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Purpose/Objective(s) Anti-CD19-directed chimeric antigen receptor T-cell therapy (CART) is a new treatment option for patients with relapsed and/or refractory non-Hodgkin lymphoma (NHL). We reviewed the outcomes of patients receiving CART and the potential role of bridging radiation therapy (bRT) in reducing local recurrences. Materials/Methods Following IRB approval, we retrospectively reviewed 120 patients with NHL who received CART between 2018 and 2020 at a multi-site single institution. Baseline clinical and treatment characteristics were compared between patients who received bRT (≤30 days prior to CART or after leukapheresis) and those who did not using chi-square and Fisher's exact tests. Overall-survival (OS) and progression-free survival (PFS) were defined from date of CART infusion and estimated by Kaplan-Meier curves. Response rate was based on the post-CART PET scan with the best attained response. Results Of 120 patients who received CART, 2 (1.7%) died soon after CART infusion from infection. Of the 118 remaining patients (88% diffuse large B-cell, 7.5% high-grade B-cell, 2.5% mantle cell, 2% primary mediastinal B-cell), 14 (12%) received bRT, while 104 (88%) did not (noRT). There were no significant differences in the baseline clinicopathological characteristics between the two groups. bRT was delivered with a median dose of 20 Gy (range 15-36) in 5 fractions (range: 3-24). No grade 2+ radiation-related toxicities were noted. Median time between end of bRT and the CART infusion was 19 days (range: 8-38). Rates of grade > 2 ICANS (21% vs 16%; P = .70) and CRS (7% vs 2%; P = .32) were not significantly different between bRT and noRT, respectively. Median follow-up was 7 months (range: 1-31). There were 42 (36%) deaths: 31 due to progression, 9 due to infection and 2 of unknown causes. The 6-month and 1-year OS were 67% and 67% for the bRT, and 76% and 63% for the noRT groups, respectively (P = .96). The median time to CART failure for the cohort was 78 days (range: 22-627). The 6-month and 1-year PFS were 47% and 47% for the bRT, and 47% and 42% for the noRT groups, respectively (P = .73). Median time to achieve the best response on PET scan was 30 days (range 22-382). Sixty patients (51%) achieved complete remission to CART, 7 (50%) in the bRT group and 53 (51%) in the noRT group, while 40 (34%) achieved partial remission, 5 (36%) in the bRT group and 35 (34%) in the noRT group (P = .97). For the entire cohort, pattern of failure analysis revealed that progression in pre-existing sites alone or in combination with new sites was the predominant site of failure in the bRT and noRT groups (86% and 88%, respectively). However, 71.4% of progressions in the bRT group occurred outside the RT field (n = 5), compared to 28.6% (n = 2) inside the RT field. Conclusion Bridging RT prior to CAR T-cell infusion is well tolerated and appears to provide excellent in-field local control. Large prospective studies evaluating the value of integrating bRT with CAR T-cell therapy are needed.

The diagnosis of brain metastasis involves high morbidity and mortality and remains an unmet clinical need in spite of being the most common tumor in the brain. Exclusion of these cancer patients from clinical trials is a major cause of their limited therapeutic options. We report a novel drug-screening platform (METPlatform) based on organotypic cultures which allows identifying effective anti-metastasis agents in the presence of the organ microenvironment. By applying this approach to brain metastasis, we identified heat shock protein 90 (HSP90) as a promising therapeutic target for CNS dissemination. DEBIO-0932, a blood-brain barrier permeable HSP90 inhibitor, shows high potency against mouse and human brain metastases from different primary origin and oncogenomic profile at clinically relevant stages of the disease, including a novel model of local relapse after neurosurgery. Furthermore, in situ proteomic analysis of brain metastases treated with the chaperone inhibitor revealed non-canonical clients of HSP90 as potential novel mediators of brain metastasis and actionable mechanisms of resistance driven by autophagy. Combined therapy using HSP90 and autophagy inhibitors showed synergistic effects compared to sublethal concentrations of each monotherapy, demonstrating the potential of METPlatform to design and test rationale combination therapies to target metastasis more effectively. Finally, we have exploited METPlatform as “avatars” to show that brain tumor PDOCs predict response of the corresponding patient to standard of care, thus proving the potential of METPlatform for improving personalized care in cancer. In conclusion, our work validates METPlatform as a potent resource for metastasis research integrating drug-screening and unbiased omic approaches that is fully compatible with human samples and questions the rationale of excluding patients with brain metastasis from clinical trials. We envision that METPlatform will be established as a clinically relevant strategy to personalize the management of metastatic disease in the brain and elsewhere.

Comprehensive analysis of post-translational modifications (PTMs) often depends on the purification of modified peptides prior to LC-MS/MS. The implementation of these enrichment methods requires thorough knowledge of the experimental conditions to achieve optimal selectivity and sensitivity. In this regard, large-scale analysis of lysine acetylation, a key PTM for multiple cellular processes, makes use of monoclonal pan-antibodies designed against this moiety. We report that the immuno-purification of lysine-acetylated peptides is hampered by the copurification of lysine carbamylated peptides, a frequent urea artifact. This specific interaction can be explained by the similar chemical structures of lysine acetylation and lysine carbamylation. As an alternative, we propose a sample preparation protocol based on sodium deoxycholate that eliminates these artifacts and dramatically improves the selectivity and sensitivity of this immuno-purification assay.

