Reproductive risk factors for breast cancer and association with novel breast density measurements among Hispanic, Black, and White women.

PURPOSE: There are differences in the distributions of breast cancer incidence and risk factors by race and ethnicity. Given the strong association between breast density and breast cancer, it is of interest describe racial and ethnic variation in the determinants of breast density. METHODS: We characterized racial and ethnic variation in reproductive history and several measures of breast density for Hispanic (n = 286), non-Hispanic Black (n = 255), and non-Hispanic White (n = 1694) women imaged at a single hospital. We quantified associations between reproductive factors and percent volumetric density (PVD), dense volume (DV), non-dense volume (NDV), and a novel measure of pixel intensity variation (V) using multivariable-adjusted linear regression, and tested for statistical heterogeneity by race and ethnicity. RESULTS: Reproductive factors most strongly associated with breast density were age at menarche, parity, and oral contraceptive use. Variation by race and ethnicity was most evident for the associations between reproductive factors and NDV (minimum p-heterogeneity:0.008) and V (minimum p-heterogeneity:0.004) and least evident for PVD (minimum p-heterogeneity:0.042) and DV (minimum p-heterogeneity:0.041). CONCLUSION: Reproductive choices, particularly those related to childbearing and oral contraceptive use, may contribute to racial and ethnic variation in breast density.

A genome-wide association study of mammographic texture variation.

BACKGROUND: Breast parenchymal texture features, including grayscale variation (V), capture the patterns of texture variation on a mammogram and are associated with breast cancer risk, independent of mammographic density (MD). However, our knowledge on the genetic basis of these texture features is limited. METHODS: We conducted a genome-wide association study of V in 7040 European-ancestry women. V assessments were generated from digitized film mammograms. We used linear regression to test the single-nucleotide polymorphism (SNP)-phenotype associations adjusting for age, body mass index (BMI), MD phenotypes, and the top four genetic principal components. We further calculated genetic correlations and performed SNP-set tests of V with MD, breast cancer risk, and other breast cancer risk factors. RESULTS: We identified three genome-wide significant loci associated with V: rs138141444 (6q24.1) in ECT2L, rs79670367 (8q24.22) in LINC01591, and rs113174754 (12q22) near PGAM1P5. 6q24.1 and 8q24.22 have not previously been associated with MD phenotypes or breast cancer risk, while 12q22 is a known locus for both MD and breast cancer risk. Among known MD and breast cancer risk SNPs, we identified four variants that were associated with V at the Bonferroni-corrected thresholds accounting for the number of SNPs tested: rs335189 (5q23.2) in PRDM6, rs13256025 (8p21.2) in EBF2, rs11836164 (12p12.1) near SSPN, and rs17817449 (16q12.2) in FTO. We observed significant genetic correlations between V and mammographic dense area (rg = 0.79, P = 5.91 × 10-5), percent density (rg = 0.73, P = 1.00 × 10-4), and adult BMI (rg = - 0.36, P = 3.88 × 10-7). Additional significant relationships were observed for non-dense area (z = - 4.14, P = 3.42 × 10-5), estrogen receptor-positive breast cancer (z = 3.41, P = 6.41 × 10-4), and childhood body fatness (z = - 4.91, P = 9.05 × 10-7) from the SNP-set tests. CONCLUSIONS: These findings provide new insights into the genetic basis of mammographic texture variation and their associations with MD, breast cancer risk, and other breast cancer risk factors.

Self-Expanding Metal Stents Do Not Adversely Affect Long-term Outcomes in Acute Malignant Large-Bowel Obstruction: A Retrospective Analysis.

