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Background & Aim According to FACT standards, the cell processing facility should perform internal audits on a regular basis. In CTMF, HPC chart completeness is defined as one of the yearly key audit topics. This study is an example of the HPC chart completeness internal audit, in which selected parameters of the HPC chart were audited and analyzed, to indicate trend and help process improvement. Methods, Results & Conclusion Methods The HPC cryopreservation processes occurred in CTMF from 06/01/2018 to 07/15/2018. Total 5 autologous patients chart, 11 processes were audited. Goal: Compliance 95% at the time of audit, 100% after corrections made. Auditor is the laboratory supervisor, who has the knowledge of the processes, and did not participate in the processes being audited, and therefore independent. Results 1. 59 missing / incomplete entries identified at the time of audit, total 604 pages, 2543 entries audited, approximately 97.7% compliance (entries completed out of all audited entries). After correction, 100% compliance. 2. Incomplete Entry Analysis-per Incomplete Type: (1) Sampling Record and Coulter/Flow print-out contributed to a big portion (20%) of all incomplete entries. Major examples are Sampling and Testing Record cover sheet) missing review, or not initialed and dated. (2) Batch Record: label control took up 1/7 of all entries missed in the batch record. All 18 “Batch Record, Others” missing items were from the last day of patient “D”’s last day of the 4-day collection. (3) 45% (5 out of 11) CryoMed print-out did not have initial and / or date. (4) Chain of Custody, Storage Record, Release Criteria were other weak areas affecting the completion rate. See Figure 1. 3. Incomplete Entry Analysis-per timing Min number of collection/process was 1, max 4. 3 patients had 2 days collections. The 4-day collection had the highest incomplete entries per processing day (7.3). Out of the 59 incomplete entries, 43 (73%) were from Processing Days, 16 (27%) were from After Processing Days (post thaw, infusion). 4. Incomplete Entry Analysis-per staff, Incomplete Rate. Figure 2. 5. Incomplete Entry Analysis-as Performer/as Reviewer. Out of the 59 incomplete entries, 47 (80%) were from performers, 12 (20%) were from reviewers. 6. Incomplete Entry Analysis-per staff as Paperwork Manager. Figure 3. Conclusion Audit result is acceptable. Recommendation is to enhance good documentation practice, enhance Paperwork Magager and facility director review in a timely fashion, especially for multiple days collections.

Background & Aim To study the Environment Monitoring (EM) activities in a hospital-based Cell Therapy Manufacturing Facility (mainly processes islet cells and HPC(s), to ensure compliance with FACT (03/2018), ISO14644 (12/2015), validation standards and facility EM SOP. Methods, Results & Conclusion Methods Available EM data from 08/2014 to 12/2017 analyzed, including initial validation EM by vendor. EM are normally performed on a monthly basis, while some months had partial or no EM done due to facility construction, schedule conflicts, or machine error. EM includes particle count (PC), air sampling (AS), contact plate bacterial & fungal (CP). See Image 1 for routine EM locations. CR: Cleanroom; GR: Gown Room; DR: Degown Room; BSC: Biosafety Cabinet. Results In the 41 months, 37 months of particle counts, 40 months of Air Sampling, 38 months of contact plate data were analyzed. Among them, (1) One was In-Process EM, all the others were At Rest EM. The In-Process particle counts were significantly higher than those At-Rest. (2) All critical ISO 5 areas were all within expected ranges for all three EM parameters. (3) Two deviations filed due to high air sampling counts, and both passed after improving operator technique and after facility cleaning. (4) In this 3 year data, particle counts and contact plates results are trending low or stable, within expected range, while Air Sampling results had some fluctuations, see Image 2 and 3. (5) Besides the regular/routine sampling locations, several non-routine sampling locations were also sampled, which detected “mold” in Incubator, “>100 CFU” in freezer, and both repeated “0 CFU” count after equipment decontamination. See Image 3. Conclusion (1) The facility's EM program monitors particulates, microbial contamination, with proper sampling sites, frequency, investigative and corrective actions when specified limits exceeded. (2) All BSC data were satisfactory and safe for cell therapy manufacturing processes. (3) Gown Room and Degown Room were built per ISO 8, and met ISO 7 requirements. (4) More In-Process EM shall be performed to provide baseline data during manufacturing. (5) Non-routine sampling in ISO unclassified areas helps detect suspected/ at risk areas, and help improve the cleanliness of the facility.

Introduction Allogeneic stem cell transplant (alloSCT) provides pts with FLT3-ITD+ AML the highest likelihood of sustained remission, but relapse rates remain high. Post-SCT maintenance therapy may improve this outcome. Objective RADIUS, a randomized, open-label, phase 2 exploratory trial (NCT01883362) investigated whether SOC ± mido after alloSCT reduced relapse rates in pts with FLT3-ITD+ AML. Methods Eligible adults (aged 18-70 y) who had undergone myeloablative alloSCT in first complete remission (hematologic recovery and transfusion independence) were enrolled after engraftment and randomized 28 to 60 days after alloSCT to receive SOC ± mido 50 mg twice daily for up to 12 (4-week) cycles. The primary endpoint was relapse-free survival (RFS) at 18 mo after alloSCT; safety, pharmacokinetics (PK), in vivo FLT3 inhibition by FLT3 plasma inhibitory activity (PIA) assay, overall survival (OS), and RFS at 24 mo after alloSCT were also assessed. The study was not adequately powered to detect a statistical difference between arms; a sample size of 60 was calculated to detect a 50% reduction in the risk of relapse with 71% power if the incidence of relapse in the SOC + mido arm was 15%. Results 60 pts were randomized (30 per arm); 30 completed 12 cycles of therapy (14 with SOC; 16 with SOC + mido). The median dose intensity was 93 mg/day (range, 15-100 mg/day). Early discontinuations were similar between arms (15 with SOC; 13 with SOC + mido), often due to adverse events (AEs; 3% vs 27%) and consent withdrawal (20% vs 7%). 19 pts (63%) had mido dose modifications (84% due to AEs; concomitant CYP3A4 inhibitor, n = 1). With SOC alone, the estimated RFS (95% CI) at 18 mo was 76% (54%-88%) vs 89% (69%-96%) with SOC + mido (HR, 0.46 [95% CI, 0.12-1.86]; P = .27); the predicted relative reduction in the risk of relapse with the addition of mido was 54%. At 24 mo, OS (95% CI) was 85% with addition of mido (65%-94%) vs 76% with SOC alone (54%-89%) (P = .3418). PIA was evaluable in 28 pts in each arm; PK was evaluated in the SOC + mido arm. There was wide interpatient variability in trough levels of mido and its active metabolites ([CGP62221] + [CGP52421/5.4]) and in the degree of FLT3 inhibition. With mido, phosphorylated FLT3 (pFLT3) levels were With SOC and SOC + mido, AEs occurred in 87% and 100% of pts; serious AEs occurred in 57% and 30% of pts, respectively. 12 pts died on study (during follow-up phase; 8 with SOC and 4 with SOC + mido [n = 4 vs n = 2 due to AML disease progression]). Conclusion Mido as maintenance therapy was safely added for ≤ 1 y after alloSCT and, when added to SOC, reduced the predicted risk of relapse at 18 mo after alloSCT by 54% (vs SOC). Correlative analysis suggests that high levels of pFLT3 inhibition may positively influence outcomes.

BACKGROUND Advanced imaging and serum biomarkers are commonly used for surveillance in patients with early-stage breast cancer, despite recommendations against this practice. Incentives to perform such low-value testing may be less prominent in integrated health care delivery systems. The purpose of the current study was to evaluate and compare the use of these services within 2 integrated systems: Kaiser Permanente (KP) and Intermountain Healthcare (IH). The authors also sought to distinguish the indication for testing: diagnostic purposes or routine surveillance. METHODS Patients with American Joint Committee on Cancer stage 0 to II breast cancer diagnosed between 2009 and 2010 were identified and the use of imaging and biomarker tests over an 18-month period were quantified, starting at 1 year after diagnosis. Chart abstraction was performed on a random sample of patients who received testing to identify the indication for testing. Multivariate regression was used to explore associations with the use of nonrecommended care. RESULTS A total of 6585 patients were identified; 22% had stage 0 disease, 44% had stage I disease, and 34% had stage II disease. Overall, 24% of patients received at least 1 imaging test (25% at KP vs 22% at IH; P = .009) and 28% of patients received at least 1 biomarker (36% at KP vs 13% at IH; P

Advanced imaging is commonly used for staging of early-stage breast cancer, despite recommendations against this practice. The objective of this study was to evaluate and compare use of imaging for staging of breast cancer in two integrated health care systems, Kaiser Permanente (KP) and Intermountain Healthcare (IH). We also sought to distinguish whether imaging was routine or used for diagnostic purposes.We identified patients with stages 0 to IIB breast cancer diagnosed between 2010 and 2012. Using KP and IH electronic health records, we identified use of computed tomography, positron emission tomography, or bone scintigraphy 30 days before diagnosis to 30 days postsurgery. We performed chart abstraction on a random sample of patients who received a presurgical imaging test to identify indication.For the sample of 10,010 patients, mean age at diagnosis was 60 years (range, 22 to 99 years); with 21% stage 0, 47% stage I, and 32% stage II. Overall, 15% of patients (n = 1,480) received at least one imaging test during the staging window, 15% at KP and 14% at IH (P = .5). Eight percent of patients received imaging before surgery, and 7% postsurgery. We found significant intraregional variation in imaging use. Chart abstraction (n = 129, 16% of patients who received presurgical imaging) revealed that 48% of presurgical imaging was diagnostic.Use of imaging for staging of low-risk breast cancer was similar in both systems, and slightly lower than has been reported in the literature. Approximately half of imaging tests were ordered in response to a sign or symptom.