Background: In CLL/SLL, ibrutinib treatment before leukapheresis improved in vivo and ex vivo expansion of the CD19-directed chimeric antigen receptor (CAR) T cell therapy tisagenlecleucel, and concurrent ibrutinib therapy improved engraftment and therapeutic efficacy of anti-CD19 CAR T cells in human xenograft mouse models (Fraietta et al. Blood. 2016;127:1117-27). Recent studies in patients with R/R CLL suggest that CD19-directed CAR T cell therapy combined with ibrutinib improves response rates with CTL119 and JCAR014 (Gill et al. Blood. 2018;132:298; Gauthier et al. Blood. 2020;135:1650-60). Liso-cel is an investigational, CD19-directed, defined composition, 4-1BB CAR T cell product administered at equal doses of CD8+ and CD4+ CAR+ T cells. We report initial safety and preliminary efficacy from the phase 1 liso-cel and ibrutinib combination cohort of the ongoing phase 1/2 TRANSCEND CLL 004 study (NCT03331198) in patients with R/R CLL/SLL. Methods: Eligible patients with CLL/SLL met ≥1 of the following: 1) received ibrutinib and progressed at time of study enrollment; 2) had high-risk features and received ibrutinib for ≥6 months (mo) with less than a complete response (CR); 3) had a Bruton tyrosine kinase (BTK) or PLCγ2 gene mutation, with or without progression on ibrutinib; 4) had received prior ibrutinib with no contraindication to reinitiating ibrutinib. Baseline disease assessments included bone marrow (BM) biopsy, complete blood count, lymphocyte enumeration, and CT scan. At enrollment, patients started or continued ibrutinib. Patients continued ibrutinib through leukapheresis and for ≥90 days after liso-cel infusion. Patients received liso-cel infusion at 50 × 106 (dose level [DL]1) or 100 × 106 (DL2) CAR+ T cells after 3 days of lymphodepletion with fludarabine/cyclophosphamide. Primary endpoints were safety and to determine the recommended dose (RD) of liso-cel in combination with ibrutinib for R/R CLL/SLL; overall response (OR) rate (CR + CR with incomplete blood count recovery [CRi] + partial response) and pharmacokinetics (PK) were exploratory endpoints. The RD was selected based on the modified toxicity probability interval algorithm. Results: At data cutoff, 19 patients received liso-cel (DL1, n=4; DL2, n=15) with ibrutinib. Median age was 60 (range, 50‒77) years, and 18 patients (95%) had high-risk cytogenetics (del[17p], n=8; TP53 mutation, n=6; unmutated IGHV, n=16). Patients had a median of 4 (range, 2‒11) prior therapies. All patients were R/R to prior ibrutinib; 14 patients (74%) had BTK inhibitor as last prior therapy and 10 (53%) had prior venetoclax. No dose-limiting toxicities were observed at either DL. The most common grade ≥3 treatment-emergent adverse events (TEAEs) were neutropenia/neutrophil count decrease (n=17; 89%), anemia (n=9; 47%), and febrile neutropenia (n=5; 26%; Table). Six patients had infections at DL2: grade 3 and grade 2 lung infection (n=1 each) and grade 2 coccidioidomycosis, scabies, skin, and gum infections (n=1 each). Ibrutinib-related AEs included diarrhea (n=7), hypertension (n=4), atrial fibrillation (n=1), and rash (n=1). No grade 5 TEAEs occurred. Fourteen patients (74%) had cytokine release syndrome (CRS; 1 grade 3) and 6 (32%) had neurological events (NEs; 3 grade ≥3). Seven patients (37%) required tocilizumab and/or corticosteroids to manage CRS and/or NEs. Preliminary PK data showed a median time to peak liso-cel expansion of 11 days across DLs (DL1, 12 days; DL2, 11 days). Of 19 patients with ≥1-mo follow-up, 18 (95%) had an OR (DL2, 100%; DL1, 75%) and 9 (47%) had a CR/CRi. One patient (5%) had stable disease. All ORs were achieved by Day 30 postinfusion, and 15 (83%) of 18 patients maintained their response at 3-mo follow-up. Of 19 patients evaluable for minimal residual disease (MRD), 17 (89%) achieved undetectable MRD in blood via flow cytometry and 15 (79%) in BM by next-generation sequencing (both sensitivity of ≤10-4). Conclusions: Preliminary data show that liso-cel in combination with ibrutinib is associated with manageable safety, including a low incidence of grade 3 CRS and grade ≥3 NEs, and promising efficacy in heavily pretreated patients with R/R CLL/SLL. No clear difference in safety was observed across DLs, and DL2 was selected as the RD for liso-cel in combination with ibrutinib in patients with R/R CLL/SLL. Updated results from the full combination cohort and additional PK/pharmacodynamic data will be reported. Table Disclosures Dorritie: Juno Therapeutics: Research Funding; Kite-Gilead: Research Funding. Munoz:Portola: Research Funding; Incyte: Research Funding; Acrotech/Aurobindo: Speakers Bureau; Alexion: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Fosunkite: Consultancy; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Innovent: Consultancy; Genentech/Roche: Research Funding, Speakers Bureau; Pfizer: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; Juno/Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Research Funding, Speakers Bureau; Beigene: Consultancy, Speakers Bureau; Millenium: Research Funding; Verastem: Speakers Bureau; Merck: Research Funding; AbbVie: Consultancy, Speakers Bureau; AstraZeneca: Speakers Bureau; Kyowa: Consultancy, Honoraria, Speakers Bureau. Stephens:Innate: Consultancy; Verastem: Research Funding; Beigene: Consultancy; Karyopharm: Consultancy, Research Funding; Acerta: Research Funding; Gilead: Research Funding; Juno: Research Funding; MingSight: Research Funding; Arqule: Research Funding; Janssen: Consultancy; Pharmacyclics: Consultancy. Gillenwater:Juno Therapeutics, a Bristol-Myers Squibb Company: Current Employment; Bristol-Myers Squibb: Current equity holder in publicly-traded company. Gong:Juno Therapeutics, a Bristol-Myers Squibb Company: Current Employment; Bristol-Myers Squibb: Current equity holder in publicly-traded company. Yang:Juno Therapeutics, a Bristol-Myers Squibb Company: Current Employment; Bristol-Myers Squibb: Current equity holder in publicly-traded company. Ogasawara:Bristol-Myers Squibb: Current Employment; Bristol-Myers Squibb: Current equity holder in publicly-traded company. Thorpe:Bristol-Myers Squibb: Current equity holder in publicly-traded company; Juno Therapeutics, a Bristol-Myers Squibb Company: Current Employment. Siddiqi:Astrazenca: Membership on an entity's Board of Directors or advisory committees; PCYC: Membership on an entity's Board of Directors or advisory committees; Juno: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; BeiGene: Other: DMC member; Juno Therapeutics, Pharmacyclics LLC, an AbbVie Company, AstraZeneca, Celgene, Kite Pharma, and BeiGene: Consultancy; Pharmacyclics LLC, an AbbVie Company, Juno Therapeutics, KITE Pharma, AstraZeneca, TG Therapeutics, Celgene, Oncternal, and BeiGene: Research Funding; Pharmacyclics LLC, an AbbVie Company, Seattle Genetics, Janssen, and AstraZeneca: Speakers Bureau; AstraZeneca: Other: Travel/accommodations/expenses.