BACKGROUND: Self-expanding metal stents as a bridge to surgery in acute malignant large-bowel obstruction has gained popularity. However, long-term oncologic outcomes have not been well established. OBJECTIVE: To investigate long-term oncologic outcomes of patients undergoing curative resection after the placement of a colonic stent compared with emergency surgery for acute malignant large-bowel obstruction. DESIGN: This is a retrospective study. SETTING: All patients presenting at 3 tertiary care centers between April 2002 and December 2012 with a diagnosis of complete malignant large-bowel obstruction were reviewed. Patients with disease distal to the hepatic flexure were selected for analysis. PATIENTS: One hundred twenty-two patients who underwent either emergency surgery or placement of a colonic stent with curative intent were included. INTERVENTIONS: Patients receiving emergency surgery within 24 hours of presenting with obstructive symptoms, including those with failed stents, were included in the emergency surgery group. All patients with clinically successful stent deployment before surgery were included in the stent group. MAIN OUTCOME MEASURES: Overall survival and disease-free survival were calculated using the Kaplan-Meier method. RESULTS: Sixty-four patients underwent emergency surgery, and 58 patients underwent placement of a self-expanding metal stent. Groups were similar in terms of sex, tumor stage and grade, and Charlson and Charlson-Age Comorbidity Index scores. Patients in the surgery group were older than patients in the stent group. There were no differences in the number of lymph nodes harvested, positive nodes, rates of vascular and perineural invasion, or utilization of chemotherapy. Thirty-day mortality after resection was similar between groups (7.41% vs 4.41%; p > 0.05). Patients who underwent colonic stenting as a bridge to surgery had similar 10-year overall survival (40.5% vs 32.7%; p = 0.13) and 10-year disease-free survival (40.2% vs 33.8%; p = 0.26) compared with those who underwent emergency surgery. Similar results were seen on intention-to-treat analysis. LIMITATIONS: This was a small retrospective study. CONCLUSIONS: Stent insertion followed by oncologic resection is associated with similar overall survival and disease-free survival compared with emergency resection. Stent insertion as a bridge to surgery should be considered in patients presenting with malignant colorectal obstruction. See Video Abstract at http://links.lww.com/DCR/B714Los Stents Metálicos Autoexpandibles No Afectan Negativamente Los Resultados A Largo Plazo En La Obstrucción Maligna Aguda Del Colon: Un Análisis Retrospectivo. ANTECEDENTES: Los stents metálicos autoexpandibles como puente a una cirugía en la obstrucción maligna aguda del colon han ganado popularidad. Sin embargo, no se han establecido bien los resultados oncológicos a largo plazo. OBJETIVO: Investigar los resultados oncológicos a largo plazo de los pacientes sometidos a resección curativa después de la colocación de un stent colónico en comparación con la cirugía de urgencia para la obstrucción maligna aguda del colon. DISEO: Estudio retrospectivo. MBITO: Entre abril de 2002 y diciembre de 2012, se revisaron todos los pacientes que acudieron a tres centros de tercer nivel con un diagnóstico de obstrucción maligna completa del colon. Se seleccionaron para el análisis los pacientes con enfermedad distal al ángulo hepático. PACIENTES: Se incluyeron 122 pacientes que fueron operados de urgencia o a una colocación de un stent colónico con intención curativa. PROCEDIMIENTOS: Los pacientes que se sometieron a cirugía de urgencia dentro de las 24 horas posteriores a la presentación de síntomas obstructivos; se incluyeron aquellos con stents fallidos en el grupo de cirugía de urgencia. Todos los pacientes con colocación clínicamente exitosa del stent antes de la cirugía se incluyeron en el grupo de stent. PRINCIPALES VARIABLES ANALIZADAS: La sobrevida global y la sobrevida libre de enfermedad se calcularon mediante el método de Kaplan-Meier. RESULTADOS: Sesenta y cuatro pacientes fueron llevados a cirugía urgente y en 58 pacientes se colocó de un stent metálico autoexpandible. Los grupos fueron similares en relación a sexo, estadio y grado del tumor, puntuación de comorbilidad de Charlson y Charlson-Age. Los pacientes del grupo de cirugía eran mayores que los del grupo de stents. No hubo diferencias en el número de ganglios linfáticos recolectados, ganglios positivos, tasas de invasión vascular y perineural o utilización de quimioterapia. La mortalidad a los 30 días después de la resección fue similar entre los grupos (7,41% frente a 4,41%; p> 0,05). Los pacientes que se sometieron a la colocación de un stent colónico como puente a la cirugía tuvieron una sobrevida general a diez años similar (40,5% vs 32,7%; p = 0,13) y una sobrevida libre de enfermedad a diez años (40,2% vs 33,8%, respectivamente; p = 0,26) en comparación a los operados de urgencia. Se observaron resultados similares en el análisis por intención de tratamiento. LIMITACIONES: Estudio retrospectivo reducido. CONCLUSIONES: La utilización de un stent y posteriormente la resección oncológica se asocia a una sobrevida general y una sobrevida libre de enfermedad similar en comparación con la resección de urgencia. La utilización de un stent como puente a la cirugía debe considerarse en pacientes que presentan obstrucción colorrectal maligna. Consulte Video Resumen en http://links.lww.com/DCR/B714. (Traducción-Dr. Lisbeth Alarcon-Bernes).

Mammographic Variation Measures, Breast Density, and Breast Cancer Risk.

