Citations

Abstract Remediation of struggling learners is a challenge faced by all educators. In recognition of this reality, and in light of contemporary challenges facing infectious diseases (ID) fellowship program directors, the Infectious Diseases Society of America Training Program Directors’ Committee focused the 2018 National Fellowship Program Directors’ Meeting at IDWeek on “Remediation of the Struggling Fellow.” Small group discussions addressed 7 core topics, including feedback and evaluations, performance management and remediation, knowledge deficits, fellow well-being, efficiency and time management, teaching skills, and career development. This manuscript synthesizes those discussions around a competency-based framework to provide program directors and other educators with a roadmap for addressing common contemporary remediation challenges.

AbstractBackgroundCurrent approaches in tracking Clostridioides difficile infection (CDI) and individualizing patient management are incompletely defined.MethodsWe recruited 468 subjects with CDI at Mayo Clinic Rochester between May and December 2016 and performed whole-genome sequencing (WGS) on C. difficile isolates from 397. WGS was also performed on isolates from a subset of the subjects at the time of a recurrence of infection. The sequence data were analyzed by determining core genome multilocus sequence type (cgMLST), with isolates grouped by allelic differences and the predicted ribotype.ResultsThere were no correlations between C. difficile isolates based either on cgMLST or ribotype groupings and CDI outcome. An epidemiologic assessment of hospitalized subjects harboring C. difficile isolates with ≤2 allelic differences, based on standard infection prevention and control assessment, revealed no evidence of person-to-person transmission. Interestingly, community-acquired CDI subjects in 40% of groups with ≤2 allelic differences resided within the same zip code. Among 18 subjects clinically classified as having recurrent CDI, WGS revealed 14 with initial and subsequent isolates differing by ≤2 allelic differences, suggesting a relapse of infection with the same initial strain, and 4 with isolates differing by >50 allelic differences, suggesting reinfection. Among the 5 subjects classified as having a reinfection based on the timing of recurrence, 3 had isolates with ≤2 allelic differences between them, suggesting a relapse, and 2 had isolates differing by >50 allelic differences, suggesting reinfection.ConclusionsOur findings point to potential transmission of C. difficile in the community. WGS better differentiates relapse from reinfection than do definitions based on the timing of recurrence.

Introduction: Anti-PD-1 monoclonal antibodies (mAbs) are highly active in relapsed/refractory classical Hodgkin lymphoma (cHL), but most patients (pts) will still relapse. Given this, allogeneic stem cell transplantation (alloHSCT) remains an important option for pts after PD-1 blockade, as it offers the possibility of cure. Prior reports have suggested that alloHSCT after PD-1 mAbs may be associated with severe immune-related complications including acute graft-versus-host disease (GVHD), veno-occlusive disease (VOD) and cytokine release/febrile non-infectious syndrome (CRS). Prior studies of alloHSCT after PD-1 blockade in cHL have been limited by the small number of pts and short follow-up, preventing an accurate assessment of long-term outcomes and complications, risk factors for early toxicity, and the impact of transplant strategies such as choice of GVHD prophylaxis. We therefore assembled a large retrospective international cohort of cHL pts who underwent alloHSCT after PD-(L)1 blockade to better answer these questions, including an assessment of the impact of post-transplant cyclophosphamide (PTCy) on efficacy and toxicity. Methods: Medical records and databases were reviewed at 26 European and United States transplant centers to identify pts with cHL who underwent an alloHSCT any