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Atrial fibrillation (AF) is an important comorbidity in patients with end-stage renal disease (ESRD) undergoing dialysis that portends increased health care utilization, morbidity, and mortality in this already high-risk population. Patients with ESRD have a particularly high stroke risk, which is further compounded by AF. However, the role of anticoagulation for stroke prophylaxis in ESRD and AF is debated. The ESRD population presents a unique challenge because of the combination of elevated stroke and bleeding risks. Warfarin has been traditionally used in this population, but it is associated with significant risks of minor and major bleeding, particularly intracranial, thus leading many clinicians to forgo anticoagulation altogether. When anticoagulation is prescribed, rates of adherence and persistence are poor, leaving many patients untreated. The direct oral anticoagulants (DOACs) may offer an alternative to warfarin in ESRD patients, but these agents have not been extensively studied in this population and uncertainties regarding comparative effectiveness (versus warfarin, each other, and no treatment) remain. In this review, we discuss the current evidence on the risk and benefits of anticoagulants in this challenging population and comparisons between warfarin and DOACs, and review future directions including options for non-pharmacologic stroke prevention.

Abstract BACKGROUND For optimizing high-grade glioma resection, 5-aminolevulinic acid is a reliable tool. However, its efficacy in low-grade glioma resection remains unclear. OBJECTIVE To study the role of 5-aminolevulinic acid in low-grade glioma resection and assess positive fluorescence rates and the effect on the extent of resection. METHODS A systematic review of PubMed, Google Scholar, and Cochrane was performed from the date of inception to February 1, 2019. Studies that correlated 5-aminolevulinic acid fluorescence with low-grade glioma in the setting of operative resection were selected. Studies with biopsy only were excluded. Positive fluorescence rates were calculated. The quality index of the selected papers was provided. No patient information was used, so Institutional Review Board approval and patient consent were not required. RESULTS A total of 12 articles met the selection criteria with 244 histologically confirmed low-grade glioma patients who underwent microsurgical resection. All patients received 20 mg/kg body weight of 5-aminolevulinic acid. Only 60 patients (n = 60/244; 24.5%) demonstrated visual intraoperative 5-aminolevulinic acid fluorescence. The extent of resection was reported in 4 studies; however, the data combined low- and high-grade tumors. Only 2 studies reported on tumor location. Only 3 studies reported on clinical outcomes. The Zeiss OPMI Pentero microscope was most commonly used across all studies. The average quality index was 14.58 (range: 10-17), which correlated with an overall good quality. CONCLUSION There is an overall low correlation between 5-aminolevulinic acid fluorescence and low-grade glioma. Advances in visualization technology and using standardized fluorescence quantification methods may further improve the visualization and reliability of 5-aminolevulinic acid fluorescence in low-grade glioma resection.

Smokers are at increased risk for surgical complications. Despite the known benefits of smoking cessation, many perioperative health care providers do not routinely provide smoking cessation interventions. The variation in delivery of perioperative smoking cessation interventions may be due to limited high-level evidence for whether smoking cessation interventions used in the general population are effective and feasible in the surgical population, as well as the challenges and barriers to implementation of interventions. Yet smoking is a potentially modifiable risk factor for improving short- and long-term patient outcomes. The purpose of the Society for Perioperative Assessment and Quality Improvement (SPAQI) Consensus Statement on Perioperative Smoking Cessation is to present recommendations based on current scientific evidence in surgical patients. These statements address questions regarding the timing and intensity of interventions, roles of perioperative health care providers, and behavioral and pharmacological interventions. Barriers and strategies to overcome challenges surrounding implementation of interventions and future areas of research are identified. These statements are based on the current state of knowledge and its interpretation by a multidisciplinary group of experts at the time of publication.

Abstract IntroductionRadiofrequency ablation (RFA) and spinal cord stimulation (SCS) are 2 common modalities used in management of various pain conditions. RFA generates heat and an electromagnetic field that can theoretically interfere with the functionality and longevity of the SCS device. This is problematic for patients who need RFA and have previously undergone implantation of an SCS device.Case DescriptionWe present a case highlighting the safe use of bipolar RFA in a patient who had previously undergone implantation of a cervical SCS device.DiscussionWe also present device‐specific industry guidelines and recommendations for performing RFA in patients following SCS device implantation.

