Citations

Abstract BACKGROUND Stereotactic radiosurgery (SRS) for benign intracranial meningiomas is an established treatment. OBJECTIVE To summarize the literature and provide evidence-based practice guidelines on behalf of the International Stereotactic Radiosurgery Society (ISRS). METHODS Articles in English specific to SRS for benign intracranial meningioma, published from January 1964 to April 2018, were systematically reviewed. Three electronic databases, PubMed, EMBASE, and the Cochrane Central Register, were searched. RESULTS Out of the 2844 studies identified, 305 had a full text evaluation and 27 studies met the criteria to be included in this analysis. All but one were retrospective studies. The 10-yr local control (LC) rate ranged from 71% to 100%. The 10-yr progression-free-survival rate ranged from 55% to 97%. The prescription dose ranged typically between 12 and 15 Gy, delivered in a single fraction. Toxicity rate was generally low. CONCLUSION The current literature supporting SRS for benign intracranial meningioma lacks level I and II evidence. However, when summarizing the large number of level III studies, it is clear that SRS can be recommended as an effective evidence-based treatment option (recommendation level II) for grade 1 meningioma.

Objective In contrast to intentionally restricting energy intake, restricting the eating window may be an option for treating obesity. By comparing time‐restricted eating (TRE) with an unrestricted (non‐TRE) control, it was hypothesized that TRE facilitates weight loss, alters body composition, and improves metabolic measures. Methods Participants (17 women and 3 men; mean [SD]: 45.5 [12.1] years; BMI 34.1 [7.5] kg/m 2 ) with a prolonged eating window (15.4 [0.9] hours) were randomized to TRE ( n = 11: 8‐hour window, unrestricted eating within window) versus non‐TRE ( n = 9: unrestricted eating) for 12 weeks. Weight, body composition (dual x‐ray absorptiometry), lipids, blood pressure, 2‐hour oral glucose tolerance, 2‐week continuous glucose monitoring, and 2‐week physical activity (actigraphy assessed) were measured during the pre‐ and end‐intervention periods. Results The TRE group significantly reduced the eating window (end‐intervention window: 9.9 [2.0] hours) compared with the non‐TRE group (end‐intervention window: 15.1 [1.1] hours) ( P < 0.01). Compared with non‐TRE, TRE decreased the number of eating occasions, weight, lean mass, and visceral fat (all P ≤ 0.05). Compared with preintervention measures, the TRE group reduced the number of eating occasions (−21.9% [30.1%]) and reduced weight (−3.7% [1.8%]), fat mass (−4% [2.9%]), lean mass (−3.0% [2.7%]), and visceral fat (−11.1% [13.4%]) (all P ≤ 0.05). Physical activity and metabolic measures remained unchanged. Conclusions In the setting of a randomized trial, TRE presents a simplified view of food intake that reduces weight.

The medial sural artery perforator (MSAP) flap is a versatile fasciocutaneous flap that has been used successfully in the reconstruction of defects across the body. In specific cases, it may prove superior to more commonly used options (e.g., anterolateral thigh flap and radial forearm free flap). Historically, a disadvantage of the MSAP flap is the relatively small surface area it provides for reconstruction. We recently encountered a patient with extensive pelvic injuries from prior trauma resulting in significant scarring and contracture of the groin, tethering of the penis, and loss of the scrotum and one testicle. The patient was unable to achieve erection from tethering and his remaining testicle had been buried in the thigh. In considering the reconstructive options, he was not a suitable candidate for a thigh-based or forearmbased flap. An extended MSAP flap measuring 25 cm×10 cm was used for resurfacing of the groin and pelvis as well as for the formation of a neoscrotum. This report is the first to document an MSAP flap utilized for simultaneous groin resurfacing and scrotoplasty. Additionally, the dimensions of this flap make it the largest recorded MSAP flap to date.

