Citations

Abstract A method for controlling the plasma creatinine concentration is described. This method uses continuous determination of the plasma creatinine concentration and a servomechanism which drives an infusion pump at a rate proportional to the difference between the actual and desired creatinine concentrations. The rate and volume of creatinine infusion necessary to maintain the desired plasma concentration provide information related to kidney function and the accumulation of creatinine in the body. Experiments using this technic and the method of data analysis are described. It has been shown that under certain conditions this technic may be used to estimate the renal clearance of creatinine and the size and nature of the space into which creatinine is distributed in the dog.

Abstract Background Although 20 pancreatic cancer susceptibility loci have been identified through genome-wide association studies in individuals of European ancestry, much of its heritability remains unexplained and the genes responsible largely unknown. Methods To discover novel pancreatic cancer risk loci and possible causal genes, we performed a pancreatic cancer transcriptome-wide association study in Europeans using three approaches: FUSION, MetaXcan, and Summary-MulTiXcan. We integrated genome-wide association studies summary statistics from 9040 pancreatic cancer cases and 12 496 controls, with gene expression prediction models built using transcriptome data from histologically normal pancreatic tissue samples (NCI Laboratory of Translational Genomics [n = 95] and Genotype-Tissue Expression v7 [n = 174] datasets) and data from 48 different tissues (Genotype-Tissue Expression v7, n = 74–421 samples). Results We identified 25 genes whose genetically predicted expression was statistically significantly associated with pancreatic cancer risk (false discovery rate < .05), including 14 candidate genes at 11 novel loci (1p36.12: CELA3B; 9q31.1: SMC2, SMC2-AS1; 10q23.31: RP11-80H5.9; 12q13.13: SMUG1; 14q32.33: BTBD6; 15q23: HEXA; 15q26.1: RCCD1; 17q12: PNMT, CDK12, PGAP3; 17q22: SUPT4H1; 18q11.22: RP11-888D10.3; and 19p13.11: PGPEP1) and 11 at six known risk loci (5p15.33: TERT, CLPTM1L, ZDHHC11B; 7p14.1: INHBA; 9q34.2: ABO; 13q12.2: PDX1; 13q22.1: KLF5; and 16q23.1: WDR59, CFDP1, BCAR1, TMEM170A). The association for 12 of these genes (CELA3B, SMC2, and PNMT at novel risk loci and TERT, CLPTM1L, INHBA, ABO, PDX1, KLF5, WDR59, CFDP1, and BCAR1 at known loci) remained statistically significant after Bonferroni correction. Conclusions By integrating gene expression and genotype data, we identified novel pancreatic cancer risk loci and candidate functional genes that warrant further investigation.

Background: Serum folate (SF), vitamin B12 (B12), and iron deficiencies (def) are common causes of nutritional anemias. These deficiencies are usually multifactorial, with nutritional and non-nutritional factors playing a role. SF, B12, and iron levels are usually ordered in the setting of anemia, and malnutrition with or without neurologic symptoms. Since folic acid fortification, the prevalence of SF def in the United States (US) is <1% in the general population. B12 def and iron def range between 6-12%, and 1-11% respectively depending on the population studied. The prevalence of nutritional anemias secondary to SF, B12, and/or iron def by racial groups in the US is poorly studied, and most data available focuses on non-Hispanic whites (NHW). We aimed to determine the prevalence of anemia secondary to nutritional deficiencies by racial groups in the US. Methods: We performed a retrospective analysis of patients with SF, B12 and iron levels at Mayo Clinic Arizona between 01/2010 and 10/2018. Race was classified according to the NIH criteria. Normal laboratory values were determined according to our lab reference and the US National Health and Nutrition Examination Survey (NHANES) III. SF levels (mcg/Lt) were defined as deficient <4, normal ≥4.0, and excess ≥20. B12 levels (ng/L) as deficient <150, borderline 150-400, normal >400-900, and excess ≥900. Iron def was determined by ferritin levels (mcg/L) as low <24, normal 24-336, elevated ≥336 