Safety and efficacy of denileukin diftitox in patients with steroid-refractory acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

Denileukin diftitox (Ontak), a recombinant protein composed of human interleukin 2 (IL-2) fused to diphtheria toxin, has selective cytotoxicity against activated lymphocytes expressing the high-affinity IL-2 receptor. We conducted a phase 1 study of denileukin diftitox in 30 patients with steroid refractory acute graft-versus-host disease (GVHD). Seven patients received 9 microg/kg intravenously on days 1 and 15; 18 received 9 microg/kg intravenously on days 1, 3, 5, 15, 17, and 19; and 5 received 9 microg/kg intravenously on days 1 to 5 and 15 to 19. Hepatic transaminase elevation was the dose-limiting toxicity (DLT), and dose level 2 was the maximum tolerated dose (MTD). Overall, 71% of patients responded with complete resolution (12 of 24; 50%) or partial resolution (5 of 24; 21%) of GVHD. Eight of 24 patients (33%) are alive at 6.3 to 24.6 months (median, 7.2 months). Denileukin diftitox is tolerable and has promising activity in steroid-refractory acute GVHD.     

Modular branched stent graft for endovascular repair of aortic arch aneurysm and dissection

PURPOSE: We describe a modular stent graft for use in endovascular repair of aneurysms of the aortic arch. METHOD: Carotid-carotid and left carotid-subclavian bypass grafts are created surgically. Two large, fully stented grafts are inserted endoluminally. The proximal component is bifurcated, with a wide proximal trunk and two distal limbs, one long and narrow, the other short and wide. This component is inserted through the carotid artery and deployed with the trunk and short wide limb in the ascending thoracic aorta; the long narrow limb opens into the innominate artery. After delivery system removal and carotid artery repair, a distal component is inserted through a femoral approach to bridge the gap between the short, wide distal limb of the proximal component and the nondilated descending thoracic aorta. The result is a branched stent graft, implanted proximally into the ascending aorta and distally into the innominate artery and descending thoracic aorta. CONCLUSION: The system has been used successfully to treat a large wide-necked pseudoaneurysm of the aortic arch.     

A roundtable discussion of aromatase inhibitors as therapy for breast cancer

This article summarizes the conclusions of a meeting of diverse breast cancer experts who discussed issues, controversies, and new clinical trial results relevant to the use of aromatase inhibitors for treating postmenopausal women with breast cancer. The new generation of aromatase inhibitors (anastrozole, letrozole, exemestane) have largely replaced megestrol acetate as a second-line therapy in postmenopausal women with hormone-responsive advanced breast cancer. In addition, anastrozole and letrozole have been shown to be superior to tamoxifen for first-line therapy. Finally, recent results suggest that anastrozole may be superior to tamoxifen as adjuvant therapy for early stage disease in postmenopausal women with hormone-responsive disease.     

The Netherlands protocol for standardisation and quantification of FDG whole body PET studies in multi-centre trials

Introduction  Several studies have shown the usefulness of positron emission tomography (PET) quantification using standardised uptake values (SUV) for diagnosis and staging, prognosis and response monitoring. Many factors affect SUV, such as patient preparation procedures, scan acquisition, image reconstruction and data analysis settings, and the variability in methodology across centres prohibits exchange of SUV data. Therefore, standardisation of 2-[¹⁸F] fluoro-2-deoxy-D-glucose (FDG) PET whole body procedures is required in multi-centre trials. Methods  A protocol for standardisation of quantitative FDG whole body PET studies in the Netherlands (NL) was defined. This protocol is based on standardisation of: (1) patient preparation; (2) matching of scan statistics by prescribing dosage as function of patient weight, scan time per bed position, percentage of bed overlap and image acquisition mode (2D or 3D); (3) matching of image resolution by prescribing reconstruction settings for each type of scanner; (4) matching of data analysis procedure by defining volume of interest methods and SUV calculations and; (5) finally, a multi-centre QC procedure is defined using a 20-cm diameter phantom for verification of scanner calibration and the NEMA NU 2 2001 Image Quality phantom for verification of activity concentration recoveries (i.e., verification of image resolution and reconstruction convergence). Discussion  This paper describes a protocol for standardization of quantitative FDG whole body multi-centre PET studies. Conclusion  The protocol was successfully implemented in the Netherlands and has been approved by the Netherlands Society of Nuclear Medicine. An erratum to this article can be found at     

Inhibitory smads and tgf-Beta signaling in glomerular cells

Smad6 and Smad7 are inhibitory SMADs with putative functional roles at the intersection of major intracellular signaling networks, including TGF-beta, receptor tyrosine kinase (RTK), JAK/STAT, and NF-kappaB pathways. This study reports differential functional roles and regulation of Smad6 and Smad7 in TGF-beta signaling in renal cells, in murine models of renal disease and in human glomerular diseases. Smad7 is upregulated in podocytes in all examined glomerular diseases (focal segmental glomerulosclerosis [FSGS], minimal-change disease [MCD], membranous nephropathy [MNP], lupus nephritis [LN], and diabetic nephropathy [DN]) with a statistically significant upregulation in "classical" podocyte-diseases such as FSGS and MCD. TGF-beta induces Smad7 synthesis in cultured podocytes and Smad6 synthesis in cultured mesangial cells. Although Smad7 expression inhibited both Smad2- and Smad3-mediated TGF-beta signaling in podocytes, it inhibited only Smad3 but not Smad2 signaling in mesangial cells. In contrast, Smad6 had no effect on TGF-beta/Smad signaling in podocytes and enhanced Smad3 signaling in mesangial cells. These data suggest that Smad7 is activated in injured podocytes in vitro and in human glomerular disease and participates in negative control of TGF-beta/Smad signaling in addition to its pro-apoptotic activity, whereas Smad6 has no role in TGF-beta response and injury in podocytes. In contrast, Smad6 is upregulated in the mesangium in human glomerular diseases and may be involved in functions independent of TGF-beta/Smad signaling. These data indicate an important role for Smad6 and Smad7 in glomerular cells in vivo that could be important for the cell homeostasis in physiologic and pathologic conditions.     