Introduction: There is a paucity of randomized trials to guide therapy for relapsed AL amyloidosis with treatment regimens generally extrapolated from experience in multiple myeloma. Methods: We conducted a retrospective review of patients who relapsed after receiving autologous stem cell transplant at Mayo Clinic. Patients treated for first relapse between January 2004 and December 2018 were included. Results: Three hundred and twenty-one patients were seen for relapsed AL amyloidosis post ASCT during the study period. Baseline characteristics were typical for a cohort with AL amyloidosis and are listed in Table1. 39% received therapy prior to transplant, conditioning in the majority (75%) was melphalan 200mg/m2. The median progression free survival from transplant (PFS1) was 30.7 months. Of the 321 patients 294 received treatment for relapsed disease. We categorized treatment regimens according to commonly used combinations and drug classes to further analyze outcomes. 34 patients were excluded from this analysis as they either proceeded directly to second ASCT (n=10) or received an atypical regimen not commonly considered for AL amyloidosis (n=24). Five categories of therapy regimens were identified, thalidomide based (n=110), melphalan plus steroids (n=31), 2nd generation immunomodulatory (IMiD) drug +/- alkylator (n=76), proteasome inhibitor (PI) +/- alkylator (n=116), PI plus IMiD (n=16), or daratumumab based (n=9). Disease and treatment characteristics for patients treated with these regimens are listed in Table 2. Patients treated with thalidomide had the shortest PFS1 (17.7 months) but PFS1 was similar for those treated with melphalan plus steroids, PI+IMiD and 2nd generation IMiDs (25.5, 24.3 and 25.6 months respectively). Patients treated with a PI +/- alkylator and daratumumab based regimen had the longest PFS1 (36.7 and 41.9 months respectively). The median duration of therapy was longer in patients treated with a 2nd generation IMiD or daratumumab based regimen (10.2, 12, 6.1, 5.5, 6.2 and 5.9 months for Dara based, 2nd generation IMiD, PI+/- alkylator, PI+IMiD, melphalan plus steroids and thalidomide based respectively). Hematologic response rate was lowest in those treated with melphalan plus steroids or thalidomide based regimens (44% and 55% respectively) and highest for patients treated with a PI+/- alkylator, (Figure 1). Progression free survival from relapsed therapy (PFS2) was longest amongst patients treated with daratumumab based regimens, PI +/- alkylator and 2nd generation IMiDs (not reached, 29.9 and 26.7 months respectively), Figure 2A. Overall survival from time of relapsed therapy favored patients treated with daratumumab based regimens, 2nd generation IMiDs and PI +/- alkylator, Figure 2b). Conclusion: A second generation IMiD based regimen or PI +/- alkylator produce high response rates and prolonged progression free and overall survival for relapsed AL amyloidosis. Patients treated with daratumumab based regimens and those treated with a PI plus IMiD also appear to do well, although numbers were low in our study. Patients treated with melphalan plus steroids or thalidomide based combinations have inferior outcomes and these regimens should be avoided. Disclosures Dispenzieri: Celgene: Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Janssen: Consultancy; Intellia: Consultancy; Akcea: Consultancy; Alnylam: Research Funding. Lacy:Celgene: Research Funding. Dingli:Karyopharm: Research Funding; Rigel: Consultancy; Millenium: Consultancy; Janssen: Consultancy; alexion: Consultancy. Leung:Takeda: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Aduro: Membership on an entity's Board of Directors or advisory committees; Omeros: Research Funding. Kapoor:Glaxo Smith Kline: Research Funding; Sanofi: Consultancy, Research Funding; Celgene: Honoraria; Cellectar: Consultancy; Amgen: Research Funding; Takeda: Honoraria, Research Funding; Janssen: Research Funding. Kumar:Takeda: Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Gertz:Medscape: Consultancy, Speakers Bureau; Prothena Biosciences Inc: Consultancy; Ionis/Akcea: Consultancy; Alnylam: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Spectrum: Consultancy, Research Funding; Appellis: Consultancy; Amgen: Consultancy; Physicians Education Resource: Consultancy; Abbvie: Other: personal fees for Data Safety Monitoring board; Research to Practice: Consultancy; Teva: Speakers Bureau; Johnson and Johnson: Speakers Bureau; DAVA oncology: Speakers Bureau; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Proclara: Membership on an entity's Board of Directors or advisory committees; i3Health: Other: Development of educational programs and materials; Springer Publishing: Patents & Royalties; Amyloidosis Foundation: Research Funding; International Waldenstrom Foundation: Research Funding; Annexon: Consultancy. OffLabel Disclosure: Daratumumab off label use for AL amyloidosis.