Syphilis recognition in HIV-positive patients has important implications. Initial data from this study, established in June 2012 to better understand the natural history of syphilis and treatment response, examine the characteristics of patients including sexual behaviour, rates of concurrent sexually transmitted infections (STI) and type of treatment given.Patients were recruited from Ireland, Poland and Germany. Data gathered included demographics, method of syphilis acquisition, stage of syphilis infection, HIV status, nadir and current CD4 counts and HIV viral suppression rates. Data were then subanalysed into HIV-positive and HIV-negative groups.Of 175 patients recruited, 68% were HIV-positive and 86.3% were men who have sex with men. Most HIV-positive patients presented with secondary syphilis (55.7% vs 13.2%) (p=0.0001) while the majority of HIV-negative patients had primary syphilis noted at the time of recruitment (47.2% vs18.9%, p=0.0002). Approximately half of all patients had a HIV RNA viral load40 copies/mL (55%). Previous syphilis infection occurred more frequently in HIV-positive than HIV-negative patients (p=0.0001). Concurrent STIs at the time of syphilis diagnosis were found in 26.8%, of whom 31 (25.4%) were HIV-positive (p=0.64). HIV-positive patients received doxycycline more frequently than their HIV-negative counterparts (33.6% vs 1.9%, p=0.0001) while HIV-negative patients were treated with long-acting penicillin in 88.7% of cases vs 58% of HIV-positive patients (p=0.0002).A 40% rate of unsuppressed viraemia, high levels of STIs and varying treatment regimens represent a public health risk for Europe, suggesting the model of sexual healthcare delivery in HIV-positive patients requires further evaluation.

The structural organization of cortical areas is not random, with topographic maps commonplace in sensory processing centers. This topographical organization allows optimal wiring between neurons, multimodal sensory integration, and performs input dimensionality reduction. In this work, a model of topographic map formation is implemented on the SpiNNaker neuromorphic platform, running in realtime using point neurons, and making use of both synaptic rewiring and spike-timing dependent plasticity (STDP). In agreement with Bamford et al. (2010), we demonstrate that synaptic rewiring refines an initially rough topographic map over and beyond the ability of STDP, and that input selectivity learnt through STDP is embedded into the network connectivity through rewiring. Moreover, we show the presented model can be used to generate topographic maps between layers of neurons with minimal initial connectivity, and stabilize mappings which would otherwise be unstable through the inclusion of lateral inhibition.

OBJECTIVE Although cognitive dysfunction persists through affective and euthymic states in bipolar disorder (BD), its neurobiological correlates remain undetermined. We explore whole-cortex intracortical myelin (ICM) and cognition in BD-I and controls. METHODS T1 -weighted images (3T) optimized for ICM measurement were analyzed using a surface-based approach. MRI signal was sampled at cortical mid-depth. Cognitive performance was measured via standardized computerized battery and paper-and-pencil Trails B. RESULTS ICM was associated with verbal memory (VM) in BD throughout a cortical network identified with pertinence to VM function, with strongest effects in left caudal middle temporal cortex and left dorsolateral prefrontal cortex (Pcorrected

Ocular graft-versus-host disease (GVHD) occurs in more than one-half of patients who develop chronic GVHD after allogeneic hematopoietic cell transplantation (HCT), causing prolonged morbidity that affects activities of daily living and quality of life. Here we provide an expert review of ocular GVHD in a collaboration between transplantation physicians and ophthalmologists through the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and the Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation. Recent updates in ocular GVHD regarding pathophysiology, preclinical models, risk factors, prevention, screening, diagnosis, response criteria, evaluation measures, and treatment are discussed. Ocular GVHD involves at least 3 biological processes: lacrimal gland dysfunction, meibomian gland dysfunction, and corneoconjunctival inflammation. Preclinical models have identified several novel pathogenic mechanisms, including the renin angiotensin system and endoplasmic reticulum stress signaling, which can be targeted by therapeutic agents. Numerous studies have identified reliable tests for establishing diagnosis and response assessment of ocular GVHD. The efficacy of systemic and topical treatment for ocular GVHD is summarized. It is important that all health professionals caring for HCT recipients have adequate knowledge of ocular GVHD to provide optimal care. ispartof: Biol Blood Marrow Transplant vol:25 issue:2 pages:e46-e54 ispartof: location:United States status: published

Historically, it has not been uncommon to find discussions of evidentialism clustering around puzzles about the evidence of perception, introspection, memory, intuition, and inference. Evidentialists have given less attention to social epistemology, with the important exception of the epistemic significance of peer disagreement. Taking its cue from this literature, in this essay I will sketch the outlines of a unified evidentialist social epistemology. At its center is a principle about higher-level evidence from the literature on disagreement, the “evidence of evidence principle,” which links our higher-level evidence about the evidence others possess for particular propositions with our own object-level evidence. I will argue that this principle is not only fruitful for understanding the effect of discovering peer disagreement, but that it also accounts for our having evidence from both group and individual testimony. The social epistemology on offer seems to accommodate the common-sense extent of our testimonial evidence, providing an insight into what is unique about social sources of evidence and what is not, as well as pointing ahead to interesting problems for evidentialists in social epistemology.

Background: The development of reduced intensity approaches for allogeneic hematopoietic cell transplantation has resulted in growing numbers of older related donors (RD) of PBSC. The effects of age on donation efficacy, toxicity, and long-term recovery in RD are poorly understood. Methods: We analyzed hematologic variables, pain, donation-related symptoms and recovery in 1211 related PBSC donors aged 18-79 enrolled in the Related Donor Safety Study (RDSafe). Results: RD >60 had a lower median CD34 level pre-apheresis compared to younger RD (age >60, 59x106/L; age 41-60, 81x106/L; age 18-40, 121x106/L; p 24L, p 60 with post-collection thrombocytopenia

Background Antivenom is the treatment of choice for snakebite, which annually kills an estimated 32,000 people in sub-Saharan Africa and leaves approximately 100,000 survivors with permanent physical disabilities that exert a considerable socioeconomic burden. Over the past two decades, the high costs of the most polyspecifically-effective antivenoms have sequentially reduced demand, commercial manufacturing incentives and production volumes that have combined to create a continent-wide vacuum of effective snakebite therapy. This was quickly filled with new, less expensive antivenoms, many of which are of untested efficacy. Some of these successfully marketed antivenoms for Africa are inappropriately manufactured with venoms from non-African snakes and are dangerously ineffective. The uncertain efficacy of available antivenoms exacerbates the complexity of designing intervention measures to reduce the burden of snakebite in sub-Saharan Africa. The objective of this study was to preclinically determine the ability of antivenoms available in Kenya to neutralise the lethal effects of venoms from the most medically important snakes in East Africa. Methods We collected venom samples from the most medically important snakes in East Africa and determined their toxicity in a mouse model. Using a ‘gold standard’ comparison protocol, we preclinically tested the comparative venom-neutralising efficacy of four antivenoms available in Kenya with two antivenoms of clinically-proven efficacy. To explain the variant efficacies of these antivenoms we tested the IgG-venom binding characteristics of each antivenom using in vitro IgG titre, avidity and venom-protein specificity assays. We also measured the IgG concentration of each antivenom. Findings None of the six antivenoms are preclinically effective, at the doses tested, against all of the most medically important snakes of the region. The very limited snake polyspecific efficacy of two locally available antivenoms is of concern. In vitro assays of the abilities of ‘test’ antivenom IgGs to bind venom proteins were not substantially different from that of the ‘gold standard’ antivenoms. The least effective antivenoms had the lowest IgG content/vial. Conclusions Manufacture-stated preclinical efficacy statements guide decision making by physicians and antivenom purchasers in sub-Saharan Africa. This is because of the lack of both clinical data on the efficacy of most of the many antivenoms used to treat patients and independent preclinical assessment. Our preclinical efficacy assessment of antivenoms available in Kenya identifies important limitations for two of the most commonly-used antivenoms, and that no antivenom is preclinically effective against all the regionally important snakes. The potential implication to snakebite treatment is of serious concern in Kenya and elsewhere in sub-Saharan Africa, and underscores the dilemma physicians face, the need for clinical data on antivenom efficacy and the medical and societal value of establishing independent preclinical antivenom-efficacy testing facilities throughout the continent., Author summary Snakebite is one of the most under-researched, under-resourced high morbidty/high mortality NTDs, as reflected by the fact that many of the antivenoms used to treat snakebite victims in sub-Saharan Africa are of uncertain and untested efficacy. This Kenya case study is the first examination of the preclinical efficacy of all available antivenoms to neutralize the venom toxic effects of the most medically important snakes in any region of sub-Saharan Africa. Our results identify serious preclinical efficacy limitations in two of the most commonly used antivenoms, that no single antivenom is effective against all regionally important snakes and that the least effective antivenoms had the lowest IgG concentrations. It is our aim that Ministry of Health medicine-supply regulators can use this data as evidence to demand more detailed efficacy evidence from manufacturers, and to justify the establishment of national/regional preclinical testing facilities. We hope this publication will also alert physicians treating African snakebite victims to check the efficacy of antivenom in their pharmacies. We have carefully qualified the extent and limitation of the results and of our interpretation of the clinical implications thereof.