Background: Patients with advanced-stage iNHL, including follicular lymphoma (FL) and marginal zone lymphoma (MZL), frequently relapse with standard treatment, underscoring a need for novel therapies. Axi-cel autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy is approved for the treatment of R/R large B cell lymphoma after ≥ 2 lines of systemic therapy. Here, we present the primary analysis of ZUMA-5, a Phase 2, multicenter, single-arm study of axi-cel in patients with R/R iNHL. Methods: Adults with FL (Grades 1-3a) or MZL (nodal or extranodal) had R/R disease after ≥ 2 lines of therapy (must include an anti-CD20 mAb plus an alkylating agent), and ECOG 0 - 1. Patients underwent leukapheresis followed by conditioning therapy (cyclophosphamide/fludarabine) and a single infusion of axi-cel at 2 × 106 CAR T cells/kg. The primary endpoint was objective response rate (ORR) by central review (per Lugano classification; Cheson, et al. J Clin Oncol. 2014). Secondary endpoints included complete response (CR) rate, duration of response (DOR), progression-free survival (PFS), overall survival (OS), incidence of adverse events (AEs), and levels of CAR T cells in blood and cytokines in serum. The primary efficacy analysis occurred when ≥ 80 treated patients with FL had ≥ 12-months follow-up. Results: As of 3/12/2020, 146 patients with iNHL (124 FL; 22 MZL) received axi-cel; 84 patients with FL had ≥ 12-months follow-up. The median age was 61 years (range, 34 - 79); 57% of patients were male. Thirty-eight percent of patients had ECOG 1, 86% had stage III/IV disease, 47% had ≥ 3 FLIPI, and 49% had high tumor bulk (GELF). Patients had a median 3 prior lines of therapy (range, 1 - 10); 64% had ≥ 3 prior lines. Progression < 2 years after initial chemoimmunotherapy (POD24) occurred in 55% of patients, and 68% were refractory to last prior treatment. Axi-cel was successfully manufactured for all enrolled patients. With a median follow-up of 17.5 months (range, 1.4 - 31.6), the ORR was 92% among efficacy-evaluable patients with iNHL (n = 104), with a 76% CR rate. In patients with FL (n = 84), the ORR was 94% (80% CR rate); in those with MZL (n = 20), the ORR was 85% (60% CR rate). ORR was comparable across key risk groups analyzed by FLIPI, POD24, GELF, refractory status, and prior lines of therapy. As of the data cutoff, 62% of all treated patients had ongoing responses (64% for FL). The medians for DOR, PFS, and OS were not reached; 12-month estimated rates were 72% (95% CI, 61 - 80), 74% (95% CI, 63 - 82), and 93% (95% CI, 86 - 97), respectively. AEs of any grade occurred in 99% of all treated patients. Grade ≥ 3 AEs occurred in 86% of patients with iNHL (85% in FL; 95% in MZL), most commonly neutropenia (33%), decreased neutrophil count (27%), and anemia (23%). Grade ≥ 3 cytokine release syndrome (CRS; per Lee, et al, Blood. 2014) occurred in 7% of patients with iNHL (6% in FL; 9% in MZL). Grade ≥ 3 neurologic events (NEs; per CTCAE v4.03) occurred in 19% of patients with iNHL (15% in FL; 41% in MZL). Most CRS (118/119) and NEs (81/87) of any grade resolved by data cutoff. Grade 5 AEs occurred in 3 patients: multisystem organ failure in the context of CRS (Day 7; related to axi-cel; n = 1 FL), aortic dissection (Day 399; unrelated to axi-cel; n = 1 FL), and coccidioidomycosis infection (Day 327; unrelated to axi-cel; n = 1 MZL). The median peak CAR T cell level was 38 cells/µL (range, 0 - 1415) in all treated patients with iNHL, with 36 cells/µL (range, 0 - 1415) in those with FL and 53 cells/µL (range, 2 - 453) in those with MZL. The AUC0 - 28 was 448 cells/µL × days (range, 6 - 19,900) in all treated patients with iNHL, with 422 cells/µL × days (range, 6 - 19,900) and 552 cells/µL × days (range, 13 - 6468) in those with FL and MZL, respectively. The median time to peak was 9 days (range, 8 - 371) in all patients, 8 days (range, 8 - 371) in patients with FL, and 15 days (range, 8 - 29) in patients with MZL. In efficacy-evaluable patients with FL, median peak CAR T cell levels were numerically greater in those with ongoing response at 12 months than in those who relapsed (P = .057). In all treated patients with FL, CAR T cell peak was associated with Grade ≥ 3 CRS (P = .031) and NEs (P = .005). Conclusions: Axi-cel had considerable and durable clinical benefit in patients with iNHL, with high ORR and CR rates. Axi-cel had a manageable safety profile, with lower rates of Grade ≥ 3 NEs observed in patients with FL vs those in patients with MZL and those previously reported in aggressive NHL (Locke, et al. Lancet Oncol. 