Purpose
We examined acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) events among 9679 women treated for breast cancer on four adjuvant Alliance for Clinical Trials in Oncology trials ...with >90 months of follow-up in order to better characterize the risk for AML/MDS in older patients receiving anthracyclines.
Methods
We used multivariable Cox regression to examine factors associated with AML/MDS, adjusting for age (≥65 vs. <65 years; separately for ≥70 vs. <70 years), race/ethnicity, insurance, performance status, and anthracycline receipt. We also examined the effect of cyclophosphamide, the interaction of anthracycline and age, and outcomes for those developing AML/MDS.
Results
On Cancer and Leukemia Group B (CALGB) 40101, 49907, 9344, and 9741, 7290 received anthracyclines; 15% were in the age ≥65 and 7% were ≥70. Overall, 47 patients developed AML/MDS (30 AML 0.3%, 17 MDS 0.2%); 83% of events occurred within 5 years of study registration. Among those age ≥65 and ≥70, 0.8 and 1.0% developed AML/MDS (vs. 0.4% for age <65), respectively. In adjusted analyses, older age and anthracycline receipt were significantly associated with AML/MDS (adjusted hazard ratio HR for age ≥65 vs. <65 = 3.13, 95% confidence interval CI 1.18–8.33; HR for anthracycline receipt vs. no anthracycline = 5.16, 95% CI 1.47–18.19). There was no interaction between age and anthracycline use. Deaths occurred in 70% of those developing AML/MDS.
Conclusions
We observed an increased risk for AML/MDS for older patients
and
those receiving anthracyclines, though these events were rare. Our results help inform discussions surrounding anticipated toxicities of adjuvant chemotherapy in older patients.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
This study investigated cerebral glucose metabolism in very early Alzheimer's disease, before a clinical diagnosis of probable Alzheimer's disease is possible, using 18Ffluorodeoxyglucose positron ...emission tomography. First, 66 patients with probable Alzheimer's disease with a spectrum of dementia severity (Mini‐Mental State Examination score, 0–23) were recruited and studied. Cortical metabolic activity was analyzed topographically using three‐dimensional stereotactic surface projections. Regression analysis was performed for each brain pixel to predict metabolic patterns of very early disease. Predictions were tested prospectively in a group of 8 patients who complained only of memory impairment without general cognitive decline (Mini‐Mental State Examination score, 25 · 1) at the time of scanning but whose condition later progressed to probable Alzheimer's disease. Both results were compared to cerebral metabolic activity in 22 age‐similar normal control subjects. Prediction and analysis of actual patients consistently indicated marked metabolic reduction (21–22%) in the posterior cingulate cortex and cinguloparietal transitional area in patients with very early Alzheimer's disease. Mean metabolic reduction in the posterior cingulate cortex was significantly greater than that in the lateral neocortices or parahippocampal cortex. The result suggests a functional importance for the posterior cingulate cortex in impairment of learning and memory, which is a feature of very early Alzheimer's disease.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Seeking antemortem markers to distinguish Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD), we examined brain glucose metabolism of DLB and AD. Eleven DLB patients (7 Lewy body variant of ...AD LBVAD and 4 pure diffuse Lewy body disease DLBD) who had antemortem position emission tomography imaging and autopsy confirmation were compared to 10 autopsy‐confirmed pure AD patients. In addition, 53 patients with clinically‐diagnosed probable AD, 13 of whom later fulfilled clinical diagnoses of DLB, were examined. Autopsy‐confirmed AD and DLB patients showed significant metabolic reductions involving parietotemporal association, posterior cingulate, and frontal association cortices. Only DLB patients showed significant metabolic reductions in the occipital cortex, particularly in the primary visual cortex (LBVAD −23% and DLBD −29% vs AD −8%), which distinguished DLB versus AD with 90% sensitivity and 80% specificity. Multivariate analysis revealed that occipital metabolic changes in DLB were independent from those in the adjacent parietotemporal cortices. Analysis of clinically‐diagnosed probable AD patients showed a significantly higher frequency of primary visual metabolic reduction among patients who fulfilled later clinical criteria for DLB. In these patients, occipital hypometabolism preceded some clinical features of DLB. Occipital hypometabolism is a potential antemortem marker to distinguish DLB versus AD.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Introduction
Eosinophilic esophagitis (EoE) is associated with allergen-driven inflammation of the esophagus and an upregulated Th2 cytokine signature. Recombinant interleukin (IL)-13 (rIL-13) ...administration to mice induces some of the hallmark features of EoE, including increased eotaxin expression and eosinophil recruitment. Inflammation in EoE has previously been shown to depend on the expression of TRAIL and MID-1, which reduced protein phosphatase 2A (PP2A) activity. The relationship between IL-13 and TRAIL signalling in esophageal eosinophilia is currently unknown.
Objective
To investigate the interaction between IL-13-driven eosinophil infiltration and TRAIL or MID-1 in the esophagus.
Method
We administered rIL-13 to wild type (WT), TRAIL-deficient (
Tnsf10
−/−
) or STAT6-deficient (STAT6
−/−
) mice and targeted MID-1 with small interfering RNA.
Results
rIL-13 administration to mice increased TRAIL and MID-1 expression in the esophagus while reducing PP2A activity. TRAIL deficient, but not STAT6 deficient mice demonstrated increased MID-1 expression and PP2A reduction upon IL-13 challenge which correlated with eosinophil infiltration into the esophagus. Silencing MID-1 expression with siRNA completely ablated IL-13 induced eosinophil infiltration of the esophagus, restored PP2A activity, and reduced eotaxin-1 expression.
