Cervical mucins are glycosylated proteins that form a protective cervical mucus. To understand the role of mucin glycans in Candida albicans infection, oligosaccharides from mouse cervical mucins ...were analyzed by liquid chromatography-mass spectrometry. Cervical mucins carry multiple alpha(1-2)fucosylated glycans, but alpha(1,2)fucosyltransferase Fut2-null mice are devoid of these epitopes. Epithelial cells in vaginal lavages from Fut2-null mice lacked Ulex europaeus agglutinin-1 (UEA-I) staining for alpha(1-2)fucosylated glycans. Hysterectomy to remove cervical mucus eliminated UEA-I and acid mucin staining in vaginal epithelial cells from wild type mice indicating the cervix as the source of UEA-I positive epithelial cells. To assess binding of alpha(1-2) fucosylated glycans on C. albicans infection, an in vitro adhesion assay was performed with vaginal epithelial cells from wild type and Fut2-null mice. Vaginal epithelial cells from Fut2-null mice were found to bind increased numbers of C. albicans compared to vaginal epithelial cells obtained from wild type mice. Hysterectomy lessened the difference between Fut2-null and wild type mice in binding of C. ablicans in vitro and susceptibility to experimental C. albicans vaginitis in vivo. We generated a recombinant fucosylated MUC1 glycanpolymer to test whether the relative protection of wild type mice compared to Fut2-null mice could be mimicked with exogenous mucin. While a small portion of the recombinant MUC1 epitopes displayed alpha(1-2)fucosylated glycans, the predominant epitopes were sialylated due to endogenous sialyltransferases in the cultured cells. Intravaginal instillation of recombinant MUC1 glycanpolymer partially reduced experimental yeast vaginitis suggesting that a large glycanpolymer, with different glycan epitopes, may affect fungal burden. PUBLICATION ABSTRACT
The first objective was to identify factors associated with prolonged hospital stay (PHS: hospitalized >42 weeks postmenstrual age) in extremely premature (EP: born less than or equal to 28 weeks ...gestation) infants. The second objective was to identify a PHS best-performing benchmark center.
This study was a retrospective cohort analysis of infants born < or =28 weeks gestation and admitted to one of 12 tertiary centers between January 1998 and October 2001. Risk-adjusted odds of PHS, defined as hospitalization beyond 42 weeks postmenstrual age, and the competing outcome, mortality, were assessed using logistic regression models.
Among 3892 EP survivors who had complete data for multivariable analysis, 685 (18%) had PHS. Variables contributing to PHS included chronic lung disease (oxygen use at discharge home or 36 week postmenstrual age) (OR 6.75; 95% CI: 5.04 to 9.03), necrotizing enterocolitis requiring surgery (OR 13.83; 95% CI: 8.05 to 23.76), and >two episodes of late-onset sepsis (OR 2.39; 95% CI: 1.66 to 3.44). Centers' risk-adjusted PHS odds differed from the reference center, which had the lowest incidence of PHS and mortality (overall P-value <0.0001). Mortality contributed to PHS, but in an opposite direction compared to other factors. Centers with lowest PHS odds were among those with highest mortality.
These findings suggest that reduction of CLD, surgical NEC, and late onset sepsis could reduce PHS in EP infants. Risk adjusted odds of PHS and mortality are both crucial for selecting a PHS best-performing center.
Background. A recent phase III trial (AZA-001) showed AZA is the first treatment to significantly extend overall survival (OS) in higher-risk MDS patients (pts) (Blood 2007; 110:817). MDS incidence ...increases with age resulting in limited treatment options, particularly for those ≥75 years of age, given the poor tolerability and ineffectiveness of cytotoxic therapies. This subgroup analysis compared the effects of AZA vs CCR on OS, hematologic improvement (HI), transfusion independence (TI), and tolerability in pts ≥75 yrs of age.
Methods. Higher-risk MDS (FAB: RAEB, RAEB-T, CMML and IPSS: Int-2 or High) pts were enrolled. All pts were pre-selected by site investigators – based on age, performance status, and comorbidities – to receive 1 of 3 CCR: best supportive care only (BSC); lowdose ara-C (LDAC), or intensive chemotherapy (IC). Pts were then randomized to AZA (75 mg/m2/d SC × 7d q 28d), or to CCR. Those randomized to AZA received AZA; those randomized to CCR received their pre-selected treatment. Randomization was stratified based on FAB subtype (RAEB and RAEB-T) and IPSS (Int-2 or High). Erythropoiesis stimulating agents were disallowed. OS was assessed using Kaplan-Meier (KM) methods and HI and TI were assessed per IWG 2000. To adjust for baseline imbalances, a Cox proportional hazards model was used, with ECOG status, LDH, number of RBC transfusions, Hgb, and presence or absence of -7/del(7q) at baseline as variables in the final model. Adverse events (AEs) were evaluated using NCI-CTC v. 2.0.
Results. Of all enrolled pts (N=358, median age 69 yrs), 87 pts (24%) were ≥75 yrs of age (AZA n=38, CCR n=49 BSC, n=33; LDAC, n=14; IC, n=2). The majority of pts randomized to CCR received BSC only, suggesting clinicians are generally reticent to use active treatment in this population. Similar to the overall AZA-001 results, treatment with AZA was associated with prolonged survival in pts ≥75 yrs of age, with KM median OS in the AZA group not reached at 17.7 months of follow-up, vs KM median OS for CCR at 10.8 months (HR: 0.48 95%CI: 0.26, 0.89; p=0.0193). In these pts, OS rates at 2 years were significantly higher in the AZA group vs CCR: 55% vs 15% (p=0.0003). Two-fold more RBC transfusion-dependent pts at baseline in the AZA group achieved TI vs CCR: 10/23 (44%) vs 7/32 (22%), p=0.1386, respectively. Similarly, more pts in the AZA group achieved HI (major + minor) vs CCR: 58% vs 39%, (p=0.0875), respectively. As previously reported, AZA was generally well tolerated. Anemia, neutropenia, and thrombocytopenia were seen in 42%, 66%, and 71% of pts in the AZA group, respectively, vs 47%, 26%, and 40% in the CCR group, who were predominately receiving BSC only. Infections were reported by 79% and 60% of AZA and CCR pts, respectively. Discontinuations due to an AE occurred in 13% of AZA and 8% of CCR pts ≥75 yrs of age.
Conclusion. Data from this subgroup analysis indicate pts ≥75 yrs of age with higher-risk MDS receiving active treatment with AZA experience significantly prolonged 2-year OS and reduced risk of death. AZA is generally well tolerated in this elderly patient population.
Background. The international, phase III, multicenter AZA-001 trial demonstrated AZA is the first treatment to significantly extend overall survival (OS) in higher-risk MDS pts (Fenaux, Blood 2007; ...110:817). The current treatment paradigm, which is based on a relationship between complete remission (CR) and survival, is increasingly being questioned (Cheson, Blood 2006; 108:419). Results of AZA-001 show CR is sufficient but not necessary to prolong OS (List, J Clin Oncol 26: 2008;abstr 7006). Indeed, the AZA CR rate in AZA-001 was modest (17%), while partial remission (PR, 12%) and hematologic improvement (HI, 49%) were also predictive of prolonged survival. This analysis was conducted to assess the median number of AZA treatment cycles associated with achievement of first response, as measured by IWG 2000-defined CR, PR, or HI (major + minor). The number of treatment cycles from first response to best response was also measured.
Methods. Pts with higher-risk MDS (FAB: RAEB, RAEB-T, or CMML, and IPSS: Int-2 or High) were included. Pts were randomized to AZA (75 mg/m2/d SC × 7d q 28d) or to a conventional care regimen (CCR). AZA treatment was continued until disease progression (or unacceptable toxicity), regardless of hematologic response. Erythropoiesis stimulating agents were not allowed.
Results. In all, 358 pts were randomized (179 to AZA and 179 to CCR). Of the 179 AZA pts, 91 (51%) achieved a CR, PR, or HI. For the 91 pts who achieved an IWG response, the median number of cycles to first response was 3 (range: 1 – 22), 81% of pts achieved a first response by 6 cycles, and 90% achieved a first response by 9 cycles. For 57% of responders (n=52), their first response was their best response; the remaining 43% (n=39) had an improvement in their response status at a median of approximately 4 additional treatment cycles (range 1–11 treatment cycles) after their first response.
Conclusions. While many pts achieving a hematologic response with AZA do so in early treatment cycles, continued AZA dosing can further improve pt responses. In the AZA-001 study, a significant OS benefit was observed compared with CCR. In this study, AZA pts received a median of 9 treatment cycles (range 1–39). For those achieving a response of HI or better, 90% did so by 9 cycles; more than 40% of responders later achieved an improved response. In the absence of unacceptable toxicity or disease progression, continued AZA treatment is appropriate and may maximize patient benefit.
Background: The phase III AZA-001 trial showed AZA is the first treatment to significantly extend OS in higher-risk MDS pts, who received a median of 9 treatment cycles (range 1 to 39) (Fenaux, Blood ...2007; 110:817). Management of AEs is important to prevent early discontinuation of AZA, before therapeutic benefit may be achieved. This analysis evaluated the frequency of the most commonly reported (≥20% of pts) AEs with AZA by cycle, and the supportive care measures used to ameliorate AEs.
Methods: Pts with higher-risk MDS (FAB-defined RAEB, RAEB-T, or CMML and IPSS Int-2 or High) were enrolled in the AZA-001 study. Pts were randomized to AZA 75 mg/m2/d SC × 7d q 28 days or to a conventional care regimen. AZA dosing cycles could be delayed based on hematologic recovery and AEs. Prophylactic G-CSF and erythropoietin were not allowed.
Results: Of 179 pts randomized to AZA, 175 received the drug and were evaluable for safety. Most patients (86%) remained on the initial dose of 75mg/m2 and did not require dose adjustments for AEs. Of the patients requiring dose reduction, 71% were managed with a single dose reduction primarily for neutropenia or thrombocytopenia. Median cycle length was 34 days (range: 15 – 92); 50% of AZA cycles were administered with no delays (at 28 days), 27% at 35 days, and 23% at >35 days. The majority of the most common AEs (≥20%), which included non-hematologic administration-related (injection site reactions, gastrointestinal) and hematologic events, were transient (median duration 13 days), nonserious, and resolved during the study. Less than 1% of AEs resulted in discontinuation of AZA and instead were commonly managed with delays in the next AZA cycle, concomitant medications, transfusions, and other measures. The median duration of injection site reactions was 12 days; none resulted in adjustment in AZA and <15% required treatment with concomitant medications (typically corticosteroids and/or antihistamines). The majority (95%) of gastrointestinal events were transient with a median duration of 1–4 days (diarrhea, nausea, vomiting) or approximately 1 week (constipation). No gastrointestinal events resulted in discontinuation of AZA and were more commonly managed (72%) with concomitant medications (eg, anti-emetics, laxatives). Most hematologic AEs were transient (>86%), occurred during the first 1–2 cycles and were mainly grade 3 or 4; however, £10% of pts experienced neutropenia, anemia, or thrombocytopenia that required hospitalization. For patients remaining on therapy, hematologic AEs decreased with subsequent cycles, paralleling response. The majority of hematologic events were managed with delays in the next AZA cycle (99%) or transfusions for anemia (87%) or thrombocytopenia (29%); <5% of pts discontinued due to a hematologic event. The median duration of fatigue and pyrexia was approximately 1 week; none of the events resulted in discontinuation or dose decrease of AZA and instead were managed by delay in the next AZA cycle in approximately 5% of patients. There were no cumulative or delayed toxicities.
Conclusions: The majority of the most common AEs (≥20%) in the AZA-001 study were transient (median duration 13 days), nonserious, and were managed by either dose delays for hematological events or supportive care measures. Clinicians should be alert to the onset, duration, and management of these events to allow patients to achieve maximum therapeutic benefit.
Table. Most Frequent (≥20% of Patients) Treatment-Emergent Adverse Events With Azacitidine in AZA-001 Study
Percent of Patients Per CycleSystem Organ Class Preferred Term *Cycles 1–2 (N=175)Cycles 3–4 (N=147)Cycles 5–6 (N=130)Cycles 7–8 (N=107)Cycles 9–10 (N=89)Patients with at least 1 individual AE occurring in ≥20% of patients in the AZA group (%)9479656565Blood and lymphatic system disorders (%)7554423636Anemia3318141114Neutropenia5031281920Thrombocytopenia5430252021Gastrointestinal disorders (%)6242252730Constipation352013917Diarrhea128455Nausea3619121411Vomiting1811586General disorders & administration site conditions (%)6244323228Fatigue1310363Injection site erythema3521181611Injection site reaction2113999Pyrexia166467*Multiple reports of the same preferred term for a patient are counted only once.
Background. Azacitidine (AZA), as demonstrated in the phase III trial (AZA-001), is the first MDS treatment to significantly prolong OS in higher-risk MDS pts (Blood 2007; 110:817). Approximately one ...third of the pts enrolled in AZA-001 were FAB RAEB-T (≥20%–30% blasts) and now meet the WHO criteria for AML (Blood 1999; 17:3835). Considering the poor prognosis (median survival <1 year) and the poor response to chemotherapy in these pts, this subgroup analysis evaluated the effects of AZA vs CCR on OS and on response rates in pts with WHO AML.
Methods. The AZA-001 trial enrolled higher-risk MDS pts (FAB: RAEB, RAEB-T, CMML and IPSS: Int-2 or High). Prior to randomization, site investigators preselected (based on age, performance status, and comorbidities) 1 of 3 CCR: best supportive care only (BSC); low-dose ara-C (LDAC), or intensive chemotherapy (IC). Pts were subsequently randomized 1:1 to AZA (75 mg/m2/d SC × 7d q 28d) or CCR; pts randomized to CCR received their investigator preselected treatment. Karyotypes were reclassified using AML standards: favorable {inv 16, t(8;21)}, unfavorable (−7/7q- or complex) and intermediate (all others including normal). OS was assessed by Kaplan-Meier (KM) methods and Cox proportional hazards model; and IWG AML criteria (J Clin Oncol 2003; 214642–9) were used to assess morphologic complete remissions (CR). Efficacy analyses included all WHO AML pts randomized. All pts were followed until death or study closure.
Results. Of 358 enrolled pts, 113 met the definition for WHO AML (median: 23% blasts) of whom 86% were considered unfit for IC and were preselected by investigators to receive a low intensity regimen (BSC or LDAC). 55 of the 113 pts were randomized to AZA and 58 pts to CCR. AZA and CCR groups had comparable baseline demographic and clinical characteristics. Of the 58 pts randomized to CCR, 5 withdrew without receiving treatment and 53 were treated with their investigator preselected treatment as follows: IC (19%;10/53), LDAC (34%; 18/53) and BSC (47 %; 25/53). Of the 55 pts randomized to AZA, 2 withdrew without receiving treatment. Median age was 70 years; 24% had an unfavorable karyotype, 72% had an intermediate karyotype (including 46% normal); no pts had a favorable karyotype. Median follow-up for OS was 20.1 months. Median (min–max) number of treatment cycles was 8 (1–39) for AZA, 2.5 (1–3) for IC; 5.5 (1–14) for LDAC; and 6 months (2 – 19) for BSC. KM median OS was 24.5 vs. 16.0 months, respectively, in the AZA and CCR groups, hazard ratio (HR)=0.47, 95% CI, 0.28 to 0.79, p=0.004, Figure. OS rates at 2 yrs were 50% and 16%, respectively, in the AZA and CCR groups, p=0.0007. There was no statistical difference in the morphologic CR rate between the AZA (18%, 10/55) and CCR groups (16%, 9/58; p=0.80). OS results in cytogenetic intermediate pts showed a significant HR favoring the AZA group (N=38) over CCR (N=43, HR= 0.47 95% CI: 0.24, 0.91, p=0.024) but not in pts with unfavorable cytogenetics: AZA (N=14) vs CCR (N=13, HR=0.66 95% CI: 0.26, 1.68, p=0.381); however, pt numbers were low. WHO AML pt outcome measures showed significant benefits with AZA: fewer infections requiring IV antibiotics per pt-year in the AZA group (0.58) vs CCR (1.14, HR=0.51 95% CI 0.29, 0.78, p=0.003); and reduced rates of hospitalization in the AZA group (3.4 per pt-year) vs CCR (4.3 per pt-year, HR=0.79 95% CI 0.62, 1.00, p=0.028). AZA was generally well tolerated.
Conclusion. AZA significantly prolongs OS with significant improvements in important pt outcomes in elderly WHO AML pts with low marrow blast counts, who currently have limited therapeutic options. Trials are ongoing to confirm the effect of AZA in elderly AML pts with more proliferative disease.
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To investigate secretory leukocyte protease inhibitor (SLPI) concentrations in tracheal lavage fluids of neonates with an endotracheal tube in place during the first month of life, and to evaluate ...the relationship of SLPI to neutrophil counts and elastase activity in patients in whom bronchopulmonary dysplasia (BPD) developed versus those in whom it did not.
A prospective, inception cohort study.
University children's hospital neonatal intensive care unit.
Fifty-three neonates who weighed < 2000 gm at birth, and who had an endotracheal tube in place, were enrolled. Forth-one patients survived to 28 days; BPD developed in 24 but not in 17 patients.
Tracheal lavage was performed on days 1, 2, 4, 7, 14, 21, and 28, and analyzed for neutrophils, elastase activity, and SLPI. Results were evaluated longitudinally for 28 days, and were compared between BPD and no-BPD groups during the first week.
SLPI concentrations increased significantly for all patients during the study period. During the first week, SLPI concentrations were similar between BPD and no-BPD groups; neutrophil counts and elastase activity were higher in the BPD group.
Patients in whom BPD ultimately developed had early evidence of increased pulmonary inflammation and a significantly less favorable protease-antiprotease balance. If elastase-induced injury contributes to the development of BPD, early therapy with recombinant SLPI might be beneficial by increasing the antielastase capacity of epithelial lining fluid.
During an 8-month study, 14 laboratories used automated analytical systems to measure total bilirubin concentrations in lyophilized bovine specimens containing 38, 169, and 253 micromol/L bilirubin ...(2.2, 9.9, and 14.8 mg/dL, respectively). The measured mean +/- SD (n, range) were: 39 +/- 7 micromol/L (n = 90, 31-53) 2.3 +/- 0.4 mg/dL (1.8-3.1); 176 +/- 29 micromol/L (n = 89, 146-222) 10.3 +/- 1.7 mg/dL (8.5-13.0); and 260 +/- 43 micromol/L (n = 103, 208-316) 15.2 +/- 2.5 mg/dL (12.1-18.5). In comparison with target values, measurements were consistently lower at 4, higher at 6, and within +/- 4% at 4 laboratories for each of the three concentrations. The measured values for each concentration remained fairly constant during the study at each laboratory. We conclude that bilirubin measurements differed significantly from the established target values at most of the participating laboratories.
It seems that during the past decade we have been witnessing an evolution of a consensus on the phenomenology and time course of various types of MRDs. We are in a stage in which definitions and ...diagnostic criteria can be developed, but their broad acceptance is still not assured. The etiology and pathophysiology are still fiercely debated, but reasonable and feasible methods for scientific elucidation of the various hypotheses are in place and are followed by solid groups. Despite the uncertainty concerning the etiology of MRDs, reasonably efficient treatment modalities do exist, and most sufferers of MRDs should expect an eventual alleviation of their symptoms if they are treated in a specialized, established, and up-to-date program.
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