69 páginas, 9 figuras, 3 tablas, Mambas (genus Dendroaspis) are among the most feared of the medically important elapid snakes found in sub-Saharan Africa, but many facets of their biology, including the diversity of venom composition, remain relatively understudied. Here, we present a reconstruction of mamba phylogeny, alongside genus-wide venom gland transcriptomic and high-resolution top-down venomic analyses. Whereas the green mambas, D. viridis, D. angusticeps, D. j. jamesoni and D. j. kaimosae, express 3FTx-predominant venoms, black mamba (D. polylepis) venom is dominated by dendrotoxins I and K. The divergent terrestrial ecology of D. polylepis compared to the arboreal niche occupied by all other mambas makes it plausible that this major difference in venom composition is due to dietary variation. The pattern of intrageneric venom variability across Dendroaspis represented a valuable opportunity to investigate, in a genus-wide context, the variant toxicity of the venom, and the degree of paraspecific cross-reactivity between antivenoms and mamba venoms. To this end, the immunological profiles of the five mamba venoms were assessed against a panel of commercial antivenoms generated for the sub-Saharan Africa market. This study provides a genus-wide overview of which available antivenoms may be more efficacious in neutralising human envenomings caused by mambas, irrespective of the species responsible. The information gathered in this study lays the foundations for rationalising the notably different potency and pharmacological profiles of Dendroaspis venoms at locus resolution. This understanding will allow selection and design of toxin immunogens with a view to generating a safer and more efficacious pan-specific antivenom against any mamba envenomation. Biological significance: The mambas (genus Dendroaspis) comprise five especially notorious medically important venomous snakes endemic to sub-Saharan Africa. Their highly potent venoms comprise a high diversity of pharmacologically active peptides, including extremely rapid-acting neurotoxins. Previous studies on mamba venoms have focused on the biochemical and pharmacological characterisation of their most relevant toxins to rationalize the common neurological and neuromuscular symptoms of envenomings caused by these species, but there has been little work on overall venom composition or comparisons between them. Only very recently an overview of the composition of the venom of two Dendroaspis species, D. angusticeps and D. polylepis, has been unveiled through venomics approaches. Here we present the first genus-wide transcriptomic-proteomic analysis of mamba venom composition. The transcriptomic analyses described in this paper have contributed 29 (D. polylepis), 23 (D. angusticeps), 40 (D. viridis), 25 (D. j. jamesoni) and 21 (D. j. kaimosae), novel full-length toxin sequences to the non-redundant Dendroaspis sequence database. The mamba genus-wide venomic analysis demonstrated that major D. polylepis venom components are Kunitz-fold family toxins. This feature is unique in relation to the relatively conserved three-finger toxin (3FTx)-dominated venom compositions of the green mambas. Venom variation was interpreted in the context of dietary variation due to the divergent terrestrial ecology of D. polylepis compared to the arboreal niche occupied by all other mambas. Additionally, the degree of cross-reactivity conservation of mamba venoms was assessed by antivenomics against a panel of commercial antivenoms generated for the sub-Saharan Africa market. This study provides a genus-wide overview to infer which available antivenoms may be capable of neutralising human envenomings caused by mambas, irrespective of the species responsible. The information gathered in this study lays the foundations for rationalising the pharmacological profiles of mamba venoms at locus resolution. This understanding will contribute to the generation of a safer and more efficacious pan-Dendroaspis therapeutic antivenom against any mamba envenomation., This study was supported by grants BFU2013-42833-P (Ministerio de Economía y Competitividad, Madrid, Spain), MR/L01839X/1 (Medical Research Council, UK), NNF13OC0005613 (the Novo Nordisk Foundation), Knud Højgaards Fond, Augustinusfonden, PE 2600/1 and the Cluster of Excellence UniCat (Deutsche Forschungsgemeinschaft, Bonn, Germany).

The newly recognized Markagunt gravity slide (MGS) represents gravitationally induced, catastrophic collapse, ca. 21–22 Ma, of the southwest sector of the Oligocene to Miocene Marysvale volcanic field in southwest Utah (USA). The ∼90-km-long slide mass consists of ∼1700–2000 km 3 of andesitic volcanic mudflow breccias and subordinate lava flows, sandstones, and intertongued regional ash-flow tuffs. The MGS extends over an area of >3400 km 2 and advanced >30 km to the south over the Miocene land surface. The low-angle basal slip surface is in Eocene–Oligocene Brian Head Formation, a weak, clay-rich, tuffaceous sedimentary unit at the base of the volcanic section. The presence of a basal zone of cataclastic and sheared breccia with associated clastic dikes, and pseudotachylyte along secondary shear planes, provides strong evidence of catastrophic emplacement. The uniformity of directional indicators, stratigraphy, and overall geometry of the MGS suggests that it represents a single-emplacement event coeval with late-stage magmatic doming of the volcanic field. The MGS thus represents one of the largest subaerial volcanic landslides on Earth, and along with the comparable Heart Mountain gravity slide in northwest Wyoming, constitutes a class of catastrophic collapse hazard not widely recognized within modern volcanic fields.

Allogeneic hematopoietic cell transplantation (alloHCT) with reduced-intensity conditioning is an appealing option for patients with high-risk multiple myeloma (MM). However, progression after alloHCT remains a challenge. Maintenance therapy after alloHCT may offer additional disease control and allow time for a graft-versus-myeloma effect. The primary objective of this clinical trial was to determine the tolerability and safety profile of maintenance lenalidomide (LEN) given on days 1 to 21 of 28 days cycles, with intrapatient dose escalation during 12 months/cycles after alloHCT. Thirty alloHCT recipients (median age, 54 years) with high-risk MM were enrolled at 8 centers between 2009 and 2012. The median time from alloHCT to LEN initiation was 96 days (range, 66 to 171 days). Eleven patients (37%) completed maintenance and 10 mg daily was the most commonly delivered dose (44%). Most common reasons for discontinuation were acute graft-versus-host disease (GVHD) (37%) and disease progression (37%). Cumulative incidence of grades III to IV acute GVHD from time of initiation of LEN was 17%. Outcomes at 18 months after initiation of maintenance were MM progression, 28%; transplantation-related mortality, 11%; and progression-free and overall survival, 63% and 78%, respectively. The use of LEN after alloHCT is feasible at lower doses, although it is associated with a 38% incidence of acute GVHD. Survival outcomes observed in this high-risk MM population warrant further study of this approach.

We conducted a study of patients with multiple myeloma (MM) undergoing allogeneic transplantation to evaluate outcome parameters. Fifty-seven consecutive patients with MM received an allogeneic transplantation between 2004 and 2011 at our institution. Patients who had received at least 1 prior autologous transplantation were included. Twenty-six patients underwent allogeneic transplantation for consolidation after a response to their first autograft, and 30 patients received an allogeneic transplantation as salvage therapy. Donor source was evenly distributed between related and unrelated. The median follow-up was 52 months. Thirty-two (57.1%) patients achieved a complete response (CR). At 5 years, 49.2% of all patients were in CR. Sixteen patients received either donor lymphocyte infusions or immune suppression withdrawal for disease progression, with a 62.5% response rate. The 5-year overall survival (OS) for all patients was 59%. The 5-year OS for the 30 patients in the consolidation group was 82% compared with 38% for those in the salvage group. In multivariate analysis, 3 factors remained significantly associated with OS. These include being in the salvage group (hazard ratio [HR], 4.05; P = .0196), acute graft-versus-host disease (aGVHD) (HR, 2.99; P = .034), and chronic graft-versus-host disease (cGVHD), which was highly protective, with a 5-year OS of 78.8% for patients with cGVHD versus 42.6% for patients without cGVHD (HR .17, P = .008). Our data show that allogeneic transplantation for MM can lead to sustained remissions. aGVHD is significantly deleterious to OS and progression-free survival, whereas cGVHD is strongly favorable, supporting an important role for the graft-versus-myeloma effect.

