Real-world outcomes in patients with ALK-positive non-small cell lung cancer treated with crizotinib.

BACKGROUND: Crizotinib has shown greater efficacy in clinical trials than chemotherapy in patients with anaplastic lymphoma kinase-positive (alk+) non-small cell lung cancer (nsclc), but little information is available on its use and outcomes in real-world settings. We therefore assessed treatment patterns and outcomes in alk+ nsclc patients treated with crizotinib in regular clinical practice. METHODS: A retrospective medical record review was conducted in North America for adults with alk+ nsclc treated with crizotinib as first- or later-line therapy for metastatic disease between 1 August 2011 and 31 March 2013 (for the United States) or 1 May 2012 and 31 March 2013 (for Canada). Crizotinib-related trial enrollees were excluded. Descriptive analyses were conducted to assess treatment patterns and objective response rate (orr). Progression-free survival (pfs) and overall survival (os) were descriptively analyzed using Kaplan-Meier methods. RESULTS: Data were extracted for 212 patients in the United States (n = 147) and Canada (n = 65). Mean (standard deviation [sd]) age was 58.9 (9.5) years, and 69% were male. Seventy-nine patients (37%) were deceased at record abstraction. Sixty-five percent (n = 137) initiated crizotinib as first-line therapy. Mean (sd) duration of crizotinib treatment was 8.7 (4.9) months. Objective response rate was 66% (69% for first-line recipients, 60% for second-/later-line). Median (95% ci) pfs and os from crizotinib initiation were 9.5 (8.7, 10.1) and 23.4 (19.5, -) months, respectively. One- and two-year survival probabilities were 82% and 49%, respectively. CONCLUSIONS: Outcomes for crizotinib recipients in this study align with previous trials, with orr appearing more favourable in first-line recipients. Our findings indicate that crizotinib outcomes in clinical studies may translate to regular clinical practice.

Neuroprotective natural antibodies to assemblies of amyloidogenic peptides decrease with normal aging and advancing Alzheimer's disease.

A number of distinct beta-amyloid (Abeta) variants or multimers have been implicated in Alzheimer's disease (AD), and antibodies recognizing such peptides are in clinical trials. Humans have natural Abeta-specific antibodies, but their diversity, abundance, and function in the general population remain largely unknown. Here, we demonstrate with peptide microarrays the presence of natural antibodies against known toxic Abeta and amyloidogenic non-Abeta species in plasma samples and cerebrospinal fluid of AD patients and healthy controls aged 21-89 years. Antibody reactivity was most prominent against oligomeric assemblies of Abeta and pyroglutamate or oxidized residues, and IgGs specific for oligomeric preparations of Abeta1-42 in particular declined with age and advancing AD. Most individuals showed unexpected antibody reactivities against peptides unique to autosomal dominant forms of dementia (mutant Abeta, ABri, ADan) and IgGs isolated from plasma of AD patients or healthy controls protected primary neurons from Abeta toxicity. Aged vervets showed similar patterns of plasma IgG antibodies against amyloid peptides, and after immunization with Abeta the monkeys developed high titers not only against Abeta peptides but also against ABri and ADan peptides. Our findings support the concept of conformation-specific, cross-reactive antibodies that may protect against amyloidogenic toxic peptides. If a therapeutic benefit of Abeta antibodies can be confirmed in AD patients, stimulating the production of such neuroprotective antibodies or passively administering them to the elderly population may provide a preventive measure toward AD.

Incidence of risk factors for myocardial infarction and other vascular diseases in patients with psoriasis.

