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Abstract The IGHV4-34 gene is very frequent (~10%) in the B cell receptor immunoglobulin (BcR IG) gene repertoire of chronic lymphocytic leukemia (CLL). Over 30% of IGHV4-34 CLL cases can be assigned to different subsets with stereotyped BcR IG. The largest is subset #4 which represents ~1% of all CLL and ~10% of IGHV4-34 CLL and is considered a prototype for indolent disease. The BcR IG of a great majority (~85%) of IGHV4-34 CLL cases carry a significant load of somatic hypermutation (SHM), often with distinctive SHM patterns. This holds especially true for stereotyped subsets and is suggestive of particular modes of interactions with the selecting antigen(s). In detail, subsets #4 and #16, both involving IgG-switched cases (IgG-CLL), exhibit the greatest sequence similarity in SHM profiles, whereas they differ in this respect from IgM/D subsets #29 and #201. Prompted by these observations, here we explored the extent that these subset-biased SHM profiles in different IGHV4-34 stereotyped subsets were reflected in distinct demographics, clinical presentation, genomic aberrations and outcomes. Within a multi-institutional series of 20,331 CLL patients, 1790 (8.8%) expressed IGHV4-34 BcR IG. Following established bioinformatics approaches for the identification of BcR IG stereotypy, 573/1790 IGHV4-34 CLL cases (32%) were assigned to stereotyped subsets; of these, 340 cases (19% of all IGHV4-34 CLL and 60% of stereotyped IGHV4-34 cases) belonged to subsets #4, #16, #29 and #201, all concerning IGHV-mutated CLL (M-CLL). Clinicobiological information was available for 275/340 patients: #4, n=150; #16, n=44; #29, n=39; and #201, n=42. Comparisons between subsets revealed no differences in gender and age distribution. Interestingly, however, 36-43% of each subset cases were young for CLL (defined as patients aged ≤55 years), which is higher compared to general CLL cohorts, where young patients generally account for ~25% of cases. In contrast, significant differences were identified between subsets regarding: (i) disease stage at diagnosis, with >90% of IgG subsets #4 and #16 diagnosed at Binet stage A versus 83% in subset #201 and 74% in subset #29 (p=0.029); (ii) CD38 expression, ranging from 1% in subset #4 to 10% in subset #201 (p=0.013); (iii) the distribution of del(13q), peaking at a remarkable 92% in subset #29 versus only 37% in subset #16 (p<0.0001). Regarding other genomic aberrations, they were either absent (NOTCH1 mutations) or rare (SF3B1 mutations, trisomy 12, del(11q), TP53 aberrations due to either del(17p) and/or TP53 mutations). The sole exception concerned a high frequency (14%) of TP53 aberrations in subset #29 (p<0.05 compared with the other subsets), which is notable for M-CLL cases in general. Time to first treatment (TTFT) could be analyzed in 228 cases. IgG subsets #4 and #16 had significantly (p=0.036) longer TTFT (median TTFT: not yet reached) compared to the IgM/D subsets #29 and #201 (median TTFT: 11 and 12 years, respectively). In conclusion, we have identified distinct clinicobiological profiles for different stereotyped IGHV4-34 M-CLL subsets, highlighting subsets #4 and #16 as particularly indolent, which is important for both medical and social reasons, especially considering that a significant proportion of patients in these subsets are diagnosed at younger ages. Our findings support the notion that BcR IG stereotypy refines prognostication in CLL, superseding the crude immunogenetic distinction based on SHM load only. Additionally, the observed heterogeneity suggests that not all M-CLL are equal, prompting further research into the underlying biological background with the ultimate aim of tailored patient management. Disclosures Tausch: Gilead: Other: Travel support. Shanafelt:Glaxo-Smith_Kline: Research Funding; Genentech: Research Funding; Celgene: Research Funding; Polyphenon E Int'l: Research Funding; Hospira: Research Funding; Janssen: Research Funding; Pharmactckucs: Research Funding; Cephalon: Research Funding. Niemann:Gilead: Consultancy; Janssen: Consultancy; Roche: Consultancy; Novartis: Other: Travel grant. Langerak:InVivoScribe: Patents & Royalties: Licensing of IP and Patent on BIOMED-2-based methods for PCR-based Clonality Diagnostics.; DAKO: Patents & Royalties: Licensing of IP and Patent on Split-Signal FISH. Royalties for Dept. of Immunology, Erasmus MC, Rotterdam, NL; Roche: Other: Lab services in the field of MRD diagnostics provided by Dept of Immunology, Erasmus MC (Rotterdam). Hallek:Celgene: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; AbbVie: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Roche: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Boehringher Ingelheim: Honoraria, Other: Speakers Bureau and/or Advisory Boards; Pharmacyclics: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Mundipharma: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Janssen: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Gilead: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding. Ghia:Janssen Pharmaceuticals: Research Funding.