According to Roderick Chisholm, there are three ways of responding to the Problem of the Criterion and they all leave something to be desired. Michael DePaul, Paul Moser, and Earl Conee have each proposed variations of a fourth way of responding to this problem that rely on reflective equilibrium. We argue that these four options for responding to the Problem of the Criterion leave one with a tough choice: accept one of the three that Chisholm describes or DePaul’s reflective equilibrium approach and beg the question or accept a reflective equilibrium response of the sort Conee and Moser propose and embrace epistemic circularity.

Objective Although hematopoietic stem cell transplant (HSCT) patients may experience neurocognitive impairment, experiences of neurobehavioral problems (including apathy and disinhibition) are understudied. These experiences reflect behavioral signs and symptoms of neurological dysfunction that can potentially reduce health-related quality of life (HRQOL). Understanding them is important because they may be confused with other diagnoses, including depression, potentially leading to inappropriate treatments. The objectives of this preliminary cross-sectional study were to describe HSCT patients' neurobehavioral functioning pre-HSCT and post-HSCT and to examine relations with HRQOL. Methods Patients (n = 42) 9 months to 3 years post-HSCT completed measures of neurobehavioral functioning to report apathy and disinhibition pre-HSCT (retrospectively) and post-HSCT (currently). Paired t-tests and McNemar tests were used to explore differences in the incidence of patient-reported neurobehavioral problems within and across time points. Regression analyses were conducted to examine relations between neurobehavioral functioning and physical and mental HRQOL. Results Elevated levels of apathy were reported by many patients post-HSCT (36%) and increased significantly from pre-HSCT to post-HSCT (p = 0.001). Hierarchical regression analysis indicated that higher levels of apathy were associated with reduced mental HRQOL (p

Objectives The incidence of human papillomavirus (HPV)-associated anal cancer is increasing. Men who have sex with men (MSM), particularly those coinfected with HIV, are disproportionately affected. Documenting the molecular epidemiology of HPV infection is important in guiding policy makers in formulating universal and/or targeted vaccine guidelines. Methods A prospective cohort study was conducted. HIV-positive and HIV-negative MSM > 18 years old were invited to participate. Provider-performed anal swabs were collected and anal HPV infection was detected using consensus primer solution phase polymerase chain reaction (PCR) followed by type-specific PCR for high-risk (HR)-HPV types 16, 18 and 31. Between-group differences were analysed using χ2 tests and Wilcoxon rank tests. Results One hundred and ninety-four MSM [mean (standard deviation (SD)) age 36 (10) years; 51% HIV-positive) were recruited. The median number of sexual contacts in the preceding 12 months was 4 (interquartile range 2-10). HIV-positive subjects had a mean (SD) CD4 count of 557 (217) cells/μL, and 84% were on highly active antiretroviral therapy (HAART). Thirty-one samples were B-globin negative and thus excluded from further analysis. A total of 113 subjects (69%) had detectable HPV DNA. Sixty-eight subjects (42%) had an HR-HPV type detected. HR HPV type 16 was detected in 44 samples (27%), HR-HPV type 18 in 26 samples (16%) and HR-HPV type 31 in 14 samples (23%). Twenty-eight subjects (17%) had more than one type of HR-HPV type detected. When HPV and HR-HPV were stratified by age, those > 35 years had a higher prevalence (P = 0.001 and P = 0.028, respectively). HIV-positive subjects were more likely than HIV-negative subjects to have any detectable HPV (77% vs. 61%, respectively; P = 0.04), to have HR-HPV type 18 or 31 (P = 0.05 and P = 0.006, respectively) and to be infected with more than one HR-HPV type (31% vs. 3%, respectively; P

Background: AlloHCT is a potentially curative treatment for patients with acute myeloid leukemia (AML) and other myeloid malignancies (MM), however has a 40% relapse rate. The 2-year post-relapse survival rate is less than 20%; sustainable remissions are rare. Multiple strategies to mitigate relapse have been employed with variable degrees of success. An as yet untested approach involves manipulation of the T-cell milieu in the post-alloHCT setting using CI. Preclinical animal models of tumors have shown that blockade of PD-1 by monoclonal antibodies(mAbs) can enhance the anti-tumor immune response and result in tumor rejection, suggesting that host mechanisms limit the antitumor response. A murine model of an anti-PD-1 mAb given at the time of transplant showed that PD-1/PD-L1 interactions decrease acute GVHD, but increase chronic GVHD suggesting that PD-1 pathway modulation may provide unique opportunities for stimulating immune regulation post-alloHCT. Use of ipilimumab (I) to treat post-transplant MM resulted in a complete response rate of 42% and decreased the Treg/Tconv cell ratio, consistent with enhancement of the graft-versus-tumor effect. The CPIT-001 Trial demonstrated the feasibility and safety of combined CI with I and nivolumab (N) as consolidation following autologous stem cell transplantation (ASCT) for high-risk hematological malignancies as well as a 67% PFS rate at 18 months post-ASCT, a significant improvement as compared with historical data. Study Design: The study employs a 3x3 design with intrapatient dose escalation. Patients will alternately be assigned to receive either N or I as a single agent. If the safety endpoint is met for each group, enrollment to the combination CI group will open. See table 1 for dosing. For all Groups, intrapatient dose escalation will be utilized. If the patient tolerates 28 days of treatment, he/she will be escalated to the next dose level and the next patient will be enrolled. Enrollment must occur within 60 days prior to HCT conditioning to allow for collection of baseline samples. Patients will start CI therapy 60 to 100 days after stem cell infusion when acute GvHD is adequately controlled on a prednisone dose of 20 mg daily or less, organ function, and peripheral counts are adequate. Key inclusion criteria at study start up included patient age 75 years or less with high risk AML or MDS undergoing alloHCT with a matched-related or 10/10 unrelated donor who were receiving non-myeloablative conditioning. Bone marrow aspiration will be performed for response evaluation approximately every 3 months post CI initiation. The primary objective is to assess the safety of CI in this patient population. Secondary objectives include efficacy, assessment of blood immune reconstitution, phenotype and TCR repertoire by sequencing, assessment of tumor site immune phenotype, TCR repertoire and PD-L1/2 expression both prior to alloHCT conditioning and at relapse. The tertiary objective is to identify specific intestinal microbial strains associated with improved outcomes in alloHCT patients treated with CI. Microbial composition in stool samples of patients will be analyzed at screening, at engraftment, at various time points post-transplant, and at time of relapse, as it occurs. Study Experience Thus Far: The study opened to accrual in May of 2017. Four patients have signed informed consent. Two patients have been treated with CI. One patient withdrew consent prior to treatment and a second patient is currently status post alloHCT, but has not yet reached day 60. One patient received 2 doses of N and the second patient received 1 dose of I. Accrual to trial has been slower than anticipated. A detailed analysis of the patient screening log was completed. It was determined that 139 patients had been screened for trial. Major reasons for being ineligible included a diagnosis of ALL (34 patients; 24%), use of a haploidentical donor (30 patients; 22%), use of a full dose conditioning regimen (14 patients; 10%), diagnosis of CML (12 pateints; 10%), age greater than 75 (12 patients; 9%), diagnosis of CMML (12 patients; 9%). Following this analysis, an amendment was filed to include patients receiving haplo identical transplant and/or myeloablative conditioning, and to expand diagnosis to include all MM including CMML, CML blast crisis, and myelofibrosis. Disclosures Koprivnikar: Amgen: Speakers Bureau; Pfizer: Honoraria; Abbvie: Speakers Bureau; Novartis: Speakers Bureau. McCloskey:Jazz: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Takeda: Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Abbvie: Speakers Bureau; Novartis: Speakers Bureau. Rowley:Fate Therapeutics: Consultancy; Allergan: Equity Ownership. OffLabel Disclosure: Nivolumab - immunomodulation Ipilimumab - immunomodulation