2019). Disclosures Chavez: Genentech: Speakers Bureau; Epizyme: Speakers Bureau; Gilead: Consultancy; Verastem: Consultancy; Novartis: Consultancy; Kite, a Gilead Company: Consultancy, Speakers Bureau; Pfizer: Consultancy; Celgene: Consultancy; AstraZeneca: Speakers Bureau; Morphosys: Consultancy, Speakers Bureau; Merck: Research Funding; Bayer: Consultancy; BeiGene: Speakers Bureau; Karyopharm: Consultancy; AbbVie: Consultancy. Sehgal:Juno Therapeutics: Research Funding; TP Therapeutics: Research Funding; Prothena: Research Funding; Gilead Sciences: Research Funding; Bristol-Myers Squibb: Research Funding; Merck: Research Funding. William:Celgene: Consultancy, Honoraria; Incyte: Research Funding; Seattle Genetics: Research Funding; Merck: Research Funding; Dova: Research Funding; Guidepoint Global: Consultancy; Kyowa Kirin: Consultancy, Honoraria. Munoz:Incyte: Research Funding; Fosunkite: Consultancy; Innovent: Consultancy; Acrotech/Aurobindo: Speakers Bureau; Verastem: Speakers Bureau; AstraZeneca: Speakers Bureau; Genentech/Roche: Research Funding, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Kyowa: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Research Funding, Speakers Bureau; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy; Janssen: Consultancy, Research Funding, Speakers Bureau; Juno/Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; Alexion: Consultancy; Beigene: Consultancy, Speakers Bureau; Merck: Research Funding; Portola: Research Funding; Millenium: Research Funding. Salles:BMS/Celgene: Honoraria, Other: consultancy or advisory role; Kite, a Gilead Company: Honoraria, Other: consultancy or advisory role ; Epizyme: Honoraria, Other: consultancy or advisory role; Janssen: Honoraria, Other: consultancy or advisory role; MorphoSys: Honoraria, Other: consultancy or advisory role; Novartis: Honoraria, Other: consultancy or advisory role; Roche: Honoraria, Other: consultancy or advisory role; Abbvie: Other: consultancy or advisory role; Autolos: Other: consultancy or advisory role; Debiopharm: Consultancy, Honoraria, Other: consultancy or advisory role; Genmab: Honoraria, Other; Karyopharm: Honoraria; Takeda: Honoraria. Munshi:Kite, a Gilead Company: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau. Maloney:Celgene: Consultancy, Honoraria, Research Funding; Bioline Rx: Consultancy, Honoraria; Juno Therapeutics: Consultancy, Honoraria, Patents & Royalties, Research Funding; Gilead Science: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; A2 Biotherapeutics: Consultancy, Current equity holder in publicly-traded company, Honoraria; Genentech: Consultancy, Honoraria. de Vos:Bayer: Consultancy; Verastem: Consultancy. Reshef:Kiadis: Research Funding; Monsanto: Consultancy; Novartis: Honoraria; Magenta: Consultancy; Atara: Consultancy, Research Funding; Celgene: Consultancy; Bristol-Myers Squibb: Research Funding; Takeda: Research Funding; Incyte: Research Funding; Pharmacyclics: Research Funding; Immatics: Research Funding; Shire: Research Funding; Bluebird: Research Funding; Gilead: Consultancy, Honoraria, Other: Travel support, Research Funding. Leslie:Epizyme: Honoraria, Speakers Bureau; Karyopharm: Honoraria, Speakers Bureau; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Speakers Bureau; BMS: Speakers Bureau; KitePharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Honoraria, Speakers Bureau; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Yakoub-Agha:Celgene: Honoraria; Novartis: Honoraria; Gilead/Kite: Honoraria, Other: travel support; Janssen: Honoraria; Jazz Pharmaceuticals: Honoraria. Oluwole:Bayer: Consultancy; Spectrum Pharmaceuticals: Consultancy; Pfizer: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding. Fung:AstraZeneca: Honoraria, Other: speakers' bureau, travel support; Genentech: Honoraria, Other: speakers' bureau, travel support; AbbVie: Honoraria, Other: speakers' bureau, travel support; Kite, a Gilead Company: Honoraria, Other: speakers' bureau, travel support; Sanotif: Honoraria, Other: speakers' bureau, travel support; Takeda: Honoraria, Other: speakers' bureau, travel support; Janssen Oncology: Honoraria, Other: speakers' bureau, travel support. Rosenblatt:Merck: Other: consultancy or advisory role ; Biograph55: Other: consultancy or advisory role, Research Funding; Synergy: Patents & Royalties; University of Miami: Other: Leadership. Rossi:Kite, a Gilead Company: Current Employment; Gilead Sciences: Current equity holder in publicly-traded company. Goyal:Kite, a Gilead Company: Current Employment. Plaks:Kite, a Gilead Company: Current Employment, Other: travel support; Gilead Sciences: Other: stock or other ownership . Yang:Kite, a Gilead Company: Current Employment. Lee:Kite, a Gilead Company: Current Employment; Gilead Sciences: Current equity holder in publicly-traded company. Godfrey:IGM Biosciences: Current Employment, Current equity holder in publicly-traded company. Vezan:Kite, a Gilead Company: Current Employment, Honoraria, Other: Travel support; Abbvie: Current equity holder in publicly-traded company; Merck: Current equity holder in publicly-traded company. Avanzi:Kite, a Gilead Company: Current Employment, Other: travel support; Gilead Sciences: Other: stock or other ownership ; MSKCC: Patents & Royalties. Neelapu:N/A: Other; Calibr: Other; Poseida: Research Funding; Cellectis: Research Funding; Merck: Other: personal fees, Research Funding; Kite, a Gilead Company: Other: personal fees, Research Funding; Adicet Bio: Other; Legend Biotech: Other; Precision Biosciences: Other: personal fees, Research Funding; Incyte: Other: personal fees; Cell Medica/Kuur: Other: personal fees; Allogene Therapeutics: Other: personal fees, Research Funding; Pfizer: Other: personal fees; Celgene: Other: personal fees, Research Funding; Novartis: Other: personal fees; Bristol-Myers Squibb: Other: personal fees, Research Funding; Unum Therapeutics: Other, Research Funding; Karus Therapeutics: Research Funding; Acerta: Research Funding; Takeda Pharmaceuticals: Patents & Royalties.