OBJECTIVE. Our previous work showed that variation measures, which represent breast architecture derived from mammograms, were significantly associated with breast cancer. For replication purposes, we examined the association of three variation measures (variation [V], which is measured in the image domain, and P1 and p1 [a normalized version of P1], which are derived from restricted regions in the Fourier domain) with breast cancer risk in an independent population. We also compared these measures to volumetric density measures (volumetric percent density [VPD] and dense volume [DV]) from a commercial product. MATERIALS AND METHODS. We examined 514 patients with breast cancer and 1377 control patients from a screening practice who were matched for age, date of examination, mammography unit, facility, and state of residence. Spearman rank-order correlation was used to evaluate the monotonic association between measures. Breast cancer associations were estimated using conditional logistic regression, after adjustment for age and body mass index. Odds ratios were calculated per SD increment in mammographic measure. RESULTS. These variation measures were strongly correlated with VPD (correlation, 0.68-0.80) but not with DV (correlation, 0.31-0.48). Similar to previous findings, all variation measures were significantly associated with breast cancer (odds ratio per SD: 1.30 [95% CI, 1.16-1.46] for V, 1.55 [95% CI, 1.35-1.77] for P1, and 1.51 [95% CI, 1.33-1.72] for p1). Associations of volumetric density measures with breast cancer were similar (odds ratio per SD: 1.54 [95% CI, 1.33-1.78] for VPD and 1.34 [95% CI, 1.20-1.50] for DV). When DV was included with each variation measure in the same model, all measures retained significance. CONCLUSION. Variation measures were significantly associated with breast cancer risk (comparable to the volumetric density measures) but were independent of the DV.

Empirically-derived synthetic populations to mitigate small sample sizes.

Limited sample sizes can lead to spurious modeling findings in biomedical research. The objective of this work is to present a new method to generate synthetic populations (SPs) from limited samples using matched case-control data (n = 180 pairs), considered as two separate limited samples. SPs were generated with multivariate kernel density estimations (KDEs) with unconstrained bandwidth matrices. We included four continuous variables and one categorical variable for each individual. Bandwidth matrices were determined with Differential Evolution (DE) optimization by covariance comparisons. Four synthetic samples (n = 180) were derived from their respective SPs. Similarity between observed samples with synthetic samples was compared assuming their empirical probability density functions (EPDFs) were similar. EPDFs were compared with the maximum mean discrepancy (MMD) test statistic based on the Kernel Two-Sample Test. To evaluate similarity within a modeling context, EPDFs derived from the Principal Component Analysis (PCA) scores and residuals were summarized with the distance to the model in X-space (DModX) as additional comparisons. Four SPs were generated from each sample. The probability of selecting a replicate when randomly constructing synthetic samples (n = 180) was infinitesimally small. MMD tests indicated that the observed sample EPDFs were similar to the respective synthetic EPDFs. For the samples, PCA scores and residuals did not deviate significantly when compared with their respective synthetic samples. The feasibility of this approach was demonstrated by producing synthetic data at the individual level, statistically similar to the observed samples. The methodology coupled KDE with DE optimization and deployed novel similarity metrics derived from PCA. This approach could be used to generate larger-sized synthetic samples. To develop this approach into a research tool for data exploration purposes, additional evaluation with increased dimensionality is required. Moreover, given a fully specified population, the degree to which individuals can be discarded while synthesizing the respective population accurately will be investigated. When these objectives are addressed, comparisons with other techniques such as bootstrapping will be required for a complete evaluation.

Combined effect of volumetric breast density and body mass index on breast cancer risk.

BACKGROUND: Breast density and body mass index (BMI) are used for breast cancer risk stratification. We evaluate whether the positive association between volumetric breast density and breast cancer risk is strengthened with increasing BMI. METHODS: The San Francisco Mammography Registry and Mayo Clinic Rochester identified 781 premenopausal and 1850 postmenopausal women with breast cancer diagnosed between 2007 and 2015 that had a screening digital mammogram at least 6 months prior to diagnosis. Up to three controls (N = 3535) were matched per case on age, race, date, mammography machine, and state. Volumetric percent density (VPD) and dense volume (DV) were measured with Volpara™. Breast cancer risk was assessed with logistic regression stratified by menopause status. Multiplicative interaction tests assessed whether the association of density measures was differential by BMI categories. RESULTS: The increased risk of breast cancer associated with VPD was strengthened with higher BMI for both premenopausal (pinteraction = 0.01) and postmenopausal (pinteraction = 0.0003) women. For BMI < 25, 25-30, and ≥ 30 kg/m2, ORs for breast cancer for a 1 SD increase in VPD were 1.24, 1.65, and 1.97 for premenopausal, and 1.20, 1.55, and 2.25 for postmenopausal women, respectively. ORs for breast cancer for a 1 SD increase in DV were 1.39, 1.33, and 1.51 for premenopausal (pinteraction = 0.58), and 1.31, 1.34, and 1.65 (pinteraction = 0.03) for postmenopausal women for BMI < 25, 25-30 and ≥ 30 kg/m2, respectively. CONCLUSIONS: The effect of volumetric percent density on breast cancer risk is strongest in overweight and obese women. These associations have clinical relevance for informing prevention strategies.

