Citations

Abstract Introduction: Defining the histologic correlates of mammographic breast density (MD) may provide insights into why elevated MD is related to increased breast cancer risk. Studies suggest that reduced terminal ductal lobular (TDLU) involution is associated with elevated MD, and both are independent breast cancer risk factors among women who have undergone a biopsy for benign breast disease (BBD). Prior digital histologic analyses of normal breast tissues revealed epithelial nuclear density (END) and TDLU involution are correlated. Accordingly, we examined associations of END with TDLU involution and MD in clinical biopsies. Methods: We analyzed 262 image-guided breast biopsies diagnosed as BBD from 224 women. TDLU involution was visually assessed as TDLU count/mm2 and TDLU span (inversely related to level of involution) in background normal tissue, evaluated using digitized images. The Genie Classifier (Aperio) was applied to images to estimate nuclei count per unit epithelial area, (END). Single X-ray Absorptiometry of pre-biopsy craniocaudal digital mammograms was applied to measure global MD (percent fibroglandular volume (%FGV)). Analysis of covariance, adjusted for age and body mass index, examined mean END differences across tertiles of TDLU/MD measures. Analyses were conducted at the biopsy level using SAS PROC GENMOD to account for within-woman correlations. All tests were two-tailed. Results: Overall, 67% of BBD biopsies were proliferative. Higher END was observed among proliferative than non-proliferative BBD (median END: 10,187 vs. 9,953 respectively; p=0.04). Among all women, END significantly increased with increasing tertiles of TDLU measures (p-trends: TDLU count/100mm2=0.0001, TDLU span=0.046). Whereas TDLU metrics were positively associated with %FGV, no relationship was observed between END and %FGV. In analyses stratified by BBD severity, however, END and %FGV were positively associated among women with non-proliferative disease (p-trend=0.04), findings not observed with proliferative disease. Conclusions: Automated END and visually assessed TDLU involution metrics were positively associated with each other and with MD. However, associations were diluted for proliferative lesions, suggesting that applying automated digital pathology tools to unsegmented digital images of whole sections of BBD biopsies does not demonstrate the same associations with MD as visual assessment of TDLU involution. Citation Format: Maeve Mullooly, Samantha Puvanesarajah, Shaoqi Fan, Ruth M. Pfeiffer, Linnea Olsson, Manila Hada, Erin L. Kirk, Pamela M. Vacek, Donald L. Weaver, John A. Shepherd, Amir P. Mahmoudzadeh, Jeff Wang, Stephen M. Hewitt, Sally D. Herschorn, Mark E. Sherman, Melissa A. Troester, Gretchen L. Gierach. Utilizing digital pathology to understand breast epithelial characteristics of benign breast disease among women undergoing diagnostic image-guided breast biopsy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3260.