Predictive control has emerged as a feasible alternative for the control of power converters for photovoltaic applications. In this work, a predictive control scheme is proposed to control a Buck converter that works attached to a photovoltaic system and to a energy storage system. The predictive control is used to control the current using the reference from the perturb and observe algorithm to assure the photovoltaic system is working on the maximum power point. To prove the proposed control scheme, simulation and experimental results are obtained. The results show clearly that the predictive control scheme applied to the buck converter is able to track the reference current coming from the pertub and observe algorithm in order to make the photovoltaic system work efficiently

Unbalanced conditions are widely present in the power systems and microgrids. Inverters are essential to convert DC current into AC current. These power converters, to work properly, have to be controlled, even under these unbalanced conditions. In this paper a new control strategy is proposed for three single-phase inverters connected to $\mathrm{a}RL$ load under unbalanced conditions. The proposed strategy takes the classical strategy and add constants to the Park transform. Thus, it is possible to control the currents to obtain proper waveforms for the currents. The proposed technique is proved using simulations and obtaining experimental results implementing experimental setups.

Solar energy is an interesting alternative to supply the growing energy requirements from industries and homes. In fact, many researchers have put effort to maximize the solar system efficiency. This paper, make a comparison between three alternatives of maximum power point tracking algorithms (MPPT) to inject the maximum power to the grid. The proposal includes only a three-phase inverter avoiding the DC-DC con- verter and therefore the control is performed throughout the DC link voltage reference. The comparison includes the total time to compute every algorithm where the TMS320F28335 DSP based board is employed. On the other hand, the three-phase power converter is controlled through nonlinear based control which decouples and linearizes the current response. The results give key lines to decide the proper MTTP algorithm considering the processing time and the desired performance.

Two types of teaching coexist today: traditional face-to-face methods and teaching based on self-learning where the student has ubiquitous access to course contents. This paper shows how tests have been made of a type of learning that is becoming more common in educational environments. This hybrid teaching method combines the Massively Open Online Course (MOOC) and students’ face-to-face work. On the one hand, the advantages of face-to-face learning are taken advantage of: teacher in the classroom, social bonds and daily work sessions. On the other hand, the advantages of distance learning are integrated: flexibility, accessible material and wide variety. Also included in the paper is a description of the equipment and the way in which it has been used with students. Finally, the paper details the educational experience carried out with students and the outcomes obtained. These pilot tests are framed within the education of STEM topics and robotics.

Different maximum power point tracking methods have been developed for photovoltaics systems to extract and inject the maximum power to the grid. This paper introduces an algorithm based on the solar mathematical model and two measuring cells, one in open circuit and other in short circuit. The proposed method uses the model and adjusts the unknown PV internal system variables to specify where the maximum power point (MPP) is placed in the plane I-V or P-V. The PV array, together with a three-phase inverter, controlled by a nonlinear feedback control algorithm, are employed to inject electric power to grid, where the dc voltage of the power converter is regulated to track the MPP. Finally, the results show the feasibility of the proposal where the MPP is accurately estimated by the proposed algorithm.

Genes can encode multiple isoforms, broadening their functions and providing a molecular substrate to evolve phenotypic diversity. Evolution of isoform function is a potential route to adapt to new environments. Here we show that de novo, beneficial alleles in the nurf-1 gene became fixed in two laboratory lineages of C. elegans after isolation from the wild in 1951, before methods of cryopreservation were developed. nurf-1 encodes an ortholog of BPTF, a large (>300 kD) multidomain subunit of the NURF chromatin remodeling complex. Using CRISPR-Cas9 genome editing and transgenic rescue, we demonstrate that in C. elegans, nurf-1 has split into two, largely non-overlapping isoforms (NURF-1.D and NURF-1.B, which we call Yin and Yang, respectively) that share only two of 26 exons. Both isoforms are essential for normal gametogenesis but have opposite effects on male/female gamete differentiation. Reproduction in hermaphrodites, which involves production of both sperm and oocytes, requires a balance of these opposing Yin and Yang isoforms. Transgenic rescue and genetic position of the fixed mutations suggest that different isoforms are modified in each laboratory strain. In a related clade of Caenorhabditis nematodes, the shared exons have duplicated, resulting in the split of the Yin and Yang isoforms into separate genes, each containing approximately 200 amino acids of duplicated sequence that has undergone accelerated protein evolution following the duplication. Associated with this duplication event is the loss of two additional nurf-1 transcripts, including the long-form transcript and a newly identified, highly expressed transcript encoded by the duplicated exons. We propose these lost transcripts are non-functional side products necessary to transcribe the Yin and Yang transcripts in the same cells. Our work demonstrates how gene sharing, through the production of multiple isoforms, can precede the creation of new, independent genes. National Institute of General Medical Sciences R01GM114170 Patrick T McGrat National Institute of General Medical Sciences R01GM121688 Ronald E Ellis.The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Sí

Summary Background Polatuzumab vedotin, an antibody–drug conjugate targeting the CD79b component of the B-cell receptor, has demonstrated activity as a single agent and in combination with rituximab in relapsed or refractory diffuse large B-cell lymphoma. In this study, we evaluated the safety and preliminary activity of polatuzumab vedotin in combination with rituximab or obinutuzumab and cyclophosphamide, doxorubicin, and prednisone (CHP) in patients with previously untreated diffuse large B-cell lymphoma. Methods This was an open-label, non-randomised study composed of a phase 1b dose escalation and a phase 2 dose expansion at 11 hospitals and health centres in the USA and France. Patients aged 18 years or older with B-cell non-Hodgkin lymphoma were eligible. Exclusion criteria included peripheral neuropathy with grade greater than 1, major surgery within 4 weeks before enrolment, known CNS involvement of lymphoma, and uncontrolled heart disease. Phase 1b dose escalation had a three-plus-three design and established the recommended phase 2 dose. Phase 2 expansion evaluated the recommended phase 2 dose of polatuzumab vedotin in patients with newly diagnosed diffuse large B-cell lymphoma with an International Prognostic Index (IPI) of 2–5. Patients received cyclophosphamide 750 mg/m2 on day 1 intravenously, doxorubicin 50 mg/m2 on day 1 intravenously, and prednisone 100 mg once daily on days 1–5 of each 21-day cycle orally (CHP), plus either rituximab 375 mg/m2 intravenously on day 1 of each cycle (R-CHP) or obinutuzumab 1000 mg intravenously on days 1, 8, and 15 of cycle 1 and on day 1 of the following cycles (G-CHP). Polatuzumab vedotin was administered on day 2 of cycles 1 and 2, and on day 1 of the following cycles at 1·0–2·4 mg/kg during the escalation phase and at the recommended phase 2 dose during the expansion phase. Treatment could last six or eight cycles, depending on investigator preference. The primary endpoints of the study were safety and tolerability, and determination of the maximum tolerated dose (or recommended phase 2 dose) of polatuzumab vedotin. All endpoints were analysed per protocol in the safety evaluable population, defined as all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01992653. Findings Between Dec 4, 2013, and July 26, 2016, 85 patients were enrolled. 82 patients were included in the safety and activity evaluable populations, 25 in phase 1b and 57 in phase 2. In light of information from other studies using polatuzumab vedotin reported during this study, in which the safety profile associated with exposure to polatuzumab vedotin at doses higher than 1·8 mg/kg every 3 weeks was not outweighed by any clinical benefit, the recommended phase 2 dose was set to 1·8 mg/kg in the R-CHP cohort and no higher doses were explored in this study. 66 patients with newly diagnosed diffuse large B-cell lymphoma received the polatuzumab vedotin recommended phase 2 dose (45 R-CHP; 21 G-CHP). In 66 patients with diffuse large B-cell lymphoma who received the recommended phase 2 dose, the most common adverse events of grade 3 or worse were neutropenia (20 [30%]), febrile neutropenia (12 [18%]), and thrombocytopenia (six [9%]). Among the 70 patients (any histology) who received the recommended phase 2 dose, 19 (27%) had grade 1 peripheral neuropathy, eight (11%) grade 2, and two (3%) grade 3. Four deaths were reported during follow-up: two treatment-related (one complication of atrial fibrillation and one septic shock) and two due to disease progression. As of the cutoff date of Dec 29, 2017, median follow-up time was 21·5 months (IQR 16·7–24·3) for the untreated diffuse large B-cell lymphoma cohort treated at the polatuzumab vedotin recommended phase 2 dose. 59 (89%) patients achieved an overall response at end of treatment (51 [77%] patients had a complete response, and eight [12%] patients had a partial response). Interpretation The safety of incorporating polatuzumab vedotin to R-CHP or G-CHP was as expected and managable. Preliminary clinical activity in newly diagnosed diffuse large B-cell lymphoma seems promising and encouraged a phase 3 trial comparing polatuzumab vedotin with R-CHP to R-CHOP. Funding F Hoffmann-La Roche/Genentech.

