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Patients with hematologic malignancies have impaired humoral immunity secondary to their malignancy and its treatment, placing them at risk of severe coronavirus disease-19 (COVID-19) infection and reduced response to vaccination.The authors retrospectively analyzed serologic responses to initial and booster COVID-19 vaccination in 378 patients with hematologic malignancy and subsequently tracked COVID-19-related outcomes.Seroconversion occurred in 181 patients (48%) after initial vaccination; patients who had active malignancy or those who were recently treated with a B-cell-depleting monoclonal antibody had the lowest rates of seroconversion. For initial nonresponders to vaccination, seroconversion after a booster dose occurred in 48 of 85 patients (56%). The seroconversion rate after the booster was similar for patients on (53%) and off (58%) active therapy (p = .82). Thirty-three patients (8.8%) developed a COVID-19 infection, and there were three COVID-19-related deaths (0.8%). Although no significant association was observed between postvaccination seroconversion and the incidence of COVID-19 infection, no patient with seroconversion died from COVID-19, and no patient who received tixagevimab/cilgavimab (N = 25) was diagnosed with a COVID-19 infection.Booster vaccinations can promote seroconversion in a significant proportion of patients who are seronegative after the initial vaccination course regardless of the specific vaccine or on/off treatment status at the time of revaccination. Although postvaccination seroconversion may not be associated with a decrease in any (including asymptomatic) COVID-19 infection, the authors' experience suggested that effective vaccination (including a booster), supplemented by passive immunization using tixagevimab/cilgavimab in case of lack of seroconversion, effectively eliminated the risk of COVID-19 death in the otherwise high-risk population.Patients with hematologic malignancy, especially lymphoma, have an impaired response to coronavirus disease 2019 (COVID-19) vaccination. In this single-institution review, less than one half of the patients studied made detectable antibodies. For those who did not make detectable antibodies after initial vaccination, over one half (65%) were able to produce antibodies after booster vaccination. By the end of February 2022, 33 of the original 378 patients had a documented COVID-19 infection. The only deaths from COVID-19 were in those who had undetectable antibodies, and no patient who received prophylactic antibody therapy developed a COVID-19 infection.

The textbook is a collection of methodological tasks. Its purpose is to prepare the future teacher for the upbringing and development of younger students in the process of teaching mathematics. The professional competencies acquired in the process of solving methodological tasks will contribute to the implementation in practice of the requirements of the federal state educational standards of primary general education and will help develop students' methodological thinking, form their ability to apply mathematical, pedagogical, psychological and methodological knowledge for the successful organization of educational activities of younger schoolchildren. Meets the requirements of the federal state educational standards of secondary vocational education of the latest generation. It is intended for students of pedagogical institutions of secondary vocational education studying in the specialty "Teaching in primary classes". It can be used by teachers and students of pedagogical universities (the direction of training "Pedagogical education"), as well as teachers working in primary classes and undergraduates.

In this multi-institutional retrospective study, we examined characteristics and outcomes of 160 patients with high-grade B-cell lymphoma, not otherwise specified (HGBL-NOS). This rare lymphoma category is defined by high-grade morphologic features, most commonly Burkitt-like, and lack of MYC rearrangements with BCL2 and/or BCL6 rearrangements (so-called double-hit). Our results show that HGBL-NOS tumors are heterogeneous: 83% had a germinal center B-cell immunophenotype, 37% a dual expressor immunophenotype (MYC and BCL2 expression), 28% (single-hit) MYC rearrangement, 13% BCL2 rearrangement, and 11% BCL6 rearrangement. Most patients presented with stage 4 disease, a high serum lactate dehydrogenase, and other high-risk clinical factors. Most frequent first-line regimens included DA-EPOCH-R (43%), R-CHOP (33%), or other intensive chemotherapy programs (11%). We found no significant differences in the rates of complete response (CR, P=0.32), progression-free (PFS, P=0.82), or overall survival (OS, P=0.60) between these chemotherapy regimens. CR was attained by 69% of patients. PFS at 2 years was 55.2% (95%CI, 46.9-62.7), and OS was 68.1% (95%CI, 59.7-75.0). In a multivariable model, the main prognostic factors for PFS and OS were poor performance status, lactate dehydrogenase >3x upper limit of normal, and a dual expressor immunophenotype. Age >60 years or presence of MYC rearrangement were not prognostic, but patients with TP53 alterations had a dismal PFS (13% at 2 years). Presence of MYC rearrangement was not predictive of better PFS in patients treated with DA-EPOCH-R versus R-CHOP. Improvements in the diagnostic criteria and therapeutic approaches beyond dose-intense chemotherapy are needed to overcome the unfavorable prognosis of patients with HGBL-NOS.

Genomic screening programs have potential to benefit individuals who may not be clinically ascertained, but little is known about the psychological impact of receiving genetic results in this setting. The current study sought to further the understanding of individuals’ psychological response to receiving an actionable genetic test result from genomic screening. Telephone surveys were conducted with patient-participants at 6 weeks and 6 months post genetic result disclosure between September 2019 and May 2021 and assessed emotional response to receiving results via the FACToR, PANAS, and decision regret scales. Overall, 354 (29.4%) study participants completed both surveys. Participants reported moderate positive emotions and low levels of negative emotions, uncertainty, privacy concern, and decision regret over time. There were significant decreases in negative emotions (p = 0.0004) and uncertainty (p = 0.0126) between time points on the FACToR scale. “Interested” was the highest scoring discrete emotion (T1 3.6, T2 3.3, scale 0–5) but was significantly lower at 6 months (

PURPOSE Burkitt lymphoma (BL) has unique biology and clinical course but lacks a standardized prognostic model. We developed and validated a novel prognostic index specific for BL to aid risk stratification, interpretation of clinical trials, and targeted development of novel treatment approaches. METHODS We derived the BL International Prognostic Index (BL-IPI) from a real-world data set of adult patients with BL treated with immunochemotherapy in the United States between 2009 and 2018, identifying candidate variables that showed the strongest prognostic association with progression-free survival (PFS). The index was validated in an external data set of patients treated in Europe, Canada, and Australia between 2004 and 2019. RESULTS In the derivation cohort of 633 patients with BL, age ≥ 40 years, performance status ≥ 2, serum lactate dehydrogenase > 3× upper limit of normal, and CNS involvement were selected as equally weighted factors with an independent prognostic value. The resulting BL-IPI identified groups with low (zero risk factors, 18% of patients), intermediate (one factor, 36% of patients), and high risk (≥ 2 factors, 46% of patients) with 3-year PFS estimates of 92%, 72%, and 53%, respectively, and 3-year overall survival estimates of 96%, 76%, and 59%, respectively. The index discriminated outcomes regardless of HIV status, stage, or first-line chemotherapy regimen. Patient characteristics, relative size of the BL-IPI groupings, and outcome discrimination were consistent in the validation cohort of 457 patients, with 3-year PFS estimates of 96%, 82%, and 63% for low-, intermediate-, and high-risk BL-IPI, respectively. CONCLUSION The BL-IPI provides robust discrimination of survival in adult BL, suitable for use as prognostication and stratification in trials. The high-risk group has suboptimal outcomes with standard therapy and should be considered for innovative treatment approaches.

Central nervous system (CNS) involvement in Burkitt lymphoma (BL) poses a major therapeutic challenge, and the relative ability of contemporary regimens to treat CNS involvement remains uncertain. We described prognostic significance of CNS involvement and incidence of CNS recurrence/progression after contemporary immunochemotherapy using real-world clinicopathologic data on adults with BL diagnosed between 2009 and 2018 across 30 US institutions. We examined associations between baseline CNS involvement, patient characteristics, complete response (CR) rates, and survival. We also examined risk factors for CNS recurrence. Nineteen percent (120/641) of patients (age 18-88 years) had CNS involvement. It was independently associated with HIV infection, poor performance status, involvement of ≥2 extranodal sites, or bone marrow involvement. First-line regimen selection was unaffected by CNS involvement (P=0.93). Patients with CNS disease had significantly lower rates of CR (59% versus 77% without; P

Individuals with credentials (Board Certified Behavior Analyst–Doctoral and Board Certified Behavior Analyst) from the Behavior Analyst Certification Board throughout the United States were asked to identify the characteristics and corresponding behaviors of individuals they consider to be exemplary in the profession. From these responses, a list of 35 characteristics and attendant behaviors was compiled into the Exemplary Behavior Analyst Checklist. This checklist contains a number of characteristics that are traditionally representative of the field (e.g., analytical, applied, conceptually systematic, technological) and relate to technical and conceptual skills. Respondents also identified a number of characteristics associated with compassion and support of clients/individuals (e.g., client centered, culturally competent, empathetic, positive/encouraging). A “top 10” list of the qualities and behaviors of exemplary behavior analysts identified by participants is presented, and a discussion regarding the implications for the training of credentialed professionals is provided.

