Time Of First Referral Research Articles

The Awareness and Knowledge of Retinopathy of Prematurity Among Pediatricians in Saudi Arabia.

Retinopathy of prematurity (ROP) affects premature low birth-weight infantswith potentially blinding complications. Early diagnosis and treatment for indicated cases are essential to prevent unfavorable effects of the disease. To determine the awareness and the level of knowledgeof ROPamong pediatricians inall regions of Saudi Arabia who worked at neonatal intensive care units. This was a cross-sectional study. This study was undertaken in the Kingdom of Saudi Arabia. A semi-self-structured online questionnaire was designed to study the awareness and knowledge of ROP. The questionnaire contained items related to demographic data, participants' level of understanding and knowledge of ROP, and items related to hospital facilities, the availability of a trained ophthalmologist, and the source of knowledge. The awareness and knowledge of ROP among pediatricians of the Kingdom of Saudi Arabia. The study included 145 pediatricians. Awareness of ROP was found in 138 participants (95.2%). Seven participants(4.8%) were not aware ofROP and were excluded from further analysis. Of the participants, 116 (84.0%), 127 (92.0%), and 130 (94.3%) had knowledge about the stages, treatment, and precautions of treatment of ROP, respectively. Of the participants, 77 (55.8%), 63 (45.7%), 113 (81.9%), and 56 (40.6%) gave the correct answer about the indications of fundus examination, exact time of the first fundus examination, place of fundus examination, and minimum number of screening fundus examination for ROP, respectively. The awareness and knowledge of ROP among pediatricians of Saudi Arabia is good, butknowledge about the indications and proper time of first referral to an ophthalmologist should be improved.

Baseline Serum Ferritin Differentially Predicts W24 Transfusion Independence Response for Momelotinib and Ruxolitinib in Patients with Myelofibrosis

Baseline Serum Ferritin Differentially Predicts W24 Transfusion Independence Response for Momelotinib and Ruxolitinib in Patients with Myelofibrosis

PNPLA3 is the dominant SNP linked to liver disease severity at time of first referral to a tertiary center

BackgroundSingle nucleotide polymorphisms (SNPs) in genes including PNPLA3, TM6SF2, HSD17B13 and SERPINA1 have been identified as risk modifiers of progression in chronic liver disease (CLD). However, it is unclear whether genotyping for these risk variants is useful in clinical routine. MethodsLiver disease severity was assessed by liver stiffness measurement (LSM) and by presence of clinical manifestations of advanced-chronic liver disease (ACLD) in 779 consecutive CLD patients at the time of referral to a tertiary center. The associations of risk variants with CLD severity were calculated individually and in a combined model using a polygenic risk-score. ResultsNon-alcoholic fatty liver disease (NAFLD) was the most common etiology (n = 511, 65.6%), and ACLD was present in 217 (27.9%) patients. The PNPLA3-G-allele remained independently associated with higher LSM (adjusted-B: 2.508 [95%CI: 0.887–4.130], P = 0.002) or the presence of ACLD (aOR: 1.562 [95%CI: 1.097–2.226], P = 0.013). SERPINA1-Z-allele was also independently associated with LSM (adjusted-B: 4.558 [95%CI: 1.182–7.934], P = 0.008), while the other risk alleles did not attain statistical significance. Combining these risk alleles into a polygenic risk-score was significantly associated with LSM (adjusted-B: 0.948 [95%CI: 0.153–1.743], P = 0.020). ConclusionPNPLA3 risk-variants are linked to liver disease severity at the time of first referral to an outpatient hepatology clinic.

Outcome of pregnancies with recent primary cytomegalovirus infection in first trimester treated with hyperimmunoglobulin: observational study.

To examine the efficacy of hyperimmunoglobulin (HIG) treatment in women with a recent primary cytomegalovirus (CMV) infection up to 14 weeks' gestation. This is an ongoing observational study conducted at the prenatal medicine departments of the University Hospitals of Tübingen, Bonn, Cologne and Erlangen, Germany, as well as at the Laboratory Prof. Gisela Enders and Colleagues in Stuttgart, Germany and the Institute for Medical Virology at the University of Tübingen, Tübingen, Germany. Enrolment criteria were the presence of confirmed recent primary CMV infection in the first trimester and a gestational age at first HIG administration of ≤ 14 weeks. The following inclusion criteria indicated a recent primary infection: low anti-immunoglobulin (Ig)-G levels, low anti-CMV-IgG avidity in the presence of a positive CMV-IgM test and no positive reactivity or just seroconversion anti-gB2-IgG-reactivity. HIG administration was started as soon as possible within a few days after the first visit. HIG was administered intravenously at a dose of 200 IU/kg maternal body weight and repeated every 2 weeks until about 18 weeks' gestation. The primary outcome was maternal-fetal transmission at the time of amniocentesis. Multivariate logistic regression analysis was used to determine significant covariates that could predict maternal-fetal transmission. We included 149 pregnancies (153 fetuses) that completed the treatment. Median maternal age and weight were 32.0 years and 65.0 kg, respectively. Median gestational age at the time of first referral to one of the four centers was 9.4 weeks. Median anti-CMV-IgG level, anti-CMV-IgM index and CMV-IgG avidity were 5.7 U/mL, 2.5 and 22.3%, respectively. HIG treatment was started at a median gestational age of 10.6 weeks and ended at a median of 17.9 weeks. Within this time frame, HIG was administered on average four times in each patient. Amniocentesis was carried out at a median gestational age of 20.4 weeks. In 143 (93.5%) of the 153 cases, the fetus was not infected. Maternal-fetal transmission occurred in 10 cases (6.5% (95% CI, 3.2-11.7%)). On uni- and multivariate logistic regression analysis, the level of anti-IgM index was the only factor associated significantly with maternal-fetal transmission at amniocentesis. However, only four (40.0%) of the 10 cases with maternal-fetal transmission had an anti-IgM index above 11.4, which corresponds to the 95th centile of pregnancies without transmission. HIG is a treatment option to prevent maternal-fetal transmission in pregnancy with a primary CMV infection. However, HIG treatment seems to be beneficial primarily in women with a recent primary infection in the first trimester or during the periconceptional period, and when it is administered at a biweekly dose of 200 IU/kg. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Decreased Survival and Increased Rate of Fibrotic Progression in Essential Thrombocythemia Chronicled after the FDA Approval Date of Anagrelide