for men, low <11, normal 11-307, elevated ≥307 for women. Demographics and clinical variables were compared between groups by chi-square test for frequency data or Kruskal Wallis rank-sum test for continuous variables. Multivariable logistic regression was used for a sample-level analysis adjusting for age and gender and using NHW as a reference group. Results: A total of 79,926 SF, 107,731 B12, and 39,827 ferritin samples from 67,683 patients were analyzed. Demographics and sample analysis are presented in Table 1. In the sample-level analysis, 23,008 (25%) had anemia with higher prevalence in the American Indian/Alaskan Native (AI/AN) 49% and African Americans (AA) 43% (p<0.001). The prevalence of SF def was 446/79,926 (0.6%), B12 def 1,548/107,731 (1.4%), and iron def 5,212/39,827 (13.1%). 23 had concomitant SF and B12 deficiency, 25 SF and iron def, and 144 B12 and iron def. The SF def prevalence by racial groups was: AI/AN 11 (1.9%), AA 19 (1.1%), NHW 378 (0.6%), Hispanic 28 (0.5%), Asian 4 (0.2%). The B12 def prevalence by racial groups was: Asian 89 (3.4%), NHW 1,274 (1.4%), Hispanic 87 (1.3%), AA 30 (1.3%), AI/AN 10 (1.3%). Iron def prevalence by racial groups: AI/AN 71 (20.5%), Asian 198 (17.6%), AA 180 (16.9%), Hispanic 432 (15.6%), NHW 4,161 (12.4%). In the multivariate sample-level analysis, the presence of anemia was higher in the AI/AN (OR: 4.51, 95%CI: 3.70-5.49, p<0.0001), AA (OR 3.34, 95%CI: 2.99-3.74, p<0.0001), Asian (OR 1.52, 95%CI: 1.35-1.73, p<0.0001) and Hispanic racial group (OR 1.41, 95%CI: 1.30-1.52, p<0.0001). SF def was more common in the AI/AN (OR: 2.94, 95%CI: 1.60-5.39, p<0.001) and AA (OR 1.71, 95%CI: 1.08-1.53, p=0.02). B12 def was more common in the Asian racial group (OR: 2.535, 95%CI: 20.03-3.16, p<0.0001). Iron def was more common in the AI/AN (OR: 1.62, 95%CI: 1.21-2.17, p<0.001), Asian (OR 1.31, 95%CI: 1.0-1.57, p=0.003), and AA racial group (OR 1.26, 95%CI: 1.05-1.52, p=0.001). Conclusions: In our cohort, we show that despite the low prevalence of nutritional anemias in the US, racial disparities exist. Major differences were observed in the prevalence of anemia, SF def and iron def especially among AI/AN and AA. These differences may be linked to medical causes, nutritional practices and other social determinants of health. More research regarding the causes of these disparities and its clinical implications on a population level are needed. Targeted strategies to improve folate, B12 and iron intake in at higher risk populations could decrease adverse outcomes and decrease healthcare disparities caused by nutritional anemias. T able 1. Sample-level comparison by race Disclosures No relevant conflicts of interest to declare.

Preeclampsia (PE) is a hypertensive disorder of pregnancy described as a condition of excessive sympathoexcitation. PE places a woman at increased risk for lifelong hypertension and cognitive impairment. Cerebral blood velocity is blunted in response to a vasoactive stimulus in women with a history of PE. This study investigated how a sympathoexcitatory stimulus affects cerebral blood velocity in women with a history of PE. Middle cerebral artery blood velocity (MCAv) and beat-to-beat mean arterial blood pressure (MAP) were measured in postmenopausal women with a history of PE ( n = 21; age = 59 ± 5 yr) and a history of a normotensive pregnancy (NP; n = 27; age = 58 ± 4 yr), at baseline, during isometric handgrip to fatigue (IHG) followed by postexercise ischemia (PEI), and a recovery period (REC). Baseline MAP and MAP responses to IHG and PEI did not differ between groups. MCAv at baseline and throughout the stimulus was lower in PE women compared with NP women ( P < 0.05 for all). MCAv increased during IHG in both groups ( P < 0.05). This increase in MCAv was greater in PE compared with NP women during IHG and REC (IHG: PE 13 ± 2% vs. NP 9 ± 2%; REC: PE 3 ± 2% vs. NP −2 ± 2%; P < 0.05 for both). Thus, a history of PE is associated with low baseline cerebral blood velocity but an augmented response to a sympathoexcitatory stimulus. These changes in cerebral blood flow regulation may lead to an increased risk for cognitive impairment in women with a history of PE.