Radiologic Features of Small Pulmonary Nodules and Lung Cancer Risk in the National Lung Screening Trial: A Nested Case-Control Study.

Purpose To extract radiologic features from small pulmonary nodules (SPNs) that did not meet the original criteria for a positive screening test and identify features associated with lung cancer risk by using data and images from the National Lung Screening Trial (NLST). Materials and Methods Radiologic features in SPNs in baseline low-dose computed tomography (CT) screening studies that did not meet NLST criteria to be considered a positive screening examination were extracted. SPNs were identified for 73 incident case patients who were given a diagnosis of lung cancer at either the first or second follow-up screening study and for 157 control subjects who had undergone three consecutive negative screening studies. Multivariable logistic regression was used to assess the association between radiologic features and lung cancer risk. All statistical tests were two sided. Results Nine features were significantly different between case patients and control subjects. Backward elimination followed by bootstrap resampling identified a reduced model of highly informative radiologic features with an area under the receiver operating characteristic curve of 0.932 (95% confidence interval [CI]: 0.88, 0.96), a specificity of 92.38% (95% CI: 52.22%, 84.91%), and a sensitivity of 76.55% (95% CI: 87.50%, 95.35%) that included total emphysema score (odds ratio [OR] = 1.71; 95% CI: 1.39, 2.01), attachment to vessel (OR = 2.41; 95% CI: 0.99, 5.81), nodule location (OR = 3.25; 95% CI: 1.09, 8.55), border definition (OR = 7.56; 95% CI: 1.89, 30.8), and concavity (OR = 2.58; 95% CI: 0.89, 5.64). Conclusion A set of clinically relevant radiologic features were identified that that can be easily scored in the clinical setting and may be of use to determine lung cancer risk among participants with SPNs. © RSNA, 2017 Online supplemental material is available for this article.

Draining Setons as Definitive Management of Fistula-in-Ano.

BACKGROUND: The ideal management for fistula-in-ano would resolve the disease while preserving anal continence. OBJECTIVE: The purpose of this study was to determine the efficacy of draining seton alone in achieving resolution or significant amelioration of symptoms for patients with fistula-in-ano. DESIGN: This was a retrospective case series involving chart review and telephone interviews. A single colorectal surgeon performed surgeries between June 1, 2005, and June 30, 2014. SETTINGS: The study was conducted by a single surgeon in a large urban city. PATIENTS: Patient ≥18 years of age presenting with fistula-in-ano of cryptoglandular origin were included. MAIN OUTCOME MEASURES: Resolution of symptoms or significant symptom improvement requiring no additional surgical management and rate of recurrence were measured. RESULTS: A total of 76 patients (53 men) met the inclusion criteria. Mean age was 45 years (range, 19-73 y). The average time to seton removal was 36.6 weeks (range, 6.0-188.0 wk). Mean follow-up was 63 months (range, 7-121 mo). Fifty-seven patients (75%) were reached for telephone interview. Fifty-six patients (73.7%) had complete symptom resolution, and 14 (18.4%) had significant amelioration of symptoms with no additional surgical management required. Six (7.9%) had persistent severe symptoms. Five (7.1%) had a recurrence after seton removal. Rates of symptom resolution and recurrence were similar between patients whose setons were removed before or after 26 weeks (median time of seton removal) from the time of placement. Twenty-one patients (27.6%) required 1 or more additional operative procedures before planned seton removal to unroof a collection and/or replace the seton, and this represented the most significant risk factor for failure of resolution or improvement or recurrence (relative risk = 7.0). LIMITATIONS: This study was retrospective and represents a single surgeon experience. CONCLUSIONS: Placement of draining seton alone is a viable treatment option for definitive symptomatic management of fistula-in-ano. Because draining setons are sphincter and function preserving, their use should be considered as primary management for fistula-in-ano. See Video Abstract at http://links.lww.com/DCR/A552.

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.

Comparison of Clinical and Automated Breast Density Measurements: Implications for Risk Prediction and Supplemental Screening.

