Hybrid management of a ruptured right subclavian artery aneurysm dissection

Aberrant right subclavian artery is the most common congenital malformation of the aortic arch (0.4%-2.0%). Aneurysms of aberrant subclavian arteries are extremely rare. This results in little experience with their treatment. We describe a case of a patient who presented to the emergency department with a dissection of an aberrant right subclavian artery that later progressed to rupture. Besides hemodynamic instability, this caused an acute superior vena cava syndrome, making airway control difficult. In the operating room, we obtained proximal control through thoracic endovascular aortic repair; median sternotomy was performed for distal control and evacuation of massive hemomediastinum

Phase III randomized study of taselisib or placebo with fulvestrant in estrogen receptor-positive, PIK3CA-mutant, HER2-negative, advanced breast cancer: the SANDPIPER trial

Background: The phase III SANDPIPER study assessed taselisib (GDC-0032), a potent, selective PI3K inhibitor, plus fulvestrant in estrogen receptor-positive, HER2-negative, PIK3CA-mutant locally advanced or metastatic breast cancer. Patients and methods: Postmenopausal women with disease recurrence/progression during/after an aromatase inhibitor were randomized 2 : 1 to receive taselisib (4 mg; taselisib arm) or placebo (placebo arm) plus fulvestrant (500 mg). Stratification factors were visceral disease, endocrine sensitivity, and geographic region. Patients with PIK3CA-mutant tumors (central cobas® PIK3CA Mutation Test) were randomized separately from those without detectable mutations. The primary endpoint was investigator-assessed progression-free survival (INV-PFS) in patients with PIK3CA-mutant tumors. Secondary endpoints included objective response rate, overall survival, clinical benefit rate, duration of objective response, PFS by blinded independent central review (BICR-PFS), safety, and time to deterioration in health-related quality of life. Results: The PIK3CA-mutant intention-to-treat population comprised 516 patients (placebo arm: n = 176; taselisib arm: n = 340). INV-PFS was significantly improved in the taselisib {7.4 months [95% confidence interval (CI), 7.26-9.07]} versus placebo arm (5.4 months [95% CI, 3.68-7.29]) (stratified hazard ratio [HR] 0.70; 95% CI, 0.56-0.89; P = 0.0037) and confirmed by BICR-PFS (HR 0.66). Secondary endpoints, including objective response rate, clinical benefit rate, and duration of objective response, showed consistent improvements in the taselisib arm. Safety was assessed in all randomized patients who received at least one dose of taselisib/placebo or fulvestrant regardless of PIK3CA-mutation status (n = 629). Serious adverse events were lower in the placebo versus taselisib arm (8.9% versus 32.0%). There were more discontinuations (placebo arm: 2.3%; taselisib arm: 16.8%) and dose reductions (placebo arm: 2.3%; taselisib arm: 36.5%) in the taselisib arm. Conclusion: SANDPIPER met its primary endpoint; however, the combination of taselisib plus fulvestrant has no clinical utility given its safety profile and modest clinical benefit

Alpelisib plus fulvestrant in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4/6 inhibitor (BYLieve): one cohort of a phase 2, multicentre, open-label, non-comparative study.