Introduction: Daratumumab is a human immunoglobulin (IgG-κ) that targets CD38 abundantly expressed on plasma cells. Data is emerging to show its efficacy as part of induction therapy for newly diagnosed multiple myeloma (MM) patients. Hematopoietic stem cells have been shown to express CD38 on the cell surface and therefore during mobilization, there is a theoretical risk of circulating daratumumab binding to and having downstream effects on these cells. Methods: We conducted a retrospective review of MM patients treated with daratumumab prior to stem cell collection and autologous stem cell transplant (ASCT) to identify any effects daratumumab therapy may have on the efficacy of the stem cells in bone marrow recovery. The study was conducted at Mayo Clinic Rochester from February 2018 to May 2019. Granulocyte colony-stimulating factor was the preferred agent used for stem cell mobilization and plerixafor was added in a demand-adapted fashion. All patients received melphalan infused at day -1 before their ASCT and the decision about dosing (200mg/m2 vs 140mg/m2) was at the physicians' discretion. Neutrophil engraftment was defined as the first date of three consecutive neutrophil counts >0.5 x 10^9/L and platelet engraftment was defined as the first date of three consecutive platelet counts >50 x 10^9/L in the absence of platelet transfusion in the preceding 7 days. Results: We identified 12 patients who received daratumumab as part of their first induction regimen (daratumumab cohort) and compared them to 129 patients who did not receive daratumumab prior to stem cell mobilization and transplant during the study period (no daratumumab cohort). Of the daratumumab cohort, 11 patients received daratumumab, ixazomib, lenalidomide, and dexamethasone and one received daratumumab, cyclophosphamide, bortezomib and dexamethasone. No differences were noted in terms of melphalan dose or the number of CD34+ stem cell infused. The median time from the last dose of daratumumab to stem cell collection was 3.9 weeks. In patients receiving daratumumab, the median time for neutrophil engraftment was three days longer compared with those who did not receive daratumumab (median of 19 days vs. 16 days, P=0.017) (Figure 1, A). Median platelet engraftment was delayed by one day, although this was not statistically significant (median of 18 days vs. 17 days, p=0.12) (Figure 1, B). A total of 6 patients (50%) from the daratumumab cohort and 52 (40%) from the no daratumumab cohort required hospital admission. Of these admissions, there was no difference between the two groups in rates of admission for fever (50% in the daratumumab group vs. 42% in the no daratumumab group, P=0.7). Conclusion: Our case series provides the first report of daratumumab delaying engraftment post transplant in myeloma patients receiving it prior to stem cell collection. A better characterization of this phenomenon is important given the increasing use of daratumumab as front line therapy prior to ASCT in patients with myeloma. Disclosures Gertz: Prothena: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Spectrum: Honoraria, Research Funding; Alnylam: Honoraria; Ionis: Honoraria. Lacy:Celgene: Research Funding. Kapoor:Sanofi: Consultancy, Research Funding; Glaxo Smith Kline: Research Funding; Cellectar: Consultancy; Janssen: Research Funding; Amgen: Research Funding; Takeda: Honoraria, Research Funding; Celgene: Honoraria. Dispenzieri:Alnylam: Research Funding; Celgene: Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Janssen: Consultancy; Intellia: Consultancy; Akcea: Consultancy. Dingli:alexion: Consultancy; Janssen: Consultancy; Millenium: Consultancy; Rigel: Consultancy; Karyopharm: Research Funding. Kumar:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding.