time after receiving a PD-1 or PD-L1 mAb. Response assessment was performed by local investigators according to Lugano 2014 criteria. Overall survival (OS), progression-free survival (PFS), cumulative incidence (CumInc) of relapse (CIR), non-relapse mortality (NRM), acute (a) and chronic (c) GVHD were estimated, as was the association between baseline variables and these outcomes. Results: Between 2014 and 2019, 150 pts were identified who underwent alloHSCT after a median of 10 (range, 1-74) doses of nivolumab (n=118), pembrolizumab (n=31), or avelumab (n=1). The median age was 31 (range 17-68) and pts had received a median of 4 (range, 2-11) lines of therapy prior to PD-(L)1 blockade. 138 pts (92%) had failed BV and 111 (74%) autologous HSCT. The best overall response to PD-(L)1 mAbs was CR for 62 pts (41%), PR for 55 (37%), SD for 17 (11%), PD for 15 (10%) and unknown for 1 (1%). Median time from last dose of PD-(L)1 mAb to alloHSCT was 80 days (range, 17-756) with 70 pts (47%) receiving intervening systemic therapy. At alloHSCT, 90 pts were in CR (60%), 45 in PR (30%), 5 in SD (3%), and 10 in PD (7%). Donors were haploidentical (n=71, 47%), matched sibling (n=29, 19%), matched unrelated (n=39, 26%), mismatched unrelated (n=7, 5%), cord blood (n=2, 1%), or unknown (n=2, 1%). Stem cell source was bone marrow (n=38, 25%), peripheral blood (n=110, 73%), or cord blood (n=2, 1%). GVHD prophylaxis included PTCy in 88 pts (59%) (69/71 (97%) with haploidentical donors; 19/79 (24%) with other donors). With a median post-alloHSCT follow-up for survivors of 23.8 months (range, 1-67), the 2y OS and PFS were 79% (95CI 71-86%) and 65% (95CI 55-73%), respectively, while the 2y CumIncs of relapse and NRM were 21% (95CI 13-29%) and 14%, (95CI, 8-22%), respectively (Fig. 1A-B). 27 pts have died, 3 due to disease and 24 to NRM, including aGVHD (n=7) and VOD (n=2). Veno-occlusive disease (VOD) occurred in 5 pts (day 100 CumInc 4%) and 29 pts (19%) developed CRS (grade 1 n=16; grade 2 n=7; grade 3 n=4; grade 4 n=2). The 6-month CumIncs of grade 2-4, grade 3-4 and grade 4 aGVHD were 39%, 16% and 8%, respectively. Hyperacute GVHD (onset ≤ 14 days after alloHSCT) occurred in 4% of pts and was fatal in 2 pts. The 2y CumInc of cGVHD was 45%. Neither receipt of > 10 doses (median) of anti-PD-(L)1 mAb nor undergoing alloHSCT ≤80 days (median) after last dose of PD-(L)1 mAb were associated with PFS or OS. However, pts with a shorter time to transplant (≤80 days) appeared to have a higher risk of severe (grade 3-4) aGVHD (6m CumInc 24% vs 9%, p=0.006). Recipients of PTCy in this cohort had lower 2y CumIncs of cGVHD (34% vs 58%, p=0.01) and relapse (12% vs 31%, p=0.02), superior 2y PFS (76% vs 54%, p=0.015), and similar rates of severe aGVHD (15% vs 18%, p=0.5), 2y NRM (12% vs 16%, p=0.5), and 2y OS (82% vs 78%, p=0.6). Conclusions: With extended follow-up of a large international cohort, our results argue that alloSCT performed after PD-(L)1 mAbs is a feasible strategy associated with an excellent PFS and a very low CIR for this disease. The use of PT-Cy appears to be associated with improved outcomes and may at present represent the optimal transplant strategy in this pt population. Figure Disclosures Corradini: kite: Honoraria; Abbvie: Honoraria; Servier: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; Roche: Honoraria; Novartis: Honoraria; KiowaKirin: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Daiichi Sankyo: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Ho:Jazz Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Consultancy; Omeros Corporation: Membership on an entity's Board of Directors or advisory committees. Jaglowski:Kite: Consultancy, Other: advisory board, Research Funding; Novartis: Consultancy, Other: advisory board, Research Funding; Juno: Consultancy, Other: advisory board; Unum Therapeutics Inc.: Research Funding. Herrera:Adaptive Biotechnologies: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; AstraZeneca: Research