Journal articles on the topic 'Holder Eric'

Research on risk assessments has illustrated many utilitarian purposes of these tools, including the robust prediction of recidivism and uniformity in correctional decision making. Recently, however, Former U.S. Attorney General Eric Holder vocalized his position that actuarial risk assessments could be unintentionally contributing to disproportionate minority contact in the correctional system. This study used data from approximately 2,600 juvenile delinquents assessed with the Ohio Youth Assessment System–Disposition Instrument to examine these claims across subsamples of White and Black youth. Bivariate and multivariate analyses indicated that the instrument predicted recidivism similarly across the two groups. There were slightly more prediction errors for Black youth than White youth; however, these differences may be the result of methodological factors rather than empirical realities. The article concluded with a discussion of the implications that potential racial biases have on risk assessment research and practice.

Concern over the injustice of the money bail system led the founders of the Vera Institute of Justice to design and implement the Manhattan Bail Project in 1961. The Project demonstrated that people with strong ties to the community could be safely released from custody without bail merely on their promise to return to court—called release on recognizance. Federal, state, and local officials should be encouraged to examine their systems and implement a more just, more rational, and less costly system of ensuring appearance and protecting public safety while those charged but presumed innocent await the disposition of the charges. Toward that end, Attorney General Eric Holder convened a national conference on bail and criminal justice in June 2011 that presented another opportunity to realize the Manhattan Bail Project's mission: bringing pretrial justice to the significant proportion of impoverished defendants brought before the criminal courts.

Background: The Blood Cancer UK TAP CLARITY trial for relapsed or refractory CLL combined IBR with VEN in order to eradicate detectable disease with a plan to stop therapy early if measurable residual disease (MRD) <0.01% (MRD4) was achieved in the peripheral blood (PB) and bone marrow (BM). Aims: To provide long term follow up data for the combination of IBR and VEN for R/R CLL patients. IWCLL response status and MRD responses status at the 38 month time point are now presented in this abstract. Methods: CLARITY is a Phase II trial combining IBR with VEN in 50 patients with R/R CLL. After 2 months of IBR, VEN was added initially at a daily dose of 10mg or 20mg/day escalating weekly to a final daily dose of 400mg/day. CLL MRD was quantified using >6 colour ERIC-standard flow cytometry (detection limit 10-5/0.001%). Paired PB & BM samples were assessed at months 8, 14, 26 and longitudinal PB samples were taken at multiple time points. Fifty-four patients were recruited from May 2016 to November 2017. The median number of prior therapies was 1 (range: 1-6). 20% patients had del(17p); 25% del(11q); 75% had unmutated IGVH. Four patients that discontinued treatment due to ibrutinib-related adverse events in the first 8 weeks before starting VEN were replaced so that, in total, 50 patients received the combination of IBR and VEN. The interruption of therapy was indicated following confirmation of a CR according to the iwCLL2008 criteria and MRD reduction <10-4 CLL cells in PB and BM (MRD4). MRD4 at month 8 indicated to stop IBR and VEN at month 14, MRD4 in PB and BM at month 14 and/or at month 26 indicated to stop IBR and VEN at month 26, while MRD detectable at month 26 indicated to stop VEN only and to continue IBR until progression or toxicity. The trial protocol was amended later in Jan 2019 to allow patients, who had not obtained an MRD4 at month 26, to have an extra 12 months of VEN in addition to IBR. Results: Of the 50 evaluable patients recruited to the study, 23 patients stopped both treatments at or before M38; the majority due to achieving MRD4 (17/23). 27/50 patients were still receiving at least one trial treatment at this time point, with M38 response data pending for 11 patients. Of the 27 evaluable patients on treatment, the overall response rate (ORR), comprising of 10 patients with CR and 3 with CRi, was 81% compared to an ORR of 91% in the 36 patients receiving at least one trial treatment at M26 respectively. One additional patient discontinued treatment due to MRD negativity after M38. Of the 18 patients stopping due to MRD negativity, 14/18 continue to have <0.01% MRD. Overall, MRD responses continued to improve after the first year of combination treatment with 24/50 (48%) patients achieving MRD4 in the BM at month 26 compared to 20/50 (40%) at month 14. After 4 months of combination, the median log CLL depletion was 2.9 (range 0.2-4.8) for patients achieving <0.01% MRD at month 26 vs. 1.4 (range 0.1-4.6) for patients with ≥0.01% MRD at month 26. Disease depletion from month 4 to month 8 was slower in all groups, with a median log CLL depletion of 1.1 (range 0.1-2.9) for patients achieving <0.01% MRD vs 0.7 (-0.4-2.3) for those with ≥0.01% MRD at month 26 respectively. After month 8 (6 months of combined IBR+VEN), patients with ≥0.01% MRD typically showed <0.5log depletion/year subsequently. Of 20 evaluable patients with <0.01% MRD at month 38, MRD depletion had already been achieved at 6 months of combination IBR+VEN in 7/20 (35%), at 12 months in 14/20 (70%), and at 24 months in 18/20 (90%). There was only one case of biochemical TLS. Other side-effects were mild and/or manageable, most commonly neutropenia (3/37 grade 2, 34/37 grade 3/4). Two Suspected Unexpected Serious Adverse Reactions (SUSARs) were reported (abdominal pain and pemphigus), 44 Serious Adverse Events (SAEs), and 1153 Adverse Events (AEs) (of which 141 were grade 3 or 4) were reported. Summary/Conclusion: After 38 months, the response to IBR+VEN is sustained despite planned discontinuation of therapy in MRD negative patients. The initial rate of disease depletion (during the first two months of combined IBR+VEN exposure) is highly predictive of longer-term response to combination IBR+VEN treatment in relapsed/refractory CLL. Patients who do not show rapid disease clearance and have persistent MRD after 12 months of combination IBR+VEN usually have stable or slowly decreasing disease levels akin to that seen in IBR monotherapy. These data will be updated at ASH 2020. Disclosures Hillmen: AbbVie: Speakers Bureau; Janssen: Speakers Bureau; Gilead: Speakers Bureau; Pharmacyclics: Other: Financial or Material spport; Morphosys: Other: Consulting fees; Sunesis: Other: Consulting fees. Brock:Invex: Other: Consulting and speaker fees; Merck: Other: Reimbursement of costs; Eli Lilly: Other: Consulting and speaker fees; AstraZeneca: Current equity holder in publicly-traded company; GlaxoSmithKline: Current equity holder in publicly-traded company. Schuh:Illumina: Other: Consulting fees; Abbvie: Other: Consulting fees; Gilead: Other: Consulting fees; Roche: Other: Consulting fees. Pettitt:Roche: Honoraria, Other: Hospitality, Research Funding; Napp: Research Funding; Celgene: Other: Hospitality, Research Funding; Chugai: Research Funding; Gilead: Honoraria, Other: Hospitality, Research Funding; Kite: Honoraria, Other: Hospitality, Research Funding; GSK: Research Funding; Novartis: Research Funding. Gribben:Janssen: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Abbvie: Honoraria; Celgene: Research Funding. Patten:Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Bloor:Abbvie: Consultancy, Honoraria, Other: Conference Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Other: Conference Funding , Speakers Bureau. Fox:Celgene: Current equity holder in publicly-traded company; Sunesis: Current equity holder in publicly-traded company; Atarabio: Current equity holder in publicly-traded company; Abbvie: Current equity holder in private company, Current equity holder in publicly-traded company; Gilead: Current equity holder in private company, Current equity holder in publicly-traded company; Adienne: Current equity holder in private company, Current equity holder in publicly-traded company; Roche: Current equity holder in private company, Current equity holder in publicly-traded company; AstraZeneca: Current equity holder in publicly-traded company; Takeda: Current equity holder in private company, Current equity holder in publicly-traded company. Forconi:Roche: Honoraria; Janssen: Honoraria, Other: Fees for cosulting or advisory role, received travel and expenses, Speakers Bureau; AbbVie: Honoraria, Other: Fees for cosulting or advisory role, received travel and expenses, Speakers Bureau; Gilead: Research Funding; Astra Zeneca: Other: Fees for cosulting or advisory role; Menarini: Other: Fees for cosulting or advisory role; Novartis: Honoraria. Rawstron:BD Biosciences (Intrasure): Patents & Royalties. Hillmen:Alexion: Consultancy, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Speakers Bureau; Acerta: Other: Financial or material support; Roche: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; Pharmacyclics: Other: Financial or material support, Research Funding; Janssen: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; Apellis: Consultancy, Research Funding, Speakers Bureau; Gilead: Other: Financial or material support, Research Funding.

The article “Factors associated with late risks of breast cancer‑specific mortality in the SEER registry”, written by José P. Leone, Carlos T. Vallejo, Michael J. Hassett, Julieta Leone, Noah Graham, Nabihah Tayob, Rachel A. Freedman, Sara M. Tolaney, Bernardo A. Leone, Eric P. Winer and Nancy U. Lin, was originally published electronically on the publisher’s internet portal on April 24, 2021 without open access. With the author(s)’ decision to opt for Open Choice the copyright of the article changed on May 11, 2021 to © The Author(s) 2021 and the article is forthwith distributed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0.

I sit to write this Introduction having just returned from a long weekend at APSA's 2010 annual conference discussing the politics of hard times. In the background is the sound of one or another cable news announcer, reminding me, for the thousandth time, that this coming weekend is the ninth anniversary of “9-11.” Controversy still rages over the plans of Muslim American citizens of the US to build a community center in lower Manhattan, two blocks from “ground zero” (or is it “Ground Zero” in deference to its apparent sacralization?). At the same time, attention has recently turned to an obscure Florida pastor, one Reverend Terry Jones, who has declared his intention to publicly burn copies of the Koran in protest of Islam and “commemoration” of 9-11. His plan has caused an outcry of opposition from national and local interfaith coalitions committed to religious and social pluralism, and provoked denunciations from a range of groups that include the Vatican and the Veterans of Foreign Wars. Numerous high-ranking Obama Administration officials, from Attorney General Eric Holder to Secretary of State Hillary Clinton, have loudly criticized the proposed Koran burning as an affront to the American commitment to tolerance. Perhaps the loudest critic has been General David Petraeus, the US Commander in Afghanistan, who has insisted that such acts seriously undermine the US military in its war against the Taliban. One of his assistants, Lt. General William Caldwell, nicely summed up this logic in a CNN interview: “There is no question about First Amendment rights; that is not the issue. The question is: What is the implication over here? It is going to jeopardize the men and women serving in Afghanistan.”

Abstract The use of novel small molecule inhibitors alone or in combination with anti-CD20 monoclonal antibodies for chronic lymphocytic leukemia (CLL) has raised a number of questions on efficacy, tolerability, long-term treatment adherence in patients with heterogeneous clinical features. To fill this gap, we designed a study focusing on treatment sequencing in patients with CLL in order to (i) compare the outcome of patients treated with chemoimmunotherapy (CIT) combinations in first-line versus those receiving Bruton's tyrosine kinase inhibitors (BTKi); (ii) characterize the efficacy and tolerability of venetoclax-based regimens; (ii) understand the impact of treatment sequencing when it comes to chemo-free options including venetoclax after BTKi and vice versa. Data from consecutive sets of patients diagnosed with CLL between 2000-2020 attended at 77 institutions affiliated with ERIC were collected and analyzed. Collected variables included: demographics, clinical stage at diagnosis, IGHV gene somatic hypermutation status; cytogenetic status for chromosomes 11q, 13q 17p and 12 determined by fluorescence in situ hybridization; TP53 gene mutation status; treatment; treatment response; discontinuation; reason for discontinuation; death. We included 9173 patients with a diagnosis of CLL who received at least one line of treatment. The median age at diagnosis was 67 years with a male:female ratio of 1.9. The median follow-up was 78 months (IQR, 48-120 months). Regarding novel targeted agents, 1860/9173 (20.2%) patients had received at least one line of treatment with BTKi (ibrutinib, n=1788; acalabrutinib, n=72) over the disease course; 631/9173 (6.9%) with venetoclax; and, 447/9173 (4.9%) with the PI3K inhibitor idelalisib. Seventy-nine patients were treated with both BTKi and venetoclax (59 BTKi followed by BCL2i, 20 vice versa). At last follow-up, 5870/9173 patients (64.0%) were alive, 3229/9173 (35.2%) died and 74/9173 (0.8%) were lost to follow-up. Patients treated with BTKi in first-line were enriched for TP53 aberrations [del(17p) 27.6%, TP53 mutation 26.3%] and unmutated IGHV genes (69%) and obtained an ORR of 87.7%. Of these, 136 (26.3%) discontinued treatment after a median of 1.2 years (0.07-5.98); main reasons of discontinuation were toxicity (40.5%) and failure (26.2%). Among 631 patients treated with venetoclax at any line, 100 (15.8%) received BCL2 +/- anti-CD20 as first-line; 170 (26.9%) as second line (125 previously treated with CIT, 27 with BTKi); and, 361 as third or subsequent line. ORR ranged between 71.5% (≥3 lines) with 30.5% CR/CRi to 90.3% (first-line) with 68.1% CR/CRi. Treatment discontinuation was due to toxicity in 28.6% of patients treated in the first-line, and 17.6% and 21.8% of patients treated in second and third-or-higher-line, respectively. Disease progression led to treatment discontinuation in 14.3%, 20.6% and 33.6% in first, second and third-or-higher line, respectively. CIT was used as front-line treatment in 5465 patients (59.6%). Of these, 2070 (37.9%) and 1018 (18.6%) patients received a second and third line of treatment, respectively. The great majority (865/1086 cases, 79.7%) of patients who received a second line before 2014 were retreated with CIT, most commonly Bendamustine-Rituximab (284/1086, 26.1%) and Fludarabine-Cyclophosphamide-Rituximab (252/1086, 23.2%); alemtuzumab monotherapy was used in 55/1086 (5%) of patients. After 2014, 415/984 patients (42.1%) were retreated with BTKi; 93 (9.5%) with venetoclax; 70 (7.2%) with idelalisib; 50 (5%) with Alemtuzumab monotherapy, and 315 (32%) with CIT. Similarly, in the third-or-higher line of treatment, most patients (86.3%) were retreated with CIT before 2014, while BTKi, BCL2i, and PI3Ki were mainly used after 2014 (in 43.1%, 15.7% and 14.7% of cases, respectively). Finally, our cohort included 1075 patients with TP53 aberrations. The ORR of patients receiving BTKis (n=171) as first-line of treatment was 86.5% (22.2 CR+64.3 PR), while the ORR with venetoclax +/- anti-CD20 (n=15) was 91% (45.5% CR+45.5 PR). Patients treated with CIT (n=694) had an ORR of 68.7% (28.3% CR+40.4% PR). In conclusion, in a large international study we provide real world data regarding the selection and sequencing of treatment in CLL, charting a major shift in treatment patterns before and after the introduction of novel trargeted agents and confirming their efficacy even in high-risk CLL. Disclosures Scarfo: Janssen: Honoraria, Other: Travel grants; Astra Zeneca: Honoraria; Abbvie: Honoraria. Iacoboni: BMS/Celgene, Gilead, Novartis, Janssen, Roche: Honoraria. Collado: Abbvie,: Other: pharmaceutical Company, Research Funding; Janssen: Other: Pharmaceutical Company, Research Funding. Galimberti: AbbVie, Janssen: Honoraria, Other: Travel grants; Incyte: Speakers Bureau. García-Serra: AbbVie: Other: Educational grands; Janssen: Other: Educational grants; Novartis: Other: Educational grants. Gozzetti: Janssen: Honoraria; AbbVie: Honoraria. Hatzimichael: Amgen, Roche, Genesis, Novartis, Bristol Mayer Squibb, Celgene, Pfizer: Consultancy; Abbvie, Amgen, Bristol Mayer Squibb, MSD, Gilead, Janssen Cilag, Genesis Pharma, Roche, Takeda: Honoraria. Herishanu: AbbVie: Honoraria, Research Funding; Janssen: Honoraria; Roche: Honoraria; Medison: Honoraria. Jaksic: Roche, Oktal-Pharma/Celtrion, Sandoz: Consultancy, Honoraria. Kater: Janssen, AstraZeneca: Other: Ad Board, steering committee, Research Funding; Abbvie: Honoraria, Other: Ad Board, Research Funding; BMS, Roche/Genentech: Other: Ad Board, , Research Funding; Genmab, LAVA: Other: Ad Board, Steering Committee. Kotsianidis: Astellas: Other: NONE, Research Funding, Speakers Bureau; Genesis: Consultancy, Other: NONE; Janssen Hellas: Consultancy, Other: NONE, Speakers Bureau; Bristol Hellas: Consultancy, Other: NONE, Research Funding, Speakers Bureau; Novartis Hellas: Consultancy, Other: NONE, Research Funding, Speakers Bureau; Abbvie: Consultancy, Other: NONE, Research Funding, Speakers Bureau. Kreitman: NIH: Patents & Royalties: Moxetumomab Pasudotox; Genentech: Research Funding; Teva: Research Funding; AstraZeneca/MedImmune: Research Funding; Innate: Research Funding; GSK/Novartis: Research Funding; Array BioPharma/Pfizer: Research Funding. Laribi: BeiGene: Other: Personal Fees; Jansen: Research Funding; Novartis: Other: Personal Fees, Research Funding; Astellas Phama, Inc.: Other: Personal Fees; AstraZeneca: Other: Personal Fees; Le Mans Hospital: Research Funding; Takeda: Other: Personal Fees, Research Funding; AbbVie: Other: Personal Fees, Research Funding; IQONE: Other: Personal Fees. Lopez-Garcia: Roche: Other: Speaker Honoraria, Travel and accommodation grants; Novonordisk: Other: Speaker Honoraria; Fresenius: Other: Speaker Honoraria; Celgene: Other: Speaker Honoraria; Abbvie: Other: Speaker Honoraria, Advisor, Travel and accommodation grants; Janssen: Other: Speaker Honoraria, Advisor, Travel and accommodation grants, Research Funding. Milosevic: Roche: Honoraria; Abbvie,: Honoraria; Janssen: Honoraria; Sandoz: Honoraria. Reda: Beigene: Consultancy; Astra Zeneca: Consultancy; Abbvie: Consultancy; Janssen: Consultancy. Ruchlemer: AbbVie: Consultancy, Honoraria, Research Funding. Šimkovič: Janssen, Gilead, Roche, AstraZeneca, and AbbVie: Other: consultancy fees, advisory board participation fees, travel grants, and honoraria; University Hospital Hradec Kralove: Current Employment; AbbVie: Consultancy, Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Merck: Current equity holder in publicly-traded company; Eli Lilly: Current equity holder in publicly-traded company; J&J: Current equity holder in publicly-traded company; Gilead: Other: Travel, Accommodations, Expenses. Špaček: AbbVie, AstraZeneca, Gilead, Janssen, and Roche: Honoraria. Tadmor: Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Visentin: Italfarmaco and Gilead: Speakers Bureau. Vassilakopoulos: AstraZeneca: Honoraria; Amgen: Honoraria, Research Funding; Pfizer: Research Funding; Dr. Reddy's: Research Funding; Novartis: Consultancy, Honoraria; GlaxoSmithKline: Honoraria, Other: Travel; Merck: Honoraria, Research Funding; Integris: Honoraria; Roche: Consultancy, Honoraria, Other: Travel; Genesis Pharma: Consultancy, Honoraria, Other: Travel; Takeda: Consultancy, Honoraria, Other: Travel, Research Funding; AbbVie: Consultancy, Honoraria; Karyopharm: Research Funding. Vitale: Janssen: Honoraria. Yáñez: Gilead-Kite, Janssen, AbbVie, AstraZeneca, Beigene, Roche, Pfizer, Jazz, BMS, and Merck: Other: Advisory board participation fees ; Janssen, AbbVie, AstraZeneca, Gilead-Kite, Roche, Pfizer, and Merck: Speakers Bureau. Antic: AbbVie, Janssen, and Roche: Honoraria. Coscia: Janssen: Honoraria, Other, Research Funding; Gilead: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria, Other. Cuneo: AstraZeneca: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau. Gaidano: Beigene: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astrazeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Guièze: Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Astrazeneca: Consultancy, Honoraria. Laurenti: AstraZeneca: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Roche: Honoraria, Research Funding; Gilead: Honoraria; Janssen: Consultancy, Honoraria; BeiGene: Honoraria. Murru: Abbvie: Consultancy, Honoraria, Other: travel and accommodation; Janssen: Consultancy, Honoraria. Sportoletti: AstraZeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Tam: Beigene: Research Funding; Janssen: Research Funding; Abbvie: Research Funding; Loxo: Honoraria; Beigene: Honoraria; Janssen: Honoraria; Abbvie: Honoraria. Trněný: Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Gilead Sciences: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Celgene: Consultancy; 1st Faculty of Medicine, Charles University, General Hospital in Prague: Current Employment; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Portola: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses. Bosch Albareda: Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria; Abbvie: Consultancy; AstraZeneca: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Kite: Honoraria; Sanofi: Honoraria; Lilly: Honoraria. Doubek: Janssen-Cilag, AbbVie, AstraZeneca, Amgen, Gilead, Novartis: Honoraria, Research Funding. Chatzidimitriou: Abbvie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Ghia: AbbVie: Consultancy, Honoraria, Research Funding; Acerta/AstraZeneca: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; ArQule/MSD: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Celgene/Juno/BMS: Consultancy, Honoraria; Gilead: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Sunesis: Research Funding. Stamatopoulos: AstraZeneca: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Janssen: Honoraria, Research Funding.

Theoretical basis 1. Maria Jarlstrom, Essi Saru, and Sinikka Vanhala, “Sustainable Human Resource Management With Salience of Stakeholders: A Top Management Perspective,” Journal of Business Ethics, 152, (2008): 703–724. 2. Benjamin A. Neville, Simon J. Bell, and Gregory J., “Stakeholder Salience Revisited: Refining, Redefining, and Refueling an Underdeveloped Conceptual Tool,” Journal of Business Ethics, 102, (2011): 357–378. 3. Mick Marchington, Fang Lee Cooke, and Gail Hebson. “Human Resource Management Across Organizational Boundaries,” Sage Handbook of Human Resource Management, (2009): 460–477. Research methodology This secondary source case is based mainly on three documents: the 20-page report by a labor union, Unite Here, titled “One Job Should Be Enough: Inequality at Starbucks”; and two reports by former U.S. Attorney General Eric Holder Jr. and Covington & Burlington, LLP. Case overview/synopsis In February 2020, Unite Here, a labor union, released a damming report about employment practices at the airport Starbucks stores operated by licensee, HMSHost. Among other charges, the report identified several instances of racial and gender discrimination that HMSHost dismissed as a ploy by a union intent on organizing its employees. The adverse publicity, however, put Starbucks Corporation in the spotlight because of the company’s publicly stated commitment to workplace equality. The recently hired Nzinga Shaw, the company’s first-ever Global Chief Inclusion and Diversity Officer, had to address the issue at HMSHost lest it adversely affect Starbucks’ reputation as a progressive employer. Complexity academic level The case is best suited for a graduate or undergraduate course in human resource management or labor relations. As diversity is typically covered in the first third of such courses, the ideal placement of this case would be in the early part of the course. As Starbucks is a well-known name, and it is very likely that students have had their own experience with Starbucks, as either a customer or an employee, the case is likely to draw their interest. Supplementary materials Teaching Notes are available for educators only. Please contact your library to gain login details or email support@emeraldinsight.com to request teaching notes.