Background: Carfilzomib (Car), a second-generation proteasome inhibitor (PI), has been approved by the US Food and Drug Administration (FDA) as therapy for relapsed and /or refractory multiple myeloma (RRMM), either as a single agent or in combination with other agents. It has proven to be superior in many ways compared to the the first generation PI, bortezomib, both in terms of superior efficacy and neuropathy related adverse effect profile. Carfilzomib has lower rate of peripheral neuropathy. In this review, we gathered data from trials which studied Carfilzomib for newly diagnosed MM (NDMM). Carfilzomib based two and three drug combination as induction regimens for the management of NDMM is an emerging approach. Through this systematic review, we explore efficacy, adverse effect profile of Car based regimens for NDMM. Methods: Per PRISMA guidelines, a thorough database search was conducted on 06/24/2019 using the following search engines; PubMed, EMBASE, Cochrane library, Scopus, Web of Science, CINAHL, and Clinicaltrials.gov. We included all published trials that used carfilzomib as an induction agent in NDMM patients and had at least response rates after induction. Results: The total number of articles identified with initial search were 1131, out of which 19 articles met our selection / eligibility criteria (n=2286). The overall response rates (ORR) after induction therapy with carfilzomib based regimens was very impressive (range: 84.3% - 100%). Two drug combination using carfilzomib and dexamethasone (n=72) had an ORR of 90% and a greater than very good partial response rate (>VGPR) of 84%. Three drug combinations used for induction therapy included carfilzomib/dexamethasone with immunomodulators (n=391) and alkylating agents (n=308). The combination of carfilzomib/dexamethasone with lenalidomide (n=189, ORR: 97% - 98%, >VGPR: 69% - 98%) and thalidomide (n=202, ORR: 90% - 94%, >VGPR: 66% - 68%) showed the best response. Alkylating agents used in combination with carfilzomib were melphalan (n=98, ORR: 90% - 93%, >VGPR: 58% - 70%), cyclophosphamide (n=192, ORR: 87% - 95%, >VGPR: 39% - 71%) and bendamustine (n=18, ORR; 100%, >VGPR: 89%). Four drug combinations with carfilzomib used were daratumumab/lenalidomide/dexamethasone (n=22, ORR: 100%, >VGPR: 90%, 12m PFS: 95%) and cyclophosphamide / thalidomide / dexamethasone (n=64, ORR; 91%, >VGPR: 69%, 24m PFS: 76%). One trial directly compared carfilzomib/melphalan/dexamethasone (n=478, ORR: 84%, >VGPR: 61%, PFS: 22.3m) with bortezomib/melphalan/dexamethasone (n=477, ORR: 79%, >VGPR: 49%, PFS: 22.1m). Another trial compared the combination of carfilzomib / dexamethasone with lenalidomide (n=315) or cyclophosphamide (n=159) that showed similar ORR (97% vs 91%) though >VGPR rate was better with lenalidomide (75% vs 60%). Efficacy data including progression free survival (PFS) for carfilzomib based regimens is reported in table 1. Most common >grade 3 hematological adverse effects reported were anemia (2% - 35%), lymphopenia (5% - 76%), thrombocytopenia (4% - 28%) and neutropenia (1% - 38%). Most Common >grade 3 non-hematological adverse events included cardiac events (5% - 10%), respiratory disorders (8% - 16%), infections (2% - 9%), hypertension (6% - 17%), renal events (9% - 10%) and hyperglycemia (6% - 23%). (Table 1) Conclusion: The overall efficacy and favorable adverse effect profile of Carfilzomib-based induction regimens seem very promising for the treatment of NDMM. Car is now approved for weekly dosing which is convenient. Due to cardiovascular toxicity seen in upto 10% cases, Car should be used very judiciously in patients with cardiovascular risk factors and heart failure. Several ongoing phase 3 clinical trials are studying Carfilzomib in various combinations will help to establish foundation for future standard therapy as well as next phase of drug development through clinical trials. Disclosures Anwer: In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

