FLT3 kinase inhibitors in the management of acute myeloid leukemia

FMS-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase (TK) expressed by immature hematopoietic cells and is important for the normal development of stem cells and the immune system. Mutations of the juxtamembranous and TK domain of the gene are described in 30%-35% of patients with acute myeloid leukemia (AML). These mutations alter the biologic properties of AML and are associated with prognosis. In recent years, there has been an enormous development of potential inhibitors of FLT3 mutations. These substances are now being studied in clinical protocols. The initial trials reveal that, unlike in patients with chronic myeloid leukemia, TK inhibitor (TKI) therapy in AML is more complex. To date, most FLT3 TKIs investigated in clinical studies show a favorable toxicity profile with considerable biologic activity. However, refractory disease and/or the rapid development of resistance toward these new drugs remain major challenges. Strategies to circumvent this unsatisfactory clinical potential of FLT3 TKIs are mainly based on the combination with cytotoxic chemotherapy. Herein, we summarize results from studies using FLT3 TKIs as single agents and report on the first clinical trials investigating FLT3 TKIs in combination with chemotherapy.     

Primary malignant sarcomas of the heart and great vessels in adult patients--a single-center experience

BACKGROUND: Sarcomas arising in the heart or the great vessels are rare entities. The prognosis of the patients is dismal. METHODS: Between January 1993 and September 2006, of 1,429 patients registered to the Sarcoma Center, 14 had a primary sarcoma of the heart or large vessels. RESULTS: Tumors were located in the left ventricle (n = 3), left/right atrium (n = 2/3), pulmonary artery (n = 2), and ventricular septum, aorta, pericardium, and inferior vena cava (n = 1 each). The most frequently encountered histologic subtypes were leiomyosarcoma and angiosarcoma. Six patients presented with distant metastases to the lungs (n = 5), lymph nodes (n = 2), and liver (n = 1). Eight patients had localized disease. Six of them underwent resection with curative intent. Of those, two developed local recurrence within 2 and 10 months from surgery. Eleven patients received palliative chemotherapy, seven of those as initial treatment. Eight patients attained a response to treatment, two had disease stabilization for 6 and 12 months. After a median follow-up of 14.5 months (range, 2-156), three patients were alive with no evidence of disease 11, 52, and 156 months after diagnosis. Two patients were alive with disease and nine patients had died. CONCLUSIONS: Patients with primary sarcomas of the heart and the large vessels were of a young age, and more than half of them presented with advanced disease. Given the promising response to chemotherapy, an optimized treatment approach including neoadjuvant chemo-/radiotherapy in patients with locally advanced disease should be pursued.     

Multicenter analysis of kidney preservation

BACKGROUND: Kidney preservation is an integral part of clinical kidney transplantation. Changes in the use of preservation methods and storage solutions, ischemic preservation times, and the relationship between ischemia time and human leukocyte antigen (HLA) match have not been extensively studied in recent years. METHODS: The Collaborative Transplant Study database was used to analyze effects of kidney preservation methods and times. Graft survival and death-censored functional survival were used as endpoints. In all, 91,674 transplants from deceased donors were analyzed using univariate and multivariate methods. RESULTS: Cold storage accounted for more than 95% of kidney preservations from 1990-2005. Increasing ischemia up to 18 hr was not detrimental for graft outcome, whereas the risk of graft failure rose with ischemia 19-24 hr to relative risk (RR) 1.09, 25-36 hr to RR 1.16, and >36 hr to RR 1.30 (P<0.001). As compared to other preservation solutions, University of Wisconsin (UW) solution was associated with significantly better outcome when ischemia exceeded 24 hr. Short ischemia did not eliminate the effect of HLA matching. Kidneys from young or old donors were affected by prolonged ischemia to similar degrees. Pulsatile machine perfusion was not superior to cold storage. CONCLUSION: Kidneys from deceased donors should ideally be transplanted within 18 hr. Within the 18-hr window, the time of ischemia has no significant influence on graft survival. UW solution should be used if preservation for longer periods is envisioned. HLA matching improves graft survival regardless of length of ischemia.     