Abstract Introduction: In the MURANO trial (NCT02005471), fixed-duration VenR (2 yrs Ven + R for the first 6 mo) improved survival and rates of undetectable minimal residual disease (MRD) over bendamustine (Benda)-R in pts with R/R CLL. Novel recurrent mutations in BCL2 and family genes (eg BAX and PMAIP1 [encoding Noxa]) have been linked to Ven resistance. We analyzed MRD+ samples from VenR-treated pts in MURANO to assess the nature and frequency of acquired mutations in BCL2 family genes (marker of emergent Ven resistance) and TP53 (may negatively impact response to re-Tx). We also analyzed the impact of these mutations on time to next CLL Tx (TTNT) and subsequent response. Methods: Pts included in this analysis received up to 2 yrs of VenR and had, at any time, ≥1 CLL cell per 100 leukocytes (high MRD+) in peripheral blood. Deep next generation sequencing (NGS) was performed without cell selection using a custom targeted NGS panel, encompassing 87 cell death related genes (coding regions and selected promoters). A CD19-enriched pre-Tx sample, analyzed by whole-exome sequencing, was available for all pts for comparison. Data cutoff was May 8, 2020, for the MURANO main study and Oct 13, 2020, for the substudy (where pts received next-line VenR following progression after initial VenR Tx). TTNT was calculated using the main study Ven completion/discontinuation date and the date of the first subsequent CLL Tx. Results: 107 samples from 42 pts, collected 21-42 mo post-Tx initiation, were evaluable. No BCL2 mutations were identified (limit of detection - variant allele frequency [VAF] 1%). Acquired BAX and PMAIP1 mutations were seen in 4 and 2 pts, respectively. Discordance between VAF and CLL MRD, and lack of proportionality in results with serial testing, suggested presence of BAX mutations in the non-CLL compartment in some pts, with further testing of sorted populations needed to clarify the source. All BAX mutations identified have been predicted to lead to loss of protein function, including 4 frameshift mutations. PMAIP1 mutations included a frameshift mutation (T86fs) and a mutation affecting gene splicing, both suggesting a loss-of-function effect. Nineteen TP53 mutations in 15/42 pts were observed across longitudinal samples (8/19 mutations in 6 pts present at baseline, 11/19 in 11 pts newly acquired, and 2 pts with both baseline and acquired mutations). Co-occurrence of TP53mut with BAXmut or PMAIP1mut was observed in 3/15 and 1/15 pts, respectively; based on VAF and assuming heterozygosity, these were likely in different clones. After Ven cessation, 28/42 (66.7%) had received an additional anti-CLL Tx by the cutoff; 19 pts received Ven-based regimens (15 in the substudy; 4 received other Ven-containing regimens per investigators' choice), 8 pts received ibrutinib (Ibr) monotherapy and 1 pt received Benda. Of the 19 pts who received Ven-based regimens (median 22.6 mo [range 11.9-38.1] post-main study end of Tx), 8 had TP53mut (5 acquired, 3 baseline), with 5/8 (63%) responding (complete response, 3 pts; partial response [PR], 2 pts). Six/11 pts (55%) with TP53-wild-type (WT) responded, all PRs. Two pts with TP53mut received Ibr as next Tx (one responded) vs 6 TP53-WT pts (all responded). The one pt treated with Benda without response had coexisting TP53mut and BAXmut. One patient with BAXmut received Ven re-Tx without response, while in pts with BAXmut and PMAIP1mut, responses to Ibr were 100% (2/2 pts) and 50% (1/2 pts), respectively (Table). No association was apparent between acquired TP53mut and TTNT, median 784 days (d; range 248-1051) vs 617 d (range 302-1142) in TP53-WT pts. Pts harboring BAXmut (n=5) had a shorter median TTNT (305 d; range 248-874) than BAX-WT pts (678 d; range 302-1142). Conclusion: No acquired BCL2 mutations were found in this analysis of pts from MURANO who received fixed-duration VenR Tx and subsequently manifest high MRD+. This suggests that fixed-duration Tx may reduce the propensity for selection of BCL2 resistance mutations, although confirmation using orthogonal methodology with higher sensitivity is required. Acquired TP53 mutations, noted in ~40% of pts, did not preclude response to subsequent Tx (primarily Ven-based regimens). Consistent with the TP53-independent mechanism of Ven, Ven re-Tx may be effective for pts with MRD+ disease who have relapsed following initial fixed-duration VenR Tx. More data are needed to better understand the significance of BAX or PMAIP1 mutations. Figure 1 Figure 1. Disclosures Seymour: Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Mei Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Morphosys: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sunesis: Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau. Wu: Roche/GNE: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Genentech, Inc.: Current Employment. Popovic: AbbVie: Current Employment, Current equity holder in publicly-traded company. Eichhorst: Consultant Department I for Internal Medicine: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Speakers Bureau; Adaptive Biotechnologies: Speakers Bureau; Hexal: Speakers Bureau; ArQule: Membership on an entity's Board of Directors or advisory committees; Oxford Biomedica (UK): Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; University Hospital of Cologne: Current Employment. Hillmen: University of Leeds: Current Employment; Abbvie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Research Funding; Pharmacyclics: Honoraria, Research Funding; AstraZeneca: Honoraria; SOBI: Honoraria. Kipps: European Research Initiative on CLL (ERIC): Honoraria; DAVA Pharmaceuticals: Speakers Bureau; Bionest Partner: Other; Celgene: Consultancy, Honoraria, Other, Research Funding; Genetech: Honoraria, Other; Genentech-Roche: Consultancy; Gilead Sciences: Consultancy, Honoraria, Other, Speakers Bureau; Janssen: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Roche: Honoraria, Other; MD Anderson Cancer Center: Research Funding; Velos: Research Funding; CRIM: Research Funding; Indy Hematology Review: Other; TG Therapeutics: Other; Verstem: Other, Speakers Bureau; University of California, San Diego: Current Employment; Pharmacyclics/AbbVie: Honoraria, Research Funding; Breast Cancer Research Foundation: Research Funding; SCOR - The Leukemia and Lymphoma Society: Research Funding; National Cancer Institute/NIH: Honoraria, Research Funding; DAVAOncology: Consultancy, Honoraria, Other; AbbVie: Consultancy, Honoraria, Other, Speakers Bureau; Oncternal Therapeutics, Inc.: Current holder of stock options in a privately-held company, Other: Stock or other ownership, Patents & Royalties: Cirmtuzumab was developed by Thomas J. Kipps in the Thomas J. Kipps laboratory and licensed by the University of California to Oncternal Therapeutics, Inc., which provided stock options and research funding to the Thomas J. Kipps laboratory., Research Funding; Genentech/Roche: Honoraria; Moores Cancer Center: Current Employment; MedImmune Inc: Research Funding; GlaxoSmithKline: Research Funding; Gilead Sciences, Inc.: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding, Speakers Bureau; Pharmacyclics LLC, an Abbvie Company: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Honoraria, Research Funding; Abbott Laboratories: Consultancy, Research Funding. Langerak: Janssen: Speakers Bureau; Gilead: Research Funding; F. Hoffmann-La Roche Ltd/Genentech, Inc.: Research Funding; Erasmus MS, University Medical Center: Current Employment. Owen: Incyte: Honoraria; AbbVie: Honoraria, Research Funding; Merck: Honoraria; AstraZeneca: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Servier: Honoraria; Pharmacyclics: Research Funding; Genentech: Research Funding; Gilead: Honoraria. Dubois: Abbvie: Research Funding; Genentech: Research Funding; Roche: Research Funding. Mellink: Cytogenetic Field: Consultancy; Genome Diagnostics Laboratory, AUMC: Current Employment; Financial support related to microarray analysis of Murano samples: Research Funding. Van Der Kevie-Kersemaekers: Amsterdam University Medical Centers: Current Employment. Dunbar: AbbVie: Current Employment. Jiang: Genentech, Inc./F.Hoffmann-La Roche Ltd: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Chyla: AbbVie: Current Employment, Current equity holder in publicly-traded company. Boyer: Roche: Current Employment. Thadani-Mulero: Roche: Current Employment, Current equity holder in publicly-traded company. Lefebure: Roche: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Harrup: AstraZeneca: Other: Advisory board. Kater: Genmab, LAVA: Other: Ad Board, Steering Committee; BMS, Roche/Genentech: Other: Ad Board, , Research Funding; Janssen, AstraZeneca: Other: Ad Board, steering committee, Research Funding; Abbvie: Honoraria, Other: Ad Board, Research Funding.

Abstract Previous studies have revealed a critical role of methylation deregulation in the onset and progression of chronic lymphocytic leukemia (CLL). In mammalian cells, DNA methylation is dynamically established by the DNA methyltransferase 3 (DNMT3) family of de novo methyltransferases DNMT3A. Although mutations of DNMT3A are rarely observed in CLL, our RNA-sequencing (RNA-seq) analysis of 107 human CLLs show that low DNMT3A expression is associated with more aggressive disease, and supports a driving role of DNMT3A loss in CLL. To test this hypothesis, we generated a conditional knock-out mouse model with B cell-restricted deletion of Dnmt3a. Homozygous Dnmt3a depletion in B cells resulted in the development of CD5+ B cell leukemia mimicking human CLL with 100% penetrance at a median age of onset of 5.3 months, and heterozygous Dnmt3a depletion yielded a disease penetrance of 89% with a median onset at 18.5 months, confirming its role as a haplo-insufficient tumor suppressor. Given the known role of Dnmt3a as a de novo methyltransferase, we first evaluated the impact of Dnmt3a depletion on global DNA methylation in non-leukemic CD5+ B cells isolated from the peritoneal cavity by cell sorting (i.e. B1a cells) using reduced representation bisulfite sequencing (RRBS). We identified a set of differentially methylated regions (DMRs) (difference>0.2), mostly hypomethylated, in Dnmt3afl/fl versus WT B1a cells (473 hypomethylated, 19 hypermethylated). Genes with dysregulated methylation were highly enriched in pathways involved in immune response (e.g., Interferon-α signaling, JAK/STAT3 signaling) and proliferation (Wnt Signaling and Notch signaling). Given the prominent hypomethylation changes observed in Dnmt3a depleted B1a cells, we investigated whether these would lead to altered gene transcript expression. Using RNA-seq, we detected 460 downregulated and 168 upregulated genes in the Dnmt3afl/fl B1a cells compared to WT B1a cells (FDR<0.05, fold change >2). Consistent with the methylation data, differentially expressed genes were likewise enriched for JAK/STAT3 signaling, Wnt Signaling and Notch signaling, supporting a direct influence of dysregulated methylation on downstream signaling cascades. We investigated the changes in methylomes of the CLL cells arising from the Dnmt3afl/fl animals. Compared to WT B1a cells, Dnmt3afl/fl CLL cells generated 1335 hypomethylated and 2369 hypermethylated DMRs in. Focusing on genes that were hypomethylated in CLL compared to WT B1a cells, we found that these were highly enriched for several oncogenic signaling pathways including Notch signaling and Wnt Signaling, consistent with the pre-leukemia findings. RNA-seq analysis identified more upregulated (n=2801) than downregulated (n=1244) genes in CLL cells compared to WT B1a cells (FDR<0.05, FC>2), supporting a role of Dnmt3a depletion in transcriptional activation. We observed a general upregulation of Notch signaling genes and the downstream Notch targets, implicating Notch activation in this CLL mouse model. Of note, we showed Dnmt3a-depleted CLL cells to be highly sensitive to Notch inhibitor DAPT both in vitro and in a transplantable mouse model. Consistently, primary human CLL cells with low DNMT3A expression were more sensitive to DAPT than those with higher DNMT3A expression (P=0.005, Spearman correlation), despite similar sensitivity to ibrutinib and venetoclax. Together, our results have confirmed the causal role of Dnmt3a downregulation in CLL generation. We provide evidence in support of the interaction between Dnmt3a-dependent methylation changes and hyperactivation of Notch signaling in transcriptional reprogramming and transformation of B1a cells into CLL. Furthermore, we demonstrate differential sensitivity of DNMT3A high and low expressing primary CLLs to Notch inhibition, indicative of consistent dependencies of human and murine CLLs. Thus, the Dnmt3a models provides a unique opportunity for the study of non-mutational Notch activation, and a useful platform for the study of Notch-signaling targeted therapeutics. Disclosures Kipps: Abbott Laboratories: Consultancy, Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an Abbvie Company: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Genentech, Inc.: Honoraria, Research Funding, Speakers Bureau; Gilead Sciences, Inc.: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; MedImmune Inc: Research Funding; Moores Cancer Center: Current Employment; Oncternal Therapeutics, Inc.: Current holder of stock options in a privately-held company, Other: Stock or other ownership, Patents & Royalties: Cirmtuzumab was developed by Thomas J. Kipps in the Thomas J. Kipps laboratory and licensed by the University of California to Oncternal Therapeutics, Inc., which provided stock options and research funding to the Thomas J. Kipps laboratory., Research Funding; AbbVie: Consultancy, Honoraria, Other, Speakers Bureau; DAVAOncology: Consultancy, Honoraria, Other; DAVA Pharmaceuticals: Speakers Bureau; Bionest Partner: Other; Celgene: Consultancy, Honoraria, Other, Research Funding; Genetech: Honoraria, Other; Genentech-Roche: Consultancy; Gilead Sciences: Consultancy, Honoraria, Other, Speakers Bureau; Janssen: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Roche: Honoraria, Other; MD Anderson Cancer Center: Research Funding; Velos: Research Funding; CRIM: Research Funding; Indy Hematology Review: Other; TG Therapeutics: Other; Verstem: Other, Speakers Bureau; University of California, San Diego: Current Employment; Pharmacyclics/AbbVie: Honoraria, Research Funding; Breast Cancer Research Foundation: Research Funding; SCOR - The Leukemia and Lymphoma Society: Research Funding; National Cancer Institute/NIH: Honoraria, Research Funding; Genentech/Roche: Honoraria; European Research Initiative on CLL (ERIC): Honoraria. Neuberg: Madrigal Pharmaceuticals: Other: Stock ownership; Pharmacyclics: Research Funding. Letai: Flash Therapeutics: Other: equity holding member of the scientific advisory board; Dialectic Therapeutics: Other: equity holding member of the scientific advisory board; Zentalis Pharmaceuticals: Other: equity holding member of the scientific advisory board. Wu: BioNTech: Current equity holder in publicly-traded company; Pharmacyclics: Research Funding.

Abstract ROR1 (Receptor tyrosine kinase-like orphan receptor 1) is an evolutionarily conserved, oncoembryonic antigen found on chronic lymphocytic leukemia (CLL) cells, but not on healthy postpartum tissues. In prior studies we found that higher-level CLL-cell expression of ROR1 associated with accelerated disease progression and unfavorable clinical outcome (Cui B. et al., Blood, 128:2931, 2016). ROR1 is a receptor for Wnt5a, which is found at high levels in plasma of patients with CLL. We found Wnt5a could enhance ERK1/2 phosphorylation and leukemia-cell proliferation (Hasan MK. et al., Leukemia, 35:1621, 2021). Moreover, Wnt5a-enhanced ERK1/2 phosphorylation and leukemia-cell proliferation could be inhibited by UC-961, a first-in-class humanized mAb specific for a functional epitope of the ROR1 extracellular domain that is undergoing phase II clinical testing (Choi MY. et al., Cell Stem Cell, 22:951, 2018). However, it is not known how Wnt5a/ROR1-signaling induces ERK1/2 activation. We performed mass spectrometry-based proteomics to interrogate immune-precipitates of Wnt5a-activated ROR1 from CLL cells and identified Grb2 (Growth Factor Receptor Bound Protein 2), a cytoplasmic protein that may interact with SOS (son of sevenless) to induce activation of Ras, which can activate the mitogen-activated protein kinase (MAPK) pathway, leading to activation of ERK1/2. We found that treatment of serum-starved CLL cells with Wnt5a induced Grb2 to associate with ROR1 and activate Ras and ERK1/2; these effects could be blocked by siRNA silencing of Grb2 or by treatment with UC-961, indicating that Wnt5a induced activation of ERK1/2 is dependent upon expression of ROR1 and Grb2. To examine the structure-function relationship(s) in the interaction(s) between ROR1 and Grb2, we used the CLL-derived leukemia cell line MEC1, which we found expresses high-levels of Wnt5a, but not ROR1. Subclones of MEC1 cells transfected to express ROR1 (MEC1-ROR1) had significantly higher levels of ERK1/2 activation than MEC1 cells; immune-precipitation studies confirmed constitutive association of Grb2 and SOS1 with ROR1. This was not observed in MEC1-ROR1-Wnt5a -/- cells in which we disrupted both alleles of WNT5a via CRISPR-Cas9. Moreover, MEC1-ROR1 cells, or MEC1-ROR1-Wnt5a -/- cells treated with Wnt5a, had significantly higher levels of activated Ras and ERK1/2 than MEC1, MEC1-Wnt5a -/-, or MEC1-ROR1-Wnt5a -/-, demonstrating that activation of Ras, MAPK, and ERK1/2 in MEC1 was dependent upon on expression of ROR1 and Wnt5a. We next examined single amino acid substitutions of proline (P) to alanine (A) in the P-X-X-P- motifs of the proline-rich domain (PRD) of ROR1 at positions 784, 808, 826 or 841. Interestingly we found that P808A of ROR1 (MEC1-ROR1 P808A), a binding site of DOCK2 and critical for activation of ERK1/2, failed to complex with Grb2, SOS1, or enhance activation of Ras compared to MEC1-ROR1 cells. Overall, our results indicate that, upon Wnt5a stimulation, a novel complex of DOCK2/Grb2/SOS1 may form at position 808 of ROR1 that leads to activation of Ras and ERK1/2, which can promote proliferation of CLL cells and potentially contribute to the noted unfavorable prognostic implication of high-level expression of ROR1 in CLL. Disclosures Kipps: VelosBio, Inc.: Research Funding; Celgene: Honoraria, Research Funding; Genentech/Roche: Honoraria; Pharmacyclics/AbbiVie: Honoraria, Research Funding; Oncternal Therapeutics, Inc.: Current equity holder in publicly-traded company, Patents & Royalties: Cirmtuzumab, Research Funding; Janssen, Gilead, Dava Oncology,: Honoraria; Breast Cancer Research Foundation: Honoraria, Research Funding; Md Anderson Cancer Center: Research Funding; Gilead: Honoraria; National Cancer Institute/NIH: Honoraria, Research Funding; OncLive: Honoraria; Specialized Center of Research (SCOR) - The Leukemia and Lymphoma Society (LLS): Research Funding; California Institute for Regenerative Medicine (CIRM): Research Funding; European Research Initiative on CLL (ERIC): Honoraria; Dava Oncology: Honoraria; Patient Power, LLC: Honoraria; iwNHL: Honoraria; NCCN CLL/SLL Hairy Cell Leukemia Panel Meeting: Honoraria.

Abstract Although T cells modified with a chimeric antigen receptor (CAR) are highly effective, durability of remissions may be limited by the poor persistence of adoptively transferred CAR T cells in patients. Growing evidence supports the idea that the pre-infusion phenotype of CAR T cells affects the efficacy of CAR T cell therapies, in part due to the increased ability of certain subsets of CAR T cells to persist long-term. Studies using conventional T cells have suggested that adoptive transfer of T cells programmed to have Th17/Tc17 effector functions can increase the anti-tumor efficacy and persistence of transferred cells when compared to adoptive transfer of non-Th17/Tc17 cells. However, standard CAR formats currently in clinical use that contain either a CD28 or 4-1BB costimulatory domain fail to generate substantial numbers of Th17/Tc17-like cells. Thus, few studies have investigated whether Th17/Tc17 CAR T cells could enhance the efficacy of CAR T cell therapies. We generated a multi-cistronic lentiviral construct encoding ROR-related Orphan Receptor gamma (RORγt), a key lineage-specifying transcription factor involved in Th17/Tc17 differentiation, followed by a murine CAR targeting CD19 that contains a CD28 costimulatory domain (1928z). RORγt expression did not hinder degranulation in response to CAR antigen upon co-culture with E2aPbx, a murine acute lymphoblastic leukemia cell line. Significantly higher numbers of RORγt-1928z CAR T cells produce IL-17 compared to 1928z CAR T cells (p<0.0001) suggesting that RORγt expression is sufficient to program type-17 effector functions in CAR T cells. To determine the impact of RORγt overexpression on CAR T cell phenotype and persistence in vivo, we adoptively transferred 1x10 6 1928z or RORγt-1928z CAR T cells into leukemia-bearing C57Bl6/J recipients and analyzed CAR T cells from the bone marrow at days 4, 11, and 31. As early as day 4 post-transfer, RORγt-1928z CAR T cells were present at significantly higher numbers than 1928z CAR T cells, and remained higher through Day 31 (0.16% of the bone marrow for 1928z CAR T cells vs 0.84% of the bone marrow for RORγt-1928z CARs; p= 0.0012, n=5 mice per group. The RORγt-1928z CAR T cells were enriched for an effector/effector memory phenotype (CD62L-) compared to 1928z CAR T cells, which were mostly of a central memory phenotype (CD62L+). Interestingly, the RORγt-1928z CAR T cells were enriched for IL-7Rα+ cells and expressed more IL7Rα than their 1928z CAR T cell counterparts (p=0.0012), suggesting an increased capacity for self-renewal in RORγt-1928z CAR T cells. Previous work from our lab has demonstrated that CAR T cells that persist after leukemia clearance have an exhausted phenotype, with increased expression of PD1 and a reduced functionality 1. After leukemia clearance, RORγt-1928z CAR T cells expressed lower levels of PD1 than their 1928z counterparts (p<0.0001). Finally, 1928z CAR T cells form a population of Eomes hiPD1 hi cells, associated with terminal exhaustion, that is absent in the RORγt-1928z CAR T cells. Taken together, our preliminary data demonstrates that overexpression of RORγt is sufficient to program type-17 effector functions in CAR T cells and suggests that RORγt overexpression can enhance the ability of CAR T cells to persist and self-renew, and prevent terminal exhaustion. RORγt overexpression may enhance persistence of CAR T cells and durability of remissions in hematologic malignancies. Furthermore, RORγt overexpression may also be a strategy to enhance CAR T cell efficacy against solid tumors, where an immunosuppressive microenvironment contributes to T cell dysfunction. Yinmeng Yang, Mark Eric Kohler, Terry J. Fry; Effect of Chronic Endogenous Antigen Stimulation on CAR T Cell Persistence and Memory Formation. Blood2017; 130 (Supplement 1): 166. doi: https://doi.org/10.1182/blood.V130.Suppl_1.166.16 Disclosures Fry: Sana Biotechnology: Current Employment, Current equity holder in publicly-traded company.

O presente trabalho analisou os fundamentos e desdobramentos das proposições seminais da ideia de geograficidade surgidas no contexto brasileiro e europeu. Considerou-se que um conjunto restrito de autores deu diferentes interpretações e articulações ao termo em questão, servindo como embasamento ao uso em novas pesquisas. Realizou-se a exploração teórica de sete autores fundamentais: Paul Michotte, Eric Dardel, Yves Lacoste, Werther Holzer, Ruy Moreira, Elvio Martins e Mariane Biteti. Atravessados estes universos teóricos, procedeu-se à análise dos modos como estas teses são articuladas nas demais pesquisas, buscando observar a adequação do sentido proposto pelo pesquisador à ideia de geograficidade, com o autor que fundamenta esta articulação. Observou-se ampla permeabilidade do termo na geografia brasileira, mas ainda possuindo desencontros entre os usos propostos e os fundamentos teóricos articulados, apontando para uma ainda existente necessidade de sistematização dos debates em torno das diferentes ideias de geograficidade que circulam.