An open question in aggressive cancers such as melanoma is how malignant cells can shift the immune system to pro-tumorigenic functions. Here we identify midkine (MDK) as a melanoma-secreted driver of an inflamed, but immune evasive, microenvironment that defines poor patient prognosis and resistance to immune checkpoint blockade. Mechanistically, MDK was found to control the transcriptome of melanoma cells, allowing for coordinated activation of nuclear factor-κB and downregulation of interferon-associated pathways. The resulting MDK-modulated secretome educated macrophages towards tolerant phenotypes that promoted CD8+ T cell dysfunction. In contrast, genetic targeting of MDK sensitized melanoma cells to anti-PD-1/anti-PD-L1 treatment. Emphasizing the translational relevance of these findings, the expression profile of MDK-depleted tumors was enriched in key indicators of a good response to immune checkpoint blockers in independent patient cohorts. Together, these data reveal that MDK acts as an internal modulator of autocrine and paracrine signals that maintain immune suppression in aggressive melanomas.

Signature-based Intrusion Detection Systems (IDS) are a key component in the cybersecurity defense strategy for any network being monitored. In order to improve the efficiency of the intrusion detection system and the corresponding mitigation action, it is important to address the problem of false alarms. In this paper, we present a comparative analysis of two approaches that consider the false alarm minimization and alarm correlation techniques. The output of this analysis provides us the elements to propose a parallelizable strategy designed to achieve better results in terms of precision, recall and alarm load reduction in the prioritization of alarms. We use Prelude SIEM as the event normalizer in order to process security events from heterogeneous sensors and to correlate them. The alarms are verified using the dynamic network context information collected from the vulnerability analysis, and they are prioritized using the HP Arsight priority formula. The results show an important reduction in the volume of alerts, together with a high precision in the identification of false alarms.

In this paper, a modified topology for developing H-bridge inverter is proposed which the number of components is lower than other inverters as well as the proposed inverter generates a high number of level with low total harmonics distortions. In the first, the new developed h-bridge inverter is proposed and then a cascaded connection of this inverter to increase the number of levels is presented. Three different methods are proposed to determine the DC power sources magnitudes and among them, the best algorithm is chosen for comparison the proposed cascaded inverter with other cascaded inverters. Finally, the proposed cascaded inverter consist of two proposed basic inverters to generate thirty-three voltage levels is simulated to evaluate the performance of the proposal.

Multilevel inverters are used in high-power medium-voltage applications, due to lower harmonics and the lower standing voltage on the power switches than conventional two and three multilevel inverters. The main drawback of multilevel inverters is, requires a high number of switching devices leads to complex their control. This paper introduces an asymmetric switch-diode multilevel inverter for cascaded multilevel inverters. The suggested asymmetric multilevel inverter generates thirty-one-levels with the reduced number of power switches and DC power supplies as well as reduced the maximum total blocking voltage on the switches. A comprehensive study among the suggested topology and other cascaded multilevel inverters are discussed to show the advantages and disadvantages of multilevel inverters. The performance of a single-phase cascaded connection consists of the two suggested multilevel inverter is evaluated in Matlab/Simulink software.

Power converters are essential for allowing increasingly more solar energy to be connected to power systems. In this paper, a model predictive control of a three-phase 7-level CHB multilevel inverter for solar energy injection is developed, using the incremental conductance algorithm for establishing an MPPT strategy which maximises PV energy from the system. In order to prove the proposed control scheme, simulations in MATLAB/Simulink are carried out. The predictive current control strategy, the dc voltage control, and the MPPT controller proved proper steady state operation and proper response in front of external disturbances. Thus, solar energy injection to the grid can be maximised using the proposed 7-level CHB multilevel inverter.

Reduced multi-level converters have been presented to enhance the efficiency by reducing the number of components which lead to reducing the size, volume and cost of converters. Predictive control is an advanced control strategy that is implemented for control of multi-level converters due to many advantages of fast response, no need proportional gain and easy to implement. To achieve these results, this paper proposes a predictive current control technique for a single-phase reduced multi-level grid-connected converter. The proposed reduced converter is a general topology for cascaded multilevel converters that reduce the number of components and generates high number of levels than traditional multi-level configurations. The proposed topology is connected to a grid and model predictive control technique is applied to control of the grid current. The model predictive control is used in two cases for the proposed 15-level reduced converter and proposed 31-level cascaded multi-level converter. Finally, to validate of the proposed reduced multi-level converter and proposed model predictive control the simulation results are presented under MATLAB/Simulink platform for proposed both converters.