Background Alpelisib, a PI3Kα-selective inhibitor and degrader, plus fulvestrant showed efficacy in hormone receptor-positive, HER2-negative, PIK3CA-mutated advanced breast cancer in SOLAR-1; limited data are available in the post-cyclin-dependent kinase 4/6 inhibitor setting. BYLieve aimed to assess alpelisib plus endocrine therapy in this setting in three cohorts defined by immediate previous treatment; here, we report results from cohort A.Methods This ongoing, phase 2, multicentre, open-label, non-comparative study enrolled patients with hormone receptor-positive, HER2-negative, advanced breast cancer with tumour PIK3CA mutation, following progression on or after previous therapy, including CDK4/6 inhibitors, from 114 study locations (cancer centres, medical centres, university hospitals, and hospitals) in 18 countries worldwide. Participants aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 2 or less, with no more than two previous anticancer treatments and no more than one previous chemotherapy regimen, were enrolled in three cohorts. In cohort A, patients must have had progression on or after a CDK4/6 inhibitor plus an aromatase inhibitor as the immediate previous treatment. Patients received oral alpelisib 300 mg/day (continuously) plus fulvestrant 500 mg intramuscularly on day 1 of each 28-day cycle and on day 15 of cycle 1. The primary endpoint was the proportion of patients alive without disease progression at 6 months per local assessment using Response Evaluation Criteria in Solid Tumors, version 1.1, in patients with a centrally confirmed PIK3CA mutation. This trial is registered with ClinicalTrials.gov, NCT03056755.Findings Between Aug 14, 2017, and Dec 17, 2019 (data cutoff), 127 patients with at least 6 months' follow-up were enrolled into cohort A. 121 patients had a centrally confirmed PIK3CA mutation. At data cutoff, median follow-up was 11·7 months (IQR 8·5-15·9). 61 (50·4%; 95% CI 41·2-59·6) of 121 patients were alive without disease progression at 6 months. The most frequent grade 3 or worse adverse events were hyperglycaemia (36 [28%] of 127 patients), rash (12 [9%]), and rash maculopapular (12 [9%]). Serious adverse events occurred in 33 (26%) of 127 patients. No treatment-related deaths were reported.Interpretation BYLieve showed activity of alpelisib plus fulvestrant with manageable toxicity in patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative advanced breast cancer, after progression on a CDK4/6 inhibitor plus an aromatase inhibitor.Funding Novartis Pharmaceuticals

Frontline Sequential Immunochemotherapy Plus Lenalidomide for Mantle Cell Lymphoma Incorporating MRD Evaluation: Phase II, Investigator-Initiated, Single-Center Study

Background: Fit patients (pts) with mantle cell lymphoma (MCL) are commonly treated with immunochemotherapy and consolidative high-dose therapy + stem cell rescue (cHDT/SCR), yet this approach has not demonstrated an overall survival (OS) benefit in a randomized trial. Outcomes for pts with high-risk MCL (TP53 aberrancy, high proliferation index, blastic histology) after cHDT/SCR are poor, and not all pts with MCL are eligible for this approach. Methods: We conducted a phase II study of sequential immunochemotherapy incorporating lenalidomide enriching for pts with high-risk disease features (defined as blastoid/pleomorphic histology and/or Ki67 >=30%). The three phases of tx were: 1) lenalidomide (15 mg daily, days 1-14) plus R-CHOP for four 21-day cycles; 2) R-HiDAC for 2 cycles (initially age-based cytarabine 1-3 g/m2; 3 g/m2 dose removed after 16 pts due to hematologic toxicity); and 3) rituximab monthly plus lenalidomide (15 mg daily) for 6 months (mos). Eligibility requirements were untreated stage II-IV MCL, KPS ≥70%, and adequate organ function; we sought ≥2/3 high-risk pts. We performed MRD testing on peripheral blood (cellular DNA) using the clonoSEQ Assay (Adaptive Biotechnologies). We obtained PET/CT and MRD testing after each phase of treatment and also MRD evaluation at 6 mos post-rituximab + lenalidomide maintenance. The primary endpoint was the rate of 3-yr progression-free survival (PFS), (acceptable PFS ≥75%, unacceptable ≤60%, based on desired proportion of high-risk pts). Results: Among 49 pts enrolled, 47 were evaluable for PFS (1 had progressive disease (PD) and 1 had toxicity during len-R-CHOP). Characteristics for 47 evaluable pts are shown in Table 1: 64% were high-risk and 18% had TP53 mutation. 