Funding; Merck: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding; Pharmacyclics: Research Funding; Immune Design: Research Funding; Kite Pharma: Consultancy, Research Funding. Blaise:Jazz Pharmaceuticals: Honoraria; Sanofi: Honoraria; Pierre Fabre medicaments: Honoraria; Molmed: Consultancy, Honoraria. Hamadani:Pharmacyclics: Consultancy; Sanofi Genzyme: Research Funding, Speakers Bureau; Merck: Research Funding; Otsuka: Research Funding; Janssen: Consultancy; Medimmune: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; Takeda: Research Funding; Celgene: Consultancy. Ansell:LAM Therapeutics: Research Funding; Affimed: Research Funding; Affimed: Research Funding; Trillium: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Mayo Clinic Rochester: Employment; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; LAM Therapeutics: Research Funding; Mayo Clinic Rochester: Employment; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; Affimed: Research Funding; Trillium: Research Funding; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; Regeneron: Research Funding; Regeneron: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Affimed: Research Funding. Nieto:Astra-Zeneca: Research Funding; Affimed: Consultancy; Affimed: Research Funding; Novartis: Research Funding. Feldman:Celgene: Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau; Pfizer: Research Funding; AbbVie: Honoraria, Other: Travel expenses, Speakers Bureau; Portola Pharma: Research Funding; Kite Pharma: Honoraria, Other: Travel expenses, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Pharmacyclics: Honoraria, Other: Travel expenses, Speakers Bureau; Kyowa Hakko Kirin: Research Funding; Eisai: Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Cell Medica: Research Funding; Roche: Research Funding; Corvus: Research Funding; Viracta: Research Funding; Trillium: Research Funding; Roche: Research Funding; Takeda: Honoraria, Speakers Bureau. McGuirk:ArticulateScience LLC: Other: Assistance with manuscript preparation; Bellicum Pharmaceuticals: Research Funding; Kite Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gamida Cell: Research Funding; Pluristem Ltd: Research Funding; Juno Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Research Funding; Novartis: Research Funding; Fresenius Biotech: Research Funding. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding. Stamatoulas Bastard:Celgene: Honoraria; Takeda: Consultancy. Houot:Bristol Myers Squibb: Honoraria; Merck Sharp Dohme: Honoraria. Manson:Bristol Myers Squibb: Honoraria. Orvain:Incyte: Honoraria; Novartis: Honoraria; Jazz Pharmaceuticals: Other: Travel & accommodations; Pfizer: Other: Travel & accommodations. Bouabdallah:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Frigault:Novartis: Consultancy; Kite/Gilead: Honoraria; Nkarta: Consultancy; Incyte: Consultancy; Juno/Celgene: Consultancy; Foundation Medicine: Consultancy; Xenetic: Consultancy. Chen:Takeda: Consultancy; Kiadis: Consultancy; Magenta: Consultancy; Abbvie: Consultancy; Incyte: Consultancy. Lynch:T.G. Therapeutics: Research Funding; Rhizen Pharmaceuticals S.A: Research Funding; Takeda Pharmaceuticals: Research Funding; Juno Therapeutics: Research Funding; Incyte Corporation: Research Funding; Johnson Graffe Keay Moniz & Wick LLP: Consultancy. Smith:AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck Sharp & Dohme Corp: Consultancy, Research Funding; Acerta Pharma BV: Research Funding; Portola Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding; Bristol-Myers Squibb (spouse): Research Funding; Denovo Biopharma: Research Funding; Genentech: Research Funding; Ignyta (spouse): Research Funding; Incyte Corporation: Research Funding; Ayala (spouse): Research Funding; Seattle Genetics: Research Funding. Byrne:Karyopharm: Research Funding. Cohen:Hutchison: Research Funding; Astra Zeneca: Research Funding; Janssen Pharmaceuticals: Consultancy; Seattle Genetics, Inc.: Consultancy, Research Funding; Bristol-Meyers Squibb Company: Research Funding; Takeda Pharmaceuticals North America, Inc.: Research Funding; Gilead/Kite: Consultancy; Genentech, Inc.: Consultancy, Research Funding; UNUM: Research Funding; ASH: Research Funding; LAM Therapeutics: Research Funding; Lymphoma Research Foundation: Research Funding. Svoboda:AstraZeneca: Consultancy; Celgene: Research Funding; Incyte: Research Funding; Pharmacyclics: Consultancy, Research Funding; Kyowa: Consultancy; Merck: Research Funding; BMS: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding. Santoro:Bayer: Consultancy, Speakers Bureau; MSD: Speakers Bureau; Arqule: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; AstraZeneca: Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Servier: Consultancy, Speakers Bureau; Takeda: Speakers Bureau; BMS: Speakers Bureau; Roche: Speakers Bureau; Abb-Vie: Speakers Bureau; Amgen: Speakers Bureau; Celgene: Speakers Bureau; Novartis: Speakers Bureau; BMS: Consultancy; Lilly: Speakers Bureau; Sandoz: Speakers Bureau; Eisai: Consultancy, Speakers Bureau. Armand:Sigma Tau: Research Funding; Otsuka: Research Funding; Pfizer: Consultancy; ADC Therapeutics: Consultancy; Tensha: Research Funding; Affimed: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Adaptive: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: 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, Speakers Bureau; Infinity: Consultancy; Genentech: Research Funding. Zinzani:Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy; Eusapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics: Honoraria, Speakers Bureau. Carlo-Stella:Servier: Consultancy, Honoraria, Other: Travel, accommodations; Genenta Science srl: Consultancy; Boehringer Ingelheim: Consultancy; F. Hoffmann-La Roche Ltd: Honoraria, Other: Travel, accommodations, Research Funding; Novartis: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Other: Travel, accommodations, Research Funding; Sanofi: Consultancy, Research Funding; Rhizen Pharmaceuticals: Research Funding; Celgene: Research Funding; Amgen: Honoraria; AstraZeneca: Honoraria; Janssen Oncology: Honoraria; MSD: Honoraria; BMS: Honoraria; Janssen: Other: Travel, accommodations; Takeda: Other: Travel, accommodations.

Background: Only a small subset of Lower risk (LR) MDS patients benefit from treatment with rhu-Erythropoietin (Epo). We previously reported that lenalidomide (LEN) restores sensitivity to Epo in MDS progenitors by inducing the formation of lipid rafts that are enriched for signaling competent, JAK2/Epo-receptor complexes (McGraw K, et. al. PLoS One 2014; Basiorka A, et. al. Cancer Res 2016). In the MDS-002 and MDS-005 trials, treatment with LEN monotherapy gave rise to RBC transfusion-independence (TI) in 26% of azanucleoside-naïve, transfusion-dependent (TD) LR, non-del(5q) MDS patients for a median of 10.2 and 7.75 months, respectively. In a pilot study of Epo-refractory LR-MDS patients, the addition of epoetin alfa (EA) to LEN treatment yielded erythroid responses in 28% of patients who were unresponsive to LEN alone, suggesting that LEN may overcome clinical resistance to augment response to rhEpo (Komrokji R, et. al. Blood 2012). To test this hypothesis, we performed a randomized phase III trial comparing treatment with LEN to LEN+EA in LR non-del(5q) MDS patients who were refractory to, or not candidates for treatment with rhEpo. Methods: Patients with Low or Intermediate-1 IPSS risk MDS with hemoglobin <9.5 g/dL who were unresponsive to rhEpo treatment or were TD (>2 units/month) with serum Epo >500mU/mL were eligible. Patients were stratified by serum Epo level and prior rhEpo (EA vs. darbepoetin vs. none) then randomized to treatment with LEN 10 mg/d x21d q4wk (Arm A) or LEN + EA 60,000U SC/wk (Arm B). The primary endpoint was major erythroid response (MER) at week 16 which was defined according to transfusion status at baseline: (1) achievement of RBC-TI for ≥ 8 consecutive weeks AND a sustained ≥1 g/dL hemoglobin rise compared to mean pre-transfusion baseline