Background. BL is a rare, high-grade B-cell lymphoma that is often studied in trials with small sample sizes. Historical definitions of "low-risk BL" vary between studies, use arbitrary cutoffs for lactate dehydrogenase (LDH), and identify a small favorable group, leaving >80-90% of patients (pts) in an undifferentiated "high-risk" category. A validated prognostic index will help compare study cohorts and better define good-prognosis pts for whom reduced treatment would be appropriate vs a poor-prognosis group in need of new approaches. Herein, we constructed and validated a simplified prognostic model for BL applicable to diverse clinical settings across the world. Methods. We derived the BL-IPI from a large real-world evidence cohort of US adults treated for BL in 2009-2018 (Evens A, Blood 2020). Progression-free survival (PFS) from diagnosis until BL recurrence, progression, death, or censoring was the primary outcome. We first determined the best prognostic cutoffs for age, LDH (normalized to local upper limit normal, ULN), hemoglobin (Hgb), and albumin. Independent risk factors were ascertained by forward stepwise selection into Cox regression from candidate variables: age, sex, HIV+ status, ECOG performance status (PS) ≥2, advanced stage (3/4), involvement of >1 extranodal site, bone marrow, central nervous system (CNS), values of LDH, Hgb, and albumin. Derivation models used multiple imputation to mitigate bias from missing data and reported hazard ratios (HR) with 95% confidence interval (CI). BL-IPI groups, defined by inspection of survival curves, were compared using log-rank test for trend. We validated performance of the BL-IPI in an external retrospective dataset of BL pts treated contemporaneously in centers from the United Kingdom, Scandinavia, Canada, and Australia. Results. Characteristics of pts in the derivation (N= 633) and validation (N=457) cohorts are shown in the Table. Age ≥40 years (yr), LDH >3xULN, Hgb 3xULN, low Hgb, and low albumin were associated with inferior PFS in univariate tests. In the multivariable model age ≥40 yr, LDH >3xULN, PS ≥2, and CNS involvement were selected as 4 independent prognostic factors; adding stage did not enhance the model. The model was simplified to 3 groups with 0 (low risk; 18% of pts), 1 (intermediate risk; 36% of pts; HR=3.14; 95%CI, 1.61-6.14), or 2-4 factors (high risk; 46% of pts; HR=6.52; 95%CI, 3.48-12.20; Fig A) with 3 yr PFS of 92%, 72%, and 53%, respectively (P Among pts with stage III/IV (historically classified as "high-risk" and constituting 78% of all pts in the cohort), the BL-IPI further discriminated subgroups with 3 yr PFS of 87%, 71%, and 52%, respectively (P In the international validation cohort, fewer pts had CNS involvement; most received CODOX-M/IVAC+R; and PFS/OS estimates at 3 yr were higher. BL-IPI categories were of similar size (low-risk 15%, intermediate-risk 35%, high-risk 50%), and provided similar risk discrimination (Harrell's C=.65 in both datasets). PFS at 3 yr was 96%, 82%, and 63%, respectively (P Conclusions. BL-IPI is a novel prognostic index specific to BL, which was validated to allow for simplified stratification and comparison of risk distribution in geographically diverse cohorts. The index identified a low-risk group with PFS >90-95%, which could be targeted with future strategies for treatment de-escalation. Conversely, only about 55-60% of pts in the high-risk group achieved cure with currently available immunochemotherapy. Disclosures Olszewski: Spectrum Pharmaceuticals: Research Funding; Genentech, Inc.: Research Funding; TG Therapeutics: Research Funding; Adaptive Biotechnologies: Research Funding. Jakobsen:Takeda: Honoraria. Collins:ADC Therapeutics: Consultancy, Honoraria; Celleron: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Speakers Bureau; Amgen: Research Funding; BeiGene: Consultancy; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Research Funding; Taekda: Consultancy, Honoraria, Other: travel, accommodations, expenses, Speakers Bureau; Roche: Consultancy, Honoraria, Other: travel, accommodations, expenses , Speakers Bureau; Pfizer: Honoraria; Celgene: Research Funding. Cwynarski:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Atara: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau. Bachanova:Incyte: Research Funding; Karyopharma: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; FATE: Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding. Danilov:Abbvie: Consultancy; BeiGene: Consultancy; Nurix: Consultancy; Celgene: Consultancy; Gilead Sciences: Research Funding; Takeda Oncology: Research Funding; Pharmacyclics: Consultancy; Bayer Oncology: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy; Astra Zeneca: Consultancy, Research Funding; Verastem Oncology: Consultancy, Research Funding; Karyopharm: Consultancy; Aptose Biosciences: Research Funding; Bristol-Myers Squibb: Research Funding; Rigel Pharmaceuticals: Consultancy. Diefenbach:Trillium: Research Funding; Millenium/Takeda: Research Funding; MEI: Research Funding; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding; Incyte: Research Funding; LAM Therapeutics: Research Funding; Denovo: Research Funding. Epperla:Pharmacyclics: Honoraria; Verastem Oncology: Speakers Bureau. Farooq:Kite, a Gilead Company: Honoraria. Feldman:Pfizer: Research Funding; Portola: Research Funding; Janssen: Speakers Bureau; AstraZeneca: Consultancy; Cell Medica: Research Funding; Seattle Genetics, Inc.: Consultancy, Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau; Viracta: Research Funding; Trillium: Research Funding; Rhizen: Research Funding; Corvus: Research Funding; BMS: Consultancy, Honoraria, Research Funding; Kite: Honoraria, Other: Travel expenses, Speakers Bureau; Celgene: Honoraria, Research Funding; Takeda: Honoraria, Other: Travel expenses; Amgen: Research Funding; Pharmacyclics: Honoraria, Other, Speakers Bureau; Abbvie: Honoraria; Bayer: Consultancy, Honoraria; Eisai: Research Funding; Kyowa Kirin: Consultancy, Research Funding. Gerrie:AbbVie: Consultancy, Honoraria, Research Funding; Astrazeneca: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Roche: Research Funding; Sandoz: Consultancy. Jagadeesh:Regeneron: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Debiopharm Group: Research Funding; MEI Pharma: Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees. Kamdar:BMS: Consultancy; Abbvie: Consultancy; Karyopharm: Consultancy; Celgene: Consultancy; AstraZeneca: Consultancy; Pharmacyclics: Consultancy; Seattle Genetics: Speakers Bureau. Karmali:Takeda: Research Funding; AstraZeneca: Speakers Bureau; BeiGene: Speakers Bureau; Karyopharm: Honoraria; BMS/Celgene/Juno: Honoraria, Other, Research Funding, Speakers Bureau; Gilead/Kite: Honoraria, Other, Research Funding, Speakers Bureau. Khan:Seattle Genetics: Research Funding; Janssen: Honoraria; Pharmacyclics: Honoraria; Bristol Myers Squibb: Research Funding; Celgene: Research Funding. Klein:Takeda: Membership on an entity's Board of Directors or advisory committees. Lossos:Verastem: Consultancy, Honoraria; Stanford University: Patents & Royalties; Seattle Genetics: Consultancy, Other; Janssen Biotech: Honoraria; NCI: Research Funding; Janssen Scientific: Consultancy, Other. Lunning:ADC Therapeutics: Consultancy; Legend: Consultancy; Acrotech: Consultancy; AstraZeneca: Consultancy, Honoraria; Aeratech: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; Verastem: Consultancy, Honoraria; TG Therapeutics: Research Funding; Novartis: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Curis: Research Funding; Bristol Meyers Squibb: Consultancy, Honoraria, Research Funding. Martin:I-MAB: Consultancy; Celgene: Consultancy; Teneobio: Consultancy; Karyopharm: Consultancy, Research Funding; Janssen: Consultancy; Sandoz: Consultancy; Bayer: Consultancy; Beigene: Consultancy; Cellectar: Consultancy; Incyte: Consultancy; Kite: Consultancy; Morphosys: Consultancy; Regeneron: Consultancy. Martinex-Calle:Abbvie: Other: Travel grant. Naik:Celgene: Other: advisory board; Sanofi: Other: advisory board. Palmisiano:Genentech: Research Funding; AbbVie: Research Funding. Phillips:Beigene: Honoraria; Roche: Research Funding. Phillips:Seattle Genetics: Consultancy; Incyte: Consultancy, Other: travel expenses; AstraZeneca: Consultancy; Karyopharm: Consultancy; Beigene: Consultancy; Bayer: Consultancy, Research Funding; BMS: Consultancy; Pharmacyclics: Consultancy; Abbvie: Consultancy, Research Funding; Cardinal Health: Consultancy. Portell:Roche/Genentech: Consultancy, Research Funding; Infinity: Research Funding; Bayer: Consultancy; Amgen: Consultancy; TG Therapeutics: Research Funding; AbbVie: Research Funding; Pharmacyclics: Consultancy; Janssen: Consultancy; Kite: Consultancy, Research Funding; Acerta/AstraZeneca: Research Funding; Xencor: Research Funding; BeiGene: Consultancy, Research Funding. Reddy:Celgene: Consultancy; BMS: Consultancy, Research Funding; Genentech: Research Funding; Abbvie: Consultancy; KITE Pharma: Consultancy. Yazdy:Abbvie: Consultancy; Genentech: Research Funding; Octapharma: Consultancy; Bayer: Honoraria. Smith:Bristol Meyers Squibb: Research Funding; Ayala: Research Funding; Seattle Genetics: Research Funding; Portola: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; Incyte: Research Funding; Ignyta: Research Funding; Genentech: Research Funding; De Novo Biopharma: Research Funding; AstraZeneca: Consultancy; Millenium/Takeda: Consultancy; Beigene: Consultancy; Bayer: Research Funding; AstraZeneca: Research Funding; Acerta Pharma BV: Research Funding; Karyopharm: Consultancy. Cheah:Celgene, F. Hoffmann-La Roche, Abbvie, MSD: Research Funding; Celgene, F. Hoffmann-La Roche, MSD, Janssen, Gilead, Ascentage Pharma, Acerta, Loxo Oncology, TG therapeutics: Honoraria. El-Galaly:F. Hoffmann-La Roche: Current Employment, Other: Support of parent study and funding of editorial support. Evens:Research To Practice: Honoraria, Speakers Bureau; Mylteni: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria, Research Funding; MorphoSys: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria.

Steadily increasing ethnic and cultural diversity in the United States has led employers to see intercultural competence as a valuable and necessary trait for those entering the workforce, including students studying psychology. One high-impact practice that may increase students’ multicultural awareness is study abroad. The current research examined the effectiveness of a cultural scavenger hunt offered during two short-term study abroad programs to increase participants’ intercultural competencies. Cultural competence was assessed in Study 1 ( N = 10) using the Miville-Guzman Universality-Diversity Scale–Short Form. Results indicated a statistically significant increase across all subscales. In Study 2 ( N = 16), the Cross-Cultural Adaptability Inventory was utilized. Results from Study 2 demonstrated statistically significant improvements in the Emotional Resilience subscale. These findings suggest that a cultural scavenger hunt may assist participants in actively engaging in the local culture and facilitate the initial development of intercultural competencies.

Research examining excellence in teaching is extensive. Nevertheless, research examining the inverse—what constitutes poor or ineffective teaching—has not been as systematic. The current research addresses this gap in the literature by examining student and faculty perceptions of the qualities and behaviors of ineffective teachers. Students and faculty identified being disrespectful as the number one perceived quality of ineffective teachers. Both groups of respondents also agreed that having weak rapport was indicative of ineffective teachers. Overall, students had a tendency to focus more on the social aspects of the student–teacher relationship, whereas faculty focused more on professional competencies. These findings provide additional support on teaching misbehaviors to avoid both in and outside of the classroom.

Genomic studies have revealed molecular mechanisms involved in the pathogenesis of Burkitt’s lymphoma, including the ID3/TCF3-dependent centroblast gene expression program, tonic PI3K-AKT-mTOR signaling, and deregulation of cell cycle and apoptosis through mutations in cyclin D3, CDKN2A, or TP53. Unfortunately, these advances have not been translated into treatment, which relies on dose-intense cytotoxic chemotherapy. While most patients achieve long-term survival, options for relapsed/refractory disease are lacking, as Burkitt lymphoma is often excluded from clinical trials of novel approaches. The lower-intensity, dose-adjusted EPOCH plus rituximab (DA-EPOCH-R) regimen constitutes a major advance allowing for treatment of older and HIV-positive patients but needs augmentation to better address the central nervous system involvement. Furthermore, DA-EPOCH-R provides a platform for the study of targeted or immunotherapeutic approaches while de-escalating cytotoxic agents and their associated adverse effects. In this review we discuss the epidemiology and molecular genetics of BL, first-line treatment considerations, and potential novel treatment strategies.

Chromatin insulators are responsible for orchestrating long-range interactions between enhancers and promoters throughout the genome and align with the boundaries of Topologically Associating Domains (TADs). Here, we demonstrate an association between gypsy insulator proteins and the phosphorylated histone variant H2Av (γH2Av), normally a marker of DNA double strand breaks. Gypsy insulator components colocalize with γH2Av throughout the genome, in polytene chromosomes and in diploid cells in which Chromatin IP data shows it is enriched at TAD boundaries. Mutation of insulator components su(Hw) and Cp190 results in a significant reduction in γH2Av levels in chromatin and phosphatase inhibition strengthens the association between insulator components and γH2Av and rescues γH2Av localization in insulator mutants. We also show that γH2Av, but not H2Av, is a component of insulator bodies, which are protein condensates that form during osmotic stress. Phosphatase activity is required for insulator body dissolution after stress recovery. Together, our results implicate the H2A variant with a novel mechanism of insulator function and boundary formation.