Cascaded H-bridge multilevel converter (CHB) is a promising topology for grid-connection systems. On the other side, model predictive controls are advanced control strategies which have many advantages for power converters applications like as fast dynamic response and easy implementation. This paper proposes a model predictive current control for a single-phase cascaded H-bridge converter topology in two modes: symmetrical and asymmetrical in the grid-connection state. The performance principle of an H-bridge converter and its cascaded connection are analyzed. Then, the mathematical model and predictive current control are explained in a grid-connected condition. The performance of the CHB topologies with the proposed predictive current control technique is evaluated by the simulation results in different conditions.

In this paper a new multilevel inverter topology is proposed for a three-phase grid-connected photovoltaic (PV) system. The proposed symmetric multilevel inverter generates seven-levels with reduced number of power switches than conventional symmetric multilevel inverters. The PV panels are connected to charge three equal capacitor voltages in each phase with appropriate PI controller. The maximum power point tracking method is extracted form PV panels by controlling of the voltage, power and current. Finally, in order to performance evaluation proposed seven-levels multilevel inverter, the proposed topology is simulated and the variation of capacitor voltages, the output voltage of inverter and grid injected current are presented.

Background: The number of people over 60 years of age is rapidly growing worldwide. The ageing of population increases the need for new public health policies and products. In this context, it is primordial to have access to the anthropometric characterisation of the elderly population. Objective: This investigation describes the somatotype components of a representative sample of elderly from Chile. Methods: In a cross-sectional anthropometric study, we assessed 200 older adults (60 to 80 years old). The study was conducted using the Heath-Carter anthropometric method, and Principal Component Analysis (PCA) to redefine and optimise the cluster definition. Statistical differences were established for male and female among the somatotype categories (endomorph, mesomorph and ectomorph) using t-test. For the analysis of the progression of a variable among the different age bins were used ANOVA and Tukey has a post hoc test. Results: the somatotype of the male and female showed a higher frequency of mesomorph-endomorph biotype (77.5% and 52.4% respectively) follow by mesomorph-endomorph in males and an endo-mesomorph in females (10.8% and 29.8% respectively). The sample differs significantly by gender with a higher endomorphic component in females from 60-80 years old. The somatochart show displacement in men and female trough the endomorphic component. The PCA and hierarchical clustering identify four main new clusters. Conclusions: These results provide evidence of an increase in gender difference regarding anthropometric parameters, also redefine the most frequent somatotype assignation in elderly adults. This information is essential for new public health policies and the design of new products..

The outcome of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) is poor, particularly in patients ineligible for stem cell transplantation or who fail induction therapy or salvage therapy. The phase 1b portion of this open-label, dose-escalation (3+3+3 design) study examined the maximum tolerated dose (MTD) and preliminary safety and activity of the regimen in transplant-ineligible adults with histologically confirmed relapsed/refractory DLBCL after at least 1 prior therapy. Patients received once-daily 560 mg ibrutinib, 375 mg/m(2) intravenous rituximab day 1 of cycles 1 to 6, and 10, 15, 20, or 25 mg lenalidomide days 1 to 21 of each 28-day cycle. Forty-five patients were treated; median time since diagnosis was 14.1 months, and 51% of the patients had non–germinal center B-cell–like (non-GCB) DLBCL, 33% had transformed DLBCL, 60% were refractory, and 27% were primary refractory. Because of dose-limiting toxicities, a de-escalation cohort (10 mg lenalidomide) was initiated, and with subsequent re-escalation up to 25 mg lenalidomide, the MTD was not reached. In response-evaluable patients, the overall response rate (ORR) was 44% (complete response [CR], 28%); among them, the ORR was 65% (CR, 41%) in non-GCB and 69% and 56% in relapsed (n = 16) and secondary refractory (n = 27) disease, respectively. Overall and for non-GCB, median response duration was 15.9 months, with 2 patients receiving therapy beyond 3 years. Phase 2 was initiated with 20 mg lenalidomide in relapsed/refractory non-GCB, whereas the phase 1b 25-mg lenalidomide cohort was being completed; an additional 25-mg cohort in phase 2 is currently ongoing. This study was registered at www.clinicaltrials.gov as #NCT02077166.

En este trabajo se promueve estudiar la viabilidad del uso de mezclas basadas en CO2 supercrítico que pueda conducir a rendimientos térmicos en los ciclos Brayton más altos que los obtenidos con el fluido estándar (s-CO2 puro). Las configuraciones que se recomienda analizar son las de Recompresión y Recompresión con enfriamiento intermedio en el compresor principal que pueden incluir más de un recalentamiento. Estas configuraciones son muy transcendentales debido a que en términos de eficiencia son las que mayores valores presentan y, además, sus costos totales por capacidad neta instalada son los más bajos en comparación con otras configuraciones.

7547 Background: KTE-X19 is an autologous anti-CD19 CAR T-cell therapy approved in the US and EU for the treatment of R/R MCL. In the ZUMA-2 study of KTE-X19 in R/R MCL, the objective response rate (ORR) at a median 17.5-mo follow-up was 92% (67% complete responses [CR]; Wang et al. ASH 2020 #1120). Here, we report results in pts with or w/o POD24, an indicator of poor outcomes (Visco et al. Br J Haematol 2019). Methods: Eligible pts with R/R MCL underwent leukapheresis and conditioning chemotherapy followed by a single infusion of KTE-X19. Efficacy results are reported for the 60 treated pts with ≥1 y of follow-up (median 17.5 mo); safety results are presented for all 68 treated pts. Results: High-risk disease characteristics were common in pts with (n=33) and w/o POD24 (n=35), although pts with POD24 had higher tumor burden and lactate dehydrogenase (LDH) levels, and more had blastoid type MCL (Table). ORR in pts with (n=28) and w/o POD24 (n=32) was 93% and 91%, with CR rates of 61% and 72%. In pts with and w/o POD24, median progression-free survival (PFS) was 11.3 mo (range, 0.9–30.3) and 29.3 mo (range, 0–35.9). Medians for duration of response (DOR) and overall survival (OS) were not reached in either group. Most common Grade ≥3 adverse events (AEs) in pts with vs w/o POD24 were neutropenia (91% vs 80%), thrombocytopenia (61% vs 46%), and anemia (55% vs 51%); Grade ≥3 cytokine release syndrome (CRS) and neurologic events occurred in 9% vs 20% and 27% vs 34%, respectively. There were no cases of Grade 5 CRS, KTE-X19–related secondary cancers, or replication-competent retrovirus in either group. In pts with vs w/o POD24, median peak CAR T-cell levels and median area under the curve were 53.4 cells/µL (range, 0.2–2566) and 583.4 cells/µL (range, 1.8–27,743.6) vs 112.4 cells/µL (range, 0.2–2589) and 1588.3 cells/µL (range, 3.8–27,238.7); by 12 mo, B cells were detectable in 8/11 (73%) vs 7/15 pts (47%) in ongoing response. Conclusions: KTE-X19 provided a high CR rate across all pts, with median DOR and OS not reached. Pts with POD24 had more aggressive high-risk disease characteristics (tumor burden, LDH levels, and blastoid MCL) and generally lower CAR T-cell expansion and PFS vs pts w/o POD24. Earlier intervention with CD19-directed CAR T-cell therapy may benefit pts with MCL with known high-risk factors. Clinical trial information: NCT02601313. [Table: see text]