Background: The discovery that gut microbial dysbiosis correlated with prognosis, immune reconstitution and development of graft-versus-host disease (GVHD) in patients undergoing allogeneic stem cell transplantation (allo-SCT) highlights the clinical relevance of the gut microbiome in shaping anti-tumor immune responses. Treatment of allo-SCT patients with antibiotics has recently been associated with increased GVHD mortality (Routy et al. 2017). Based on these studies and the association of distinct gut bacteria with increased efficacy to PD-1 blockade in patients with solid tumors (Derosa et al. 2018), we performed a retrospective analysis to determine if infection treated with antibiotics affected the outcomes of multiple myeloma (MM) patients after autologous SCT (ASCT). Methods: A list of all MM patients treated at our institution between January 2012 through December 2015 was obtained and 1095 patients were identified. A comprehensive review of the electronic medical record (EMR) of the first 142 who received ASCT was performed. Information was collected from diagnosis to the date of last contact. Baseline characteristics, treatment history, transplant course, antibiotic treatment, and infection severity using common terminology criteria for adverse event (CTCAE) version 4 were reviewed. Prophylactic antibiotics were excluded. Response was measured and defined using the International Myeloma Working Group Criteria. Progression free survival (PFS) and overall survival (OS) were estimated using log rank tests. Cox hazard stepwise regression model examined for multiple factors affecting PFS and OS using the Akaike information criterion. Results: Of the 142 patients, 93 (65%) were Durie Salmon (DS) III, 20 (14%) were Revised International Staging System (R-ISS) III, 44 (31%) had high-risk cytogenetics, and 76 (54%) were male. The median age at diagnosis was 60. Although there was a similar frequency of DS III (67% vs 61%) and high-risk cytogenetics (35% vs 25%) among patients in the antibiotic and non-antibiotic treated groups, there was an over-representation of R-ISS 3 (19% v 4%) patients in the antibiotic-treated group. Treatment with antibiotics was associated with decreased median PFS (2.38 vs 6.58 years (yrs), p =0.00003) (Figure 1a) and decreased median OS (7.43 vs 17.39 yrs, p = Multivariate analysis demonstrated progression risk associated with beta-lactam use (HR-2.25, 95% CI, 1.31 - 3.85, p = 0.003), and DSS III (HR-2.28, 95% CI, 1.23 - 4.21, p = 0.009). Multivariate analysis demonstrated increased mortality associated with antibiotic treatment (HR-5.70, 95% CI, 1.34 - 34.29, p = 0.019) and decreased mortality risk with age younger than 65 (HR-0.24, 95% CI, 0.07 - 0.81, p = 0.022). For both PFS and OS, there was no statistical significance demonstrated in multivariate analysis for gender, fluoroquinolone treatment, high risk cytogenetics, R-ISS 3, or CTCAE grade. Conclusion: In this preliminary study, antibiotic use and infection severity predicted for decreased PFS and OS compared to patients who did not receive antibiotics in MM patients undergoing ASCT. Treatment with at least 2 classes of antibiotics-fluoroquinolones and beta-lactams, predicted for decreased PFS and OS. Multivariate analysis showed increased progression risk with beta lactams and DSS III as well as increased mortality risk with antibiotic treatment and advanced age. The study was limited by its relatively small sample size, retrospective nature, and the high correlation among infection and antibiotic groups that affected the multivariate analysis. Work is underway at our institution to further elucidate the impact of antibiotics on microbial diversity and patient survival. Disclosures Goldberg: COTA: Equity Ownership; Bristol-Myers Squibb: Consultancy; Cancer Outcomes Tracking and Analysis (COTA) Inc.: Equity Ownership. Rowley:Allergan: Equity Ownership; Fate Therapeutics: Consultancy. Siegel:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Biran:Merck: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Bristol Meyers Squibb: Research Funding.

Background: Salvage autologous hematopoietic stem cell transplantation (HSCT) is an effective treatment for patients with relapsed multiple myeloma (MM). Adequate HPSC after multiple cycles of dose-intense melphalan (mel) can be harvested, cryopreserved, and stored to allow for such future transplants. Many investigators reported sustained CD34+ cell viability using in vitro assays such as colony forming units (CFU-GM) potency of HPSCs after long term storage. Data on engraftment outcomes using these products demonstrating in vivo viability are limited. This study describes a large single center experience evaluating the engraftment potential of HPSC used in salvage transplantation after long-term storage in patients with MM, in comparison to initial treatment. Study Design and Methods: We conducted a retrospective chart review of patients with MM undergoing salvage HSCT, whose initial cell collection occurred between January 2002 and May 2016. This review identified 59 patients, all conditioned for initial transplants with dose-intense Mel 200 mg/m2, and who received autologous HPSC stored > 1 year after initial HSCT. HPSC were cryopreserved and stored in vapor phase liquid nitrogen at a temperature of ≤-150°C. Conditioning regimens for salvage transplants were mel (n=11), mel/bortezomib (bor) (n=32), mel/bor/thalidomide (n=6), BEAM (n=1), and Super BEAM (n=9). Patients who received a planned tandem transplant only (less than a year apart) were excluded. For patients receiving tandem HSCT followed by salvage HSCT, the first of the tandem HSCTs was considered for this analysis (n=5). Differences in CD34+ cell doses and days to engraftment between first and salvage transplant were tested using a paired 2-tailed t-test. Univariate and multivariable linear regressions were used to determine association between storage time and days to engraftment. Results: From 2002 to 2017, transplant data from 59 MM patients were analyzed (Table 1). Forty-nine (83%) patients had a Salmon Durie stage IIIA or IIIB at first diagnosis. The median age at first diagnosis was 57.5 (range, 36-73) years. A median collection dose of 16.0 × 106 CD34+ cells per kilogram (range, 7.9-62.5) was reached during HPSC collection with a median of 3 collections (range, 1-7) per patient. All 59 patients collected upon first mobilization attempt. The median age of patients at time of first and salvage transplants was 59 and 62 years, respectively. As predicted, the patient's age at salvage transplant was significantly greater than the age at first transplant (p500 /uL) at a median of 11 days after both the first and salvage transplant (ranges, 9-18 and 8-15 respectively, p=0.041) (Figure 1). The median time to sustained platelet engraftment (>20 x 109/L) was 13 days (range, 9-36) after first HSCT and 14 days (range 8-45) after salvage HSCT (p=0.842) (Figure 1). The CD34 dose for the salvage transplant was significantly higher than the first transplant, with patients undergoing the first HSCT receiving a median CD34+ cell dose of 5.3 × 106/kg (range 3.0-14.1), compared to a median of 6.1 × 106/kg (range 3.4-13.8) for the salvage HSCT (p=0.04). There was no association between the CD34 dose infused and days to ANC (p=0.755) or platelet (p=0.669) engraftment. After adjusting for age at transplant and CD34 dose, there was no association between duration of cryopreservation and days to ANC (p=0.658) and platelet (p=0.725) engraftment (Figure 2). There were no graft failures reported in either the first or salvage HSCT. Conclusion: Long-term cryopreservation did not affect engraftment outcomes in patients with MM receiving salvage autologous HSCT, despite the addition of salvage chemotherapy. There was no association between engraftment kinetics and storage duration in patients receiving a salvage transplant when controlling for CD34 dose and recipient age. Although it is possible that these cell products may have lost HPSC viability but still contained more than adequate viable HSC for HSCT, there was no evidence of delayed engraftment, particularly of platelets, suggestive of low numbers of viable HSCT. Disclosures Biran: Celgene: Consultancy, Honoraria; Bristol Meyers Squibb: Research Funding; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Goldberg:Bristol-Myers Squibb: Consultancy; Cancer Outcomes Tracking and Analysis (COTA) Inc.: Equity Ownership; COTA: Equity Ownership. Siegel:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Rowley:Allergan: Equity Ownership; Fate Therapeutics: Consultancy.

Introduction: Patients with high-risk multiple myeloma (HRMM) who have undergone autologous stem cell transplant (ASCT) will inevitably relapse and have a progression free survival (PFS) ranging from 8-14 months (Gaballa et al, American Journal of Hematology, 2016) and 24-39 months while on lenalidomide (Len) maintenance therapy (Jackson et al, The Lancet Oncology, 2019). Unlike in solid tumors, PD-1 blockade has no single agent activity in relapsed and refractory multiple myeloma (MM) patients suggesting that immune stimulating agents, immunomodulatory agents (IMiDs), such as lenalidomide (Len) or pomalidomide (Pom) are necessary in combination with anti-PD-1 blockade to increase depth and duration of response post-ASCT. The Keynote-023 study revealed an overall response rate (ORR) of 76% with the combination of pembrolizumab (Pem), Len and dexamethasone (Dex). Similarly, the Keynote 135 study using the combination of Pem, Pom, and Dex revealed an ORR of 60%. Unfortunately, the phase III studies comparing an IMiD vs Pem with the IMiD upfront at the early relapsed setting were halted because of increased deaths on the Pem arm and a decreased median PFS. With our Phase II study currently on clinical hold by the FDA, we are presenting here the 2-year follow-up of the original patient cohort including some preliminary safety and efficacy data of Pem-Len-Dex in HRMM patients as post-ASCT consolidation (NCT02906332). Methods: Patients with HRMM who have undergone induction therapy followed by single or tandem melphalan-based ASCT were considered eligible 2-6 months post ASCT. HRMM criteria are defined by any of the following: ISS stage 3; del 13q by cytogenetics; FISH with 1q amplification, 1p deletion (del), p53 del, t(4;14), t(14;16), t(14;20), hypodiploidy; or a high-risk gene expression profile score. Patients were excluded if they had progression of disease at time of screening or if there was evidence of organ dysfunction. Patients received Pem 200 mg IV at day 1;Len 25 mg po daily at days 1-14; and Dex 40 mg daily at days 1,8,15 of a 21-day cycle for a total of 2 cycles and then an additional 2 cycles of Pem + Len without Dex at the same dose and frequency. Survival outcomes post-ASCT were measured using the log-rank test. Results: Of 15 patients screened, 12 received at least one dose of therapy and were deemed evaluable. One patient withdrew consent and did not follow up after cycle 2. Baseline characteristics are shown in Table 1. Thirty-three percent were ISS 3, 66.7% had a p53 deletion by FISH, 41.6% received induction Bortezomib-Len-Dex; 33% received induction Carfilzomib-Len-Dex, and the remaining 24.9% received other bortezomib-based induction. Best ORR during the 2 year follow up showed 8 patients (73%) achieving stringent complete remission, 2 patients (18%) showing complete remission and 1 (9%) achieving very good partial remission. Table 2 shows best response to treatment by cycle of therapy. Table 3 shows best response during follow-up visits, which were 3 months apart. Of the 11 patients who completed therapy, 8 had minimal residual disease (MRD) status assessed and among them, 7 were MRD negative by flow cytometry, tested 30 days after the fourth cycle. With a median follow-up of 32.2 months, median PFS was 27.6 months. The PFS rates at 1 year and 2 year are 91.3% and 65.2%, respectively. All patients had adverse events (AEs), AEs were attributed to Pem, Len, or Dex rather than from ASCT. Of the 90 AEs that were reported, 5.6% were grade 3 and 94% were grade 1 or 2 (Table 3). The most common hematologic AE was neutropenia (41.7%), with 3 pts (25%) grade 1 and 2, and 2 pts (16.6%) grade 3. The most common non-hematologic AEs were intermittent constipation (16.6%), diarrhea (16.6%), fatigue (8.3%), and increased ALT (8.3%) and were graded as 1 or 2. Non-hematologic grade 3 AEs occurred in 2 pts and included hypoxia and maculopapular rash. There was 1 serious AE, H. influenza pneumonia requiring inpatient admission, which was not considered to be related to Pem. Conclusions: The combination of Pem, Len, and Dex given to HRMM patients in the post-ASCT consolidation setting is well tolerated. In comparison to historical controls of HRMM patients post-ASCT with a median PFS of 8-14 months, the PFS rates of 91.3% and 65.2% at 1 and 2 year post-ASCT respectively suggest an efficacy signal for the use of Pem, Len, and Dex as post-ASCT consolidation. Larger prospective studies are needed to validate these results. Disclosures Siegel: Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Rowley:Allergan: Equity Ownership; Fate Therapeutics: Consultancy. Biran:Amgen: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Bristol Meyers Squibb: Research Funding.