Introduction: Treatment of older patients (pts) with PCNSL is challenging due to the prevalence of comorbidities, frailty, and complexities with delivery of chemotherapy (CT). The optimal induction CT and consolidation regimens for older PCNSL pts is unknown. Moreover, there are few large scale prognostication studies available, including analysis of geriatric assessments (GA). We analyzed detailed characteristics, treatment patterns and outcomes with prognostication across 17 academic centers. Methods: We conducted a large, RW retrospective study of newly diagnosed PCNSL pts (1/2008-1/2019) ages ≥ 60 years (yrs). Survival rates were estimated by Kaplan-Meier with differences assessed by log rank test. We detailed Cumulative Index Rating Scale-Geriatric (CIRS-G) scores & other GAs. Univariate associations were derived via Cox model with variables p Results: Among 491 initial cases, n=450 cases were verified for diagnosis & follow-up. Clinical features included: median age 71 yrs (60-88); male 47%; elevated LDH 30%; creatinine clearance 1 site). Cerebral involvement predominated in 75% with deep structure involvement in 20% & cerebellum in 5%. CSF involvement was documented in 13% of pts (unchecked in 26%). For GA at diagnosis, the median CIRS-G score was 6 (range 0-27) and impaired self-care activities of daily living (ADLs) were noted in 36%. Furthermore, geriatric syndrome (ie, dementia, delirium, depression, and/or falls) was present in 45% of pts. Induction therapy included CT in 91% of pts (of whom 82% had rituximab (Rtx)) and radiation therapy (RT) in 8%. The most common chemotherapy regimens were: high-dose methotrexate (HD MTX) or HD MTX with Rtx (MR) in 38%; HD MTX/procarbazine/vincristine (MPV) +/- Rtx 30%; HD MTX/temozolomide/Rtx (MTR) 22%; Rtx alone 2%; and HD MTX/cytarabine/thiotepa/Rtx (MATRIX) in 2%. Median MTX dosing for all pts was 3.5 g/m2 (range 1-8 g/m2), and by 3 most common regimens (all g/m2): MTR 5.1; MR 5.4; MPV 3.1 (P With 42 month median follow-up (1-125), 3-yr PFS & OS for all pts were 38% & 52%, respectively (Fig 1A/1B). On MVA, factors associated with inferior PFS were: advancing age (continuous HR 1.05, P Conclusions: Older pts with PCNSL have suboptimal outcomes, with 2/3 progressing in the first several years. GA is an important prognostic tool, and could be used to stratify pts in future investigations. In addition, use of Rtx, increasing MTX dose, and the MTR regimen were associated with improved outcomes. Disclosures Reddy: Genentech: Research Funding; Abbvie: Consultancy; KITE Pharma: Consultancy; Celgene: Consultancy; BMS: Consultancy, Research Funding. Bachanova:Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharma: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; FATE: Research Funding; BMS: Research Funding; Incyte: Research Funding. Bond:Seattle Genetics: Honoraria. Goldlust:COTA: Other; BMS: Membership on an entity's Board of Directors or advisory committees, Other: travel; Tocagen: Membership on an entity's Board of Directors or advisory committees, Other: travel; Novocure: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: travel, Research Funding, Speakers Bureau; Boston Biomedical: Consultancy; Cortice Bio: Consultancy, Other: travel; WEX: Consultancy, Other: travel. Spurgeon:Beigene: Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy; Bristol-Myers Squibb: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Acerta: Research Funding; AstraZeneca: Research Funding; Genmab: Research Funding; VelosBio: Consultancy, Research Funding; Cardinal Health: Honoraria; Verastem: Research Funding. Epperla:Verastem Oncology: Speakers Bureau; Pharmacyclics: Honoraria. Karmali:Takeda: Research Funding; Karyopharm: Honoraria; AstraZeneca: Speakers Bureau; BeiGene: Speakers Bureau; BMS/Celgene/Juno: Honoraria, Other, Research Funding, Speakers Bureau; Gilead/Kite: Honoraria, Other, Research Funding, Speakers Bureau. Naik:Celgene: Other: advisory board; Sanofi: Other: advisory board. Martin:Celgene: Consultancy; Bayer: Consultancy; Janssen: Consultancy; Sandoz: Consultancy; I-MAB: Consultancy; Teneobio: Consultancy; Beigene: Consultancy; Cellectar: Consultancy; Incyte: Consultancy; Kite: Consultancy; Morphosys: Consultancy; Karyopharm: Consultancy, Research Funding; Regeneron: Consultancy. Smith:Genentech/Roche: Consultancy, Other: Support of parent study and funding of editorial support, Research Funding; TG Therapeutics: Consultancy, Research Funding; FortySeven: Research Funding; Karyopharm: Consultancy, Research Funding; Pharmacyclics: Research Funding; BMS: Consultancy; Janssen: Consultancy; Celgene: Consultancy, Research Funding; Acerta: Research Funding. Rubenstein:Kymera: Research Funding. Kahl:ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy; Celgene Corporation: Consultancy; AstraZeneca Pharmaceuticals LP: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; Pharmacyclics LLC: Consultancy; Roche Laboratories Inc: Consultancy; BeiGene: Consultancy, 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; Acerta: Consultancy, Research Funding. Evens:Merck: Consultancy, Honoraria, Research Funding; Research To Practice: Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria, Research Funding; MorphoSys: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Mylteni: Consultancy, Honoraria.

Background Primary CNS lymphoma (PCNSL) is a rare non-Hodgkin lymphoma that is often associated with immunosuppressed states. The Epstein-Barr Virus (EBV) may play a role in tumor pathogenicity in some cases. The objective of this study was to examine the patient characteristics, tumor pathology, and survival outcomes associated with EBV tumor status in patients with PCNSL. Methods This was a retrospective subset analysis from 17 academic medical centers that included 439 patients of ages 60 years and above with PCNSL (David K et al. ASH 2020). The associations between EBV status and clinical or demographical variables were tested by Fisher's exact test, Wilcoxon rank-sum test, or CMH trend test. Kaplan-Meier estimator was used to estimate survival probability. Survival difference between groups was tested by log-rank test for statistical significance. Confidence interval of survival rate was calculated using Greenwood's formula. Results A total of 247 patients with available EBV status were included in this analysis. Median age was 71 (range 60-84) and 44.5% were male. Notably, none of the patients were HIV-positive. Twenty-five patients (10.1%) had EBV positive tumors as detected by EBER (EBV-encoded RNA) in-situ hybridization or LMP1 immunohistochemistry (IHC), 17 of which were solid organ transplant (SOT)-related post-transplant lymphoproliferative disorders (PTLD) and 8 of which were not PTLD. All EBV-positive non-PTLDs were diffuse large B-cell lymphoma. Three (15%) SOT-related PTLDs were EBV-negative. Patient characteristics analyzed included age at diagnosis, sex, ECOG performance status, history of prior or concurrent malignancies, history of solid organ transplant or autoimmune disease, history of allogeneic stem cell transplant, and immunosuppressive treatment. Of these, only a history of solid organ transplant or autoimmune disease (P Tumor characteristics analyzed included expression of C-MYC, BCL2, CD5, cell of origin markers (BCL6, MUM1, CD10), and CD20 through IHC, C-MYC and BCL2 translocation through FISH, histology, and involvement of brain parenchyma, CSF, spinal cord, and eyes. EBV-positive tumors were associated with low C-MYC (p=0.047) and BCL6 (p=0.0006) expression on immunohistochemistry, but not other factors. There were no significant differences in tumor characteristics between those with EBV-positive PTLD and EBV-positive non-PTLD. Among patients with PTLD, 30% (n=6) did not receive primary chemotherapy, and the most common treatment regimens were high-dose methotrexate (HD-MTX) with or without rituximab (n=5) and rituximab alone (n=3). However, there was no significant difference in outcomes among PTLD patients who received chemotherapy or those who did not. Among EBV-positive non-PTLD patients, only 12.5% (n=1) did not receive primary chemotherapy and the most common treatment regimens were methotrexate/rituximab/temozolomide (n=3) and HD-MTX with or without rituximab (n=3). There was no difference in overall or progression free survival between patients with EBV-positive and EBV-negative tumors, or in outcomes among SOT-related PTLD patients regardless of EBV status. However, patients with EBV-positive non-PTLD PCNSL had better overall survival compared to patients with EBV-positive PTLD and EBV-negative tumors (p=0.033, Figure). Conclusions In this large observational study of older patients with PCNSL, the incidence of EBV positive tumors was overall low and was most commonly associated with SOT-related PTLD. Mycophenolate mofetil was the most common immunosuppressive medication. In those without PTLD, there were no patient or tumor factors that were associated with EBV status. Unexpectedly, non-PTLD EBV-positive PCNSL had superior outcomes to EBV-positive PTLD and EBV-negative PCNSL. Future studies of EBV-positive non-PTLDs are warranted to further evaluate the potential impact of EBV latency and the immune response on the tumor microenvironment. Disclosures Reddy: BMS: Consultancy, Research Funding; Celgene: Consultancy; Abbvie: Consultancy; Genentech: Research Funding; KITE Pharma: Consultancy. Bachanova:Karyopharma: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; FATE: Research Funding; Incyte: Research Funding; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding. Bond:Seattle Genetics: Honoraria. Goldlust:Tocagen: Membership on an entity's Board of Directors or advisory committees, Other: travel; BMS: Membership on an entity's Board of Directors or advisory committees, Other: travel; WEX: Consultancy, Other: travel; Cortice Bio: Consultancy, Other: travel; Boston Biomedical: Consultancy; COTA: Other; Novocure: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: travel, Research Funding, Speakers Bureau. Spurgeon:Gilead: Research Funding; Genentech: Research Funding; Cardinal Health: Honoraria; Bristol-Myers Squibb: Research Funding; VelosBio: Consultancy, Research Funding; Acerta: Research Funding; Janssen: Consultancy, Research Funding; AstraZeneca: Research Funding; Pharmacyclics: Consultancy; Beigene: Research Funding; Verastem: Research Funding; Genmab: Research Funding. Epperla:Verastem Oncology: Speakers Bureau; Pharmacyclics: Honoraria. Karmali:AstraZeneca: Speakers Bureau; Karyopharm: Honoraria; Takeda: Research Funding; BeiGene: Speakers Bureau; Gilead/Kite: Honoraria, Other, Research Funding, Speakers Bureau; BMS/Celgene/Juno: Honoraria, Other, Research Funding, Speakers Bureau. Naik:Celgene: Other: advisory board; Sanofi: Other: advisory board. Smith:Janssen: Consultancy; Celgene: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; BMS: Consultancy; FortySeven: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding; Genentech/Roche: Consultancy, Other: Support of parent study and funding of editorial support, Research Funding; TG Therapeutics: Consultancy, Research Funding. Rubenstein:Kymera: Research Funding. Kahl:BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca Pharmaceuticals LP: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy; AbbVie: Consultancy; Genentech: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche Laboratories Inc: Consultancy; Pharmacyclics LLC: Consultancy. Evens:Abbvie: Consultancy, Honoraria; Research To Practice: Honoraria, Speakers Bureau; MorphoSys: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria, Research Funding; Mylteni: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding. Martin:Kite: Consultancy; Morphosys: Consultancy; Regeneron: Consultancy; Incyte: Consultancy; Cellectar: Consultancy; Beigene: Consultancy; Bayer: Consultancy; I-MAB: Consultancy; Sandoz: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy, Research Funding; Teneobio: Consultancy; Celgene: Consultancy.