▪Background:Anagrelide clinical trials in myeloproliferative neoplasms (MPN) were pioneered by the late Murray N. Silverstein M.D.(1928-1998) of the Mayo Clinic and the first publication involving 20 patients, including 17 with essential thrombocythemia (ET), appeared in 1988 (study launched in October 1985) (N Engl J Med 1988;318:1292). A larger study involving 577 patients, including 335 with ET, was subsequently published in 1992 and led to FDA approval in March 1997 (Am J Med 1992;92:69). Anagrelide has also been evaluated, in controlled studies, for its efficacy and safety as first-line therapy for ET; the results of these studies suggested that anagrelide was not inferior to hydroxyurea, in one study (Blood 2013;121:1720), but might have been harmful to patients in, the second study (N Engl J Med 2005;353:33); in the latter study, patients receiving anagrelide experienced higher incidences of arterial thrombosis, bleeding complications and fibrotic progression. These observations raised significant concern regarding an adverse survival impact of anagrelide in ET; unfortunately, the follow-up period of formal controlled studies were too short to accurately address the particular concern.Methods:The current study represents a retrospective examination of the potential impact of anagrelide therapy on survival and disease complication rates in ET. The study population was recruited from a consecutive cohort of adult patients (age ≥18 years) with MPN seen at the Mayo Clinic from 10/27/1967 through 12/29/2017. Diagnosis and determinations of fibrotic and/or leukemic transformations, were in strict accordance with the 2016 World Health Organization criteria (Blood 2016;127:2391). Statistical analyses were based on clinical and laboratory parameters obtained at the time of first referral to the Mayo Clinic which, in the majority of cases, coincided with initial diagnosis. All patients were followed from diagnosis until death or date of last follow-up or contact. Follow-up was until April 2018 and data collected via medical records or in certain cases, by directly contacting patients or their physicians. Survival and time-to-event curves were prepared using the Kaplan-Meier method and compared by the log-rank test. The JMP® Pro 13.0.0 software package was used for all analyses (SAS Institute, Cary, NC, USA).Results:1,076 patients with ET were considered (median age 58 years; females 63%); international prognostic scoring system for ET (IPSET; Blood 2012;120:1197) risk distribution was 28% high, 42% intermediate and 30% low; driver mutational status was JAK2 61%, CALR 25%, triple-negative 11% and MPL 3%. Comparison of cases diagnosed before (n=433) and after (n=643) the FDA approval date of anagrelide (1997) revealed the former cohort to be younger (median 57 vs 60 years; p=0.003), although the difference in IPSET risk distribution was not significant (p=0.14).Figures 1a, 1b, 1c and 1d illustrate overall (OS), myelofibrosis-free (MFFS), leukemia-free (LFS) and thrombosis-free survival data comparing ET patients diagnosed before and after the 1997 FDA approval date for anagrelide; a significant difference was apparent for OS (p=0.006; HR 1.4, 95% CI 1.1-1.7) and MFFS (p<0.001; HR 4.2, 95% CI 2.7-6.5), in favor of patients diagnosed prior to 1997; during multivariable analysis that included IPSET and sex, the significant difference in both OS and MFFS were sustained; the difference in OS was most apparent after the first decade of diagnosis with 10- and 20-year survival rates of 75% and 50% for diagnosis prior to 1997 vs 72% and 21% for diagnosis between 1997 and 2017 (figure 1a); the 10- and 20-year risk of fibrotic progression was 3% and 15% for diagnosis prior to 1997 and 14% and 46% for diagnosis after 1997 (figure 1b); there was no impact on LFS (p=0.32; Figure 1c) or TFS (p=0.18; Figure 1d). Similarly stratified survival data in polycythemia vera (n=665) and primary myelofibrosis (n=1,282) showed no impact on survival (p=0.3 and 0.17, respectively).Conclusions:In a retrospective, but otherwise unbiased comparative analysis, we show significantly decreased OS and MFFS in ET patients diagnosed after the FDA approval date of anagrelide (1997); the increased risk of fibrotic progression noted is consistent with results of earlier prospective data (N Engl J Med 2005;353:33). Our observations regarding OS requires confirmation in a prospective controlled setting. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Molecular Correlates of Anemia in Primary Myelofibrosis

