Purpose: Epigenetic changes play a role and cooperate with genetic alterations in the pathogenesis of myelodysplastic syndromes (MDS).
We conducted a phase II multicenter study on the combination of ...the DNA-methyltransferase inhibitor 5-azacytidine (5-AZA)
and the histone deacetylase inhibitor valproic acid (VPA) in patients with higher risk MDS.
Experimental Design: We enrolled 62 patients with MDS (refractory anemia with excess blasts, 39 patients; refractory anemia with excess blasts
in transformation, 19 patients; and chronic myelomanocytic leukemia (CMML), 4 patients) and an International Prognostic Scoring
System (IPSS) rating of Intermediate-2 (42 patients) or high (20 patients). VPA was given to reach a plasma concentration
of >50 μg/mL, then 5-AZA was added s.c. at 75 mg/m 2 for 7 days in eight monthly cycles.
Results: The median overall survival was 14.4 months. At a median follow-up of 12 months (range, 0.7-21.0), the disease progressed
in 20 patients, with 21% cumulative incidence of progression. Of 26 patients who completed eight cycles, 30.7% obtained complete
or partial remission, 15.4% had a major hematologic improvement, whereas 38.5% showed stable disease. Drug-related toxicity
was mild. Favorable prognostic factors for survival were IPSS Intermediate-2 and plasma VPA of â¥50 μg/mL (log rank = 0.013
and 0.007, respectively). Analysis of polymorphisms important for the metabolism of the drugs used in the trial showed that
carriers of the CYP2C19*2 variant of cytochrome P450 required higher VPA doses to achieve the target VPA plasma concentration
of 50 μg/mL on day 1 of 5-AZA treatment ( P = 0.0021).
Conclusion: Our data show that the 5-AZA/VPA combination is active and safe in patients with MDS with a poor prognosis. Achievement of
VPA therapeutic levels may indeed increase 5-AZA efficacy.
Ethmoidal dural arteriovenous fistulas (DAVFs) are rare and aggressive lesions, usually treated by microsurgical disconnection of the fistula. Transarterial embolization rarely is performed because ...of the risk of retinal ischemia. Transvenous embolization has been reported as an alternative approach. We describe our experience in transvenous embolization of ethmoidal DAVFs and review the literature focusing on technical and safety aspects of the procedure.
We retrospectively identified 4 patients with ethmoidal DAVFs treated by transvenous embolization in a single center. Clinical data and angiographic images were reviewed. We reviewed the literature after PubMed searching for articles describing patients treated by a transvenous approach.
One patient was treated by transvenous coiling and 3 patients by retrograde Onyx injection through a detachable-tip microcatheter. Three fistulas drained in an ascending cortical frontal vein and one drained posteriorly in the olfactory vein. In all patients the fistula was occluded, in one case an asymptomatic hemorrhage occurred. In the literature 12 further cases of transvenous embolization of ethmoidal DAVFs have been reported.
Transvenous embolization is an effective approach for the treatment of ethmoidal DAVFs in properly selected patients. Onyx injection through detachable-tip microcatheters increases the feasibility of the intervention.
Cytokines play a pivotal role in Hodgkin's lymphoma (HL). Because interleukin-6 (IL-6) induces expression of hepcidin, one of the principal regulators of iron metabolism, we studied the contribution ...of hepcidin in anemia in HL at diagnosis.
Plasma samples from 65 patients with HL were analyzed for hepcidin levels using a combination of weak cation exchange chromatography and time-of-flight mass spectrometry; cytokine levels were analyzed using enzyme-linked immunosorbent assays and parameters of iron metabolism and acute-phase reaction.