Abstract Background Recurrent Clostridioides difficile infection (rCDI) is an urgent public health threat associated with significant mortality and medical cost. Microbiota therapy is gaining acceptance as a strategy to reduce rCDI recurrence. We present the final 24-month analysis of clinical safety, efficacy, and microbiome restoration from a Phase 2 open-label trial of RBX2660 for prevention of CDI recurrence. Methods Participants with multi-recurrent CDI received <2 doses of RBX2660 delivered via enema 7 days apart in this multicenter, open-label Phase 2 study. Efficacy was defined as the absence of CDI recurrence through 56 days after the last dose and was compared with 8-week recurrence-free rates for a historical control cohort that received standard-of-care antibiotic therapy. Fisher exact test compared the proportion of treatment participants who were CDI-free by age and sex. Durability was defined as continued absence of CDI episodes beyond 8 weeks. Safety and durability assessments occurred at 3, 6, 12, and 24 months. Participant stool samples were collected prior to and for up to 720 days after treatment, and microbiome changes were assessed by shallow shotgun sequencing. Results The efficacy of RBX2660 to prevent rCDI at 8 weeks (78.9%; 112/142) was higher than the CDI-free rate in the historical control group (30.7%, 23/75; P < 0.0001). Age and sex did not impact efficacy. Among participants who achieved treatment success at 8 weeks and were evaluable for long-term durability (n = 95), 8 experienced a new CDI episode by the 24-month follow-up for an overall durability of 91.6%. The safety profile was consistent with previous reports for RBX2660. In total, 503 stool samples from 110 treatment responders were analyzed. Within 7 days of treatment, the relative abundance of Bacteroidia and Clostridia remained shifted higher than pre-treatment levels while Gammaproteobacteria and Bacilli declined sharply after treatment, and these changes persisted to at least 24 months. Conclusion RBX2660, a microbiota-based drug, was safe and efficacious for preventing rCDI with clinical durability to 24 months after treatment, independent of age or sex, and RBX2660 durability associated with durable microbiome shifts from pre-treatment to a healthier composition. Disclosures Robert Orenstein, DO, Rebiotix Inc. (Advisor or Review Panel member), Sarah Mische, PhD, Rebiotix Inc. (Employee), Ken Blount, PhD, Rebiotix Inc. (Employee), Lindy Bancke, PharmD, Rebiotix Inc. (Employee), Xin Su, MD, MSci, Rebiotix Inc. (Employee), Dana Walsh, PhD, Rebiotix Inc. (Employee), Adam Harvey, PhD, Rebiotix Inc. (Employee), Carlos Gonzalez, MS, Rebiotix Inc. (Consultant), Dale N. Gerding, MD, Rebiotix Inc. (Board Member).