Background: Anemia is one of the most prominent symptoms in primary myelofibrosis (PMF) and is often associated with inferior quality of life and survival. Current drugs, including JAK inhibitors, are suboptimal in the treatment of PMF-associated anemia and better information on its pathogenesis is critical for the development of more effective drugs. In the current study of JAK2/CALR/MPL annotated patients with PMF, we examined its correlation with both "driver" and "non-driver mutations", as well as cytogenetic abnormalities, in order to gain better insight into its pathogenesis.Methods: Study patients were selected based on availability of "driver" mutation information. PMF diagnosis was according to World Health Organization criteria (Blood. 2009;114:937). Previously published methods were used for CALR, JAK2 and MPL mutation analyses and determination of CALR variants (Blood. 2014;124:2465). Considering their relatively high mutational frequency in PMF, subsets of patients were also screened for ASXL1, spliceosome component (SF3B1, U2AF1, SRSF2, ZRSR2) and TET2 mutations. Cytogenetic analysis and reporting was done according to the International System for Human Cytogenetic Nomenclature. Statistical analyses considered clinical and laboratory parameters obtained at time of first referral at the Mayo Clinic.Results: Analysis was conducted on 722 patients (median age 64 years; 64% males). DIPSS-plus risk distribution was 14% low, 17% intermediate-1, 37% intermediate-2 and 33% high. All patients were annotated for JAK2/CALR/MPL mutations as well as CALR variants; 477 harbored JAK2, 139 CALR and 41 MPL mutations; 65 patients were triple-negative. The 139 CALR -mutated patients included type 1/type 1-like (n =115) and type 2/type 2-like (n =24). Non-driver mutations screened included ASXL1 (n =480; mutated 38%), SRSF2 (n =474; mutated 14%), U2AF1 (n =457; mutated 16%), SF3B1 (n =328; mutated 8%), ZRSR2 (n =180; mutated 11%) and TET2 (n =180; mutated 18%). Karyotype was normal in 60%, favorable in 28% and unfavorable in 12%.Anemia was defined as being absent (normal sex-adjusted hemoglobin level; n =110; 15%), mild (hemoglobin level of ≥10 g/dL but below sex-adjusted normal value; n =263; 36%), moderate (hemoglobin level below 10 g/dL but not transfusion-dependent; n =108; 15%) and severe (transfusion-dependent anemia; n =241; 33%).Presence of at least mild anemia was associated with abnormal karyotype (p=0.006) with no difference between favorable and unfavorable abnormalities, U2AF1 (p=0.002), TET2 (p=0.02) and ASXL1 (p=0.04) mutations; other significant associations included male sex and older age. Presence of moderate to severe anemia was associated with U2AF1 (p<0.0001), SRSF2 (p=0.007) and driver mutations other than CALR type 1/type 1-like (p<0.0001). Presence of severe anemia was associated with U2AF1 (p<0.0001), SRSF2 (p=0.003) and non-CALR driver mutations (17% incidence in both types of CALR variants vs 51% in triple negative, 35% JAK2, 39% MPL mutated cases; p<0.0001). An association with older age but not gender was also noted for both moderate to severe and severe anemia (p<0.0001). During multivariable analysis, independent associations with moderate to severe anemia were confirmed for U2AF1 (p<0.0001), SRSF2 (p=0.007) and age (p=0.0001), but not driver mutation profile (p=0.30). A similar analysis for severe anemia also identified U2AF1, SRSF2 and age as being significantly relevant.Conclusions: The current study identifies older age and the spliceosomal mutations U2AF1 and SRSF2 as having strong and independent association with moderate to severe anemia in PMF. Targeting the spliceosome machinery or its mutant components offers a potential approach in the treatment of PMF-associated anemia. DisclosuresPardanani:Stemline: Research Funding.

Suivi d’indicateurs dans le bilan d’activité d’une équipe mobile de soins palliatifs : un levier pour l’amélioration des pratiques

Early integrated palliative care is recommended in patients with incurable disease. Despite their development, hospital-based palliative care teams (PCT) are introduced late in the course of standard oncology care. The objective of this study is to describe the activity of an academic hospital-based PCT, using a standard format, which integrates indicators of early introduction and quality of end of life care, thus allowing a systematic analysis of its practice. The annual activity of the PCT is described from 2007 to 2012. Data are collected for each patient prospectively by the team: reasons for referral and activities of PCT, performance status and chemotherapy at the time of first referral, visit to emergency and admission to ICU. The number of patients referred to the PCT increased from 337 patients in 2007 to 539 in 2012, among whom 90% were cancer patients, 84% at metastatic stage. Relief of symptoms was the most frequent reason for referral. In 2012, 280 (64%) patients were receiving chemotherapy and 41% had a PS≤2 at the time of first referral. Half patients died each year (270 in 2012); 17% of these received chemotherapy in their last 14 days of life, 3% visited emergency room twice and 13% were admitted in ICU, once during their last month of life, 48% died in hospice or at home. The use of a standard format to describe the activity of hospital-based PCTs, the timing of their introduction and the quality of care is feasible. The generalization of this format for monitoring to assess the curative medicine interface/palliative could be a lever for improving the integration of palliative care.

Retrospective Comparison Of Survival and Leukemic Transformation In Myelofibrosis Patients Treated With Ruxolitinib Versus Momelotinib Versus Fedratinib Versus Pomalidomide