The 2016 World Health Organization (WHO) classification has designated two categories of high-grade B-cell lymphoma (HGBCL): HGBCL with MYC and BLC2 and/or BCL6 rearrangements (often referred to as...

We examined outcomes of 244 patients with marginal zone lymphoma (MZL) diagnosed in 2010-2020, of which 25 (10%) expressed CD5. CD5 expression was present in 22% of splenic, 8% of nodal, and 5% of extranodal MZL, and showed frequent blood/bone marrow involvement, elevated lactate dehydrogenase, and TP53 deletions. CD5 expression was not associated with progression-free or overall survival, but it conferred a significantly higher risk of histologic transformation (22% versus 4% at 5 years, p = 0.002). Among patients receiving first-line rituximab monotherapy, CD5 expression was associated with lower response rate (30% versus 77%, p = 0.006), PFS (25% versus 45% at 3 years, p = 0.003) and OS (44% versus 77%, p = 0.010), whereas CD5 status did not significantly affect outcomes of patients receiving bendamustine with rituximab (P for interaction = 0.012 for progression-free survival). CD5-positive MZL may have a propensity to leukemic dissemination, histologic transformation, and may derive benefit from first-line bendamustine/rituximab rather than rituximab alone.

COVID-19 infection has been associated with an increased incidence of thrombotic events leading to poor patient outcomes. Given the rapid rise of the COVID-19 pandemic, the ability to conduct prospective trials has been limited and data regarding the use of standard-dose versus intermediate-dose thromboprophylaxis, use of empiric therapeutic anticoagulation, and use of extended-duration thromboprophylaxis after discharge has been largely based upon observational data without any high-quality prospective data guiding their use. In this article, we will review the incidence and frequency of arterial and venous thrombotic events along with the current literature surrounding the use of intermediate-dose thromboprophylaxis, empiric therapeutic anticoagulation, and use of extended-duration thromboprophylaxis for patients hospitalized with COVID-19.

Chromatin insulators are responsible for mediating long-range interactions between enhancers and promoters throughout the genome and align with the boundaries of topologically associating domains (TADs). Here, we demonstrate an interaction between proteins that associate with thegypsyinsulator and the phosphorylated histone variant H2Av (γH2Av), a marker of DNA double strand breaks.Gypsyinsulator components colocalize with γH2Av throughout the genome. Mutation of insulator components prevents stable H2Av phosphorylation in polytene chromatin. Phosphatase inhibition strengthens the association between insulator components and γH2Av and rescues γH2Av localization in insulator mutants. We also show that γH2Av is a component of insulator bodies, and that phosphatase activity is required for insulator body dissolution after recovery from osmotic stress. We further demonstrate a tight association between γH2Av and TAD boundaries. Together, our results indicate a novel mechanism linking insulator function with a histone H2A variant and with genome stability.

Data addressing prognostication in patients with HIV related Burkitt lymphoma (HIV-BL) currently treated remain scarce. We present an international analysis of 249 (United States: 140; United Kingdom: 109) patients with HIV-BL treated from 2008 to 2019 aiming to identify prognostic factors and outcomes. With a median follow up of 4.5 years, the 3-year progression-free survival (PFS) and overall survival (OS) were 61% (95% confidence interval [CI] 55% to 67%) and 66% (95%CI 59% to 71%), respectively, with similar results in both countries. Patients with baseline central nervous system (CNS) involvement had shorter 3-year PFS (36%) compared to patients without CNS involvement (69%; P < .001) independent of frontline treatment. The incidence of CNS recurrence at 3 years across all treatments was 11% with a higher incidence observed after dose-adjusted infusional etoposide, doxorubicin, vincristine, prednisone, cyclophosphamide (DA-EPOCH) (subdistribution hazard ratio: 2.52; P = .03 vs other regimens) without difference by CD4 count 100/mm3. In multivariate models, factors independently associated with inferior PFS were Eastern Cooperative Oncology Group (ECOG) performance status 2-4 (hazard ratio [HR] 1.87; P = .007), baseline CNS involvement (HR 1.70; P = .023), lactate dehydrogenase >5 upper limit of normal (HR 2.09; P < .001); and >1 extranodal sites (HR 1.58; P = .043). The same variables were significant in multivariate models for OS. Adjusting for these prognostic factors, treatment with cyclophosphamide, vincristine, doxorubicin, and high-dose methotrexate, ifosfamide, etoposide, and high-dose cytarabine (CODOX-M/IVAC) was associated with longer PFS (adjusted HR [aHR] 0.45; P = .005) and OS (aHR 0.44; P = .007). Remarkably, HIV features no longer influence prognosis in contemporaneously treated HIV-BL.

Digital PCR (dPCR) technology has been proven to be highly sensitive and accurate in detecting copy number variations (CNV). However, a higher-order multiplexing dPCR assay for measuring SMN1 and SMN2 copy numbers in spinal muscular atrophy (SMA) samples has not been reported. Described here is a rapid multiplex SMA dPCR genotyping assay run on a fully integrated dPCR instrument with five optical channels. The hydrolysis probe-based multiplex dPCR assay quantifies SMN1, SMN2, and the total SMN (SMN1 + SMN2) while using RPPH1 gene as an internal reference control. The quadruplex assay was evaluated with characterized control DNA samples and validated with 15 blinded clinical samples from a previously published study. SMN1 and SMN2 copy numbers were completely concordant with previous results for both the control and blinded samples. The dPCR-based SMA copy number determination was accomplished in 90 min with a walk-away workflow identical to real-time quantitative PCR (qPCR). In summary, presented here is a simple higher-order multiplexing solution on a novel digital PCR platform to meet the growing demand for SMA genotyping and prognostics.

Gastric and gastroesophageal junction (GEJ) cancer is one of the most common malignancy worldwide. In unresectable or metastatic disease, the prognosis is poor and is generally less than a year. Standard front-line chemotherapy includes two- or three-drug regimens with the addition of trastuzumab in HER2-positive disease. With an increased understanding of the biology of cancer over the past few decades, targeted therapies have made their way into the treatment paradigm of many cancers. They been examined in the first- and second-line settings in the treatment of gastroesophageal cancer though has yielded few viable treatment options. One success is ramucirumab either as monotherapy or in combination with paclitaxel is the preferred choice in second-line therapy. While immunotherapy has been considered a breakthrough in oncology over the past decade, the response rates in gastric and gastroesophageal cancers have been relatively low compared to other cancers, resulting in its limited approval and mostly reserved for second-line therapy or beyond. In this article, we will review the standard first- and second-line treatment regimens. Furthermore, this article will review the use of targeted therapies and immunotherapy in treatment of gastric and gastroesophageal cancers. Lastly, we will touch upon future treatment strategies that are currently under investigation.

Heparin-induced thrombocytopenia (HIT) remains a difficult clinical diagnosis, even with the under-utilized standardized scoring systems, like the '4T' score, to aid in clinical decision-making. Our quality improvement study sought to assess the use of '4T' score, improve the use of HIT antibody (HITA) testing and improvement management of possible HIT by implementing an in-line calculator with guidance within our electronic medical record (EMR) at our institution. We retrospectively reviewed patient charts between October 2017 and October 2018, assessing practices before and after implementation of the '4T' in-line calculator in April 2018. HITA were ordered inappropriately (for 4T4) in 141 (67%) of 210 instances (75 before and 66 after). We found no statistically significant difference in positive predictive value (PPV) or 4T documentation in provider notes after its implementation. We were able to identify problematic areas in HIT management, such as the ordering of non-heparin anticoagulants, and implement additional changes addressing these problems.

Introduction: Among a large number of immunomodulation agents, a special role belongs to herbal medicines. They differ in relative harmlessness and high efficiency, both with system and local use. Clinical and immunological efficacy of Esberitox phytopreparation (Schaper&Brummer, Germany) in a number of diseases of viral and microbial origin has been shown. This report presents data on the effect of Esberitox on the factors of local immunity of the oral cavity in patients with chronic pharyngitis, tonsillitis and periodontitis with systemic use of Esberitox in monotherapy. Methods: The oropharyngeal secret of 10 patients with chronic tonsillitis (CT), 11 patients with chronic pharyngitis (CP), (all patients after tonsillectomy), 10 patients with chronic periodontitis was investigated. Patients were given monotherapy with «Esberitox» for 10 days (CP), according to the manufacturer's instructions for use of the drug. In addition, 9 practically healthy persons (K) of the same age (18-50 years) were examined. The ELISA method was used to determine the class A immunoglobulins (secretory and monomeric), IgG, α-interferon, interleukin-1β, levels of immune complexes. Statistics: Mann-Whitney U-test. Results: Studies have shown that in patients with chronic inflammatory diseases of the oral cavity there is a decrease in the protective factors of local immunity – the level of secretory IgA, antiviral factor – α-interferon and an increase in the level of pro-inflammatory cytokine – interleukin-1β, monomeric form of IgA and the number of immune complexes. The use of «Esberitox» as a monotherapy was accompanied by an increase in the concentration of class A secretory immunoglobulin, the «normalization» of the α-interferon content (increase in concentration) and interleukin-1β (decrease in content). Conclusion: The resulting positive effects from the use of esberitox allow us to recommend the drug as part of the complex therapy of chronic diseases of the oropharynx, and in the form of monotherapy.

We examined adults with untreated Burkitt lymphoma (BL) from 2009 to 2018 across 30 US cancer centers. Factors associated with progression-free survival (PFS) and overall survival (OS) were evaluated in univariate and multivariate Cox models. Among 641 BL patients, baseline features included the following: median age, 47 years; HIV+, 22%; Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2 to 4, 23%; >1 extranodal site, 43%; advanced stage, 78%; and central nervous system (CNS) involvement, 19%. Treatment-related mortality was 10%, with most common causes being sepsis, gastrointestinal bleed/perforation, and respiratory failure. With 45-month median follow-up, 3-year PFS and OS rates were 64% and 70%, respectively, without differences by HIV status. Survival was better for patients who received rituximab vs not (3-year PFS, 67% vs 38%; OS, 72% vs 44%; P < .001) and without difference based on setting of administration (ie, inpatient vs outpatient). Outcomes were also improved at an academic vs community cancer center (3-year PFS, 67% vs 46%, P = .006; OS, 72% vs 53%, P = .01). In multivariate models, age ≥ 40 years (PFS, hazard ratio [HR] = 1.70, P = .001; OS, HR = 2.09, P < .001), ECOG PS 2 to 4 (PFS, HR = 1.60, P < .001; OS, HR = 1.74, P = .003), lactate dehydrogenase > 3× normal (PFS, HR = 1.83, P < .001; OS, HR = 1.63, P = .009), and CNS involvement (PFS, HR = 1.52, P = .017; OS, HR = 1.67, P = .014) predicted inferior survival. Furthermore, survival varied based on number of factors present (0, 1, 2 to 4 factors) yielding 3-year PFS rates of 91%, 73%, and 50%, respectively; and 3-year OS rates of 95%, 77%, and 56%, respectively. Collectively, outcomes for adult BL in this real-world analysis appeared more modest compared with results of clinical trials and smaller series. In addition, clinical prognostic factors at diagnosis identified patients with divergent survival rates.