value in TD patients; and (2) a >2 g/dL rise in hemoglobin without transfusion for ≥ 8 consecutive weeks in non-TD patients (<4U RBC/8 wks). Arm A non-responders were offered cross-over to combined therapy. Results: Among 205 patients randomized, 14 were excluded from the primary analysis due to a 4 month interruption in drug supply. Among the 195 evaluable patients, 96 were assigned to Arm A and 99 to Arm B. Baseline characteristics were well balanced between arms with 85% of patients heavily TD, receiving a median of 4 units/8 weeks. Overall, 93% of patients received prior treatment with Epo and 18% azanucleosides. In an intent to treat analysis, 28/99 patients (28.3%) in Arm B achieved MER compared to 11/96 (11.5%) in Arm A (P=0.004). Among 136 patients who completed 16 weeks of study treatment, 28/72 (38.9%) and 10/64 (15.6%) achieved MER, respectively (P=0.004). Forty-four Arm A non-responders crossed over to combination-therapy with 11 patients (25%) experiencing a MER. Multivariable logistic regression analysis identified only treatment with LEN + EA as an independent covariate for erythroid response (P=0.01). Responses were durable with MER median duration of 23.8 months in Arm B compared to 13 months in Arm A. There was no significant difference in the frequency or distribution of >Grade 3, non-hematologic adverse events between treatment arms. Two patients progressed to AML while on study (Arm A), and no thromboembolic events were reported. Conclusions: LEN restores sensitivity to rhEpo in otherwise refractory, LR-non-del(5q) MDS patients to yield a significantly higher frequency of durable major erythroid responses compared to LEN alone. The addition of LEN to EA treatment is an effective strategy for the management of Epo-refractory patients with a potential duration of benefit extending to years. Disclosures List: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Verma:Janssen: Research Funding; BMS: Research Funding; Stelexis: Equity Ownership, Honoraria; Acceleron: Honoraria; Celgene: Honoraria. Maciejewski:Novartis: Consultancy; Alexion: Consultancy. Komrokji:JAZZ: Speakers Bureau; Novartis: Speakers Bureau; JAZZ: Consultancy; Agios: Consultancy; Incyte: Consultancy; DSI: Consultancy; celgene: Consultancy; pfizer: Consultancy. Luger:Onconova: Research Funding; Pfizer: Honoraria; Seattle Genetics: Research Funding; Cyslacel: Research Funding; Biosight: Research Funding; Ariad: Research Funding; Agios: Honoraria; Genetech: Research Funding; Jazz: Honoraria; Daichi Sankyo: Honoraria; Kura: Research Funding; Celgene: Research Funding. Mattison:Pfizer: Membership on an entity's Board of Directors or advisory committees. Altman:Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Theradex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Glycomimetics: Consultancy, Honoraria, Other: Data Safety and Monitoring Committee; Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; France Foundation: Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; prIME Oncology: Speakers Bureau; PeerView: Speakers Bureau; Cancer Expert Now: Consultancy; Novartis: Consultancy; Biosight: Other: US Lead. Claxton:Astellas Pharma: Other: Pharma support of clinical studies; Merck Sharp & Dohme Corp.: Other: Pharma support of clinical studies; Cyclacel Pharmaceuticals, Inc.: Other: Pharma support of clinical studies; Medimmune Inc.: Other: Pharma support of clinical studies; Novartis Pharmaceuticals: Other: Pharma support of clinical studies; Celgene Corporation: Other: Pharma support of clinical studies; Incyte Corporation: Other: Cyclacel Pharmaceuticals, Inc; Daiichi Sankyo Co. and Ambit Biosciences Corp: Other: Pharma support of clinical studies. Artz:Miltenyi: Research Funding. Tallman:Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellerant: Research Funding; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biosight: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Lenalidomide used for treatment non-del 5q myelodysplastic syndromes.