Abstract Introduction: B-cell activating factor receptor (BAFF-R) enhances the survival and regulation of normal and malignant B cells. VAY736 is a human monoclonal antibody (mAb) targeting BAFF-R that targets BAFF-R+ B cells for elimination by antibody-dependent cell-mediated cytotoxicity (ADCC). VAY736 has anti-leukemia activity in preclinical CLL models that is superior to that of anti-CD20 mAbs (McWilliams EM, et al. Blood Adv 2019;3:447-460). Although Bruton's tyrosine kinase inhibitors (BTKis; acalabrutinib, ibrutinib) are the current standard of care for CLL, the indefinite length of monotherapy required may result in cumulative clinical or economic toxicity and/or acquired treatment resistance. In preclinical models, adding VAY736 to ibrutinib significantly improved survival and reduced disease burden, suggesting that this combination may augment the anti-leukemia response and allow patients (pts) to discontinue ibrutinib. Methods: This dose escalation/expansion trial (NCT03400176) enrolled pts with CLL undergoing either first- or second-line therapy with ibrutinib and whose disease failed to achieve a complete response (CR) after >1 year of therapy or who had CLL with a mutation associated with ibrutinib resistance. Pts received oral ibrutinib (420 mg) once daily and VAY736 IV at 0.3, 1, 3, or 9 mg/kg once every 2 weeks. In the expansion, pts were enrolled into 2 arms depending on whether ibrutinib resistance mutations were present at baseline. Pts received VAY736 + ibrutinib for up to 6 28-day cycles. After 6 cycles, pts with a CR discontinued VAY736 and received ibrutinib for an additional 2 cycles; all other pts continued VAY736 + ibrutinib for those 2 cycles. Pts achieving undetectable minimal residual disease (uMRD) at C9D1 could discontinue ibrutinib at the investigator's discretion. This study aimed to characterize the safety and tolerability of VAY736 + ibrutinib, determine the recommended dose for expansion (RDE), and explore the efficacy of this combination. Results: A total of 32 pts (median age 65 years; ECOG PS 0: 91%) were treated prior to data cutoff (May 10, 2021). Overall, 19 pts completed therapy and 4 discontinued VAY736 + ibrutinib (primarily due to disease progression); 4 pts remain on VAY736 + ibrutinib and 5 pts continue to receive ibrutinib. Of the enrolled pts, 44% had CLL cells with mutations associated with ibrutinib resistance (mainly [71%] BTKC481); the median number of prior regimens was 1 (range: 0.0-14.0); median duration of prior ibrutinib therapy was 3.5 years (range: 0.2-8.3). Baseline cytogenetics were (not mutually exclusive): 19% del(17)(p13.1), 75% unmutated IGHV, 59% stimulated complex karyotypes (≥3 abnormalities), 34% del(11)(q22.3), 44% del(13)(q14), and 6% +12. No dose-limiting toxicities were observed and the RDE was 3 mg/kg, based on pharmacokinetics, exposure-to-response relationship, pharmacodynamics, safety, and in vitro ADCC. Twelve (38%) pts experienced AEs of Grade ≥3, most common (occurring in ≥2 pts) were neutrophil count decreased (n=5), lymphocyte count decreased (n=2), hypophosphatemia (n=2), and elevated lipase (n=2). The overall response at C9D1 for evaluable pts (n=21) was 38% CR, 5% CRi, 14% PR, 24% SD, and 19% PD (Fig. 1A). Thirteen (41%) pts achieved uMRD in blood. Eight pts (42%, 8/19) and 8 pts (42%, 8/19) had uMRD in blood and bone marrow (BM) at end of treatment (EoT), respectively. Among those, 6 pts were elected to discontinue ibrutinib and remained off treatment for 0.2-26.2 months and were still off therapy at the data cutoff. The median percentage change from baseline in MRD was -99.0% (range: -100.0% to -16.7%) and -97.3% (range: -100.0% to 1346.3%) in blood and BM, respectively. None of the pts who enrolled with CLL cells lacking mutations associated with ibrutinib resistance (11/11) developed mutations by C9D1. Although 1 pt with PLCG2 mutation eradicated mutant clones at EoT with VAY736, the response may vary depending on the type of mutation (Fig. 1B). Conclusions: VAY736 + ibrutinib was well tolerated with an acceptable safety profile enabling dose expansion. Clinical activity was observed including multiple pts attaining uMRD status in blood and BM, allowing 6 to discontinue ibrutinib therapy for an extended period. These data provide clinical evidence of the potent anti-leukemia activity of VAY736 and the potential to safely discontinue ibrutinib or other BTKi by VAY736 add-on therapy. Figure 1 Figure 1. Disclosures Rogers: AbbVie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy; Pharmacyclics: Consultancy; Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Janssen: Research Funding. Flinn: TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding; AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Sarah Cannon Research Institute: Current Employment; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding; Johnson & Johnson: Current holder of individual stocks in a privately-held company; Seattle Genetics: Research Funding. Stephens: TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Epizyme: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; JUNO: Research Funding; Arqule: Research Funding; AstraZeneca: Consultancy; Abbvie: Consultancy; Mingsight: Research Funding; CSL Behring: Consultancy; Celgene: Consultancy; Innate Pharma: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kipps: Oncternal Therapeutics, Inc.: Current equity holder in publicly-traded company, Patents & Royalties: Cirmtuzumab, Research Funding; Pharmacyclics/AbbiVie: Honoraria, Research Funding; Genentech/Roche: Honoraria; Celgene: Honoraria, Research Funding; VelosBio, Inc.: Research Funding; Janssen, Gilead, Dava Oncology,: Honoraria; Breast Cancer Research Foundation: Honoraria, Research Funding; Md Anderson Cancer Center: Research Funding; Gilead: Honoraria; National Cancer Institute/NIH: Honoraria, Research Funding; OncLive: Honoraria; Specialized Center of Research (SCOR) - The Leukemia and Lymphoma Society (LLS): Research Funding; California Institute for Regenerative Medicine (CIRM): Research Funding; European Research Initiative on CLL (ERIC): Honoraria; Dava Oncology: Honoraria; Patient Power, LLC: Honoraria; iwNHL: Honoraria; NCCN CLL/SLL Hairy Cell Leukemia Panel Meeting: Honoraria. Larson: TORL biotherapeutics: Current holder of individual stocks in a privately-held company; Abbvie: Research Funding; Bioline: Research Funding; BMS: Research Funding; Celgene: Research Funding; GSK: Research Funding; Janssen: Research Funding; Juno: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Takeda: Research Funding. McGarry: Novartis Institutes for Biomedical Research: Current Employment. Hassounah: Novartis Institutes for Biomedical Research: Current Employment, Patents & Royalties: unrelated . Gou: Novartis Pharma AG: Current Employment. Woo: Novartis: Current Employment, Current equity holder in publicly-traded company. Byrd: Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria; Newave: Membership on an entity's Board of Directors or advisory committees; Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees.

Abstract Background: Chronic lymphocytic leukemia (CLL) is the most prevalent leukemia where the majority of patients (pts) experiences a relapse or becomes refractory after a first-line treatment. This study assesses the economic burden associated with early vs late disease progression among pts with relapsed and refractory (R/R) CLL and identifies factors that are associated with further disease progression. Method: CLL pts with an indicator of R/R disease were selected from the Truven MarketScan database (>25 million commercially insured lives annually; 2000-2013) based on diagnoses and treatment patterns. Pts were ≥18 years in age, continuously enrolled in their health plan for ≥6 months prior to (baseline period) and ≥1 month after the first indicator of R/R CLL. The index date was defined as the date of the first R/R indicator. As a first step, pts who progressed following the first indicator of R/R CLL were identified and classified into two mutually exclusive cohorts: 1) pts with early progression (<12 months after index date) and 2) pts with late progression (≥12 months after index date). Healthcare resource utilization (HRU) and costs ($2013 US) were measured over the period from index date up to end of continuous healthcare plan enrollment (study period) and were compared between early vs late progression cohorts using multivariate generalized linear regression models. HRU and costs were reported per-pt-per-month (PPPM). As a second step, the full sample of pts with R/R CLL was used to identify factors associated with a risk of early progression using Cox proportional hazard models. Results: Of the 4,387 R/R CLL pts selected, 2,238 (51%) pts had a progression following the first indicator of R/R CLL. Median time to first progression following the index date was 14.5 months. Among pts who progressed, 69.3% had early progression and 30.7% had late progression. Characteristics of pts with early vs late progression were similar in terms of age, sex ratio, and region of residence. The main differences between cohorts were in terms of baseline comorbidities - a higher proportion of pts in the early progression cohort had hypertension, deficiency anemias, and coagulation deficiency. Quan Charlson Comorbidity Index (CCI) was also higher in the early progression cohort compared to the late progression cohort (2.61 vs 2.48, p<.01). Over the study period, the early progression cohort had higher HRU: 54% more inpatient (IP) admissions, 85% more IP days, 27% more emergency room visits, and 31% more outpatient (OP) visits (all p<.01) compared to the late progression cohort. After adjusting for baseline confounding factors, pts in the early progression cohort also had higher total healthcare costs by $3,008 PPPM (mean costs $8,018 vs. $4,639), mainly driven by higher OP (adjusted difference $1,838) and IP (adjusted difference $848) costs (all p<.01). Among the full sample of R/R CLL pts (4,387 pts), time between CLL diagnosis and the firs indicator of R/R CLL (< 12 months; HR=1.20), and comorbidities, including a higher CCI (CCI≥3; HR=1.19), rheumatoid arthritis (HR=1.49), and substance-related and addictive disorders (HR=1.94) were found to be significantly associated with a higher risk of early progression. Results were generally consistent with a sensitivity analysis, where early vs late progression was defined using a 6-months cut-off. Conclusions: R/R CLL pts who experienced early progression had more comorbidities and incurred significantly higher healthcare resources and costs than pts with late progression, suggesting that delaying progression in the fast progressing R/R CLL pts can reduce the economic burden. Time from CLL diagnosis to R/R CLL and comorbidities were the main predictors of early progression. Disclosures Guerin: Janssen Scientific Affairs, Janssen-Ortho, Inc., Merck & Co., Inc., Merck Frosst Canada, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Ogilvy Renault, Ortho-Clinical Diagnostics, Inc., Otsuka America Pharmaceutical, Inc.,:Consultancy; Pfizer Canada, Inc.,RX&D, Sanofi, Savient Pharmaceuticals, Inc., Shire Pharmaceuticals Inc., Sunovion Pharmaceuticals Inc.,Takeda Global Research & Development Center, Inc., Takeda Pharmaceuticals U.S.A., Inc: Consultancy; AbbVie Inc., Alcon Laboratories, Bayer Healthcare Pharmaceuticals, LLC, Celgene Corporation, Cempra Inc., Centocor Ortho Biotech, Cooley LLP, Cyberonics, Inc., DLA Piper, Eli Lilly & Company,Forest Laboratories, Inc., Genentech, Inc., GlaxoSmithKline,: Consultancy, Other: Annie Guerin is an employee of Analysis Group Inc, which has received consultancy fees from AbbVie for this research. Ray:AbbVie Inc.: Employment, Other: Stock Holder . Gauthier:Sunovion Pharmaceuticals Inc.,Takeda Pharmaceuticals U.S.A., Inc.: Consultancy, Other: Genevieve Gauthier is an employee of Analysis Group Inc, which has received consultancy fees from the listed organizations; AbbVie Inc., Celgene Corporation, Eli Lilly & Company, Genentech, Inc., GlaxoSmithKline, Janssen Scientific Affairs, LLC, Novartis Pharmaceuticals Corporation, Pfizer Canada, Inc., Sanofi, Savient Pharmaceuticals, Inc., Shire Pharmaceuticals Inc.,:Consultancy, Other: Genevieve Gauthier is an employee of Analysis Group Inc, which has received consultancy fees from the listed organizations. Hsu:AbbVie Inc: Employment, Other: Stock holder . Zhdanava:AbbVie Inc., Genentech, Inc., Merck Frosst Canada, Novartis Pharmaceuticals Corporation,Shire Pharmaceuticals Inc., Takeda Pharmaceuticals U.S.A., Inc.: Other: Maryia Zhdanava is an employee of Analysis Group Inc, which has received consultancy fees from AbbVie for this research. Wu:Celgene Corporation, Centocor Ortho Biotech, Cephalon, Inc., ConvaTec Inc., Corus Pharma, Inc., Eli Lilly & Company, Eli Lilly & Company, Ethicon, Inc., Forest Laboratories, Inc., Genentech, Inc., GlaxoSmithKline, Janssen Global Services, LLC,: Consultancy; Janssen Pharmaceutica, Inc., Janssen Scientific Affairs, LLC, Lilly Research Laboratories, McNeil Consumer & Specialty Pharmaceuticals, MedImmune, LLC, Melinta Therapeutics, Inc., Millennium Pharmaceuticals, Inc.,: Consultancy; AbbVie Inc., Alcon Laboratory, Astellas Pharma Inc., Astellas Pharma US, Inc., AstraZeneca, Barger & Wolen LLP, Bayer Healthcare Pharmaceuticals, LLC, Biosense Webster, Inc., Blue Cross Blue Shield Association, Boehringer Ingelheim, Bristol-Myers Squibb: Consultancy, Other: Eric Q Wu, is an employee of Analysis Group which has received consultancy fees from AbbVie for this research; Molecular Insight Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Ortho McNeil Pharmaceuticals, Inc., Sanofi, Savient Pharmaceuticals, Inc., Shire Pharmaceuticals Inc.,: Consultancy; Takeda Global Research & Development Center, Inc., Takeda Pharmaceuticals U.S.A., Inc., TAP Pharmaceutical Products, Inc., Vertex Pharmaceuticals Incorporated: Consultancy.

Nach der Neuordnung der deutschen Vertriebsgebiete des HACH LANGE-Verbundes ist der Konzern bemüht, für seine Kunden im nordwestlichen Raum eine Plattform zur Weiterbildung und zum Erfahrungsaustausch zu schaffen. Zu diesem Zweck wurde das Osnabrücker Abwasser-Symposium vorbereitet und am 9. Dezember 2015 erfolgreich durchgeführt. Knapp 50 Teilnehmer trafen sich im Steigenberger Hotel Remarque, das sich in der Ausstattung sehr ambitioniert dem berühmten Sohn seiner Geburtsstadt, dem Schriftsteller Erich Maria Remarque, verbunden fühlt. Gemeinsam mit Prof. Dr.-Ing. Holger Scheer, Emscher Wassertechnik GmbH, Essen, bereitete die HACH-Arbeitsgruppe um Klaus D. Schmidt diese fachlich niveauvolle Tagung vor und konnte renommierte Fachleute als Referenten gewinnen.

Background: Ibrutinib (IBR) inhibits CLL proliferation and effects prolonged remission without eradicating disease. Obinutuzumab (OBI) is an anti-CD20 monoclonal antibody that can effect depletion of measurable residual disease (MRD) below 0.01%. In the IcICLLe study (ISRCTN12695354), 20 treatment-naïve (TN) CLL patients & 20 with relapsed/refractory (R/R) CLL received IBR until complete remission with &lt;0.01% MRD in the bone marrow (BM) or disease progression. The IcICLLe Extension Study examined the efficacy/safety of combining IBR & OBI in 40 patients with R/R CLL and was open to the IcICLLe R/R cohort. Initial results after 1 month of combination treatment indicated that adding OBI to IBR improved CLL depletion, and 3-5 year follow-up data is now available. Aim: To assess the long-term MRD response status for patients treated with IBR as a sole agent or in combination with OBI. Patients: Patients received continuous IBR (420mg OD) with the addition of 6 cycles of OBI given over 6 months in the extension study. 20 TN patients received IBR monotherapy; 20 R/R patients (median 2 prior treatments, range 1-7) initiated IBR monotherapy of which 10/20 enrolled in the Extension study receiving OBI after &gt;1year of IBR monotherapy; and 30 IBR-naïve R/R (median 1 prior treatment, range 1-3) started OBI 24 hours after first IBR dose. MRD assessment was performed according to ERIC guidelines with a maximum detection limit of 0.001%/10-5. Results: IBR monotherapy in TN patients was well tolerated with 18/20 patients alive and 13/20 remaining on IBR after median 4.9 years follow-up (range 0-5.9). IBR was stopped due to toxicity (3), progression/relapse (2) or other causes (2). IBR-monotherapy resulted in median 0.65 log depletion per year in years 1-2, followed by relatively stable disease levels (median 0.2 log depletion per year) in the subsequent 3 years in 13/20 evaluable patients. Only 1 patient showed &gt;0.3log increase in PB MRD level and this preceded clinical progression. No patients achieved an IWCLL CR/CRi and MRD was &gt;0.01% in PB/BM in all patients at all time points. In the R/R group initially receiving IBR-monotherapy, 11/20 patients remain alive and 3/20 remain on IBR after a median 3.9 years follow-up (range 0.3-5.3). In this heavily pre-treated group, 10 did not enrol on the OBI Extension study (1 died, 1 progression/relapse, 4 ineligible/other causes, 4 patient preference) with 10/20 receiving OBI at median 16.2 months (range 13-19) after starting IBR-monotherapy of which 7/10 had resolved any lymphadenopathy pre-OBI. 2/10 achieved MRD-negative remission and stopped treatment, while 6/10 have since stopped IBR due to death (2), progression/relapse (3) or other causes (1). 30 R/R patients with no prior IBR exposure (most in first relapse) started IBR & OBI at the same time: 26/30 remain alive and 18/30 remain on IBR after median 3.0 years follow-up (range 0.8-4.2). IBR was stopped in 2/30 patients achieving MRD-negative remission while 10 stopped IBR due to death (2), disease progression/transformation (3), toxicity (4), or patient decision (1). There were no Grade 5 adverse events related to OBI. 3 months post-OBI, patients with &gt;1 year prior IBR-monotherapy achieved a higher response rate (CR/CRi 50% vs. 30%), MRD response (&lt;0.01% BM MRD in 50% vs. 6%) and a greater depth of remission (3.1 vs. 1.5 log reduction) compared to IBR-naive patients despite greater number of prior treatment lines. The deepest PB MRD responses were observed 6-12 months after the last OBI infusion. MRD levels showed little change in the following year to month 24 (median 0 log depletion, range 1.3 log depletion to 2.5 log increase). After 2 years of IBR exposure, the MRD levels shows a similar pattern to TN patients on IBR monotherapy, being generally very stable (&lt;0.3log increase) except in 7 patients showing &gt;0.3log increase at two sequential timepoints of which 4/7 have shown clinical disease progression and 3/7 still have low (&lt;1%) but rising MRD levels. Conclusions: The addition of OBI to IBR may substantially improve depletion of CLL cells from the PB and BM. A greater impact in MRD response rate and depth was seen when OBI was introduced after &gt;1 year of IBR treatment and tumour bulk was low. One fifth of patients maintain &lt;0.01% MRD up to 3 years after combined IBR+OBI, demonstrating that response improvements associated with OBI are sustainable in some cases. Figure 1 Disclosures Rawstron: Abbvie: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Roche: Honoraria, Research Funding. Hillmen:AbbVie: Speakers Bureau; Janssen: Speakers Bureau; Gilead: Speakers Bureau; Pharmacyclics: Other: Financial or Material spport; Morphosys: Other: Consulting fees; Sunesis: Other: Consulting fees. Brock:AstraZeneca: Current equity holder in publicly-traded company; GlaxoSmithKline: Current equity holder in publicly-traded company; Eli Lilly: Other: Consulting and speaker fees; Invex: Other: Consulting and speaker fees; Merck: Other: Reimbursement of costs. Patten:Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Pettitt:Chugai: Research Funding; Gilead: Honoraria, Other: Hospitality, Research Funding; Kite: Honoraria, Other: Hospitality, Research Funding; Celgene: Other: Hospitality, Research Funding; GSK: Research Funding; Novartis: Research Funding; Napp: Research Funding; Roche: Honoraria, Other: Hospitality, Research Funding. Fox:Abbvie: Honoraria, Research Funding; Adienne: Honoraria, Research Funding; AstraZeneca: Research Funding; Celgene: Research Funding; Sunesis: Research Funding; Atarabio: Research Funding; Roche: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Gilead: Honoraria, Research Funding. Bloor:Abbvie: Consultancy, Honoraria, Other: Conference Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Other: Conference Funding , Speakers Bureau. Hillmen:Apellis: Consultancy, Research Funding, Speakers Bureau; Gilead: Other: Financial or material support, Research Funding; AstraZeneca: Consultancy, Speakers Bureau; Acerta: Other: Financial or material support; Roche: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; Pharmacyclics: Other: Financial or material support, Research Funding; Janssen: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; Alexion: Consultancy, Research Funding, Speakers Bureau.

Introduction: Teenagers as holders of the baton for the next generation of the nation must be maintained in their growth and development. The phenomenon of juvenile delinquency today can be found in society.Purposes of Devotion: Community Service Activities are expected to provide answers about the development of juvenile delinquency and its legal consequences. The purpose of building legal awareness for children from juvenile delinquency is to provide education and understanding of legal regulations relating to children so that children in the future are not affected to commit acts of violence from juvenile delinquency that can lead to legal repercussions or consequences for the child. Method of Devotion: Carrying out legal counseling activities in Erie Hamlet, Nusaniwe Country, Ambon City, Maluku through panel discussions in which the presenters take turns presenting the material then followed by a question and answer session between the presenters and participants.Results of the Devotion: Teenagers as holders of the baton for the next generation of the nation must be maintained in their growth and development. Efforts to tackle juvenile delinquency cannot be done alone, but in overcoming it there must be cooperation between all elements, namely parents, the school, in this case the teacher who acts as a parent in the school, the government and the community.

In the beginning of the 1940s the sacrificial site at Käringsjön, in Halland, south-west Sweden, was investigated by Holger Arbman and Erik Floderus. Some years later the archaeological results were presented by Arbman in an exhaustive publication. Since then the site has been regarded as a typical example of the sacrificial sites used by the peaceful agrarian populations in the practice of the fertility cult. In this paper Käringsjön is brought up to renewed discussion. This is done i.a. by means of a structural analysis, in which is shown a very conscious use of the site. The sacrificial depositions are seen to closely correspond to the annual changes of the sun's movement in the sky when rising and setting on the horizon. It is here suggested that the sacrifices took place not only during different seasons but also at different times during the twenty-four hour day. Finally, the paper also deals with the questions of whether Käringsjön should be seen as a sacrificial site of local or of regional importance, and why the site was suddenly abandoned around 400 A.D.

This article examines popular music listening in light of recent research in auditory perception and spatial experience, record production, and virtual reality, while considering parallel developments in digital pop music production practice. The discussion begins by considering theories of listening and embodiment by Brandon LaBelle, Eric Clarke, Salomè Voegelin and Linda Salter, examining relations between listening subjects and aural environments, conceptualising listening as a process of environmental ‘inhabiting’, and considering auditory experience as the real-time construction of ‘reality’. These ideas are discussed in relation to recent research on popular music production and perception, with a focus on matters of spatial sound design, the virtual ‘staging’ of music performances and performing bodies, digital editing methods and effects, and on shifting relations between musical spatiality, singer-persona, audio technologies, and listener. Writings on music and virtual space by Martin Knakkergaard, Allan Moore, Ragnhild Brøvig-Hanssen & Anne Danielsen, Denis Smalley, Dale Chapman, Kodwo Eshun and Holger Schulze are discussed, before being related to conceptions of VR sound and user experience by Jaron Lanier, Rolf Nordahl & Niels Nilsson, Mel Slater, Tom Garner and Frances Dyson. This critical framework informs three short aural analyses of digital pop tracks released during the last 10 years - Titanium (Guetta & Sia 2010), Ultralight Beam (West 2016) and 2099 (Charli XCX 2019) - presented in the form of autoethnographic ‘listening notes’. Through this discussion on personal popular music listening and virtual spatiality, a theory of pop listening as embodied inhabiting of simulated narrative space, or virtual story-world, with reference to ‘aural-dominant realities’ (Salter), ‘sonic possible worlds’ (Voegelin), and ‘sonic fictions’ (Eshun), is developed. By examining personal music listening in relation to VR user experience, this study proposes listening to pop music in the 21st century as a mode of immersive, embodied ‘storyliving’, or ‘storydoing’ (Allen & Tucker).

Anticipating total war: the German and American experiences, 1871–1914. By Manfred Boemeke, Roger Chickering, and Stig Förster. New York and Cambridge: Cambridge University Press, 1999. Pp. ix+506. ISBN 0-521-62294-8. £55.00.German strategy and the path to Verdun: Erich von Falkenhayn and the development of attrition, 1870–1916. By Robert T. Foley. Cambridge: Cambridge University Press, 2005. Pp. xiv+316. ISBN 0-521-84193-3. £45.00.Europe's last summer: who started the Great War in 1914? By David Fromkin. New York: Knopf, 2004. Pp. xiii+368. ISBN 0-375-41156-9. £26.95.The origins of World War I. Edited by Richard F. Hamilton and Holger H. Herwig. Cambridge: Cambridge University Press, 2003. Pp. xiii+552. ISBN 0-521-81735-8. £35.00.Geheime Diplomatie und öffentliche Meinung: Die Parlamente in Frankreich, Deutschland und Grossbritanien und die erste Marokkokrise, 1904–1906. By Martin Mayer. Düsseldorf: Droste, 2002. Pp. 382. ISBN 3-7700-5242-0. £44.80.Helmuth von Moltke and the origins of the First World War. By Annika Mombauer. Cambridge: Cambridge University Press, 2001. Pp. xvi+344. ISBN 0-521-79101-4. £48.00.The origins of the First World War: controversies and consensus. By Annika Mombauer. London: Pearson Education, 2002. Pp. ix+256. ISBN 0-582-41872-0. £15.99.Inventing the Schlieffen plan: German war planning, 1871–1914. By Terence Zuber. Oxford: Oxford University Press, 2002. Pp. xi+340. ISBN 0-19-925016-2. £52.50.As Richard Hamilton and Holger Herwig remark in the introduction to their edited collection of essays on the origins of the First World War, thousands of books (and countless articles) have been written on the subject, a veritable flood that began with the outbreak of the conflict in 1914 and continues to this day. This enduring interest is understandable: the First World War was, in George Kennan’s still apt phrase, the ‘great seminal catastrophe’ of the twentieth century. Marking the end of the long nineteenth century and the beginning of the short twentieth century, the war amounted to an earthquake whose seismic shocks and after-shocks resonated decades afterwards both inside and outside of the belligerent countries. The Bolshevik Revolution, the growth of fascist and Nazi movements, the accelerated emergence of the United States as a leading great power, the economic depression of the 1930s – these and other developments all have their roots in the tempest of war during 1914–18. Given the momentous nature of the conflict, it is little wonder that scholars continue to investigate – and to argue about – its origins. At the same time, as Hamilton and Herwig suggest, the sheer number of existing studies places the onus on scholars themselves to justify their decision to add to this historiographical mountain. This being so, in assessing the need for a new work on the origins of the war, one might usefully ask whether it fulfills one of several functions.