7515 Background: POD24 is an indicator of poor survival in iNHL (Casulo & Barr. Blood. 2019). In the ZUMA-5 Phase 2 study of axi-cel anti-CD19 CAR T-cell therapy in pts with R/R iNHL, overall response rates (ORR) after 17.5 months median follow-up were similarly high in those with and without POD24 (93% and 92%; Jacobson et al. ASH 2020. #700). Here, we report updated outcomes with longer follow-up in pts with POD24 in ZUMA-5. Methods: Adults with R/R follicular lymphoma (FL) or marginal zone lymphoma (MZL) after ≥2 lines of therapy underwent leukapheresis followed by conditioning therapy and axi-cel infusion (2×106 CAR T cells/kg). Axi-cel–treated pts with available data on progression after an anti-CD20 mAb + alkylating agent were included. The updated efficacy analysis occurred when ≥80 treated pts with FL had ≥18 months follow-up. Results: Of 129 pts at baseline, 81 pts (63%; 68 FL, 13 MZL) had POD24 and 48 pts (37%; 40 FL, 8 MZL) did not have POD24. Median prior lines of therapy in pts with and without POD24 were 3 and 3.5, respectively. High-risk characteristics of pts with and without POD24 included stage III/IV disease, 83% and 94%; ≥3 FLIPI, 44% and 43%; high tumor bulk (GELF), 51% and 44%; and refractory disease, 77% and 63%, respectively. With 23.3 months median follow-up, ORR among efficacy-evaluable pts with POD24 (n = 61) and without POD24 (n = 37) was 92% each (complete response rates, 75% and 86%). At data cutoff, 52% of pts with POD24 and 70% without POD24 had ongoing responses. Median duration of response, progression-free survival, and overall survival were not reached in pts with and without POD24; 18-month estimated rates were 60% and 78%, 55% and 84%, and 85% and 94%, respectively. Incidences of Grade ≥3 adverse events were similar in pts with and without POD24 (84% and 88%), including cytopenias (69% and 65%) and infections (15% and 21%). Grade ≥3 cytokine release syndrome (CRS) occurred in 9% and 2% of pts with and without POD24, respectively; Grade ≥3 neurologic events (NEs) occurred in 17% of pts each. Median times to onset were similar in pts with and without POD24 for CRS (4 days each) and NEs (8 days and 7 days); median durations of CRS (7 days and 5 days) and NEs (11 days and 13 days) were also similar between groups. In efficacy-evaluable pts with FL, median peak CAR T-cell levels were similar in pts with and without POD24 (35.8 cells/μL and 34.5 cells/μL). Peak levels of key inflammatory biomarkers and axi-cel product attributes were generally similar in pts with and without POD24. Conclusions: Axi-cel showed a high rate of durable responses in pts with POD24 iNHL, a population with high-risk disease. Efficacy results, as well as safety and pharmacological profiles, appeared largely comparable between groups, with the exception of PFS rates. Clinical trial information: NCT03105336.

Introduction The prognostic value of B-cell lymphoma 2 (BCL2) expression in de novo diffuse large B-cell lymphoma (DLBCL) treated with immunochemotherapy is of interest to define a target patient population for clinical development of BCL2 inhibitors. We aimed to develop a reproducible immunohistochemistry algorithm and assay to determine BCL2 protein expression and assess the prognostic value of BCL2 in newly diagnosed DLBCL cohorts. Patients and Methods The prospectively defined algorithm incorporated BCL2 staining intensity and percentage of BCL2-positive cells. Functionally relevant cutoffs were based on the sensitivity of lymphoma cell lines to venetoclax. This assay was highly reproducible across laboratories. The prognostic impact of BCL2 expression was assessed in DLBCL patients from the phase 3 MAIN (n = 230) and GOYA (n = 366) trials, and a population-based registry (n = 310). Results Approximately 50% of tumors were BCL2 positive, with a higher frequency in high International Prognostic Index (IPI) and activated B-cell–like DLBCL subgroups. BCL2 expression was associated with poorer progression-free survival in the MAIN study (hazard ratio [HR], 1.66; 95% confidence interval [CI], 0.81-3.40; multivariate Cox regression adjusted for IPI and cell of origin). This trend was confirmed in the GOYA and registry cohorts in adjusted multivariate analyses (GOYA: HR, 1.72; 95% CI, 1.05-2.82; registry: HR, 1.89; 95% CI, 1.29-2.78). Patients with BCL2 immunohistochemistry-positive and IPI-high disease had the poorest prognosis: 3-year progression-free survival rates were 51% (GOYA) and 37% (registry). Conclusion Findings support use of our BCL2 immunohistochemistry scoring system and assay to select patients with BCL2-positive tumors for future studies.

Computer-aided teaching of practical subjects in engineering education poses new challenges. Computers have to be configured to support the particular requirements of each subject. Virtual environments allow the building of a virtual machine (VM) tailored to the requirements of each subject, allowing flexible, versatile, and low-cost laboratory configurations. However, the use of multiple VM at a shared computing facility poses new problems on the lab sessions, both technical and performance related. To solve these challenges, we have developed the VM on-demand tool. This tool automates the adaptation of each VM to the environment in which it is deployed. As a result, the creation of computer-aided engineering laboratories on a shared computing facility using VM is possible and profitable.