Purpose To compare the classification of breast density with two automated methods, Volpara (version 1.5.0; Matakina Technology, Wellington, New Zealand) and Quantra (version 2.0; Hologic, Bedford, Mass), with clinical Breast Imaging Reporting and Data System (BI-RADS) density classifications and to examine associations of these measures with breast cancer risk. Materials and Methods In this study, 1911 patients with breast cancer and 4170 control subjects matched for age, race, examination date, and mammography machine were evaluated. Participants underwent mammography at Mayo Clinic or one of four sites within the San Francisco Mammography Registry between 2006 and 2012 and provided informed consent or a waiver for research, in compliance with HIPAA regulations and institutional review board approval. Digital mammograms were retrieved a mean of 2.1 years (range, 6 months to 6 years) before cancer diagnosis, with the corresponding clinical BI-RADS density classifications, and Volpara and Quantra density estimates were generated. Agreement was assessed with weighted κ statistics among control subjects. Breast cancer associations were evaluated with conditional logistic regression, adjusted for age and body mass index. Odds ratios, C statistics, and 95% confidence intervals (CIs) were estimated. Results Agreement between clinical BI-RADS density classifications and Volpara and Quantra BI-RADS estimates was moderate, with κ values of 0.57 (95% CI: 0.55, 0.59) and 0.46 (95% CI: 0.44, 0.47), respectively. Differences of up to 14% in dense tissue classification were found, with Volpara classifying 51% of women as having dense breasts, Quantra classifying 37%, and clinical BI-RADS assessment used to classify 43%. Clinical and automated measures showed similar breast cancer associations; odds ratios for extremely dense breasts versus scattered fibroglandular densities were 1.8 (95% CI: 1.5, 2.2), 1.9 (95% CI: 1.5, 2.5), and 2.3 (95% CI: 1.9, 2.8) for Volpara, Quantra, and BI-RADS classifications, respectively. Clinical BI-RADS assessment showed better discrimination of case status (C = 0.60; 95% CI: 0.58, 0.61) than did Volpara (C = 0.58; 95% CI: 0.56, 0.59) and Quantra (C = 0.56; 95% CI: 0.54, 0.58) BI-RADS classifications. Conclusion Automated and clinical assessments of breast density are similarly associated with breast cancer risk but differ up to 14% in the classification of women with dense breasts. This could have substantial effects on clinical practice patterns. (©) RSNA, 2015 Online supplemental material is available for this article.

Colonic perforation with intraluminal stents and bevacizumab in advanced colorectal cancer: retrospective case series and literature review.

BACKGROUND: Self-expanding metal stents (SEMS) are increasingly used in the treatment of malignant large bowel obstruction in the setting of inoperable colorectal cancer. Perforation is a well-known complication associated with these devices. The addition of the vascular endothelial growth factor inhibitor bevacizumab is suspected to increase the rate, but the extent of the increase is not known. METHODS: We retrospectively reviewed the records of patients receiving SEMS in tertiary hospitals in Calgary, Alta., between October 2001 and January 2012. RESULTS: We reviewed the records of 87 patients with inoperable colorectal cancer who received SEMS during our study period. Nine perforations occurred in total: 4 of 30 (13%) patients who received no chemotherapy, 3 of 47 (6%) who received chemotherapy but no bevacizumab, and 2 of 10 (20%) who received chemotherapy and bevacizumab. These two patients received bevacizumab with FOLFIRI after SEMS placement, and they had peritoneal disease. CONCLUSION: Our case series and other studies suggest that bevacizumab may increase the risk of colonic perforation in the setting of SEMS. Caution should be used when combining these therapies.

CONTEXTE: Les endoprothèses métalliques auto-expansibles (EMAE) sont de plus en plus utilisées pour le traitement de l'obstruction colique d'origine maligne dans le contexte d'un cancer colorectal inopérable. La perforation est une complication bien connue de ces dispositifs et on soupçonne que l'ajout de l'inhibiteur du facteur de croissance de l'endothélium vasculaire bevacizumab en accroît le taux, mais l'ampleur de cette augmentation est inconnue. MÉTHODES: Nous avons passé en revue de manière rétrospective les dossiers de patients traités par EMAE dans des hôpitaux de soins tertiaires de Calgary, en Alberta, entre octobre 2001 et janvier 2012. RÉSULTANTS: Nous avons examiné les dossiers de 87 patients atteints d'un cancer colorectal inopérable ayant reçu une EMAE durant la période de notre étude. En tout, 9 perforations ont été enregistrées, soit chez 4 patients sur 30 (13 %) qui n'avaient pas reçu de chimiothérapie, chez 3 patients sur 47 (6 %) traités par chimiothérapie sans bevacizumab et chez 2 patients sur 10 (20 %) ayant reçu une chimiothérapie et du bevacizumab. Ces 2 patients avaient été traités par bevacizumab avec FOLFIRI après la pose de l'EMAE et présentaient une atteinte péritonéale. CONCLUSION: Selon notre série de cas et d'autres études, le bevacizumab pourrait accroître le risque de perforation du côlon dans le contexte de l'EMAE. La prudence s'impose lorsqu'on utilise ces traitements concomitamment.