Abstract CD3-targeted T cell engagers are potent anti-tumor therapies, but their development often requires management of cytokine release syndrome (CRS). One strategy to reduce CRS is subcutaneous dosing, which is hypothesized to mitigate CRS by reducing the maximum drug concentration (Cmax) and preserve efficacy by maintaining the same minimum drug concentration (Cmin) as intravenous dosing. Although promising for mitigating CRS, this approach is limited by its increased immunogenicity risks. A T cell engager designed to be dosed intravenously but engineered to mimic the PK properties of subcutaneous dosing could alleviate CRS without increasing immunogenicity. Here we describe TriTAC-XR, a platform of T cell engager prodrugs designed to become slowly activated in systemic circulation. This extended-release mechanism results in a slow build-up of circulating active drug and minimizes the Cmax/Cmin ratio, similar to subcutaneous dosing. TriTAC-XR prodrugs were engineered by adding a peptide mask and protease-cleavable linker to the N-terminus of a TriTAC, a constitutively active and half-life extended T cell engager. The mask binds to the anti-CD3ε domain and inhibits T cell binding. Upon cleavage by systemic proteases, active T cell engager is released. In vitro, TriTAC-XR has markedly reduced binding to recombinant CD3ε protein and to primary T cells as well as reduced potency in functional T cell-dependent cellular cytotoxicity (TDCC) assays compared to its unmasked active drug. In cynomolgus monkeys, TriTAC-XRs targeting multiple tumor antigens resulted in a gradual build-up of active drug during the first week post dose and significantly lower Cmax/Cmin ratios than comparable constitutively active TriTACs. Modeling based on these PK data predicts that TriTAC-XR dosed intravenously will result in a slower build-up of active drug and smaller Cmax/Cmin ratios than TriTAC dosed intravenously or subcutaneously. Cytokine release and target cell depletion in cynomolgus monkeys were used to compare the therapeutic index of TriTAC-XR to TriTAC. A single dose of FLT3-targeting TriTAC-XR resulted in 100-fold protection in cytokine release and similar FLT3 expressing cell depletion when compared to an equivalent FLT3-targeting TriTAC. Similarly, repeat dosing of a TriTAC-XR targeting B cells resulted in complete B cell depletion with substantially lower cytokines than a comparable TriTAC. TriTAC-XR is expected to improve the safety of T cell engagers by reducing CRS and may increase clinical dosing convenience by enabling higher doses that will extend dosing intervals. Citation Format: Kathryn Strobel Kwant, Sony S. Rocha, Timothy Yu, Katrina Stephenson, Raphaela Rose Banzon, Sydney Vollhardt, Golzar Hemmati, Evan Callihan, Wade H. Aaron, Subramanian Thothathri, Jessica O'Rear, Eric Bragg, Willis Kwong, Hubert Situ, Avneel Hundal, Stephen Yu, Taggra Jackson, Kevin Carlin, Yinghua Xiao, Maria Rosalyn Dayao, Linh To, Nick Bergo, Kevin Wright, Richard Austin, Holger Wesche, Bryan Lemon, S. Jack Lin. TriTAC-XR: An extended-release T cell engager platform designed to minimize cytokine release syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2861.

Abstract Tumor-associated calcium signal transducer 2 (Trop2) is a cell surface glycoprotein that promotes cell renewal, proliferation and tumorigenesis. Trop2 is homogenously overexpressed in numerous solid tumor types, including breast, head and neck, prostate, bladder, and non-small cell carcinoma; however, Trop2 is also expressed in several normal tissues, including skin, respiratory tract, and female reproductive organs. Although Trop2-targeted antibody drug conjugates (ADCs) have demonstrated clinical activity, with regulatory approvals in subsets of breast and bladder cancers, their broader utility is still hampered by off-target payload-mediated toxicities. To address this issue, and to avoid on-target off-tumor toxicities, we developed a Trop2-targeting ProTriTAC™ (Protease-activated Tri-specific T cell Activating Construct), a T cell engager prodrug which is engineered to be preferentially activated in tumor tissue. ProTriTACs consists of three humanized antibody-derived binding domains on a single polypeptide chain: anti-albumin for half-life extension, anti-CD3 for T cell engagement, and anti-target antigen for tumor cell engagement. The anti-albumin domain, bearing a masking moiety and a protease-cleavable linker, keeps the prodrug inert by inhibiting binding of the adjacent anti-CD3 domain to T cells. Cleavage of the linker by tumor-associated proteases removes the anti-albumin domain along with the masking moiety to reveal a potent active drug that directs T cell killing within the tumor. As designed, in vitro binding and functional assays show that the protease-activated T cell engager has &gt;1000-fold improved binding to primary human T cells and ~100-fold improved T cell killing compared to its intact masked prodrug. In immunodeficient mice reconstituted with human T cells, anti-Trop2 ProTriTAC demonstrated robust anti-tumor activity in multiple xenograft tumor models, including HCC70 (breast), CAL27 (head and neck), and HPAFII (pancreatic), with complete tumor regression as low as 30 μg/kg. To determine the potential toxicity and toxicokinetic characteristics of anti-Trop2 ProTriTAC, an intra-animal dose escalation was conducted in cynomolgus monkeys until individual maximum tolerated dose (MTD). The starting dose was 20 μg/kg with weekly 3-fold dose escalations until MTD. The one-month study revealed that anti-Trop2 ProTriTAC was tolerated at the 180 μg/kg dose level, but not at the next higher dose level of 540 μg/kg. Toxicokinetics, gross pathology, histopathology, and cytokine data will be presented. The preclinical activity in rodent tumor models, coupled to its tolerability in cynomolgus monkeys, support the development of anti-Trop2 ProTriTAC as a therapeutic in a broad range of Trop2-expressing solid tumors. Citation Format: Sony S. Rocha, Regina Lin, Maria R. Dayao, Raphaela Rose Banzon, Subramanian Thothathri, Kevin J. Wright, Wade Aaron, Yinghua Xiao, Nick Bergo, Linh To, Mabel Bush, Manasi Barath, Timothy Yu, Willis Kwong, Hubert Situ, Eric Bragg, Jessica O'Rear, Kevin Carlin, Stephen Yu, Maritza Solorio, Bryan Lemon, Richard Austin, Holger Wesche, S. Jack Lin. TROP2 ProTriTAC™, a protease-activated T cell engager prodrug targeting TROP2 for the treatment of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2928.

Abstract Regulatory T (Treg) cells in the tumor microenvironment have an immune suppressive function, and their presence is associated with poor prognosis. Depletion of Treg cells may be a mechanism to sensitize tumors and represents a novel strategy for cancer immunotherapy. High expression of chemokine receptor CCR8 has been found in Treg cells in microenvironments of numerous tumors but not on Treg cells in systemic lymphoid tissues. The ability to selectively kill Treg cells in tumor environments may provide an opportunity for therapy that leaves Treg function intact elsewhere in the body where they normally mediate tolerance to self-antigen. We sought to identify CCR8 antibodies for therapeutics and designed an antibody discovery strategy to address the challenges of this target. CCR8 is a member of the G protein-coupled receptor (GPCR) family. Like many GPCRs, CCR8 is a valuable therapeutic target but is challenging to target using antibodies due to its poor expression, membrane-dependent structure, small extracellular regions, and poor immunogenicity due to sequence conservation. We developed an antibody discovery platform (MPS) that specifically addresses each of these challenges through use of advanced immunization techniques and evolutionarily divergent host species (chickens) for robust immune responses against conserved targets. We extensively engineered CCR8 antigen to enable high expression for immunization. When sufficient antibody diversity using our standard immunization techniques was not obtained, we developed mRNA immunization techniques for this program. Using these approaches, we were able to identify a panel of high-affinity antibodies that bind in the nanomolar or subnanomolar range with high specificity. We will present data from our antibody discovery campaign including mRNA immunization, binding profiles, GPCR functional data, and the ability of the antibodies to kill Treg cells in vitro using both ADCC and antibody-drug conjugates (ADC). Citation Format: Brad Screnci, Hayley Roth, Sarah Campbell, David Tucker, Colleen Fenn-Ulke, Erin Rosenberg, Meghan Pitts, Naomi Saint-Jean, Jawhara Karam, Paige Murphy, Daniela Reyes, Janae Latta, Kyle Guldner, Samantha Gilman, Tim Phillips, L. Joe Stafford, Breanna Tyrell, Kristen Shema, Chidananda Sulli, Nick Molino, Allison Snyder, Marianne Assogba, Janvi Shah, McKayla Zimmerman, Trevor Barnes, Riley Payne, Alyssa Cunningham, Elisabeth Charrier, Holden Ohl, Kyle Doolan, Ileine Sanchez, Joseph B. Rucker, Ross Chambers, Benjamin Doranz. Discovery of CCR8 antibodies targeting regulatory T cells to enable tumor sensitization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1543.

Abstract Integrin-β6 (ITGB6) is a transmembrane protein that partners exclusively with the integrin-αV subunit to form the integrin-αVβ6 heterodimer. Due to its roles in tissue remodeling and cancer pathogenesis, therapeutic targeting of integrin-αVβ6 has been investigated for both fibrotic diseases and cancers. ITGB6 is homogenously overexpressed in numerous solid tumor types, including breast, head and neck, pancreatic, and non-small cell lung cancers. Additionally, its expression is an unfavorable prognostic marker in multiple cancers. However, past attempts to therapeutically target ITGB6 have been hindered by its expression in several normal tissues, including bladder, skin, lung, kidney, and muscle. For example, clinical testing of an integrin αVβ6-targeting monoclonal antibody was discontinued reportedly due to toxicity concerns. To reduce on-target/off-tumor toxicities from ITGB6 expression in normal tissues and to enable safe targeting of ITGB6 in solid tumors, we developed an ITGB6-targeting ProTriTAC™ (Protease-activated Tri-specific T cell Activating Construct), a T cell engager prodrug which is engineered to be preferentially activated in tumor tissue. ProTriTACs consists of three humanized antibody-derived binding domains on a single polypeptide chain: anti-albumin for half-life extension, anti-CD3 for T cell engagement, and anti-target antigen for tumor cell engagement. The anti-albumin domain, bearing a masking moiety and a protease-cleavable linker, keeps the prodrug inert by inhibiting binding of the adjacent anti-CD3 domain to T cells. Cleavage of the linker by tumor-associated proteases removes the anti-albumin domain along with the masking moiety to reveal a potent active drug that directs T cell killing within the tumor. As designed, in vitro binding and functional assays show that the protease-activated T cell engager has &gt;1000-fold improved binding to human T cells and ~100-fold improved T cell killing compared to the intact masked prodrug. In immunodeficient mice reconstituted with human T cells, anti-ITGB6 ProTriTAC demonstrated robust anti-tumor activity in multiple ITGB6-expressing xenograft tumor models, including HCC70 (breast), CAL27 (head and neck), and HPAFII (pancreatic), with complete tumor regression as low as 30 μg/kg. To determine the potential toxicity and toxicokinetic characteristics of anti-ITGB6 ProTriTAC, an intra-animal dose escalation was conducted in cynomolgus monkeys. Starting at 20 μg/kg with weekly 3-fold dose escalations, anti-ITGB6 ProTriTAC was well tolerated up to 540 μg/kg, which was the highest dose tested. The preclinical activity in rodent tumor models, coupled to its tolerability in cynomolgus monkeys, support the development of anti-ITGB6 ProTriTAC as a therapeutic in a broad range of ITGB6-expressing solid tumors. Citation Format: Regina J. Lin, Sony S. Rocha, Maria R. Dayao, Subramanian Thothathri, Raphaela Rose Banzon, Kevin J. Wright, Wade Aaron, Yinghua Xiao, Nick Bergo, Linh To, Mabel Bush, Manasi Barath, Yi Yang, Timothy Yu, Willis Kwong, Hubert Situ, Eric Bragg, Jessica O'Rear, Kevin Carlin, Stephen Yu, Maritza Solorio, Bryan Lemon, Richard Austin, Holger Wesche, S. Jack Lin. ITGB6 ProTriTAC™, a protease-activated T cell engager prodrug targeting Integrin-β6 for the treatment of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2927.

Abstract Background : Ibr, an established standard of care in CLL, is a once-daily Bruton tyrosine kinase inhibitor with significant progression-free survival (PFS) and overall survival benefit shown in multiple randomized phase 3 studies in first-line CLL. Ven, an oral BCL-2 inhibitor approved as a single agent or combined with rituximab or obinutuzumab for CLL treatment, achieves high rates of undetectable MRD (uMRD). Ibr and Ven, with distinct and complementary mechanisms of action, work synergistically to mobilize CLL cells from lymph nodes and lymphoid niches, enhance cell killing, and eliminate distinct CLL cell populations. CAPTIVATE (PCYC-1142; NCT02910583) is an international, multicenter phase 2 study evaluating first-line Ibr + Ven in 2 cohorts: MRD and Fixed-Duration (FD). Patients (pts) first received 3 cycles of Ibr followed by 12 cycles of combined Ibr + Ven. In the primary analysis of the MRD cohort, pts with Confirmed uMRD who after fixed duration treatment were randomized to placebo or continued Ibr had similar post-randomization 1-year DFS rates (95% and 100%, respectively) (Wierda, ASH 2020). Two-year post-randomization results are presented. Methods : Pts aged &lt;70 years with previously untreated CLL received 3 cycles of Ibr lead-in then 12 cycles of combined Ibr + Ven (oral Ibr 420 mg/day; oral Ven ramp-up to 400 mg/day). During cycle 16, pts with Confirmed uMRD (defined as uMRD serially over ≥2 assessments ≥3 mo apart, and in both peripheral blood [PB] and bone marrow [BM]) were randomized 1:1 to receive double-blind treatment with placebo or single-agent Ibr. Pts who did not meet the definition of Confirmed uMRD were randomized 1:1 to receive open-label treatment with single-agent Ibr or continued Ibr + Ven. Endpoints presented include 2-year DFS rate (defined as survival without progression [PD] or MRD relapse post-randomization) in pts with Confirmed uMRD randomized to placebo vs Ibr, rates of uMRD (&lt;10 -4 by 8-color flow cytometry), investigator-assessed best response per iwCLL, investigator-assessed PFS, and adverse events (AEs). Results : 164 pts were enrolled. Median age was 58 years (range, 28-69). High-risk features included unmutated IGHV (60% of pts), del(17p)/TP53 mutation (20%), complex karyotype (19%), and del(11q) without del(17p) (17%). After 12 cycles of Ibr + Ven, 149 pts were randomized: Confirmed uMRD to placebo (n=43) or Ibr (n=43); without Confirmed uMRD to Ibr (n=31) or Ibr + Ven (n=32). Median overall follow-up was 38.2 mo (range, 15.0-47.9); median post-randomization follow-up was 24.0 mo (range, 5.8-33.1). In pts with Confirmed uMRD randomized to placebo versus Ibr, no new DFS events occurred since the primary analysis; 2-year DFS rates post-randomization remained unchanged at 95% (placebo) vs 100% (Ibr), for a 4.7% difference (95% CI -1.6-10.9) and overall log-rank P=0.1573 (Figure 1). In the placebo and Ibr arms post-randomization, modest improvements were observed in complete response (CR) rates, including CR with incomplete bone marrow recovery (CRi) (Figure 2). Estimated 36-mo PFS rates were 95% with placebo and 100% with Ibr. In pts without Confirmed uMRD randomized to Ibr vs Ibr + Ven, greater improvements in best uMRD rates and CR/CRi rates were observed with Ibr + Ven than with Ibr post-randomization (Figure 2). Estimated 36-mo PFS rates were 97% with both Ibr and Ibr + Ven. Median treatment duration was 36.8 mo (range, 0.5-47.9) in all pts (N=164). Modest differences in AEs were observed across treatment arms post-randomization. During the overall study period across all-treated pts, the most frequent grade 3/4 AEs were neutropenia (36%), hypertension (10%), thrombocytopenia (5%), and diarrhea (5%). With up to 48 mo of treatment, AEs led to discontinuation of Ibr or Ven in 13% of pts; no new safety signals emerged. Conclusions : First-line Ibr + Ven is an all-oral, once-daily, chemotherapy-free regimen that provides deep responses in pts with CLL. With an additional year of follow-up and no new MRD relapses, PDs or deaths in pts with confirmed uMRD, the 2-year DFS rate in the MRD-guided placebo arm remained high at 95% while 3-year PFS rates were ≥95% across all randomized treatment arms. The results in pts with Confirmed uMRD support the potential for treatment-free remission with fixed-duration treatment, including in pts with high-risk features. High rates of uMRD were achieved; the safety profile of Ibr + Ven was consistent with known safety profile for each agent. Figure 1 Figure 1. Disclosures Ghia: Acerta/AstraZeneca: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; ArQule/MSD: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Celgene/Juno/BMS: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Sunesis: Research Funding; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Research Funding. Allan: Celegene: Research Funding; AstraZeneca Pharmaceuticals LP, Genentech, a member of the Roche Group, Janssen Biotech Inc, TG Therapeutics Inc.: Research Funding; AbbVie: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria; Genentech: Consultancy, Research Funding; TG Therapeutics: Research Funding; Epizyme: Consultancy; AbbVie Inc, AstraZeneca Pharmaceuticals LP, BeiGene, Janssen Biotech Inc, Pharmacyclics LLC: Consultancy; AbbVie Inc, Ascentage Pharma, Epizyme, Genentech, a member of the Roche Group, Janssen Biotech Inc, Pharmacyclics LLC: Other: Advisory Committee. Siddiqi: Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Juno therapeutics: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Other: DSM Member, Speakers Bureau; PCYC: Speakers Bureau; Jannsen: Speakers Bureau; Dava Oncology: Honoraria; ResearchToPractice: Honoraria. Kipps: Janssen: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Roche: Honoraria, Other; MD Anderson Cancer Center: Research Funding; Velos: Research Funding; CRIM: Research Funding; Indy Hematology Review: Other; TG Therapeutics: Other; Verstem: Other, Speakers Bureau; University of California, San Diego: Current Employment; Pharmacyclics/AbbVie: Honoraria, Research Funding; Breast Cancer Research Foundation: Research Funding; SCOR - The Leukemia and Lymphoma Society: Research Funding; National Cancer Institute/NIH: Honoraria, Research Funding; Genentech/Roche: Honoraria; European Research Initiative on CLL (ERIC): Honoraria; Bionest Partner: Other; Celgene: Consultancy, Honoraria, Other, Research Funding; Genetech: Honoraria, Other; Genentech-Roche: Consultancy; Gilead Sciences: Consultancy, Honoraria, Other, Speakers Bureau; DAVA Pharmaceuticals: Speakers Bureau; DAVAOncology: Consultancy, Honoraria, Other; AbbVie: Consultancy, Honoraria, Other, Speakers Bureau; Oncternal Therapeutics, Inc.: Current holder of stock options in a privately-held company, Other: Stock or other ownership, Patents & Royalties: Cirmtuzumab was developed by Thomas J. Kipps in the Thomas J. Kipps laboratory and licensed by the University of California to Oncternal Therapeutics, Inc., which provided stock options and research funding to the Thomas J. Kipps laboratory., Research Funding; Moores Cancer Center: Current Employment; MedImmune Inc: Research Funding; GlaxoSmithKline: Research Funding; Gilead Sciences, Inc.: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding, Speakers Bureau; Pharmacyclics LLC, an Abbvie Company: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Honoraria, Research Funding; Abbott Laboratories: Consultancy, Research Funding. Kuss: Commonwealth Serum Laboratories: Other: Stock or other ownership; AbbVie: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Merck: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Kyowa Kirin: Consultancy, Honoraria; Mundipharma: Consultancy, Honoraria; Roche Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Janssen: Speakers Bureau. Opat: AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sandoz: Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; CSL: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Monash Health: Current Employment; BeiGene: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GIlead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding. Flinn: Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding; Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Sarah Cannon Research Institute: Current Employment; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding; Johnson & Johnson: Current holder of individual stocks in a privately-held company; Seattle Genetics: Research Funding. Badoux: Janssen: Honoraria; AbbVie: Honoraria, Other: Travel, Accommodations, Expenses. Tedeschi: Beigene: Honoraria, Speakers Bureau; AstraZeneca: Honoraria, Speakers Bureau; AbbVie: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau. Gonzalez-Barca: Kiowa: Consultancy, Speakers Bureau; Eusapharma: Consultancy; Janssen: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau; Takeda: Speakers Bureau; Roche: Other: Travel, Accommodations, Expenses; AbbVie: Other: Travel, Accommodations, Expenses, Speakers Bureau. Pagel: Pharmacyclics/AbbVie: Consultancy; Gilead: Consultancy; Actinium Pharmaceuticals: Consultancy; Kite, a Gilead Company: Consultancy; BeiGene: Consultancy; Epizyme: Consultancy; MEI Pharma: Consultancy; AstraZeneca: Consultancy; Incyte/MorphoSys: Consultancy. Jacobs: AstraZeneca: Consultancy, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding, Speakers Bureau; ADC Therapeutics: Consultancy; Adaptive Biotechnologies: Consultancy; MEI Pharma: Research Funding; TeneoBio: Research Funding; SecuraBio: Consultancy, Speakers Bureau; Verastem: Consultancy; TG Therapeutics: Research Funding, Speakers Bureau; Jannsen: Speakers Bureau; Genentech: Consultancy; AbbVie: Consultancy, Speakers Bureau. Szafer-Glusman: AbbVie: Current Employment, Other: Stock or other ownership. Zhou: AbbVie: Current Employment, Other: Stock and other ownership. Ninomoto: AbbVie: Current Employment, Other: Stock or other ownership. Dean: Pharmacyclics: Current Employment, Other: Stock or other ownership; AbbVie: Other: Stock Ownership. Tam: Pharmacyclics: Honoraria; BeiGene: Consultancy, Honoraria; Loxo: Consultancy; AbbVie: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Novartis: Honoraria. Wierda: Janssen: Research Funding; AstraZeneca: Research Funding; GSK/Novartis: Research Funding; Acerta Pharma Inc.: Research Funding; Karyopharm: Research Funding; Xencor: Research Funding; Oncternal Therapeutics, Inc.: Research Funding; Loxo Oncology, Inc.: Research Funding; Genentech: Research Funding; Sunesis: Research Funding; Miragen: Research Funding; Cyclacel: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Juno Therapeutics: Research Funding; Gilead Sciences: Research Funding; KITE Pharma: Research Funding; Genzyme Corporation: Consultancy; AbbVie: Research Funding. OffLabel Disclosure: Ibrutinib in combination with venetoclax is not approved in any indication.

