Safety and efficacy of itraconazole compared to amphotericin B as empirical antifungal therapy for neutropenic fever in patients with haematological malignancy

BACKGROUND: Safety, tolerability and efficacy of itraconazole and amphotericin B (AMB) were compared for empirical antifungal treatment of febrile neutropenic cancer patients. PATIENTS AND METHODS: In an open, randomised study, 162 patients with at least 72 h of antimicrobial treatment received either intravenous followed by oral itraconazole suspension or intravenous AMB for a maximum of 28 days. Permanent discontinuation of study medication due to any adverse event was the primary safety parameter. Efficacy parameters included response and success rate for both treatment groups. RESULTS: Significantly fewer itraconazole patients discontinued treatment due to any adverse event (22.2 vs. 56.8% AMB; p < 0.0001). The main reason for discontinuation was a rise in serum creatinine (1.2% itraconazole vs. 23.5% AMB). Renal toxicity was significantly higher and more drug-related adverse events occurred in the AMB group. Intention-to-treat (ITT) analysis showed favourable efficacy for itraconazole: response and success rate were both significantly higher than for AMB (61.7 vs. 42% and 70.4 vs. 49.3%, both p < 0.0001). Treatment failure was markedly reduced in itraconazole patients (25.9 vs. 43.2%), largely due to the better tolerability. CONCLUSIONS: Itraconazole was tolerated significantly better than conventional AMB and also showed advantages regarding efficacy. This study confirms the role of itraconazole as a useful and safe agent in empirical antifungal therapy of febrile neutropenic cancer patients.     

Functional diagnosis of residual lymphomas after radiochemotherapy with positron emission tomography comparing FDG- and FLT-PET

Positron emission tomography (PET) using 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) is used as a functional imaging technique for the staging and follow-up of lymphomas. However, additional information about the tumor proliferation rate using 3'-deoxy-3'-[(18)F]fluorothymidine (FLT) may be useful for the assessment of prognosis. We enrolled 48 patients with Hodgkin's (n = 15) and non-Hodgkin's lymphoma (n = 33) with residual masses >2 cm examined by tracer studies with FDG and FLT. The results were related to median overall and progression-free survival. In 15 out of 48 patients analysed using FDG, positive results were found. Using FLT, 10 out of 48 patients were positive. 33 patients were FDG negative. Eight patients were positive both using FDG and FLT. Overall survival for patients with a negative PET scan was significantly higher than for patients with positive PET, irrespective of the tracer used. FLT alone was able to discriminate between patients with long or short overall survival. However, there was no statistical significance comparing FDG/FLT negative versus FDG negative alone. Although FDG detected more lesions than did FLT, the additional biological characterization of tumor tissue with respect to proliferation by FLT might be useful by providing complementary information for the identification of recurrence. However, the present data show no advantage of combined FDG/FLT studies over FDG alone with respect to the prediction of survival.     

Inhibition of platelet glycoprotein Ib and its antithrombotic potential

The platelet receptor glycoprotein (GP)Ib-IX-V complex plays a dominant role in the first steps of platelet adhesion and arterial thrombus formation. Through its interaction with the multimeric plasma protein von Willebrand factor (VWF), which is bound to the damaged subendothelial structures, GPIb-IX-V tethers the platelets from the flowing blood thereby slowing them down. This step is a prerequisite for the collagen receptors to participate in firm adhesion resulting in the formation of a first platelet layer which is the basis for further thrombus formation. Recently, other ligands for GPIb-IX-V besides the extensively studied VWF have been identified, such as: alpha-thrombin, coagulation factor XII (FXII), high molecular weight kininogen (HMWK), factor XI (FXI), integrin Mac-1 and P-selectin. In this review, the interaction of GPIb-IX-V with its different ligands is described and the anticipated or demonstrated in vivo effects are discussed.     

Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis

Polycythemia vera (PV), essential thrombocythemia (ET), and myeloid metaplasia with myelofibrosis (MMM) are clonal disorders arising from hematopoietic progenitors. An internet-based protocol was used to collect clinical information and biological specimens from patients with these diseases. High-throughput DNA resequencing identified a recurrent somatic missense mutation JAK2V617F in granulocyte DNA samples of 121 of 164 PV patients, of which 41 had homozygous and 80 had heterozygous mutations. Molecular and cytogenetic analyses demonstrated that homozygous mutations were due to duplication of the mutant allele. JAK2V617F was also identified in granulocyte DNA samples from 37 of 115 ET and 16 of 46 MMM patients, but was not observed in 269 normal individuals. In vitro analysis demonstrated that JAK2V617F is a constitutively active tyrosine kinase.     