Hepcidin plasma levels were significantly higher in HL patients when compared with controls, independent of the presence of anemia (P = .001). In the subset of patients with anemia, hepcidin levels inversely correlated with hemoglobin levels (P = .01). Analyzing parameters of iron metabolism, hepcidin levels showed a positive correlation with ferritin (P < .001) and an inverse correlation to iron and iron-binding capacity. Hepcidin strongly correlated to IL-6 levels (P < .001) but not to IL-10 or thymus and activation-regulated cytokine (TARC)/chemokine (C-C motif) ligand 17 (CCL17) levels. In a multivariate regression analysis, IL-6 and fibrinogen levels were independently associated with hepcidin. Higher hepcidin levels were observed in patients with more aggressive disease characteristics: stage IV disease (P = .01), presence of B symptoms (P = .03), and International Prognostic Score > 2 (P = .005).
Our findings suggest that in HL, hepcidin is upregulated by IL-6. Elevated hepcidin levels result in iron restriction and signs of anemia of chronic inflammation, although hepcidin-independent mechanisms contribute to development of anemia in HL.
Ovarian tumours are usually surgically removed because of the presumed risk of complications. Few large prospective studies on long-term follow-up of adnexal masses exist. We aimed to estimate the ...cumulative incidence of cyst complications and malignancy during the first 2 years of follow-up after adnexal masses have been classified as benign by use of ultrasonography.
In the international, prospective, cohort International Ovarian Tumor Analysis Phase 5 (IOTA5) study, patients aged 18 years or older with at least one adnexal mass who had been selected for surgery or conservative management after ultrasound assessment were recruited consecutively from 36 cancer and non-cancer centres in 14 countries. Follow-up of patients managed conservatively is ongoing at present. In this 2-year interim analysis, we analysed patients who were selected for conservative management of an adnexal mass judged to be benign on ultrasound on the basis of subjective assessment of ultrasound images. Conservative management included ultrasound and clinical follow-up at intervals of 3 months and 6 months, and then every 12 months thereafter. The main outcomes of this 2-year interim analysis were cumulative incidence of spontaneous resolution of the mass, torsion or cyst rupture, or borderline or invasive malignancy confirmed surgically in patients with a newly diagnosed adnexal mass. IOTA5 is registered with ClinicalTrials.gov, number NCT01698632, and the central Ethics Committee and the Belgian Federal Agency for Medicines and Health Products, number S51375/B32220095331, and is ongoing.
Between Jan 1, 2012, and March 1, 2015, 8519 patients were recruited to IOTA5. 3144 (37%) patients selected for conservative management were eligible for inclusion in our analysis, of whom 221 (7%) had no follow-up data and 336 (11%) were operated on before a planned follow-up scan was done. Of 2587 (82%) patients with follow-up data, 668 (26%) had a mass that was already in follow-up at recruitment, and 1919 (74%) presented with a new mass at recruitment (ie, not already in follow-up in the centre before recruitment). Median follow-up of patients with new masses was 27 months (IQR 14–38). The cumulative incidence of spontaneous resolution within 2 years of follow-up among those with a new mass at recruitment (n=1919) was 20·2% (95% CI 18·4–22·1), and of finding invasive malignancy at surgery was 0·4% (95% CI 0·1–0·6), 0·3% (<0·1–0·5) for a borderline tumour, 0·4% (0·1–0·7) for torsion, and 0·2% (<0·1–0·4) for cyst rupture.
Our results suggest that the risk of malignancy and acute complications is low if adnexal masses with benign ultrasound morphology are managed conservatively, which could be of value when counselling patients, and supports conservative management of adnexal masses classified as benign by use of ultrasound.
Research Foundation Flanders, KU Leuven, Swedish Research Council.
The synthesis of a poly(3,5-tricyclo2.2.1.0
2,6
heptylene) poly(norbornadiene) (PNBD) mediated by the TiCl
4
/Et
2
AlCl catalytic system is reported. This polymer is characterized by a rigid ...nortricyclene repeating structure and unique 3,5-enchainment and is obtained through a transannular cationic polymerization of norbornadiene involving both double bonds. The new PNBD is crystalline with high glass transition and melting temperatures due to the rigid tricyclic repeating structure.