45 completed maintenance (1 had PD during R-HiDAC and 1 withdrew to pursue cHDT/SCR) and 43 achieved complete response (CR), 1 stable disease, and 1 PD at end of treatment (EoT), yielding overall response rate of 91%, all CR (Figure 1). With a median follow-up of 2.8 yrs among survivors, the 3-yr PFS was 64% (95 CI 50, 82) and OS 85% (95 CI 74, 99). Three-yr PFS differed by TP53 status (14% mut vs. 85% wt, P < 0.0001, Table 2). Of 4 pts with PD, 3 had TP53 mutation and 1 had an unknown mutation status. Among TP53 wt pts, there was no significant difference in outcomes by risk (Table 2). MRD results were not obtained in 4 pts. Among 45 pts with MRD results, tumor clonal characterization for MRD evaluation was successful in 87% (39/45). MRD results are shown in Figure 2. Examining the initial phase of treatment (len-R-CHOP and R-HiDAC), among 37 pts with results at 1x10-5 sensitivity (1E5) following len-RCHOP, a substantial proportion (32%, 12/37 pts) remained MRD+ and 11 of 12 MRD+ pts post len-RCHOP converted to MRD- following R-HiDAC. At 1x10-6 sensitivity (1E6) following R-HiDAC, 5/20 pts were MRD+, and among responding pts, shorter median PFS was observed in MRD+ versus MRD- pts (23.1 mos vs. NR, P = 0.03). Examining the final phase of treatment (rituximab + lenalidomide maintenance) and observation period, among 37 pts with MRD results at 1E5 at EoT, 4 were MRD+, 2 of which were simultaneous (within 2 weeks of testing) with relapse; the remaining two MRD+ pts had median PFS 4.9 mos versus 37.4 mos for the 32 non-relapsed MRD- pts (P < 0.001). At 1E6, 6 pts who were MRD- at EoT converted to MRD+ after 6 mos of observation. MRD status at 1E6 at 6-mos post-EOT correlated with PFS: among 20 non-relapsed pts (6 MRD+, 14 MRD-), median PFS was 30.8 mos for MRD- versus 13.2 mos for MRD+ (P = 0.02). Conclusions: In a novel approach of sequential immunochemotherapy plus lenalidomide enrolling majority high-risk pts, outcomes for TP53-mutant pts were poor and we did not reach our primary endpoint of 3-yr PFS ≥75%. Among TP53-wt pts, this treatment program was highly effective even among pts with elevated Ki-67 (>=30%) and was associated with a high response rate, a 3-yr rate of PFS of 85%, and a high rate of MRD- at EoT. A substantial proportion of pts converted to MRD- after receipt of R-HiDAC, highlighting the efficacy of cytarabine in MCL. There was a high rate of MRD- after induction chemoimmunotherapy (Len-R-CHOP + R-HiDAC) at 1E5 (97%) and at 1E6 (80%), and the latter predicted remission duration. Several pts converted from MRD- to MRD+ at 6-mos post-EOT and eventually relapsed, suggesting that a more prolonged period of maintenance may be beneficial. Finally, MRD at 1E6 at 6 mos following EoT predicted response duration. Disclosures Batlevi: Life Sci, GLG, Juno/Celgene, Seattle Genetics, Kite: Consultancy; Janssen, Novartis, Epizyme, Xynomics, Bayer, Autolus, Roche/Genentech: Research Funding. Dogan:National Cancer Institute: Research Funding; EUSA Pharma: Consultancy; Takeda: Consultancy; Seattle Genetics: Consultancy; Corvus Pharmaceuticals: Consultancy; Physicians Education Resource: Consultancy; Roche: Consultancy, Research Funding; AbbVie: Consultancy. Drullinsky:Novartis: Research Funding; Roche: Research Funding. Gerecitano:Janssen: Current Employment. Hamlin:Portola Pharmaceutics: Consultancy; J&J Pharmaceuticals: Research Funding; Juno Therapeutics: Consultancy; Celgene: Consultancy; Incyte: Research Funding; Molecular Templates: Research Funding; Portola: Research Funding; Karyopharm: Consultancy. Ho:Invivoscribe, Inc.: Honoraria. Jacob:Adaptive Biotechnologies: Current Employment, Current equity holder in publicly-traded company. Matasar:Rocket Medical: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy; Takeda: Consultancy, Honoraria; GlaxoSmithKline: Honoraria, Research Funding; IGM Biosciences: Research Funding; Janssen: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Immunovaccine Technologies: Honoraria, Research Funding; Merck: Consultancy; Bayer: Consultancy, Honoraria, Research Funding; Juno Therapeutics: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Teva: Consultancy; Genentech, Inc.: Consultancy, Honoraria, Research Funding. Moskowitz:Incyte: Research Funding; Imbrium Therapeutics, L.P.: Consultancy; Seattle Genetics: Consultancy; Miragen Therapeutics: Consultancy; Merck: Consultancy; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Merck: Research Funding. Mullins:Adaptive Biotechnologies: Current Employment, Other: shareholder. Straus:Elsevier: Membership on an entity's Board of Directors or advisory committees, Other: CME writer; NY Lymphoma Rounds: Consultancy; Imedex, Inc.: Speakers Bureau; Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees; Targeted Oncology: Consultancy, Speakers Bureau; ASH: Other: Conference in December 2019 on HL to other physicians during ASH; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; OncLive: Speakers Bureau; Takeda Pharmaceuticals: Research Funding, Speakers Bureau. Younes:BioPath: Consultancy; Daiichi Sankyo: Consultancy; Takeda: Consultancy; Novartis: Consultancy; AstraZeneca: Current Employment; BMS: Consultancy; Curis: Consultancy; Epizyme: Consultancy; HCM: Consultancy; Janssen: Consultancy. Zelenetz:Amgen: Consultancy; Celgene: Research Funding; Genentech/Roche: Consultancy; Sandoz: Research Funding; Novartis: Consultancy; Janssen: Consultancy; Adaptive Biotechnology: Consultancy; Celgene: Consultancy; Gilead: Consultancy; BeiGene: Membership on an entity's Board of Directors or advisory committees; Gilead: Research Funding; MorphoSys: Research Funding; MEI Pharma: Research Funding; Roche: Research Funding. Kumar:Celgene: Honoraria, Other: Honoraria for Advisory Board; Astra Zeneca: Honoraria, Other: Honoraria for Advisory Board; Celgene: Research Funding; Pharmacyclics: Research Funding; Adaptive Biotechnologies,: Research Funding; AbbVie: Research Funding; Seattle Genetics: Research Funding; Kite Pharmaceuticals: Honoraria, Other: Honoraria for Advisory Board

Interim Analysis from a Prospective Multicenter Study of Next-Generation Sequencing Minimal Residual Disease Assessment and CT Monitoring for Surveillance after Frontline Treatment in Diffuse Large B-Cell Lymphoma

Background: Diffuse large B-cell lymphoma (DLBCL) is frequently curable after frontline therapy, however, relapses can occur after achievement of a PET-negative complete remission (CR). Early detection of relapse may be associated with improved outcomes with second-line curative intent therapy or novel therapies. Controversy exists regarding the utility of post-therapy surveillance imaging which is associated with patient (pt) anxiety, radiation exposure, false-positive results, and cost. A retrospective study found that serial minimal residual disease (MRD) monitoring during DLBCL surveillance could identify pts at risk of relapse before clinical evidence of disease (Roschewski, Lancet Oncol, 2015). In this multicenter prospective study, we assessed whether a next-generation sequencing (NGS)-based MRD assay could be used for early detection of molecular relapse in DLBCL. Methods: Eligible pts with DLBCL or high-grade B-cell lymphoma (HGBCL) who received anthracycline-containing chemotherapy were enrolled across five cancer centers. In pts who achieved a PET-negative CR, serial peripheral blood