Citations

BACKGROUNDWomen with atypical hyperplasia (AH) on breast biopsy have a substantially increased risk of breast cancer (BC). Here the BC risk for the extent and subtype of AH is reported for 2 separate cohorts.METHODSAll samples containing AH were included from 2 cohorts of women with benign breast disease (Mayo Clinic and Nashville). Histology review quantified the number of foci of atypical ductal hyperplasia (ADH) and atypical lobular hyperplasia (ALH). The BC risk was stratified for the number of AH foci within AH subtypes.RESULTSThe study included 708 Mayo AH subjects and 466 Nashville AH subjects. In the Mayo cohort, an increasing number of foci of AH was associated with a significant increase in the risk of BC both for ADH (relative risks of 2.61, 5.21, and 6.36 for 1, 2, and ≥3 foci, respectively; P for linear trend = .006) and for ALH (relative risks of 2.56, 3.50, and 6.79 for 1, 2, and ≥3 foci, respectively; P for linear trend = .001). In the Nashville cohort, the relative risks of BC for ADH were 2.70, 5.17, and 15.06 for 1, 2, and ≥3 foci, respectively (P for linear trend < .001); for ALH, the relative risks also increased but not significantly (2.61, 3.48, and 4.02, respectively; P = .148). When the Mayo and Nashville samples were combined, the risk increased significantly for 1, 2, and ≥3 foci: the relative risks were 2.65, 5.19, and 8.94, respectively, for ADH (P < .001) and 2.58, 3.49, and 4.97, respectively, for ALH (P = .001).CONCLUSIONSIn 2 independent cohort studies of benign breast disease, the extent of atypia stratified the long‐term BC risk for ADH and ALH. Cancer 2016;122:2971‐2978. © 2016 American Cancer Society.

AbstractBackgroundNausea and vomiting are classic symptoms of gastroparesis. It remains unclear if characteristics of nausea and vomiting are similar in different etiologies of gastroparesis. The aims of this article were as follows: to describe characteristics of nausea and vomiting in patients with gastroparesis and to determine if there are differences in nausea and vomiting in diabetic (DG) and idiopathic gastroparesis (IG).MethodsGastroparetic patients enrolling in the NIDDK Gastroparesis Registry underwent assessment with history and questionnaires assessing symptoms, quality of life, and a questionnaire characterizing nausea and vomiting.Key ResultsOf 159 gastroparesis patients (107 IG, 52 DG), 96% experienced nausea, whereas 65% experienced vomiting. Nausea was predominant symptom in 28% and vomiting was predominant in 4%. Nausea was severe or very severe in 41%. PAGI‐SYM nausea/vomiting subscore was greater with increased vomiting severity, but not nausea severity in DG than IG. Nausea was related to meals in 71%; lasting most of the day in 41%. Increasing nausea severity was related to decreased quality of life. Nausea often preceded vomiting in 82% of patients and vomiting often relieved nausea in 30%. Vomiting was more common in DG (81%) compared to IG (57%; p = 0.004). Diabetic patients more often had vomiting in the morning before eating, during the night, and when not eating.Conclusions & InferencesNausea is present in essentially all patients with gastroparesis irrespective of cause and associated with decreased quality of life. In contrast, vomiting was more prevalent, more severe, and occurred more often in DG than IG. Thus, characteristics of vomiting differ in IG vs DG.

Objective The objective of this study was the determination of the role of calcitonin gene-related peptide (CGRP) in the induction of medication overuse headache (MOH)-related migraine in an injury-free preclinical model. Methods Rats were primed by a 7-day period of exposure to acute migraine therapies including sumatriptan and morphine. After an additional 14-day drug-free period, rats were exposed to putative migraine triggers including bright light stress (BLS) or nitric oxide (NO) donor in the presence or absence of TEV48125, a fully humanized CGRP antibody. Cutaneous allodynia (CA) was used as an outcome measure and CGRP blood and cerebrospinal fluid (CSF) levels were measured. Results BLS and NO donor challenge evoked delayed, long-lasting CA selectively in rats that were previously treated with sumatriptan or morphine. BLS produced a significant increase in CGRP in the plasma, but not CSF, in animals that were previously exposed to sumatriptan compared to saline controls. TEV48125 did not modify baseline tactile thresholds or produce behavioral side effects, but significantly inhibited both BLS- and NO donor-induced CA in animals that were previously primed with sumatriptan or morphine; an isotype control protein that does not bind CGRP had no effect. Interpretation These data suggest that acute migraine medications may promote MOH in susceptible individuals through CGRP-dependent mechanisms and that anti-CGRP antibodies may be a useful clinical strategy for the treatment of MOH.

