Umgelter and colleagues have reported that there is a general reluctance to treat cirrhotic patients with renal failure with volume resuscitation. ...they are critical of the accuracy of diagnosing ...hepatorenal syndrome (HRS) using the infusion of pre-defined doses of albumin as recommended in our paper. 1 Finally, they do not seem to share the opinion that HRS, once established, is no longer responsive to simple volume expansion, and therefore suggest investigating a goal-directed approach of treatment.
The review and verification of credentials and the granting of clinical privileges are required of every hospital to ensure that members of the medical staff are competent and qualified to provide ...specified levels of patient care. The credentialing process involves the following: (1) assessment of the professional and personal background of each practitioner seeking privileges; (2) assignment of privileges appropriate for the clinician's training and experience; (3) ongoing monitoring of the professional activities of each staff member; and (4) periodic reappointment to the medical staff on the basis of objectively measured performance. We examine the essential elements of a credentials review for initial and renewed medical staff appointments along with suggested criteria for the delineation of clinical privileges. Sample forms for the delineation of privileges can be found on the American Academy of Pediatrics Committee on Hospital Care Web site (http://www.aap.org/visit/cmte19.htm). Because of differences among individual hospitals, no 1 method for credentialing is universally applicable. The medical staff of each hospital must, therefore, establish its own process based on the general principles reviewed in this report. The issues of medical staff membership and credentialing have become very complex, and institutions and medical staffs are vulnerable to legal action. Consequently, it is advisable for hospitals and medical staffs to obtain expert legal advice when medical staff bylaws are constructed or revised.
Abstract 937
. Activating in-tandem duplication (ITD) mutations within the FLT3 juxtamembrane region are detected in ∼25% of adult acute myeloid leukemia (AML) cases and portend a poor prognosis. ...AC220 (quizartinib) is a potent selective investigational FLT3/KIT inhibitor with encouraging preliminary clinical activity, as evidenced by a composite complete remission rate of 43% in 53 chemotherapy refractory/relapsed AML patients evaluable for an interim analysis of the ongoing phase II study in FLT3-ITD+ relapsed/refractory AML (Cortes et al, EHA 2011 abstract 1019). Many patients who initially respond ultimately suffer disease progression. We sought to utilize the clinical efficacy of AC220 to determine if FLT3-ITD is a valid therapeutic target in human AML. A saturation mutagenesis strategy identified amino acid substitutions at three amino acid residues (F691, D835, Y842) in FLT3-ITD that confer a high degree of resistance to AC220 in vitro. Of these, substitutions at F691 and D835 conferred the greatest degree of relative resistance.
. To assess the validity of FLT3-ITD as a therapeutic target in AML, we analyzed paired pretreatment and relapse samples obtained from a cohort of 9 FLT3-ITD-positive AML patients enrolled in the exploratory part of the ongoing phase II study of AC220 in relapsed/refractory AML (clinicaltrials.gov NCT00989261) who relapsed after initially achieving morphologic clearance of bone marrow blasts to <5% on treatment. Through RT-PCR subcloning and sequencing of the FLT3 kinase domain, we observed evolution of one or more acquired kinase domain mutations on the FLT3-ITD containing allele in all 9 cases at relapse. Clinically detected mutations were restricted to the “gatekeeper” residue F691 and/or the activation loop residue D835 (F691L, n=3, D835Y, n=4; D835V, n=2, D835F, n=1). Each of these mutations successfully transformed Ba/F3 cells to IL-3 independence and conferred substantial resistance to AC220 in cell growth and cell-based biochemical assays. All of the AC220-resistant mutations conferred substantial in vitro cross-resistance to sorafenib, which has been reported to harbor clinical activity in a small number of FLT3-ITD-associated AML cases.
In an expanded analysis of genomic DNA samples from 30 patients enrolled in the exploratory part of the Phase II study who discontinued study drug for any reason, we observed the occurrence of acquired mutations in the kinase domain (D835 and F691) in a total of 10 of 30 (33%) patients at the off study timepoint. One patient had a D835Y mutation prior to going on AC220.
Molecular docking studies were undertaken to provide mechanistic insights into the structural basis of resistance conferred by AC220-resistant mutations. These studies revealed that AC220 likely binds strongly to the DFG-out inactive FLT3 kinase domain. AC220 directly interacts with the gatekeeper residue F691, explaining the drug-resistance associated with the F691L mutation. Mutations at D835 and Y842 may potentially de-stabilize the inactive conformation, and result in a more active, AC220 binding-deficient FLT3 kinase. Indeed, substitutions at these residues are known to activate FLT3 in the absence of an ITD mutation.