Biomechanical evaluation of fixation of clavicular fractures

Reproducible fractures of the midshaft of the clavicle were created in 14 fresh frozen human cadaveric clavicles. Under the three-point bending loading by a materials testing machine, the load to failure of fixation of the clavicular fractures treated with steel reconstruction plates (five specimens) and Herbert cannulated bone screw (nine specimens), was compared with a group control formed by five specimens of clavicles without osteosynthesis material. No statistically significant differences were observed between the three groups. In consequence and in terms of biomechanics, in clavicular acute fractures, both plating and intramedullary Herbert cannulated bone screw may be utilized in the treatment of these lesions.     

Association of a CYP4A11 variant and blood pressure in black men

CYP4A11 arachidonic acid monooxygenase oxidizes endogenous arachidonic acid to 20-hydroxyeicosatetraenoic acid, a renal vasoconstrictor and natriuretic. Cyp4a deficiency causes hypertension in male mice, and a loss-of-function variant (T8590C) of CYP4A11 is associated with hypertension in white individuals. Hypertension and hypertensive renal disease are more common among black than white individuals, but the relationship between genetic variation at CYP4A11 and hypertension in black individuals is not known. This study tested the hypothesis that the CYP4A11 T8590C polymorphism is associated with higher BP or clinical outcomes in 732 black Americans with hypertensive renal disease participating in the African American Study of Kidney Disease (AASK). Men with the 8590CC genotype had significantly higher systolic BP (CC 156.5 +/- 22.6 versus 148.4 +/- 24.3 mmHg in CT and TT combined; P = 0.04) and pulse pressure (P = 0.04) at baseline; this association was not observed among women. In addition, this genotype was associated with higher systolic and diastolic BP at 36-mo follow-up among those randomly assigned to the lower BP arm of the AASK. Among all participants (or men but not women) with proteinuria, the 8590CC genotype was associated with an increased cumulative incidence of ESRD or death, controlling for randomization and clinical characteristics. In summary, the CYP4A11 8590CC genotype is associated with increased BP in black men with hypertensive nephrosclerosis and is associated with adverse clinical outcomes in those with baseline proteinuria. These data support a role for renal monooxygenases and 20-hydroxyeicosatetraenoic acid in the regulation of BP and renal function in men.     

Neutrophil stimulation with granulocyte colony-stimulating factor worsens ventilator-induced lung injury and mortality in rats

BACKGROUND: Based on the association between the neutrophil and ventilator-induced lung injury, the authors hypothesized that neutrophil inhibition with fucoidin would be beneficial and stimulation with granulocyte colony-stimulating factor (G-CSF) would be harmful in a rat model of lethal ventilator-induced lung injury. METHODS: Animals (n = 111) were randomly assigned to be pretreated with fucoidin, G-CSF, or placebo (control) before 4 h of low-tidal-volume (10 ml/kg) or high-tidal-volume (40 ml/kg) mechanical ventilation. RESULTS: All low-volume animals survived. With high volumes, compared with controls, fucoidin did not improve survival (3 of 20 control animals and 5 of 20 fucoidin animals died; P = 0.51) but G-CSF significantly worsened it (18 of 22 animals died; P < 0.001). Circulating neutrophils were increased early with G-CSF and late with fucoidin with low and high tidal volumes (P < 0.05 for each treatment and tidal volume). Fucoidin decreased lung neutrophils, but these were only significant with high tidal volumes, whereas G-CSF increased lung neutrophils but only significantly with low tidal volumes (P < or = 0.01 for each). Fucoidin did not alter any cardiopulmonary measure significantly. Compared with control, G-CSF increased airway pressures with high tidal volumes and worsened lung edema and arterial oxygen with both tidal volumes (P < 0.05 for each). CONCLUSIONS: In this model, neutrophil stimulation by G-CSF increased lung dysfunction and with high tidal volumes worsened survival rates. Extrapolated clinically, neutrophil stimulation either by agents such as G-CSF or conditions such as sepsis may aggravate ventilator-induced lung injury.     

Plantar forefoot pressure changes after second metatarsal neck osteotomy

BACKGROUND: The aim of this study was to evaluate plantar pressure changes after second metatarsal neck osteotomy using the Weil technique. METHODS: Six below-knee cadaver specimens were used. Each specimen was held in a custom-built apparatus and loaded to 500 N for a period of 3 seconds. Using a computerized Musgrave pedobarograph, pressure measurements were made before and after osteotomy in both neutral and 45-degree heel rise positions. All osteotomies were made at an angle of approximately 20 degrees relative to the long axis of the metatarsal shaft. The metatarsal heads were displaced proximally by 5 mm and fixed with a single Kirschner wire. RESULTS: After osteotomy there was an average decrease in pressure beneath the second metatarsal from 70.6 to 45.1 kPa in neutral and from 813.0 to 281.4 kPa in heel rise, representing statistically significant (p < or = 0.05) decreases of 36% and 65%, respectively. There also were significant decreases beneath the third metatarsal in both neutral (39%) and heel rise (37%), and beneath the fourth metatarsal in neutral position (28%). A significant pressure increase occurred beneath the first metatarsal in neutral (23%). No significant pressure changes occurred under the fifth metatarsal in either position. CONCLUSION: Overall, our results indicated that the Weil metatarsal neck osteotomy is effective at offloading the second metatarsal head at neutral and heel rise positions.