Abstract Abstract 278 Background: Overactive JAK-STAT signaling as a result of gain-of-function mutations (eg, JAK2V617F) and/or high circulating levels of inflammatory cytokines is considered to play a key role in the pathogenesis of myeloproliferative neoplasms. Ruxolitinib, a selective oral inhibitor of JAK1 and JAK2, demonstrated a significant reduction in spleen volume (SV) and improvements in myelofibrosis (MF)-related symptoms in a double-blind placebo-controlled trial (COMFORT-I). The objective of this analysis was to evaluate the efficacy of ruxolitinib across patient (pt) subgroups in COMFORT-I. Methods: Pts with MF were randomized to start placebo or ruxolitinib at a dose of 15 mg or 20 mg PO BID depending on baseline platelet count (100–200 ×109/L or >200 ×109/L, respectively). The dose was optimized for efficacy and safety during treatment. SV change was measured by MRI; MF symptoms were assessed using a daily diary (modified Myelofibrosis Symptom Assessment Form [MFSAF] v2.0) over 1 wk prior to dosing and throughout the 24 wks of dosing. The percent changes from baseline to wk 24 in SV and MFSAF Total Symptom Score (TSS, a measure of combined scores for abdominal discomfort, pain under ribs on left side, early satiety, itching, night sweats, and bone/muscle pain) were compared for ruxolitinib and placebo pts across the following subgroups: MF disease subtype, age, International Prognosis Scoring System (IPSS) risk group, presence/absence of JAK2V617F mutation, baseline hemoglobin, baseline spleen size (palpable spleen length), and baseline TSS. Survival was estimated by Kaplan-Meier method. Changes in SV and TSS Across Subgroups: 309 pts were randomized: 155 to ruxolitinib and 154 to placebo. Ruxolitinib demonstrated consistent benefit compared with placebo in both SV and TSS across all subgroups evaluated (Table). The impact of symptom severity on response was evaluated by baseline TSS quartiles (maximum score for TSS = 60). Ruxolitinib pts with baseline TSS of <8.5, 8.5-<16.5, 16.5-<25.5 and ≥25.5 had mean percent changes in SV of −28.0, −31.4, −31.7 and −34.8, respectively, vs +8.1 for all placebo pts combined. The mean percent change in TSS for these same subgroups was −40.5, −47.2, −48.1 and −48.2 vs +41.8 for all placebo pts combined. These data indicate that pts with modest to marked symptoms all benefit from ruxolitinib therapy in terms of both SV and TSS. Survival Analysis: 13 ruxolitinib and 24 placebo pts died during the study or during extended follow-up (median follow-up of 52 and 51 wks, respectively), representing a hazard ratio (95% CI) of 0.499 (0.254, 0.98) (p=0.0395). For ruxolitinib- and placebo-treated pts, respectively, the probability of survival (95% CI) >48 wks was 0.98 (0.92, 0.99) and 0.90 (0.81, 0.95) for pts with baseline hemoglobin values ≥10 g/dL and 0.84 (0.72, 0.91) and 0.77 (0.63, 0.86) for pts with baseline hemoglobin <10 g/dL. Conclusions: Pts receiving ruxolitinib had higher response rates than placebo based on reductions in SV and improvements in TSS at wk 24 regardless of baseline subgroup: MF disease subtype, age (≤65 or >65 y), IPSS risk group (intermediate-2 or high-risk), presence or absence of JAK2V617F mutation, hemoglobin level (≥10 g/dL or <10 g/dL), palpable spleen length (≤10 cm or >10 cm), and symptom severity (TSS quartile). In addition, the overall survival analysis suggested a benefit with ruxolitinib therapy over placebo. Disclosures: Verstovsek: Incyte: Research Funding. Mesa:Incyte: Research Funding; Lilly: Research Funding; SBio: Research Funding; Astra Zeneca: Research Funding; NS Pharma: Research Funding; Celgene: Research Funding. Gotlib:Incyte: Consultancy, Research Funding. Levy:Incyte: Employment, Equity Ownership. Gupta:Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Catalano:Incyte: Honoraria; Novartis: Honoraria. Deininger:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Genzyme: Research Funding. Miller:Incyte: Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau. Winton:Incyte: Consultancy. Arcasoy:Incyte: Research Funding. Lyons:Alexion: Consultancy, Honoraria; Telik: Research Funding; Incyte: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Research Funding. Vaddi:Incyte: Employment. Erickson-Viitanen:Incyte: Employment. Sun:Incyte: Employment. Sandor:Incyte: Employment. Kantarjian:Incyte: Research Funding; Novartis: Consultancy, Research Funding.