13
C NMR spectra indicate that the chains of PNBD contain only
exo
/
exo
(
xx
) and
exo
/
endo
(
xn
) nortricyclene repeating monomeric units. Models of the chain conformation and crystal structure of PNBD are also reported. Models of low conformational energy of isotactic and syndiotactic chains of PNBD have been obtained from the regular enchainment of
xx
and
xn
units. The model of the isotactic (
xx)
m
chain with
s
(2/1) helical symmetry assumes a nearly
trans
-planar conformation, whereas the models of the syndiotactic (
xn-xn)
m
and (
nx-xn)
m
chains with
t
c
and
t
i
symmetries, respectively, assume the conformations (TG
−
G
−
TG
+
G
+
)
n
and (G
−
TTTG
+
T)
n
, respectively. Ideal limit ordered models of the crystal structure have been obtained from the X-ray powder diffraction data and the conformational energy analysis. A good agreement between experimental and calculated powder diffraction profiles has been obtained for a limit ordered model of packing of syndiotactic chains (
nx-xn)
m
of PNBD with
t
i
symmetry in an orthorhombic unit cell with axes
a
= 6.6 Å,
b
= 11.0 Å, and
c
= 6.84 Å according to the monoclinic space group
P
2
1
/
c
. The real crystal structure of PNBD is disordered because of the possible presence of configurational disorder in the chains due to possible random enchainment of nortricyclene monomeric units in the
xx
,
xn
and
nx
configurations that produces conformational and packing disorder.
When norbornadiene is polymerized with TiCl
4
/Et
2
AlCl catalytic system, a unique 3,5-poly(norbornadiene) is obtained. This new polymer is able to crystallize notwithstanding the presence of configurational disorder and packing disorder.
β-ketoimines are extensively applied for the synthesis of organometallic complexes intended as (pre)catalysts for a variety of chemical transformations. We were interested in the synthesis of two Cr ...complexes bearing a simple bidentate β-ketoimine (L), with different ligand binding modes, as well as their application as a precatalyst in the polymerization of olefins. Complex 1 (L2CrCl3) was obtained by direct reaction of L with CrCl3(THF)3, while, for the synthesis of complex 2 (LCrCl2), the ligand was first deprotonated with nBuLi, giving the β-ketoiminato ligand L─Li+, and then reacted with CrCl3(THF)3. Characterization of the complexes proved that the Cr(III) ion is coordinatively bonded to L in 1, while it is covalently bonded to L in 2. The complexes were then used as precatalysts for the polymerization of ethylene and various cyclic olefins. Upon activation with methylaluminoxane, both the complexes exhibited poor activity in the polymerization of ethylene, whilst they exhibit good productivity in the polymerization of cyclic olefins, affording semicrystalline oligomers, without a significant difference between 1 and 2. To gain more insight, we investigated the reaction of the complexes with the Al-cocatalyst by IR and UV-Vis spectroscopies. The results proved that, in case of 1, the Al-activator deprotonates the ligand, bringing to the formation of an active species analogous to that of 2.
With the aim of reviewing critical concepts and producing recommendations for the management of chronic myelomonocytic leukemia, key questions were selected according to the criterion of clinical ...relevance. Recommendations were produced using a Delphi process and four consensus conferences involving a panel of experts appointed by the Italian Society of Hematology and affiliated societies. This report presents the final statements and recommendations, covering patient evaluation at diagnosis, diagnostic criteria, risk classification, first-line therapy, monitoring, second-line therapy and allogeneic stem cell transplantation. For the first-line therapy, the panel recommended that patients with myelodysplastic-type chronic myelomonocytic leukemia and less than 10% blasts in bone marrow should be managed with supportive therapy aimed at correcting cytopenias. In patients with myelodysplastic-type chronic myelomonocytic leukemia with a high number of blasts in bone marrow (≥ 10%), supportive therapy should be integrated with the use of 5-azacytidine. Patients with myeloproliferative-type chronic myelomonocytic leukemia with a low number of blasts (<10%) should be treated with cytoreductive therapy. Hydroxyurea is the drug of choice to control cell proliferation and to reduce organomegaly. Patients with myeloproliferative-type chronic myelomonocytic leukemia, and a high number of blasts should receive polychemotherapy. Both in myelodysplastic-type and myeloproliferative-type chronic myelomonocytic leukemia, allogeneic stem cell transplantation should be offered within clinical trials in selected patients.