samples were obtained every 3 months (mos) and CT scans every 6 mos for 2 years (yrs) post-treatment. The clonoSEQ® next generation sequencing (NGS) MRD assay (Adaptive Biotechnologies, Seattle, WA) that leverages multiplex PCR followed by NGS to identify and track rearrangements of IgH, V-J, D-J and IgK/L loci and translocations in Bcl1/2-IgH was used. MRD positive was defined as any detectable rearrangement and MRD negative as no evidence of rearrangement. We also reported MRD positivity above the limit of detection (LOD) (observations required to have 95% reproducibility). Interim futility analysis was performed after approximately 50% of anticipated relapses occurred to assess the preliminary sensitivity of the assay. Progression-free survival (PFS) was defined as time from treatment start date to relapse or death. Results: 501 pts were enrolled and 401 were evaluable (pre-treatment tumor pathology available, completed frontline treatment, and achieved PET-negative CR at end-of-treatment). Baseline characteristics were median age of 62 yrs (range 19-95), male sex 58%, advanced stage 61%, and poor-risk by R-IPI 40% (Table 1). Histologies included DLBCL, NOS (86%), primary mediastinal B-cell lymphoma (6%), HGBCL (5%), T-cell rich B-cell lymphoma (1%), and other (1%). Pts received regimens including RCHOP x 6 cycles (36%), REPOCH x 6 cycles (20%), clinical trial (15%), combined modality therapy (RCHOP+RT) (10%), and other RCHOP variations (19%). Among the 401 evaluable pts, 44 relapses have occurred as of June 1, 2020. In 47% of pts (18/38), clinical relapse was detected using surveillance imaging alone (typically CT CAP with IV contrast) in an otherwise asymptomatic pt with a normal physical exam and laboratory evaluation. Clinical relapse was detected by clinical symptoms alone in 11% (4/28), by the evaluation of an oncologist alone in 0%, and by imaging and clinical symptoms and/or evaluation by an oncologist in 42% (16/38) (missing data in 6 pts). With a median follow-up of 2.2 yrs, the 2-yr PFS was 88.1% (84.8, 91.4) (Figure 1). Advanced age, advanced stage, and poor-risk R-IPI were associated with inferior PFS. Of the 44 relapses, 43 pts were included in the interim analysis and tumor-specific clonotypes were identified in 39 pts (91%). In 56% (22/39), the MRD assay was positive at or before clinical relapse. In 38% (15/39), the MRD assay was positive above the limit of detection at or prior to clinical relapse, with only 10 relapses detected more than 3 mos prior to relapse, reflecting the poor clinical sensitivity of the assay. The NGS-MRD assay was more sensitive in the acellular (plasma cell-free DNA) than in the cellular (circulating leukocytes) compartment. Results: Overall outcomes are excellent for DLBCL and HGBCL pts who achieve PET-negative complete remission. In interim analysis, surveillance MRD assessment using the clonoSEQ® assay fails to consistently identify pts at risk of recurrence before clinical evidence of relapse in DLBCL. In a prospective analysis, a substantial proportion (47%) of clinical relapses are detected by imaging in asymptomatic pts, supporting the value of CT surveillance imaging in DLBCL, particularly for pts with advanced stage or high-risk disease. Additional analyses are forthcoming for MRD assessment in all pts, including those in remission. Disclosures Kumar: Celgene: Research Funding; Pharmacyclics: Research Funding; Adaptive Biotechnologies,: Research Funding; AbbVie: Research Funding; Seattle Genetics: Research Funding; Celgene: Honoraria, Other: Honoraria for Advisory Board; Astra Zeneca: Honoraria, Other: Honoraria for Advisory Board; Kite Pharmaceuticals: Honoraria, Other: Honoraria for Advisory Board. Westin:Kite: Consultancy, Research Funding; Curis: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Amgen: Consultancy; Astra Zeneca: Consultancy, Research Funding; Morphosys: Consultancy, Research Funding; 47: Research Funding; Janssen: Consultancy, Research Funding; BMS: Consultancy, Research Funding. Nowakowski:Curis: Consultancy; Seattle Genetics: Consultancy; Nanostrings: Research Funding; MorphoSys: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Kite: Consultancy; Denovo: Consultancy; Kymera: Consultancy; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other. Lossos:Verastem: Consultancy, Honoraria; Seattle Genetics: Consultancy, Other; NCI: Research Funding; Stanford University: Patents & Royalties; Janssen Biotech: Honoraria; Janssen Scientific: Consultancy, Other. Batlevi:Life Sci, GLG, Juno/Celgene, Seattle Genetics, Kite: Consultancy; Janssen, Novartis, Epizyme, Xynomics, Bayer, Autolus, Roche/Genentech: Research Funding. Drullinsky:Roche: Research Funding; Novartis: Research Funding. Gerecitano:Janssen: Current Employment. Hamlin:Celgene: Consultancy; Karyopharm: Consultancy; Juno Therapeutics: Consultancy; Portola: Research Funding; Molecular Templates: Research Funding; Incyte: Research Funding; J&J Pharmaceuticals: Research Funding; Portola Pharmaceutics: Consultancy. Horwitz:ASTEX: Consultancy; Affirmed: Consultancy; Vividion Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Myeloid Therapeutics: Consultancy; Miragen: Consultancy; Kura Oncology: Consultancy; Janssen: Consultancy; GlaxoSmithKline: Consultancy; Daiichi Sankyo: Research Funding; C4 Therapeutics: Consultancy; Beigene: Consultancy; Portola: Consultancy, Research Funding; Mundipharma: Consultancy; Innate Pharma: Consultancy; Corvus: Consultancy; Trillium: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Infinity/Verastem: Research Funding; Forty Seven: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Aileron: Consultancy, Research Funding; ADCT Therapeutics: Consultancy, Research Funding. Jacob:Adaptive Biotechnologies: Current Employment, Current equity holder in publicly-traded company. Joffe:AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees. von Keudell:Bayer: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding. Lahoud:MorphoSys: Other: Advisory Board. Matasar:Bayer: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Rocket Medical: Consultancy, Research Funding; Teva: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Daiichi Sankyo: Consultancy; IGM Biosciences: Research Funding; Janssen: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Immunovaccine Technologies: Honoraria, Research Funding; Merck: Consultancy; Juno Therapeutics: Consultancy; Genentech, Inc.: Consultancy, Honoraria, Research Funding. Mullins:Adaptive Biotechnologies: Current Employment, Other: shareholder. Noy:Pharmacyclics: Research Funding; NIH: Research Funding; Rafael Pharma: Research Funding; Janssen: Consultancy; Pharmacyclics: Consultancy; Medscape: Consultancy; Targeted Oncology: Consultancy; Morphosys: Consultancy. Straus:Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; ASH: Other: Conference in December 2019 on HL to other physicians during ASH; Elsevier: Membership on an entity's Board of Directors or advisory committees, Other: CME writer; OncLive: Speakers Bureau; Takeda Pharmaceuticals: Research Funding, Speakers Bureau; NY Lymphoma Rounds: Consultancy; Targeted Oncology: Consultancy, Speakers Bureau; Imedex, Inc.: Speakers Bureau; Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees. Younes:Takeda: Consultancy; HCM: Consultancy; AstraZeneca: Current Employment; Novartis: Consultancy; Daiichi Sankyo: Consultancy; Janssen: Consultancy; Epizyme: Consultancy; BMS: Consultancy; BioPath: Consultancy; Curis: Consultancy. Zelenetz:MEI Pharma: Research Funding; MorphoSys: Research Funding; Sandoz: Research Funding; Celgene: Research Funding; Roche: Research Funding; Gilead: Research Funding; Genentech/Roche: Consultancy; Gilead: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Novartis: Consultancy; Adaptive Biotechnology: Consultancy; BeiGene: Membership on an entity's Board of Directors or advisory committees