Abstract Purpose: Volumetric breast density and body mass index (BMI) are increasingly used for breast cancer risk stratification. We examine if the effect of volumetric breast density on breast cancer risk increases with increasing BMI. Methods: Participants were from two case-control studies within mammography practices, the San Francisco Mammography Registry and the Mayo Clinic Rochester, Breast Screening Practice. Breast cancers were included if diagnosed between January 2007 and 2015 and with a screening full-field digital mammogram at least 6 months prior to diagnosis; the earliest mammogram within 5 years of diagnosis was selected. Up to three controls were matched to each case on age, race, date, mammography machine, and state of residence. Volumetric percent density (VPD), dense volume (DV) and non-dense volume (NDV) were measured using VolparaTM software. Breast cancer risk was assessed using logistic regression stratified by menopause status and adjusted for matching factors, family history of breast cancer, parity/age at first birth, and postmenopausal hormone therapy. Models for DV were additionally adjusted for NDV, and NDV models for DV. Multiplicative interactions were fit between BMI categories [<25 (underweight), 25-30 (normal weight) and >30 (overweight/obese) kg/m2] and VPD, DV, and NDV, and trend tests assessed for increasing odds ratios (OR) with increasing BMI. Results: A total of 781 premenopausal and 1850 postmenopausal breast cancers and 3535 controls were included in the analysis. Median age of premenopausal women was 45 years (IQR: 6.1) and 63.3 years (IQR: 14) for postmenopausal women. Cases vs. controls had greater VPD and DV for both premenopausal (VPD: 14.9% vs. 12.0%, DV: 74.1 cm3 vs. 64.4 cm3) and postmenopausal women (VPD: 6.8% vs. 6.1%, DV: 53.4 cm3 vs. 48.0 cm3)(all p's<0.001). Trends between increasing BMI and VPD were evident for both pre (ptrend=0.0007) and postmenopausal (ptrend=0.0005) women. Among premenopausal women, the odds ratio (OR) for breast cancer associated with a 10% increase in VPD was of 1.39, 2.19 and 2.88 for BMI <25, 25-30 and >30 kg/m2 (p-trend=0.0007), respectively. For DV, OR's were 1.39, 1.33 and 1.51 for a 1 SD increase in DV, respectively, though the interaction with DV was not significant (ptrend=0.68). Among postmenopausal women, a 10% increase in VPD was associated with OR's of 1.35, 2.03, 3.6 for BMI <25, 25-29, >30-kg/m2 (ptrend =0.0001), respectively, and 1.31, 1.34 and 1.65 for a 1 SD increase in DV (ptrend =0.01), respectively. Associations between NDV and breast cancer risk did not differ by BMI category for premenopausal (ptrend =0.52) or postmenopausal (ptrend =0.07) women. Conclusions: The effect of VPD on breast cancer risk is strongest in overweight/obese women. As volumetric breast density and BMI are commonly used in clinical risk stratification, these differences in risk have high clinical relevance for informing prevention decisions. Citation Format: Natalie J. Engmann, Christopher G. Scott, Matthew R. Jensen, Stacey J. Winham, Lin Ma, Kathleen R. Brandt, Amir Mahmoudzadeh, Serghei Malkov, Dana Whaley, Carrie Hruska, Fang Fang Wu, Diana L. Miglioretti, Aaron D. Norman, John Heine, John Shepherd, Vernon S. Pankratz, Celine M. Vachon, Karla Kerlikowske. Overweight and obese women with high volumetric breast density at high breast cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3226.

In studies on six experienced subjects lying supine, cardiac output and oxygen content of femoral venous blood were measured with the subject at rest, during the increase in muscle blood flow caused by intravenous infusion of epinephrine, during mild leg exercise, and during identical exercise combined with an infusion. The oxygen content of the blood from the exercising limb was much higher (average, 50%) during an infusion than when no infusion was given (average, 32%). The mean increase in cardiac output during the combined maneuver (8.2 liters/min) almost equaled the sum of the increases during the separate infusion (3.7 liters) and during exercise (4.7 liters). All individual studies showed approximately this same result. Thus, the additional blood supplied to the leg muscles by the infusion did not appear to be used for metabolic purposes during exercise. cardiac output; muscle blood flow Submitted on March 22, 1963

Normal subjects have been studied to assess the response of the capacitance vessels in the forearm during supine leg exercise. Measurements were made of changes in forearm volume (strain-gauge and water-filled plethysmographs) at a given pressure in the large forearm veins, of changes in pressure in the forearm veins with the circulation to the forearm arrested and in “isolated” vein segments. The results were consistent and demonstrated that exercise with a work load of 270–810 kg/min caused constriction of forearm capacitance vessels via the sympathetic nerves proportional to the severity of the exercise. Venoconstriction also occurred in the hand, and in the calf during arm exercise. Local exercise of the forearm muscles during supine leg exercise, which increased forearm blood flow by dilating the resistance vessels, did not prevent the increase in venous tone in the forearm. Thus a reflex increase in tone in the limb veins, both in the exercising and in the nonexercising parts, contributes to the cardiovascular adaptation to exercise. venoconstriction in exercising and nonexercising limbs; reflex venoconstriction with exercise graded to severity of work; reflex venoconstriction with exercise mediated through sympathetic nerves Submitted on June 15, 1964

