Reproductive factors and mammographic density within the International Consortium of Mammographic Density: A cross-sectional study.

BACKGROUND: Elevated mammographic density (MD) for a woman's age and body mass index (BMI) is an established breast cancer risk factor. The relationship of parity, age at first birth, and breastfeeding with MD is less clear. We examined the associations of these factors with MD within the International Consortium of Mammographic Density (ICMD). METHODS: ICMD is a consortium of 27 studies with pooled individual-level epidemiological and MD data from 11,755 women without breast cancer aged 35-85 years from 22 countries, capturing 40 country-& ethnicity-specific population groups. MD was measured using the area-based tool Cumulus. Meta-analyses across population groups and pooled analyses were used to examine linear regression associations of square-root (√) transformed MD measures (percent MD (PMD), dense area (DA), and non-dense area (NDA)) with parity, age at first birth, ever/never breastfed and lifetime breastfeeding duration. Models were adjusted for age at mammogram, age at menarche, BMI, menopausal status, use of hormone replacement therapy, calibration method, mammogram view and reader, and parity and age at first birth when not the association of interest. RESULTS: Among 10,988 women included in these analyses, 90.1% (n = 9,895) were parous, of whom 13% (n = 1,286) had ≥ five births. The mean age at first birth was 24.3 years (Standard deviation = 5.1). Increasing parity (per birth) was inversely associated with √PMD (ß: - 0.05, 95% confidence interval (CI): - 0.07, - 0.03) and √DA (ß: - 0.08, 95% CI: - 0.12, - 0.05) with this trend evident until at least nine births. Women who were older at first birth (per five-year increase) had higher √PMD (ß:0.06, 95% CI:0.03, 0.10) and √DA (ß:0.06, 95% CI:0.02, 0.10), and lower √NDA (ß: - 0.06, 95% CI: - 0.11, - 0.01). In stratified analyses, this association was only evident in women who were post-menopausal at MD assessment. Among parous women, no associations were found between ever/never breastfed or lifetime breastfeeding duration (per six-month increase) and √MD. CONCLUSIONS: Associations with higher parity and older age at first birth with √MD were consistent with the direction of their respective associations with breast cancer risk. Further research is needed to understand reproductive factor-related differences in the composition of breast tissue and their associations with breast cancer risk.

Variations in Practice and Geographic Disparities Between Dedicated Multidisciplinary Clinics for BRCA1/BRCA2 Mutation Carriers in Israel.

BACKGROUND: Population screening for the BRCA mutations in Ashkenazi Jewish women was recently implemented in Israel and is expected to lead to a 10-fold increase in the diagnosis of asymptomatic carriers. Performing the screening follow-up within multidisciplinary dedicated clinics for carriers is recommended for early detection and risk reduction. OBJECTIVES: : To determine the availability, capacity, and practices of dedicated screening clinic for BRCA carriers in Israel. METHODS: A telephone-based survey of all public hospitals in Israel was conducted October 2020 to August 2021 to determine whether they had a dedicated clinic. Dedicated clinics were defined as multidisciplinary screening clinics offering at least breast and gynecological screening and risk reducing services on site. The clinic director or nurse navigator answered a questionnaire about screening practices followed by a semi-structured interview. RESULTS: Of the ten dedicated BRCA clinics found in Israel, nine participated. Approximately 4500 BRCA carriers are currently being followed. No specialized clinics are available in the southern district or in the northernmost half of the northern district of Israel, leading to a disparity between periphery and center. Screening recommendations, although asserted as adhering to international guidelines, vary among clinics including age at initiating of clinical exam, use of adjunct imaging modalities, and follow-up during lactation and after risk reducing surgery. CONCLUSIONS: There is a suboptimal distribution of dedicated clinics for BRCA carriers in Israel. Nationally centralized attempt to create guidelines that will unify screening practices is warranted, especially considering the expected increase in demand.

The association of age at menarche and adult height with mammographic density in the International Consortium of Mammographic Density.