Abstract Background: Thrombotic and hemorrhagic complications are commonly encountered in uncontrolled essential thrombocythemia (ET). Both anagrelide and hydroxyurea (HU) have proven efficacious in cytoreduction as well as reducing these events and remain first line therapy for most high-risk ET patients. Independent of their role in risk-reduction, little is known about how these therapies impact patient symptomatology or quality of life. In this study, we compared the clinical and symptomatic profiles of ET patients receiving HU or anagrelide against patients with no previous experience with these agents. Methods: Data was assessed from a prospectively collected international database of ET patients in which demographics, disease features, and ET symptoms utilizing the myeloproliferative neoplasm symptom assessment form (MPN-SAF; Scherber et al, 2011). The MPN-SAF includes the patient's perceptions of common MPN-related symptoms and overall quality of life (QOL) on a 0 (absent) to 10 (worst imaginable) scale. Total symptom score (TSS) was computed based on symptom items using the published scoring algorithm on a 0 (all reported symptoms absent) to 100 (all reported symptoms worst imaginable) scale. ET risk scores were calculated using the IPSET scoring algorithm (Passamonti 2012). Thrombocytopenia was defined as a platelet count <100 x 10(9)/L, anemia was defined as hemoglobin<10 g/dL and leukopenia was defined as a white blood cell count <4.0 x 10(9)/L. Associations between the MPN-SAF individual symptoms were investigated using chi-square test for categorical data and ANOVA F-test for continuous variables. Results Hydroxyurea vs. HU Naive A total of 402 ET patients with active HU use were compared to 392 ET patients with no history of HU use. Patients using HU were older (63.5 years vs. 52.3 years, p<0.001) and had a greater concentration of both high risk (24.9% vs. 11.4%, p=0.001) and intermediate risk (53.9% vs 38.4%, p<0.001) patients. They also had a higher rate of prior thrombosis (29.8% vs 11.3%, p<0.001) and leukopenia (10.1% vs. 3.0%, p<0.001). No differences were noted between gender, a history of prior hemorrhage, red blood cell transfusion requirements, or the presence of anemia/thrombocytopenia. In comparing symptom profiles, no significant differences were noted between TSS or individual symptoms with the exception of slightly more severe cough in HU patients (1.5 vs. 1.1, p=0.02, Figure 1). Anagrelide vs. Anagrelide Naive A total of 49 ET patients with active anagrelide use were compared to 794 ET patients with no history of anagrelide use. Patients using anagrelide had a longer mean disease duration (8.1 years vs. 5.8 years) and were more anemic (9.1% vs. 1.2%, p<0.001). No differences were noted between age, gender, risk scores, the presence of leukopenia/thrombocytopenia, a history of prior thrombosis or hemorrhage complications or red blood cell transfusion requirements. Additionally, there were no significant differences between TSS or individual symptom items (Figure 1). HU vs. Anagrelide A total of 402 patients currently using HU were compared to 39 patients currently using anagrelide. Overall, HU users were slightly older (63.5 years vs. 55.1 years, p<0.001) with a greater population of patients meeting high risk criteria (24.9% vs. 2.8%, p=0.002) and having a history of prior thrombosis (29.8% vs. 12.8%, p=0.02). Patients receiving anagrelide had a slightly longer disease duration (8.2 years vs. 6.0 years, p=0.0446). In comparing symptom profiles, no differences were noted in TSS or individual symptom items between cohorts. Discussion In this retrospective analysis, it does not appear cytoreduction with either HU and/or anagrelide has a significant impact on ET symptom burden despite reducing vascular events. Importantly, the higher risk scores in HU patients did not translate directly into greater patient symptomatology supporting previous studies demonstrating a poor association between these two items. Prospective trials measuring ET symptom change, in the setting of randomized trials will better quantify impact of cytoreduction on symptom burden as well as quantify impact of newer agents such as interferon or jak inhibition. Figure 1. Symptom Comparisons Between HU, Anagrelide and Other Therapy Figure 1. Symptom