Citations

Abstract Multinucleation is found in more than one third of tumors and is linked to increased tolerance for mutation, resistance to chemotherapy, and invasive potential. The integrity of the genome depends on proper execution of the cell cycle, which can be altered through mechanotransduction pathways as the tumor microenvironment stiffens during tumorigenesis. Here, we show that signaling downstream of matrix metalloproteinase-3 (MMP3) or TGFβ, known inducers of epithelial–mesenchymal transition (EMT), also promotes multinucleation in stiff microenvironments through Snail-dependent expression of the filament-forming protein septin-6, resulting in midbody persistence, abscission failure, and multinucleation. Consistently, we observed elevated expression of Snail and septin-6 as well as multinucleation in a human patient sample of metaplastic carcinoma of the breast, a rare classification characterized by deposition of collagen fibers and active EMT. In contrast, a soft microenvironment protected mammary epithelial cells from becoming multinucleated by preventing Snail-induced upregulation of septin-6. Our data suggest that tissue stiffening during tumorigenesis synergizes with oncogenic signaling to promote genomic abnormalities that drive cancer progression. Significance: These findings reveal tissue stiffening during tumorigenesis synergizes with oncogenic signaling to promote genomic abnormalities that drive cancer progression. Cancer Res; 78(9); 2277–89. ©2018 AACR.

Transcatheter pulmonary valve placement is emerging as a standard therapy for dysfunctional right ventricular outflow tract conduits. The Melody transcatheter pulmonary valve is indicated for use in the management of pediatric and adult patients with right ventricular outflow tract conduits measuring at least 16 mm in diameter. This is the first reported case of placement in a patient with a left ventricular assist device. We outline the preprocedural evaluation process, the procedural methods, and the outcomes of a successful implantation in a complex patient. With a team-based approach including thoughtful preprocedural evaluation, and close monitoring, successful deployment of a transcatheter pulmonary valve is possible in complex patients in the setting of mechanical circulatory support.

Abstract In breast adipose tissue, macrophages that encircle damaged adipocytes form “crown-like structures of breast” (CLS-B). Although CLS-B have been associated with breast cancer, their role in benign breast disease (BBD) and early carcinogenesis is not understood. We evaluated breast biopsies from three age-matched groups (n = 86 each, mean age 55 years), including normal tissue donors of the Susan G. Komen for the Cure Tissue Bank (KTB), and subjects in the Mayo Clinic Benign Breast Disease Cohort who developed cancer (BBD cases) or did not develop cancer (BBD controls, median follow-up 14 years). Biopsies were classified into histologic categories, and CD68-immunostained tissue sections were evaluated for the frequency and density of CLS-B. Our data demonstrate that CLS-B are associated with BBD: CLS-B–positive samples were significantly less frequent among KTB biopsies (3/86, 3.5%) than BBD controls (16/86 = 18.6%, P = 0.01) and BBD cases (21/86 = 24%, P = 0.002). CLS-B were strongly associated with body mass index (BMI); BMI < 25: 7% CLS-B positive, BMI 25–29: 13%, and BMI ≥ 30: 29% (P = 0.0005). Among BBD biopsies, a high CLS-B count [>5 CLS-B/sample: 10.5% (BBD cases) vs 4.7% (BBD controls), P = 0.007] conferred a breast cancer OR of 6.8 (95% CI, 1.4–32.4), P = 0.02, after adjusting for adipose tissue area (cm2), histologic impression, and BMI. As high CLS-B densities are independently associated with an increased breast cancer risk, they may be a promising histologic marker of breast cancer risk in BBD. Cancer Prev Res; 11(2); 113–9. ©2017 AACR.

Infection is a serious complication of left ventricular assist device (LVAD) therapy. However, an optimal antimicrobial surgical infection prophylaxis (SIP) regimen for LVAD implantation is not well established. We retrospectively reviewed all adults who underwent continuous-flow LVAD implantation from February 2007 to March 2015 at Mayo Clinic Rochester. Left ventricular assist device infection (LVADI) was defined using criteria published by the International Society for Heart and Lung Transplant. Patients excluded from the analysis included those who did not have HeartMate II or HeartWare device, patients with incomplete documentation of SIP, and those with an actively treated infection at the time of LVAD implantation. We compared risk of LVAD-specific and LVAD-related infections and all-cause mortality between SIP regimens at postoperative day 90 and 1 year using Kaplan–Meier time-to-event analyses. During study period, 239 adults underwent continuous-flow LVAD implantation at our institution where 199 patients received single-drug and 40 received multidrug SIP regimen. Median patient age was 62 years. Left ventricular assist device infection occurred in three patients (1.5%) in the single-drug group versus two patients (5.0%) in the multidrug group at 90 days (p = 0.4). There was no difference in infection-free (p = 0.4) and overall survival (p = 0.9) between two groups at 1 year. In conclusion, there was no clear benefit of using multidrug regimen as it did not impact infection-free survival or all-cause mortality compared with single-drug regimen. Prospective clinical trials are needed to further define the optimal SIP regimen for LVAD implantation.