BACKGROUND: Early age at menarche and tall stature are associated with increased breast cancer risk. We examined whether these associations were also positively associated with mammographic density, a strong marker of breast cancer risk. METHODS: Participants were 10,681 breast-cancer-free women from 22 countries in the International Consortium of Mammographic Density, each with centrally assessed mammographic density and a common set of epidemiologic data. Study periods for the 27 studies ranged from 1987 to 2014. Multi-level linear regression models estimated changes in square-root per cent density (√PD) and dense area (√DA) associated with age at menarche and adult height in pooled analyses and population-specific meta-analyses. Models were adjusted for age at mammogram, body mass index, menopausal status, hormone therapy use, mammography view and type, mammographic density assessor, parity and height/age at menarche. RESULTS: In pooled analyses, later age at menarche was associated with higher per cent density (ß√PD = 0.023 SE = 0.008, P = 0.003) and larger dense area (ß√DA = 0.032 SE = 0.010, P = 0.002). Taller women had larger dense area (ß√DA = 0.069 SE = 0.028, P = 0.012) and higher per cent density (ß√PD = 0.044, SE = 0.023, P = 0.054), although the observed effect on per cent density depended upon the adjustment used for body size. Similar overall effect estimates were observed in meta-analyses across population groups. CONCLUSIONS: In one of the largest international studies to date, later age at menarche was positively associated with mammographic density. This is in contrast to its association with breast cancer risk, providing little evidence of mediation. Increased height was also positively associated with mammographic density, particularly dense area. These results suggest a complex relationship between growth and development, mammographic density and breast cancer risk. Future studies should evaluate the potential mediation of the breast cancer effects of taller stature through absolute breast density.

Correlation between cumulative mammographic density and age-specific incidence of breast cancer: A biethnic study in Israel.

Women with the most extensive breast density, have a 4- to 6-fold higher cancer risk than women with the lowest density. This cross-sectional study evaluated associations of cumulative mammographic density in two distinct ethnic groups with the respective age-specific breast cancer incidences in the population. The study compared four cohorts of 200 women each aged 35 to 49 and 50 to 74, representing Jewish and Arab ethnicity. Breast density measures were calculated from screening mammograms, using a thresholding software (Cumulus). Breast cancer specific incidence values were obtained from the National Cancer Registry. The percent mammographic density was lower for women aged 50 to 74 than 35 to 49 years, both for Jews: 11.7 vs 23.1 and for Arabs: 11.6 vs 18.3. In contrast, the cumulative density increased with age, from 37.30 to 181.24 in Jews, compared to 21.26 to 108.03 in Arabs. Similar trends in breast cancer incidence rates per 100 000 in the Israeli population were apparent, with an increase from 92.95 to 381.91 in Jews, compared to 48.6 to 244.44 in Arabs. Comparing cumulative density of the cohort with respective age-specific breast cancer incidence in the population yielded a highly significant correlation: Jews; r = .97, P < .0001 and Arabs: r = .86, P = .007. A strong association was found between the log of cumulative density and the log of cancer incidence, as well. Our study identified correlations between cumulative mammographic density and breast cancer incidence in two distinct populations. The findings should prompt research to enhance our understanding of the pathogenesis of breast cancer, and lead to novel insights into measures of prevention.

Association Between Polyp Detection Rate and Post-Colonoscopy Cancer Among Patients Undergoing Diagnostic Colonoscopy.

Postcolonoscopy colorectal cancer (PCCRC) can arise from missed cancers, missed premalignant lesions, incomplete resection, and new cancers with an accelerated route to cancer.1.

Early assessment of the first wave of the COVID-19 pandemic on cancer screening services: The International Cancer Screening Network COVID-19 survey.

Screening can decrease the burden of breast, cervical, and colorectal cancers. The COVID-19 pandemic led many countries to suspend cancer screening services as part of their response to the pandemic. The International Cancer Screening Network (ICSN) carried out an online survey to assess the effects of the first wave of the COVID-19 pandemic on cancer screening. A 33-item survey was distributed to 834 email addresses to gather information about settings and assess decision-making processes that led to cancer screening suspension. Information about communication, impact on resources, and patient follow-up was collected. Quantitative data was analyzed as frequencies overall and by setting, while a comment section under each survey item captured nuanced details. Responses were recategorized into 66 settings, representing 35 countries. Most settings suspended cancer screening services (n = 60, 90.9%) in March 2020 (n = 45, 68.2%), guided by a government decision (n = 51, 77.3%). Few settings made the decision whether to suspend services based on a preparedness plan (n = 17, 25.8%). In most settings, professionals were reassigned (n = 41, 62.1%) and infrastructure repurposed (n = 35, 53.0%). The first wave of the COVID-19 pandemic has had profound effects on cancer screening worldwide, including the suspension of services in almost all settings. Most settings were unprepared to deal with the scale of the pandemic but demonstrated flexibility in the response. These results contribute to inform, through experiences and lessons learned, the next steps for the global cancer screening community to further evaluate the impact of COVID-19 and prepare for future disruptions.