Telmisartan (TMS) is an angiotensin receptor blocker with anti-inflammatory properties and little or no clinical immunosuppressive effect. We undertook an unblinded, single arm, pilot study of TMS (160 mg/d p.o.) for prevention of acute graft vs. host disease (aGvHD) in recipients of HLA matched allogeneic hematopoietic stem cell transplants (HSCTs). Primary endpoints of Grade II or >Grade III aGvHD (1994 Consensus Conference on Acute GVHD Grading) were compared with 178 similar HSCT historical controls over the preceding 3 yrs at our institution: 26% >Grade III, 74% Grade II. Safety endpoints included engraftment, relapse/progression by day (d) 180, non-relapse mortality by d 180, and serious drug-related adverse reactions. Experimental data were collected on blood endotoxin levels and stool microbiome composition. The study was powered to detect 20% or 50% reduced rates of, respectively, Grade II or >Grade III. We report results from a planned interim analysis triggered when the first 22 evaluable patients (pts) reached d 100. Of 27 evaluable pts, 24 were beyond d 180 by completion of this interim analysis. The study was designed to treat pts for two days prior to, and day of HSCT, and for an additional 98 days post-transplant, but pts were considered evaluable if they completed >14 days of post- transplant TMS, including pre-determined dose reductions. One enrollee received TMS for 13 days post-HSCT and was excluded from analysis. Five pts received 14-24 days of drug (4 by choice, 1 died of sepsis). More than half the evaluable patients (17/27) completed >94 days of post-HSCT therapy, including 6 who experienced an episode of hypotension. Almost half (13/27) received >80% of the full 101 day dose (16,160 mg), including 5 who experienced hypotension. Of the 6 enrollees receiving Safety Endpoints: All pts engrafted promptly (ANC >500/uL, platelet >20,000/uL). Peripheral donor CD3+ T cell median and range of chimerism on days 28 and 84 were 99.5% (37-100) and 100.0% (36-100); bone marrow donor CD34+ cell chimerism was 97.0% (62-100). There was a single NRM during the 180 d study, and no graft rejection or increase in relapse or progression. Four relapses occurred within 180 days, and 2 more after d 180, resulting in two relapse deaths (d 370, and d 600). Primary Endpoints:A single individual developed hyperacute Grade III skin GvHD on day 7 p-HSCT. Another 12 of 27 patients developed Grade 2 aGvHD, one after the conventional 100 d window (d 141). Compared with historical controls, the incidence of aGvHD was significantly reduced for Grade II (p < 0.005) and Grade >III (p = 0.01), using the two-tailed Z-test of proportions. Experimental Endpoints: Acute GvHD is associated with increased gut permeability, bacterial translocation, and loss of gut microbiome diversity. Endotoxemia, an indicator of intestinal integrity, as measured by the endotoxin activity assay (EAA, Spectral Medical) reached septic levels in 40% of patients during pre-transplant conditioning (d -3 - d 0), and subsequently returned to, or maintained, non-septic levels from week 5 onward in 90% of patients, with an overall downward group trend of EAA scores during 180 days of follow up. Genotyping and analysis of bacterial V4 16S ribosomal DNA from weekly stool samples of the first 10 evaluable patients revealed no decrease in OTU richness or Shannon diversity at any time point pre- vs. post- treatment. Among the 5 most abundant phyla, Bacteroidetes was significantly less abundant post-treatment compared to pre-treatment. Among the 8 most abundant families, Bacteroidaceae significantly decreased post- vs. pre- treatment. While historic microbiome controls from our institution are not available, our finding of increased Bacteroidetes is in contrast to reported decreased Bacteroidetes in allogeneic HSCTs not receiving TMS, but may resemble changes after autologous HSCT. This trial, funded by the Gateway Foundation, is ongoing. Preliminary results indicate TMS is well tolerated, with a beneficial impact on aGvHD and no increased relapse or NRM, with excellent engraftment, and preservation of anti-tumor effect, intestinal barrier integrity, and gut microbial diversity. Disclosures Iyengar: Hackensack University Medical Center: Patents & Royalties: Telmisartan use patent.. Rowley:Allergan: Equity Ownership; Fate Therapeutics: Consultancy. Schwartz:Hackensack University Medical Center: Patents & Royalties: Telmisartan use patent. OffLabel Disclosure: Telmisartan. Indicated for treatment of hypertension.

Introduction: Patients (pts) with high-risk multiple myeloma (HRMM) experience early disease progression post autologous stem cell transplant (ASCT). The median progression free survival (PFS) for HRMM pts undergoing ASCT with lenalidomide (len) maintenance ranges between 27 and 42 months in high risk pts and 22 months in ultra-high risk, defined by two or more adverse cytogenetic abnormalities such as: gain(1q), t(4;14), t(14;16),t(14;20), or del(17p)( Chakraborty et al, Leukemia,2018 and Jackson et al, Lancet, 2018). Elotuzumab, a humanized IgG kappa monoclonal antibody against SLAM-F7 (CS-1), is approved in combination with len and dexamethasone (ERd) in pts with relapsed MM (Dimopoulus et al, BJH, 2017). It directly activates natural killer (NK) cells and mediates myeloma cell death by antibody-dependent cell mediated cytoxicity. We hypothesized that administration of ERd as post-ASCT consolidation will enhance an immune-competent phenotype, by restoring NK cells and effector T-cell populations at a time of maximal disease de-bulking, and will ultimately improve outcomes among pts with HRMM. Methods: Thirty-one HRMM patients who achieved stable disease or better were treated beginning at 30-90 days post ASCT with ERd (29/31 pts) or elotuzumab/pomalidomide )/dex (EPd) (2/31 pts) between September 2016 and February 2019. With institutional review board approval, electronic medical records were reviewed for baseline characteristics, treatment history, adverse events (AE) while on therapy as defined by common terminology criteria for adverse events (CTCAE), and survival outcomes. Treatment with ERd or EPd was administered for 4 consecutive 28-day cycles per standard dosing regimens with a tapering or discontinuation of corticosteroids per investigator discretion with cycles 3 and 4. HRMM was defined by any of the following: ISS or Revised-ISS stage 3, CD-138 selected FISH with del 17p, 1q21 gain, t(4;14), t(14;16), and t(14;20), cytogenetics with 13q del or complex karyotype, and/or high-risk gene expression profile score. Ultra-HR pts were defined by having both del 13q and 1q21 gain by FISH based on recent unpublished COMPASS data. Minimal residual disease (MRD) was evaluated upon achievement of very good partial remission or complete remission using 10-color multiparametric flow cytometry. PFS was measured using the log-rank test. Response criteria was defined per International Myeloma Working Group criteria. Results: Baseline characteristics of all 31 patients are shown in Table 1. Thirty-four percent were ISS-3, 71% (22/31 pts) had high-risk FISH, of which 19% were ultra-high risk (6/22 pts). Seven pts (22.6%) underwent tandem-ASCT pre-consolidation. Of the 8 pts who had GEP testing, 2 (25%) were high risk. Best response to treatment by cycle is depicted in Table 2. Consolidative ERd/EPd deepened response compared to post-ASCT with 71.4% vs 19.4% achieving stringent complete remission (sCR). Post-consolidation, 19.3% vs 12.9%, pre-consolidation, achieved MRD negativity. With a median follow-up of 24.8 months, median PFS was 31.4 months (Figure 1). There was no significant association between median PFS and variables such as tandem ASCT and ultra-HR using multivariate cox regression. Although all pts experienced at least one AE while on therapy, only 1 patient (3.22%) experienced a grade 3 AE. Hematologic AEs included: anemia (48%), neutropenia (45%), and thrombocytopenia (52%), while the most common non-hematologic AEs included: fatigue (32%), malaise (23%), and back pain (19%). One patient experienced a serious AE (SAE) which was PCP pneumonia requiring hospitalization, resulting in early discontinuation from therapy. There was no treatment-related mortality. Conclusion: ERd or EPd as 4 months of fixed duration consolidation therapy post-ASCT resulted in a median PFS of 31.4 months amongst pts with HRMM, similar to or perhaps surpassing historical reports of HRMM pts receiving lenalidomide maintenance until progression. This therapy may offer comparable, if not superior, outcomes while having the advantage of allowing for significant time without therapy and perhaps improving quality of life and financial toxicity. This study is limited due to its retrospective nature. Larger prospective studies evaluating fixed duration ERd/EPd in HRMM patients post ASCT should be conducted. Disclosures Rowley: Allergan: Equity Ownership; Fate Therapeutics: Consultancy. Goldberg:COTA: Equity Ownership; Bristol-Myers Squibb: Consultancy; Cancer Outcomes Tracking and Analysis (COTA) Inc.: Equity Ownership. Siegel:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Biran:Bristol Meyers Squibb: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Merck: Research Funding.