Introduction The United States Thrombotic Microangiopathy (USTMA) Consortium consists of high-volume US referral centers that are committed to collaborative research in TMAs. The USTMA Immune Thrombotic Thrombocytopenic Purpura (iTTP) registry has compiled retrospective data on demographics, treatments and outcomes in patients with iTTP to create the world's largest database of patients with this rare disease. While there is consensus on the use of therapeutic plasma exchange (TPE) for treatment of iTTP, there are no large randomized trials on which to base use of rituximab. The drug is frequently used for refractory or relapsed iTTP, but is currently being used more frequently for de novo (first episode) iTTP. We queried the USTMA iTTP registry to determine whether relapse free survival (RFS) is superior when rituximab is added to TPE and corticosteroids for treatment of iTTP. We hypothesized that the addition of rituximab would improve RFS at 5 years in both de novo and relapsing iTTP. Methods Following IRB approval at each institution, investigators independently reviewed individual patient records to confirm diagnostic criteria and entered demographic, treatment and outcomes data into the REDCap database housed at the University of North Carolina. The diagnosis of iTTP was defined as ADAMTS13 < 10% or ADAMTS13 < 20% with an inhibitor or antibody detected at any point or a clinical diagnosis of iTTP based on presenting characteristics, response to treatment and/or relapsing phenotype before ADAMTS13 testing became available (N=173). Relapse was defined as a recurrence of iTTP after at least 30 days of remission (recurrence within 30 days was considered an exacerbation, or continuation of the prior episode). To explore the effect of rituximab added to TPE and corticosteroids, we first assessed the treatment effect in de novo iTTP patients and then separately in relapse. We constructed Kaplan-Meier curves to compare RFS for patients treated with rituximab plus corticosteroids versus corticosteroids alone in both groups, and compared RFS at specific time points using the Klein method. To better understand whether other patient variables had an effect on RFS in both de novo episodes and relapses, ordinary (time-to-event) and mixed-effects (recurrent time-to-event) Cox proportional hazards models were used to examine the relationships of treatment, race/ethnicity, sex, age, treatment year, and presenting signs/symptoms with the outcome. Analyses were conducted using R version 3.5.2 (R Foundation for Statistical Computing, Vienna, Austria). Results As of July, 2019, the USTMA database contains 775 unique study patients with a confirmed diagnosis of iTTP with 1397 unique iTTP episodes. The treatment of patients' de novo iTTP episode was available for analysis in 375 patients, 188 of whom were treated with corticosteroids alone, 131 with corticosteroids plus rituximab, and 56 with other therapies. RFS was significantly higher in patients treated with corticosteroids and rituximab compared to those treated with corticosteroids alone at 1 year (0.93 vs. 0.78, p=0.0002) and 3 years (0.82 vs. 0.66, p=0.004) but not 5 years (0.60 vs. 0.56, p=0.39). In addition, the risk of relapse decreased with later treatment year for de novo iTTP (hazard ratio (HR) 0.95, 95% CI 0.92-0.99, p=0.03), consistent with rituximab use increasing over time, and was increased in African Americans compared with Caucasians (HR 1.83, 1.10-3.06, p=0.02). We then explored the treatment effect in all iTTP relapses (743 relapses in 426 patients). Here, a significant (p=0.0007) interaction between treatment and race was found. Among African Americans, we found no difference in RFS when rituximab was added (HR 1.15, 0.81-1.62, p=0.43). However, among Caucasians, RFS was significantly improved when rituximab was added (HR 0.15, 0.06-0.35, p<0.0001). Conclusions For de novo iTTP, adding rituximab to corticosteroids for immunosuppression likely delays but does not prevent relapse. Unlike in de novo disease, in patients with relapsed iTTP, we found a novel and significant interaction between race and treatment: while Caucasians had significantly improved RFS with the addition of rituximab, there was no effect on RFS in African Americans. Further investigation is warranted to determine the mechanisms of this difference in the response to rituximab in relapsed iTTP to improve outcomes in African Americans. Figure Disclosures Marshall: Sanofi: Membership on an entity's Board of Directors or advisory committees. Farland:Sanofi: Membership on an entity's Board of Directors or advisory committees. Metjian:Sanofi: Membership on an entity's Board of Directors or advisory committees. Raval:Bayer, Inc: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees. Liles:Imara: Other: PI on Clinical trial- Sickle cell ; Shire: Other: PI on clinical trial Sickle cell ; Novartis: Other: PI on clinical trial Sickle cell . Baumann Kreuziger:CSL Behring: Consultancy; Vaccine Injury Compensation Program: Consultancy. McCrae:Rigel Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Sanofi Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Dova Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pfizer Pharmaceutical: Membership on an entity's Board of Directors or advisory committees. Chaturvedi:Shire/Takeda: Research Funding; Sanofi: Consultancy; Alexion: Consultancy. Zheng:Clotsolution: Other: Co-Founder; Shire/Takeda: Research Funding; Ablynx/Sanofi: Consultancy, Speakers Bureau; Alexion: Speakers Bureau. Cataland:Ablynx/Sanofi: Consultancy, Research Funding; Alexion: Consultancy, Research Funding. Off Label Disclosure: rituximab for immunosuppression in TTP.