To more precisely assess the frequency and identity of resistance-conferring mutations at relapse, we analyzed a subset of samples using single molecule real-time (SMRT™; Pacific Biosciences, Menlo Park, CA) sequencing, which can generate reads of sufficient length to enable focused interrogation of the kinase domain of FLT3-ITD alleles. With this assay, more than 350 reads of >1000 nucleotides were reliably obtained. Analyses of pretreatment and relapse samples from four patients confirmed the presence of resistance-conferring FLT3-ITD kinase domain mutations at F691 or D835 at relapse in 36–60% of FLT3-ITD sequence reads. Additionally, this method detected polyclonal resistance in two of the four samples assessed.
. Our studies validate FLT3-ITD as a therapeutic target in a proportion of AML cases, and demonstrate that the clinical activity of AC220 is mediated by FLT3-ITD inhibition. AC220-resistant FLT3-ITD gatekeeper and activation loop mutations identified in clinical samples from relapsing patients represent high-value therapeutic targets for next-generation FLT3 inhibitors.
Off Label Use: AC220 is an investigational agent and has no approved drug indication in AML. Chin:Pacific Biosciences: Employment. Hunt:Ambit Biosciences: Employment. Levis:Ambit Biosciences, Inc: Consultancy. Travers:Pacific Biosciences: Employment. Wang:Pacific Biosciences: Employment. Kasarskis:Pacific Biosciences: Employment, Equity Ownership. Schadt:Pacific Biosciences: Employment, Equity Ownership.
Our objective was to test the short-term efficacy and feasibility of two stress-reduction approaches for the treatment of hypertension in older African Americans, focusing on subgroup analysis by sex ...and by high and low risk on six measures of hypertension riskpsychosocial stress, obesity, alcohol use, physical inactivity, dietary sodium-potassium ratio, and a composite measure. The study involved a follow-up subgroup analysis of a 3-month randomized, controlled, single-blind trial conducted in a primary care, inner-city health center. Subjects were 127 African American men and women, aged 55 to 85 years, with diastolic pressure of 90 to 104 mm Hg and systolic pressure less than or equal to 179 mm Hg. Of these, 16 did not complete follow-up blood pressure measurements. Mental and physical stress-reduction approaches--the Transcendental Meditation technique and progressive muscle relaxation, respectively--were compared with a lifestyle modification education control and with each other. Both systolic and diastolic pressures changed from baseline to follow-up for both sexes and for high and low risk level (defined by median split) on the six measures of hypertension risk. Compared with education control subjects, women practicing the Transcendental Meditation technique showed adjusted declines in systolic (10.4 mm Hg, P < .01) and diastolic (5.9 mm Hg, P < .01) pressures. Men in this treatment group also declined in both systolic (12.7 mm Hg, P < .01) and diastolic (8.1 mm Hg, P < .001) pressures compared with control subjects. Women practicing muscle relaxation did not show a significant decrease compared with control subjects, and men declined significantly in diastolic pressure only (6.2 mm Hg, P < .01). For the measure of psychosocial stress, both the high and low risk subgroups using the Transcendental Meditation technique declined in systolic (high risk, P = .0003; low, P = .06) and diastolic (high risk, P = .001; low, P = .008) pressures compared with control subjects, whereas for muscle relaxation, blood pressure dropped significantly only in the high risk subgroup and only for systolic pressure (P = .03) compared with control subjects. For each of the other five risk measures, Transcendental Meditation subjects in both the high and low risk groups declined significantly in systolic and diastolic pressures compared with control subjects. Effects of stress reduction on blood pressure were found to generalize to both sexes and diverse risk factor subgroups and were significantly greater in the Transcendental Meditation treatment group. These effects (along with high compliance) even in individuals with multiple risk factors for hypertension clearly warrant longer-term investigation in this and other populations. (Hypertension. 1996;28:228-237.)
Objective:This review focuses on a comprehensive, sophisticated system of natural medicine that appears to hold promise for prevention of chronic diseases and disabilities, loss of independence, ...suffering, and health care costs often associated with “usual” aging. Methods:The authors discuss the negative impact of usual aging on our society, with its rapidly growing percentage of elderly, and the challenge of promoting “successful aging.” Emphasis is given to research literature suggesting that Maharishi Vedic Medicine (MVM) is particularly effective in retarding usual aging. Results:Proposed mechanisms for the antiaging effects ofMVMinclude reductions in physiological and psychological stress and enhancement of homeostatic and self-repair processes. Conclusions:The authors conclude that this set of innovative strategies may help society achieve recommended health objectives for disease prevention and health promotion in older adults and that widespread implementation of this self-empowering, prevention-oriented approach in the elderly is feasible, cost effective, and timely.
PDF