В статье проанализированы вопросы защиты морской среды. Рассмотрены основные проблемы и пути их решения по материалам 71 сессии Комитета по защите морской среды 2017 года Международной морской организации. В статье конкретизированы основные требования по

Warfarin is an oral anticoagulant widely prescribed for a variety of thromboembolic indications including venous thromboembolism (VTE), deep vein thrombosis (DVT) and the prevention of stroke associated for atrial fibrillation (AF) 1. Warfarin requires ongoing monitoring of Internationalised Normalised Ratio (INR) due to a narrow therapeutic index and interactions with numerous drugs 2. The time in therapeutic range (TTR) is often used to indicate the quality of warfarin therapy due to the established correlation between higher mean TTR and reduced complications such as bleeding and thromboembolism 3. TTR is strongly associated with bleed risk, but increased bleeding with warfarin has also been associated with patient comorbidities and concurrent administration of other medication linked to bleeding including antiplatelet agents and non‐steroidal anti‐inflammatories (NSAIDs) 4.

Health care delivery is increasingly influenced by the emerging concepts of precision health and the learning health care system. Although not synonymous with precision health, genomics is a key enabler of individualized care. Delivering patient-centered, genomics-informed care based on individual-level data in the current national landscape of health care delivery is a daunting challenge. Problems to overcome include data generation, analysis, storage, and transfer; knowledge management and representation for patients and providers at the point of care; process management; and outcomes definition, collection, and analysis. Development, testing, and implementation of a genomics-informed program requires multidisciplinary collaboration and building the concepts of precision health into a multilevel implementation framework. Using the principles of a learning health care system provides a promising solution. This article describes the implementation of population-based genomic medicine in an integrated learning health care system-a working example of a precision health program.

Background: The term HGBL, NOS was introduced by the World Health Organization (WHO) in 2016 for aggressive B-cell lymphomas with Burkitt lymphoma-like (BLL) or blastoid cytomorphology that lack double-hit genetics and do not meet criteria for other entities. Diagnostic patterns and prognosis of these rare tumors are not well understood. We examined the characteristics and outcomes of patients (pts) with HGBL, NOS diagnosed in 17 academic centers across the United States. Methods: We collected retrospective data on HGBL, NOS cases diagnosed by academic hematopathologists in 2017-2021; 8 centers performed a local review by lymphoma pathology experts to confirm fulfillment of the WHO criteria; pathology reports were reviewed centrally. We excluded pts not tested for MYC rearrangement (MYC-R), any double/triple-hit, diffuse large B-cell, or lymphoblastic lymphomas. Immunohistochemistry (IHC) and cytogenetic tests were done locally. Outcomes included rates of complete response (CR), progression-free (PFS) and overall survival (OS) estimated with 95% confidence intervals (CI). Results: Among 126 pts with HGBL, NOS, median age was 64 years (range 18-91), 67% were male, and 3 were HIV+. Advanced stage was present in 68%, poor performance status (PS, ECOG ≥2) in 21%, high serum lactate dehydrogenase (LDH) in 68%, extranodal (EN) sites in 79%, central nervous system (CNS) involvement in 6%, and International Prognostic Index (IPI) ≥ 3 in 55%. Cytomorphology was reported as BLL in 59 (47%) cases, blastoid in 28 (22%), and unspecified in 39 (31%). By IHC, 83% had germinal center B-cell (GCB) phenotype. Using cases with available data, CD10 was expressed in 79%, BCL6 in 81%, MUM1/IRF4 in 48%, MYC in 73%, BCL2 in 55% (dual MYC/BCL2 expressor [DEL]: 37%), CD5 in 13%, and median Ki-67 was 95%. MYC-R (single-hit) was detected in 27% (Fig A), MYC extra copies (EC) in 9%, BCL2-R in 13%, and BCL6-R in 10%. MYC-EC were present in 16% of cases with BCL2-R or BCL6-R, and BCL2/BCL6-EC in 12% of those with MYC-R. Blastoid tumors were more likely than BLL to involve >1 EN site or to have BCL2-R (Fig B). 9 cases were assessed by next generation sequencing and 5 (56%) had a TP53 mutation. Cases which underwent confirmatory pathology review (N=74) did not differ from others clinically but more often had a well-defined HGBL morphology (77% vs 58%, P=.031) and less often MYC-R (20% vs. 37%, P=.004). The most common first-line regimens (among treated pts, N=121) were DA-EPOCH-R (50%) and RCHOP (35%), with few pts receiving HyperCVAD/MA (5%) or CODOX-M±IVAC (2%); 97% received rituximab, and 44% CNS prophylaxis. Pts selected for DA-EPOCH-R vs. RCHOP were younger (median 61 vs. 68 years, P=.006), more often had stage 3/4 (P=.04), BLL morphology (56% vs. 29%, P=.009) or MYC-R (31% vs. 14%, P=.06). CR was attained in 62% of pts, whereas 20% had progressive disease. The most frequent salvage regimens (± rituximab) included ICE (N=12), DHAP (N=6), and GemOx (N=5). 3 pts underwent autologous, and 3 allogeneic transplant (2/3 subsequently relapsed). 13 received chimeric antigen receptor (CAR) T-cells, with response noted in 7 (54%) and CR in 4 (31%); HGBL relapsed in 3/7 (43%) responders. With median follow-up of 2.7 years, 39% of pts relapsed, and 33% died. Of 49 observed relapses, 13 (27%) involved the CNS. PFS estimate at 2 years was 51% (95% CI, 42-60%) and OS was 68% (95% CI, 58-76%; Fig C). PFS and OS were not significantly associated with age or PS, but stage and LDH were prognostic (Fig D-G). Furthermore, PFS did not differ by BLL/blastoid morphology, MYC-R status or DEL status, but non-GCB tumors had somewhat worse PFS (Fig H-J). We observed no significant PFS (or OS) difference between pts selected for RCHOP vs. DA-EPOCH-R (P=.83 for PFS, Fig K; P=.55 for OS) in aggregate or in any subset, except for de novo tumors with BLL morphology (N=41), where DA-EPOCH-R showed a superior 2-year PFS (73% vs 38% for RCHOP, P=.027; stratified by IPI: P=.040, Fig L). Conclusions: HGBL, NOS, as diagnosed in current academic practice, is highly heterogeneous, highlighting the need to classify high-grade lymphomas using molecular rather than morphologic features. Considering poor survival in all age groups (except for few pts with early stage and normal LDH), lack of prognostic significance of MYC-R, DEL status, or cytomorphology, HGBL, NOS needs prospective trials to delineate prognostic biomarkers, the role of intensified chemotherapy, and novel therapeutic approaches. Figure 1 Figure 1. Disclosures Landsburg: Triphase: Research Funding; Takeda: Research Funding; Curis: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: DSMB member; ADCT: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees. Hughes: Acerta Pharma: Research Funding; AstraZeneca: 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; Genzyme: Consultancy; Janssen: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Sandoval-Sus: SeaGen, Janssen, MassiveBio, TG: Other: Advisory Board; BMS: Other: Advisory Board, Speakers Bureau. Kothari: Incyte pharmaceuticals: Consultancy, Honoraria; Karyopharm pharmaceuticals: Consultancy, Honoraria. Torka: TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Smith: Acerta Pharma BV: Research Funding; ADC Therapeutics: Consultancy; AstraZeneca: Consultancy, Research Funding; De Novo Biopharma: Research Funding; Ignyta (spouse): Research Funding; Beigene: Consultancy, Research Funding; Portola Pharmaceuticals: Research Funding; Incyte: Consultancy; Incyte Corporation: Research Funding; Karyopharm: Consultancy; KITE pharm: Consultancy; Merck Sharp & Dohme Corp: Research Funding; Ayala (spouse): Research Funding; Bayer: Research Funding; Genentech: Research Funding; Bristol Myers Squibb (spouse): Research Funding; Millenium/Takeda: Consultancy. Epperla: Genzyme: Honoraria; Karyopharm: Other: Ad Board; Beigene: Speakers Bureau; Verastem: Speakers Bureau. Bond: Kite/Gilead: Honoraria. Naik: Sanofi: Other: Virtual Advisory Board Member ; Takeda: Other: Virtual Advisory Board Member ; Kite: Other: Virtual Advisory Board Member. Kamdar: ADC Therapeutics: Consultancy; AbbVie: Consultancy; KaryoPharm: Consultancy; Kite: Consultancy; Adaptive Biotechnologies: Consultancy; AstraZeneca: Consultancy; Celgene (BMS): Consultancy; TG Therapeutics: Research Funding; Genentech: Research Funding; Genetech: Other; Celgene: Other; SeaGen: Speakers Bureau. Haverkos: Viracta Therapeutics: Consultancy. Karmali: BMS/Celgene/Juno: Consultancy, Research Funding; Takeda: Research Funding; Roche: Consultancy; Epizyme: Consultancy; Janssen/Pharmacyclics: Consultancy; EUSA: Consultancy; Genentech: Consultancy; Karyopharm: Consultancy; AstraZeneca: Speakers Bureau; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; Morphosys: Consultancy, Speakers Bureau; BeiGene: Consultancy, Speakers Bureau. Vose: Kite, a Gilead Company: Honoraria, Research Funding. Olszewski: PrecisionBio: Research Funding; Celldex Therapeutics: Research Funding; TG Therapeutics: Research Funding; Acrotech Pharma: Research Funding; Genentech, Inc.: Research Funding; Genmab: Research Funding.