BACKGROUND: Recent cross-sectional studies reported a higher prevalence of diabetes and other risk factors for cardiovascular disease in patients with psoriasis than in the general population. OBJECTIVES: To estimate the cumulative incidences of risk factors for myocardial infarction and other vascular diseases after a first recorded diagnosis of psoriasis and the hazard ratio (HR) for these conditions in patients with psoriasis compared with the general population. METHODS: We used the General Practice Research Database to conduct a cohort study of 44,164 patients with a first-time diagnosis of psoriasis and 219,784 nonpsoriasis comparison subjects psoriasis-matched on age, sex and index date. RESULTS: HRs were increased among patients with psoriasis vs. the comparison cohort for incident diabetes [HR 1.33; 95% confidence interval (CI) 1.25-1.42], hypertension (HR 1.09; 95% CI 1.05-1.14), obesity (HR 1.18; 95% CI 1.14-1.23) and hyperlipidaemia (HR 1.17; 95% CI 1.11-1.23). Patients with psoriasis also had higher risks of incident myocardial infarction (HR 1.21; 95% CI 1.10-1.32), angina (HR 1.20; 95% CI 1.12-1.29), atherosclerosis (HR 1.28; 95% CI 1.10-1.48), peripheral vascular disease (HR 1.29; 95% CI 1.13-1.47) and stroke (HR 1.12; 95% CI 1.00-1.25). CONCLUSIONS: Risk factors for cardiovascular disease as well as myocardial infarction and other vascular diseases occur with higher incidence in patients with psoriasis than in the general population. Further work is needed to investigate whether these associations involve causal factors related to psoriasis or its treatment.

Cortical excitability and age-related volumetric MRI changes.

OBJECTIVE: Normative data on transcranial magnetic stimulation (TMS)-derived measures of cortical excitability in the elderly is sparse. Nevertheless, elderly subjects are included as controls in studies utilizing TMS to investigate disease states. Age-associated increased ventricular cerebrospinal fluid CSF (vCSF) and white matter hyperintensity (WMH) MRI volumes have uncertain significance in non-demented elderly. Information regarding cortical excitability in neurologically intact elderly would augment our understanding of the pathophysiology of aging and assist in the interpretation of TMS studies involving elderly subjects. METHODS: Twenty-four healthy elderly subjects underwent TMS testing to determine outcomes of resting motor threshold (RMT) cortical silent period (cSP) and central motor conduction time for examination in relation to WMH, vCSF, and CNS volumes. RESULTS: Increased vCSF and WMH volumes were associated with decreased right and left hemisphere RMT. Smaller CNS volumes were associated with decreased right hemisphere RMT and shorted cSP. CONCLUSIONS: Commonly observed age-associated MRI changes are associated with findings consistent with increased cortical excitability. SIGNIFICANCE: Age-related MRI findings likely reflect changes at a cellular level, and may influence cognitive and motor integrity in the elderly. Future TMS studies investigating cortical excitability may wish to consider neuroimaging markers of neurodegeneration prior to enrolling elderly subjects as controls.

Randomized placebo-controlled study of recombinant human interleukin-11 to prevent chemotherapy-induced thrombocytopenia in patients with breast cancer receiving dose-intensive cyclophosphamide and doxorubicin.

PURPOSE: Thrombocytopenia may compromise cancer treatment, causing chemotherapy dose reductions, schedule alterations, or the need for platelet transfusions. We evaluated the efficacy and safety of recombinant human interleukin-11 (rhIL-11; Neumega, Genetics Institute, Inc, Cambridge, MA), a novel thrombopoietic growth factor, in reducing the need for platelet transfusions in patients who undergo dose-intensive chemotherapy. PATIENTS AND METHODS: Women with advanced breast cancer received cyclophosphamide (3,200 mg/m2) and doxorubicin (75 mg/m2) plus granulocyte colony-stimulating factor (G-CSF; 5 microg/kg/d). Patients were randomized to blinded treatment with placebo or 50 microg/kg/d rhIL-11 subcutaneously for 10 or 17 days after the first two chemotherapy cycles. RESULTS: Seventy-seven patients were randomized and constitute the intent-to-treat (ITT) population. Sixty-seven patients (the assessable subgroup) either completed both cycles without a major protocol violation (n = 62) or received a platelet transfusion before treatment was discontinued after the first cycle. In the ITT population, rhIL-11 significantly decreased the requirement for platelet transfusions; 27 of 40 (68%) patients who received rhIL-11 did not require transfusions, compared with 15 of 37 (41%) in the placebo group (P = .04). Treatment with rhIL-11 significantly reduced the total number of platelet transfusions required in the assessable subgroup (P = .03) and the time to platelet recovery to more than 50,000/microL in the second cycle (P = .01). Most adverse events associated with rhIL-11 were reversible, mild to moderate in severity, and likely related to fluid retention. CONCLUSION: rhIL-11 is safe and effective in reducing treatment-associated thrombocytopenia and the need for platelet transfusions in patients who undergo dose-intensive chemotherapy, and thus may permit chemotherapy to be administered as planned at intended doses and thereby maximize the potential for a successful outcome.