AbstractObjectivePerforate the expanded polytetrafluoroethylene membrane of the GORE® CARDIOFORM Septal Occluder (GSO) and GORE® CARDIOFORM ASD Occluder (GCA) after implantation.BackgroundPercutaneous transseptal access to the left atrium is necessary for many structural and electrophysiological procedures. The potential need to access the left atrium may influence decision‐making for patent foramen ovale or atrial septal defect closure.MethodsSixteen canines underwent implantation of equal number GSO or GCA devices. A transseptal crossing procedure was performed through the device 85 (±1) days postoccluder implantation. The crossing procedure was performed utilizing commercially available equipment: radiofrequency/SureFlex sheath and standard needle/Mullin's sheath. Progressive dilation of the perforation was performed to allow passage of a 12 French Mullin's sheath into the left atrium.ResultsLeft atrial access was achieved in all cases. Postmortem analysis demonstrated passage through both occluder discs in all radiofrequency/SureFlex sheath cases (4 GSO, 4 GCA) and half of the standard needle/Mullin's sheath cases (3 GSO, 1 GCA). The remaining standard needle/Mullin's sheath cases demonstrated perforation through the right atrial disc but passage around the septal aspect of the left atrial disc, thus not perforating the left atrial disc. No acute embolic complications from the procedure were observed.ConclusionsLeft atrial access may be achieved through the GSO or GCA devices after implantation and endothelialization. The combination of a radiofrequency needle and steerable sheath provides benefit over a standard needle and Mullin's sheath in accomplishing passage through both occluder discs.

Background. Desensitization protocols for HLA-incompatible living donor kidney transplantation (ILDKT) vary across centers. The impact of these, as well as other practice variations, on ILDKT outcomes remains unknown. Methods. We sought to quantify center-level variation in mortality and graft loss following ILDKT using a 25-center cohort of 1358 ILDKT recipients with linkage to Scientific Registry of Transplant Recipients for accurate outcome ascertainment. We used multilevel Cox regression with shared frailty to determine the variation in post-ILDKT outcomes attributable to between-center differences and to identify any center-level characteristics associated with improved post-ILDKT outcomes. Results. After adjusting for patient-level characteristics, only 6 centers (24%) had lower mortality and 1 (4%) had higher mortality than average. Similarly, only 5 centers (20%) had higher graft loss and 2 had lower graft loss than average. Only 4.7% of the differences in mortality (P < 0.01) and 4.4% of the differences in graft loss (P < 0.01) were attributable to between-center variation. These translated to a median hazard ratio of 1.36 for mortality and 1.34 of graft loss for similar candidates at different centers. Post-ILDKT outcomes were not associated with the following center-level characteristics: ILDKT volume and transplanting a higher proportion of highly sensitized, prior transplant, preemptive, or minority candidates. Conclusions. Unlike most aspects of transplantation in which center-level variation and volume impact outcomes, we did not find substantial evidence for this in ILDKT. Our findings support the continued practice of ILDKT across these diverse centers.

Abstract Background: Studies demonstrate breast cancer risk reduction of 50-65% with the use of endocrine therapy (ET) and yet drug uptake and adherence in this setting is suboptimal even among high risk women. A Polygenic Risk Score (PRS) comprised of 77 BC genetic susceptibility loci (Single Nucleotide Polymorphisms (SNP)) can provide a personalized risk assessment and potentially influence ET adherence. We assessed ET adherence at 1 year comparing women whose risk estimate increased due to PRS versus women whose risk estimate decreased due to PRS. The effect of ET use on quality of life (hot flashes, night sweats, vaginal dryness, weight gain, joint pain) was evaluated. Methods: Eligible women required either a 5 year Gail Model risk of ≥3% or 10 year IBIS ( International Breast Intervention Study or Tyrer-Cuzick model) of ≥5%. Women with a history of breast cancer (BC) or hereditary BC syndrome were excluded. High risk women were counseled at baseline using their Gail and IBIS risk scores and ET options were discussed including benefits and risks. Participants completed a self-reported questionnaire at baseline to assess their understanding of breast cancer risk and decision to take preventive ET. Blood samples were obtained and genotyped for 77 SNPs, and the odds ratio from the SNPs were used to modify the IBIS and Gail risk estimates. The BC -PRS risk estimate information was shared with study participants that reflected the IBIS and Gail risk estimates for 5 year, 10 year, & lifetime BC risk with and without the PRS. Follow up questionnaires at year 1 were administered to assess drug adherence and ET usage on quality of life. Results: 151 women were enrolled at Mayo Clinic Rochester and CancerCare Manitoba from 2016 to 2017. The median age was 56.1 (range 36-76.4), 35.6% were premenopausal, 98.7% were Caucasian and 64.7% had&gt;1 family member with BC. Median 5yr, 10yr, & lifetime IBIS- PRS risk estimates were 3.8% (2.0-11.5), 7.9% (5.0-23.1), and 25.3% (5.5 to 92.2). At year 1 (n=112 women) 46 % of those with an increase in risk when considering the BC-PRS score and 16 % with a decrease in risk were taking ET ( p&lt; 0.001). Types of ET taken: tamoxifen-18, raloxifene- 3, exemestane -14 and missing-1. Women taking ET reported weight gain ( 19.4% vs 6.7%, p=0.04) and more joint pain ( 27.8 % vs 12%, p=0.04) when compared to women not taking ET. Conclusion: In high risk women, BC-PRS risk estimates in addition to standard BC risk calculators had a significant impact on preventive ET adherence. ET use was associated with weight gain and joint pain. Citation Format: Sandhya Pruthi, Julian O Kim, Daniel Schaid, Andrew Cooke, Christina Kim, Benjamin Goldenberg, Jason Sinnwell, Debjani Grenier, Fergus Couch, Celine Vachon. Impact of the breast cancer polygenic risk score on preventive endocrine therapy adherence and endocrine therapy usage on quality of life - The Genetic Risk Estimate (GENRE) trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD3-03.