Introduction Amyloidosis is a rare disease and there are currently no FDA approved therapies for AL amyloidosis. Most of the therapeutic and disease data come from expert guidelines, consensus and retrospective review papers. There is a paucity of data specifically for relapsed/refractory AL amyloidosis (RRAL). We conducted this systematic review of clinical trials, retrospective and prospective cohort studies to evaluate patterns of relapse and therapeutic options for RRAL. Methods PubMed and Clinicaltrials.gov were searched for clinical trials, retrospective and prospective cohort studies on RRAL. Studies were selected according to PRISMA guidelines. Cross-trial comparison of included studies and meta-analysis could not be performed for a number of reasons but mainly due to a limited number of studies on one particular treatment regimen. Results From a total of 511 studies, 11 studies (n= 698 patients) met our inclusion criteria. Five were phase I/II clinical trials, five retrospective cohort studies, and one prospective cohort study. Most studies had less than 50 patients. The largest study, a retrospective cohort by Tandon et al. included 366 patients. Mean age was 61.2. Three studies reported 2 median prior lines of therapy (n= 22, 28, and 84 patients); two reported 3 median prior lines of therapy (n= 25 and 24) and 6 studies didn't specify this data. Prior treatment options included proteasome inhibitors (PI), most commonly bortezomib (n= 259), followed by melphalan (n=211), high dose melphalan and stem cell transplant (HDM/SCT [n= 207]) and IMiDs most commonly lenalidomide (n=154). Time to progression (TTP) from first-line treatment was reported in only 4 studies as 1 month, 5 months, 5 months and 34 months respectively. The study reporting a TTP of 34-months had 11 patients who received HDM/SCT as first line treatment. Three studies reported information about their criteria for initiation of subsequent treatment. Subsequent treatment was mostly a combination regimen with dexamethasone or an alkylating agent. The only agent evaluated as single agent was bortezomib in a phase I/II clinical trial by Reece et al. Therapeutic options for RRAL are PI (non-specific) based therapy (n= 145), lenalidomide (n= 105), bortezomib (n= 99), IMiD (non-specific) based therapy (n=83), melphalan based therapy (n= 33), carfilzomib (n=28), pomalidomide (n=27), ASCT (n= 25), daratumumab (n=25) and bendamustine (n=22). Efficacy: Hematologic responses were reported to be following: bortezomib + dexamethasone/melphalan (85%, n=17/20), daratumumab + dexamethasone (76%, n= 19/25), HDM/ASCT (73%, n= 8/11), single agent bortezomib (67%, n=23/34), carfilzomib ± dexamethasone (63%, n= 15/24), lenalidomide + dexamethasone (61%, n=51/84), bendamustine + dexamethasone (55%, 11/22) and pomalidomide + dexamethasone (50%, 12/24). Five of eleven studies reported organ responses which ranged from 18% to 23%. The studies which reported organ responses had evaluated the following agents: single agent bortezomib, carfilzomib ± dexamethasone, lenalidomide + dexamethasone, and bendamustine + dexamethasone. Best survival outcomes were seen with bortezomib with median overall survival (OS) 62 months. With bendamustine and dexamethasone (retrospective cohort study n=22) median OS was 31 months. With lenalidomide + dexamethasone (prospective cohort study n=24 ) median OS was 14 months. For the remaining studies, the median OS was either not reported or not reached at the time of presentation of data. Conclusion AL amyloidosis patients progressing after front line therapy show good responses with bortezomib (median overall survival of 62 months). Novel combinations using lenalidomide, pomalidomide, carfilzomib, daratumumab, and bendamustine show promising efficacy. Ongoing trials of daratumumab (AMYDARA trial) and ixazomib (TOURAMALINE-AL1) will bring further insight into therapeutic armamentarium for RRAL patients. After relapse, a salvage HDM/ASCT can be considered. Comparisons of regimen efficacy between studies are not practical because of multiple factors which include but are not limited to heterogenous nature of AL patients, small sample sizes, variable prior treatments, exposure to novel agents, observational study versus clinical trial and variable endpoints. Table Disclosures Anwer: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; In-Cyte: Speakers Bureau.