Although HER2‐positive breast cancers demonstrate a propensity for central nervous system (CNS) metastasis, it is unknown whether other HER2‐positive tumors, including adenocarcinomas of the esophagus/gastroesophageal junction (EAC), share this characteristic. Insight into this association may inform the development of HER2‐targeted therapies that penetrate the blood‐brain barrier. We examined HER2 overexpression and gene amplification in 708 patients with EAC who underwent curative‐intent surgery during a time period (1980–1997) when no patient received HER2‐targeted therapy. We identified patients whose site of first cancer recurrence was CNS and those who had a CNS relapse at any time. After a median follow‐up of 61.2 months, 3.4% (24/708) of patients developed CNS relapse (all involved the brain). Patients with HER2‐positive (vs ‐negative) primary tumors showed a higher 5‐year cumulative incidence of CNS relapse as first recurrence (5.8% vs. 1.2%; p = 0.0058) and at any time (8.3% vs. 2.4%; p = 0.0062). In a multivariable model that included covariates previously associated with HER2 or with CNS relapse in breast cancer, HER2 positivity was the only variable that was statistically significantly associated with shorter time to CNS relapse as first recurrence (p = 0.0026) or at any time (hazard ratio 4.3 [95% confidence interval 1.8 to 10.3]; p = 0.001). These are the first data in a non‐breast cancer to demonstrate an association between HER2 positivity and higher CNS relapse risk after surgery, and suggest that HER2‐positive EACs have a predilection for CNS metastases.

Abstract Background Women with benign breast disease (BBD) have an increased risk for breast cancer (BC). Almost 30% of all BCs develop in women with prior BBD. Information about the features of the expected BCs after BBD would enable individualized surveillance and prevention strategies for these women. We sought to characterize BCs developing in a large cohort of women with BBD. Methods Our cohort includes 13,485 women who underwent breast biopsy for mammographic or palpable concern between 1967-2001. Biopsy slides were reviewed and classified as nonproliferative (NP), proliferative disease without atypia (PDWA), or atypical hyperplasia (AH). BCs were identified by follow-up questionnaires, medical records, and Tumor Registry data. BC tissues were obtained and reviewed. Results With a median follow-up of 15.8 years, 1273 women developed BC. Most BCs were invasive (81%), among which 61% were ductal, 13% mixed ductal/lobular, and 14% lobular. Two thirds were intermediate or high-grade, and 29% were node positive. Cancer characteristics were similar across the three histologic categories of BBD, with similar frequency of DCIS and invasive disease, tumor size, time to invasive BC, histologic type of BC, nodal positivity and HER2 positivity. Women with AH had a higher frequency of ER+ BC (91%) vs women with PD (80%) or NP (85%), p=0.02. Conclusion A substantial proportion of all BCs develop in women with prior BBD. We show that the majority of BCs after BBD are invasive tumors of ductal type, with a substantial proportion node positive. 84% of cancers were ER-positive. Chemoprevention should be strongly encouraged in higher-risk women with BBD. Citation Format: Visscher DW, Frost MH, Hartmanan LC, Frank RD, Vierkant RA, McCullough AE, Winham SJ, Vachon C, Ghosh K, Brandt KR, Farrell AM, Tarabishy Y, Hieken TJ, Haddad TC, Kraft RA, Radisky DC, Degnim AC. Clinicopathologic features of breast cancers that develop in women with previous benign breast disease. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-10-19.