BackgroundThe impact of JAK inhibitor (JAKi) therapy on the natural history of myelofibrosis remains unclear. While a Phase 3 study showed that overall survival of ruxolitinib-treated intermediate-2 or high-risk myelofibrosis patients was superior as compared to placebo-treated patients, it remains unclear whether such an advantage would persist in patients receiving standard therapy, and whether this result is generalizable to other JAK inhibitors. We conducted a sponsor-independent, single-center retrospective analysis of overall and leukemia-free survival after long-term follow up in patients receiving JAKi treatment with comparison to two control populations: (i) a contemporaneously diagnosed (2005 onwards) primary myelofibrosis (PMF) patient cohort receiving standard therapy (JAKi and pomalidomide naïve); and (ii) a pomalidomide treated patient cohort (JAKi-naïve). MethodsBaseline clinical, cytogenetic and molecular data were collected at the onset of study treatment with the first JAKi or pomalidomide, or at the time of first referral for patients receiving standard therapy. Information regarding bone marrow karyotype and DIPSS-plus risk status was available for all patients. Information on survival and leukemic transformation was updated in July 2013. ResultsThe 3 patient groups were: (i) JAKi-treated: n=157, median age 65 years, range 34-89. DIPSS-plus risk: Low/Int-1 20 (13%), Int-2 66 (42%), and High 71 (45%). Median follow up from first JAKi treatment was 30 months (range 1-67 months); during this period, 72 deaths (46%) and 14 (9%) leukemic transformations were documented. The first JAKi was ruxolitinib in 51 patients (33%), momelotinib (CYT387) in 79 (50%), and fedratinib (SAR302503) in 27 (17%). The proportion of patient deaths and leukemic transformation (median follow up, range) per specific JAKi was: ruxolitinib 57% and 12% (40 months, 2-67), momelotinib 43% and 9% (29 months, 1-42), and fedratinib 33% and 4% (21 months, 2-53), respectively.(ii) Control#1 (Pomalidomide-treated): n=69, median age 67 years, range 36-87. DIPSS-plus risk: Low/Int-1 0 (0%), Int-2 28 (41%), and High 41 (59%). Median follow up was 25 months (range 2-70 months); during this period, 47 deaths (68%) and 7 (10%) leukemic transformations were documented.(iii) Control# 2 (Standard therapy): n=319, median age 66 years, range 22-90. DIPSS-plus risk: Low/Int-1 98 (31%), Int-2 122 (38%), and High 99 (31%). Median follow up from time of referral was 18 months (range 1-92 months); during this period, 101 deaths (32%) and 18 (6%) leukemic transformations were documented. For patients with Int-2 or high-risk disease (n=221), 92 deaths (42%) and 13 (6%) leukemic transformations were recorded (median follow up 16 months, range 1-92).The survival analysis focused on DIPSS-plus Int-2 and high-risk patients for all groups, reflecting the population predominantly selected for treatment on JAKi clinical trials. There was no significant difference in the median overall survival of myelofibrosis patients treated with JAKi (39 months) versus standard therapy (35 months) versus pomalidomide (26 months) (p=0.12) (Figure). The 5-year survival rates were 31%, 33% and 26%, respectively. Similarly, the median overall survival of patients treated with ruxolitinib (35 months), momelotinib (37 months) or fedratinib (42 months) was not significantly different (p=0.4). Baseline DIPSS-plus status (ie, Int-2 vs. high-risk) effectively stratified JAKi treated patients in terms of overall survival (median survival 31 vs. 60 months; p=0.0002). [Display omitted] There was no significant difference in leukemia-free survival when comparing JAKi-treated patients versus standard therapy verus pomalidomide-treated patients (p=0.6) (Figure). The estimated 5-year risk of leukemic transformation was 17%, 12% and 13%, respectively. [Display omitted] ConclusionsWith long-term follow up, myelofibrosis patients receiving JAKi therapy exhibited similar overall and leukemia-free survival as compared to two control populations (DIPSS-plus matched standard therapy and pomalidomide-treated patients). Baseline DIPSS-plus status was a powerful predictor of overall survival in JAKi treated patients. While underscoring the limitation of a non-head-to-head retrospective comparison, there was no significant difference in overall or leukemia-free survival when comparing individual JAKi drugs. Disclosures:Pardanani:Bristol Myers Squibb: Clinical trial support Other; Sanofi: Clinical trial support, Publication support services, Clinical trial support, Publication support services Other; PharmaMar: Clinical trial support, Clinical trial support Other; JW Pharmaceutical Corp.: Clinical trial support, Clinical trial support Other. Off Label Use: Use of Ruxolitinib, Momelotinib, Fedratinib and Pomalidomide for treatment of Myelofibrosis in Clinical Trial setting.

Associations and prognostic interactions between circulating levels of hepcidin, ferritin and inflammatory cytokines in primary myelofibrosis

Iron homeostasis is dysregulated in primary myelofibrosis (PMF), given the high prevalence of anemia, need for red blood cell (RBC) transfusions, and disease-associated inflammatory state. We measured plasma hepcidin levels in 203 consecutive PMF patients at the time of first referral; hepcidin levels were significantly higher as compared to healthy controls (P < 0.0001), and were correlated with hemoglobin of <10 g/dL, RBC transfusion requirement, serum ferritin of >500 µg/L, higher dynamic international prognostic scoring system (DIPSS)-plus risk category, the presence of circulating blasts, age of >65 years, and leukocyte count of <4 × 10(9) /L. Increased hepcidin levels predicted for inferior survival independent of six out of the eight DIPSS-plus prognostic parameters (hazard ratio [HR] = 1.8; P = 0.02), but not when RBC transfusion requirement, hemoglobin of <10 g/dL, or increased serum ferritin were included in the Cox model. Multivariable analysis that considered the four overlapping prognostic variables revealed that increased hepcidin (HR = 1.9; P = 0.03) and increased ferritin (HR = 2.3; P = 0.04), but not hemoglobin of <10 g/dL or RBC transfusion requirement, independently retained their significance for predicting survival. Accordingly, increased levels of both hepcidin and serum ferritin (seen in 29% of patients) predicted inferior survival independent of DIPSS-plus or increased inflammatory cytokine levels (HR = 2.4; P = 0.002), and could be considered in future prognostic models for PMF.

Comprehensive Cytokine Profiling in Systemic Mastocytosis: Prognostic Relevance of Increased Plasma IL-2R Levels.