Hexachlorobenzene stimulates uroporphyria in low affinity AHR mice without increasing CYP1A2

Adult female Fisher 344 rats received drinking water containing 0, 4, 40, 100, or 200 parts per million of dimethylarsinic acid or 100 parts per million of arsenate for 14 days. Urine was collected during the last 24 h of exposure. Tissues were then taken for analysis of dimethylated and trimethylated arsenicals; urines were analyzed for these arsenicals and their thiolated derivatives. In dimethylarsinic acid-treated rats, highest concentrations of dimethylated arsenic were found in blood. In lung, liver, and kidney, concentrations of dimethylated arsenic exceeded those of trimethylated species; in urinary bladder and urine, trimethylated arsenic predominated. Dimethylthioarsinic acid and trimethylarsine sulfide were present in urine of dimethylarsinic acid-treated rats. Concentrations of dimethylated arsenicals were similar in most tissues of dimethylarsinic acid- and arsenate-treated rats, including urinary bladder which is the target for dimethylarsinic acid-induced carcinogenesis in the rat. Mean concentration of dimethylated arsenic was significantly higher (P<0.05) in urine of dimethylarsinic acid-treated rats than in arsenate-treated rats, suggesting a difference between treatment groups in the flux of dimethylated arsenic through urinary bladder. Concentrations of trimethylated arsenic concentrations were consistently higher in dimethylarsinic acid-treated rats than in arsenate-treated rats; these differences were significant (P<0.05) in liver, urinary bladder, and urine. Concentrations of dimethylthioarsinic acid and trimethylarsine sulfide were higher in urine from dimethylarsinic acid-treated rats than from arsenate-treated rats. Dimethylarsinic acid is extensively metabolized in the rat, yielding significant concentrations of trimethylated species and of thiolated derivatives. One or more of these metabolites could be the species causing alterations of cellular function that lead to tumors in the urinary bladder.     

Bullying and fighting among adolescents - Do drinking motives and alcohol use matter?

The present study investigates the direct and indirect links (through alcohol use) between adolescents' drinking motives and violent behaviors (i.e. bullying and fighting). Structural equation models were estimated based on a national representative sample of 5419 8th to 10th graders in Switzerland (mean age 15.0, SD=.86). Results demonstrate that enhancement motives were only indirectly linked (through alcohol use) to violent behaviors, whereas coping motives were both directly and indirectly linked, particularly among girls. No consistent link was found for social motives. Despite the negative indirect link (through alcohol use), conformity motives were the strongest predictor of bullying and fighting among boys, and even stronger than alcohol use itself. To conclude, drinking motives have a bearing on other problem behaviors besides excessive drinking, and may be useful for early identification and intervention for students who are likely to experience a variety of problems.     

Expression of cyclooxygenase isozymes during morphogenesis and cycling of pelage hair follicles in mouse skin: precocious onset of the first catagen phase and alopecia upon cyclooxygenase-2 overexpression

Cyclooxygenase (COX)-1 and -2 catalyze the key reaction in prostaglandin biosynthesis. Whereas COX-1 is found in most tissues, COX-2, with a few exceptions, is not expressed in normal tissues but becomes transiently induced in the course of inflammatory reactions. In many neoplastic epithelia, COX-2 is constitutively overexpressed. Here we show that COX isozymes are spatiotemporally expressed during morphogenesis of dorsal skin epithelium of NMRI mice. COX-1 and COX-2 mRNA and protein were detected in embryonic and postnatal epidermal tissue by RT-PCR, northern blot, and immunoblot analysis indicating that both isoforms may contribute to prostaglandin production. Being barely detectable in interfollicular epidermis and resting hair follicles of adult mice, COX-2 protein appeared in embryonic skin first in epidermal precursor cells and later on in the basal cells and the peridermal layer of the stratified epidermis. In the course of pelage hair follicle morphogenesis, COX-2 remained expressed in the basal interfollicular compartment and, in addition, became apparent in elongated hair germs and hair pegs and later on in the outer root sheath cells of the distal and proximal hair follicles as well as in basal sebaceous gland cells. During the subsequent synchronous phases of hair cycling, COX-2 expression declined in catagen, was barely detectable in telogen, and was reinduced in the basal outer root sheath and basal sebaceous gland cells of anagen hair follicles. COX-1 immunosignals were detected predominantly in the interfollicular spinous and granular layers of the developing, neonatal, and adult epidermis but not in follicular epithelial cells of developing or cycling hair follicles. Dendritic cells in the interfollicular epidermis and distal hair follicles were also COX-1-positive. Transgenic overexpression of COX-2 under the control of a keratin 5 promoter in basal cells of the interfollicular and follicular epidermis induced a precocious entry into the first catagen stage of postnatal hair follicle cycling and a subsequent disturbance of hair follicle phasing. Furthermore, transgenic mice developed an alopecia. Inhibition of transgenic COX-2 activity by feeding the specific COX-2 inhibitor valdecoxib suppressed the development of alopecia, indicating that COX-2-mediated prostaglandin synthesis is involved in hair follicle biology.     