Radiation-induced autophagy potentiates immunotherapy of cancer via up-regulation of mannose 6-phosphate receptor on tumor cells in mice.

There is a significant body of evidence demonstrating that radiation therapy (XRT) enhances the effect of immune therapy. However, the precise mechanisms by which XRT potentiates the immunotherapy of cancer remain elusive. Here, we report that XRT potentiates the effect of immune therapy via induction of autophagy and resultant trafficking of mannose-6-phopsphate receptor (MPR) to the cell surface. Irradiation of different tumor cells caused substantial up-regulation of MPR on the cell surface in vitro and in vivo. Down-regulation of MPR in tumor cells with shRNA completely abrogated the combined effect of XRT and immunotherapy (CTLA4 antibody) in B16F10-bearing mice without changes in the tumor-specific responses of T cells. Radiation-induced MPR up-regulation was the result of redistribution of the receptor to the cell surface. This effect was caused by autophagy with redirection of MPR to autophagosomes in a clathrin-dependent manner. In autophagosomes, MPR lost its natural ligands, which resulted in subsequent trafficking of empty receptor(s) back to the surface. Together, our data demonstrated a novel mechanism by which XRT can enhance the effect of immunotherapy and the molecular mechanism of this process.

Reproductive Factors Related to Childbearing and a Novel Automated Mammographic Measure, V.

BACKGROUND: We investigated the associations between several reproductive factors related to childbearing and the variation (V) measure (a novel, objective, single summary measure of breast image intensity) by menopausal status. METHODS: Our study included 3,814 cancer-free women within the Nurses' Health Study (NHS) and NHSII cohorts. The data on reproductive variables and covariates were obtained from biennial questionnaires closest to the mammogram date. V-measures were obtained from mammographic images using a previously developed algorithm capturing the standard deviation of pixel values. We used multivariate linear regression to examine the associations of parity, age at first birth, time between menarche and first birth, time since last pregnancy, and lifetime breastfeeding duration with V-measure, adjusting for breast cancer risk factors, including the percentage of mammographic density (PMD). We further examined whether these associations were statistically accounted for (mediated) by PMD. RESULTS: Among premenopausal women, none of the reproductive factors were associated with V. Among postmenopausal women, inverse associations of parity and positive associations of age at first birth with V were mediated by PMD (percent mediated: nulliparity: 66.7%, P < 0.0001; parity: 50.5%, P < 0.01; age at first birth 76.1%, P < 0.001) and were no longer significant in PMD-adjusted models. Lifetime duration of breastfeeding was positively associated with V [>36 vs. 0 ≤1 months ß = 0.29; 95% confidence interval (CI) 0.07; 0.52, Ptrend < 0.01], independent of PMD. CONCLUSIONS: Parity, age at first birth, and breastfeeding were associated with postmenopausal V. IMPACT: This study highlights associations of reproductive factors with mammographic image intensity.

Comparison of percent density from raw and processed full-field digital mammography data.

INTRODUCTION: Mammographic density has been established as a strong risk factor for breast cancer, primarily using digitized film mammograms. Full-field digital mammography (FFDM) is replacing film mammography, has different properties than film, and provides both raw and processed clinical display representation images. We evaluated and compared FFDM raw and processed breast density measures and their associations with breast cancer. METHODS: A case-control study of 180 cases and 180 controls matched by age, postmenopausal hormone use, and screening history was conducted. Mammograms were acquired from a General Electric Senographe 2000D FFDM unit. Percent density (PD) was assessed for each FFDM representation using the operator-assisted Cumulus method. Reproducibility within image type (n = 80) was assessed using Lin's concordance correlation coefficient (rc). Correlation of PD between image representations (n = 360) was evaluated using Pearson's correlation coefficient (r) on the continuous measures and the weighted kappa statistic (κ) for quartiles. Conditional logistic regression was used to estimate odds ratios (ORs) for the PD and breast cancer associations for both image representations with 95% confidence intervals. The area under the receiver operating characteristic curve (AUC) was used to assess the discriminatory accuracy. RESULTS: Percent density from the two representations provided similar intra-reader reproducibility (rc= 0.92 for raw and rc= 0.87 for processed images) and was correlated (r = 0.82 and κ = 0.64). When controlling for body mass index, the associations of quartiles of PD with breast cancer and discriminatory accuracy were similar for the raw (OR: 1.0 (ref.), 2.6 (1.2 to 5.4), 3.1 (1.4 to 6.8), 4.7 (2.1 to 10.6); AUC = 0.63) and processed representations (OR: 1.0 (ref.), 2.2 (1.1 to 4.1), 2.2 (1.1 to 4.4), 3.1 (1.5 to 6.6); AUC = 0.64). CONCLUSIONS: Percent density measured with an operator-assisted method from raw and processed FFDM images is reproducible and correlated. Both percent density measures provide similar associations with breast cancer.