Abstract Background: Cirmtuzumab (Cirm) is a humanized monoclonal antibody that inhibits the tumor promoting activity of ROR1 and has demonstrated additive/synergistic activity with many anticancer agents, including ibrutinib (Ibr). Methods: Patients (Pts) with relapsed or refractory (RR) MCL or treatment-naïve (TN) or RR CLL were enrolled. In Part 1 (Dose Escalation), doses of Cirm IV q2wks x5 then q4wks of 2-16 mg/kg and 300 or 600 mg were examined. Safety of Cirm alone was assessed during the first 28 days, then Ibr was started at approved doses for each indication. Cirm 600 mg IV q2wks x3 then q4wks in combination with Ibr starting day 0 was chosen as the recommended dosing regimen for use in Part 2 (Expansion) and Part 3 (CLL only, Cirm/Ibr vs. Ibr). MCL Part 1 is closed, and Part 2 is open for enrollment. CLL Parts 1, 2 & 3 are closed for enrollment. Results: As of 18Jun2021 data cutoff, 28, 34 and 28 pts were treated in MCL Parts 1 & 2, CLL Parts 1 & 2, and CLL Part 3 (Cirm/Ibr (n=18) or Ibr (n=10)). In Parts 1 & 2 MCL, the median number (#) of prior systemic regimens was 1.5 (1-4) including pts relapsing after Ibr (n=4), auto-SCT (n=6), auto-SCT/allo-SCT (n=1), or auto-SCT/CAR-T (n=1). Ki-67 ≥30% and extra-nodal disease was present in 54% and 68% of pts, respectively. The median # of prior systemic regimens for CLL Parts 1 & 2 and CLL Part 3 (RR), was 2 (1-15) including auto-SCT (n=1), and 2 (1-6). Pts entered with Rai staging ≥ Grade 2 in 71% and 64%. Safety (MCL and CLL): Most frequent treatment emergent (TEAEs) (≥30%) for both MCL and CLL pts treated with Cirm/Ibr (N=80), (all grades; regardless of causality) included contusion & fatigue (both 40.0%), and diarrhea (37.5%). Most frequent (≥5%) Grade ≥3 TEAEs, regardless of causality included hypertension (10.0%), fatigue, neutropenia, pneumonia, and atrial fibrillation (all 6.3%), leukocytosis and anemia (both 5.0%). Grade ≥3 TEAEs of myelosuppression, regardless of causality, include anemia (5.0%), thrombocytopenia (1.3%), and neutropenia (6.3%). Most TEAEs in MCL or CLL pts were considered related by Investigator to Ibr alone 64% or 84% vs. Cirm alone 14.3% or 16%. Efficacy (MCL): The best response of 20 evaluable pts in Parts 1 & 2 included CR 35%, PR 45%, SD 10%, and 10% PD. At a median follow-up of 14.9 mos., the objective response rate (ORR), clinical benefit rate (CBR) and median duration of response (DOR) for overall, ≥30% Ki-67, and &gt;1 prior systemic regimen subgroups, were 80%, 90% and (not reached) NR (95% CI: 11.9, NR), 81.8%, 81.8% and 13.8 (95% CI: 8.7, NR), and 90%, 100% and NR (95% CI: 8.7, NR). Responses occurred in all evaluable pts who received prior SCT+/- CAR-T (4CR, 2PR) or prior Ibr (2CR, 2PR). The median PFS (mPFS) for overall, pts achieving CR, and &gt;1 prior systemic regimen subgroups were all NR with varying 95% CI: (16.5, NR), (0.03, NR), and (0.03, NR). Efficacy (CLL): The best response of 34 evaluable pts in Parts 1 & 2 included 94.1% ORR, 11.8% CR, 82.3% PR/PR-L, and 5.9% SD for a CBR of 100%. In Part 3, evaluable Cirm/Ibr TN (n=8) or RR (n=7) and Ibr TN (n=4) or RR (n=3) arms achieved 100% or 85.7% and 100% or 100% ORR, 12.5% or 0% and 0% or 0% CR, 87.5% or 85.7% and 100% or 100% PR/PR-L, 0% or 14.3% and 0% or 0% SD. No pts had PD as best response. All pts had a CBR of 100%. For Parts 1 & 2, at a median follow-up of 24.8 mos., the DOR for overall and &gt;1 prior systemic regimen subgroups, was NR (8.3, 35.9) and NR (12.0, 29.6). In Part 3, at a median follow-up of 14.7 mos., the DOR for TN or RR Cirm/Ibr and Ibr arms is NR (7.7, 18.6) or NR (9.2, 14.8) and NR (11.2, 18.5) or NR (8.3, 14.2). The mPFS (Parts 1 & 2) for overall, pts achieving CR, and &gt;1 prior systemic regimen subgroups were NR (9.1, 35.8), NR (95% CI: 22.5, NR), and NR (9.1, 35.2). In Part 3, mPFS for TN or RR Cirm/Ibr and Ibr arms is all NR. Conclusions: Cirm/Ibr is well-tolerated. ORR, CR, DOR, and mPFS were similar across all subgroups of MCL and CLL pts regardless of number of prior systemic regimens or poor risk factors. Striking responses were observed in patients with MCL as evidenced by a mPFS that was NR (95% CI: 16.5, NR), CR of 35%, and a DOR of NR (95% CI: 11.9, NR) within the study period. These data compare very favorably to the mPFS of 12.8 mos, CR of 20%, and a DOR of 18.6 mos., reported for Ibr alone (Rule 2017). For CLL pts treated with Cirm/Ibr, results continue to be encouraging as they mature. The study is ongoing, with MCL enrollment expanded to include Cirm + Ibr in pts who have had an inadequate response to an Ibr regimen, or who are refractory to approved BTKi agents. Figure 1 Figure 1. Disclosures Lee: Oncternal: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Seagen: Research Funding; BMS: Honoraria, Research Funding; Aptitude Health: Honoraria; Guidepoint: Honoraria; Century Therapeutics: Consultancy; Pharmacyclics: Research Funding; Janssen: Honoraria. Choi: Abbvie: Other: Institution: Research Grant/Funding; Pharmacyclics: Other: Institution: Research Grant/Funding; Oncternal: Other: Institution: Research Grant/Funding; Velosbio: Other: Institution: Research Grant/Funding; Merck: Other: Institution: Research Grant/Funding; Geron: Other: Institution: Research Grant/Funding. Siddiqi: Celgene: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kite Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Speakers Bureau; Oncternal: Research Funding; TG Therapeutics: Research Funding. Wierda: Acerta Pharma Inc.: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; AstraZeneca: Research Funding; Cyclacel: Research Funding; Karyopharm: Research Funding; Xencor: Research Funding; Oncternal Therapeutics, Inc.: Research Funding; KITE Pharma: Research Funding; Miragen: Research Funding; Janssen: Research Funding; Gilead Sciences: Research Funding; Juno Therapeutics: Research Funding; Genentech: Research Funding; GSK/Novartis: Research Funding; Sunesis: Research Funding; Loxo Oncology, Inc.: Research Funding; Genzyme Corporation: Consultancy; AbbVie: Research Funding. Tuscano: BMS: Research Funding; Seattle Genetics: Research Funding; Takeda: Research Funding; Acrotech: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Abbvie: Research Funding. Leslie: Abbvie: Consultancy, Honoraria; PCYC/Janssen: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Speakers Bureau; Karyopharm Therapeutics: Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; BeiGene: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy; Celgene/BMS: Consultancy, Honoraria, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau; Kite, a Gilead Company: Consultancy, Honoraria, Speakers Bureau; Epizyme: Consultancy, Honoraria, Speakers Bureau; Seagen: Consultancy, Honoraria, Speakers Bureau; Merck: Consultancy. Breitmeyer: Oncternal Therapeutics: Current Employment, Membership on an entity's Board of Directors or advisory committees. Yazji: Oncternal Therapeutics: Current Employment. Wang: Oncternal Therapeutics: Current Employment. Wang: OMI: Honoraria; Moffit Cancer Center: Honoraria; Chinese Medical Association: Honoraria; Newbridge Pharmaceuticals: Honoraria; DTRM Biopharma (Cayman) Limited: Consultancy; InnoCare: Consultancy, Research Funding; Scripps: Honoraria; Mumbai Hematology Group: Honoraria; VelosBio: Consultancy, Research Funding; BioInvent: Research Funding; Hebei Cancer Prevention Federation: Honoraria; Epizyme: Consultancy, Honoraria; Anticancer Association: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Lilly: Research Funding; Physicians Education Resources (PER): Honoraria; Dava Oncology: Honoraria; Clinical Care Options: Honoraria; Molecular Templates: Research Funding; BeiGene: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Research Funding; Acerta Pharma: Consultancy, Honoraria, Research Funding; Imedex: Honoraria; Juno: Consultancy, Research Funding; Celgene: Research Funding; Genentech: Consultancy; Loxo Oncology: Consultancy, Research Funding; Kite Pharma: Consultancy, Honoraria, Research Funding; Miltenyi Biomedicine GmbH: Consultancy, Honoraria; The First Afflicted Hospital of Zhejiang University: Honoraria; Bayer Healthcare: Consultancy; BGICS: Honoraria; CAHON: Honoraria; Oncternal: Consultancy, Research Funding; CStone: Consultancy. Jamieson: Forty Seven Inc.: Patents & Royalties. Kipps: Genentech-Roche: Consultancy; Gilead Sciences: Consultancy, Honoraria, Other, Speakers Bureau; Janssen: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Roche: Honoraria, Other; MD Anderson Cancer Center: Research Funding; Velos: Research Funding; CRIM: Research Funding; Indy Hematology Review: Other; TG Therapeutics: Other; Verstem: Other, Speakers Bureau; University of California, San Diego: Current Employment; Pharmacyclics/AbbVie: Honoraria, Research Funding; Breast Cancer Research Foundation: Research Funding; SCOR - The Leukemia and Lymphoma Society: Research Funding; National Cancer Institute/NIH: Honoraria, Research Funding; Genentech/Roche: Honoraria; European Research Initiative on CLL (ERIC): Honoraria; Genetech: Honoraria, Other; Celgene: Consultancy, Honoraria, Other, Research Funding; Bionest Partner: Other; DAVA Pharmaceuticals: Speakers Bureau; DAVAOncology: Consultancy, Honoraria, Other; AbbVie: Consultancy, Honoraria, Other, Speakers Bureau; Oncternal Therapeutics, Inc.: Current holder of stock options in a privately-held company, Other: Stock or other ownership, Patents & Royalties: Cirmtuzumab was developed by Thomas J. Kipps in the Thomas J. Kipps laboratory and licensed by the University of California to Oncternal Therapeutics, Inc., which provided stock options and research funding to the Thomas J. Kipps laboratory., Research Funding; Moores Cancer Center: Current Employment; MedImmune Inc: Research Funding; GlaxoSmithKline: Research Funding; Gilead Sciences, Inc.: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding, Speakers Bureau; Pharmacyclics LLC, an Abbvie Company: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Honoraria, Research Funding; Abbott Laboratories: Consultancy, Research Funding.

Else Roesdahl reaches 60l first met Else Roesdahl in 1969, when, newly graduated, she was working as an assistant in the National Museum. This was the foun­dation of a friendship which spans her professional career.Else was born on Als and her sense of history and her fierce in dependence is based in the background of her family, which was deeply involved in the politics of Sønderjylland after 1864. Although she studied in Copenhagen, she returned to Jutl and with her husband, Erich Lange, in 1970, and soon became firmly established in Aarhus University.As a student (and later as a postgraduate) she took par t in P.V. Glob’s Bahrain expedi­tions .The three seasons she spent there deep­ly influenced her development as an archae­ologist and scholar. The dig excited her sense of adventure and stimulated her to travel in India, Afghanistan, Iran and Egypt, develop­ing an interest in pottery and glass originally in stilled by her father, a learned collector. At home she took part in many other excavations. She is, for example, proud of the fact that at Skuldelev she found the beautiful stem of Wreck 3.Concentrating on the Viking Age she became, through such outlets as the Viking Congress, party to an innovative critical interdisciplin ary approach to the period. Nowhere is this better expressed than in the annual and successful tværfaglige Vikingesymposium, of which she is one of the most influential organisers, or in the foundation of the Aarhus Centre for Viking and Medieval Studies. She excavated with Olaf Olsen at all the Trelleborg fortresses, and in 1970 joined him in the newly- founded department of medieval archaeology at Moesgård. Succeeding as head of department in 1981, she was promoted professor in 1996.Although engaged with the whole of the Middle Ages, her first enthusiasm was for the Viking Age. With Olaf Olsen and Holger Schmidt, she published the Fyrkat excava­tions in 1977, and it is a tribute to the academic integrity of both Olaf and Else that, though differing in their conclusions, they did not fall out – disproving the adage, ‘archaeology is not a discipline, it’s a vendetta’.Much in demand internationally, she was deeply in volved in the organisation of the Vikings in England exhibition in 1981-2, and was the coordinator of the magnificent exhibition Viking og Hvidechrist in 1992-3. The catalogue which she edited for this exhibition, together with her books Danmarks Vikingetid and Vikingernes Verden, are now central to any stud y of the Viking Age and have been translated into many languages. She has edited many other books, most recently Dagligliv i Danmarks middelalder, and,with Mogens Bencard, wrote the pionering Dansk middel­alderlertøj.She has many honours – among them the Dannebrog, a LittD from Dublin, a special professorship at Nottingham, and corresponding fellowships of learned bodies in Germany and England – but it is her friendship, scholarship and wit that we celebrate on her sixtieth birthday.David M .WilsonCastletown Isle of ManOversat til dansk af Annette Lerche Trolle

Grundtvig Europa, og Den tredje VerdenAf Holger Bernt HansenProblemstillingen forudsætter, at overvejelser om den aktuelle kultur- og samfundssituation kombineres med historiske perspektiver, såvel om Grundtvigs tanker som også angående den historiske udvikling i forholdet mellem Europa og Den tredje Verden.En kritisk analyse af den nuværende situation i den gamle verden fører til et resultat, der umiddelbart tager sig særdeles pessimistisk ud: b.de det kulturelle arvegods og samfundsidealerne synes at befinde sig midt i en proces præget af nedbrydning og forfald. Det gælder sansen for historien, respekten for det nedarvede; samtidig synes begreber som nation og folk at v.re blevet problematiseret; endvidere kan vi observere, hvordan nøgleinstitutioner som stat og kirke er inde i en forandringsproces, samtidig med at værdinormer skifter karakter.Denne situation overvejes nu i sammenh.ng med den historiske kendsgerning, at Europa i b.de dette og sidste århundrede har været præget af en eurocentrisk forståelse af civilisation med en deraf følgende identifikation af europæisk kulturarv og civilisation slet og ret. Dette forhold havde også vidtrækkende følger for den missionspraksis, der i overvejende grad var bestemmende for de europæiske missionsselskaber, således at koloniseringspolitik og missionsstrategi betingede hinanden.Betragter man imidlertid denne intolerante og ekspansionistiske holdning i forhold til Grundtvigs syn på folkekultur og alle folkeslagenes plads inden for universalhistorien, vil man se, at Grundtvigs tanker har en ganske anderledes tendens end den, der efter hans egen levetid blev den rådende. Ikke desto mindre konstaterer forfatteren i den aktuelle situation en ny og forstærket tendens til europæisk arrogance og magtbevidsthed.Som en kritisk replik ind i denne situation anf.res dels nogle aspekter fra Grundtvigs egen tankeverden, dels nogle eksempler på en mere konstruktiv m.de at anskue forholdet mellem Europa og den tredje verden på. Blandt disse eksempler er der navnlig grund til at faste opmærksomhed ved Kachi Ozumbas erfaringer i forbindelse med forsøget på at omplante Grundtvigs skoletanker til Nigeria. Der lægges vægt på, at der er tale om alt andet end en bevidstløs overtagelse af grundtvigske klicheer, men tværtimod en omhyggelig sigtning og tilpasning. (Se i denne forbindelse K. Ozumbas eget bidrag her i bindet).Endvidere diskuteres Erica Simons bestræbelser på en nyformulering af Grundtvigs skoletanker i sammenh.ng med bevægelsen for ’négritude’, der i 1950’erne var en betydelig faktor i henseende til en øget forståelse for afrikansk folkekultur. Det påpeges imidlertid, at det, med al respekt i øvrigt, også Er påkrævet at stille kritiske spørgsmål til tankegangen bag ’négritude’; f.eks. havde tankegangen en udtalt elitær tendens.Afsluttende diskuteres nødvendigheden af en skånsom afvejning af, hvor det kan forekomme konstruktivt at inddrage Grundtvigs tanker, og hvor det er påkrævet at foretage en justering. Som eksempel på behovet for en revision anføres de problemer, der knytter sig til nation og folkelighed. Nationer og stater er i tredje-verdens sammenh.ng ofte kunstdannelser, der historisk set går tilbage til koloniherrerne. Derfor er det uundgåeligt at tilf.je kategorier som det etniske og stammefællesskabet, hvis man vil finde ind til de strukturer, der bærer modersmålet og det historiske fællesskab. Som en vej frem kan det derfor måske vise sig nødvendigt at tale om demokratisk vækkelse i stedet for national genopvågnen. Nationalitetstanken kan jo, som vi har set sørgeligt mange eksempler på de seneste år, vise sig at v.re b.de fremmedgørende og brugbar som instrument for undertrykkelse af mindretal. Spørgsmålet er da, om vi vil have bedre mulighed for at gengive de universelt gyldige værdier, Grundtvig sigtede til med sin forståelse af den levende folkeånd, hvis vi i stedet benytter det ret forståede demokrati-ideal som ledetråd.