AbstractAbstract 2836 Background:The clinical phenotype of systemic mastocytosis (SM) is highly variable; establishing prognosis in terms of overall survival or risk of transformation to aggressive disease for those with non-indolent and indolent disease variants, respectively, is not trivial. Similar to other clonal hemopathies, mast cell (MC) activation and/or stromal response to clonal MC expansion likely results in a dysregulated immuno cellular/cytokine profile; analysis of this aspect of SM may provide additional prognostic information within the context of well established parameters such as the World Health Organization (WHO) SM classification system. Here, we conducted a comprehensive analysis of circulating cytokines/chemokines with clinicopathologic and clinical outcome correlations in a cohort of SM patients seen at our institution. Methods:The diagnosis of SM and its subclassification were established according to WHO criteria. Inclusion in this study required availability of archived plasma, bone marrow biopsy, and cytogenetic information at the time of first referral. Follow up information including data on survival and disease progression were updated in July 2012. Concentrations of plasma cytokines were analyzed in duplicate by using Multiplex Bead-Based Luminex technology (Invitrogen, Carlsbad, CA). Results:Forty six SM patients met the above stipulated criteria; 25 (54%) were male and the median age at referral was 61 years (range 21–85). Subclassification of patients per WHO criteria was: indolent SM (ISM) 23 (50%), aggressive SM (ASM) 8 (17%) and SM with associated clonal hematological non-MC lineage disease (SM-AHNMD) 15 (33%).When the distribution of 30 cytokines was considered across the 3 SM sub groups, only interleukin (IL)-8 was significantly different (SM-AHNMD > ISM/ASM; p=0.0002). For ISM patients, increased levels of sIL-2R were associated with presence of B-findings (p=0.0046) including splenomegaly (p=0.001) and serum tryptase levels >200 ng/mL (p=0.0046), and decreased levels of IL-8 and hepatocyte growth factor (HGF) with MC mediator-release symptoms (p <0.05). Increased levels of sIL-2R (r2=0.6; p<0.0001) and RANTES (r2=0.37; p=0.0013) were correlated with bone marrow MC burden, and sIL-2R (r2=0.34; p=0.004) and MIG (r2=0.42; p=0.0012) with serum tryptase levels in ISM patients; similar findings were noted for the overall cohort.At a median follow up of 28 months (range 0–116), 20 (43%) deaths, and 3 (13%) and 1 (2%) transformations to ASM and mast cell leukemia, respectively, were recorded for the overall cohort. In univariate analysis, increased sIL-2R levels were predictive for inferior overall survival (p=0.005); this prognostic significance was maintained in multivariate analysis after adjusting for other known prognostic variables individually (i.e. WHO SM subtypes, age >65 years, hemoglobin <10 g/dL, thrombocytopenia, weight loss or hypoalbuminemia) (all p <0.05). Increased sIL-2R (>75th percentile) effectively stratified patients in the overall cohort into 2 well-delineated risk groups for overall survival (median survival 109 vs. 26 months; p=0.0004) (Figure). This sIL-2R threshold was also able to risk stratify patients within ISM (median survival not reached vs. 38 months) and non-ISM (median survival 31 vs. 5 months) categories (p <0.0001). Conclusions:The current study demonstrates s-IL2R to be a key inflammatory cytokine in SM; it is significantly correlated with a phenotype of high systemic MC burden and in this regard, is an attractive surrogate for treatment response in clinical practice, if validated. The predictive value of sIL-2R for overall survival is akin to similar observations in primary myelofibrosis and diffuse large B-cell lymphoma; in this study, it was noted to be independent of conventional measures of organopathy from MC infiltration, and thus may reflect a novel pathogenetic process in SM, mediated by dysregulated inflammatory and/or immuno cellular pathways. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Associations and Prognostic Interactions Between Circulating Levels of Hepcidin, Ferritin, and Inflammatory Cytokines in Primary Myelofibrosis.