Comparisons Between HU, Anagrelide and Other Therapy Disclosures Kiladjian: Incyte Corporation: Consultancy; Novartis: Other: Travel grant; Research Funding paid to institution (Hôpital Saint-Louis et Université Paris Diderot); Novartis: Consultancy. Zweegman:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Harrison:Sanofi: Honoraria, Speakers Bureau; Shire: Speakers Bureau; Gilead: Honoraria; CTI Biopharma: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Cervantes:Sanofi-Aventis: Consultancy; Novartis: Consultancy, Speakers Bureau; CTI-Baxter: Consultancy, Speakers Bureau. Barbui:Novartis: Speakers Bureau. Etienne:ARIAD: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: Congress Travel/Accomodations, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau. Roy:Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding. te Boekhorst:Novartis: Consultancy; CTI Biopharma: Consultancy. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Speakers Bureau; Novartis: Other: Research Funding paid to institution (University of Florence), Research Funding; Baxalta: Membership on an entity's Board of Directors or advisory committees. Mesa:Novartis. Research- incyte, Gilead, cti, Genentech, promedior, NS Pharma: Consultancy.

Introduction: Despite advances in treatment strategy, multiple myeloma (MM) remains a challenging, incurable disease as patients (pts) often relapse. Here we describe preclinical data of a novel cereblon (CRBN) E3 ligase modulatory compound (CELMoD), iberdomide (IBER; CC-220), as well as clinical and translational data from a current phase 1/2 clinical trial (NCT02773030). These data support a differentiated profile for IBER from immunomodulatory agents (IMiD agents), and development of IBER as a foundation of combination therapy for the treatment of relapsed/refractory MM (RRMM). Methods: Preclinical analyses were performed on pomalidomide (POM)-sensitive and acquired-resistant MM cell lines and peripheral blood mononuclear cells from healthy volunteers. Eligible pts enrolled on the clinical trial had RRMM and had received ≥ 2 prior regimens, containing at least an IMiD agent and proteasome inhibitor (PI), and had experienced disease progression within 60 days of last MM therapy. Escalating doses of IBER were given on Days 1-21, in combination with dexamethasone (DEX; 40 mg; 20 mg in pts aged > 75 years) on Days 1, 8, 15, and 22, of each 28-day cycle. Immunohistochemistry (IHC) data on CRBN, Ikaros, Aiolos, and ZFP91 expression was obtained from pt bone marrow specimens at screening and at Cycle 2, Day 15. Immune profiling was evaluated by flow cytometry of peripheral blood at Cycle 1, Day 1 and Cycle 2, Day 15. Primary objectives were to evaluate maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), safety, and preliminary efficacy. Results: Preclinically, IBER exhibited potent tumoricidal anti-MM and immunostimulatory activity. IBER was more potent than lenalidomide (LEN) or POM in overcoming the immunosuppressive activity of bortezomib (BORT), inducing a more than twofold increase in T cell proliferation in the presence of BORT. IBER also enhanced the antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity of daratumumab (DARA), leading to deeper responses than combinations with LEN or POM. Further differentiating from both LEN and POM, IBER showed activity alone and in combination with BORT or DARA in POM-resistant MM cell lines. As of June 28, 2019, 69 pts with RRMM had received IBER + DEX. Median age was 65 years (range 33-80), and median number of prior regimens was 5 (range 2-12). Prior therapies included autologous stem cell transplantation (80%), LEN (100%), POM (70%), PIs (100%), DARA (71%) and anti-BCMA (6%), including CAR T cells. Clinical activity was observed across all dose levels with an overall response rate (ORR) of 29%, clinical benefit rate of 45%, and disease control rate of 80%. ORR was 30%, 28% and 29% in IMiD agent-refractory, DARA-refractory and Quad-class (IMiD agents/PIs/steroids/CD-38 antibodies)-refractory pts, respectively. IBER + DEX showed a favorable safety profile, with grade 3-4 neutropenia, infections, and thrombocytopenia, occurring in 29%, 25%, and 12% of pts, respectively. To date, IBER doses range from 0.3 to 1.3 mg and the MTD/RP2D has not yet been reached. Pharmacodynamic immunophenotyping