Novel allyl cobalt complexes, i.e., (η3-C4H7)(η4-C4H6)Co(PCyPh2) (1), (η3-C4H7)(η4-C4H6)Co(PMePh2) (2) and (η3-C5H9)(η4-C5H8)Co(PMePh2) (3), were synthesized by reacting CoCl2(PRPh2)2 (R = methyl, ...cyclohexyl) with 1,3-butadiene or isoprene in presence of metallic zinc. The complexes were fully characterized by Nuclear Magnetic Resonance (NMR) spectroscopy (1H and 2D experiments); in case of 1, single crystals, suitable for X-ray analysis, were obtained and the molecular structure was determined. The allyl cobalt phosphine complexes alone gave highly crystalline 1,2 polymers from 1,2-propadiene, but they did not polymerize 1,3-dienes. Nevertheless, in the presence of a stoichiometric amount of methylaluminoxane (MAO), they were able to polymerize 1,3-butadiene and substituted 1,3-butadienes such as isoprene, (E)-1,3-pentadiene, (E)-1,3-hexadiene, and (E)-3-methyl-1,3-pentadiene. Specifically, 1/MAO gave predominantly syndiotactic 1,2 polymers from 1,3-butadiene and terminally substituted 1,3-butadienes (e.g., 1,3-pentadiene and 1,3-hexadiene), but it was practically not active in the polymerization of internally substituted 1,3-butadienes (e.g., isoprene and 3-methyl-1,3-pentadiene); 2/MAO and 3/MAO exhibited instead an opposite behavior, giving predominantly isotactic 1,2 polymers from 3-methyl-1,3-pentadiene, and showing very low activity in the polymerization of 1,3-butadiene, 1,3-pentadiene and 1,3-hexadiene. The results obtained are interesting from the mechanistic point of view, and some hypotheses to explain this particular behavior were formulated.
BackgroundExperience with the endovascular treatment of cerebral aneurysms by flow diverter devices (FDDs) is limited to four devices (Pipeline, Covidien; FRED, Microvention; Silk, Balt Extrusion; ...Surpass, Stryker), as reported in different studies.ObjectiveTo describe the initial experience and the technical innovations of a new-generation FDD (p64 Flow Modulation Device, Phenox, Bochum, Germany).MethodsBetween December 2014 and February 2015, six intracranial aneurysms in five patients (four women, one man; mean age 63 years) were treated with the p64 Flow Modulation Device.ResultsImmediate post-treatment angiography showed reduced flow into all aneurysms. No long-term angiographic data are available. The device may be easily deployed and totally retrieved with a unique mechanical detachment. No periprocedural technical complications occurred. No early or delayed aneurysm rupture, no ischemic or hemorrhagic complications, and no neurological morbidity or death were seen.ConclusionsTreatment of cerebral aneurysms with the p64 Flow Modulation Device is a safe procedure with no technical complications. The mechanical detachment and the 100% retrievability are significant advantages of this new device. However, large prospective studies with long-term clinical and angiographic follow-up are necessary to assess the role of the p64 in the endovascular treatment of intracranial aneurysms.
The historical buildings of a nation are the tangible signs of its history and culture. Their preservation deserves considerable attention, being of primary importance from a historical, cultural, ...and economic point of view. Having a scalable and reliable monitoring system plays an important role in the Structural Health Monitoring (SHM): therefore, this paper proposes an Internet of Things (IoT) architecture for a remote monitoring system that is able to integrate, through the Virtual Reality (VR) paradigm, the environmental and mechanical data acquired by a wireless sensor network set on three ancient buildings with the images and context information acquired by an Unmanned Aerial Vehicle (UAV). Moreover, the information provided by the UAV allows to promptly inspect the critical structural damage, such as the patterns of cracks in the structural components of the building being monitored. Our approach opens new scenarios to support SHM activities, because an operator can interact with real-time data retrieved from a Wireless Sensor Network (WSN) by means of the VR environment.
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