Objectives: Noise pollution in pediatric intensive care units (PICU) contributes to poor sleep and may increase risk of developing delirium. The Environmental Protection Agency (EPA) recommends <45 decibels (dB) in hospital environments. The objectives are to assess the degree of PICU noise pollution, to develop a delirium bundle targeted at reducing noise, and to assess the effect of the bundle on nocturnal noise pollution. Methods: This is a QI initiative at an academic PICU. Thirty-five sound sensors were installed in patient bed spaces, hallways, and common areas. The pediatric delirium bundle was implemented in 8 pilot patients (40 patient ICU days) while 108 non-pilot patients received usual care over a 28-day period. Results: A total of 20,609 hourly dB readings were collected. Hourly minimum, average, and maximum dB of all occupied bed spaces demonstrated medians [interquartile range] of 48.0 [39.0-53.0], 52.8 [48.1-56.2] and 67.0 [63.5-70.5] dB, respectively. Bed spaces were louder during the day (10AM to 4PM) than at night (11PM to 5AM) (53.5 [49.0-56.8] vs. 51.3 [46.0-55.3] dB, P < 0.01). Pilot patient rooms were significantly quieter than non-pilot patient rooms at night (n=210, 45.3 [39.7-55.9]) vs. n=1841, 51.2 [46.9-54.8] dB, P < 0.01). The pilot rooms compliant with the bundle had the lowest hourly nighttime average dB (44.1 [38.5-55.5]). Conclusions: Substantial noise pollution exists in our PICU, and utilizing the pediatric delirium bundle led to a significant noise reduction that can be perceived as half the loudness with hourly nighttime average dB meeting the EPA standards when compliant with the bundle.

Abstract Introduction: MutHER is a phase II trial that demonstrated the anti-tumor activity of the pan-HER inhibitor neratinib in HER2mut, non-amplified MBC. The major challenges to accrue to this trial were the large number of pts to screen for the 2-3% HER2mut population and the high rate (24%) of poor quality tumor DNA for sequencing. The goals of this ctDNA study were: 1) the concordance of HER2mut detected by ctDNA versus tumor testing; 2) the incidence of ctDNA HER2mut in HER2 non-amplified MBC; 3) changes in HER2mut variant allele frequency (VAF) on neratinib therapy. Methods: A sample size of 30 negative (neg) controls was needed to ensure 90% confidence if ctDNA testing has &gt;90% specificity in detecting HER2mut. Thus, plasma from MBC pts obtained at screening for MutHER trial (Neg control: 40 pts without HER2mut on tumor testing; Positive (pos) control: 14 pts with known HER2mut who received neratinib) were subjected to Guardant360 ctDNA 70-gene panel sequencing (all exons of HER2 included). ctDNA from the 14 neratinib treated pts were also analyzed at week (wk) 4 and upon progression. ctDNA data from MBC pts clinically tested at Guardant Health were interrogated for HER2mut incidence. Results: Among the 14 pts with tumor pos for HER2mut, ctDNA sequencing identified the same HER2mut in 11, discrepant HER2mut in 1, and neg in 2. The 2 pts with ctDNA neg for HER2mut had progressive disease (PD) and stable disease (SD &gt; 6 months) on neratinib, respectively. Among the 40 neg controls, 8 were not evaluable (no detectable ctDNA or assay unsuccessful) and all 32 successfully sequenced cases were neg for HER2mut. The sensitivity and specificity of ctDNA for HER2mut detection was 11/14 (79%, 90% CI: 53-94%) and 32/32 (100%, 90% CI: 91-100%), respectively. Among the 11 paired baseline and wk 4 samples, 9 (82%) had lower HER2mut VAFs at wk 4 than at baseline, with 1 complete response (CR), 1 partial response (PR), 5 SD, and 4 PD at wk 8 as best tumor response. Two pts had higher wk 4 ctDNA HER2mut VAFs and both had radiographic PD at wk 8. The absolute HER2mut VAF levels at wk 4 were significantly associated with TTP (Spearman rho=-0.69, p=0.02) and tumor size change (rho=0.67, p=0.05). The HER2mut VAFs were significantly higher at progression than wk 4 in all pts (p&lt;0.01). One pt acquired a new HER2mut T798I, which is analogous to the gate-keeper mutation EGFR T790M. The incidence of HER2mut without amplification in unselected consecutive MBC clinically tested by Guardant360 was 3% (48/1,584), with mutation pattern similar to published tumor testing data. Conclusions: ctDNA sequencing is sensitive and highly specific in detecting HER2mut, offering a non-invasive method to identify pts for trials of HER2mut-targeted therapy. Decreased HER2mut VAFs at wk 4 was observed in 82% of cases, consistent with the on-target effect of neratinib. Increased HER2mut VAFs at wk 4 is a potential early marker of progression. Citation Format: Cynthia Ma, Ron Bose, Feng Gao, Rachel Freedman, Melinda Telli, Gretchen Kimmick, Eric Winer, Michael Naughton, Matthew Goetz, Christy Russell, Debu Tripathy, Melody Cobleigh, Andres Forero, Timothy Pluard, Carey Anders, Shana Thomas, Jill Anderson, Caroline Bumb, Kimberly Banks, Richard Lanman, Richard Bryce, Alshad Lalani, John Pfeifer, Daniel Hays, Mark Pegram, Kimberly Blackwell, Philippe Bedard, Hussam Al-Kateb, Matthew Ellis. Circulating tumor DNA (ctDNA) sequencing for HER2 mutation (HER2mut) screening and response monitoring to neratinib in metastatic breast cancer (MBC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT011. doi:10.1158/1538-7445.AM2017-CT011