changes were dose-dependent. Treatment with IBER (at doses > 0.75mg) + DEX doubled the percentage of proliferating T cells and NK cells (P < 0.001 for each) and increased activated and effector memory CD8+ and CD4+ T cells by > 50% (P < 0.01 for each subset). Pharmacodynamic changes in pt bone marrow by quantitative IHC scoring showed significant degradation of substrates (Ikaros, P = 0.006; Aiolos, P < 0.001; ZFP91, P < 0.001) and downregulation of c-myc (P = 0.027), including in pts refractory to POM and with low CRBN expression. Conclusions: IBER + DEX has shown notable clinical activity and favorable tolerability in heavily pretreated pts with RRMM, including pts refractory to prior IMiD therapy. Preclinical and translational data suggest a differentiated profile of IBER from IMiD agents in regard to activity in POM-resistant models, potency in combination with BORT and DARA, and by inducing changes in CD4+ T cells that were not observed in pts treated with POM from prior studies. Taken together, these data support a differentiated profile for IBER from IMiD agents, and the clinical development of IBER as a foundation of combination therapy for the treatment of RRMM. This study is ongoing, and includes cohorts evaluating the combinations of IBER + DEX with DARA, BORT, and carfilzomib. Updated results will be presented at the meeting. Disclosures Lonial: Karyopharm: Consultancy; GSK: Consultancy; Takeda: Consultancy, Research Funding; Celgene Corporation: Consultancy, Research Funding; Amgen: Consultancy; Genentech: Consultancy; Janssen: Consultancy, Research Funding; BMS: Consultancy. Amatangelo:Celgene Corporation: Employment, Equity Ownership. Popat:Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria; Takeda: Honoraria, Other: travel, accommodations, expenses; Janssen: Honoraria, Other: travel support to meetings. Minnema:Gilead: Honoraria; Celgene Corporation: Honoraria, Research Funding; Amgen: Honoraria; Servier: Honoraria; Jansen Cilag: Honoraria. Zonder:Alnylam: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Intellia: Consultancy, Membership on an entity's Board of Directors or advisory committees; Caelum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Larsen:Janssen Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Oriol Rocafiguera:Celgene Corporation: Consultancy, Speakers Bureau; Janssen: Consultancy; Amgen: Consultancy, Speakers Bureau. Rodriguez Otero:Celgene Corporation: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria; Takeda: Consultancy; BMS: Honoraria; Kite Pharma: Consultancy. Badros:Celgene Corporation: Consultancy; Amgen: Consultancy. Siegel:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Jagannath:Bristol-Myers Squibb: Consultancy; Janssen Pharmaceuticals: Consultancy; Karyopharm Therapeutics: Consultancy; AbbVie: Consultancy; Merck & Co.: Consultancy; Celgene Corporation: Consultancy. Bringhen:Bristol-Myers Squibb: Honoraria; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy. Gironella:Amgen: Honoraria; Janssen: Honoraria; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kaiser:Takeda, Janssen, Celgene, Amgen: Honoraria, Other: Travel Expenses; Abbvie, Celgene, Takeda, Janssen, Amgen, Abbvie, Karyopharm: Consultancy; Celgene, Janssen: Research Funding. Cook:Janssen, Takeda, Sanofi, Karyopharm, Celgene: Consultancy, Honoraria, Speakers Bureau; Amgen, Bristol-Myers Squib, GlycoMimetics, Seattle Genetics, Sanofi: Honoraria; Celgene, Janssen-Cilag, Takeda: Honoraria, Research Funding. Gamberi:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sonneveld:SkylineDx: Research Funding; Takeda: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Honoraria; Amgen: Honoraria, Research Funding. Nguyen:Celgene Corporation: Employment, Equity Ownership. Chen:Celgene Corporation: Employment, Equity Ownership. Homan:Celgene Corporation: Employment. Bjorklund:Celgene Corporation: Employment, Equity Ownership. Wang:Celgene Corporation: Employment, Equity Ownership. Pierceall:Celgene Corporation: Employment, Equity Ownership. Bensmaine:Celgene Corporation: Employment, Equity Ownership. Thakurta:Celgene: Employment, Equity Ownership. Peluso:Celgene Corporation: Employment. Van De Donk:Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; AMGEN: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees.