Mechanisms involved in the formation of professional identity by medical students.

BACKGROUND: Despite in-depth discussions regarding professional identity of doctors, there is still a gap in our understanding of how this professional identity actually evolves. OBJECTIVE: To outline some major mechanisms involved in formation of medical students' professional identity. METHODS: A qualitative study based on thematic analysis. 296 diary entries, written by eight medical students as part of the three-year course 'Becoming a Physician,' were reviewed. The course, conducted in small groups, gradually exposes students to the clinical field, and emphasizes awareness to marginalized populations, and interpersonal communication skills. RESULTS: Following the social constructivist learning theory, where learners individually and socially construct meaning attributed to their experiences, we identified three major mechanisms based on students' written reflections. These include linking current experiences to past; comparing different types or aspects of knowledge, doctors or medicine; and future perspective taking. CONCLUSIONS: This study sheds light on the possible mechanisms used by medical students in forming their professional identity prior to their clinical training. Knowing these mechanisms can help medical educators better understand and support their students in formation of their professional identities. Conducting reflective writing could serve as an effective tool for learners to comprehend the meanings of their experiences.

Epidemiologic Surveillance in Israel of Cryptosporidium, a Unique Waterborne Notifiable Pathogen, and Public Health Policy.

BACKGROUND: Cryptosporidium is a major threat to water supplies worldwide. Various biases and obstacles in case identification are recognized. In Israel, Cryptosporidiosis was included among notifiable diseases in 2001 in order to determine the burden of parasite-inflicted morbidity and to justify budgeting a central drinking water filtration plant. OBJECTIVES: To summarize the epidemiologic features of 14 years of Cryptosporidium surveillance and to assess the effects of advanced water purification treatment on the burden of disease. METHODS: From 2001 to 2014, a passive surveillance system was used. Cases were identified based on microscopic detection in stool samples. Confirmed cases were reported electronically to the Israeli Ministry of Health. Overall rates as well as age, gender, ethnicity and specific annual incidence were calculated per 100,000 population in five age groups: 0-4, 5-14, 15-44, 45-64, > 65 years. RESULTS: A total of 522 Cryptosporidium cases were reported in all six public health districts. More cases were detected among Jews and among males, and mainly in young children, with a seasonal peak during summer. The Haifa sub-district reported 69% of the cases. Most were linked to an outbreak from the summer of 2008, which was attributed to recreational swimming pool activity. Cases decreased after installation of a central filtration plant in 2007. CONCLUSIONS: As drinking water in Israel is treated to maximal international standards, the rationale for further inclusion of Cryptosporidium among mandatory notifiable diseases should be reconsidered. Future surveillance efforts should focus on timely detection of outbreaks using molecular high-throughput testing.

Mammographic density and ageing: A collaborative pooled analysis of cross-sectional data from 22 countries worldwide.

