The IL‐13/IL‐4Rα axis is involved in tuberculosis‐associated pathology

Human tuberculosis (TB) is a leading global health threat and still constitutes a major medical challenge. However, mechanisms governing tissue pathology during post‐primary TB remain elusive, partly because genetically or immunologically tractable animal models are lacking. In human TB, the demonstration of a large relative increase in interleukin (IL)‐4 and IL‐13 expression, which correlates with lung damage, indicates that a subversive T helper (TH)2 component in the response to Mycobacterium tuberculosis (Mtb) may undermine protective immunity and contribute to reactivation and tissue pathology. Up to now, there has been no clear evidence regarding whether IL‐4/IL‐13‐IL‐4 receptor‐α (Rα)‐mediated mechanisms may in fact cause reactivation and pathology. Unfortunately, the virtual absence of centrally necrotizing granulomas in experimental murine TB is associated with a poor induction of a TH2 immune response. We therefore hypothesize that, in mice, an increased production of IL‐13 may lead to a pathology similar to human post‐primary TB. In our study, aerosol Mtb infection of IL‐13‐over‐expressing mice in fact resulted in pulmonary centrally necrotizing granulomas with multinucleated giant cells, a hypoxic rim and a perinecrotic collagen capsule, with an adjacent zone of lipid‐rich, acid‐fast bacilli‐containing foamy macrophages, thus strongly resembling the pathology in human post‐primary TB. Granuloma necrosis (GN) in Mtb‐infected IL‐13‐over‐expressing mice was associated with the induction of arginase‐1‐expressing macrophages. Indirect blockade of the endogenous arginase inhibitor l ‐hydroxyarginine in Mtb‐infected wild‐type mice resulted in a strong arginase expression and precipitated a similar pathology of GN. Together, we here introduce an experimental TB model that displays many features of centrally necrotizing granulomas in human post‐primary TB and demonstrate that IL‐13/IL‐4Rα‐dependent mechanisms leading to arginase‐1 expression are involved in TB‐associated tissue pathology. © 2014 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

Augmented therapy improves outcome for pediatric high risk acute lymphocytic leukemia: results of Children's Oncology Group trial P9906

Background

The augmented BFM regimen improves outcome for children with NCI high acute lymphoblastic leukemia (ALL). Patient age, sex, and presenting white blood cell count (WBC) can be used to identify a subset of approximately 12% of children with B‐precursor ALL that had a 5‐year continuous complete remission (CCR) rate of only about 50% on earlier Pediatric Oncology Group (POG) trials.

Procedures

Children's Oncology Group trial P9906 evaluated a modified augmented BFM regimen in 267 patients with particularly high risk B‐precursor ALL. Minimal residual disease (MRD) was assessed in blood at day 8 and in marrow at day 29 of induction and correlated with outcome.

Results

The 5‐year CCR probability for patients in P9906 was significantly better than that observed for similar patients on POG trials 8602/9006 (62.2 ± 3.7% vs. 50.6 ± 2.4%; P = 0.0007) but similar to POG 9406 (63.5 ± 2.4%; P = 0.81). Interim analysis showed poor central nervous system (CNS) control, especially in patients with initial WBC ≥100,000/microliter. Day 29 marrow MRD positive (≥0.01%) vs. negative patients had 5 year CCR rates of 37.1 ± 7.4% vs. 72.6 ± 4.3%; day 8 blood MRD positive vs. negative patients had 5 year CCR rates of 57.1 ± 4.6% vs.83.6 ± 6.3%. End induction marrow MRD predicted marrow but not CNS relapse. In multivariate analysis, day 29 MRD > 0.01%, initial WBC ≥ 100,000/µl, male gender, and day 8 blood MRD > 0.01% were significant prognostic factors.

Conclusions

Augmented BFM therapy improved outcome for children with higher risk ALL. Day 8 blood and day 29 marrow MRD were strong prognostic factors in these patients. Pediatr Blood Cancer 2011; 57: 569–577. © 2011 Wiley‐Liss, Inc.

     

Time-to-antibiotic administration as a quality of care measure in children with febrile neutropenia: a survey of pediatric oncology centers

Time-to-antibiotic administration (TTA) has been suggested as a quality-of-care (QOC) measure for pediatric oncology patients with febrile neutropenia (FN). Unknown, however, is to what extent pediatric oncology centers utilize TTA. Therefore, we designed and administered an electronic survey (68% response rate) of programs in the Children's Oncology Group to assess TTA utilization. Nearly half of respondents track TTA. Most reported using a benchmark of less than 60 min from arrival. TTA is a commonly used QOC measure for pediatric FN despite an absence of studies establishing its validity and a lack of data supporting its impact on outcomes of FN.     

The Auckland Cataract Study: demographic, corneal topographic and ocular biometric parameters

Purpose : To determine patient demographics and the ocular biometric parameters in patients presenting for cataract surgery within the public hospital system, in a defined New Zealand population. Method : Prospective study of 502 eyes of 488 consecutive patients undergoing cataract surgery. A clinical assessment, including refraction, keratometry (K), A‐scan ultrasound and Orbscan II computerized topography was performed on each eye. Results : The mean age of the group was 74.9 ± 9.8 years (mean ± SD) with a female predominance (62%). Ethnic origin included 72% European, 8% Maori, 10% Pacific Islander, 4% Asian, 3% Indian and 3% other ethnic origins. The mean Log MAR visual acuity of eyes prior to cataract surgery was 0.88 ± 0.57 (approximately 6/48^–1). Corneal topographic (keratometric) maps were classified into five groups: 34% round, 10% oval, 31% symmetrical bow tie, 12% asymmetrical bow tie and 13% irregular. The mean steepest K measurement was 44.1 ± 1.7 D, the median keratometric astigmatism 0.89 D (range 0.0–6.5 D) and the steepest corneal meridian was horizontal in 50% and vertical in 43%. Seven per cent of corneas were spherical. Refraction revealed a mean sphere of 0.0 ± 3.1 D and a mean cylinder of –1.2 (range 0.0–7.5 D). Refractive astigmatism was with‐the‐rule in 15%, against‐the‐rule in 50% and oblique in 15%, with 20% spherical. Axial length was a mean of 23.14 ± 1.03 mm. Conclusion : Patients presenting for cataract surgery in this study were predominantly elderly, female, of European Caucasian ethnicity and exhibited relatively poor corrected visual acuity in the affected eye. Interestingly, 41% of eyes demonstrated bow‐tie topographic patterns, largely exhibiting with‐the‐rule astigmatism. However, assessment by keratometry or refraction highlighted against‐the‐rule more frequently; this may have implications for combined cataract and astigmatic surgery. The mean axial length was slightly shorter than expected for a group of predominantly European ethnic origin, although the mean refractive error was emmetropic.     

Assessment of proxy-reported responses as predictors of motor and sensory peripheral neuropathy in children with B-lymphoblastic leukemia

Chemotherapy-induced peripheral neuropathy (CIPN), a common condition in children with acute lymphoblastic leukemia, can be challenging to diagnose. Using data from Children's Oncology Group AALL0932 physical function study, we sought to determine if parent/guardian proxy-reported responses from the Pediatric Outcomes Data Collection Instrument could identify children with motor or sensory CIPN diagnosed by physical/occupational therapists (PT/OT). Four variables moderately discriminated between children with and without motor CIPN (c-index 0.76, 95% confidence interval [CI]: 0.64–0.84), but sensory and optimism-corrected models had weak discrimination (c-index sensory models 0.65, 95% CI: 0.54–0.74). New proxy-report measures are needed to identify children with PT/OT diagnosed CIPN.