Introduction: Patients (pts) with CLL may be at particular risk of severe COVID-19 given advanced age and immune dysregulation. Two large series with limited follow-up have reported outcomes for pts with CLL and COVID-19 (Scarfò, et al. Leukemia 2020; Mato, et al. Blood 2020). To provide maximal clarity on outcomes for pts with CLL and COVID-19, we partnered in a worldwide effort to describe the clinical experience and validate predictors of survival, including potential treatment effects. Methods: This international collaboration represents a partnership between investigators at 141 centers. Data are presented in two cohorts. Cohort 1 (Co1) includes pts captured through efforts by European Research Initiative on CLL (ERIC), Italian CAMPUS CLL Program, and Grupo Español de Leucemia Linfática Crónica. The validation cohort, Cohort 2 (Co2), includes pts from US (66%), UK (23%), EU (7%), and other countries (4%). There is no overlap in cases between cohorts. CLL pts were included if COVID-19 was diagnosed by PCR detection of SARS-CoV-2 and they required inpatient hospitalization. Data were collected retrospectively 2/2020 - 5/2020 using standardized case report forms. Baseline characteristics, preexisting comorbidities (including cumulative illness rating scale (CIRS) score ≥6 vs. &lt;6), CLL treatment history, details regarding COVID-19 course, management, and therapy, and vital status were collected. The primary endpoint of this study was to estimate the case fatality rate (CFR), defined as the proportion of pts who died among all pts hospitalized with COVID-19. Chi-squared test was used to compare frequencies; univariable and multivariable analyses utilized Cox regression. Predictors of inferior OS in both Co1 and Co2 were included in multivariable analyses. Kaplan-Meier method was used to estimate overall survival (OS) from time of COVID-19 diagnosis (dx). Results: 411 hospitalized, COVID-19 positive CLL pts were analyzed (Co1 n=281, Co2 n=130). Table 1 describes baseline characteristics. At COVID-19 dx, median age was 72 in Co1 (range 37-94) and 68 in Co2 (range 41-98); 31% (Co1) and 45% (Co2) had CIRS ≥6. In Co1, 48% were treatment-naïve and 26% were receiving CLL-directed therapy at COVID-19 dx (66% BTKi ± anti-CD20, 19% Venetoclax ± anti-CD20, 9.6% chemo/chemoimmunotherapy (CIT), 1.4% PI3Ki, 4% other). In Co2, 36% were never treated and 49% were receiving CLL-directed therapy (65% BTKi ± anti-CD20, 19% Venetoclax ± anti-CD20, 9.4% multi-novel agent combinations, 1.6% CIT, 1.6% PI3Ki, 1.6% anti-CD20 monotherapy, 1.6% other). Most pts receiving CLL-directed therapy had it held at COVID-19 diagnosis (93% in Co1 and 81% in Co2). Frequency of most COVID-19 symptoms/laboratory abnormalities were similar in the two cohorts including fever (88% in both), lymphocytosis (ALC ≥30 x 109/L; 27% vs. 21%), and lymphocytopenia (ALC &lt; 1.0 x 109/L; 18% vs. 28%), while others varied between Co1 and Co2 (p&lt;0.0001), including cough (61% vs. 93%), dyspnea (60% vs. 84%), fatigue (13% vs. 77%). Median follow-up was 24 days (range 2-86) in Co1 and 17 days (1-43) in Co2. CFRs were similar in Co1 and Co2, 30% and 34% (p=0.45). 54% and 43% were discharged while 16% and 23% remained admitted at last follow-up in Co1 and Co2, respectively. The proportion of pts requiring supplemental oxygen was similar (89% vs. 92%) while rate of ICU admission was higher in Co2 (20% vs. 48%, p&lt;0.0001). Figure 1 depicts OS in each cohort. Univariable analyses demonstrated that age and CIRS ≥6 significantly predicted inferior OS in both cohorts, while only age remained an independent predictor of inferior OS in multivariable analyses (Table 2). Prior treatment for CLL (vs. observation) predicted inferior OS in Co1 but not Co2. Conclusions : In the largest cancer dx-specific cohort reported, pts with CLL hospitalized for COVID-19 had a CFR of 30-34%. Advanced patient age at COVID-19 diagnosis was an independent predictor of OS in two large cohorts. This CFR will serve as a benchmark for mortality for future outcomes studies, including therapeutic interventions for COVID-19 in this population. The effect of CLL treatment on OS was inconsistent across cohorts; COVID-19 may be severe regardless of treatment status. While there were no significant differences in distribution of current lines of therapy between cohorts, prior chemo exposure was more common in Co1 vs. Co2, which may account for difference in OS. Extended follow-up will be presented. Disclosures Roeker: American Society of Hematology: Research Funding; Abbott Laboratories: Other: spouse with minority ownership interest ; AbbVie: Other: spouse with minority ownership interest . Scarfo:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Honoraria; Gilead: Membership on an entity's Board of Directors or advisory committees. Abrisqueta:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Speakers Bureau. Eyre:AbbVie: Consultancy, Honoraria, Other: travel support; Gilead: Consultancy, Honoraria, Other: travel support; Janssen: Consultancy, Honoraria, Other: travel support; KITE, AZ, Loxo Oncology at Lilly: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Muntañola Prat:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants; participated in advisory boards; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants; participated in advisory boards; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants; participated in advisory boards. Villacampa:AstraZeneca: Other: advisory role; Merck Sharp & Dohme: Honoraria. Leslie:AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Speakers Bureau; KitePharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene/BMS: Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics/Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Epizyme: Speakers Bureau; Karyopharm: Speakers Bureau; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Allan:Acerta, Genentech, Abbvie, Sunesis, Ascentage, Pharmacyclics, Janssen, AstraZeneca, BeiGene: Consultancy; Celgene, Genentech, Janssen, TG Therapeutics: Research Funding; Abbvie, Janssen, AstraZeneca, Pharmacyclics: Honoraria. Furman:Incyte: Consultancy; Genentech: Consultancy; Sunesis: Consultancy; Pharmacyclics: Consultancy; Loxo Oncology: Consultancy; Oncotarget: Consultancy; Janssen: Consultancy, Speakers Bureau; TG Therapeutics: Consultancy, Research Funding; Abbvie: Consultancy; Beigene: Consultancy; AstraZeneca: Consultancy, Research Funding; Acerta: Consultancy; Verastem: Consultancy. Pagel:BeiGene, Astrazeneca, Loxo Oncology, Gilead: Consultancy. Hernandez-Rivas:Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Rovi: Membership on an entity's Board of Directors or advisory committees. Patel:Genentech: Consultancy, Speakers Bureau; Adaptive Biotechnologies: Consultancy; Janssen: Consultancy, Speakers Bureau; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy; Kite: Consultancy; Pharmacyclics: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Research Funding, Speakers Bureau. Motta:Roche: Honoraria; Janssen: Honoraria. Lamanna:AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Verastem: Research Funding; Bei-Gene: Research Funding; TG Therapeutics: Research Funding; Acerta: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche-Genentech: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Vitale:Janssen: Honoraria. Kamdar:Roche: Research Funding. Österborg:BeiGene: Research Funding; Kancera: Current equity holder in publicly-traded company, Research Funding; Sanofi: Consultancy; Karolinska Univeristy Hospital, Stockholm, Sweden: Current Employment. Hanson:Janssen-Cilag: Research Funding; Gilead: Research Funding; AbbVie: Honoraria. Eichhorst:ArQule: Consultancy, Honoraria, Other: travel support, Research Funding; BeiGene: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: travel support, Research Funding; Oxford Biomedica: Consultancy, Honoraria, Other: travel support, Research Funding; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding; F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding; Novartis: Consultancy, Honoraria, Other: travel support, Research Funding. Reda:Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Varettoni:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel/accommodations/expenses; AbbVie: Other: Travel/accommodations/expenses; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees. Marchetti:Gilead: Consultancy; Novartis: Speakers Bureau; Amgen: Speakers Bureau; AbbVie: Other: Sponsored meetings; Takeda: Other: Sponsored meetings; Pfeizer: Other: Sponsored meetings. Munir:F. Hoffmann-La Roche: Consultancy, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland; Alexion: Honoraria. Zabalza:Janssen: Honoraria, Other: travel grants; Roche: Other: travel grants; Novartis: Other: travel grants. Janssens:Amgen: Consultancy, Other: travel grants; speaker fees; Abbvie: Consultancy, Other: travel grants; speaker fees; Celgene: Consultancy, Other: travel grants; speaker fees; Janssen: Consultancy, Other: travel grants; speaker fees; Gilead: Consultancy, Other: travel grants; speaker fees; Novartis: Consultancy, Other: travel grants; speaker fees; Sanofi-Genzyme: Consultancy, Other: travel grants; speaker fees; Roche: Consultancy, Other: travel grants; speaker fees. Niemann:AstraZeneca: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Sunesis: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Danish Cancer Society: Honoraria, Research Funding; Novo Nordisk Foundation: Honoraria, Research Funding. Perini:Takeda: Honoraria; Janssen: Honoraria, Speakers Bureau; Abbvie: Speakers Bureau. Patten:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Honoraria. Marasca:Roche: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Honoraria. Iyengar:Janssen: Honoraria; Gilead: Honoraria. Ferrari:Abbvie: Honoraria. El-Sharkawi:Roche: Other: Conference fees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Itchaki:Abbvie Inc: Consultancy, Research Funding. Ma:Novartis: Research Funding; Juno: Research Funding; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Kite: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Bioverativ: Consultancy, Honoraria; BeiGene: Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding; TG Therapeutics: Research Funding. Van Der Spek:AMGEN: Other: Teaching activities. Seymour:Seattle Genetics: Research Funding; Merck: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen/Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Genentech: Research Funding; Bristol-Myers Squibb: Research Funding. Rigolin:Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mauro:Roche: Other; Octopharma: Other; Takeda-Shire: Other; Gilead: Other; Janssen: Other; Abbvie: Other. Laurenti:Janssen: Honoraria; Gilead: Honoraria; AbbVie: Honoraria; Roche: Honoraria. Levin:Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel compensation; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: travel compensation; Roche: Membership on an entity's Board of Directors or advisory committees, Other: travel compensation. Špaček:Gilead: Honoraria; Abbvie: Honoraria; Janssen: Honoraria. Walewska:AbbVie: Other: sponsored for educational meetings, Speakers Bureau; Janssen: Other: sponsored for educational meetings, Speakers Bureau; Gilead: Speakers Bureau; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees. Wiestner:Pharmacyclics LLC, an AbbVie Company; Acerta, Merck, Nurix, Verastem, and Genmab: Research Funding; National Institutes of Health: Patents & Royalties: and other intellectual property. Broom:Gilead: Other: Travel support, Speakers Bureau. Kater:Abbvie: Research Funding; Roche: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Genentech: Research Funding. Ujjani:AstraZeneca: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Verastem Oncology: Consultancy, Honoraria; Gilead/Kite: Consultancy, Research Funding; Atara: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; MorphoSys: Consultancy. Vandenberghe:Celgene: Other: sponsorship to attend Lugano lymphoma meeting in 2019; Gilead: Other: travel grants, Research Funding; Abbvie: Other: travel grants, Research Funding; Janssen: Other: travel grants; Roche: Other: travel grants, Research Funding. Chong:Novartis: Membership on an entity's Board of Directors or advisory committees; Tessa: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; KITE Pharma: Membership on an entity's Board of Directors or advisory committees. Pu:Takeda Pharmaceuticals: Consultancy. Brown:Janssen, Teva: Speakers Bureau; Gilead, Loxo, Sun, Verastem: Research Funding; Abbvie, Acerta, AstraZeneca, Beigene, Invectys, Juno/Celgene, Kite, Morphosys, Novartis, Octapharma, Pharmacyclics, Sunesis, TG Therapeutics, Verastem: Consultancy. Trentin:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Octapharma: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Shire: Honoraria. Farina:Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Sanchez:Abbvie: Other: travel grants; Amgem: Other: travel grants; Janssen: Other: travel grants; Celgene: Other: travel grants; Roche: Other: travel grants. Shadman:Abbvie, Genentech, Astra Zeneca, Sound Biologics , Pharmacyclics, Verastem, ADC therapeutics, Beigene, Cellectar, BMS, Morphosys and Atara Biotherapeutics: Consultancy; Mustang Bio, Celgene, Pharmacyclics, Gilead, Genentech, Abbvie, TG therapeutics, Beigene, Astra Zeneca, Sunesis, Beigene: Research Funding. Foglietta:Janssen: Honoraria; Gilead: Honoraria. Jaksic:Roche: Honoraria; Janssen: Honoraria; Abbvie: Honoraria. Sportoletti:AbbVie: Honoraria; Janssen: Honoraria. Barr:Morphosys: Consultancy; Gilead: Consultancy; AstraZeneca: Consultancy, Research Funding; Verastem: Consultancy; Seattle Genetics: Consultancy; TG therapeutics: Consultancy, Research Funding; Abbvie/Pharmacyclics: Consultancy, Research Funding; Celgene: Consultancy; Merck: Consultancy; Genentech: Consultancy; Janssen: Consultancy. Ruchlemer:Abbvie Inc: Consultancy, Research Funding. Kersting:Celgene: Other: travel grant; Janssen: Research Funding; Abbvie: Research Funding. Huntington:Pharmacyclics: Honoraria; AbbVie: Consultancy; Novartis: Consultancy; Genentech: Consultancy; DTRM: Research Funding; Celgene: Consultancy, Research Funding; Bayer: Consultancy, Honoraria; Astrazeneca: Honoraria; TG Therapeutics: Research Funding. Herishanu:Roche: Honoraria; Sanofi: Honoraria; Medison: Honoraria; Janssen: Honoraria; Abbvie: Honoraria; AstraZeneca: Honoraria. Jacobs:TG Therapeutics, Inc.: Research Funding; Astra Zeneca: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Pharmacyclics: Research Funding, Speakers Bureau; Seattle Genetics: Consultancy; Verastem: Consultancy; Janssen: Consultancy, Speakers Bureau; Genentech: Speakers Bureau; Sanofi Genzyme: Speakers Bureau. Portell:BeiGene: Consultancy, Research Funding; Pharmacyclics: Consultancy; TG Therapeutics: Research Funding; Infinity: Research Funding; Roche/Genentech: Consultancy, Research Funding; Xencor: Research Funding; Bayer: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Kite: Consultancy, Research Funding; Acerta/AstraZeneca: Research Funding; AbbVie: Research Funding. Rambaldi:Sanofi: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Astellas: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); BMS/Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); University of Milan: Current Employment; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support of parent study and funding of editorial support. Received travel support., Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support from Gilead.; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Research grant from Amgen Inc.; Omeros: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Advisory board and speaker fees from Pfizer.. Brander:Verastem: Consultancy, Honoraria, Other, Research Funding; NCCN: Other; Novartis: Consultancy, Other; Teva: Consultancy, Honoraria; Tolero: Research Funding; NCCN: Other; Novartis: Consultancy, Other; Teva: Consultancy, Honoraria; Tolero: Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; ArQule: Consultancy, Other, Research Funding; Ascentage: Other, Research Funding; AstraZeneca: Consultancy, Honoraria, Other, Research Funding; BeiGene: Other, Research Funding; DTRM: Other, Research Funding; Genentech: Consultancy, Honoraria, Other, Research Funding; Juno/Celgene/BMS: Other, Research Funding; MEI Pharma: Other, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Other, Research Funding; Pfizer: Consultancy, Other; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding. Rossi:Abbvie: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Advisory board; Astellas: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Coscia:Karyopharm Therapeutics: Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Coombs:Abbvie: Consultancy, Honoraria; Genentech: Honoraria; AstraZeneca: Honoraria; MEI Pharma: Honoraria; LOXO Oncology: Honoraria; Octapharma: Honoraria; Novartis: Honoraria. Schuster:Novartis, Genentech, Inc./ F. Hoffmann-La Roche: Research Funding; AlloGene, AstraZeneca, BeiGene, Genentech, Inc./ F. Hoffmann-La Roche, Juno/Celgene, Loxo Oncology, Nordic Nanovector, Novartis, Tessa Therapeutics: Consultancy, Honoraria. Foà:Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cuneo:Astra Zeneca: Honoraria; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bosch:Jansen: Honoraria; Abbvie: Honoraria; Novartis: Honoraria; Astra Zeneca: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Roche: Honoraria. Stamatopoulos:AstraZeneca: Honoraria; Janssen, Gilead, Abbvie: Honoraria, Research Funding. Ghia:Adaptive, Dynamo: Consultancy, Honoraria; Novartis: Research Funding; BeiGene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Celgene/Juno: Consultancy, Honoraria; Lilly: Consultancy, Honoraria; MEI: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Gilead: Consultancy, Honoraria, Research Funding; ArQule: Consultancy, Honoraria; Acerta/AstraZeneca: Consultancy, Honoraria. Mato:Adaptive: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; BeiGene: Consultancy; LOXO: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding.

In the Garden of EdenThe covers of the first three volumes of Kuml show photographs of fine Danish antiquities. Inside the volumes have articles on the Stone Age, the Bronze Age and the Iron Age in Jutland, which is to be expected as Kuml is published by the Jutland Archaeological Society. However, in 1954 the scene is moved to more southern skies. This year, the cover is dominated by a date palm with two huge burial mounds in the background. In side the book one reads no less than six articles on the results from the First Danish Archaeological Bahrain Expedition. P.V. Glob begins with: Bahrain – Island of the Hundred Thousand Burial Mounds, The Flint Sites of the Bahrain Desert, Temples at Barbar and The Ancient Capital of Bahrain, followed by Bibby’s Five among Bahrain’s Hundred Thousand Burial Mounds and The Well of the Bulls. The following years, reports on excavations on Bahrain and later in the sheikhdoms of Qatar, Kuwait and Abu Dhabi are on Kuml’s repertoire.However, it all ends wit h the festschrift to mark Glob’s 60th anniversary, Kuml 1970, which has three articles on Arab archaeology and a single article in 1972. For the past thirty years almost, the journal has not had a single article on Arabia. Why is that? Primarily because the character of the museum’s work in the Arabian Gulf changed completely. The pioneers’ years of large-scale reconnaissance and excavations were succeeded by labourous studies of the excavated material – the necessary work preceding the final publications. Only in Abu Dhabi and Oman, Karen Frifelt carried on the pioneer spirit through the 1970s and 1980s, but she mainly published her results in in ternational, Englishlanguage journals.Consequently, the immediate field reports ended, but the subsequent research into Arab archaeology – carried out at the writing desk and with the collections of finds– still crept into Kuml. From 1973 , the journal contained a list of the publications made by the Jutland Archaeological Society (abbreviated JASP), and here, the Arab monographs begin to make their entry. The first ones are Holger Kapel’s Atlas of the Stone Age Cultures of Qatar from 1967 and Geoffrey Bibby’s survey in eastern Saudi Arabia from 1973. Then comes the Hellenistic excavations on the Failaka island in Kuwait with Hans Erik Mathiesen’s treatise on the terracotta figurines (1982), Lise Hannestad’s work on the ceramics (1983) and Kristian Jeppesen’s presentation of the temple and the fortifications (1989). A similar series on the Bronze Age excavations on Failaka has started with Poul Kjærum’s first volume on the stamp and cylinder seals (1983) and Flemming Højlund’s presentation of the ceramics (1987). The excavations on the island of Umm an-Nar in Abu Dhabi was published by Karen Frifelt in two volumes on the settlement (1991) and the graves (1995), and the ancient capital of Bahrain was analysed by H. Hellmuth Andersen and Flemming Højlund in two volumes on the northern city wall and the Islamic fort (1994) and the central, monumental buildings (1997) respectively.More is on its way! A volume on Islamic finds made on Bahrain has just been made ready for printing, and the Bronze Age temples at the village of Barbar is being worked up. Danish and foreign scholars are preparing other volumes, but the most important results of the expeditions to the Arabian Gulf have by now been published in voluminous series.With this, an era has ended, and Moesgård Museum’s 50th anniversary in 1999 was a welcome opportunity of looking back at the Arabian Gulf effort through the exhibition Glob and the Garden ef Eden. The Danish Bahrain expeditions and to consider what will happen in the future.How then is the relation ship between Moesgård Museum and Bahrain today, twenty-three years after the last expedition – now that most of the old excavations have been published and the two originators of the expeditions, P.V. Glob and Geoffrey Bibby have both died?In Denmark we usually consider Bahrain an exotic country with an exciting past. However, in Bahrain there is a similar fascination of Denmark and of Moesgård Museum. The Bahrain people are wondering why Danish scholars have been interested in their small island for so many years. It was probably not a coincidence when in the 1980s archaeologist and ethnographers from Moesgård Museum were invited to take part in the furnishing of the exhibitions in the new national museum of Bahrain. Today, museum staff from Arab countries consider a trip to Moesgård a near-pilgrimage: our collection of Near East artefacts from all the Gulf countries is unique, and the ethnographic collections are unusual in that they were collected with thorough information on the use, the users and the origin of each item.The Bahrain fascination of Moesgård Museum. was also evident, when the Bahrain minister of education, Abdulaziz Al-Fadl, visited the museum in connection with the opening of the Bahrain exhibition in 1999.Al-Fadl visited the museum’s oriental department, and in the photo and film archive a book with photos taken by Danish members of the expeditions to the Arabian Gulf was handed over to him. Al-Fadl was absorbed by the photos of the Bahrain of his childhood – the 1950s and 1960s – an un spoilt society very different from the modern Bahrain. His enthusiasm was not lessened when he saw a photo of his father standing next to P.V. Glob and Sheikh Salman Al Khalifa taken at the opening of Glob’s first archaeological exhibition in Manama, the capital. At a banquet given by Elisabeth Gerner Nielsen, the Danish minister of culture, on the evening following the opening of the Glob exhibition at Moesgård, Al-Fadl revealed that as a child, he had been on a school trip to the Danish excavations where – on the edge of the excavation – he had his first lesson in Bahrain’s prehistory from a Danish archaeologist (fig. 1).Another example: When attending the opening of an art exhibition at Bahrain’s Art Centre in February 1999, I met an old Bahrain painter, Abdelkarim Al-Orrayed, who turned out to be a good friend of the Danish painter Karl Bovin, who took part in Glob’s expeditions. He told me, how in 1956, Bovin had exhibited his paintings in a school in Manama. He recalled Bovin sitting in his Arabian tunic in a corner of the room, playing a flute, which he had carved in Sheikh Ibrahim’s garden.In a letter, Al-Orrayed states: ”I remember very well the day in 1956, when I met Karl Bovin for the first time. He was drawin g some narrow roads in the residential area where I lived. I followed him closely with my friend Hussain As-Suni – we were twentythree and twenty-one years old respectively. When he had finished, I invited him to my house where I showed him my drawings. He looked at them closely and gave me good advice to follow if I wanted to become a skilful artist – such as focusing on lines, form, light, distance, and shadow. He encouraged me to practice outdoors and to use different models. It was a turning point in our young artists’ lives when Hussein and I decided to follow Bovin’s instructions. We went everywhere – to the teahouses, the markets, the streets, and the countryside – and practised there, but the sea was the most fascinating phenomenon to us. In my book, An Introduction to Modern Art in Bahrain, I wrote about Bovin’s exhibitions in the 1950s and his great influence on me as an artist. Bovin’s talent inspired us greatly in rediscovering the nature and landscape on Bahrain and gave us the feeling that we had much strength to invest in art. Bovin contributed to a new start to us young painters, who had chosen the nature as our main motif.”Abdelkarim Al-Orrayed was the first Bahrain painter to live of his art, and around 1960 he opened a studio from which he sold his paintings. Two of his landscape watercolours are now at Moesgård.These two stories may have revealed that Bahrain and Moesgard Museum have a common history, which both parts value and wish to continue. The mutual fascination is a good foundation to build on and the close bonds and personal acquaintance between by now more generations is a valuable counterbalance to those tendencies that estrange people, cultures, and countries from one another.Already, more joint projects have been initiated: Danish archaeology students are taking part in excavations on Bahrain and elsewhere in the Arabic Gulf; an ethnography student is planning a long stay in a village on Bahrain for the study of parents’ expectations to their children on Bahrain as compared with the conditions in Denmark; P.V. Glob’s book, Al-Bahrain, has been translated into Arabic; Moesgård’s photos and films from the Gulf are to become universally accessible via the Internet; an exhibition on the Danish expeditions is being prepared at the National Museum of Bahrain, and so forth.Two projects are to be described in more detail here: New excavations on Bahrain that are to investigate how fresh water was exploited in the past, and the publication of a book and three CDs, Music in Bahrain, which will make Bahrain’s traditional music accessible not just to the population of Bahrain, but to the whole world.New excavations on BahrainFor millennia, Bahrain was famous for its abundance of fresh water springs, which made a belt of oases across the northern half of the island possible. Natural fertility combined with the favourable situation in the middle of the Arab Gulf made Bahrain a cultural and commercial centre that traded with the cities of Mesopotamia and the IndusValley already in the third millennium BC.Fresh water also played an important part in Bahrain’s ancient religion, as seen from ar chaeological excavations and Mesopotamian cuneiform tablets: A magnificent temple of light limestone was built over a spring, and according to old texts, water was the gods’ gift to Bahrain (Dilmun).Although fresh water had an overwhelming importance to a parched desert island, no studies have been directed towards the original ”taming” of the water on Bahrain. Therefore, Moesgård Museum is now beginning to look into the earliest irrigation techniques on the island and their significance to Bahrain’s development.Near the Bahrain village of Barbar, P.V. Glob in 1954 discovered a rise in the landscape, which was excavated during the following years. It turned out that the mound covered three different temples, built on top of and around each other. The Barbar temple was built of whitish ashlars and must have been an impressive structure. It has also gained a special importance in Near East research, as this is the first and only time that the holy spring chamber, the abzu, where the god Enki lived, has been un earthed (fig. 2).On the western side of the Barbar temple a monumental flight of steps, flank ed on both sides by cult figures, was leading through a portal to an underground chamber with a fresh water spring. In the beautiful ashlar walls of this chamber were three openings, through which water flowed. Only the eastern out flow was investigated, as the outside of an underground stonebuilt aqueduct was found a few metres from the spring chamber.East of the temple another underground aqueduct was followed along a 16-m distance. It was excavated at two points and turned out almost to have the height of a man. The floor was covered with large stones with a carved canal and the ceiling was built of equally large stones (fig. 3).No doubt the spring chamber was a central part of the temple, charge d with great importance. However, the function of the aqueducts is still unknown. It seems obvious that they were to lead the fresh water away from the source chamber, but was this part of a completely ritual arrangement, or was the purpose to transport the water to the gardens to be used for irrigation?To clarify these questions we will try to trace the continuations of the aqueducts using different tracing techniques such as georadar and magnetometer. As the sur roundings of Barbar temple are covered by several metres of shifting sand, the possibilities of following the aqueducts are fine, if necessary even across a great distance, and if they turn out to lead to old gardens, then these may be exposed under the sand.Underground water canals of a similar construction, drawing water from springs or subsoil water, have been used until modern times on Bahrain, and they are still in use in Iran and on the Arabian Peninsula, especially in Oman, where they supply the gardens with water for irrigation. They are called qanats and are usually considered built by the Persians during periods when the Achaemenid or Sassanid kings controlled Arabia (c. 500 BC-c. 600 AD). However, new excavation results from the Oman peninsula indicate that at least some canal systems date from c. 1000 BC. It is therefore of utmost interest if similar sophisticated transportation systems for water on Bahrain may be proven to date from the time of the erection of the Barbar temple, i.e. c. 2000 BC.The finds suggest that around this time Bahrain underwent dramatic changes. From being a thinly inhabited island during most of the 3rd millennium BC, the northern part of the island suddenly had extensive burial grounds, showing a rapid increase in population. At the same time the major settlement on the northern coast was fortified, temples like the one at Barbar were built, and gigantic ”royal mounds” were built in the middle of the island – all pointing at a hierarchic society coming into existence.This fast social development of Dilmun must have parallelled efficiency in the exploitation of fresh water resources for farm ing to supply a growing population with the basic food, and perhaps this explains the aqueducts by Barbar?The planned excavatio ns will be carried out in close cooperation between the National Museum of Bahrain and Aarhus University, and they are supported financially by the Carlsberg Foundation and Bahrain’s Cabinet and Information Ministry.The music of BahrainThe composer Poul Rovsing Olsen (1922-1982) was inspired by Arab and Indian music, and he spent a large part of his life studying traditional music in the countries along the Arabian Gulf. In 1958 and 1962-63 he took part in P.V. Glob’s expeditions to Arabia as a music ethnologist and in the 1970s he organised stays of long duration here (fig. 4).The background for his musical fieldwork was the rapid development, which the oil finds in the Gulf countries had started. The local folk music would clearly disappear with the trades and traditions with which they were connected.” If no one goes pearl fishing anymore, then no one will need the work songs connected to this work. And if no one marries according to tradition with festivity lasting three or sometimes five days, then no one will need the old wedding songs anymore’’.It was thus in the last moment that Rovsing Olsen recorded the pearl fishers’ concerts, the seamen’s shanties, the bedouin war songs, the wedding music, the festival music etc. on his tape recorder. By doing this he saved a unique collection of song and music, which is now stored in the Dansk Folkemindesamling in Copenhagen. It comprises around 150 tapes and more than 700 pieces of music. The instruments are to be found at the Musikhistorisk Museum and Moesgård Museum (fig. 5).During the 1960s and 1970s Rovsing Olsen published a number of smaller studies on music from the Arabian Gulf, which established his name as the greatest connoisseur of music from this area – a reputation, which the twenty years that have passed since his death have not shaken. Rovsing Olsen also published an LP record with pearl fisher music, and with the music ethnologist Jean Jenkins from the Horniman Museum in London he published six LP records, Music in the World of Islam with seven numbers from the Arabian Gulf, and the book Music and Musical Instruments in the World of Islam (London 1976).Shortly before his death, Rovsing Olsen finished a comprehensive manuscript in English, Music in Bahrain, where he summed up nearly twenty-five years of studies into folk music along the Arabian Gulf, with the main emphasis on Bahrain. The manuscript has eleven chapters, and after a short introduction Rovsing Olsen deals with musical instruments, lute music, war and honour songs of the bedouins, festivity dance, working songs and concerts of the pearl fishers, music influenced front Africa, double clarinet and bag pipe music, religious songs and women’s songs. Of these, eighty-four selected pieces of music are reproduced with notes and commented in the text. A large selection of this music will be published on three CDs to go with the book.This work has been anticipated with great expectation by music ethnologists and connoisseurs of Arabic folk music, and in agreement with Rovsing Olsen’s widow, Louise Lerche-Lerchenborg and Dansk Folkemindesamling, Moesgård Museum is presently working on publishing the work.The publication is managed by the Jutland Archaeological Society and Aarhus University Press will manage the distribution. The Carlsberg Foundation and Bahrain’s Cabinet and Information Ministry will cover the editing and printing expenses.The publication of the book and the CDs on the music of Bahrain will be celebrated at a festivity on Bahrain, at the next annual cultural festival, the theme of which will be ”mutual inspiration across cultural borders” with a focus on Rovsing Olsen. In this context, Den Danske Trio Anette Slaato will perform A Dream in Violet, a music piece influenced by Arabic music. On the same occasion singers and musicians will present the traditional pearl fishers’ music from Bahrain. In connection with the concert on Bahrain, a major tour has been planned in cooperation with The Danish Institute in Damascus, where the Danish musicians will also perform in Damascus and Beirut and give ”masterclasses” in chamber music on the local music academies. The concert tour is being organised by Louise Lerche-Lerchenborg, who initiated one of the most important Danish musical events, the Lerchenborg Musical Days,in 1963 and organised them for thirty years.ConclusionPride of concerted effort is not a special Danish national sport. However,the achievements in the Arabian Gulf made by the Danish expeditions from the Århus museum are recognised everywhere. It is only fair to use this jubilee volume for drawing attention to the fact that the journal Kuml and the publications of the Jutland Archaeological Society were the instruments through which the epoch-making investigations in the Gulf were nude public nationally and internationally.Finally, the cooperationon interesting tasks between Moesgård Museum and the countries along the Arabian Gulf will continue. In the future, Kuml will again be reporting on new excavations in the palm shadows and eventually, larger investigation s will no doubt find their way to the society’s comprehensive volumes.Flemming HøjlundMoesgård MuseumTranslated by Annette Lerche Trolle

The attorney-client privilege is one of the oldest and most basic tenets of American common law. Over the years, however, this privilege has eroded away as it applies to corporations. Beginning in 1999 with the promulgation of a memorandum issued by then-Deputy Attorney General Eric H. Holder (the Holder Memo), the Department of Justice has consistently pursued a policy of “compelled waiver” with regard to corporations. This Department policy has been repeatedly reaffirmed over the years in subsequent memoranda from Deputy Attorney General Larry D. Thompson (the Thompson Memo), Acting Deputy Attorney General Robert D. McCallum, Jr. (the McCallum Memo),6 and Deputy Attorney General Paul J. McNulty (the McNulty Memo).