Abstract Background: TNBC is the most aggressive sub-type of breast cancer and has limited targeted therapies. Atezolizumab was recently FDA-approved for patients with advanced PD-L1+ TNBC. In a well-characterized cohort of patients with early-stage TNBC, we used the FDA-approved PD-L1 SP142 companion assay for atezolizumab to score whole tumor sections for PD-L1 expression. We determined the frequency and scoring distribution of PD-L1 in these tumors and evaluated PD-L1 status for associations with clinicopathologic variables and outcomes. Methods: Whole tumor sections from 498 women with surgically-treated, non-(distant) metastatic TNBC (ER/PR &lt;1% & HER2-negative by central review) were semi-quantitatively scored for % of PD-L1-staining tumor cells (TC) or tumor-associated immune cells (IC) (PD-L1 SP142, Ventana, performed in CAP/CLIA-certified clinical laboratory). Per FDA assay guidelines, PD-L1+ tumors were defined as ≥1% of tumor-associated immune cells (IC) staining per tumor area. Baseline clinical characteristics, histopathologic features, Ki-67 proliferative indices (PI), and stromal tumor infiltrating lymphocytes (TILs) were correlated with PD-L1 status. The impact of tumoral PD-L1 status on invasive disease-free survival (IDFS) and overall survival (OS) was assessed using Cox proportional hazards models. Results: The majority of tumors were pT1-T2 (95%), pN0-1 (85%), and grade 3 (90%) with Ki-67 &gt;15% (80%). 228/498 (46%) tumors were PD-L1+, distributed as IC score 1-5%: 21%, 6-10%: 13%, 11-20%: 5% and &gt;20%: 7%. 270/498 (54%) were PD-L1-. 43 (8.6%) of tumors had PD-L1 staining in TC (all but 1 were also IC+). PD-L1 IC expression was associated with larger tumor size (p = 0.005), higher nodal stage (≥pN1: 43% vs. 31%, p &lt; 0.001), higher grade (grade 3: 95% vs. 86%, p&lt; 0.001), higher Ki-67 PI (&gt;15%: 88% vs. 69%, p &lt;0.001), and stromal TILs (median score: 40% vs. 10%; p &lt; 0.001). PD-L1 IC status was not associated with patient age. Among histologic subtypes, PD-L1+ tumors were more frequently medullary type (31% vs. 6%) and less frequently metaplastic type (4% vs 10%). At time of this analysis, median follow-up for IDFS and OS were 11 years and 7.2 years, respectively. By univariable analysis, absence of PD-L1 IC expression was associated with poorer IDFS (median: 15.5 vs. 20 years, p = 0.04) and OS (9.5 vs. 17.5 years, p &lt; 0.05).By multivariable analysis, tumor size, stromal TILs, nodal status, and adjuvant chemotherapy (CTX) were significantly associated with IDFS. Age, stromal TILs, nodal status, and receipt of adjuvant CTX were associated with OS. PD-L1+ tumors trended toward improved IDFS (statistical significance not reached), HR: 0.68 (95% CI: 0.45-1.03, p= 0.068) but not OS: 0.90 (95% CI: 0.52-1.57, p= 0.32). Conclusion: Using the PD-L1 SP142 companion assay, almost half of early-stage TNBC were PD-L1+ (IC). However, PD-L1 expression correlated with increasing tumor size and nodal burden, as well as histologic grade, Ki-67 PI, stromal TILs and lymphocyte-enriched subtypes. PD-L1 was associated with improved IDFS and OS in univariable analysis but not multivariable analysis. The majority of the PD-L1+ tumors (73%) had IC scores ≤10%, with heterogeneous tumoral staining. Given the low (1%) assay threshold for positivity, these data emphasize the utility of evaluating PD-L1 in whole tumor sections rather than tissue cores. Citation Format: Jodi M Carter, Mei-Yin C Polley, Jason P Sinnwell, Roberto A Leon-Ferre, Fergus J Couch, Krishna R Kalari, Judy C Boughey, Minetta C Liu, Daniel W Visscher, Matthew P Goetz. Frequency, characteristics and prognostic factors of PD-L1+ triple negative breast cancer using the PD-L1 SP142 companion assay [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD1-08.

