Citations

AbstractBackgroundGene expression profiling is emerging as a tool for tuberculosis diagnosis and treatment response monitoring, but limited data specific to Indian children and incident tuberculosis infection (TBI) exist.MethodsSixteen pediatric Indian tuberculosis cases were age- and sex-matched to 32 tuberculosis-exposed controls (13 developed incident TBI without subsequent active tuberculosis). Longitudinal samples were collected for ribonucleic acid sequencing. Differential expression analysis generated gene lists that identify tuberculosis diagnosis and tuberculosis treatment response. Data were compared with published gene lists. Population-specific risk score thresholds were calculated.ResultsSeventy-one genes identified tuberculosis diagnosis and 25 treatment response. Within-group expression was partially explained by age, sex, and incident TBI. Transient changes in gene expression were identified after both infection and treatment. Application of 27 published gene lists to our data found variable performance for tuberculosis diagnosis (sensitivity 0.38–1.00, specificity 0.48–0.93) and treatment response (sensitivity 0.70–0.80, specificity 0.40–0.80). Our gene lists found similarly variable performance when applied to published datasets for diagnosis (sensitivity 0.56–0.85, specificity 0.50–0.85) and treatment response (sensitivity 0.49– 0.86, specificity 0.50–0.84).ConclusionsGene expression profiles among Indian children with confirmed tuberculosis were distinct from adult-derived gene lists, highlighting the importance of including distinct populations in differential gene expression models.

Abstract Aims As health systems around the world increasingly look to measure and improve the value of care that they provide to patients, being able to measure the outcomes that matter most to patients is vital. To support the shift towards value-based health care in atrial fibrillation (AF), the International Consortium for Health Outcomes Measurement (ICHOM) assembled an international Working Group (WG) of 30 volunteers, including health professionals and patient representatives to develop a standardized minimum set of outcomes for benchmarking care delivery in clinical settings. Methods and results Using an online-modified Delphi process, outcomes important to patients and health professionals were selected and categorized into (i) long-term consequences of disease outcomes, (ii) complications of treatment outcomes, and (iii) patient-reported outcomes. The WG identified demographic and clinical variables for use as case-mix risk adjusters. These included baseline demographics, comorbidities, cognitive function, date of diagnosis, disease duration, medications prescribed and AF procedures, as well as smoking, body mass index (BMI), alcohol intake, and physical activity. Where appropriate, and for ease of implementation, standardization of outcomes and case-mix variables was achieved using ICD codes. The standard set underwent an open review process in which over 80% of patients surveyed agreed with the outcomes captured by the standard set. Conclusion Implementation of these consensus recommendations could help institutions to monitor, compare and improve the quality and delivery of chronic AF care. Their consistent definition and collection, using ICD codes where applicable, could also broaden the implementation of more patient-centric clinical outcomes research in AF.

Abstract Philadelphia-negative Myeloproliferative Neoplasms (MPN), including Polycythemia Vera (PV), Essential Thrombocythemia (ET), Myelofibrosis (Primary [PMF] and secondary to PV and ET [PPV-, PET-MF] and unclassified MPN (U-MPN), are associated with an increased risk of venous thrombosis in unusual sites, such as splanchnic vessels (SVT). SVT can lead to complications such as portal hypertension, esophageal and gastric varices, ascites,hepatic failure and biliopathy. According to a meta-analysis MPN is the underlying cause of portal vein thrombosis (PVT) in 31.5% and Budd Chiari syndrome (BCS) in 40.9% of cases (Smalberg, 2012); a more in-depth analysis of clinical characteristics and evolution of MPN-associated SVT has been hampered by heterogeneity of cohorts comprising small number of cases. We conducted a retrospective multicenter study in patients (pts) with SVT associated with WHO2008-diagnosed MPN, with the aim to describe patient characteristics, disease course and prognostic factors with potential implications for clinical practice. Data were collected from 16 international hematologic centers in the framework of the Italian AGIMM and the IWG-MRT groups. We collected 519 cases of pts with PVT, splenic or mesenteric vein thrombosis (75.1%) and BCS (24.9%) associated with MPN. We used as comparator a cohort of 1686 controls (Ctr) represented by MPN without (w/o) SVT: 741 ET (43.9%), 684 PV (39.7%), 261 PMF (15.5%). Frequency of MPN associated with SVT was 37.8% ET (n=196), 36.8% PV (n=191), 15.4% MF (n=80), 10% U-MPN (n=52). Median follow-up was 89.9 months (mo) (range 0.5-430). For SVT vs Ctr group females were 54.5% vs 44.4% in PV (P=0.001), 68.4 vs 63.5% (p=0.13) in ET, 63.7% vs 29.1% in PMF (p<0.0001); median age at MPN diagnosis (dg) was 43.5 yr (range 12-90) vs 60.6 yr (range 12-93) (p<0.0001). Age at SVT dg was 44 yr (range 15-85). In 240 cases (46.7%) MPN and SVT dg were coincident, in 121 (23.6%) SVT occurred before MPN dg (median 26 mo, range 4-307) and in 153 (29.8%) during MPN follow up (median 68 mo, range 4-362). JAK2V617F mutation was found in 94% PV vs 94% in Ctr, 84% vs 61% ET (p<0.0001), 88.1% vs 68% PMF (p=0.006) and in 93% U-MPN. Erythropoietin-independent colonies (EEC) were evaluated in 111 SVT pts and found in 80 (72%), accounting for 38/48 PV (79%), 31/44 ET (70.5%), 9/12 PMF (75%) and 2/7 U-MPN (28.6%). At dg, SVT PV pts had lower hemoglobin levels than Ctr: median was 17.4 g/dL vs 18.5 g/dL (p<0.0001) in male, 16.9 g/dL vs 17.7 g/dL (p=0.0006) in female. A co-existing thrombophilic status was found in 38.5% SVT vs 11.8% of Ctr (p<0.0001). Recurrent SVT occurred in 12.2% of pts with a rate of 1.6% person/year (CI 1.2-2.1); risk of venous thrombosis other than SVT was increased in SVT group vs Ctr (p=0.02), with no difference for arterial thrombosis. Hemorrhage was more frequent in SVT group (32%) vs Ctr (7.2%)(p<0.0001), mainly related to esophageal varices, which were present in 66.9% of SVT pts. There was no difference in evolution to MF and acute leukemia (AL) for PV and ET pts with and w/o SVT, while risk of AL was lower in MF with SVT (p<0.00001). Overall survival was shorter in ET pts with SVT vs Ctr (p<0.0001). In PMF survival was better in SVT group (p<0.00001) and was associated with a higher proportion of SVT pts in lowest risk categories: IPSS low 65%, intermediate-1 20%, intermediate-2 10% and high 5% compared with 15%, 34%, 25% and 26% in Ctr group. At last FU, 79/519 pts (15.2%) had died; causes of death were evolution to AL (15.4%), other cancers (13.8%), disease progression without AL (10.8%), SVT (10.8%), hepatic failure and venous thrombosis other than SVT (7.7% each), heart failure and arterial thrombosis (6.2% each), hemorrhage (5.5%), renal failure and infection (4.6% each). Therapy after SVT included anticoagulation in 77%, antiaggregant in 21.2% and combination in 1.8%; 70% received cytotoxic drugs; 12.4% were treated with transjugular porto-systemic shunt. Beta blocker therapy was used in 48.5% of pts and correlated with improved survival (p=0.041) MPN associated with SVT correlated with younger age and female sex and might antedate the clinical phenotype in a quarter of the patients. MPN-associated SVT equally affected PV and ET, was more likely to occur in the presence of JAK2V617F or underlying thrombophilia and predicted recurrent venous but not arterial thrombosis. The apparent association of SVT with better or worse prognosis in PMF and ET, respectively, requires further investigation. Disclosures No relevant conflicts of interest to declare.

Abstract We conducted a two-stage Simon phase II, multi-center study in two groups: related and unrelated donor transplants. Based on the results of a previously conducted prospective study (MPD-RC 101, Rondelli et al, Blood, 2014) demonstrating relatively poor outcome in the unrelated donor arm due to high non-relapse mortality and graft failure (GF), we sought to improve this noted disparate outcome. The hypothesis driving this trial was that pre-transplant JAK1/2 inhibition would result in an increase in performance status, reduction in splenomegaly and inflammatory cytokine expression leading to improved HCT outcome. In the unrelated arm in the first 11 patients, the trial was to be terminated if 6 or more failures (GF or death due to any cause by 100 days post-transplant) were observed. In the related arm in the first 11 patients, the trial was to be terminated if 3 or more failures were observed. Key eligibility criteria included diagnosis of primary MF or post-PV MF or post-ET MF, age 18-70 years, and DIPSS int-2/high risk disease or int-1 risk disease with at least one additional risk factor. Patients could have received up to 6 months of ruxolitinib prior to enrollment provided that there was no evidence of loss of response to ruxolitinib during this period. Ruxolitinib was given for 56 days followed by a 4-day taper ending day -6. The conditioning regimen utilized was IV fludarabine 40 mg/m2 IV and IV busulfan 2.0 mg/KBW IV once daily for 4 days from days -5 to -2. GVHD prophylaxis consisted of cyclosporine or tacrolimus and methotrexate. Patients undergoing unrelated donor HCT also received low dose thymoglobulin (0.5 mg/KBW on day -3/2.0 mg/KBW on day -2 & day -1). The study has enrolled 21 patients (related, 7; unrelated, 14) with a median age of 59 years (range 39-70). 17 (81%) patients had palpable splenomegaly with median spleen size of 11 cm, and 16 patients had int-2/high risk disease. Of the 21 patients, 19 patients received transplantation (related 5/7 [71%], unrelated 14/14 [100%] underwent transplant). Two patients in the related arm did not proceed with transplantation as one progressed to acute myeloid leukemia (baseline blast count 14%) and another experienced sudden death of unknown cause the day after starting ruxolitinib. In addition, there was one GF in the related arm. Due to these 3 failures in the related arm, further enrollment was stopped in this arm per protocol criteria. In the unrelated arm, there were 4 failures (Table 1), and the study met the protocol criteria for further enrollment. Mean percent reduction from baseline to day -9 in palpable spleen length below the left costal margin was 30% (p=0.04) in 12 patients with palpable spleen. 5/12 (42%) had any reduction, and 4/12 (33%) had ≥50% reduction. From baseline to best score on day -9 or day -5, 11/19 (58%) patients with data had any improvement in MPN-SAF Total Symptom Score, and 7/19 (37%) had ≥50% reduction. Of the 19 patients undergoing transplant, ruxolitinib was tapered off successfully in all patients with no significant withdrawal syndrome or delay in transplant noted. In the pre-transplant phase, most common Grade 3 or higher toxicity considered to be related to ruxolitinib was anemia (6/21, 29%), and one patient had legionella pneumonia deemed not related to ruxolitinib. Median time to neutrophil recovery (> 0.5 x 109/L) and platelet recovery (>20 x 109/L) was 19 and 19.5 days. By day 100, 7/19 (37%) experienced Grade 2-4 acute GVHD (G2 in 5, G3 in 2). In the first 30 days post HCT, most common Grade 3 or higher toxicity was febrile neutropenia seen in 5/19 (26%) patients. In all 21 patients from time of registration with median follow-up of 5.8 months, 6-mo overall survival was 75% (95% CI 44-90%). For the 19 transplant recipients, 6-mo OS was 83% (95% CI 55-94%) from date of transplant. Conclusions: Stage 1 trial results highlight important observations. First, ruxolitinib may not be suitable for all myelofibrosis patients pre-transplant, eg, alternative approaches might be more appropriate in the context of accelerating disease. Second, we demonstrated a safe approach for tapering ruxolitinib prior to transplant which allowed patients to commence conditioning with reduced spleen size and symptoms. Third, pre-transplant ruxolitinib does not appear to have any adverse impact on early post-HCT outcomes following unrelated donor transplant, although Stage 2 enrollment will be required to better assess the potential benefits of this approach. Disclosures Gupta: Novartis: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Research Funding. Yacoub:Incyte: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; Alexion: Honoraria. Mesa:Promedior: Research Funding; Celgene: Research Funding; CTI: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Galena: Consultancy; Ariad: Consultancy; Novartis: Consultancy. Mead:Novartis: Honoraria, Research Funding, Speakers Bureau. Mascarenhas:Novartis: Other: DSMB , Research Funding; Roche: Research Funding; Promedior: Research Funding; Janssen: Research Funding; CTI Biopharma: Research Funding; Incyte: Other: Clinical Trial Steereing Committee, Research Funding.

Purpose The Mayo Clinic Biobank was established to provide a large group of patients from which comparison groups (ie, controls) could be selected for case–control studies, to create a prospective cohort with sufficient power for common outcomes and to support electronic health record (EHR) studies. Participants A total of 56 862 participants enrolled (21% response rate) into the Mayo Clinic Biobank from Rochester, Minnesota (77%, n=43 836), Jacksonville, Florida (18%, n=10 368) and La Crosse, Wisconsin (5%, n=2658). Participants were all Mayo Clinic patients, 18 years of age or older and US residents. Findings to date Overall, 43% of participants were 65 years of age or older and female participants were more frequent (59%) than males at all sites. Most participants resided in the Upper Midwest regions of the USA (Minnesota, Iowa, Illinois or Wisconsin), Florida or Georgia. Self-reported race among Biobank participants was 90% white. Here we provide examples of the types of studies that have successfully utilised the resource, including (1) investigations of the population itself, (2) provision of controls for case–control studies, (3) genotype-driven research, (4) EHR-based research and (5) prospective recruitment to other studies. Over 270 projects have been approved to date to access Biobank data and/or samples; over 200 000 sample aliquots have been approved for distribution. Future plans The data and samples in the Mayo Clinic Biobank can be used for various types of epidemiological and clinical studies, especially in the setting of case–control studies for which the Biobank samples serve as control samples. We are planning cohort studies with additional follow-up and acquisition of genetic information on a large scale.