Asynchronous regional brain volume losses in presymptomatic to moderate AD.

To determine if rates and locations of brain volume loss associated with AD are phase-specific, occurring prior to clinical onset and at later stages, we performed longitudinal volumetric MRI analysis on 155 subjects enrolled in a prospective study of aging and dementia. Subjects were divided by Clinical Dementia Rating (CDR) scale into stages of Normal (CDR 0 --> 0), Very Mild (CDR 0 --> 0.5 and 0.5 --> 0.5), Mild (CDR 0.5 --> 1.0 and 1.0 --> 1.0) and Moderate (CDR 1.0 --> 2.0 and 2.0 --> 2.0) dementia. Rates of volume change in CSF spaces, lobar and medial temporal lobe regions were analyzed for group differences across stages. Annual rates of ventricular volume change differed between non-demented and very mild group (p<0.01). In later severity stages, ventricular, temporal, basal ganglia-thalamic region and total volumes show change. Rates of volume loss increase as dementia progresses, but not uniformly in all regions. These regional and phase-specific volume changes form targets for monitoring disease-modifying therapies at clinically relevant, defined stages of dementia.

Effects of recombinant human interleukin-11 (Neumega rhIL-11 growth factor) on megakaryocytopoiesis in human bone marrow.

We examined the effects of recombinant human interleukin 11 (rhIL-11) on in vivo human hematopoiesis. Twelve women with advanced breast cancer and no evidence of bone marrow (BM) involvement were treated with 10, 25, 50, or 75 micrograms/kg/day of rhIL-11 administered subcutaneously for 14 consecutive days. Examination of bone marrow trephine biopsies obtained before and after rhIL-11 treatment revealed unchanged BM cellularity at all doses, and a statistically significant increase in megakaryocyte (MK) frequencies (from 0.5 +/- 0.1% to 1.0 +/- 0.3%) following administration of the two highest doses (p < 0.001). The BM biopsies also showed an increased proportion of immature myeloid and erythroid precursors following 14 days of treatment in all cases. The mean proportion of marrow cells stained with PC10, a monoclonal antibody (mAb) that recognizes the proliferating cell nuclear antigen (PCNA), increased from 16.3 +/- 5.7% to 45.8 +/- 17.1% (p < 0.001) following the two highest treatment doses. Most of the PC10+ cells were promyelocytes and proerythroblasts. In this same group, the proportion of PC10+ MKs increased from 28.3 +/- 11.5% to 56.8 +/- 24.3% (p < 0.01) after treatment, while megakaryocyte ploidy analysis revealed a greater number of higher ploidy (64N) megakaryocytes following rhIL-11 treatment (p < 0.012). Numbers of BM and peripheral blood (PB) CD34+, CD34+DR+, and CD34+DR- cells did not change following rhIL-11 treatment. Following rhIL-11 therapy at the highest dose studied, a 3- and 10-fold increase in the number of committed BM MK progenitor cells (CFU-MK) was observed in two of three patients, while no change was seen in the number of the other BM or PB progenitor cells examined. rhIL-11 administration was also associated with an increase in BM reticulin content (fibrosis grade 1-2) in 7 patients. These results indicate that the administration of rhIL-11 to patients with normal hematopoiesis stimulates MK endoreduplication, PCNA expression, and, at high doses, increases MK and CFU-MK progenitor cell numbers. In addition, rhIL-11 was able to stimulate precursor cells of different marrow lineages without affecting the number of assayable progenitor cells.

Characterizing the white matter hyperintensity penumbra with cerebral blood flow measures.

OBJECTIVE: White matter hyperintensities (WMHs) are common with age, grow over time, and are associated with cognitive and motor impairments. Mechanisms underlying WMH growth are unclear. We aimed to determine the presence and extent of decreased normal appearing white matter (NAWM) cerebral blood flow (CBF) surrounding WMHs to identify 'WM at risk', or the WMH CBF penumbra. We aimed to further validate cross-sectional finding by determining whether the baseline WMH penumbra CBF predicts the development of new WMHs at follow-up. METHODS: Sixty-one cognitively intact elderly subjects received 3 T MPRAGE, FLAIR, and pulsed arterial spin labeling (PASL). Twenty-four subjects returned for follow-up MRI. The inter-scan interval was 18 months. A NAWM layer mask, comprised of fifteen layers, 1 mm thick each surrounding WMHs, was generated for periventricular (PVWMH) and deep (DWMH) WMHs. Mean CBF for each layer was computed. New WMH and persistent NAWM voxels for each penumbra layer were defined from follow-up MRI. RESULTS: CBF in the area surrounding WMHs was significantly lower than the total brain NAWM, extending approximately 12 mm from both the established PVWMH and DWMH. Voxels with new WMH at follow-up had significantly lower baseline CBF than voxels that maintained NAWM, suggesting that baseline CBF can predict the development of new WMHs over time. CONCLUSIONS: A CBF penumbra exists surrounding WMHs, which is associated with future WMH expansion. ASL MRI can be used to monitor interventions to increase white matter blood flow for the prevention of further WM damage and its cognitive and motor consequences.

The effect of 8-methoxypsoralen-plus ultraviolet light on cell-virus interaction: the transforming infection; effect of PUVA on the transformation of baby hamster kidney cells by polyoma virus.

Pre-treatment of baby hamster kidney (BHK) cells with 8-methoxypsoralen (8-MOP) plus ultraviolet (UV) light enhances the frequency of their transformation by polyoma (Py) virus. Of the doses tested, 0.5 microgram/ml 8-MOP plus 0.3 J/cm2 UV-light results in maximal (30-fold) stimulation of viral transformation. 8-MOP alone does not affect viral transformation and UV-light alone causes only a slight increase in the transformation frequency. Thus the drug and light act synergistically in promoting the effect. Treatment of BHK cells with drug plus light without Py infection does not lead to a transformed morphology. A drug-light combination (0.01 microgram/ml 8-MOP plus 1.2 J/cm2 UV) that inhibits cellular DNA synthesis to 75% of control at 28 hr after treatment results in a 6-fold stimulation of the transformation frequency.

Sex differences in the corpus callosum with aging.

The present study examined sex differences in the area and age-related atrophy of the corpus callosum (CC) of 76 healthy elderly subjects using magnetic resonance imaging. The cerebellum and pons served as noncortical control structures. CC area and its subregions were also related to cognitive performance. Women had a slightly larger posterior sector of the CC than men. Women but not men showed age-related atrophy of the anterior and middle sectors of the CC but not the posterior sector. Cerebellum and pons size was similar in men and women, and neither showed age-related atrophy. CC area was related to visual memory in women but not men; no other significant cognitive to structure area relationships were found. These findings show that selective age related atrophy of the CC differs in men and women late in life.

Sex differences in prefrontal volume with aging and Alzheimer's disease.

We used volumetric magnetic resonance imaging to examine sex differences in prefrontal tissue volumes of healthy aged and patients with Alzheimer's disease (AD). Healthy subjects had greater total prefrontal volume than AD, and men had greater total prefrontal volume than women (ps < or = 0.02). This was true for both gray and white matter volumes. There were no interactions between group and sex for total prefrontal volume. An exploratory analysis of each group suggested that sex differences in both gray and white matter in healthy aging are not sustained in AD.

Oldest-old healthy brain function. The genomic potential.

There will be a remarkable increase in the number of people older than 85 years--the oldest-old--in the next 50 years. This age group is especially vulnerable to increasing disabilities, many of which are the result of the aging nervous system. Among these aging changes, the most devastating and likely to have the greatest impact on our society is the development of dementia. Since dementia is present in the majority of those who live to the current maximum of the human life span, this suggests that dementia is a normal aging event. Although the exact causes of this common cognitive failure in the oldest-old are not known, there is recent evidence from genetic studies of aging and Alzheimer disease to suggest that there are a number of susceptibility genes that may modify or delay the onset of late-life brain failure. These gene families form a natural target for devising strategies for significantly delaying the onset of late-life dementia.

Selective preservation and degeneration within the prefrontal cortex in aging and Alzheimer disease.