A comparison of calibration data from full field digital mammography units for breast density measurements.

BACKGROUND: Breast density is a significant breast cancer risk factor measured from mammograms. The most appropriate method for measuring breast density for risk applications is still under investigation. Calibration standardizes mammograms to account for acquisition technique differences prior to making breast density measurements. We evaluated whether a calibration methodology developed for an indirect x-ray conversion full field digital mammography (FFDM) technology applies to direct x-ray conversion FFDM systems. METHODS: Breast tissue equivalent (BTE) phantom images were used to establish calibration datasets for three similar direct x-ray conversion FFDM systems. The calibration dataset for each unit is a function of the target/filter combination, x-ray tube voltage, current × time (mAs), phantom height, and two detector fields of view (FOVs). Methods were investigated to reduce the amount of calibration data by restricting the height, mAs, and FOV sampling. Calibration accuracy was evaluated with mixture phantoms. We also compared both intra- and inter-system calibration characteristics and accuracy. RESULTS: Calibration methods developed previously apply to direct x-ray conversion systems with modification. Calibration accuracy was largely within the acceptable range of ± 4 standardized units from the ideal value over the entire acquisition parameter space for the direct conversion units. Acceptable calibration accuracy was maintained with a cubic-spline height interpolation, representing a modification to previous work. Calibration data is unit specific, can be acquired with the large FOV, and requires a minimum of one reference mAs sample. The mAs sampling, calibration accuracy, and the necessity for machine specific calibration data are common characteristics and in agreement with our previous work. CONCLUSION: The generality of our calibration approach was established under ideal conditions. Evaluation with patient data using breast cancer status as the endpoint is required to demonstrate that the approach produces a breast density measure associated with breast cancer.

Breast Density Analysis Using Digital Breast Tomosynthesis.

We evaluated an automated percentage of breast density (BD) technique (PDa) with digital breast tomosynthesis (DBT) data. The approach is based on the wavelet expansion followed by analyzing signal dependent noise. Several measures were investigated as risk factors: normalized volumetric; total dense volume; average of the DBT slices (slice-mean); a two-dimensional (2D) metric applied to the synthetic images; and the mean and standard deviations of the pixel values. Volumetric measures were derived theoretically, and PDa was modeled as a function of compressed breast thickness. An alternative method for constructing synthetic 2D mammograms was investigated using the volume results. A matched case-control study (n = 426 pairs) was analyzed. Conditional logistic regression modeling, controlling body mass index and ethnicity, was used to estimate odds ratios (ORs) for each measure with 95% confidence intervals provided parenthetically. There were several significant findings: volumetric measure [OR = 1.43 (1.18, 1.72)], which produced an identical OR as the slice-mean measure as predicted; [OR =1.44 (1.18, 1.75)] when applied to the synthetic images; and mean of the pixel values (volume or 2D synthetic) [ORs ~ 1.31 (1.09, 1.57)]. PDa was modeled as 2nd degree polynomial (concave-down): its maximum value occurred at 0.41×(compressed breast thickness), which was similar across case-control groups, and was significant from this position [OR = 1.47 (1.21, 1.78)]. A standardized 2D synthetic image was produced, where each pixel value represents the percentage of BD above its location. The significant findings indicate the validity of the technique. Derivations supported by empirical analyses produced a new synthetic 2D standardized image technique. Ancillary to the objectives, the results provide evidence for understanding the percentage of BD measure applied to 2D mammograms. Notwithstanding the findings, the study design provides a template for investigating other measures such as texture.

Breast density analysis of digital breast tomosynthesis.