Introduction: Risk stratification of patients with light chain (AL) amyloidosis at diagnosis is invaluable. Currently, the Mayo 2012 staging system is mainly used to risk-stratify patients. We evaluated the role of increased mean corpuscular volume (MCV) at diagnosis in predicting survival. Methods: We conducted a retrospective study of patients with newly diagnosed AL amyloidosis seen at Mayo Clinic, Rochester between January 2006 through December 2015. The diagnosis of AL was confirmed with biopsy and the determination of organ involvement was according to consensus criteria. Staging was done according to the Mayo 2012 staging system and patients with stage III/IV were considered to have advanced stage disease. Patient and disease factors were compared for categorical and continuous variables using the χ2 and the Wilcoxon signed rank tests, respectively. Overall survival (OS) was defined as the time from diagnosis to death of any cause. Survival analysis was done using the Kaplan-Meier method. Results: A total of 1064 patients were identified and were divided into two groups: those with an MCV ≥ 96 fl (Elevated MCV, n=180) and those with an MCV <96 fl (Low MCV, n=884). The median age at diagnosis for the whole cohort was 64, with an interquartile range (IQR) of 57-71. Overall, 222 (23%) had Mayo 2012 stage 1, 199 (21%) had stage 2, 239 (25%) had stage 3, and 290 (31%) had stage 4 disease. Patients with an elevated MCV were more likely to be more than 65 years old compared to patients with a low MCV (61% vs. 44%, p<0.0001). They were also likely to have an advanced Mayo 2012 stage (68% vs. 53%, P=0.0008). The median OS was significantly lower in patients with an elevated MCV compared to patients with a low MCV (median PFS 13 months vs. 41 month, respectively, P<0.0001)(Figure 1). On a univariable analysis, predictors of OS were advanced Mayo 2012 stage (RR 3.26, P<0.001) and MCV ≥ 96 (RR 1.6, P<0.0001). On the multivariable analysis, both variables remained predictors of OS [advanced Mayo 2012 stage (RR 3.19, P<0.001) and MCV ≥ 96 (RR 1.3, P=0.016)]. Conclusion: The median OS was shorter by 28 months in newly diagnosed AL amyloidosis patients with an MCV ≥ 96 compared to patients with an MCV<96. An elevated MCV was predictive of shorter survival, independent of the Mayo Stage. This variable is easily available, measured in all newly diagnosed patients, and provides valuable prognostic information for the treating physician. Disclosures Dispenzieri: Intellia: Consultancy; Takeda: Research Funding; Pfizer: Research Funding; Janssen: Consultancy; Alnylam: Research Funding; Celgene: Research Funding; Akcea: Consultancy. Lacy:Celgene: Research Funding. Dingli:alexion: Consultancy; Janssen: Consultancy; Millenium: Consultancy; Rigel: Consultancy; Karyopharm: Research Funding. Leung:Takeda: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Omeros: Research Funding; Aduro: Membership on an entity's Board of Directors or advisory committees. Kapoor:Sanofi: Consultancy, Research Funding; Celgene: Honoraria; Cellectar: Consultancy; Janssen: Research Funding; Amgen: Research Funding; Takeda: Honoraria, Research Funding; Glaxo Smith Kline: Research Funding. Gertz:i3Health: Other: Development of educational programs and materials; Alnylam: Consultancy; Celgene: Consultancy; Appellis: Consultancy; Teva: Speakers Bureau; Spectrum: Consultancy, Research Funding; Annexon: Consultancy; Springer Publishing: Patents & Royalties; Amyloidosis Foundation: Research Funding; Amgen: Consultancy; Medscape: Consultancy, Speakers Bureau; Physicians Education Resource: Consultancy; Abbvie: Other: personal fees for Data Safety Monitoring board; Research to Practice: Consultancy; Ionis/Akcea: Consultancy; Prothena Biosciences Inc: Consultancy; Janssen: Consultancy; International Waldenstrom Foundation: Research Funding; Proclara: Membership on an entity's Board of Directors or advisory committees; Johnson and Johnson: Speakers Bureau; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; DAVA oncology: Speakers Bureau. Kumar:Takeda: Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding.