Citations

PurposeProgression-free survival (PFS) has previously been established as a surrogate for overall survival (OS) for first-line metastatic colorectal cancer (mCRC). Because mCRC treatment has advanced in the last decade with extended OS, this surrogacy requires re-examination.MethodsIndividual patient data from 16,762 patients were available from 22 first-line mCRC studies conducted from 1997 to 2006; 12 of those studies tested antiangiogenic and/or anti–epidermal growth factor receptor agents. The relationship between PFS (first event of progression or death) and OS was evaluated by using R2statistics (the closer the value is to 1, the stronger the correlation) from weighted least squares regression of trial-specific hazard ratios estimated by using Cox and Copula models.ResultsForty-four percent of patients received a regimen that included biologic agents. Median first-line PFS was 8.3 months, and median OS was 18.2 months. The correlation between PFS and OS was modest (R2, 0.45 to 0.69). Analyses limited to trials that tested treatments with biologic agents, nonstrategy trials, or superiority trials did not improve surrogacy.ConclusionIn modern mCRC trials, in which survival after the first progression exceeds time to first progression, a positive but modest correlation was observed between OS and PFS at both the patient and trial levels. This finding demonstrates the substantial variability in OS introduced by the number of lines of therapy and types of effective subsequent treatments and the associated challenge to the use of OS as an end point to assess the benefit attributable to a single line of therapy. PFS remains an appropriate primary end point for first-line mCRC trials to detect the direct treatment effect of new agents.

ABSTRACTThe ionic liquid 1‐ethyl‐3‐methyl imidazolium chloride (EMIM Cl) and the amino acid l‐arginine hydrochloride (l‐ArgHCl) have been successfully used to improve the yield of oxidative refolding for various proteins. However, the molecular mechanisms behind the actions of such solvent additives—especially of ionic liquids—are still not well understood. To analyze these mechanisms, we have determined the transfer free energies from water into ionic liquid solutions of proteinogenic amino acids and of diketopiperazine as peptide bond analogue. For EMIM Cl and 1‐ethyl‐3‐methyl imidazolium diethyl phosphate, which had a suppressive effect on protein refolding, as well as for l‐ArgHCl favorable interactions with amino acid side chains, but no favorable interactions with the peptide backbone could be observed. A quantitative analysis of other ionic liquids together with their already published effects on protein refolding showed that only solvent additives within a certain range of hydrophobicity, chaotropicity and kosmotropicity were effective for the refolding of recombinant plasminogen activator. © 2014 Wiley Periodicals, Inc. Biopolymers 101: 1129–1140, 2014.

Abstract Background and aims Affect balance reflects relative levels of negative affect (NA) and positive affect (PA) and includes four styles: Healthy (low NA/high PA), Depressive (high NA/low PA), Reactive (high NA/high PA) and Low (low NA/low PA). These affect balance styles may have important associations with clinical outcomes in patients with fibromyalgia. Herein, we evaluated the severity of core fibromyalgia symptom domains as described by the Outcomes Research in Rheumatology-Fibromyalgia working group in the context of the four affect balance styles. Methods Data from 735 patients with fibromyalgia who completed the Brief Pain Inventory, Multidimensional Fatigue Inventory, Profile of Mood States, Medical Outcomes Sleep Scale, Multiple Ability Self-Report Questionnaire, Fibromyalgia Impact Questionnaire-Revised, Medical Outcomes Study Short Form-36, and Positive and Negative Affect Schedule were included in this analysis. Results The majority (51.8%) of patients in our sample had a Depressive affect balance style; compared to patients with a Healthy affect balance style, they scored significantly worse in all fibromyalgia symptom domains including pain, fatigue, sleep disturbance, dyscognition, depression, anxiety, stiffness, and functional status ( P = <.001 to .004). Overall, patients with a Healthy affect balance style had the lowest level of symptoms, while symptom levels of those with Reactive and Low affect balance styles were distributed in between those of the Depressive and Healthy groups. Conclusions and implications The results of our cross-sectional study suggest that having a Healthy affect balance style is associated with better physical and psychological symptom profiles in fibromyalgia. Futures studies evaluating these associations longitudinally could provide rationale for evaluating the effect of psychological interventions on affect balance and clinical outcomes in fibromyalgia.

The ionic liquid N‐ethyl‐N′‐methyl imidazolium chloride (EMIMCl) has been described as being very efficient in promoting refolding of the recombinant plasminogen activator rPA. Our study reveals that molar concentrations of EMIMCl increase the solubility of native and unfolded proteins due to favorable interactions with amino acid side chains rather than favorably interacting with the peptide backbone. This delicate balance of favorable interactions with side chains and unfavorable interactions with the peptide backbone provides a molecular explanation of how EMIMCl suppresses protein aggregation and simultaneously promotes refolding. By contrast, high concentrations of EMIMCl denature proteins because of a reduced water content and strong favorable interactions with amino acid side chains. This denatured species is not soluble and aggregates because, in contrast to the classical denaturants, guanidine hydrochloride and urea, EMIMCl does not solubilize the peptide backbone.Structured digital abstract PNP and PNP bind by molecular sieving (1, 2, 3, 4)

The earliest recorded application of therapeutic hypothermia in medicine spans about 5000 years; however, its use has become widespread since 2002, following the demonstration of both safety and efficacy of regimens requiring only a mild (32°C-35°C) degree of cooling after cardiac arrest. We review the mechanisms by which hypothermia confers neuroprotection as well as its physiological effects by body system and its associated risks. With regard to clinical applications, we present evidence on the role of hypothermia in traumatic brain injury, intracranial pressure elevation, stroke, subarachnoid hemorrhage, spinal cord injury, hepatic encephalopathy, and neonatal peripartum encephalopathy. Based on the current knowledge and areas undergoing or in need of further exploration, we feel that therapeutic hypothermia holds promise in the treatment of patients with various forms of neurologic injury; however, additional quality studies are needed before its true role is fully known.

Background and Purpose— Hemicraniectomy and Durotomy Upon Deterioration From Infarction-Related Swelling Trial (HeADDFIRST) was a randomized pilot study to obtain information necessary to design a Phase III trial to evaluate the benefit of surgical decompression for brain swelling from large supratentorial cerebral hemispheric infarction. Methods— All patients with stroke were screened for eligibility (age 18–75 years, National Institutes of Health Stroke Scale ≥18 with Item 1a<2 [responsive to minor stimulation], and CT demonstrating unilateral, complete middle cerebral artery territory infarction by specific imaging criteria). All enrolled patients were treated using a standardized medical treatment protocol. Those with both ≥4 mm of pineal shift and deterioration in level of arousal or ≥7.5 mm of anteroseptal shift within 96 hours of stroke onset were randomized to continued medical treatment only or medical treatment plus surgery. Death at 21 days was the primary outcome measure. Results— Among 4909 screened patients, only 66 (1.3%) patients were eligible for HeADDFIRST. Forty patients were enrolled, and 26 patients developed the requisite brain swelling for randomization. All who failed to meet randomization criteria were alive at 21 days. Mortality at 21 and 180 days was 40% (4/10) in the medical treatment only and 21% (3/14) and 36% (5/14) in the medical treatment plus surgery arms, respectively. Conclusions— HeADDFIRST randomization criteria effectively distinguished low from high risk of death from large supratentorial cerebral hemispheric infarction. Lower mortality in the medical treatment only group than in other published trials suggests a possible benefit to standardizing medical management. These results can inform the interpretation of recently completed European trials concerning patient selection and medical management. Clinical Trial Registration— This trial was not registered because enrollment began before July 1, 2005.

AbstractResearch demonstrates that patients with fibromyalgia who have higher positive and lower negative affect have lower symptom burden. Affect has been shown to be associated with resilience. This study examined the relationship between affect, resilience and fibromyalgia symptom burden in a clinical sample of patients with fibromyalgia. We hypothesized that (a) positive and negative affect would be associated with fibromyalgia symptom burden; (b) resilience would be associated with positive and negative affect; (c) resilience would be associated with fibromyalgia symptom burden; and (d) the connection between resilience and fibromyalgia symptom burden would be mediated by both positive and negative affect. A sample of 858 patients with fibromyalgia completed questionnaires. Mediation modelling revealed statistically significant direct effects of resilience on fibromyalgia symptom burden (β = −0.10, P < 0.001) and statistically significant indirect effects of resilience on fibromyalgia symptom burden through affect (β = −0.36, P < 0.001), suggesting that both resilience and affect influence fibromyalgia symptom burden. Our results suggest that improving affect through resiliency training could be studied as a modality for improving fibromyalgia symptom burden. Copyright © 2013 John Wiley & Sons, Ltd.