Conclusion
IL-13-driven eosinophil infiltration of the esophagus induced eosinophilia and eotaxin-1 expression in a STAT6-dependent and MID-1-dependent manner. This study highlights a novel mechanism employed by IL-13 to perpetuate eosinophil infiltration.
To validate an in vivo method for mapping acetylcholinesterase (AChE) activity in human brain, preparatory to monitoring inhibitor therapy in AD.
AChE activity is decreased in postmortem AD brain. ...Lacking a reliable in vivo measure, little is known about central activity in early AD, when the disease is commonly targeted by AChE inhibitor drug therapy.
Intravenous N-11Cmethylpiperidin-4-yl propionate (11CPMP) served as an in vivo AChE substrate. AChE activity was defined using cerebral PET for tracer kinetic estimates of the local rate of 11CPMP hydrolysis in 26 normal controls and 14 patients with AD. Eleven AD patients also had concomitant in vivo cerebral measures of vesicular acetylcholine transporter (cholinergic terminal) density and glucose metabolism.
Cerebral AChE activity measures 1) were independent of changes in tracer delivery to cerebral cortex; 2) agreed with reported postmortem data concerning normal relative cerebral distributions, absence of large age-effect in normal aging, and deficits in AD; 3) correlated in AD cerebral cortex with concomitant in vivo measures of cholinergic terminal deficits, but not with metabolic deficits; and 4) agreed quantitatively with predicted level of cerebral AChE inhibition induced by physostimine.
This in vivo PET method provided valid measures of central AChE activity in normal subjects and AD patients. Applied in early AD, it should facilitate inhibitor treatment by confirming central inhibition, optimizing drug dosage, identifying likely responders, and testing surrogate markers of therapeutic response.
To map presynaptic cholinergic terminal densities in normal aging (n = 36), Alzheimer's disease (AD) (n = 22), and Parkinson's disease (PD) (n = 15), we performed single‐photon emission computed ...tomography using 123Iiodoben‐zovesamicol (IBVM), an in vivo marker of the vesicular acetylcholine transporter. We used coregistered positron emission tomography with 18Ffluorodexyglucose for metabolic assessment and coregistered magnetic resonance imaging for atrophy assessment. In controls (age, 22–91 years), cortical IBVM binding declined only 3.7% per decade. In AD, cortical binding correlated inversely with dementia severity. In mild dementia, binding differed according to age of onset, but metabolism did not. With an onset age of less than 65 years, binding was reduced severely throughout the entire cerebral cortex and hippocapus (about 30%), but with an onset age of 65 years or more, binding reductions were restricted to temporal cortex and hippocampus. In PD without dementia, binding was reduced only in parietal and occipital cortex, but demented PD subjects had extensive cortical binding decreases similar to early‐onset AD. We conclude that cholinergic neuron integrity can be monitored in living AD and PD patients, and that it is not so devastated in vivo as suggested by postmortem choline acetylransferase activity (50–80%).
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Spontaneous intracranial hypotension (SIH) causes postural headache and neurologic symptoms owing to traction and brain compression. A 66-year-old man with chronic headache and progressive ...personality and behavioral changes typical of frontotemporal dementia was examined. He had MRI findings of SIH with low CSF pressure. His headache, dementia, and imaging abnormalities abated after treatment with prednisone. SIH can cause reversible frontotemporal dementia, and should be considered when dementia and behavioral changes are accompanied by headache.
Aims To measure bone density and neuropathy in both feet in Type 1 and Type 2 patients with unilateral Charcot osteoarthropathy and controls.
Methods Calcaneal bone density, temperature and ...vibration thresholds were compared between 17 Type 1 diabetic patients with osteoarthropathy and 47 Type 1 controls and between 18 Type 2 diabetic patients and 48 Type 2 controls. As well as the Charcot foot, the non‐Charcot foot was studied to assess osteopenia at onset of osteoarthropathy.
Results In Type 1 diabetes, bone density was reduced in the non‐Charcot foot compared with controls Z‐score: −1.7 ({−1.9}–{−1.4}) vs. −0.2 ({−1.1}–{0.5}), P < 0.0001, median (interquartile range); but not in Type 2 diabetes Z‐score: 0.15 ({−0.45}–{0.85}) vs. 0.3 ({−0.5}–{0.9}), P = 0.675. Bone density in the Charcot foot was lower compared with the non‐Charcot foot in both Type 1 Z‐score: −2.0 ({−2.8}–{−1.4}) vs. −1.7 ({−1.9}–{−1.4}), P = 0.018 and Type 2 diabetes Z‐score: −0.2 ({−1.4}–{0.1}) vs. 0.3 ({−0.5}–{0.9}), P = 0.001. In Type 1 diabetes, bone density of the non‐Charcot foot was reduced compared with that in Type 2 (P < 0.0001). Body mass index was lower in Type 1 than in Type 2 Charcot patients (P = 0.007). Type 2 patients had high temperature (P = 0.001) and vibration thresholds (P < 0.0001) in the non‐Charcot foot compared with Type 2 controls whereas Type 1 patients had a high temperature threshold (P = 0.01) but not vibration threshold compared with Type 1 controls (P = 0.077).
Conclusion Bone density was reduced in the non‐Charcot foot in Type 1 but not in Type 2 diabetes. Type 2 patients had high temperature and vibration thresholds in contrast to Type 1 patients who had a high temperature threshold only.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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