AbstractAs part of the Department of Justice’s comprehensive review of the Asset Forfeiture Program, then Attorney General Eric Holder issued a memo on January 16th, 2015 restricting the adoption of state-level asset forfeitures by federal agencies. This paper seeks to predict what impact, if any, this change in policy will have on the use and abuse of civil asset forfeiture by examining the history of and literature surrounding civil asset forfeiture. Given this policy’s narrow scope and lax definitions that exempt most cases where it would be applicable, it is unlikely that this policy will have a substantial impact. Alternative methods of limiting the abuse of both federal adoption and civil asset forfeiture as a whole are proposed.

Propõe-se a compreender o pensamento dardeliano sobre a paisagem e seu desdobramento na fenomenologia paisagística, questionando se há alguma contribuição do pensamento filosófico da paisagem de Eric Dardel. Logo, esse artigo retoma a base da filosofia da paisagem de Dardel, sob os marcos teorico da pesquisa Holzer e Marandola Jr., para analisarem a influência de filósofos como Martin Heidegger e Maurice Merleau-Ponty, enquanto atores da fenomenologia e os desdobramentos do pensamento dardeliano, a fim de discutir o papel da fenomenologia em sua construção teórica paisagística de outros autores e em outros propostas filosóficas. Utiliza-se pesquisa bibliográfica, método dedutivo e perspectiva qualitativa, com proposta explicativa e descritiva mediante uso de bibliografias, sob abordagem interdisciplinar baseada principalmente nas áreas filosóficas e geográficas. Reconhece-se a importância do seu pensamento sobre o tema da paisagem e a sua influência em outros estudiosos.

The influence of big data affects all aspects of life, including insurance. With car insurance, companies have the ability to go beyond the traditional driving history and current usage questions to customize policies for each holder, especially with the introduction of monitoring technology that is either installed directly into the car or accessed via cell phone. Most consumers who are interested in usage-based insurance coverage are willing to sacrifice any concerns with data security for the trade off of financial savings, but car insurance companies must be aware of the ethics of their actions and work to protect user data. Erie Insurance Company is specifically analyzed in this article as an example.

AbstractObjectiveTo evaluate nationwide implementation of a Guidebook designed to standardize safety practices across VA‐delivered and VA‐purchased care (i.e., Community Care) and identify lessons learned and strategies to improve them.Data Sources and Study SettingQualitative data collected from key informants at 18 geographically diverse VA facilities across 17 Veterans Integrated Services Networks (VISNs).Study DesignWe conducted semi‐structured interviews from 2019 to 2022 with VISN Patient Safety Officers (PSOs) and VA facility patient safety and quality managers (PSMs and QMs) and VA Facility Community Care (CC) staff to assess lessons learned by examining organizational contextual factors affecting Guidebook implementation based on the Consolidated Framework for Implementation Research (CFIR).Data Collection/Extraction MethodsInterviews were conducted virtually with 45 facility staff and 10 VISN PSOs. Using directed content analysis, we identified CFIR factors affecting implementation. These factors were mapped to the Expert Recommendations for Implementing Change (ERIC) strategy compilation to identify lessons learned that could be useful to our operational partners in improving implementation processes. We met frequently with our partners to discuss findings and plan next steps.Principal FindingsSix CFIR constructs were identified as both facilitators and barriers to Guidebook implementation: (1) planning for implementation; (2) engaging key knowledge holders; (3) available resources; (4) networks and communications; (5) culture; and (6) external policies. The two CFIR constructs that were only barriers included: (1) cosmopolitanism and (2) executing implementation.ConclusionsOur findings suggest several important lessons: (1) engage all collaborators involved in implementation; (2) ensure end‐users have opportunities to provide feedback; (3) describe collaborators' purpose and roles/responsibilities clearly at the start; (4) communicate information widely and repeatedly; and (5) identify how multiple high priorities can be synergistic. This evaluation will help our partners and key VA leadership to determine next steps and future strategies for improving Guidebook implementation through collaboration with VA staff.

The traditional pagan view of human tragedy which existed several centuries back in the ancient Greek religious myths was transposed not only to Western Europe but also to the African context in the literary representation of reality in tragedy. Common religious metaphysics across cultures occasionally occasion common conception of human tragedy across generations of human history, but such cosmological cross-cultural convergence does not take for granted their dynamic perspectives on the role of fate in human tragedy. To be sure, the audiences of each time, view and appreciate tragedy within their unique geo-political and cultural milieu. In this sense, Erich Auerbach’s new historicist reading and post-modern montage of texts and commentaries validly confirms humanity’s representation of reality from their religious and traditional customary dispensations across space and time. Coming into the world in the West African Nigerian Yoruba metaphysical universe, the tragic personage holds his fate in his own hands. The gods and supernatural beings in the invisible realms claim foreknowledge of the fate which the tragic hero brings into the world, yet do not influence the fate-holder in the winding trail of life to the fulfillment of tragic fate. The gods in the mythico-religious worldview of the Yoruba natives permit the fulfilment of prehistoric fate based on the fate-holder’s individuality, as dictated by his carnal nature. This paper therefore posits that tragedy occurs as a product of the constant working of fate in the tragic hero which fulfills itself in a tragic conflict through the hero’s free-will, according to the prophecy of the gods in Ola Rotimi’s The gods are not to blame. This is more so in the Aristotelian concept of catharsis in tragedy due to the interplay between prehistoric fate and historic fate, the latter being the product of the former. <p> </p><p><strong> Article visualizations:</strong></p><p><img src="/-counters-/edu_01/0876/a.php" alt="Hit counter" /></p>

Abhandlungen und Aufsätze Robert Gramsch-Stehfest, Von der Metapher zur Methode. Netzwerkanalyse als Instrument zur Erforschung vormoderner Gesellschaften . . . . . . . . . . . . . . . . . . . . . . 1 Sarah-Maria Schober, Zibet und Zeit. Timescapes eines frühneuzeitlichen Geruchs 41 Buchbesprechungen Crailsheim, Eberhard /Maria D. Elizalde (Hrsg.), The Representation of External Threats. From the Middle Ages to the Modern World (Wolfgang Reinhard) . . . . 79 Höfele, Andreas / Beate Kellner (Hrsg.), Natur in politischenOrdnungsentwürfen der Vormoderne. Unter Mitwirkung von Christian Kaiser (Stefano Saracino) 80 Jütte, Robert / Romedio Schmitz-Esser (Hrsg.), Handgebrauch. Geschichten von der Hand aus dem Mittelalter und der Frühen Neuzeit (Barbara Stollberg- Rilinger) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 Tomaini, Thea (Hrsg.), Dealing with the Dead. 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Eine Studie zur Verteilung, Mobilisierung und Wirkungsmächtigkeit militärisch relevanter Ressourcen im Siebenjährigen Krieg am Beispiel des Jahres 1757 (Tilman Stieve) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174 Frey,Linda /Marsha Frey,TheCulture of French Revolutionary Diplomacy.In the Face of Europe (Christine Vogel) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176 Wagner, Johann Conrad, „Meine Erfahrungen in dem gegenwärtigen Kriege“. Tagebuch des Feldzugs mit Herzog Carl August von Weimar (Michael Kaiser) 178 Zamoyski, Adam, Napoleon. Ein Leben (Hans-Ulrich Thamer) . . . . . . . . . . . . . . . . . . . 180

1. Make a list of things to do2. Copy list of things left undone from previous list3. Add items to list of new things needing to be done4. Add some of the things already done from previous list and immediately cross off so as to put off the feeling of an interminable list of never accomplishable tasks5. Finish writing list and sit back feeling an overwhelming sense of listlessnessIt started so well. Get up: make list: get on. But lists can breed listlessness. It can’t always be helped. The word “list” referring to a sequence of items comes from the Italian and French words for “strip”—as in a strip of material. The word “list” that you find in the compound “listlessness” comes from the old English word for pleasing (to list is to please and to desire). To be listless is to be without desire, without the desire to please. The etymologies of list and listless don’t correspond but they might seem to conspire in other ways. Oh, and by the way, ships can list when their balance is off.I list, like a ship, itemising my obligations to job, to work, to colleagues, to parenting, to family: write a reference for such and such; buy birthday present for eighty-year-old dad; finish article about lists – and so on. I forget to add to the list my necessary requirements for achieving any of this: keep breathing; eat and drink regularly; visit toilet when required. Lists make visible. Lists hide. I forget to add to my list all my worries that underscore my sense that these lists (or any list) might require an optimism that is always something of a leap of faith: I hope that electricity continues to exist; I hope my computer will still work; I hope that my sore toe isn’t the first sign of bodily paralysis; I hope that this heart will still keep beating.I was brought up on lists: the hit parade (the top one hundred “hit” singles); football leagues (not that I ever really got the hang of them); lists of kings and queens; lists of dates; lists of states; lists of elements (the periodic table). There are lists and there are lists. Some lists are really rankings. These are clearly the important lists. Where do you stand on the list? How near the bottom are you? Where is your university in the list of top universities? Have you gone down or up? To list, then, for some at least is to rank, to prioritise, to value. Is it this that produces listlessness? The sense that while you might want to rank your ten favourite films in a list, listing is something that is constantly happening to you, happening around you; you are always in amongst lists, never on top of them. To hang around the middle of lists might be all that you can hope for: no possibility of sudden lurching from the top spot; no urgent worries that you might be heading for demotion too quickly.But ranking is only one aspect of listing. Sometimes listing has a more flattening effect. I once worked as a cash-in-hand auditor (in this case a posh name for someone who counts things). A group of us (many of whom were seriously stoned) were bussed to factories and warehouses where we had to count the stock. We had to make lists of items and simply count what there was: for large items this was relatively easy, but for the myriad of miniscule parts this seemed a task for Sisyphus. In a power-tool factory in some unprepossessing town on the outskirts of London (was it Slough or Croydon or somewhere else?) we had to count bolts, nuts, washers, flex, rivets, and so on. Of course after a while we just made it up—guesstimates—as they say. A box of thousands of 6mm metal washers is a homogenous set in a list of heterogeneous parts that itself starts looking homogenous as it takes its part in the list. Listing dedifferentiates in the act of differentiating.The task of making lists, of filling-in lists, of having a list of tasks to complete encourages listlessness because to list lists towards exhaustiveness and exhaustion. Archives are lists and lists are often archives and archived. Those that work on lists and on archives constantly battle the fatigue of too many lists, of too much exhaustiveness. But could exhaustion be embraced as a necessary mood with which to deal with lists and archives? Might listlessness be something of a methodological orientation that has its own productivity in the face of so many lists?At my university there resides an archive that can appear to be a list of lists. It is the Mass-Observation archive, begun at the end of 1936 and, with a sizeable hiatus in the 1960s and 1970s, is still going today. (For a full account of Mass-Observation, see Highmore, Everyday Life chapter 6, and Hubble; for examples of Mass-Observation material, see Calder and Sheridan, and Highmore, Ordinary chapter 4; for analysis of Mass-Observation from the point of view of the observer, see Sheridan, Street, and Bloome. The flavour of the project as it emerges in the late 1930s is best conveyed by consulting Mass-Observation, Mass-Observation, First Year’s Work, and Britain.) It was begun by three men: the filmmaker Humphrey Jennings, the poet and sociologist Charles Madge, and the ornithologist and anthropologist-of-the-near Tom Harrisson. Both Jennings and Madge were heavily involved in promoting a form of social surrealism that might see buried forces in the coincidences of daily life as well as in the machinations and contingency of large political and social events (the abdication crisis, the burning of the Crystal Palace—both in late 1936). Harrisson brought a form of amateur anthropology with him that would scour football crowds, pub clientele, and cinema queues for ritualistic and symbolic forms. Mass-Observation quickly recruited a large group of voluntary observers (about a thousand) who would be “the meteorological stations from whose reports a weather-map of popular feeling can be compiled” (Mass-Observation, Mass-Observation 30). Mass-Observation combined the social survey with a relentless interest in the irrational and in what the world felt like to those who lived in it. As a consequence the file reports often seem banal and bizarre in equal measure (accounts of nightmares, housework routines, betting activities). When Mass-Observation restarted in the 1980s the surrealistic impetus became less pronounced, but it was still there, implicit in the methodology. Today, both as an on-going project and as an archive of previous observational reports, Mass-Observation lives in archival boxes. You can find a list of what topics are addressed in each box; you can also find lists of the contributors, the voluntary Mass-Observers whose observations are recorded in the boxes. What better way to give you a flavour of these boxes than to offer you a sample of their listing activities. Here are observers, observing in 1983 the objects that reside on their mantelpieces. Here’s one:champagne cork, rubber band, drawing pin, two hearing aid batteries, appointment card for chiropodist, piece of dog biscuit.Does this conjure up a world? Do we have a set of clues, of material evidence, a small cosmology of relics, a reduced Wunderkammer, out of which we can construct not the exotic but something else, something more ordinary? Do you smell camphor and imagine antimacassars? Do you hear conversations with lots of mishearing? Are the hearing aid batteries shared? Is this a single person living with a dog, or do we imagine an assembly of chiropodist-goers, dog-owners, hearing aid-users, rubber band-pingers, champagne-drinkers?But don’t get caught imagining a life out of these fragments. Don’t get stuck on this list: there are hundreds to get through. After all, what sort of an archive would it be if it included a single list? We need more lists.Here’s another mantelpiece: three penknives, a tube of cement [which I assume is the sort of rubber cement that you get in bicycle puncture repair kits], a pocket microscope, a clinical thermometer.Who is this? A hypochondriacal explorer? Or a grown-up boy-scout, botanising on the asphalt? Why so many penknives? But on, on... And another:1 letter awaiting postage stamp1 diet book1 pair of spare spectacles1 recipe for daughter’s home economics1 notepad1 pen1 bottle of indigestion tablets1 envelope containing 13 pence which is owed a friend1 pair of stick-on heels for home shoe repairing session3 letters in day’s post1 envelope containing money for week’s milk bill1 recipe cut from magazine2 out of date letters from schoolWhat is the connection between the daughter’s home economics recipe and the indigestion tablets? Is the homework gastronomy not quite going to plan? Or is the diet book causing side-effects? And what sort of financial stickler remembers that they owe 13p; even in 1983 this was hardly much money? Or is it the friend who is the stickler? Perhaps this is just prying...?But you need more. Here’s yet another:an ashtray, a pipe, pipe tamper and tobacco pouch, one decorated stone and one plain stone, a painted clay model of an alien, an enamelled metal egg from Hong Kong, a copper bracelet, a polished shell, a snowstorm of Father Christmas in his sleigh...Ah, a pipe smoker, this much is clear. But apart from this the display sounds ritualistic – one stone decorated the other not. What sort of religion is this? What sort of magic? An alien and Santa. An egg, a shell, a bracelet. A riddle.And another:Two 12 gauge shotgun cartridges live 0 spread Rubber plantBrass carriage clockInternational press clock1950s cigarette dispenser Model of Panzer MKIV tankWWI shell fuseWWI shell case ash tray containing an acorn, twelve .22 rounds of ammunition, a .455 Eley round and a drawing pinPhoto of Eric Liddell (Chariots of Fire)Souvenir of Algerian ash tray containing marbles and beach stonesThree 1930s plastic duck clothes brushesLetter holder containing postcards and invitations. Holder in shape of a cow1970s Whizzwheels toy carWooden box of jeweller’s rottenstone (Victorian)Incense holderWorld war one German fuse (used)Jim Beam bottle with candle thereinSol beer bottle with candle therein I’m getting worried now. Who are these people who write for Mass-Observation? Why so much military paraphernalia? Why such detail as to the calibrations? Should I concern myself that small militias are holding out behind the net curtains and aspidistra plants of suburban England?And another:1930s AA BadgeAvocado PlantWooden cat from MexicoKahlua bottle with candle there in1950s matchbook with “merry widow” cocktail printed thereonTwo Britain’s model cannonOne brass “Carronade” from the Carron Iron Works factory shopPhotography pass from Parkhead 12/11/88Grouse foot kilt pinBrass incense holderPheasant featherNovitake cupBlack ash tray with beach pebbles there inFull packet of Mary Long cigarettes from HollandPewter cocktail shaker made in ShanghaiI’m feeling distance. Who says “there in” and “there on?” What is a Novitake cup? Perhaps I wrote it down incorrectly? An avocado plant stirs memories of trying to grow one from an avocado stone skewered in a cup with one “point” dunked in a bit of water. Did it ever grow, or just rot? I’m getting distracted now, drifting off, feeling sleepy...Some more then – let’s feed the listlessness of the list:Wood sculpture (Tenerife)A Rubber bandBirdJunior aspirinToy dinosaur Small photo of daughterSmall paint brushAh yes the banal bizarreness of ordinary life: dinosaurs and aspirins, paint brushes and rubber bands.But then a list comes along and pierces you:Six inch piece of grey eyeliner1 pair of nail clippers1 large box of matches1 Rubber band2 large hair gripsHalf a piece of cough candy1 screwed up tissue1 small bottle with tranquillizers in1 dead (but still in good condition) butterfly (which I intended to draw but placed it now to rest in the garden) it was already dead when I found it.The dead butterfly, the tranquillizers, the insistence that the mantelpiece user didn’t actually kill the butterfly, the half piece of cough candy, the screwed up tissue. In amongst the rubber bands and matches, signs of something desperate. Or maybe not: a holding on (the truly desperate haven’t found their way to the giant tranquillizer cupboard), a keeping a lid on it, a desire (to draw, to place a dead butterfly at rest in the garden)...And here is the methodology emerging: the lists works on the reader, listing them, and making them listless. After a while the lists (and there are hundreds of these lists of mantle-shelf items) begin to merge. One giant mantle shelf filled with small stacks of foreign coins, rubber bands and dead insects. They invite you to be both magical ethnographer and deadpan sociologist at one and the same time (for example, see Hurdley). The “Martian” ethnographer imagines the mantelpiece as a shrine where this culture worships the lone rubber band and itinerant button. Clearly a place of reliquary—on this planet the residents set up altars where they place their sacred objects: clocks and clippers; ammunition and amulets; coins and pills; candles and cosmetics. Or else something more sober, more sombre: late twentieth century petite-bourgeois taste required the mantelpiece to hold the signs of aspirant propriety in the form of emblems of tradition (forget the coins and the dead insects and weaponry: focus on the carriage clocks). And yet, either way, it is the final shelf that gets me every time. But it only got me, I think, because the archive had worked its magic: ransacked my will, my need to please, my desire. It had, for a while at least, made me listless, and listless enough to be touched by something that was really a minor catalogue of remainders. This sense of listlessness is the way that the archive productively defeats the “desire for the archive.” It is hard to visit an archive without an expectation, without an “image repertoire,” already in mind. This could be thought of as the apperception-schema of archival searching: the desire to see patterns already imagined; the desire to find the evidence for the thought whose shape has already formed. Such apperception is hard to avoid (probably impossible), but the boredom of the archive, its ceaselessness, has a way of undoing it, of emptying it. It corresponds to two aesthetic positions and propositions. One is well-known: it is Barthes’s distinction between “studium” and “punctum.” For Barthes, studium refers to a sort of social interest that is always, to some degree, satisfied by a document (his concern, of course, is with photographs). The punctum, on the other hand, spills out from the photograph as a sort of metonymical excess, quite distinct from social interest (but for all that, not asocial). While Barthes is clearly offering a phenomenology of viewing photographs, he isn’t overly interested (here at any rate) with the sort of perceptional-state the viewer might need to be in to be pierced by the puntum of an image. My sense, though, is that boredom, listlessness, tiredness, a sort of aching indifference, a mood of inattentiveness, a sense of satiated interest (but not the sort of disinterest of Kantian aesthetics), could all be beneficial to a punctum-like experience. The second aesthetic position is not so well-known. The Austrian dye-technician, lawyer and art-educationalist Anton Ehrenzweig wrote, during the 1950s and 1960s, about a form of inattentive-attention, and a form of afocal-rendering (eye-repelling rather than eye-catching), that encouraged eye-wandering, scanning, and the “‘full’ emptiness of attention” (Ehrenzweig, The Hidden Order 39). His was an aesthetics attuned to the kind of art produced by Paul Klee, but it was also an aesthetic propensity useful for making wallpaper and for productively connecting to unconscious processes. Like Barthes, Ehrenzweig doesn’t pursue the sort of affective state of being that might enhance such inattentive-attention, but it is not hard to imagine that the sort of library-tiredness of the archive would be a fitting preparation for “full emptiness.” Ehrenzweig and Barthes can be useful for exploring this archival mood, this orientation and attunement, which is also a disorientation and mis-attunement. Trawling through lists encourages scanning: your sensibilities are prepared; your attention is being trained. After a while, though, the lists blur, concentration starts to loosen its grip. The lists are not innocent recipients here. Shrapnel shards pull at you. You start to notice the patterns but also the spaces in-between that don’t seem to fit sociological categorisations. The strangeness of the patterns hypnotises you and while the effect can generate a sense of sociological-anthropological homogeneity-with-difference, sometimes the singularity of an item leaps out catching you unawares. An archive is an orchestration of order and disorder: however contained and constrained it appears it is always spilling out beyond its organisational structures (amongst the many accounts of archives in terms of their orderings, see Sekula, and Stoler, Race and Along). Like “Probate Inventories,” the mantelpiece archive presents material objects that connect us (however indirectly) to embodied practices and living spaces (Evans). The Mass-Observation archive, especially in its mantelpiece collection, is an accretion of temporalities and spaces. More crucially, it is an accumulation of temporalities materialised in a mass of spaces. A thousand mantelpieces in a thousand rooms scattered across the United Kingdom. Each shelf is syncopated to the rhythms of diverse durations, while being synchronised to the perpetual now of the shelf: a carriage clock, for instance, inherited from a deceased parent, its brass detailing relating to a different age, its mechanism perpetually telling you that the time of this space is now. The archive carries you away to a thousand living rooms filled with the momentary (dead insects) and the eternal (pebbles) and everything in-between. Its centrifugal force propels you out to a vast accrual of things: ashtrays, rubber bands, military paraphernalia, toy dinosaurs; a thousand living museums of the incidental and the memorial. This vertiginous archive threatens to undo you; each shelf a montage of times held materially together in space. It is too much. It pushes me towards the mantelshelves I know, the ones I’ve had a hand in. Each one an archive in itself: my grandfather’s green glass paperweight holding a fragile silver foil flower in its eternal grasp; the potions and lotions that feed my hypochondria; used train tickets. Each item pushes outwards to other times, other spaces, other people, other things. It is hard to focus, hard to cling onto anything. Was it the dead butterfly, or the tranquillizers, or both, that finally nailed me? Or was it the half a cough-candy? I know what she means by leaving the remnants of this sweet. You remember the taste, you think you loved them as a child, they have such a distinctive candy twist and colour, but actually their taste is harsh, challenging, bitter. There is nothing as ephemeral and as “useless” as a sweet; and yet few things are similarly evocative of times past, of times lost. Yes, I think I’d leave half a cough-candy on a shelf, gathering dust.[All these lists of mantelpiece items are taken from the Mass-Observation archive at the University of Sussex. Mass-Observation is a registered charity. For more information about Mass-Observation go to http://www.massobs.org.uk/]ReferencesBarthes, Roland. Camera Lucida. Translated by Richard Howard. London: Fontana, 1984.Calder, Angus, and Dorothy Sheridan, eds. Speak for Yourself: A Mass-Observation Anthology 1937–1949. Oxford: Oxford UP, 1985.Ehrenzweig, Anton. The Psychoanalysis of Artistic Vision and Hearing: An Introduction to a Theory of Unconscious Perception. Third edition. London: Sheldon Press, 1965. [Originally published in 1953.]---. The Hidden Order of Art. London: Paladin, 1970.Evans, Adrian. “Enlivening the Archive: Glimpsing Embodied Consumption Practices in Probate Inventories of Household Possessions.” Historical Geography 36 (2008): 40-72.Highmore, Ben. Everyday Life and Cultural Theory. London: Routledge, 2002.---. Ordinary Lives: Studies in the Everyday. Abingdon: Routledge, 2011.Hubble, Nick. Mass-Observation and Everyday Life: Culture, History, Theory, Houndmills and New York: Palgrave, 2006.Hurdley, Rachel. “Dismantling Mantelpieces: Narrating Identities and Materializing Culture in the Home.” Sociology 40, 4 (2006): 717-733Mass-Observation. Mass-Observation. London: Fredrick Muller, 1937.---. First Year’s Work 1937-38. London: Lindsay Drummond, 1938.---. Britain. Harmondsworth: Penguin, 1939.Sekula, Allan. “The Body and the Archive.” October 39 (1986): 3-64.Sheridan, Dorothy, Brian Street, and David Bloome. Writing Ourselves: Mass-Observation and Literary Practices. Cresskill, New Jersey: Hampton Press, 2000.Stoler, Ann Laura. Race and the Education of Desire: Foucault’s History of Sexuality and the Colonial Order of Things. Durham and London: Duke UP, 1995. Stoler, Ann Laura. Along the Archival Grain: Epistemic Anxieties and Colonial Common Sense. Princeton: Princeton UP, 2009.