BACKGROUND: The prefrontal cortex (PFC) is a heterogeneous cortical structure that supports higher cognitive functions, including working memory and verbal abilities. The PFC is vulnerable to neurodegeneration with healthy aging and Alzheimer disease (AD). OBJECTIVE: We used volumetric magnetic resonance imaging to determine whether any region within the PFC is more vulnerable to deterioration with late aging or AD. METHODS: Volumetric analysis of PFC regions was performed on younger healthy elderly subjects (n = 26; 14 men and 12 women [mean age, 71.7 years] for aging analysis; 12 men and 14 women [mean age, 71.4 years] for AD analysis), oldest healthy elderly (OHE) subjects (n = 22 [11 men and 11 women]; mean age, 88.9 years), and patients with AD (n = 22 [12 men and 10 women]; mean age, 69.8 years). RESULTS: The OHE subjects had less PFC white matter than did young healthy elderly subjects. The orbital region was selectively preserved relative to other PFC regions in the OHE subjects. Subjects with AD had less total PFC gray matter than did age-matched healthy subjects and significantly less volume in the inferior PFC region only. CONCLUSIONS: Orbital PFC is selectively preserved in OHE subjects. In contrast, degeneration within the PFC with AD is most prominent in the inferior PFC region. Thus, degeneration within the PFC has a regionally distinct pattern in healthy aging and AD.

The efficacy of Ginkgo biloba on cognitive function in Alzheimer disease.

OBJECTIVE: To determine the effect of treatment with Ginkgo biloba extract on objective measures of cognitive function in patients with Alzheimer disease (AD) based on formal review of the current literature. METHODS: An attempt was made to identify all English and non-English-language articles in which G. biloba extract was given to subjects with dementia or cognitive impairment. Inclusion criteria for the meta-analysis were (1) sufficiently characterized patients such that it was clearly stated there was a diagnosis of AD by either Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition, or National Institute of Neurological Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria, or there was enough clinical detail to determine this by our review; (2) clearly stated study exclusion criteria, ie, those studies that did not have stated exclusions for depression, other neurologic disease, and central nervous system-active medications were excluded; (3) use of standardized ginkgo extract in any stated dose; (4) randomized, placebo-controlled and double-blind study design; (5) at least 1 outcome measure was an objective assessment of cognitive function; and (6) sufficient statistical information to allow for meta-analysis. RESULTS: Of more than 50 articles identified, the overwhelming majority did not meet inclusion criteria, primarily because of lack of clear diagnoses of dementia and AD. Only 4 studies met all inclusion criteria. In total there were 212 subjects in each of the placebo and ginkgo treatment groups. Overall there was a significant effect size of 0.40 (P<.0001). This modest effect size translated into a 3% difference in the Alzheimer Disease Assessment Scale-cognitive subtest. CONCLUSIONS: Based on a quantitative analysis of the literature there is a small but significant effect of 3- to 6-month treatment with 120 to 240 mg of G. biloba extract on objective measures of cognitive function in AD. The drug has not had significant adverse effects in formal clinical trials but there are 2 case reports of bleeding complications. In AD, there are limited and inconsistent data that preclude determining if there are effects on noncognitive behavioral and functional measures as well as on clinician's global rating scales. Further research in the area will need to determine if there are functional improvements and to determine the best dosage. Additional research will be needed to define which ingredients in the ginkgo extract are producing its effect in individuals with AD.

Prefrontal gray and white matter volumes in healthy aging and Alzheimer disease.

OBJECTIVES: To quantify the contribution of gray and white matter volumes to total prefrontal volume in healthy aging. To determine if prefrontal tissue volumes distinguish healthy aging from Alzheimer disease (AD). DESIGN: Volumes of total prefrontal cortex, prefrontal gray matter, and prefrontal white matter were compared among young healthy elderly (YHE) (n = 14; mean age, 70 years), old healthy elderly (OHE) (n = 14; mean age, 90 years), and subjects with AD (n = 14; mean age, 70 years) by analysis of variance. Additionally, Pearson correlations were performed between volumes and age. RESULTS: Old healthy elderly and subjects with AD had significantly less total prefrontal volume (approximately 15% less in both groups) and prefrontal white matter volume (approximately 30% less and 20% less in the OHE and AD groups, respectively) than YHE, but there were no differences between the OHE and AD groups. There was a significant difference in gray-white matter volume ratio with OHE having a higher ratio than YHE. Subjects with AD did not differ from YHE or OHE in this ratio. There were significant negative correlations between age and total prefrontal volume and age and prefrontal white matter volume in the healthy subjects. CONCLUSIONS: In the very old, the decline of white matter volume is disproportionately greater than the decline of gray matter volume. In subjects with AD both gray and white matter loss contribute to the decline of prefrontal volume. This is demonstrated by the gray-white matter ratio that does not differ between YHE and subjects with AD. Thus, it is likely that AD is different from accelerated aging.