AbstractAbstract 2831 Background and Aims:Primary myelofibrosis (PMF) is characterized by ineffective erythropoiesis, an underlying inflammatory state and potentially, iron overload in the setting of red cell transfusions. The potential interaction between these clinical variables and assessment of their independent prognostic contribution, if any, is of interest within the context of well established prognostic parameters including the DIPSS-plus model and increased circulating levels of inflammatory cytokines (J Clin Oncol. 2011 Apr 1;29(10):1356–63). Consequently, we studied the relationship between circulating levels of hepcidin (a surrogate for inflammation, iron stores and ineffective erythropoiesis), ferritin (iron stores and inflammation), red cell transfusion need (ineffective erythropoiesis) and soluble inflammatory cytokine levels in PMF patients. Methods:The diagnosis of PMF was according to WHO criteria. Inclusion in this study required availability of archived plasma, bone marrow biopsy, and cytogenetic information at the time of first referral. Plasma total hepcidin levels were measured by ELISA (USCN Life Sciences, Wuhan, China). Serum ferritin was measured as part of routine clinical assessment (normal range: males: 24–336 mcg/L; females: 11–307 mcg/L). Concentrations of plasma cytokines were analyzed in duplicate by using Multiplex Bead-Based Luminex technology (Invitrogen, Carlsbad, CA). Results:Two hundred and three PMF patients met the above stipulated criteria; 136 (67%) were males and the median age at referral was 63 years (range 17–83). Their dynamic international prognostic scoring system (DIPSS)-plus risk categorization was: low-risk 22 (11%), intermediate-1 26 (13%), intermediate-2 85 (42%) and high-risk 70 (34%).Hepcidin levels (median 156279 pg/mL; range 8082–2088002) were strongly correlated with serum ferritin (n=146; median 207 mcg/L; range 14–5367) (r2=0.43, p <0.0001). Both were directly correlated with red cell transfusion need and age, and inversely with hemoglobin level (all p <0.05); however, there was no correlation with increased levels of inflammatory cytokines (>3 standard deviation above mean of normal controls for IL-2 and/ or IL-8) (p>0.05).At a median follow up of 35 months, 104 (51%) deaths and 18 (9%) leukemic transformations were recorded. In univariate analysis, increased levels of hepcidin (HR=2.0; p=0.0006) and ferritin (HR=2.7; p<0.0001) were predictive of inferior overall survival and this significance was sustained during multivariable analysis that included either increased inflammatory cytokine levels (HR=3.2 and 2.7, respectively) or transfusion need (HR=1.7 and 2.2, respectively) as covariates. When all 4 variables (i.e. increased levels of hepcidin, ferritin, inflammatory cytokines and transfusion need) were considered together in the Cox model, only increased inflammatory cytokine levels retained their prognostic significance (HR=2.7; p=0.0046). Furthermore, neither increased ferritin nor increased hepcidin levels were prognostically significant for overall survival when tested either individually or together against the DIPSS-plus model (p>0.05).In univariate analysis, increased hepcidin level, but not increased ferritin or transfusion need, was predictive for inferior leukemia-free survival (HR=2.8; p=0.04) and this significance was sustained in multivariable analysis that included either cytogenetic risk categories (very-high risk versus high-risk versus other) (HR=2.7; p=0.046) or thrombocytopenia (platelet count <100 × 109/L) (HR=2.7; p=0.047) as covariates. Conclusions:Circulating levels of hepcidin and ferritin are highly correlated variables in PMF and appear to provide redundant prognostic information for overall survival in this setting. The lack of correlation with inflammatory cytokines suggests that ineffective erythropoiesis may be the common link for their apparent prognostic value noted during univariate analysis. In contrast to inflammatory cytokines, neither hepcidin or ferritin levels were useful as a complement to the DIPSS-plus prognostic model in the current analysis. The relationship between hepcidin and leukemia-free survival is intriguing however the pathogenetic mechanism remains obscure and needs confirmation in additional patients. Disclosures:No relevant conflicts of interest to declare.

Prognostic Irrelevance of Vitamin D Insufficiency in Myeloproliferative Neoplasms and De Novo Myelodysplastic Syndromes

Abstract 5158 Background:Vitamin D insufficiency is commonly observed in clinical practice. Observational studies have suggested an association of vitamin D insufficiency with increased risk of cancer development. Further, vitamin D insufficiency has been associated with poorer prognosis in solid tumors as well as hematologic malignancies, including non-Hodgkin lymphoma and chronic lymphocytic leukemia. In this study, we examined the clinical and prognostic correlates of low plasma levels of 25-hydroxyvitamin D (25[OH]D), which reflects whole-body vitamin D stores, in a cohort of myeloproliferative neoplasm (MPN) and myelodysplastic syndrome (MDS) patients. Methods:We studied a total of 409 patients: 247 (60%) had primary myelofibrosis (PMF), 74 (18%) de novo MDS, 63 (15%) polycythemia vera (PV) and 25 (6%) essential thrombocythemia (ET). Inclusion criteria required availability of archived plasma, bone marrow aspirate and biopsy and cytogenetic information at the time of first referral to our institution. Vitamin D measurements were performed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). For the purposes of this study, plasma 25(OH)D levels <10 ng/mL indicated severe deficiency, <25 ng/mL insufficiency, and 25–80 ng/mL optimal levels. Results:Patient characteristics were as follows: (i) PMF: median age=63 years, >65 years=41%, males=68% and serum creatinine above the upper normal limit (UNL)=15%; (ii) MDS: median age=72 years, >65 years=77%, males=69% and creatinine >UNL=12%; (iii) PV median age=61 years, >65 years=37% and males=50%; and (iv) ET: median age=48 years, >65 years=10% and males=28%.Median (range) plasma 25(OH)D levels (ng/mL) were as follows: PMF 25 (0–60), PV 27 (6.8–51), ET 31 (6–50) and MDS 30 (7.7–72) (p=0.005). The proportion of patients with 25(OH)D insufficiency were: PMF 48%, PV 43%, ET 28% and MDS 28% (p=0.01). Similarly, the proportion of patients with severe 25(OH)D deficiency were: PMF 9%, PV 3%, ET 12% and MDS 1% (p=0.05).In PMF and MDS, 25(OH)D insufficiency was not significantly correlated with age (≤65 vs. >65 years), gender, red cell transfusion need, DIPSS-plus/IPSS category, hemoglobin (<10 vs. ≥10 g/dL), thrombocytopenia (<100 vs. ≥100 × 109/L), circulating blasts, unfavorable karyotype, serum creatinine >UNL, or JAK2V617F (PMF only) (p>0.05).25(OH)D insufficiency was not predictive of inferior overall survival (OS) in PMF, MDS, PV, or ET (p>0.05). Similarly, in PMF and MDS, 25(OH)D insufficiency was not predictive of inferior leukemia-free survival (LFS) (p>0.05). Severe 25(OH)D deficiency was infrequently observed in MDS or PV patients; in PMF or ET patients, there was no prognostic impact of severe 25(OH)D deficiency on OS or LFS (p>0.05). Conclusions:Vitamin D insufficiency is relatively common in PMF, PV, ET and de novo MDS however this finding had no prognostic value for OS in the aforementioned patients. In PMF and MDS patients, low 25(OH)D levels had no clearly identifiable clinical correlates and further did not have prognostic value for LFS. Disclosures:No relevant conflicts of interest to declare.