BACKGROUND: Mammographic density (MD) is one of the strongest breast cancer risk factors. Its age-related characteristics have been studied in women in western countries, but whether these associations apply to women worldwide is not known. METHODS AND FINDINGS: We examined cross-sectional differences in MD by age and menopausal status in over 11,000 breast-cancer-free women aged 35-85 years, from 40 ethnicity- and location-specific population groups across 22 countries in the International Consortium on Mammographic Density (ICMD). MD was read centrally using a quantitative method (Cumulus) and its square-root metrics were analysed using meta-analysis of group-level estimates and linear regression models of pooled data, adjusted for body mass index, reproductive factors, mammogram view, image type, and reader. In all, 4,534 women were premenopausal, and 6,481 postmenopausal, at the time of mammography. A large age-adjusted difference in percent MD (PD) between post- and premenopausal women was apparent (-0.46 cm [95% CI: -0.53, -0.39]) and appeared greater in women with lower breast cancer risk profiles; variation across population groups due to heterogeneity (I2) was 16.5%. Among premenopausal women, the √PD difference per 10-year increase in age was -0.24 cm (95% CI: -0.34, -0.14; I2 = 30%), reflecting a compositional change (lower dense area and higher non-dense area, with no difference in breast area). In postmenopausal women, the corresponding difference in √PD (-0.38 cm [95% CI: -0.44, -0.33]; I2 = 30%) was additionally driven by increasing breast area. The study is limited by different mammography systems and its cross-sectional rather than longitudinal nature. CONCLUSIONS: Declines in MD with increasing age are present premenopausally, continue postmenopausally, and are most pronounced over the menopausal transition. These effects were highly consistent across diverse groups of women worldwide, suggesting that they result from an intrinsic biological, likely hormonal, mechanism common to women. If cumulative breast density is a key determinant of breast cancer risk, younger ages may be the more critical periods for lifestyle modifications aimed at breast density and breast cancer risk reduction.

Mammographic density assessed on paired raw and processed digital images and on paired screen-film and digital images across three mammography systems.

BACKGROUND: Inter-women and intra-women comparisons of mammographic density (MD) are needed in research, clinical and screening applications; however, MD measurements are influenced by mammography modality (screen film/digital) and digital image format (raw/processed). We aimed to examine differences in MD assessed on these image types. METHODS: We obtained 1294 pairs of images saved in both raw and processed formats from Hologic and General Electric (GE) direct digital systems and a Fuji computed radiography (CR) system, and 128 screen-film and processed CR-digital pairs from consecutive screening rounds. Four readers performed Cumulus-based MD measurements (n = 3441), with each image pair read by the same reader. Multi-level models of square-root percent MD were fitted, with a random intercept for woman, to estimate processed-raw MD differences. RESULTS: Breast area did not differ in processed images compared with that in raw images, but the percent MD was higher, due to a larger dense area (median 28.5 and 25.4 cm2 respectively, mean √dense area difference 0.44 cm (95% CI: 0.36, 0.52)). This difference in √dense area was significant for direct digital systems (Hologic 0.50 cm (95% CI: 0.39, 0.61), GE 0.56 cm (95% CI: 0.42, 0.69)) but not for Fuji CR (0.06 cm (95% CI: -0.10, 0.23)). Additionally, within each system, reader-specific differences varied in magnitude and direction (p < 0.001). Conversion equations revealed differences converged to zero with increasing dense area. MD differences between screen-film and processed digital on the subsequent screening round were consistent with expected time-related MD declines. CONCLUSIONS: MD was slightly higher when measured on processed than on raw direct digital mammograms. Comparisons of MD on these image formats should ideally control for this non-constant and reader-specific difference.

[ETHICS, MORALS AND SOCIETY IN PERSONALIZED MEDICINE].

Following the completion of the human genome project, genomic medicine including personalized medicine, widely based on pharmacogenetics and pharmacogenomics, is rapidly developing. This breakthrough should benefit humankind thanks to tailoring the most appropriate prevention, interventions and therapies to each individual, minimizing adverse side effects, based on inter-personal genetic variety and polymorphism. Yet wide spectrum ethical, legal and social issues carry significant implications regarding individuals, families, society and public health. The main issues concern genomic information and autonomy, justice and equity, resources allocation and solidarity, challenging the traditional role of medicine and dealing with unlimited boundaries of knowledge. Those issues are not new nor exceptional to genomic medicine, yet their wide unlimited scope and implications on many aspects of life renders them crucial. These aspects will be discussed in light of Beauchamp and Childress' four principles: non-maleficence, beneficence, autonomy and justice, and main moral philosophies, Kant's autonomy, Utilitarianism which promotes the common good, and Rawls' Theory of Justice.

[Psychological and familial aspects of the familial breast and ovarian cancer genetic counseling process].