Background: Recent studies reported low rates of seroconversion response to COVID-19 vaccination in patients (pts) with hematologic malignancies (HMs). Vaccine choice among the 3 FDA-authorized products (BNT162b2/Pfizer-BioNTech, mRNA-1273/Moderna, or Ad26.COV2.S/J&J), prior therapy, and disease-specific factors may affect seroconversion. Addressing these factors may improve seroconversion rates and identify pts at risk of severe COVID-19 infection despite vaccination. Methods: We conducted a retrospective study of adults with HMs vaccinated in our center between 2/2021 and 7/2021, excluding pts with prior COVID-19 infection. Seroconversion was assessed by the qualitative SARS-CoV-2 Total Antibody Test (IgG/IgM against Receptor Binding Domain [RBD], Wondfo USA, Willowbrook, IL). A subset of samples was tested by the semi-quantitative Abbott AdviseDx SARS-CoV-2 IgG II assay (IgG against RBD). For univariate associations (UVA) we used Fisher's exact test for categorical variables, and fractional polynomial fits for continuous variables to examine non-linearity. Multivariable analysis (MVA) used a robust Poisson model reporting risk ratio (RR) with 95% confidence intervals (CI). Results: Among 239 eligible pts, median age was 70 (range, 28-94), and 112 (47%) were female. HMs included aggressive B-cell lymphomas (n=74, 31%), indolent B-cell lymphomas (n=52, 22%), chronic lymphocytic leukemia (CLL, n=30, 13%), other lymphomas (n-19, 8%), plasma cell neoplasms (n=43, 18%), and myeloid cancers (n=21, 9%); 140 pts (59%) received BNT162b2/Pfizer, 74 (31%) mRNA-1273/Moderna, and 23 (10%) Ad26.COV2.S/J&J vaccines (2 pts had undetermined vaccine type). HM was active in 100 pts (42%), whereas 108 (45%) pts were in remission after treatment, and 31 (13%) on watchful waiting (WW, never treated); 141 (59%) had a prior exposure to an anti-B-cell monoclonal antibody, and 22 (9%) prior stem cell transplantation. Overall, 99 pts (41%; binomial 95% CI, 35-48%) showed post-vaccination seroconversion upon testing at median 10 weeks from first vaccine. Seroconversion was significantly less frequent among pts with lymphomas compared with plasma cell or myeloid neoplasms (overall P=.020; Fig A). It was also less frequent after prior anti-B-cell antibody exposure (29% vs 59%, P In a MVA (Fig. J), vaccination with mRNA-1273 remained significantly associated with higher rate of seroconversion compared with BNT162b2 (RR=0.59; 95%CI, 0.44-0.79) or Ad26.COV2.S (RR=0.35; 95%CI, 0.16-0.77). Higher seroconversion rate was also associated with remission (RR=1.98; 95%CI, 1.42-2.76) or WW status (RR=1.72; 95%CI 1.02-2.89) compared with active disease, and higher lymphocyte count. Exposure to anti-B-cell antibodies remained associated with lack of seroconversion (RR=0.66; 95%CI, 0.44-0.99). Seroconversion was borderline less frequent in CLL than lymphomas, and higher with plasma cell or myeloid disorders. Results were similar in the subset of pts (n=191) with prior treatment, adjusting for time from last chemotherapy(data not shown). The anti-COVID-19 IgG titers on semiquantitative test (n=47, all after mRNA-based vaccines) were also lower in pts with active disease compared with those in remission (P=.065) or under WW (P=.028), and in those with prior anti-B-cell antibody (P=.0095). Conclusions: Pts with HMs demonstrate overall low rates of seroconversion after vaccination against COVID-19, particularly when they have active disease or are on/after B-cell depleting monoclonal antibody therapy. The mRNA vaccines (particularly mRNA-1273) appear to have elicited superior responses compared with the adenovirus-based product. Pts with active HMs or those within 2 years of last therapy should be particularly aware of the risk of infection despite vaccines and should be considered for strategies to enhance anti-COVID-19 immunity regardless of age. Figure 1 Figure 1. Disclosures Olszewski: TG Therapeutics: Research Funding; PrecisionBio: Research Funding; Celldex Therapeutics: Research Funding; Acrotech Pharma: Research Funding; Genentech, Inc.: Research Funding; Genmab: Research Funding.

Introduction: Central nervous system (CNS) relapse in diffuse large B-cell lymphoma (DLBCL) is uncommon but is associated with poor outcomes. In selected high risk patients (pts), high dose methotrexate (HDMTX) is often used as CNS prophylaxis with frontline (1L) DLBCL therapy despite uncertain efficacy, optimum dose and timing of delivery. A recent UK study (Wilson et al 2020) showed that intercalated HDMTX (i-HDMTX) was associated with increased toxicity and R-CHOP delays compared to end of treatment (EOT) delivery. Although hypothesis generating, the study size was insufficient to determine whether EOT was non-inferior in terms of CNS relapse risk. Methods: We conducted an international, multicentre retrospective analysis of consecutive DLBCL or high grade BCL pts between 2007-20 from 47 centers in Europe, Australia and N. America. Pts were included if they received R-CHOP or R-CHOP-like 1L therapy with curative intent as well as HDMTX CNS prophylaxis (≥1 cycle). Concurrent intrathecal (IT) prophylaxis was permitted. Pts with known CNS involvement at baseline and those treated with more intensive protocols (e.g. R-DA-EPOCH) were excluded. i-HDMTX was defined as any pt receiving a HD-MTX cycle before the final R-CHOP cycle. CNS relapse events were excluded if occurring after first systemic lymphoma relapse/progression. Time to event endpoints were measured from diagnosis to first event or censor and analysed using Kaplan-Meier and Cox regression methods. Time to CNS relapse was analysed using competing risk Fine and Gray method (for death and non-synchronous systemic relapse). To mitigate for possible immortality bias in the EOT arm, a landmark analysis for pts alive and free from progression at 6 months was conducted. We aimed to exclude a 5% difference in 2-year (y) CNS relapse rates. Results: 1,384 pts were analysed. 750 received i-HDMTX and 634 received EOT HDMTX. Key baseline characteristics are summarised in Table 1. Median follow up was 37.9 months. 44.2% had high CNS IPI (4-6) with no significant difference between i-HDMTX and EOT groups (45.1% vs 43.1%, p=0.087). ≥2 cycles of HDMTX were used in 86.6% with no difference between groups (85.6% vs 87.9%, p=0.22). Concurrent IT prophylaxis use was higher for EOT pts (55.6% vs 38.1% p 78 CNS relapses (42 i-HDMTX, 36 EOT) were observed: parenchymal in 41 (53%), parenchymal and leptomeningeal in 16 (21%) and isolated leptomeningeal in 21 (27%). There was no significant difference in 2y CNS relapse rates between i-HDMTX and EOT in all pts: 5.2% vs 3.9%, adjusted hazard ratio (HR) 0.92 (95% CI 0.58-1.47), p=0.74, 2y difference -0.2% (-2.0-2.5) or landmark analysis: 2.8% vs 4.1%, HR: 0.93 (0.56-1.55), p=0.79, 2y difference: -0.3% (-1.8-2.2%) (Fig 1a/b). Exploratory analyses focusing on pts with isolated CNS relapse (n=57) demonstrated similar results (2y rates 3.6% vs 3.0%, p=0.99). On multivariable analysis (MVA) of risk factors for CNS relapse, renal/adrenal involvement was the only variable associated with increased CNS relapse risk (adjusted HR 1.74 (1.03-2.92), p=0.038). Notably, IT prophylaxis was not associated with reduction in CNS relapse. In 600 high CNS IPI (4-6) pts, there was no difference in CNS relapse risk between i-HD-MTX and EOT (3y rates 9.4% vs 8.6%, HR 0.92 (95% CI 0.52-1.62)). In a composite high risk group including CNS IPI 4-6 and/or any of the following: ≥3 extranodal sites, renal, adrenal, testicular or breast involvement (n=885) there was no difference in 3y CNS relapse rates between groups (i-HDMTX 7.6% vs EOT 7.4%, HR 0.94 (0.58-1.53)). Progression-free survival (PFS) and overall survival (OS) in the i-HDMTX and EOT groups were as follows: 3y PFS 70.7% vs 76.7% (p=0.098), 3y OS 79.9% vs 87.0% (p=0.0016). However, there were no PFS/OS differences between groups on landmark analysis (n=1259) (Fig 1c). On analysis of pts experiencing ≥1 R-CHOP delay of ≥7 days, use of i-HDMTX was the only factor on MVA associated with increased delays (p Discussion: We found no evidence that EOT delivery increases CNS relapse risk when compared to i-HDMTX in this large analysis of pts treated with 1L R-CHOP. Delays to R-CHOP cycles were increased with i-HDMTX. Findings in a high risk subgroup were unchanged and rates of CNS relapse in this HDMTX treated group were similar to published comparable high risk cohorts receiving infrequent CNS prophylaxis. Where HDMTX prophylaxis is used, delivery could be deferred until R-CHOP completion. Figure 1 Figure 1. Disclosures Wilson: Takeda: Other: Conference fees; Janssen: Other: Conference fees; Abbvie: Honoraria. Eyre: Janssen: Honoraria; Secura Bio: Consultancy, Honoraria; Gilead/KITE: Honoraria, Other: Travel support for conferences, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Other: Travel to conferences; AstraZeneca: Honoraria, Research Funding; Loxo Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Beigene: Honoraria, Research Funding. Ahearne: Pfizer: Research Funding; Takeda: Honoraria; Roche: Honoraria. Schorb: Roche: Research Funding; Riemser Pharma GmbH: Honoraria, Research Funding; AbbVie: Research Funding. Ku: Antegene: Consultancy; Roche: Consultancy; Genor Biopharma: Consultancy. Narkhede: Genentech/Roche: Research Funding; Gilead: Research Funding; Genmab: Other: Medical writing support, Research Funding; TG Therapeautics: Research Funding. Lewis: AstraZeneca: Consultancy, Honoraria; Janssen: Honoraria, Patents & Royalties; Novartis: Patents & Royalties; Roche: Consultancy, Honoraria. Øvlisen: Abbvie: Other: Travel expenses. Santarsiere: Janssen: Honoraria. Shah: Abbvie, Janssen and Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Roulin: Janssen: Other: Travel and meetings. Manos: Bristol-Myers Squibb: Other: Travel and meetings. Hamad: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Lopez-Garcia: Roche: Other: Speaker Honoraria, Travel and accommodation grants; Janssen: Other: Speaker Honoraria, Advisor, Travel and accommodation grants, Research Funding; Abbvie: Other: Speaker Honoraria, Advisor, Travel and accommodation grants; Celgene: Other: Speaker Honoraria; Fresenius: Other: Speaker Honoraria; Novonordisk: Other: Speaker Honoraria. El-Galaly: ROCHE Ltd: Ended employment in the past 24 months; Abbvie: Other: Speakers fee. Cheah: Beigene: Consultancy, Honoraria, Other: advisory; AbbVie: Research Funding; Celgene: Research Funding; AstraZeneca: Consultancy, Honoraria, Other: advisory; Loxo/Lilly: Consultancy, Honoraria, Other: advisory; TG Therapeutics: Consultancy, Honoraria, Other: advisory; Roche: Consultancy, Honoraria, Other: advisory and travel expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: advisory; MSD: Consultancy, Honoraria, Other: advisory, Research Funding; Gilead: Consultancy, Honoraria, Other: advisory; Ascentage pharma: Consultancy, Honoraria, Other: advisory. Ferreri: Gilead, Novartis, Juno, PletixaPharm, Roche, Incyte: Membership on an entity's Board of Directors or advisory committees; BMS, Beigene, Pharmacyclics, Hutchison Medipharma, Amgen, Genmab, ADC Therapeutics, Gilead, Novartis, Pfizer: Research Funding. Fox: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Other: speaker fees. Cwynarski: Gilead: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Atara: Consultancy; Celgene: Consultancy; Takeda: Consultancy, Other: travel to scientific conferences, Speakers Bureau; Kite, a Gilead Company: Consultancy, Other: travel to scientific conferences, Speakers Bureau; Janssen: Consultancy, Other: travel to scientific conferences; Roche: Consultancy, Other: travel to scientific conferences, Speakers Bureau; BMS/Celgene: Other: travel to scientific conferences. McKay: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Other: Travel Support; KITE: 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, Other: Travel Support; Janssen: Honoraria, Other: Travel Support; Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

В статье изложены основные аспекты борьбы с пиратством и вооруженным разбоем против судоходства, как составной части свободы открытого моря. Рассмотрены и проанализированы требования Международной конвенции о подготовке и дипломировании моряков и несении