Abstract Background Women with atypical hyperplasia (AH) are at an approximately four-fold increased risk of subsequent breast cancer (BC). Mammographic breast density (MBD) is a well-established risk factor for BC, but its contribution to BC risk in women with AH remains an open question. We previously reported no association between MBD [measured by Wolfe's parenchymal pattern (PP)] and BC risk in a cohort of 147 women with AH. Here, we present results in an expanded cohort of 459 women diagnosed with AH between 1985 and 2001. Methods The Mayo Clinic Benign Breast Disease Cohort includes 13,485 women who had benign core and/or excisional biopsy 1967-2001. Biopsy tissues were reviewed by our study pathologist to determine presence of AH. MBD was available from clinical records starting in 1985, coded as PP (the standard for 1985-1996) or BI-RADS (1997-2001) density criteria. The original four-level PP (N1-fatty, P1-ductal prominence &lt;25% of breast, P2-ductal prominence &gt;25%, DY-dysplasia) and BI-RADS (fatty, scattered densities, heterogeneously dense, extremely dense) measures were re-categorized as low, moderate or high MBD by combining the middle two categories for each. BC events and clinical information were obtained by questionnaires, medical records and the Mayo Clinic Tumor Registry. Women were followed from benign biopsy to date of BC, death or last contact. Standardized incidence ratios (SIRs) were generated overall and within subgroups defined by density measure (PP vs. BI-RADS), number of atypical foci, and BMI by dividing the observed number of BCs by population-based expected values. Cox regression was used to estimate MBD hazard ratios after adjustment for demographic and clinical variables. Results Of the 551 women diagnosed with AH between 1985 and 2001, 459 (83%) had MBD data within 1 year prior to biopsy. Of these, 68 (15%) had low, 221 (48%) had moderate, and 170 (37%) had high MBD, respectively. Over a median follow-up of 11.7 years, 80 BCs were observed. SIRs for breast cancer did not differ significantly across density categories, overall or within any subgroups examined (see Table). Cox regression adjusting for age, BMI and density measure (PP vs. BI-RADS) also failed to identify an association with MBD (p=0.55). Low MBDModerate MBDHigh MBD N / BCsSIR (95% CI)N / BCsSIR (95% CI)N / BCsSIR (95% CI)P-valueOverall68/123.5 (1.8,6.1)221/393.6 (2.5,4.9)170/293.4 (2.3,4.8)0.97MBD Measure PP59/113.6 (1.8,6.5)85/153.0 (1.7,5.0)130/243.3 (2.2,5.0)0.87BI-RADS9/12.7 (0.1,14.7)136/244.0 (2.6,6.0)40/53.4 (1.1,7.9)0.90No. Atypical Foci 147/62.3 (0.9,5.1)123/182.8 (1.7,4.4)96/163.5 (2.0,5.8)0.63214/47.5 (2.0,19.1)58/134.8 (2.6,8.3)41/62.5 (0.9,5.5)0.213+7/26.7 (0.8,24.0)40/84.4 (1.9,8.6)33/74.0 (1.0,8.2)0.83BMI &lt;2525/21.5 (0.2,5.4)75/184.9 (2.9,7.7)101/173.4 (2.0,5.5)0.1625-2919/54.9 (1.6,11.3)68/92.8 (1.3,5.2)36/42.1 (0.6,5.4)0.4530+23/54.8 (1.6,11.2)76/123.0 (1.6,5.3)32/74.0 (1.6,8.2)0.67SIRs compare observed numer of BCs to expected using Iowa SEER data. Analyses account for the effects of age and calendar period. P-value is test of heterogeneity in SIRs across columns. Conclusions We found no evidence of an association between MBD and subsequent BC in women with AH. Citation Format: Vierkant RA, Degnim AC, Hartmann LC, Frank RD, Radisky DC, Visscher DW, Frost MH, Winham SJ, Ghosh K, Vachon CM. No evidence of association between mammographic breast density and risk of breast cancer in women with atypical hyperplasia. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-09-05.

Background: Advance care planning (ACP) is an instrumental mechanism aimed at preserving patient autonomy. Numerous interventions have been proposed to facilitate the implementation of ACP; however, rates of completed advance directives (ADs) are universally low. Patient electronic portal messaging is a newer tool in patient–provider communication which has not been studied as a method to promote ACP. In this study, we hypothesized that the use of ACP-specific patient electronic messages would increase rates of AD completion in patients aged 65 years and older in an academic primary care practice. Methods: All primary care patients, aged 65+, who had previously enrolled in a patient electronic messaging system, within an academic primary care practice, were included for randomization. Two hundred patients were randomized to receive an electronic message. The primary outcome was the proportion of patients in each group who completed an AD, 3 months after intervention. Secondary outcomes included clinical utility of the completed ADs and proportion of patients who viewed their electronic messages. Results: The intervention group completed an AD 5.5% of the time when compared to 2% in the control group (odds ratio 3.2 [1.6-6.3]). Up to 74.5% of patients opened their electronic messages. Conclusion: Among primary care patients aged 65 years and older, use of AD-specific electronic messaging statistically significantly increased the rate of AD completion, but the absolute number of completed AD remained relatively low. These data suggest that this valuable communication tool holds opportunities for further improvement. Older, frailer adults were more likely to complete an AD, and prompted directives were more likely to include a written expression of the individual’s health-care values and preference.