Mammography shifted to digital breast tomosynthesis (DBT) in the US. An automated percentage of breast density (PD) technique designed for two-dimensional (2D) applications was evaluated with DBT using several breast cancer risk prediction measures: normalized-volumetric; dense volume; applied to the volume slices and averaged (slice-mean); and applied to synthetic 2D images. Volumetric measures were derived theoretically. PD was modeled as a function of compressed breast thickness (CBT). The mean and standard deviation of the pixel values were investigated. A matched case-control (CC) study (n = 426 pairs) was evaluated. Odd ratios (ORs) were estimated with 95% confidence intervals. ORs were significant for PD: identical for volumetric and slice-mean measures [OR = 1.43 (1.18, 1.72)] and [OR = 1.44 (1.18, 1.75)] for synthetic images. A 2nd degree polynomial (concave-down) was used to model PD as a function of CBT: location of the maximum PD value was similar across CCs, occurring at 0.41 × CBT, and PD was significant [OR = 1.47 (1.21, 1.78)]. The means from the volume and synthetic images were also significant [ORs ~ 1.31 (1.09, 1.57)]. An alternative standardized 2D synthetic image was constructed, where each pixel value represents the percentage of breast density above its location. Several measures were significant and an alternative method for constructing a standardized 2D synthetic image was produced.

Techniques to produce and evaluate realistic multivariate synthetic data.

Data modeling requires a sufficient sample size for reproducibility. A small sample size can inhibit model evaluation. A synthetic data generation technique addressing this small sample size problem is evaluated: from the space of arbitrarily distributed samples, a subgroup (class) has a latent multivariate normal characteristic; synthetic data can be generated from this class with univariate kernel density estimation (KDE); and synthetic samples are statistically like their respective samples. Three samples (n = 667) were investigated with 10 input variables (X). KDE was used to augment the sample size in X. Maps produced univariate normal variables in Y. Principal component analysis in Y produced uncorrelated variables in T, where the probability density functions were approximated as normal and characterized; synthetic data was generated with normally distributed univariate random variables in T. Reversing each step produced synthetic data in Y and X. All samples were approximately multivariate normal in Y, permitting the generation of synthetic data. Probability density function and covariance comparisons showed similarity between samples and synthetic samples. A class of samples has a latent normal characteristic. For such samples, this approach offers a solution to the small sample size problem. Further studies are required to understand this latent class.

The influence of mammogram acquisition on the mammographic density and breast cancer association in the Mayo Mammography Health Study cohort.

INTRODUCTION: Mammographic density is a strong risk factor for breast cancer. Image acquisition technique varies across mammograms to limit radiation and produce a clinically useful image. We examined whether acquisition technique parameters at the time of mammography were associated with mammographic density and whether the acquisition parameters confounded the density and breast cancer association. METHODS: We examined this question within the Mayo Mammography Health Study (MMHS) cohort, comprised of 19,924 women (51.2% of eligible) seen in the Mayo Clinic mammography screening practice from 2003 to 2006. A case-cohort design, comprising 318 incident breast cancers diagnosed through December 2009 and a random subcohort of 2,259, was used to examine potential confounding of mammogram acquisition technique parameters (x-ray tube voltage peak (kVp), milliampere-seconds (mAs), thickness and compression force) on the density and breast cancer association. The Breast Imaging Reporting and Data System four-category tissue composition measure (BI-RADS) and percent density (PD) (Cumulus program) were estimated from screen-film mammograms at time of enrollment. Spearman correlation coefficients (r) and means (standard deviations) were used to examine the relationship of density measures with acquisition parameters. Hazard ratios (HR) and C-statistics were estimated using Cox proportional hazards regression, adjusting for age, menopausal status, body mass index and postmenopausal hormones. A change in the HR of at least 15% indicated confounding. RESULTS: Adjusted PD and BI-RADS density were associated with breast cancer (p-trends < 0.001), with a 3 to 4-fold increased risk in the extremely dense vs. fatty BI-RADS categories (HR: 3.0, 95% CI, 1.7 - 5.1) and the ≥ 25% vs. ≤ 5% PD categories (HR: 3.8, 95% CI, 2.5 - 5.9). Of the acquisition parameters, kVp was not correlated with PD (r = 0.04, p = 0.07). Although thickness (r = -0.27, p < 0.001), compression force (r = -0.16, p < 0.001), and mAs (r = -0.06, p = 0.008) were inversely correlated with PD, they did not confound the PD or BI-RADS associations with breast cancer and their inclusion did not improve discriminatory accuracy. Results were similar for associations of dense and non-dense area with breast cancer. CONCLUSIONS: We confirmed a strong association between mammographic density and breast cancer risk that was not confounded by mammogram acquisition technique.