Changes in cardiac output, stroke volume, and systemic blood pressure have been correlated with changes in muscle blood flow during the periods of initial transient and subsequent sustamed vasodilatation during intravenous infusion of epinephrine. In the initial phase blood pressure decreased slightly; forearm blood flow increased by 308%, cardiac output by 50%, and stroke volume by 10%. During the sustained phase the systolic blood pressure increased; corresponding increases for the other measurements were 87, 47, and 25%, respectively. The lack of correlation between these changes in cardiac output and forearm blood flow suggests that in the transient phase vasodilatation does not occur simultaneously in all muscle groups. Stroke volume makes a greater contribution to the increased output during the sustained phase. Submitted on May 29, 1961

Cardiac output was measured simultaneously with blood flow in hand and forearm in eight healthy subjects before and during body heating. The heating was carried out by immersing the feet and legs in water at 44 C. and wrapping the body with blankets. After 50 min of heating the oral temperature had risen to between 99.5 and 100.8 F. The cardiac output had increased by 1.9—4.5 (mean 3.3) liters/min, mainly because of an increase in heart rate. The blood flow through the fingers increased rapidly to reach maximal values soon after heating started, whereas the forearm blood flow, like the cardiac output, increased gradually throughout the heating period. Since the increase in limb blood flow is confined to the skin vessels and since there is no evidence that flow to the internal organs is increased, the total increase in skin flow amounts on the average to 1.8 liters/m2/min. Submitted on June 2, 1961

Dilution curves were obtained by sampling from the aortic root or a carotid artery after injection of indicator dye into the pulmonary artery in five dogs at rest and during exercise. On four occasions a common sampling system was used; curves were recorded simultaneously and in parallel from a cuvette oximeter assembly with a slow dynamic response and from a phototube densitometer with a fast response. In the fifth study, separate slow and fast sampling systems were used interchangeably with the two detecting instruments. Values for cardiac output were similar with the two instruments; maximal divergence for any single observation was 9% from the line of identity. The aortic root is a favorable sampling site for such a comparison, since extrapolation of the dilution curves is usually unnecessary. Under these conditions measurement of cardiac output was not influenced by the dynamic response characteristics of the sampling-detecting-recording system. When mean transit times of the respective curves were corrected for instrumental delay, there was also satisfactory agreement in values for “central” blood volume. However, since the time correction for the densitometer is relatively small, it is the preferable instrument for this measurement. Submitted on October 24, 1960

With the use of a strain-gauge plethysmograph, the effect of a brief (0.3 sec) contraction of the forearm muscles on forearm blood flow has been studied in eight healthy adults. An increase in flow due to dilatation of the muscle vessels could be detected within a second after the completion of the contraction. This increase was proportional to the strength of the contraction. The blood flow was maximal immediately and decreased rapidly. A second contraction of the same magnitude made during the period of increased flow caused an additional increase in flow. The maximal increase in flow caused by a strong brief contraction was only about 25% of that recorded after strong repeated rhythmic contractions or a sustained contraction. Cervical sympathectomy did not change these findings, indicating the local nature of the response. Since breathing oxygen failed to reduce the dilatation for a given strength of contraction, it is unlikely that oxygen lack was the stimulus for vasodilatation. The oxygen saturation of blood that drained the muscles could not be determined accurately immediately after contraction because at this time, muscle venous blood was contaminated by venous blood from the skin. exercise-induced vasodilatation; local mechanism of vasodilatation; venous O2 saturation during muscle contraction; brachial arterial pressure during vasodilatation; speed of muscle vasodilatation Submitted on May 8, 1963

Ten consecutive time trials were run at 2-day intervals by six racing greyhounds over a 5/16-mile track. Cardiac denervation was then performed on four dogs, and a sham operation that included removal of the pericardium was performed on two dogs. After cardiac denervation, one dog died and another was rejected from the study because of a massive intrathoracic hemorrhage. The time trials were repeated with the addition of telemetry of the heart rate in the four survivors. There was no significant difference between mean preoperative and postoperative race times in the control group. The mean postoperative running speeds of 33.6 and 33.3 mph in the denervated group, although representing a significant slowing of 1.1 and of 2.1 mph, respectively, from preoperative values, indicate the adequate manner in which the denervated heart meets the circulatory demands of maximal running effort. cardiac output; heart rate and exercise Submitted on March 11, 1964