Engraftment syndrome (ES) is a well-defined entity characterized by non-infectious fever and other clinical manifestations including skin rash, pulmonary infiltrates, diarrhea, weight gain and neurological symptoms which happens in the setting of autologous HSCT during early neutrophil recovery phase. (Spitzer ,2001).These clinical manifestations usually occur immediately before or at the time of neutrophil engraftment possibly due to the release of inflammatory cytokines. ES may require therapy with corticosteroids and other immunosuppressive drugs. Our study cohort included 645 patients with multiple myeloma treated with autologous stem cell transplantation between January 2010 and June 2019. The majority of patients had a single autologous transplant (80%), 18 % received a second autologous transplant and 3 patients had a third autologous transplant. Fifty seven percent of patients were male, 61 % had IgG myeloma and 50 percent had standard risk cytogenetics. Sixty three percent of patients were under the age of 65 years. ES was defined as a combination of at least 2 symptoms not attributed to other causes, including non-infectious fever, diarrhea, skin rash, pulmonary infiltrates or hepatic dysfunction, occurring from 3 days prior to 10 days post engraftment. (Cornell ,2015).One hundred and ninety seven patients in this cohort met the criteria for engraftment syndrome of whom 173 were treated with corticosteroids and 9 required the addition of tacrolimus or cyclosporine. Univariate and multivariate statistical analyses were performed looking at risk factors for the development of ES and the overall effect of ES on patient outcome. Results of our univariate analysis showed that age >65, female sex, use of plerixafor were significant risk factors for developing engraftment syndrome while use of cyclophosphamide-based mobilization had significantly reduced risk. Multivariate analysis using Gray Fine model revealed that patients over 65 years were twice as likely to develop ES than patients who were younger than 65 years (HR=1.881, CI: 1.405 to 2.518). Females had a 36% higher risk of ES than male patients (HR=1.355, CI: 1.011 to 1.815). Patients who were infused with more than 7x106 CD34+ cells/kg had a 40% reduced risk of developing ES (HR=0.559, CI: 0.385 to 0.812). Receiving the new formulation of melphalan: EVOMELAⓇ, as preparative regimen, was associated with a 60% increased risk of developing ES compared to patients treated with the standard formulation (HR=1.597, CI: 1.116 to 2.285). The use of plerixafor was found to be a risk factor for ES even when adjusted for age(HR=1.463,CI:1.024 to 2.089). Follow- up of patients that did not develop ES (n=445) had a median of 59 months (IQR: 29.0 -80.0months), range: 0 - 136 months. Follow-up time of patients that developed ES (n=197) was 41.0 months (IQR: 16.0 - 66.0 months), range: 0.0 - 131 months.An overall survival analysis of patients who developed engraftment syndrome showed a trend for improved survival in patients who did not develop engraftment syndrome, however this did not meet statistical significance and PFS curves were similar with no statistically significant difference between the two groups. Our study of this large cohort of patients suggests that selection of mobilization regimen and conditioning chemotherapy could decrease the incidence of ES, thereby decreasing morbidity and prolonged hospital stay. There can also be a consideration for pre-emptive treatment of patients in the very high risk category based on age, gender and available cell dose. Disclosures Siegel: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Rowley:Allergan: Equity Ownership; Fate Therapeutics: Consultancy. Biran:Amgen: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Bristol Meyers Squibb: Research Funding. Goldberg:Cancer Outcomes Tracking and Analysis (COTA) Inc.: Equity Ownership; Bristol-Myers Squibb: Consultancy; COTA: Equity Ownership. Goy:Takeda: Other: Grants outside of the submitted work; Hackensack University Medical Center, RCCA: Employment; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work, Research Funding; Hakensackumc: Research Funding; University of Nebraska: Research Funding; Astrazenca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Other: Grants outside of the submitted work, Research Funding; Pharmacyclics/Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work; COTA: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: leadership role for profit healthcare company; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

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The ten-eleven translocation 1 ( TET1 ) gene is the founding member of the TET family of enzymes (TET1/2/3) that convert 5-methylcytosine to 5-hydroxymethylcytosine. Although TET1 was first identified as a fusion partner of the mixed lineage leukemia ( MLL ) gene in acute myeloid leukemia carrying t(10,11), its definitive role in leukemia is unclear. In contrast to the frequent down-regulation (or loss-of-function mutations) and critical tumor-suppressor roles of the three TET genes observed in various types of cancers, here we show that TET1 is a direct target of MLL-fusion proteins and is significantly up-regulated in MLL -rearranged leukemia, leading to a global increase of 5-hydroxymethylcytosine level. Furthermore, our both in vitro and in vivo functional studies demonstrate that Tet1 plays an indispensable oncogenic role in the development of MLL -rearranged leukemia, through coordination with MLL-fusion proteins in regulating their critical cotargets, including homeobox A9 ( Hoxa9 )/myeloid ecotropic viral integration 1 ( Meis1 )/pre-B-cell leukemia homeobox 3 ( Pbx3 ) genes. Collectively, our data delineate an MLL-fusion/Tet1/Hoxa9/Meis1/Pbx3 signaling axis in MLL -rearranged leukemia and highlight TET1 as a potential therapeutic target in treating this presently therapy-resistant disease.

In experimental models, ex vivo induced T-cell rapamycin resistance occurred independent of T helper 1 (Th1)/T helper 2 (Th2) differentiation and yielded allogeneic CD4+ T cells of increased in vivo efficacy that facilitated engraftment and permitted graft-versus-tumor effects while minimizing graft-versus-host disease (GVHD). To translate these findings, we performed a phase 2 multicenter clinical trial of rapamycin-resistant donor CD4+ Th2/Th1 (T-Rapa) cells after allogeneic-matched sibling donor hematopoietic cell transplantation (HCT) for therapy of refractory hematologic malignancy. T-Rapa cell products, which expressed a balanced Th2/Th1 phenotype, were administered as a preemptive donor lymphocyte infusion at day 14 post-HCT. After T-Rapa cell infusion, mixed donor/host chimerism rapidly converted, and there was preferential immune reconstitution with donor CD4+ Th2 and Th1 cells relative to regulatory T cells and CD8+ T cells. The cumulative incidence probability of acute GVHD was 20% and 40% at days 100 and 180 post-HCT, respectively. There was no transplant-related mortality. Eighteen of 40 patients (45%) remain in sustained complete remission (range of follow-up: 42-84 months). These results demonstrate the safety of this low-intensity transplant approach and the feasibility of subsequent randomized studies to compare T-Rapa cell-based therapy with standard transplantation regimens. This trial was registered at www.cancer.gov/clinicaltrials as #NCT 00077480.

The photocatalytic water oxidation activity of hematite (α-Fe2O3) has been greatly enhanced by incorporating hematite nanoparticles on the reduced graphene oxide (rGO) nanosheets. Photoelectrochemical measurement results show that coupling the hematite nanoparticles with the rGO greatly increases the photocurrent and reduces the charge recombination rate. Transient absorption spectroscopy and time-domain terahertz spectroscopy have provided the direct evidence that the photogenerated electrons have transferred as the mobile carriers from α-Fe2O3 to rGO, which enhances the charge separation and suppresses the charge recombination. This work has provided new insight into the mechanism of photocatalysis enhancement by reduced graphene oxide, which has implications in the design of semiconductor/graphene heterojunction photocatalysts.