Abstract Background: Triple Negative Breast Cancer (TNBC) affects approximately 15-20% of BC patients, yet accounts for a disproportionately higher rate of BC morbidity and mortality, in part due to lack of targeted therapies. Using well-validated antibodies, we have found that estrogen receptor beta (ERβ) protein is expressed in approximately 20% of TN breast tumors. We have demonstrated that ligand-mediated activation of ERβ with estradiol (E2) or ERβ-selective agonists decreases tumor cell proliferation, invasion, and migration in vitro, as well as primary tumor growth and metastatic spread in vivo. As such, we aimed to elucidate the mechanisms by which ERβ elicits its anti-cancer effects in TNBC. Methods: RNAseq and ChIPseq were used to identify ERβ and NFκB regulomes and cistromes in TNBC cells. The global effects of ERβ on H3K27Ac and H3K27Me3 were also assessed via ChIPseq. The influence of ERβ on NFκB signaling was determined using co-immunoprecipitation, luciferase assays transcriptional readouts and ChIPseq. The involvement of EZH2 in mediating ERβ’s suppression of NFκB signaling and cancer cell phenotypes was determined using pharmacological approaches. Results: Pathway analysis of ERβ-regulated genes identified NFκB and inflammatory signaling as being highly suppressed in response to E2 treatment. Numerous NFκB target genes were among the most down-regulated genes by ERβ. ChIPseq revealed that ERβ primarily associated with estrogen response elements (EREs), but was also highly enriched at NFκB binding sites following E2 treatment. However, ERβ had no impact on TNFα-mediated NFκB phosphorylation or nuclear localization, but was shown to physically associate with NFκB protein. Using an NFκB reporter construct and qPCR, ERβ was shown to block TNFα-mediated induction of NFκB signaling and NFκB target gene expression. Globally, RNAseq identified 373 genes to be significantly regulated by TNFα in TNBC cells, of which 107 were blocked in the presence of E2+TNFα. Interestingly, E2+TNFα treatment induced novel NFκB binding sites compared to TNFα alone as identified by ChIPseq for NFκB. ChIPseq also demonstrated that ligand-mediated activation of ERβ significantly diminished an activating histone mark (H3K27Ac) at many of these NFκB target genes while enhancing a repressive mark (H3K27Me3). These modifications were shown to occur through the recruitment of the histone methyltransferase, EZH2, to enhancer elements of these NFκB target genes. Drug-mediated blockade of EZH2 activity reversed suppression of NFκB target gene expression by ERβ. Finally, knockdown of NFκB expression inhibited the anti-cancer effects of ERβ while expression of a constitutively active form of NFκB enhanced ERβ’s inhibitory effects. Conclusions: Our data suggest that ERβ elicits its anti-cancer effects, in part, via formation of a novel co-repressor complex consisting of ERβ, NFκB, and EZH2. These data are in keeping with prior observations of the importance of NFκB signaling as it relates to TNBC cell proliferation and invasion, and that decreased expression of NFκB target genes is associated with improved outcomes in TNBC patients. Currently, a Mayo Breast SPORE prospective study is underway to investigate the efficacy of estradiol for the treatment of metastatic ERβ+TNBC and to further evaluate the cross-talk between ERβ and NFκB signaling. Citation Format: Kirsten GM Aspros, Adam W Nelson, Zhenqing Ye, Zhifu Sun, Igor Chernukhin, Jason S Carroll, James N Ingle, Matthew P Goetz, John R Hawse. Estrogen receptor beta repurposes EZH2 to inhibit oncogenic NFκB signaling in triple negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-05-02.