Breast cancer is the most prevalent malignancy among women, whilst ovarian cancer is less common but carries a graver prognosis. Carriers of the BRCA mutations have a few-fold higher risk for those diseases. Genetic counseling for the families at risk has been available for almost two decades, since the definition of the mutation. The existence of the deleterious mutation has implications beyond the individual level and touches the lives and future of many other family members. Being part of a BRCA family has medical as well as psychosocial implications. Various barriers and facilitators must be dealt with during the process of sharing the information with kins. Most families cope well with those issues, while some require the guidance of professionals. Special subpopulations, i.e. non-carrier women in BRCA families, young carriers and men who are under minimal personal threat but might transfer the mutation to their off springs, have special needs which should be addressed. The desired outcome of the counseling process is achievement of normal adaptation which balances life in the shadow of uncertainty and threat with the ability to lead a normal life. The process of counseling is multidisciplinary, and along with the advances in scientific and medical aspects, the ethical, legal and social implications (ELSI) have also been developed. The professional personnel escorting those families need to develop and maintain specific skills.

Racial/ethnic and socioeconomic disparities in colorectal cancer screening in a large organization with universal insurance before and during the coronavirus disease 2019 pandemic.

OBJECTIVES: Israel is regarded as a country with a developed economy and a moderate income inequality index. In this population-based study, we aimed to measure the inequalities in colorectal cancer screening within Clalit Health, an organization with universal insurance, before and during the coronavirus disease 2019 pandemic. SETTING: Retrospective analysis within Clalit Health Services, Israel. METHODS: We evaluated the rate of being up to date with screening (having a colonoscopy within 10 years or a fecal occult blood test within 1 year) and the colonoscopy completion rate (having a colonoscopy within 6 months of a positive fecal occult blood test) among subjects aged 50-75 in 2019-2021. RESULTS: In 2019, out of 918,135 subjects, 61.3% were up to date with screening; high socioeconomic status: 65.9% (referent), medium-socioeconomic status: 60.1% (odds ratio 0.81, 95% confidence interval 0.80-0.82), low-socioeconomic status: 59.0% (odds ratio 0.75, 95% confidence interval 0.74-0.75); Jews: 61.9% (referent), Arabs: 59.7% (odds ratio 0.91, 95% confidence interval 0.90-0.92), Ultraorthodox-Jews: 51.7% (odds ratio 0.77, 95% confidence interval 0.75-0.78). Out of 21,308 with a positive fecal occult blood test, the colonoscopy completion rate was 51.8%; high-socioeconomic status: 59.8% (referent), medium-socioeconomic status: 54.1% (odds ratio 0.79, 95% confidence interval 0.73-0.86), low-socioeconomic status: 45.5% (odds ratio 0.60, 95% confidence interval 0.56-0.65); Jews: 54.7% (referent), Ultraorthodox-Jews: 51.4% (odds ratio 0.91, 95% confidence interval 0.90-0.92), Arabs: 44.7% (odds ratio 0.77, 95% confidence interval 0.75-0.78). In 2020-2021, there was a slight drop in the rate of being up to date with screening, while most of the discrepancies were kept or slightly increased with time. CONCLUSIONS: We report significant inequalities in colorectal cancer screening before and during the coronavirus disease 2019 pandemic in Israel, despite a declared policy of equality and universal insurance.

The use of artificial intelligence to identify subjects with a positive FOBT predicted to be non-compliant with both colonoscopy and harbor cancer.

BACKGROUND: Subjects with a positive Fecal Occult Blood Test (FOBT) that are non-compliant with colonoscopy are at increased risk for colorectal cancer (CRC). Yet, in clinical practice, many remain non-compliant. AIMS: To evaluate whether machine learning models (ML) can identify subjects with a positive FOBT predicted to be both non-compliant with colonoscopy within six months and harbor CRC (defined as the "target population"). METHODS: We trained and validated ML models based on extensive administrative and laboratory data about subjects with a positive FOBT between 2011 and 2013 within Clalit Health that were followed for cancer diagnosis up to 2018. RESULTS: Out of 25,219 included subjects, 9,979(39.6%) were non-compliant with colonoscopy, and 202(0.8%) were both non-compliant and harbored cancer. Using ML, we reduced the number of subjects needed to engage from 25,219 to either 971 (3.85%) to identify 25.8%(52/202) of the target population, reducing the number needed to treat (NNT) from 124.8 to 19.4 or to 4,010(15,8%) to identify 55.0%(52/202) of the target population, NNT = 39.7. CONCLUSION: Machine learning technology may help healthcare organizations to identify subjects with a positive FOBT predicted to be both non-compliant with colonoscopy and harbor cancer from the first day of a positive FOBT with improved efficiency.