Abstract Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3′ region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25–2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63–5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71–4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12–11.54; P = 0.0002). No genotype–phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. Significance: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.

Abstract INTRODUCTION The impact of treatment on both the quality and the quantity of life, i.e. the ‘net clinical benefit’, should be considered to facilitate shared decision making. Two methods that combine survival and health-related quality of life (HRQoL) data: Quality Adjusted Effect Sizes (QASES) and Joint Modelling (JM) were applied to gain insight in the net clinical benefit. METHODS The net clinical benefit in one RCT (EORTC 26951 comparing radiotherapy (RT) + PCV chemotherapy versus RT alone) was calculated as a proof of concept for other trials. With the QASES method, effect sizes for differences in survival and HRQoL between treatment arms were calculated. JM allows simultaneous modeling of a longitudinal outcome (HRQoL), and a time-to event outcome (survival). HRQoL scales/items that were selected for primary analysis in the main study were also selected for this analysis: fatigue, global health, social functioning, communication deficit, seizures, physical functioning, and nausea/vomiting. RESULTS 288/386 patients completed baseline HRQoL forms and were included in the analysis. Overall survival (OS) was significantly longer with combined treatment (42.3 vs. 30.6 months). The percentage of patients who experienced a clinically relevant deterioration (≥10 points) in nausea/vomiting, fatigue, social functioning and global health up to one year after treatment compared to baseline was larger in the RT+PCV arm. QASES corresponded to a reduction in the median OS difference from 9.7 months up till 5.5 months, given equal weights to OS and HRQoL. JM analyses resulted in a theoretical loss of treatment effect in OS of 2–6% when adjusting for HRQoL. CONCLUSION Both methods showed that adjusting for the impact of treatment on a relevant HRQoL parameter reduced the survival benefit in the experimental treatment arm compared to standard treatment arm. Applying these methods may facilitate communicating the impact of treatment to patients in clinical practice.

Abstract BACKGROUND A major impediment to improving neuro-oncology outcomes is poor clinical trial accrual. METHODS We convened a multi-stakeholder group including Society for Neuro-Oncology, Response Assessment in Neuro-Oncology, patient advocacy groups, clinical trial cooperative groups, and other partners to determine how we can improve trial accrual. RESULTS We described selected factors contributing to poor trial accrual and possible solutions. We focused on patient and community factors, disparities, physician and provider factors, clinical trial factors, and site and organizational factors CONCLUSIONS We will implement strategies with the intent to double accrual to neuro-oncology trials over the next 5 years.

BACKGROUND The midface is an area of high demand for minimally invasive cosmetic procedures, that is, soft-tissue filler injections. OBJECTIVE To investigate the functional anatomy behind the facial overfilled syndrome observed after soft-tissue filler injections. MATERIALS AND METHODS The clinical part of the study enrolled 25 volunteers (12 men and 13 women, Caucasians); the anatomical part included 72 fresh frozen cephalic specimens obtained from 32 male and 40 female body donors. 3D surface scanning procedures were applied to calculate the maximal anterior projection of the midface. RESULTS Upon smiling, the point of maximal anterior projection shifted cranially in men by 12.43 ± 8.8 mm (difference between resting and smiling; p < .001) and by 8.75 ± 4.1 mm in women (p < .001). Cadaveric dissections identified a septum originated from the underside of the zygomaticus major muscle forming a transversely running boundary between the buccal space and the deep midfacial fat compartments. CONCLUSION Facial overfilled syndrome can potentially be explained by the presence of the transverse facial septum. Dynamic filling—injecting small amounts of filler and asking the patient to smile repeatedly during the procedure—seems to be a viable way to avoid this adverse event during soft-tissue filler injection.

The recent advent of endovascular procedures has created the unique opportunity to collect and analyze thrombi removed from cerebral arteries, instigating a novel subfield in stroke research. Insights into thrombus characteristics and composition could play an important role in ongoing efforts to improve acute ischemic stroke therapy. An increasing number of centers are collecting stroke thrombi. This paper aims at providing guiding information on thrombus handling, procedures, and analysis in order to facilitate and standardize this emerging research field.