Abstract Benign breast disease, a known risk factor for subsequent breast cancer, includes a histological spectrum of lesions that can be subdivided based on the overall impression into non-proliferative lesions, proliferative lesions without atypia, and atypical hyperplasia. Yet little is known about the molecular characteristics of benign breast tissue from African American women, who suffer from disproportionately high breast cancer mortality rates. 72 breast samples from African American women were obtained. RNA was extracted from archival formalin-fixed, paraffin-embedded (FFPE) blocks. Gene expression profiling was performed on these samples using the Affymetrix HTA2.0 exon array chip. A fit linear model using generalized least squares identified probe sets with differential expression in benign-in situ and benign-invasive breast cancer paired lesions. 36 benign and 36 breast cancer paired lesions were included in the study. In the benign-in situ set (n=20), 978 probe sets were differentially expressed (threshold: fold-change, 1.50; p &lt; 0.05). Probe sets mapped to 125 annotated genes, of which 69 (55.2%) were involved in cancer. The benign-invasive set (n=52) identified 351 differentially expressed probe sets that mapped to 84 annotated genes, of which 61 (72.6%) had known cancer significance. Genes involved in cellular growth and proliferation were significantly over-expressed in both benign-in situ and benign-invasive lesions (p-values &lt; 0.0104). In the population of 36 paired samples, differentially expressed genes were found to regulate the estrogen receptor (ESR1) through distinct network associations. Many genes are differentially expressed by benign and breast cancer lesions, and in situ/invasive histology contribute to the distinct molecular characteristics and pathways of breast malignancy. Our findings highlight the first study to assess expression profiling of paired benign and breast cancer lesions among African American women. Citation Format: Andreana Natalie Holowatyj, Julie J. Ruterbusch, Rouba Ali-Fehmi, Sudeshna Bandyopadhyay, Christine Mehner, Melody Stallings Mann, Gregory Dyson, Derek Radisky, Michele L. Cote. Expression profiling of paired benign and breast cancer lesions in African American women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4253. doi:10.1158/1538-7445.AM2017-4253

Abstract Purpose: Based on promising preclinical data, we conducted a single-arm phase II trial to assess the clinical benefit rate (CBR) of neratinib, defined as complete/partial response (CR/PR) or stable disease (SD) ≥24 weeks, in HER2mut nonamplified metastatic breast cancer (MBC). Secondary endpoints included progression-free survival (PFS), toxicity, and circulating tumor DNA (ctDNA) HER2mut detection. Experimental Design: Tumor tissue positive for HER2mut was required for eligibility. Neratinib was administered 240 mg daily with prophylactic loperamide. ctDNA sequencing was performed retrospectively for 54 patients (14 positive and 40 negative for tumor HER2mut). Results: Nine of 381 tumors (2.4%) sequenced centrally harbored HER2mut (lobular 7.8% vs. ductal 1.6%; P = 0.026). Thirteen additional HER2mut cases were identified locally. Twenty-one of these 22 HER2mut cases were estrogen receptor positive. Sixteen patients [median age 58 (31–74) years and three (2–10) prior metastatic regimens] received neratinib. The CBR was 31% [90% confidence interval (CI), 13%–55%], including one CR, one PR, and three SD ≥24 weeks. Median PFS was 16 (90% CI, 8–31) weeks. Diarrhea (grade 2, 44%; grade 3, 25%) was the most common adverse event. Baseline ctDNA sequencing identified the same HER2mut in 11 of 14 tumor-positive cases (sensitivity, 79%; 90% CI, 53%–94%) and correctly assigned 32 of 32 informative negative cases (specificity, 100%; 90% CI, 91%–100%). In addition, ctDNA HER2mut variant allele frequency decreased in nine of 11 paired samples at week 4, followed by an increase upon progression. Conclusions: Neratinib is active in HER2mut, nonamplified MBC. ctDNA sequencing offers a noninvasive strategy to identify patients with HER2mut cancers for clinical trial participation. Clin Cancer Res; 23(19); 5687–95. ©2017 AACR.