Introduction Autologous fat grafting (AFG) is a popular and effective method of breast reconstruction after mastectomy; however, the oncological safety of AFG remains in question. The aim of this study was to determine whether AFG increases the risk of cancer recurrence in the reconstructed breast. Methods A matched, case-control study was conducted from 2000 to 2017 at the senior author's institution. Inclusion was limited to female patients who underwent mastectomy and breast reconstruction with or without AFG. Data were further subdivided at the breast level. χ2 analyses were used to test the association between AFG status and oncologic recurrence. A Cox proportional-hazards model was constructed to assess for possible differences in time to oncologic recurrence. The probability of recurrence was determined by Kaplan-Meier analyses and confirmed with log-rank testing. Results Overall, 428 breasts met study criteria. Of those, 116 breasts (27.1%) received AFG, whereas 312 (72.9%) did not. No differences in the rates of oncologic recurrence were found between the groups (8.2% vs 9.0%, P < 1.000). Unadjusted (hazard ratio = 1.03, confidence interval = 0.41–2.60, P < 0.957) and adjusted hazard models showed no statistically significant increase in time to oncologic recurrence when comparing AFG to non-AFG. In addition, no statistical differences in disease-free survival were found (P = 0.96 by log rank test). Conclusion Autologous fat grafting for breast reconstruction is oncologically safe and does not increase the likelihood of oncologic recurrence. Larger studies (eg, meta analyses) with longer follow-up are needed to further elucidate the long-term safety of AFG as a reconstructive adjunct.

The 25th Annual Congress of the International Liver Transplantation Society was held in Toronto, Canada, from May 15 to 18, 2019. Surgeons, hepatologists, anesthesiologists, critical care intensivists, radiologists, pathologists, and research scientists from all over the world came together with the common aim of improving care and outcomes for liver transplant recipients and living donors. Some of the featured topics at this year’s conference included multidisciplinary perioperative care in liver transplantation, worldwide approaches to organ allocation, donor steatosis, and updates in pediatrics, immunology, and radiology. This report presents excerpts and highlights from invited lectures and select abstracts, reviewed and compiled by the Vanguard Committee of International Liver Transplantation Society. This will hopefully contribute to further advances in clinical practice and research in liver transplantation.

Abstract Background Breast cancer treatment is based on estrogen receptors (ERs), progesterone receptors (PRs), and human epidermal growth factor receptor 2 (HER2). At the time of metastasis, receptor status can be discordant from that at initial diagnosis. The purpose of this study was to determine the incidence of discordance and its effect on survival and subsequent treatment in patients with breast cancer brain metastases (BCBM). Methods A retrospective database of 316 patients who underwent craniotomy for BCBM between 2006 and 2017 was created. Discordance was considered present if the ER, PR, or HER2 status differed between the primary tumor and the BCBM. Results The overall receptor discordance rate was 132/316 (42%), and the subtype discordance rate was 100/316 (32%). Hormone receptors (HR, either ER or PR) were gained in 40/160 (25%) patients with HR-negative primary tumors. HER2 was gained in 22/173 (13%) patients with HER2-negative primary tumors. Subsequent treatment was not adjusted for most patients who gained receptors—nonetheless, median survival (MS) improved but did not reach statistical significance (HR, 17–28 mo, P = 0.12; HER2, 15–19 mo, P = 0.39). MS for patients who lost receptors was worse (HR, 27–18 mo, P = 0.02; HER2, 30–18 mo, P = 0.08). Conclusions Receptor discordance between primary tumor and BCBM is common, adversely affects survival if receptors are lost, and represents a missed opportunity for use of effective treatments if receptors are gained. Receptor analysis of BCBM is indicated when clinically appropriate. Treatment should be adjusted accordingly. Key Points 1. Receptor discordance alters subtype in 32% of BCBM patients. 2. The frequency of receptor gain for HR and HER2 was 25% and 13%, respectively. 3. If receptors are lost, survival suffers. If receptors are gained, consider targeted treatment.