Case: Two young adult (aged 25 and 21 years) patients presented with sarcomas of the proximal ulna. To achieve an oncological margin, the proximal ulna required resection. Owing to the complex biomechanics of the elbow joint, reconstructive options are limited and have a high complication rate. The elbow was reconstructed with a transposition of the radial neck to the trochlea of the humerus in both patients. At over 2 years of follow-up, both patients have a stable and functional elbow. Conclusions: Transposition of the radial neck to the trochlea of the humerus provides a biological reconstruction in this complex problem.

ABSTRACTBackground:Natural history models for primary sclerosing cholangitis (PSC) are derived from adult patient data, but have never been validated in children. It is unclear how accurate such models are for children with PSC.Methods:We utilized the pediatric PSC consortium database to assess the Revised Mayo Clinic, Amsterdam‐Oxford, and Boberg models. We calculated the risk stratum and predicted survival for each patient within each model using patient data at PSC diagnosis, and compared it with observed survival. We evaluated model fit using the c‐statistic.Results:Model fit was good at 1 year (c‐statistics 0.93, 0.87, 0.82) and fair at 10 years (0.78, 0.75, 0.69) in the Mayo, Boberg, and Amsterdam‐Oxford models, respectively. The Mayo model correctly classified most children as low risk, whereas the Amsterdam‐Oxford model incorrectly classified most as high risk. All of the models underestimated survival of patients classified as high risk. Albumin, bilirubin, AST, and platelets were most associated with outcomes. Autoimmune hepatitis was more prevalent in higher risk groups, and over‐weighting of AST in these patients accounted for the observed versus predicted survival discrepancy.Conclusions:All 3 models offered good short‐term discrimination of outcomes but only fair long‐term discrimination. None of the models account for the high prevalence of features of autoimmune hepatitis overlap in children and the associated elevated aminotransferases. A pediatric‐specific model is needed. AST, bilirubin, albumin, and platelets will be important predictors, but must be weighted to account for the unique features of PSC in children.

Abstract Background Cardiac implantable electronic device-related infective endocarditis (CIED-IE) comprises 10–57% of total CIED infections. Patients with definite CIED-IE who fulfill both major modified Duke criteria have not been well characterized. Methods Data from the Multicenter Electrophysiologic Device Infection Cohort, a prospective, multinational study of CIED infections were used to describe a subset of patients with CIED-IE who met both major Duke criteria for definite IE (bloodstream infection and intracardiac vegetations [VEG]). Results Of 433 patients with CIED infection, 144 (33.3%) had definite CIED-IE. The median age was 68 years and 77.1% were male. Twelve (8.3%) had past CIED infection. Seventy-seven patients (53.5%) had permanent pacemakers, 38 (26.4%) had implantable cardioverter defibrillators, and 29 (20.1%) had combination devices. The median time following the last device procedure was 550 days. CIED-IE was early in 60 patients (41.7%) and late in 84 (58.3%). Most patients presented with fever (77.8%) and sepsis (44.4%) with a median symptom duration of 7 days. On echocardiography, lead VEG was noted in 125 patients (86.8%) and valvular VEG in 54 patients (37.5%) with the tricuspid valve involved in 56.5%. On the basis of VEG location, there were 90 patients (62.5%) with isolated lead-associated IE (LAE), 19 patients (13.2%) with isolated valve-associated IE (VAE), and 35 patients (24.3%) with both (LVAE). All patients had positive blood cultures and 63/119 (52.9%) had positive lead cultures. The predominant organism in blood was Staphylococcus aureus (42.4%), followed by coagulase-negative staphylococci (20.1%). CIED removal occurred in 131 patients (91%). There were 25 deaths during the index hospitalization and 34 total deaths (24.3%) by 6 months. Mortality correlated with age >75 (P = 0.023) and sepsis on presentation (P = 0.052). Infecting organism, site of VEG, and device removal did not impact the risk of death. Conclusion Definite CIED-IE is relatively common. The majority of patients tend to have late-onset infection and often present with sepsis. S. aureus is the dominant organism causing definite CIED-IE. Isolated LAE occurs in 63% of patients. Older age and sepsis on admission are associated with higher mortality. Disclosures All authors: No reported disclosures.