Abstract Background: The combination of cyclin dependent 4/6 kinase inhibitors (CDK4/6i) with endocrine therapy (ET) has resulted in clinically significant improvements in progression-free survival (PFS) and overall survival (OS) in hormone-receptor (HR)-positive metastatic breast cancer (MBC). However, most patients’ disease ultimately progresses on CDK4/6i and ET. Therefore, further research is necessary to understand the mechanisms driving primary and secondary resistance. PROMISE is a multicenter prospective cohort study enrolling women with HR-positive MBC commencing treatment with palbociclib + letrozole (1st line) or palbociclib + fulvestrant (2nd Line). The study provides a comprehensive “omic” assessment of blood, tumor, urine and the fecal microbiome to identify molecular or cellular features associated with primary endocrine resistance (e.g. disease progression ≤ 12 months on treatment) and acquired resistance to CDK 4/6i. Additionally, patient derived xenografts and organoids are created to test new drug strategies designed to overcome resistance to CDK 4/6i and ET. Here, we present initial sequencing results from pretreatment biospecimens collected from PROMISE study participants. Methods: On-study tumor biopsies and blood samples were collected for DNA/RNA sequencing (TempusTM). The analyzed biospecimens were all obtained prior to initiation of palbociclib and ET. We correlated patient clinical characteristics (phenotypes) with molecular data and responses to protocol treatment. The data were analyzed using a series of cutting-edge bioinformatics pipelines for somatic and germline mutations in addition to copy number alterations (CNAs). The study database was locked for analysis on 06/20/2019. Results: We analyzed the somatic single nucleotide variants/INDELs (sSNV/INDEL) profiles across the tumor samples to determine the genes that were least likely to occur as a result of background mutation processes. Twenty-six patients had somatic copy number alterations (sCNA) and/or sSNV/INDEL in at least one of 18 genes with the most significant sSNV/INDEL profiles (p &lt; 0.03) which included clinically and biologically relevant genes. The genes with the most statistically significant sSNV/INDEL mutation profiles were GATA3, PIK3CA, CDH1, and ESR1 (p &lt; 0.0009). We observed a high percentage of tumors with somatic alterations in GATA3 (23% sSNV/INDEL, 15% sCNA), PIK3CA (38%, 12%), CDH1 (19%, 50%) and ESR1 (19%, 58%). ESR1 mutations were more frequent in patients receiving 2nd line treatment. Other frequently altered genes included TP53 (15%, 46%), MAP2K4 (8%, 50%), DNAAF1 (8%, 50%), and CDKN1B (8%, 35%). Further, ZNF317 and F3 were altered in 9 and 7 patients, respectively. Twenty-four samples had alterations in at least one of the CDK4/6 pathway genes (RB1, CCNE2, CCND1, CDK6, ESR1, CDKN2A, CCND3, CDK4, CDK2 and CCNE1). Four patients progressed on therapy; three of the four patients had mutations in PIK3CA, and one had a mutation in ESR1. Results of the RNA sequencing data (N=26) will be presented at the SABCS meeting. Conclusions: This is the first report of a prospective study designed to characterize the genomic landscape of ER+/HER2- MBC prior to palbociclib treatment. We observed high frequencies of known targetable alterations in PIK3CA and ESR1, including in patients that progress, which is consistent with previous reports. RNA sequencing data will be presented at the meeting. Citation Format: Ciara C O Sullivan, Krishna R Kalari, Vera J Suman, Peter T Vedell, Ann Moyer, Erin Carlson, Jason Sinnwell, Tejaswi Alaparthi, Xiaojia Tang, Kevin Thompson, Jaeyun Sung, Alvaro Moreno-Aspitia, Donald Northfelt, Minetta C Liu, Tufia C Haddad, Prema Peethambaram, Saranya Chumsri, Kathryn J Ruddy, Karthik V Giridhar, Roberto A Leon-Ferre, Paula Gill, Mohammad Ranginwala, Asad Javed, Sameer Batoo, Brendan P. McMenomy, Richard Weinshilboum, Liewei Wang, Matthew P Goetz. Comprehensive tumor sequencing to identify biomarkers of palbociclib response: First report of the PROMISE study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-11-07.