P.1.036 Neurophysiological markers of cognitive disorders and 1H-magnetic resonance spectroscopy in dorsolateral prefrontal cortex of first-episode patients

Objectives: Event-related potential (ERP) abnormalities to target stimuli are reliably found in schizophrenia. However, as people with schizophrenia are thought to have difficulty discerning the relevance of incoming sensory stimuli it is also important to examine ERPs to non-targets. To differentiate between potential trait markers of the disease and deficits that might be associated with the consequence of illness chronicity, this study investigated ERPs to both target and non-target stimuli in groups of people with either first episode or chronic schizophrenia (CSz).Methods: Using an auditory oddball paradigm, ERPs to target, non-target before target (Nt before) and non-target after target (Nt after) stimuli were analysed for 40 patients with CSz, 40 patients with first episode schizophrenia (FESz) and two groups of normal controls matched for age and sex with their patient counterparts.Results: The FESz group showed the same pattern of amplitude disturbance as the CSz group to both targets (reduced N100, N200, P300 and increased P200) and non-targets (reduced N100) compared to controls. Both CSz and FESz groups also failed to show the changes to the P200–N200 component between targets and non-target stimuli that was exhibited by controls (smaller earlier P200 to targets vs. increased delayed P200 to non-targets) or the reduction in N100 amplitude of ERPs to the Nt after stimuli compared with ERPs to the Nt before stimuli. Previous literature has focussed on the sensitivity of P300 deficits in classifying persons into schizophrenia and non-schizophrenia groups. This study demonstrated improved accuracy in the classification of patients with schizophrenia from controls using discriminant analysis of target and non-target N100 and P200 components.Conclusions: The results suggest that ERP disturbances are evident at the time of first referral to mental health services and may be a potential trait (rather than secondary effect) of the illness. It is important to include both target and non-target stimuli processing, and their interrelationship in future research.

Circulating Interleukin (IL)-8, IL-2R, IL-12, and IL-15 Levels Are Independently Prognostic in Primary Myelofibrosis: A Comprehensive Cytokine Profiling Study

Abnormal cytokine expression accompanies myelofibrosis and might be a therapeutic target for Janus-associated kinase (JAK) inhibitor drugs. This study describes the spectrum of plasma cytokine abnormalities in primary myelofibrosis (PMF) and examines their phenotypic correlates and prognostic significance. Patients included in this study were required to have archived plasma, bone marrow biopsy, and cytogenetic information available at the time of first referral to the Mayo Clinic. Multiplex biometric sandwich immunoassay was used to measure plasma levels of 30 cytokines. In total, 127 PMF patients were studied; comparison with normal controls (n = 35) revealed significantly increased interleukin-1β (IL-1β), IL-1RA, IL-2R, IL-6, IL-8, IL-10, IL-12, IL-13, IL-15, tumor necrosis factor α (TNF-α), granulocyte colony-stimulating factor (G-CSF), interferon alfa (IFN-α), macrophage inflammatory protein 1α (MIP-1α), MIP-1β, hepatocyte growth factor (HGF), IFN-γ-inducible protein 10 (IP-10), monokine induced by IFN-γ (MIG), monocyte chemotactic protein 1 (MCP-1), and vascular endothelial growth factor (VEGF) levels and decreased IFN-γ levels. In treatment-naive patients (n = 90), increased levels of IL-8 (P < .001), IL-2R (P < .001), IL-12 (P < .001), IL-15 (P = .001), and IP-10 (P = .003) were independently predictive of inferior survival. A similar multivariable analysis that included all 127 study patients confirmed the prognostic value of these five cytokines, and IL-8, IL-2R, IL-12, and IL-15 remained significant when risk stratification, according to the recently revised Dynamic International Prognostic Scoring System (DIPSS plus), was added to the multivariable model. Leukemia-free survival was predicted by IL-8, which was also the only cytokine associated with ≥ 1% circulating blasts. Other cytokine-phenotype associations included increased IL-8 and constitutional symptoms; IL-2R, IL-12, and transfusion need; IL-2R, IL-8, and leukocytosis; IP-10 and thrombocytopenia; HGF, MIG, IL-1RA, and marked splenomegaly; and IL-1RA, IL-2R, IP-10, MIP-1β, and JAK2V617F. A two-cytokine (IL-8/IL-2R) -based risk categorization delineated prognostically different groups within specific DIPSS plus risk categories. This study signifies the presence of specific cytokine-phenotype associations in PMF and a prognostically relevant plasma cytokine signature that might prove useful as a laboratory tool for predicting and monitoring treatment response.

Utilization of Evidence Based Medications in Patients Prior to the Time of First Referral to Outpatient Heart Failure Clinics of the Canadian Heart Failure Network (CHFN)

Utilization of Evidence Based Medications in Patients Prior to the Time of First Referral to Outpatient Heart Failure Clinics of the Canadian Heart Failure Network (CHFN)

Effects of late referral to a nephrologist in patients with chronic renal failure