В статье излагаются основные проблемы опасной для жизни смешанной миграции по морю. Эти проблемы рассматривались в мае 2016 года на 96-ой сессии Комитета по безопасности на море Международной морской организации в качестве вопроса высокого уровня. В стать

Background: CNS invasion in aggressive lymphoma (including diffuse large B-cell [DLBCL], double-hit [DHL], Burkitt [BL] and plasmablastic lymphoma [PBL]) remains a major diagnostic and therapeutic challenge. Parenchymal CNS invasion requires a brain biopsy to diagnose, and conventional CSF evaluations lack sensitivity. Furthermore, determining which patients (pts) without CNS disease at diagnosis might be at high risk of future CNS relapse, and thus would most benefit from aggressive CNS prophylaxis, is difficult. Predictors that use clinical variables (e.g. the CNS-IPI) can select a high-risk group with ~10% risk of CNS relapse, but ~50% of events occur in low/intermediate-risk groups. We evaluated a novel CSF assay that detects clonotype-specific cell-free DNA (cfDNA) by next-generation sequencing (NGS) combined with multiplex PCR (Chang T et al, BMC Cancer 2020). This assay can identify minimal residual disease (MRD) in the plasma of pts with DLCBL and can predict systemic relapse (Roschewski et al, Lancet Oncol 2015). Methods: To examine the diagnostic sensitivity of the NGS-MRD assay in the CSF, we prospectively collected CSF from 6 pts with lymphomas who had known parenchymal or leptomeningeal CNS invasion. We also tested stored DNA from historical CSF samples of 8 pts with CNS lymphoma who tested negative by conventional IGH-PCR. We then enrolled 19 pts with newly diagnosed high-risk lymphomas without CNS invasion to examine the prognostic value of the NGS-MRD assay in the CSF collected at diagnosis. In the two-step assay, tumor-specific clonotype sequences were first identified from genomic DNA in primary tumor specimens using NGS of rearranged IGK, IGH (VJ or DJ), and IGL loci. Tumor-specific clonotypes were then selected for tracking in the CSF (split into acellular CSF fluid and cell pellet) and in paired plasma samples. The assay quantitated copy numbers of each tracked sequence per mL of acellular CSF or per 106 cells in the pellet, as well as tumor clonotype frequency (%) per all B-cells. Results: The NGS-MRD detected tumor-specific clonotype in 100% of CSF samples from pts with known CNS lymphoma (n=6; Fig A), including pts with isolated parenchymal-only CNS disease that was not detected by CSF cytology, flow cytometry, or IGH-PCR. For pts with CNS parenchymal disease, median cfDNA copy count in the CSF fluid was 2 /mL (range, 0.4-929) and median clonotype frequency was 9.0% (range, 0.03-68.9%). For pts with leptomeningeal disease, these values were 2233 /mL (1.2-5620) and 37% (1.7-98.4%), respectively (Fig. B). Furthermore, the NGS-MRD assay detected tumor clonotypes in DNA isolates from 6 historical CSF samples (collected in 2014-2018) of pts with known CNS disease, in which lymphoma was not detectable by conventional IGH-PCR (2 additional historical samples failed DNA quality check). Among 19 newly diagnosed pts with no known CNS invasion (median age 57, 42% women, median LDH 352 IU/L), 12 (63%) had DLBCL with high risk of CNS relapse by virtue of high CNS-IPI or epidural tumor, and 7 had other high-risk histologies (2 DHL, 2 BL, HIV+ PBL, and 2 lymphoblastic leukemias). The CSF NGS-MRD assay was positive for tumor-specific clonotype in 8 pts (42%). Median cfDNA copy count in the CSF fluid was 3 /mL (range, 0.9-15.6) and median clonotype frequency was 18.6% (range, 1.4-28.5%). We observed no significant correlation between the amount of cfDNA and number of red cells /mL of CSF (a measure of potential CSF contamination by blood during collection procedure; Fig. C) or between the amount of cfDNA in plasma and in CSF (Fig. D). With median follow-up of 11 months, no pts with negative baseline NGS-MRD assay in CSF relapsed, whereas 2 of 10 with a positive assay had a CNS relapse (12-month incidence, 29%; Fig. E), despite both pts having negative CNS imaging, CSF cytology, flow cytometry, and IGH-PCR at diagnosis. Conclusions: In this proof-of-concept study, the NGS-MRD CSF assay showed 100% sensitivity for diagnosing intraparenchymal CNS invasion in aggressive lymphomas that were not detected in the CSF using conventional methods. In a prospective cohort of newly diagnosed pts without baseline CNS invasion but at high clinical risk for CNS relapse, the assay identified lymphoma-derived cfDNA in 42% of cases. The 100% sensitivity and 100% negative predictive value of the assay for subsequent CNS relapse warrants further prospective evaluation as a potential tool for personalizing CNS-directed prophylaxis. Disclosures Olszewski: Spectrum Pharmaceuticals: Research Funding; TG Therapeutics: Research Funding; Adaptive Biotechnologies: Research Funding; Genentech, Inc.: Research Funding. Mullins:Adaptive Biotechnologies: Current Employment, Other: shareholder.

Introduction: There are few data about prognostication and outcomes in patients (pts) with HIV-BL treated in the cART era. Optimal treatment strategies to minimize treatment-related mortality (TRM) remain unclear and current recommendations are based on small studies. We conducted a multicenter international analysis to identify prognostic factors and outcomes in pts with HIV-BL treated in the cART era. Methods: This retrospective analysis included a subcohort from a recent study across 30 US sites (Evens et al. Blood 2020) augmented by data from 5 UK centers treated 2009-2018. Progression-free (PFS) and overall survival (OS) were estimated by Kaplan-Meier & differences assessed by log-rank test. Univariate (UVA) associations were derived via Cox model and multivariable (MVA) models were constructed by forward selection of significant variables with P Results: 249 (US: 140 & UK: 109) pts with newly diagnosed HIV-BL were included. Clinical features included median age 43 (IQR 35-50 years [yrs]); male sex: 84%; ECOG PS: 2-4: 48%; elevated LDH: 85% (> 3x upper limit of normal (ULN) 49% & >5xULN 39%); >1 extranodal (EN) site: 60%; any CNS involvement (CNSinv) 25%; and +bone marrow (BM) 46%. MYC rearrangement was reported in 93% of pts with t(8;14) in 49%, break-apart probe in 41% and MYC-light chain in 3%; the rest had classical BL with negative MYC testing (4%) or missing result (3%) (otherwise classical BL). Median CD4 count was 217 (IQR 90-392 cells/µL) with 68% pts having CD4>100 cells/µL. At BL diagnosis, HIV viral load was detectable in 55%; 39% of pts were on cART. Baseline features were similar between the US & UK cohorts with significant differences only in ECOG PS 2-4 (32% vs 65%; P Tx regimens included: CODOX-M/IVAC (Magrath) 60%, DA-EPOCH 25%, HyperCVAD/MA 13%, & other 1%; most pts (87%) received rituximab (R). Similar regimens were used in pts with baseline CNSinv: Magrath 64%, DA-EPOCH 24% & HyperCVAD 12%. In the US, pts most frequently received DA-EPOCH (42%) followed by Magrath (32%) & HyperCVAD/MA (24%), whereas in the UK, 96% received Magrath. R was more frequently given in the US (94% vs 79%, P With median follow-up of 4.5 yrs, 3-yr PFS & OS were 61% & 66%, respectively, and nearly identical in both countries (Fig A). Pts with CD4>100 cells/µL had better 3-yr PFS (Fig B) & OS (68% vs 57% P=0.03). We observed significantly worse outcomes in pts with baseline CNSinv (3-yr PFS 36% vs 69%, P The incidence of CNS recurrence at 3 yr across all Tx was 11%. Higher incidence was observed with DA-EPOCH (P=0.032 vs other regimens; Fig F) with no difference according to CD4 count. Variables associated with PFS & OS on UVA included: ECOG PS 2-4, >1 EN, +BM, baseline CNSinv, LDH>ULN, CD4 5xULN (HR 2.09, P1 EN sites (HR 1.58 P=0.043). The same variables were significant on MVA for OS. Adjusting for all of the prognostic variables, Tx with Magrath was associated with longer PFS (adjusted HR, 0.45, P=0.005). Conclusions: These data represent the largest analysis of HIV-BL to date. There were favorable tolerance and outcomes with intensive R-containing regimens with Magrath being associated with lower TRM and the highest PFS. In addition, prognostic factors for pt outcomes were associated with lymphoma characteristics rather than with HIV-related features. Pts with baseline CNSinv represent a high-risk group with unmet therapeutic needs. Disclosures Alderuccio: Oncinfo: Honoraria; Puma Biotechnology: Other: Family member; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; OncLive: Honoraria; Inovio Pharmaceuticals: Other: Family member; Foundation Medicine: Other: Family member; Forma Therapeutics: Other: Family member; Agios Pharmaceuticals: Other: Family member. Olszewski:Spectrum Pharmaceuticals: Research Funding; TG Therapeutics: Research Funding; Adaptive Biotechnologies: Research Funding; Genentech, Inc.: Research Funding. Evens:Epizyme: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Mylteni: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding; MorphoSys: Consultancy, Honoraria; Research To Practice: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria. Collins:Gilead: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; MSD: Consultancy, Honoraria, Research Funding; Taekda: Consultancy, Honoraria, Other: travel, accommodations, expenses, Speakers Bureau; BeiGene: Consultancy; Roche: Consultancy, Honoraria, Other: travel, accommodations, expenses , Speakers Bureau; Celleron: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau; Celgene: Research Funding; Amgen: Research Funding; Pfizer: Honoraria. Danilov:Astra Zeneca: Consultancy, Research Funding; Verastem Oncology: Consultancy, Research Funding; Takeda Oncology: Research Funding; Gilead Sciences: Research Funding; Bayer Oncology: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy; Nurix: Consultancy; Celgene: Consultancy; Aptose Biosciences: Research Funding; Bristol-Myers Squibb: Research Funding; Rigel Pharmaceuticals: Consultancy; Karyopharm: Consultancy; Pharmacyclics: Consultancy; BeiGene: Consultancy; Abbvie: Consultancy. Jagadeesh:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Debiopharm Group: Research Funding; MEI Pharma: Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; Regeneron: Research Funding. Reddy:Genentech: Research Funding; Abbvie: Consultancy; BMS: Consultancy, Research Funding; Celgene: Consultancy; KITE Pharma: Consultancy. Farooq:Kite, a Gilead Company: Honoraria. Bond:Seattle Genetics: Honoraria. Khan:Celgene: Research Funding; Janssen: Honoraria; Pharmacyclics: Honoraria; Bristol Myers Squibb: Research Funding; Seattle Genetics: Research Funding. Yazdy:Bayer: Honoraria; Genentech: Research Funding; Octapharma: Consultancy; Abbvie: Consultancy. Karmali:Karyopharm: Honoraria; Takeda: Research Funding; AstraZeneca: Speakers Bureau; BeiGene: Speakers Bureau; BMS/Celgene/Juno: Honoraria, Other, Research Funding, Speakers Bureau; Gilead/Kite: Honoraria, Other, Research Funding, Speakers Bureau. Martin:Janssen: Consultancy; Regeneron: Consultancy; Bayer: Consultancy; Sandoz: Consultancy; I-MAB: Consultancy; Beigene: Consultancy; Cellectar: Consultancy; Incyte: Consultancy; Kite: Consultancy; Morphosys: Consultancy; Celgene: Consultancy; Teneobio: Consultancy; Karyopharm: Consultancy, Research Funding. Diefenbach:Bristol-Myers Squibb: Consultancy, Research Funding; Denovo: Research Funding; Genentech, Inc.: Consultancy, Research Funding; Incyte: Research Funding; LAM Therapeutics: Research Funding; MEI: Research Funding; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Millenium/Takeda: Research Funding; Trillium: Research Funding. Klein:Takeda: Membership on an entity's Board of Directors or advisory committees. Haverkos:Viracta THerapeutics: Consultancy. Epperla:Verastem Oncology: Speakers Bureau; Pharmacyclics: Honoraria. Caimi:Amgen: Other: Advisory Board; Bayer: Other: Advisory Board; Kite Pharma: Other: Advisory Board; ADC Therapeutics: Other: Advisory Board, Research Funding; Celgene: Speakers Bureau; Verastem: Other: Advisory Board. Kamdar:Roche: Research Funding. Feldman:Eisai: Research Funding; Pfizer: Research Funding; Kyowa Kirin: Consultancy, Research Funding; Portola: Research Funding; Janssen: Speakers Bureau; AstraZeneca: Consultancy; Trillium: Research Funding; Cell Medica: Research Funding; Amgen: Research Funding; Pharmacyclics: Honoraria, Other, Speakers Bureau; Abbvie: Honoraria; Bayer: Consultancy, Honoraria; Viracta: Research Funding; Rhizen: Research Funding; Corvus: Research Funding; BMS: Consultancy, Honoraria, Research Funding; Kite: Honoraria, Other: Travel expenses, Speakers Bureau; Celgene: Honoraria, Research Funding; Takeda: Honoraria, Other: Travel expenses; Seattle Genetics, Inc.: Consultancy, Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau. Smith:AstraZeneca: Consultancy; Millenium/Takeda: Consultancy; Karyopharm: Consultancy; Beigene: Consultancy; Seattle Genetics: Research Funding; Ayala: Research Funding; Bayer: Research Funding; AstraZeneca: Research Funding; Acerta Pharma BV: Research Funding; Bristol Meyers Squibb: Research Funding; Portola: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; Incyte: Research Funding; Ignyta: Research Funding; Genentech: Research Funding; De Novo Biopharma: Research Funding. Portell:Amgen: Consultancy; Pharmacyclics: Consultancy; AbbVie: Research Funding; Janssen: Consultancy; TG Therapeutics: Research Funding; Bayer: Consultancy; BeiGene: Consultancy, Research Funding; Xencor: Research Funding; Kite: Consultancy, Research Funding; Acerta/AstraZeneca: Research Funding; Infinity: Research Funding; Roche/Genentech: Consultancy, Research Funding. Naik:Celgene: Other: advisory board; Sanofi: Other: advisory board. Lossos:Janssen Biotech: Honoraria; Verastem: Consultancy, Honoraria; Stanford University: Patents & Royalties; NCI: Research Funding; Seattle Genetics: Consultancy, Other; Janssen Scientific: Consultancy, Other. Cwynarski:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Atara: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau.