Fewer intensive care unit refusals and a higher capacity utilization by using a cyclic surgical case schedule

PURPOSE: Mounting health care costs force hospital managers to maximize utilization of scarce resources and simultaneously improve access to hospital services. This article assesses the benefits of a cyclic case scheduling approach that exploits a master surgical schedule (MSS). An MSS maximizes operating room (OR) capacity and simultaneously levels the outflow of patients toward the intensive care unit (ICU) to reduce surgery cancellation. MATERIALS AND METHODS: Relevant data for Erasmus MC have been electronically collected since 1994. These data are used to construct an MSS that consisted of a set of surgical case types scheduled for a period or cycle. This cycle was executed repetitively. During such a cycle, surgical cases for each surgical department were scheduled on a specific day and OR. The experiments were performed for the Erasmus University Medical Center and for a virtual hospital. RESULTS: Unused OR capacity can be reduced by up to 6.3% for a cycle length of 4 weeks, with simultaneous optimal leveling of the ICU workload. CONCLUSIONS: Our findings show that the proposed cyclic OR planning policy may benefit OR utilization and reduce surgical case cancellation and peak demands on the ICU.     

11C]PIB binding in Parkinson's disease dementia

[(11)C]PIB ((11)C-6-OH benzothiazole) reflects the regional distribution of amyloid (beta-sheeted proteins) in patients with Alzheimer's disease (AD). Proteinaceous inclusions in Parkinson's disease with dementia (PDD), so-called Lewy bodies, also consist of fibrillar, misfolded proteins, chiefly alpha-synuclein. To test whether PDD subjects show specific amyloid binding in vivo and whether this could reflect fibrillar alpha-synuclein accumulation, we investigated 10 PDD subjects with [(11)C]PIB-PET. Radioligand binding was compared to that in 11 control and 6 AD subjects. Furthermore, postmortem sections of 4 patients with Parkinson's disease (PD), therefrom 2 with dementia (PDD), and of 6 controls were stained with PIB to evaluate the histological distribution of the fluorescent ligand in the brainstem. In PET, only 2 PDD patients displayed increased PIB binding to cortical amyloid comparable to AD patients. The other 8 patients showed control-like cortical findings but elevated PIB binding in the pons and mesencephalon. Fluorescence microscopy showed PIB binding to Lewy bodies and neuromelanin in the substantia nigra of PD and PDD brainstem sections, but not in controls. These data suggest that PIB-PET can be used to further differentiate PDD with respect to cortical amyloid. Furthermore, we provide evidence that--in addition to nonspecific binding--PIB uptake in the brainstem may also reflect PDD related amyloid.     

Baseline [18F]-FDOPA kinetics are predictive of haloperidol-induced changes in dopamine turnover and cognitive performance: A positron emission tomography study in healthy subjects

The telencephalic dopamine innervations contribute to the modulation of cognitive processing. However, the relationship between cognitive effects of D(2/3)-receptor antagonism and dopamine transmission is not described in healthy subjects. We therefore tested effects of acute haloperidol (5 mg/d over 3 days) on continuous performance task (CPT) performance and 6-[(18)F]-fluoro-l-DOPA (FDOPA) PET parameters. Nine physically and mentally healthy male men performed two FDOPA-PET scans including arterial plasma withdrawal. Over 3 days before the second scan, all subjects were treated with 5 mg/d haloperidol orally. Using our novel steady-state analysis, we calculated the intrinsic rate of the cerebral FDOPA utilization (K), the turnover of [(18)F]fluorodopamine formed in brain (k(loss)) and the storage for FDOPA and its brain metabolites (V(d)). Furthermore, a ds-CPT and EPS-screening was performed before every PET scan. We found that FDOPA kinetics in those normal subjects with relatively high baseline K showed a more pronounced sensitivity to haloperidol treatment, manifesting in reduced storage capacity and elevated turnover of [(18)F]fluorodopamine, whereas subjects with lower K showed the opposite pattern of responses. Furthermore, low baseline K predicted improvements in the CPT task after haloperidol, whereas participants with higher baseline K showed a decline in cognitive performance. We conclude that the initial increase of [(18)F]fluorodopamine turnover after acute haloperidol challenge is associated with an over-stimulation in individuals with initially more pharmacologically responsive dopamine systems, but optimizes cognitive performance in those with lower normal FDOPA utilization at baseline. We hypothesize that these effects may be driven by D(1)-receptor mediated transmission during D(2) blockade.