Plasticity in the aging brain. Reversibility of anatomic, metabolic, and cognitive deficits in normal-pressure hydrocephalus following shunt surgery.

The course of idiopathic normal-pressure hydrocephalus was studied in a 78-year-old woman with a 4-year history of progressive dementia who underwent neuropsychologic testing, quantitative x-ray computed tomography, magnetic resonance imaging, and positron emission tomography with fludeoxyglucose F 18 to measure rates of regional cerebral glucose utilization. Preshunt cognitive testing demonstrated progressive deterioration during 2 years, and positron emission tomography showed significant reductions in regional cerebral glucose utilization of 34% to 49% as compared with age- and sex-matched control subjects in frontal, temporal, parietal, and whole brain regions. Periodic testing, carried out during a 2-year period after shunt surgery, showed steady improvement in clinical status. Parallel to the clinical changes, there was a significant reversal in neuropsychologic test scores with increased brain volume and increased regional cerebral glucose utilization in several brain regions. These results documented the considerable potential for recovery of compromised brain function in older subjects even after 4 years of progressive brain disease.

Neurologic evaluation of the optimally healthy oldest old.

OBJECTIVE: Individuals aged 85 years or older (the "oldest old") are the fastest-growing age group in the United States. Because there is little information characterizing expected neurologic function in this group, our goal was to determine clinical neurologic traits characteristic of the optimally healthy oldest old. DESIGN: Standardized neurologic evaluation findings of optimally healthy persons older than 84 years compared with those of equally healthy control subjects aged 65 to 74 years. SETTING: Community-based, longitudinal aging study. PARTICIPANTS: Community-residing, consecutively recruited volunteers who were screened for the absence of chronic disease or medication use. MAIN OUTCOME MEASURE: Standardized neurologic examination coded into ordinal or interval variables. RESULTS: Significant between-group differences were greatest for tests of mental status, sensory function (ie, smell, hearing, vibratory discrimination, and stereognosis), oculomotor function, distal movement speed, and balance. Discriminant function analysis suggests that of these changes, membership in the oldest group is best predicted by poor performance on clinical tests of balance (heel-toe walking and one-leg balancing with eyes closed), smell, and visual pursuit. CONCLUSIONS: Many neurologic signs appear with aging that cannot be attributed to disease, even in the very old. Deficits in balance, olfaction, and visual pursuit discriminate best between the aging changes of the healthy very old and changes seen in younger elderly persons.

Cerebrospinal fluid somatostatin and neuropeptide Y. Concentrations in aging and in dementia of the Alzheimer type with and without extrapyramidal signs.

Cerebrospinal fluid somatostatin and neuropeptide Y concentrations were measured in 26 healthy normal subjects, 27 patients with dementia of the Alzheimer type (DAT), and seven patients with DAT with extrapyramidal signs (EDAT). In healthy normal subjects, there was no significant correlation between age and either somatostatin or neuropeptide Y concentration. However, the concentrations of both peptides correlated significantly with each other. In patients with DAT and EDAT, the concentrations of somatostatin (17.5 +/- 5.0 and 16.4 +/- 5.0 pg/mL, respectively) were significantly reduced relative to age-matched control subjects (23.1 +/- 8.2 pg/mL) but were unrelated to dementia severity and did not change significantly during the progression of the disease. Neuropeptide Y concentrations did not differ significantly between the age-matched control, DAT, and EDAT groups (38.2 +/- 12.8, 37.0 +/- 12.3, and 30.3 +/- 7.8 pg/mL, respectively). These results suggest that in DAT, dysfunction of cortical somatostatin but not neuropeptide Y transmitter systems is reflected by reduced cerebrospinal fluid concentrations.