Abstract Abstract 5146 Background: Myelofibrosis (MF) is characterized by splenomegaly, debilitating symptoms, hematologic abnormalities, and shortened survival. COMFORT-I is a Phase III randomized, double-blind, placebo-controlled study of the JAK1 and JAK2 inhibitor ruxolitinib in patients (pts) with MF. The placebo arm of this ongoing study provides a unique population in which to assess the clinical burden of MF in a controlled setting. Methods: 151 pts with intermediate-2 or high-risk primary-MF (PMF), post-polycythemia vera-MF (PPV-MF), or post-essential thombocythemia-MF (PET-MF) who were not candidates for other therapies were randomized to receive placebo in COMFORT-I after a 28-day washout of previous MF therapies. Assessments included MF symptoms measured daily using an electronic diary (modified Myelofibrosis Symptom Assessment Form [MFSAF] v2.0), spleen volume measured every 12 wks by blinded abdominal MRI or CT scans, and laboratory measures at least monthly through wk 24. The Patient-Reported Outcomes Measurement System (PROMISE) Fatigue and Patient Global Impression of Change (PGIC) questionnaires were administered at each visit. Pts with missing data (baseline or post-baseline assessment measured), or pts who withdrew or crossed over to active treatment before a study visit were not included in analyses. Results: 151 pts received 1 or more doses of placebo (median exposure 204 days). The study included 65% high-risk and 35% intermediate-2 risk pts, with a median of 2.5 years since diagnosis. 55% had PMF, 31% PPV-MF, and 14% PET-MF. Regardless of prior MF therapy (57% were on hydroxyurea), there was continual worsening of symptoms over time as assessed by the MFSAF Total Symptom Score (TSS, comprised of scores for night sweats, itching, abdominal pain and discomfort, early satiety and bone/muscle pain) (see Figure). At wk 24, mean/median spleen volume increased by +8.1%/+8.5%, and both intermediate-2 and high-risk pts demonstrated progressive disease over the course of the study. Mean/median PROMIS Fatigue score worsened by 9.1%/6.5%. Mean/median score for the PGIC (a 7-point scale ranging from 1 = very much improved to 7 = very much worse, with 4 = no change) was 4.2/4.0 at wk 24; 19.6% of pts reported feeling much worse or very much worse. Mean/median total body weight changed from 72.0 kg/72.2 kg to 70.1 kg/69.7 kg at wk 24. Hematology assessments (median, baseline vs wk 24) were as follows: hemoglobin, 105 vs 106 g/L; platelets, 233 vs 219 x109/L; neutrophils, 14.8 vs 16.0 x109/L; white blood cell count, 18.4 vs 20.1 x109/L. Two of 151 pts had new-onset (new or worsening) grade 3 or grade 4 thrombocytopenia, and 23/151 pts had new-onset grade 3 or grade 4 anemia. 16 pts met protocol-specified criteria for unblinding and crossover to active treatment before wk 24, which was a 25% increase in MRI-based spleen volume either with or without increased pain or weight loss; thus, mean and median values reported at wk 24 may represent an underestimate of the degree of worsening in disease parameters. Conclusion: The signs and symptoms of MF continued to worsen over a 6-month time frame in this placebo population. The data illustrate the progressive nature of MF and support the need for effective therapeutic interventions. Moreover, treatment benefit must be benchmarked against continual evolution of the disease in the absence of treatment. Early recognition of the debilitating symptoms of MF and intervention with effective therapy to prevent continual worsening of the disease should be strongly considered. Disclosures: Verstovsek: Incyte: Research Funding. Mesa:Incyte: Research Funding; Lilly: Research Funding; SBio: Research Funding; Astra Zeneca: Research Funding; NS Pharma: Research Funding; Celgene: Research Funding. Gotlib:Incyte: Consultancy, Research Funding. Levy:Incyte: Employment, Equity Ownership. Gupta:Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Catalano:Incyte: Honoraria; Novartis: Honoraria. Deininger:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Genzyme: Research Funding. Miller:Incyte: Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau. Winton:Incyte: Consultancy. Arcasoy:Incyte: Research Funding. Lyons:Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Telik: Research Funding; Alexion: Consultancy, Honoraria; Novartis: Research Funding. Vaddi:Incyte: Employment. Erickson-Viitanen:Incyte: Employment. Sun:Incyte: Employment. Sandor:Incyte: Employment. Kantarjian:Incyte: Research Funding; Novartis: Consultancy, Research Funding.