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(Stephan Steiner, Wien) „Inquisitionis Hispanicae Artes“: The Arts of the Spanish Inquisition. Reginaldus Gonsalvius Montanus. A Critical Edition of the „Sanctae Inquisitionis Hispanicae Artes aliquot“ (1567) with a Modern English Translation, hrsg. v. Marcos J. Herráiz Pareja / Ignacio J. García Pinilla / Jonathan L. Nelson (Heterodoxia Iberica 2), Leiden / Boston 2018, Brill, VII u. 515 S., € 187,00. (Wolfram Drews, Münster) Lattmann, Christopher, Der Teufel, die Hexe und der Rechtsgelehrte. Crimen magiae und Hexenprozess in Jean Bodins „De la Démonomanie des Sorciers“ (Studien zur europäischen Rechtsgeschichte, 318), Frankfurt a. M. 2019, Klostermann, XVI u. 390 S., € 69,00. (Andreas Flurschütz da Cruz, Bamberg) Gorrochategui Santos, Luis, The English Armada. The Greatest Naval Disaster in English History, übers. v. Peter J. Gold, London / New York 2018, VIII u. 323 S. / Abb., £ 26,99. 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State Administration and Economy in Early Modern Europe (People, Markets, Goods, 10), Woodbridge / Rochester 2017, Boydell Press, XI u. 315 S., £ 25,00. (Justus Nipperdey, Saarbrücken) Fludd, Robert, Utriusque Cosmi Historia. Faksimile-Edition der Ausgabe Oppenheim/Frankfurt, Johann Theodor de Bry, 1617 - 1624, 4 Bde. in 5 Teilbde., hrsg. u. mit ausführlichen Einleitungen versehen v. Wilhelm Schmidt-Biggemann (Clavis pansophiae, 5), Stuttgart-Bad Cannstatt 2018, Frommann-Holzboog, XXX u. 2198 S., € 1980,00. (Martin Mulsow, Gotha / Erfurt) Rebitsch, Robert (Hrsg.), 1618. Der Beginn des Dreißigjährigen Krieges, Wien / Köln / Weimar 2017, Böhlau, 229 S., € 24,00. (Fabian Schulze, Neu-Ulm / Augsburg) Kilián, Jan, Der Gerber und der Krieg. Soziale Biographie eines böhmischen Bürgers aus der Zeit des Dreißigjährigen Krieges, Berlin 2018, Berliner Wissenschafts-Verlag, 247 S., € 49,00. (Robert Jütte, Stuttgart) Caldari, Valentina / Sara J. Wolfson (Hrsg.), Stuart Marriage Diplomacy. Dynastic Politics in Their European Context, 1604 - 1630 (Studies in Earl Modern Cultural, Political and Social History, 31), Woodbridge / Rochester 2018, The Boydell Press, XVIII u. 367 S., £ 75,00. (Martin Foerster, Hamburg) Blakemore, Richard J. / Elaine Murphy, The British Civil Wars at Sea, 1638 - 1653, Woodbridge 2018, The Boydell Press, X u. 225 S. / Abb., £ 65,00. (Jann M. Witt, Laboe) Deflers, Isabelle / Christian Kühner (Hrsg.), Ludwig XIV. - Vorbild und Feindbild. Inszenierung und Rezeption der Herrschaft eines barocken Monarchen zwischen Heroisierung, Nachahmung und Dämonisierung / Louis XIV - fascination et répulsion. Mise en scène et réception du règne d’un monarque baroque entre héroïsation, imitation et diabolisation (Studien des Frankreich-Zentrums der Albert-Ludwigs-Universität Freiburg, 25), Berlin 2018, Schmidt, 296 S. / Abb., € 69,95. (Anuschka Tischer, Würzburg) Pérez Sarrión, Guillermo, The Emergence of a National Market in Spain, 1650 - 1800. Trade Networks, Foreign Powers and the State, übers. v. Daniel Duffield, London [u. a.] 2017, Bloomsbury Academic, XXI u. 331 S., £ 26,09. (Hanna Sonkajärvi, Rio de Janeiro) Alimento, Antonella / Koen Stapelbroek (Hrsg.), The Politics of Commercial Treaties in the Eighteenth Century. Balance of Power, Balance of Trade, Cham 2017, Palgrave Macmillan, XI u. 472 S., € 103,99. (Justus Nipperdey, Saarbrücken) McDowell, Paula, The Invention of the Oral. Print Commerce and Fugitive Voices in Eighteenth-Century Britain, Chicago / London 2017, University of Chicago Press, XIII u. 353 S. / Abb., $ 45,00. (Markus Friedrich, Hamburg) Bernhard, Jan-Andrea / Judith Engeler (Hrsg.), „Dass das Blut der heiligen Wunden mich durchgehet alle Stunden“. Frauen und ihre Lektüre im Pietismus, Zürich 2019, Theologischer Verlag Zürich, 161 S. /Abb., € 21,90. (Helga Meise, Reims) Hammer-Luza, Elke, Im Arrest. Zucht-‍, Arbeits- und Strafhäuser in Graz (1700 - 1850) (Mitteilungen des Instituts für Österreichische Geschichtsforschung. Ergänzungsband, 63; Forschungen zur geschichtlichen Landeskunde der Steiermark, 83), Wien / Köln / Weimar 2019, Böhlau, 556 S. / Abb., € 85,00. (Simon Karstens, Trier) Oldach, Robert, Stadt und Festung Stralsund. Die schwedische Militärpräsenz in Schwedisch-Pommern 1721 - 1807 (Quellen und Studien aus den Landesarchiven Mecklenburg-Vorpommerns, 20), Köln / Weimar / Wien 2018, Böhlau, 518 S. / Abb., € 60,00. (Michael Busch, Rostock) Koller, Ekaterina E., Religiöse Grenzgänger im östlichen Europa. Glaubensenthusiasten um die Prophetin Ekaterina Tatarinova und den Pseudomessias Jakob Frank im Vergleich (1750 - 1850) (Lebenswelten osteuropäischer Juden, 17), Wien / Köln / Weimar 2019, Böhlau, 352 S., € 60,00. (Agnieszka Pufelska, Lüneburg) Häberlein, Mark / Holger Zaunstöck (Hrsg.), Halle als Zentrum der Mehrsprachigkeit im langen 18. Jahrhundert (Hallesche Forschungen, 47), Halle a. d. S. 2017, Verlag der Franckeschen Stiftungen, VI u. 265 S. / Abb., € 56,00. (Martin Gierl, Göttingen) Geffarth, Renko / Markus Meumann / Holger Zaunstöck (Hrsg.), Kampf um die Aufklärung? Institutionelle Konkurrenzen und intellektuelle Vielfalt im Halle des 18. Jahrhunderts, Halle a. d. S. 2018, Mitteldeutscher Verlag, 334 S., € 50,00. (Martin Gierl, Göttingen) Giro d’Italia. Die Reiseberichte des bayerischen Kurprinzen Karl Albrecht (1715/16). Eine historisch-kritische Edition, hrsg. v. Andrea Zedler / Jörg Zedler (Beihefte zum Archiv für Kulturgeschichte, 90), Wien / Köln / Weimar 2019, Böhlau, 694 S. / Abb., € 90,00. (Michael Maurer, Jena) Backerra, Charlotte, Wien und London, 1727 - 1735. Internationale Beziehungen im frühen 18. Jahrhundert (Veröffentlichungen des Instituts für europäische Geschichte Mainz, 253), Göttingen 2018, Vandenhoeck &amp; Ruprecht, 474 S., € 80,00. (Michael Schaich, London) Gottesdienst im Bamberger Dom zwischen Barock und Aufklärung. Die Handschrift des Ordinarius L des Subkustos Johann Graff von 1730 als Edition mit Kommentar, hrsg. v. Franz Kohlschein / Werner Zeißner unter Mitarbeit v. Walter Milutzki (Studien zur Bamberger Bistumsgeschichte, 9), Petersberg 2018, Imhoff, 687 S. / Abb., € 79,00. (Tillmann Lohse, Berlin / Leipzig) Warnke, Marcus, Logistik und friderizianische Kriegsführung. Eine Studie zur Verteilung, Mobilisierung und Wirkungsmächtigkeit militärisch relevanter Ressourcen im Siebenjährigen Krieg am Beispiel des Jahres 1757 (Quellen und Forschungen zur Brandenburgischen und Preußischen Geschichte, 50), Berlin 2018, Duncker &amp; Humblot, 696 S. / Abb., € 139,90. (Tilman Stieve, Aachen) Frey, Linda / Marsha Frey, The Culture of French Revolutionary Diplomacy. In the Face of Europe (Studies in Diplomacy and International Relations), Cham 2018, Palgrave Macmillan, XI u. 300 S., € 149,79. (Christine Vogel, Vechta) Wagner, Johann Conrad, „Meine Erfahrungen in dem gegenwärtigen Kriege“. Tagebuch des Feldzugs mit Herzog Carl August von Weimar, hrsg. v. Edith Zehm (Schriften der Goethe-Gesellschaft, 78), Göttingen 2018, Wallstein, 552 S. / Abb. / Faltkarte, € 59,00. (Michael Kaiser, Köln / Bonn) Zamoyski, Adam, Napoleon. Ein Leben. Aus dem Englischen übers. v. Ruth Keen / Erhard Stölting, München 2018, Beck, 863 S. / Abb., € 29,95. (Hans-Ulrich Thamer, Münster)

Leeuwen, Richard van, Narratives of Kingship in Eurasian Empires, 1300 – 1800 (Rulers and Elites, 11), Leiden / Boston 2017, Brill, VI u. 278 S. / Abb., € 109,00; als E-Book: Open Access. (Tobias Winnerling, Düsseldorf) Kruijtzer, Gijs / Thomas Ertl (Hrsg.), Law Addressing Diversity. Pre-Modern Europe and India in Comparison (13th–18th Centuries), Berlin / Boston 2017, de Gruyter Oldenbourg, VIII u. 220 S., € 59,95. (Anna Dönecke, Bielefeld) Blockmans, Wim / Mikhail Krom / Justyna Wubs-Mrozewicz (Hrsg.), The Routledge Handbook of Maritime Trade around Europe 1300 – 1600 (Routledge History Handbooks), London / New York 2017, Routledge, XIX u. 502 S. / Abb., £ 185,00. (Patrick Schmidt, Rostock) Pohl-Zucker, Susanne, Making Manslaughter. Process, Punishment and Restitution in Württemberg and Zurich, 1376 – 1700 (Medieval Law and Its Practice, 22), Leiden / Boston 2017, Brill, X u. 335 S., € 105,00; als Brill MyBook € 25,00. (Gerd Schwerhoff, Dresden) „… da ist Im gnedigklich geholffen worden“. Spätmittelalterliche und frühneuzeitliche Mirakelberichte aus Geisenfeld, hrsg. v. Marianne Heimbucher / Richard Kürzinger (Abensberger Beiträge zur bayerischen Kulturgeschichte, 3), Regensburg 2018, Pustet, 167 S. / Abb., € 19,95. (Doris Gruber, Wien) Schneidmüller, Bernd / Stefan Weinfurter / Michael Matheus / Alfried Wieczorek (Hrsg.), Die Päpste. Amt und Herrschaft in Antike, Mittelalter und Renaissance (Die Päpste, 1), Regensburg 2016, Schnell &amp; Steiner, 504 S. / Abb., € 39,95. (Klaus Herbers, Erlangen) Zimmermann, Norbert / Tanja Michalsky / Alfried Wieczorek / Stefan Weinfurter (Hrsg.), Die Päpste und Rom zwischen Spätantike und Mittelalter. Formen päpstlicher Machtentfaltung (Die Päpste, 3), Regensburg 2017, Schnell &amp; Steiner, 320 S. / Abb., € 29,95. (Klaus Herbers, Erlangen) Freund, Stephan / Klaus Krüger, Kaisertum, Papsttum und Volkssouveränität im hohen und späten Mittelalter. Studien zu Ehren von Helmut G. Walther (Jenaer Beiträge zur Geschichte, 12), Frankfurt a. M. [u. a.] 2017, Lang, 166 S. / Abb., € 39,95. (Manuel Kamenzin, Bochum) Kopp, Vanina, Der König und die Bücher. Sammlung, Nutzung und Funktion der königlichen Bibliothek am spätmittelalterlichen Hof in Frankreich (Beihefte der Francia, 80), Ostfildern 2016, Thorbecke, 396 S. / Abb., € 59,00. (Georg Jostkleigrewe, Münster) Jullien, Eva, Die Handwerker und Zünfte der Stadt Luxemburg im Spätmittelalter (Städteforschung. Reihe A: Darstellungen, 96), Köln / Weimar / Wien 2017, Böhlau, 320 S. / graph. Darst., € 40,00. (Markus Gneiß, Wien) Wallnöfer, Adelina, Die politische Repräsentation des gemeinen Mannes in Tirol. Die Gerichte und ihre Vertreter auf den Landtagen vor 1500 (Veröffentlichungen des Südtiroler Landesarchivs, 41), Innsbruck 2017, Universitätsverlag Wagner, 550 S. / Abb., € 49.00. (Christoph Haidacher, Innsbruck) Selart, Anti / Matthias Thumser (Hrsg.), Livland – eine Region am Ende der Welt? Forschungen zum Verhältnis zwischen Zentrum und Peripherie im späten Mittelalter / Livonia – a Region at the End of the World? Studies on the Relations between Centre and Periphery in the Later Middle Ages (Quellen und Studien zur baltischen Geschichte, 27), Köln / Weimar / Wien 2017, Böhlau, 519 S. / Abb., € 65,00. (Dennis Hormuth, Marburg) Förster, Ulrike, Selbstverständnis im Spannungsfeld zwischen Diesseits und Jenseits. Die Lübecker Ratsherrenwitwen Telse Yborg (gest. vor 1442), Wobbeke Dartzow (gest. 1441/42) und Mette Bonhorst (gest. 1445/46) (Kieler Werkstücke. Reihe E: Beiträge zur Sozial- und Wirtschaftsgeschichte, 13), Frankfurt a. M. [u. a.] 2017, Lang, 262 S., € 55,95. (Rolf Hammel-Kiesow, Lübeck) Elvert, Jürgen, Europa, das Meer und die Welt. Eine maritime Geschichte der Neuzeit, München 2018, Deutsche Verlags-Anstalt, 591 S. / Abb., € 45,00. (Wolfgang Reinhard, Freiburg i. Br.) Trakulhun, Sven, Asiatische Revolutionen. Europa und der Aufstieg und Fall asiatischer Imperien (1600 – 1830) (Globalgeschichte, 29), Frankfurt a. M. / New York 2017, Campus, 396 S. / Abb., € 45,00. (Nadine Amsler, Frankfurt a. M.) Meier, Johannes, Bis an die Ränder der Welt. Wege des Katholizismus im Zeitalter der Reformation und des Barock, Münster 2018, Aschendorff, 368 S. / Abb., € 29,80. (Wolfgang Reinhard, Freiburg i. Br.) Meier, Johannes, Die Stimme erheben. Studien zur Kirchengeschichte Lateinamerikas und der Karibik, hrsg. v. Annegret Langenhorst / Christoph Nebgen / Veit Straßner (Studies in the History of Christianity in the Non-Western World, 30), Wiesbaden 2018, Harrassowitz, 324 S., € 49,00. (Wolfgang Reinhard, Freiburg i. Br.) Hacke, Daniela / Paul Musselwhite (Hrsg.), Empire of the Senses. Sensory Practices of Colonialism in Early America (Early American History Series, 8), Leiden / Boston 2018, Brill, IX u. 334 S. / Abb., € 135,00; als Brill MyBook € 25,00. (Philip Hahn, Tübingen) Freist, Dagmar, Glaube – Liebe – Zwietracht. Religiös-konfessionell gemischte Ehen in der Frühen Neuzeit (Bibliothek Altes Reich, 14), Berlin / Boston 2017, de Gruyter Oldenbourg, XII u. 504 S., € 79,95. (Anke Hufschmidt, Hagen) Bues, Almut (Hrsg.), Frictions and Failures. Cultural Encounters in Crisis (Deutsches Historisches Institut Warschau. Quellen und Studien, 34), Wiesbaden 2017, Harrassowitz , VI u. 229 S., € 54,00. (Katrin Keller, Wien) Cremer, Annette C. / Anette Baumann / Eva Bender (Hrsg.), Prinzessinnen unterwegs. Reisen fürstlicher Frauen in der Frühen Neuzeit (Bibliothek Altes Reich, 22), Berlin / Boston 2018, de Gruyter, VII u. 301 S. / Abb., € 59,95. (Katrin Keller, Wien) Renzi, Silvia di / Marco Bresadola / Maria Conforti (Hrsg.), Pathology in Practice. Diseases in Dissections in Early Modern Europe (The History of Medicine in Context), London / New York 2018, Routledge, IX u. 236 S. / Abb., £ 115,00. (Robert Jütte, Stuttgart) Bičevskis, Raivis / Jost Eickmeyer / Andris Levans / Anu Schaper / Björn Spiekermann / Inga Walter (Hrsg.), Baltisch-deutsche Kulturbeziehungen vom 16. bis 19. Jahrhundert. Medien – Institutionen – Akteure, Bd. 1: Zwischen Reformation und Aufklärung (Akademiekonferenzen, 28), Heidelberg 2017, Universitätsverlag Winter, 508 S. / Abb., € 52,00. (Heiko Droste, Stockholm) Hacke, Daniela, Konfession und Kommunikation. Religiöse Koexistenz und Politik in der Alten Eidgenossenschaft – Die Grafschaft Baden 1531 – 1712, Köln / Weimar / Wien 2017, Böhlau, 579 S., € 70,00. (Thomas Kirchner, Aachen) Imbruglia, Girolamo, The Jesuit Missions of Paraguay and a Cultural History of Utopia (1568 – 1789) (Studies in Christian Mission, 51), Leiden / Boston 2017, Brill, VII u. 323 S. / Abb., € 133,00. (Wolfgang Reinhard, Freiburg i. Br.) Jerše, Sašo, Im Schutz und Schirm des Reiches. Spielräume der Reichspolitik der innerösterreichischen Landstände im 16. Jahrhundert (Veröffentlichungen der Kommission für Neuere Geschichte Österreichs, 110), Wien / Köln / Weimar 2016, Böhlau, 290 S., € 48,00. (William D. Godsey, Wien) Eine Währung für das Reich. Die Akten der Münztage zu Speyer 1549 und 1557, hrsg. v. Oliver Volckart (Deutsche Handelsakten des Mittelalters und der Neuzeit, 23), Stuttgart 2017, Steiner, CII u. 445 S., € 78,00. (Sebastian Steinbach, Heidelberg) Walter, Peter / Günther Wassilowsky (Hrsg.), Das Konzil von Trient und die katholische Konfessionskultur (1563 – 2013). Wissenschaftliches Symposium zum Anlass des 450. Jahrestages des Abschlusses des Konzils von Trient, Freiburg i. Br. 18.–21. September 2013 (Reformationsgeschichtliche Studien und Texte, 163), Münster 2016, Aschendorff, X u. 569 S. / Abb., € 69,00. (Markus Friedrich, Hamburg) Iwanov, Iwan A., Die Hanse im Zeichen der Krise. Handlungsspielräume der politischen Kommunikation im Wandel (1550 – 1620) (Quellen und Darstellungen zur hansischen Geschichte. Neue Folge, 61), Köln / Weimar / Wien 2016, Böhlau, 419 S. / Faltkarte, € 55,00. (Ole Meiners, Lübeck) Spierling, Karen E. / Erik A. de Boer / R. Ward Holder (Hrsg.), Emancipating Calvin. Culture and Confessional Identity in Francophone Reformed Communities. Essays in Honor of Raymond A. Mentzer, Jr. (Brill’s Series in Church History and Religious Culture, 76), Leiden / Boston 2018, Brill, XXX u. 306 S. / Abb., € 89,00. (Volker Reinhardt, Fribourg) Tammen, Annika, Frühmoderne Staatlichkeit und lokale Herrschaftsvermittlung. Normgebung und Herrschaftspraxis im Herzogtum Holstein des 17. und 18. Jahrhunderts (IZRG-Schriftenreihe, 18), Bielefeld 2017, Verlag für Regionalgeschichte, 408 S. / Abb., € 34,00. (Stefan Brakensiek, Essen) Goudriaan, Elisa, Florentine Patricians and Their Networks. Structures behind the Cultural Success and the Political Representation of the Medici Court (1600 – 1660) (Rulers and Elites, 14), Leiden / Boston 2017, Brill, XVIII u. 479 S. / Abb., € 179,00; € 25,00 als Brill MyBook. (Volker Reinhardt, Fribourg) Harrison, Thomas, The Ark of Studies, hrsg. v. Alberto Cevolini (De diversis artibus, 102), Turnhout 2017, Brepols, XIII u. 142 S. / Abb., € 60,00. (Markus Friedrich, Hamburg) Die „litterae annuae“ der Gesellschaft Jesu von Glückstadt (1645 bis 1772), der „Catalogus mortuorum“ (1645 – 1799) und der „Liber benefactorum“ (1676 – 1727) der Glückstädter katholischen Gemeinde, 2 Halbbde., hrsg. v. Christoph Flucke / Martin J. Schröter (Quellen und Forschungen zur Geschichte Schlesweg-Holsteins, 125), Münster 2017, Aschendorff, 922 S. / Abb., € 49,00. (Markus Friedrich, Hamburg) Bevilacqua, Alexander, The Republic of Arabic Letters. Islam and the European Enlightenment, Cambridge / London 2018, Belknap Press of Harvard University Press, XV u. 340 S. / Abb., $ 35,00. (Lars Behrisch, Utrecht) Rus, Dorin-Ioan, Wald- und Ressourcenpolitik im Siebenbürgen des 18. Jahrhunderts (Neue Forschungen zur ostmittel- und südeuropäischen Geschichte, 9), Frankfurt a. M. [u. a.] 2017, Lang, 460 S. / Abb., € 82,95. (Elisabeth Johann, Wien) Affolter, Andreas, Verhandeln mit Republiken. Die französisch-eidgenössischen Beziehungen im frühen 18. Jahrhundert (Externa, 11), Köln / Weimar / Wien 2017, Böhlau, 455 S., € 70,00. (Lothar Schilling, Augsburg) Lacher, Reimar F., „Friedrich, unser Held“. Gleim und sein König (Schriften des Gleimhauses Halberstadt, 9), Göttingen 2017, Wallstein, 167 S. / Abb., € 19,90. (Wolfgang Burgdorf, München) Schönfuß, Florian, Mars im hohen Haus. Zum Verhältnis von Familienpolitik und Militärkarriere beim rheinischen Adel 1770 – 1830 (Herrschaft und soziale Systeme in der Frühen Neuzeit, 22), Göttingen 2017, V&amp;R unipress, 478 S. / Abb., € 65,00. (Horst Carl, Gießen)