that early menopause reduces breast cancer risk, and that menopause is associated with a reduction in mammographic densities.

PIP: In California, physicians randomly assigned 21 women aged 25-40 to either the contraceptive group or the control group as part of a study aimed to determine whether or not a hormonal contraceptive regimen with reduced estrogen and progestogen levels affects mammographic densities. Eligibility criteria included premenopausal women with a 5-fold greater than normal risk of breast cancer, no prior cancer, bone mineral density not less than 2 standard deviations below normal, normal cholesterol, and a normal physical and pelvic examination. The contraceptive group received intramuscular injection of 7.5 mg leuprolide acetate depot every 28 days, 0.625 mg oral conjugated estrogen for 6 out of 7 days every week, and 10 mg oral medroxyprogesterone acetate for 13 days every fourth 28-day cycle. The reduction in mammographic densities in women on the contraceptive regimen between baseline and 1 year was significantly different than that of the controls whose mammographic densities remained essentially the same (p = 0.039). Cases had significantly more change in fibrous septae between baseline and 1 year than did controls (+0.82 units vs. -0.07; p = 0.0048). These results indicate that lower levels of estrogen and progestogen reduces mammographic densities, which may reduce the risk of breast cancer since increased mammographic densities are linked to an increased risk of breast cancer. Reduced mitotic activity in breast epithelial cells during menopause and with lower levels of estrogen and progestogen (i.e., reduced mammographic densities) suggest that early menopause may also protect against breast cancer.

Risk factors for invasive cervical cancer among Latinas and non-Latinas in Los Angeles County.

A case-control study among white women in Los Angeles County was conducted to investigate etiologic factors that might explain the high rates of invasive cervical cancer among Latinas. Two hundred patients with invasive squamous cell carcinoma of the uterine cervix and matched (age, sex, preferred language, and neighborhood) controls were interviewed, 98 pairs in English and 102 pairs in Spanish. Seven factors were found to contribute independently and significantly (P less than .01) to risk, each after adjustment for the other six: years since last Pap smear, years of education (protective), frequency-years douching, pack-years of smoking, years of barrier contraceptive use (protective), number of sexual partners before age 20, and recognized episodes of genital warts. An eighth variable, interval in years between menarche and first intercourse, was the second variable to enter the stepwise logistic regression analysis but lost its statistical significance when sexual partners before age 20 entered the model. Together, these eight variables accounted for almost 99% of the risk. There were no significant interactions between any of these variables and age, language of interview, or birth in a Latin country. There was no increased risk associated with use of oral contraceptives, either before or after adjustment for the other significant factors. Compared to English-speaking controls, Spanish-speaking controls smoked less, douched less, had fewer sexual partners before 20, and had essentially the same average interval between menarche and first intercourse and the same average number of episodes of genital warts; however, they had had a longer interval since their last Pap smear, fewer years of barrier contraceptive use, and fewer years of education. Education, presumably a correlate of an inadequately measured etiologic risk factor (possibly papillomavirus infection), was responsible for the greatest difference in risk between the Spanish- and English-speaking cases.