SummaryPatients with myelofibrosis (MF) have significant debilitating symptoms, physical disabilities, and poor health‐related quality of life (HRQoL). Here, we report post‐hoc analyses of the impact of ruxolitinib, a potent and selective JAK1 and JAK2 inhibitor, on disease‐related symptoms and HRQoL in MF patients from the large phase 3 COMFORT‐II study (N = 219). During the follow‐up period of 48 weeks, HRQoL and MF‐associated symptoms improved from baseline for ruxolitinib‐treated patients but remained the same or worsened for best available therapy (BAT)‐treated patients. Based on the European Organization for Research and Treatment of Cancer QoL Questionnaire core 30 items (EORTC QLQ‐C30), treatment‐induced differences in physical and role functioning, fatigue, and appetite loss significantly favoured ruxolitinib versus BAT from week 8 (P < 0·05) up to week 48 (P < 0·05). Ruxolitinib resulted in significantly higher response rates in global health status/QoL and Functional Assessment of Cancer Therapy‐Lymphoma (FACT‐Lym) summary scores versus BAT at most time points (P < 0·05). Significant improvements in the Lymphoma subscale (including symptoms of pain, fever, itching, fatigue, weight loss, loss of appetite, and other patient concerns), FACT‐General, FACT‐Lym trial outcome index, and FACT‐Lym total were also observed with ruxolitinib versus BAT starting at week 8 and continuing thereafter. Overall, these data demonstrated that ruxolitinib improved HRQoL in MF patients and further support the use of ruxolitinib for the treatment of symptomatic MF.

AbstractUtilizing billing records, we identified patients seen at Mayo Clinic with a diagnosis or history of fibromyalgia who were then contacted for enrollment in a fibromyalgia research registry. Fibromyalgia was confirmed through medical record review. Eligible patients were mailed an invitation that included a demographic questionnaire and the Fibromyalgia Research Survey. The Fibromyalgia Research Survey yields a widespread pain score (scale range 0–19) and a symptom severity score (scale range 0–12). A total of 4,034 patients returned the completed survey; 92.8% were female, their mean age was 57.4 (±13.4), and 83.7% were from the Midwest region of the United States. The mean widespread pain score for all participants was 11.3 (±4.5) and the mean symptom severity score was 8.2 (±2.4), indicating moderate‐to‐severe fibromyalgia symptoms, which is not unusual for patients presenting to a tertiary care center. Using a systematic process, we describe the creation of a fibromyalgia registry for future research.

Background and Purpose CGS 19755 is a competitive N -methyl- d -aspartate (NMDA) receptor antagonist that limits neuronal damage in animal stroke models. The objectives of this multicenter (7 centers), randomized, double-blind, placebo-controlled, ascending-dose phase IIa study were to evaluate the safety and tolerability of CGS 19755 and obtain pharmacokinetic and preliminary data on its efficacious dose range in patients treated within 12 hours of hemispheric ischemic stroke. Methods At each dose level, 6 patients were randomized to one or two intravenous bolus doses of CGS 19755, and 2 patients were randomized to placebo. An unblinded safety and monitoring committee evaluated results at each dose before ascending to the next level. All patients at the first level (1 mg/kg) received two doses separated by 12 hours. The first 2 patients at 2 mg/kg received two doses, but adverse experiences occurred in both; subsequent patient groups received single doses of 2.0, 1.75, or 1.5 mg/kg. Results Adverse experiences (agitation, hallucinations, confusion, paranoia, and delirium) occurred in all 6 patients treated with 2 mg/kg, and in 3 of 5 at 1.75 mg/kg. Similar but milder adverse experiences were noted in 4 of 7 patients at 1.5 mg/kg and 1 of 6 patients at 1.0 mg/kg. Adverse experiences began between 20 minutes and 22 hours (mean, 8 hours) after treatment and lasted 2 to 60 hours (mean, 24 hours). Mortality was 1 of 8 in patients receiving placebo and 3 of 24 in treated patients. In treated survivors, median and mean percent improvement in National Institutes of Health Stroke Scale scores from baseline to terminal visit (mean, 86 days) was comparable at all doses, and 95% of treated patients had Barthel Index scores of ≥70 at the terminal visit. Conclusions We conclude that a single intravenous dose of 1.5 mg/kg CGS 19755 is safe and tolerable in patients with acute ischemic stroke. An efficacy trial is indicated.