Background. CD5 expression is rare in MZL and has been historically characterized in case series of splenic (SMZL) and nodal (NMZL) MZL (Baseggio et al., haematologica, 2010; Jaso et al., Am J Clin Pathol, 2013; Salido et al., Blood 2010). These studies reported similar outcomes with CD5+ and CD5- MZL but did not examine the significance of CD5 in the context of modern immunochemotherapy. BR is a regimen increasingly used for treatment of MZL, but many patients can initially receive R monotherapy (R-mono) with no detriment to survival (Olszewski et al., ASH 2019). There are no biomarkers predictive of differential response to R-mono or BR. We examined outcomes of these treatments in MZL according to CD5 expression. Methods. We collected clinicopathologic data on patients with MZL (SMZL, NMZL, and extranodal MZL of the mucosa-associated lymphoid tissue [MALT]) diagnosed in our center between 2010 and 2020. CD5+ MZL was diagnosed by expert academic hematopathologists after excluding chronic lymphocytic leukemia and mantle cell lymphoma by immunophenotypic evaluation and cytogenetic/fluorescent in-situ hybridization studies. For prognostication, we assigned subtype-specific prognostic scores: MALT-IPI (Thieblemont et al., Blood 2017), IIL score for SMZL (Arcaini et al., Blood 2006), and standard IPI for NMZL. We examined overall response rate (ORR), progression-free (PFS) and overall survival (OS), calculated from the start of therapy, according to CD5 expression and first-line therapy. Survival was compared using log-rank tests stratified by age, MZL subtype, and stage. Results. The study included 213 patients with SMZL (N=51, 24%), NMZL (N=46, 22%), and MALT (N=116, 54%), with median age of 68 years at diagnosis, and with 52% women. Overall, 23 MZLs (10.8%) were CD5+. CD5 expression was most common in SMZL (24%), then NMZL (11%), and rare in MALT lymphoma (5%; P=.003). CD5+ cases showed del(7q) in 9%, trisomy 12 in 17%, and CD23 expression in 9%. All tested CD5+ cases had a positive peripheral blood flow cytometry (100% vs 65% of CD5- cases, P The most common first-line treatments were R-mono (29%), radiation therapy (23%), BR (20%), and surgery (15%). CD5 expression was not prognostic for PFS (stratified log-rank, P=.29, Fig. A) or OS (P=.08; Fig. B) in the entire cohort, or within the subgroup of NMZL/SMZL only (P=.46 for PFS and P=.31 for OS). However, outcomes differed according to CD5+/- status between patients treated with first-line R-mono or BR. ORR to R-mono was significantly lower for CD5+ than CD5- MZL (22% vs. 78%, P=.003), whereas ORR to BR did not differ (100% and 93%, respectively, P=.72). Similarly, PFS after R-mono was significantly worse for CD5+ than CD5- MZL (P=.036; Fig. C), while it did not significantly differ after BR (P=.64; P for interaction between treatments=.030). CD5 expression was also associated with significantly worse OS among patients receiving R-mono (P=.047) but not among those receiving BR (P=.56; Fig. D). Results were similar in the subgroup of SMZL/NMZL cases. Conclusions. To our knowledge, this is the first study examining CD5 expression as a prognostic and predictive biomarker for outcomes of R-based immunochemotherapy in MZL. CD5+ MZL was characterized by disseminated presentation with universal peripheral blood involvement, but after adjustment for other factors, CD5 expression was not independently prognostic. However, we observed worse response rates, PFS, and OS for CD5+ MZL treated with first-line R monotherapy, but not among those treated with BR, suggesting that the BR combination might be preferable in this subgroup. Disclosures Olszewski: Spectrum Pharmaceuticals: Research Funding; Genentech, Inc.: Research Funding; Adaptive Biotechnologies: Research Funding; TG Therapeutics: Research Funding.

Supplemental_material_TOP for Short-Term Study Abroad in Psychology: Effects of a Cultural Scavenger Hunt on the Development of Intercultural Competence by Ryan M. Zayac, Sydney Miller, Wolfgang Lenhard, Amber Paulk and Kirby Chrysler in Teaching of Psychology

Comment on "A microRNA cluster in the Fragile-X region expressed during spermatogenesis targets FMR1" by Ramaiah et al.

We document remarkably efficient thermo-mechanical erosion by a small-volume lava flow. Downcutting by a basaltic-andesite lava flow on the steep-sided Momotombo volcano, Nicaragua, occurred at 100 times the rate commonly reported for thermal erosion in lava flow fields, even though this flow was small-volume (0.02 km^3) and effused at a low rate for

The treatment of advanced, solid-tumor oncology has been reshaped over the last eight years with the development and FDA approval of several immune checkpoint inhibitors (ICIs) comprised of monoclonal antibodies targeting either PD-1, PD-L1, or CTLA-4 across numerous disease states and indications. Yet, despite their vast expansion of use in both solid-tumor and hematologic malignancies, gastrointestinal cancers have had limited approvals to date. This review article will focus on the use of the currently studied, approved uses and the potential future roles of ICIs in the treatment of cancers of the upper gastrointestinal tract through recent updates on ongoing studies and discussion of phase III studies underway. A single immunotherapy agent, Pembrolizumab, is the only currently approved treatment option in subset of patients with unresectable locally advanced, recurrent, or metastatic esophageal, gastroesophageal, or gastric cancers after failure or intolerance of initial systemic treatments. The only patients who are currently considered for treatment with ICI are those with tumors that are either microsatellite instability-high (MSI-H), DNA mismatch repair deficient (dMMR), or in those with esophageal, GEJ, or gastric adenocarcinomas that have at least one-percent expression of PD-L1 after failing at least two lines of systemic therapy based on early results from the KEYNOTE-059 trial released in 2017, or second-line treatment of locally advanced or metastatic esophageal squamous cell carcinoma (ESCC) with combined positive score (CPS) of 10 or greater based on the combined results from KEYNOTE-180 and KEYNOTE-181 in 2019. However, despite these limited successes thus far, there are numerous ongoing studies evaluating several ICIs for efficacy and safety in esophageal, GEJ, and gastric cancers. These agents are being studied in countless aspects of these malignancies: from neoadjuvant and adjuvant treatment in resectable disease to first-line treatment and beyond in the advanced, unresectable, or metastatic setting. In this article we will review the currently approved agents as well as ongoing clinical trials that will be approaching completion in the next 5 years, potentially altering the landscape of treatment in upper GI malignancies.

Despite prescribing guidance, limited data exist to describe the use of apixaban in patients with end-stage renal disease (ESRD) requiring hemodialysis (HD). Current apixaban dosing recommendations for this patient population are based largely on a single-dose pharmacokinetic study of eight patients. We describe the clinical application and pharmacodynamic monitoring of apixaban in a 62-year-old 156-kg African-American woman with nonvalvular atrial fibrillation and ESRD requiring hemodialysis who developed calciphylaxis while receiving warfarin therapy. Based on a multidisciplinary clinical judgment decision due to concern for drug accumulation after multiple doses in patients with ESRD receiving HD, she was anticoagulated with apixaban 2.5 mg twice/day, as opposed to 5 mg twice/day as recommended by the package insert. Antifactor Xa monitoring was used, and resultant peak and trough apixaban concentrations were above the upper limit of detection for our clinical laboratory (more than 2.00 IU/ml). On day 7 of her hospitalization, the patient developed gastrointestinal bleeding, and apixaban was discontinued; no further clinical signs of bleeding occurred during her subsequent hospitalization course. Use of the Naranjo Adverse Drug Reaction Probability Scale indicated a probable relationship (score of 6) between apixaban exposure and the manifestation of gastrointestinal bleeding. The patient ultimately died 44 days after the acute bleeding event; however, coagulation concerns were not implicated in the patient's death. To our knowledge, this is the first case report that describes apixaban use and associated antifactor Xa monitoring in a patient with ESRD receiving HD, and it provides concern for current apixaban dosing recommendations in this patient population. Further pharmacokinetic and clinical data are likely necessary to better characterize apixaban use in these patients to optimize safety and efficacy.