Group Mentoring for Junior Medical Students-the Mentor in the Reflection Cycle.

PURPOSE: To describe the experience and perceptions of physicians involved in group mentoring of undergraduate pre-clinical medical students. METHOD: We conducted a cross-sectional questionnaire-based survey on perceptions of mentors regarding their motivation, personal development, reflective experience, and burnout. All the participants were mentors to undergraduate pre-clinical medical students in the course "Becoming a Physician." This unique course focuses on various aspects of medical professionalism and aims to increase awareness and sensitivity to patients, especially of disadvantaged populations, and to promote sensitive effective communication skills. Mentors in the course are expected to serve as role models to their students. RESULTS: Of 36 mentors, 33 (91.7%) responded. The most frequent motivations to join the course were to contribute to students' personal, social, and professional development and to contribute to educating more compassionate physicians. The topics discussed most in the groups were the meaning of being a physician and ethical dilemmas. Mentors expressed that they gained professional growth and opportunities to reflect on the complexity of physicians' training and work. They perceived their highest success as being able to serve as role models for their students and provide them broad perspectives. Mentors stated that they failed in trying to facilitate content learning, and were disturbed by students' lack of punctuality. Group mentors scored relatively low on the Maslach Burnout Inventory for Physicians. DISCUSSION: This study provides insights on the experience of mentorship of medical school students, and on mentors' perceptions regarding their teaching experience and personal and professional development. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40670-020-01146-1.

Delayed Colonoscopy Following a Positive Fecal Test Result and Cancer Mortality.

BACKGROUND: A fecal test followed by diagnostic colonoscopy for a positive result is a widely endorsed screening strategy for colorectal cancer (CRC). However, the relationship between the time delay from the positive test to the follow-up colonoscopy and CRC mortality has not been established. METHODS: From a population-based screening program, we identified CRC patients newly diagnosed from 2005 through 2015 by a positive fecal occult test followed by a colonoscopy. The primary outcome measure was CRC-specific mortality according to four categories for the time elapsed between the positive result and the subsequent colonoscopy. RESULTS: The 1749 patients underwent colonoscopies within 0-3 months (n = 981, 56.1%), 4-6 months (n = 307, 17.5%), 7-12 months (n = 157, 9.0%), and later than 12 months (n = 304, 17.4%). CRC-specific deaths according to exposure groups were: 13.8% (135 of 981) for 0-3 months, 10.7% (33 of 307) for 4-6 months (crude hazards ratio [HR] = 0.74, 95% confidence interval [CI] = 0.51 to 1.14), 11.5% (18 of 157) for 7-12 months (crude HR = 0.83, 95% CI = 0.51 to 1.42), and 22.7% (69 of 304) for longer than 12 months (crude HR = 1.40, 95% CI = 1.04 to 1.90). The only variable that was associated with mortality risk was the number of positive slides (P = .003). High positivity was twice the value in the 0-3 as the longer-than-12 months group: 51.9% vs 25.0% and similar for the 4-6 and 7-12 months groups (38.1% and 36.5%), respectively. The adjusted HRs for CRC mortality were 0.81 (95% CI = 0.55 to 1.19); 0.83 (95% CI = 0.50 to 1.41), and 1.53 (95% CI = 1.13 to 2.12, P = .006) for the 4-12, 7-12, and longer-than-12-months groups, respectively, compared with the shortest delay group. CONCLUSIONS: Among screen-diagnosed CRC patients, performance of colonoscopy more than 12 months after the initial positive fecal occult blood test was associated with more advanced disease and higher mortality due to CRC.

Oral Bisphosphonates and Improved Survival of Breast Cancer.