We lack information about the role of late diagnosis of end-stage renal disease (ESRD), late nephrological referral and its impact on biochemical variables and first hospitalization in East Anatolia, Turkey. For a total of 101 ESRD patients, dialysis was initiated between January 1998 and December 2002 at the Yuzuncu Yil University Hospital. Early referral (ER) and late referral (LR) were defined as the time of first referral or admission to a nephrologist greater or less than 12 weeks, respectively, before initiation of haemodialysis (HD). The need for urgent dialysis was less among the early referral cases compared with the late referral cases (P = 0.03). Patients with LR started dialysis with lower levels of haemoglobin (8.6 vs 9.5 g/dL, P < 0.05) bicarbonate (16 vs 12 mEq/lt, P < 0.03) and albumin (2.9 vs 3.29 mg/dL, P < 0.02) and with higher serum levels of blood urea nitrogen (173 vs 95 mg/dL, P < 0.001), creatinine (10 vs 7.9 mg/dL, P < 0.001) and potassium (5.3 vs 4.8, P < 0.04). Hospitalization duration beginning at dialysis was significantly longer in the LR group (27.3 +/- 24) compared with the ER group (13.4 +/- 7.5, P < 0.001). When the groups were compared in terms of distance between the patients home and hospital, there were significantly more patients living far away from hospital (i.e. >100 km) in the LR group compared with the ER (P < 0.0001) group. Early referral to a nephrology unit and/or early diagnosis of ESRD results in better biochemical variables, shorter first hospitalization length and a higher percentage of elective construction of AVF and the availability to start with an alternative dialysis modality (i.e. CAPD).

Ten years of glaucoma blindness in Fife 1990-99 and the implications for ophthalmology, optometry and rehabilitation services.

The aim of this study was to determine the characteristics of the patients in Fife who were registered as blind with a main diagnosis of glaucoma between 1990 and 1999. The case notes of 87 people were studied. The average age at registration was 78 years (S.D. = 14). By the time of first referral to hospital, more than half were already aware of visual loss. Forty-five per cent of referrals had no optometry input. Compliance with treatment was poor in at least 26% of patients. Only 44% had glaucoma surgery. There were significant findings with regard to mental health, particularly dementia, which was eventually present in 24%. At least one-third of patients had a hearing impairment. One-third of those registered as blind could have been registered earlier. However, staff from the local provider of rehabilitation and social work services for the blind were shown to have provided prompt and helpful support to 95% of those registered. Consideration should be given to the way in which elderly patients with advanced glaucoma are managed, with awareness of mental health and hearing problems and emphasis on early referral to rehabilitation services.

Lack of association of ACE/angiotensinogen genotype with renal function in autosomal dominant polycystic kidney disease.

ACE polymorphisms have recently been shown to associate with worse renal and or cardiovascular outcome, with the D allele widely reported as a risk factor for cardiovascular disease. In autosomal dominant polycystic kidney disease (ADPKD), there are conflicting reports of an association between ACE polymorphisms and disease phenotype. There are no previous reports of any association between angiotensinogen polymorphisms and clinical phenotype in ADPKD. We examined the ACE I/D and angiotensinogen M235T polymorphisms in 176 patients with ADPKD. Patients are categorized into three groups according to the reason for initial investigation. Clinical history and examination findings were recorded at the time of first referral. A cohort of 17 patients had progressive renal impairment observed after 3 or more years of follow-up. Reciprocal creatinine against time was plotted in this group. From the patient population of 176, a total of 33 patients reached end-stage renal failure (ESRF) or a serum creatinine greater than 500 microm/liter. ACE genotype and M235T polymorphism frequencies were compared across groups. Serum creatinine and presence of hypertension and onset of ESRF were taken as outcome variables; age and source of referral were taken as confounding variables. There was no association of any genotype or allele with either creatinine, inverse creatinine, hypertension, or age at end-stage renal failure. These findings do not support the proposition that ACE genotype or angiotensinogen polymorphisms are associated with a worse prognosis in patients with ADPKD.

Rate of decline in renal function in Indo-Asians and Whites with diabetic nephropathy.

The incidence of end-stage renal failure (ESRF) is higher in the Indo-Asian ethnic group as compared to the White. To investigate whether this might be associated with faster rates of progression to ESRF in Indo-Asian diabetic patients, we studied a total of 39 Type 2 diabetic patients, using the Department of Nephrology database showing serial serum creatinine measurements from the time of first referral to the clinic until they reached a level of >500 micromol l(-1) or ESRF requiring renal replacement therapy (RRT), either dialysis or renal transplantation. They were grouped into Indo-Asian (n = 24) and White (n = 15). The rate of progression of those who developed ESRF, calculated as the slope of log serum creatinine against time, was not significantly different between the Indo-Asian and White patients, p = 0.73. We conclude that the higher incidence of ESRF in the Indo-Asian Type 2 diabetic patient with nephropathy is therefore not due to a faster rate of deterioration in renal function.

Changing Patterns in Uveitis of Childhood

Although uveitis is relatively uncommon in children, its diagnosis and management present a distinct clinical challenge for the physician. An improved knowledge of disease patterns and associated morbidity will help in the care of children with uveitis. The authors reviewed the records of 130 patients with onset of uveitis at 16 years of age or younger. The etiology of uveitis, complications encountered, treatment administered, and visual results were analyzed. Uveitis associated with juvenile rheumatoid arthritis (JRA) was the largest group (41.5%) followed by idiopathic uveitis (21.5%) and pars planitis (15.3%). Twenty-six percent of the eyes had less than 20/200 visual acuity at the time of first referral. Patients with JRA had the highest rate of complications: cataract (71%), glaucoma (30%), band keratopathy (66%), and hypotony (19%). The most frequent complication of pars planitis was maculopathy (55%). Final visual acuity was less than 20/200 in 26% of eyes with JRA, 10.5% with pars planitis, and 14% with idiopathic uveitis. Uveitis beginning in childhood is a serious disease associated with sight-threatening complications. Juvenile rheumatoid arthritis-associated uveitis remains a leading cause of ocular morbidity in patients with childhood uveitis. Increased awareness by pediatricians, rheumatologists, and ophthalmologists of the seriousness of ocular complications of uveitis in childhood may lead to earlier diagnosis and more effective treatment regimens in the future.