MicroRNA-9 (miR-9) is emerging as a critical regulator of organ development and neurogenesis. It is also deregulated in several types of solid tumors; however, its role in hematopoiesis and leukemogenesis is not yet known. Here we show that miR-9 is detected in hematopoietic stem cells and hematopoietic progenitor cells, and that its expression increases during hematopoietic differentiation. Ectopic expression of miR-9 strongly accelerates terminal myelopoiesis and promotes apoptosis in vitro and in vivo. Conversely, in hematopoietic progenitor cells, the inhibition of miR-9 with a miRNA sponge blocks myelopoiesis. Ecotropic viral integration site 1 (EVI1), required for normal embryogenesis, is considered an oncogene because its inappropriate up-regulation induces malignant transformation in solid and hematopoietic cancers. Here we show that EVI1 binds to the promoter of miR-9-3, leading to DNA hypermethylation of the promoter and repression of miR-9. Moreover, miR-9 expression reverses a myeloid differentiation block that is induced by EVI1. Our findings indicate that EVI1, when inappropriately expressed, delays or blocks myeloid differentiation at least in part by DNA hypermethylation and down-regulation of miR-9. It was reported that Forkhead box class O genes ( FoxO s) inhibit myeloid differentiation and prevent differentiation of leukemia-initiating cells. Here we identify both FoxO1 and FoxO3 as direct targets of miR-9 in hematopoietic cells and find that up-regulation of FoxO3 inhibits miR-9–induced myelopoiesis. These results reveal a unique role of miR-9 in myelopoiesis and in the pathogenesis of EVI1-induced myeloid neoplasms and provide insights into the epigenetic regulation of miR9 in tumorigenesis.

We report on design of a multi-color laser set up that allows for high spectral, time and spatial resolution imaging based on second- and third-order optical nonlinearities in soft condensed matter. Two femtosecond optical parametric oscillators (OPOs) are pumped simultaneously to provide intrinsically synchronized pulses at more than a dozen tunable colors across visible and infrared wavelengths. We demonstrate the use of independently tunable OPOs in a variety of imaging modalities. In one useful application, we explore brain tissue in a two-photon absorption fluorescence imaging experiment with near infrared optical pulses (λ ~ 1,070 nm). We also demonstrate second and sum-frequency generation microscopies in different tissues. Results from application of time-resolved, three-color coherent anti-stokes Raman scattering in tissue are presented to demonstrate feasibility of quantitative spectroscopic imaging.

BACKGROUND: The purpose of this retrospective medical record review was to report on recidivism to the ICU among adult postoperative cardiac and thoracic patients managed with a respiratory therapy assess-and-treat (RTAT) protocol. Our primary null hypothesis was that there would be no difference in all-cause unexpected readmissions and escalations between the RTAT group and the physician-ordered respiratory care group. Our secondary null hypothesis was that there would be no difference in primary respiratory-related readmissions, ICU length of stay, or hospital length of stay. METHODS: We reviewed 1,400 medical records of cardiac and thoracic postoperative subjects between January 2015 and October 2016. The RTAT is driven by a standardized patient assessment tool, which is completed by a registered respiratory therapist. The tool develops a respiratory severity score for each patient and directs interventions for bronchial hygiene, aerosol therapy, and lung inflation therapy based on an algorithm. The protocol period commenced on December 1, 2015, and continued through October 2016. Data relative to unplanned admissions to the ICU for all causes as well as respiratory-related causes were evaluated. RESULTS: There was a statistically significant difference in the all-cause unplanned ICU admission rate between the RTAT (5.8% [95% CI 4.3–7.9]) and the physician-ordered respiratory care (8.8% [95% CI 6.9–11.1]) groups (P = .034). There was no statistically significant difference in respiratory-related unplanned ICU admissions with RTAT (36% [95% CI 22.7–51.6]) compared with the physician-ordered respiratory care (53% [95% CI 41.1–64.8]) group (P = .09). The RTAT protocol group spent 1 d less in the ICU (P CONCLUSIONS: RTAT protocol implementation demonstrated a statistically significant reduction in all-cause ICU readmissions. The reduction in respiratory-related ICU readmissions did not reach statistical significance.

Purpose To identify a robust prognostic gene expression signature as an independent predictor of survival of patients with acute myeloid leukemia (AML) and use it to improve established risk classification. Patients and Methods Four independent sets totaling 499 patients with AML carrying various cytogenetic and molecular abnormalities were used as training sets. Two independent patient sets composed of 825 patients were used as validation sets. Notably, patients from different sets were treated with different protocols, and their gene expression profiles were derived using different microarray platforms. Cox regression and Kaplan-Meier methods were used for survival analyses. Results A prognostic signature composed of 24 genes was derived from a meta-analysis of Cox regression values of each gene across the four training sets. In multivariable models, a higher sum value of the 24-gene signature was an independent predictor of shorter overall (OS) and event-free survival (EFS) in both training and validation sets (P < .01). Moreover, this signature could substantially improve the European LeukemiaNet (ELN) risk classification of AML, and patients in three new risk groups classified by the integrated risk classification showed significantly (P < .001) distinct OS and EFS. Conclusion Despite different treatment protocols applied to patients and use of different microarray platforms for expression profiling, a common prognostic gene signature was identified as an independent predictor of survival of patients with AML. The integrated risk classification incorporating this gene signature provides a better framework for risk stratification and outcome prediction than the ELN classification.

Sinovenous thrombosis (SVT) is a well-recognized and serious complication in children treated for acute leukemia. This frequently occurs during or immediately upon completion of induction therapy and is commonly attributed to asparaginase therapy.Headache is the first and most common clinical symptom to occur during the early development of SVT. With advancement of the thrombosis, the clinical symptoms can progress to increased sleepiness, focal neurological deficit, seizures, and altered consciousness. We report the case of a 4-year-old girl who presented after several days of headaches and anorexia, which then progressed to seizures, left-sided weakness, and altered consciousness. She was later found to have a widespread and occlusive SVT with right cerebral hemorrhagic infarction. This case is notable for the extensive nature of the cerebral SVT and the child's complete clinical recovery from the neurological event. The report discusses the relation of the thrombosis and leukemia and also emphasizes the importance of early recognition and prompt management, while incorporating a collaborative multidisciplinary approach to prevent long-term consequences.

The increasing number of older adults with blood-related disorders and the introduction of reduced-intensity conditioning regimens has led to increases in hematopoietic stem cell (HSC) transplantation among older adults and a corresponding increase in the age of siblings who donate HSCs to these patients. Data regarding the donation-related experiences of older donors are lacking. The Related Donor Safety Study aimed to examine/compare health-related quality of life (HRQoL) of older versus younger HSC donors. Sixty peripheral blood stem cell (PBSC) donors ages 18 to 60 years and 104 PBSC donors age60 years completed validated questionnaires before donation and 4 weeks and 1 year after donation. Before donation, older donors had poorer general physical health (t = -3.27; P = .001) but better mental health (t = 2.11; P .05). There were no age differences in multiple other donation-related factors. At 4 weeks after donation, there were no group differences in general physical/mental health, but older donors were less likely to report donation-related pain (t = -2.26; P .05) and concerns (t = -3.38; P = .001). At both 4 weeks and 1 year after donation, there were no significant differences in the percentage of each age group feeling physically back to normal or in the number of days it took donors to feel completely well. There was no evidence that increasing age within the older donor group was associated with poorer donation-related HRQoL. Taken together, these data support the current practice of HSC donation by sibling donors above age 60, providing no evidence of worsening HRQoL up to 1 year after donation in individuals up to age 76.

Imaging and postmortem studies into the severe mental illnesses of major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ) have revealed deficiencies in the myelination of deep white matter tracts of the brain. Recent studies have further suggested that deficits could extend to myelinated fibers running through the cortex in those illnesses. Disruptions in this intracortical myelin may underlie functional symptomology in MDD, BD, and SZ; thus, in this study, we hypothesized that individuals with these illnesses may have reduced myelin staining relative to controls in the cerebral cortex. We stained 60 sections of dorsolateral prefrontal cortex for myelin with Luxol® fast blue in four groups: 15 BD, 15 MDD, 15 SZ, and 15 controls with no psychiatric illness. We digitally measured optical tissue attenuation reflecting the amount of myelin staining across six cortical depths in the middle frontal gyrus (MFG), in superficial white matter in the crown of the MFG, and in deep white matter. We found that a diagnosis of MDD or SZ meant that optical tissue attenuation was significantly reduced in the shallowest depths of the cortex. Furthermore, there was a trend toward reduced optical tissue attenuation in all illnesses across all myelinated regions we studied. These results encourage future studies into potential reductions in intracortical myelin in severe mental illness.