Purpose: Bisphosphonates are used for treatment or prevention of osteoporosis and of bone metastases. The use of oral bisphosphonates was suggested to be associated with reduced risk of developing breast cancer, and their positive influence on breast cancer survival was only demonstrated with third-generation bisphosphonates. We studied the association of use of oral bisphosphonates after breast cancer diagnosis on overall and breast cancer survival.Experimental Design: A nested case-control analysis was performed using data from the population-based Breast Cancer in Northern Israel Study (BCINIS). Participants were postmenopausal women with newly diagnosed breast cancer insured by Clalit. Use of second-generation bisphosphonates (alendronate and/or risedronate) was identified using computerized prescription records. The analysis was restricted to women who did not use bisphosphonates prior to diagnosis.Results: In a cohort of 3,731 postmenopausal women with breast cancer, followed up for an average of 70 months, there were 799 cases of death which were matched to 15,915 control periods of living breast cancer cases. Use of bisphosphonates after diagnosis for at least 18 months was significantly more common among survivors than among their matched controls who died, adjusted for tumor stage/grade (overall survival: OR = 0.63, 0.41-0.96, P = 0.03; breast cancer-specific survival: OR = 0.28, 0.09-0.91, P = 0.035). A similar advantageous effect, but statistically underpowered, was found in estrogen receptor (ER)-positive, ER-negative, and HER2neu-positive tumors.Conclusions: The use of oral bisphosphonates, by postmenopausal, probably osteoporotic, women initiated after diagnosis of breast cancer was associated with a significant improvement in overall and breast-specific odds of survival. Clin Cancer Res; 23(7); 1684-9. ©2016 AACR.

International Consortium on Mammographic Density: Methodology and population diversity captured across 22 countries.

Mammographic density (MD) is a quantitative trait, measurable in all women, and is among the strongest markers of breast cancer risk. The population-based epidemiology of MD has revealed genetic, lifestyle and societal/environmental determinants, but studies have largely been conducted in women with similar westernized lifestyles living in countries with high breast cancer incidence rates. To benefit from the heterogeneity in risk factors and their combinations worldwide, we created an International Consortium on Mammographic Density (ICMD) to pool individual-level epidemiological and MD data from general population studies worldwide. ICMD aims to characterize determinants of MD more precisely, and to evaluate whether they are consistent across populations worldwide. We included 11755 women, from 27 studies in 22 countries, on whom individual-level risk factor data were pooled and original mammographic images were re-read for ICMD to obtain standardized comparable MD data. In the present article, we present (i) the rationale for this consortium; (ii) characteristics of the studies and women included; and (iii) study methodology to obtain comparable MD data from original re-read films. We also highlight the risk factor heterogeneity captured by such an effort and, thus, the unique insight the pooled study promises to offer through wider exposure ranges, different confounding structures and enhanced power for sub-group analyses.

Associated Links Among Smoking, Chronic Obstructive Pulmonary Disease, and Small Cell Lung Cancer: A Pooled Analysis in the International Lung Cancer Consortium.

BACKGROUND: The high relapse and mortality rate of small-cell lung cancer (SCLC) fuels the need for epidemiologic study to aid in its prevention. METHODS: We included 24 studies from the ILCCO collaboration. Random-effects panel logistic regression and cubic spline regression were used to estimate the effects of smoking behaviors on SCLC risk and explore their non-linearity. Further, we explored whether the risk of smoking on SCLC was mediated through COPD. FINDINGS: Significant dose-response relationships of SCLC risk were observed for all quantitative smoking variables. Smoking pack-years were associated with a sharper increase of SCLC risk for pack-years ranged 0 to approximately 50. The former smokers with longer cessation showed a 43%quit_for_5-9 years to 89%quit_for_≥ 20 years declined SCLC risk vs. subjects who had quit smoking < 5 years. Compared with non-COPD subjects, smoking behaviors showed a significantly higher effect on SCLC risk among COPD subjects, and further, COPD patients showed a 1.86-fold higher risk of SCLC. Furthermore, smoking behaviors on SCLC risk were significantly mediated through COPD which accounted for 0.70% to 7.55% of total effects. INTERPRETATION: This is the largest pooling study that provides improved understanding of smoking on SCLC, and further demonstrates a causal pathway through COPD that warrants further experimental study.