Genomic profiling reveals subsets of dedifferentiated liposarcoma to follow separate molecular pathways

With the aim to provide more insight into their biology, a series of 79 liposarcomas (LS) representative of all main subtypes was analysed for chromosomal imbalances using comparative genomic hybridization. Based on the genetic data, unsupervised hierarchical clustering unveiled two main LS clusters, each with two subclusters, one comprising three subsets. The first main cluster consisted of one larger subcluster, being characterised by gains/high-level amplifications of chromosomal subregions 12q13–q15, and exclusively included well-differentiated and dedifferentiated LS. A smaller subcluster was set apart on the basis of recurrent gains of 20q13 and 8q24, and mainly comprised pleomorphic and myxoid/round cell LS. The larger subcluster was subdivided into three subsets, one with nearly exclusive overrepresentations of 12q13–q15, the second with additional frequent gains of 1q21–q24, and the third with further recurrent overrepresentations of 6q22–q24, 20q13, and 12q24 and frequent losses of 13q14–q21 and 11q22–q23. While the first subset comprised both well-differentiated and dedifferentiated LS, the second and third subsets entirely included dedifferentiated LS. The second main cluster was characterised by recurrent overrepresentations of 5p13–p15, 1q21–q24, 1p12–p21, and 17p11.2–p12 and essentially comprised pleomorphic and myxoid/round cell LS. A separation of this second main cluster into two subclusters was based on additional gains on 22q13 and losses on 1q42–q43. Genomic profiling reveals genetically distinct subsets of dedifferentiated LS, which are clearly different from pleomorphic, myxoid/round cell, and, for some subsets, from well-differentiated LS. These data indicate that dedifferentiated LS follow separate tumourigenic pathways and that genetic analysis is important to unravel these differences.     

Imagery rehearsal for posttraumatic nightmares: A randomized controlled trial

One hundred twenty‐four male Vietnam War veterans with chronic, severe posttraumatic stress disorder (PTSD) were randomly assigned to imagery rehearsal (n = 61) or a credible active comparison condition (n = 63) for the treatment of combat‐related nightmares. There was pre‐post change in overall sleep quality and PTSD symptoms for both groups, but not in nightmare frequency. Intent‐to‐treat analyses showed that veterans who received imagery rehearsal had not improved significantly more than veterans in the comparison condition for the primary outcomes (nightmare frequency and sleep quality), or for a number of secondary outcomes, including PTSD. Six sessions of imagery rehearsal delivered in group format did not produce substantive improvement in Vietnam War veterans with chronic, severe PTSD. Possible explanations for findings are discussed.     

Optimization of the isolation, culture, and characterization of equine umbilical cord blood mesenchymal stromal cells

Mesenchymal stromal cells (MSC) represent a promising population for supporting new clinical concepts in cellular therapy. A wide diversity of isolation procedures for MSC from umbilical cord blood (UCB) has been described for humans. In contrast, a few data are available in horses. In the current study, a sedimentation method using hydroxyethyl starch and a method based on the lysis of red blood cells using ammonium chloride (NH(4)Cl) were compared with two density gradient separation methods (Ficoll-Paque and Percoll). Adherent cell colonies could be established using all four isolation methods. The mononuclear cell recovery after Percoll separation, however, resulted in significantly more putative MSC colonies; and, therefore, this isolation method was used for all further experiments. Culture conditions such as cell density and medium or serum coating of the wells did not significantly affect putative MSC recovery. Isolated MSC using Percoll were subsequently differentiated toward the osteogenic, chondrogenic, and adipogenic lineage. In addition, MSC were phenotyped by multicolor flow cytometry based on their expression of different cell protein markers. Cultured MSC were CD29, CD44, and CD90-positive and CD79α, Macrophage/Monocyte and MHC II-negative. In conclusion, this study reports optimized protocols to isolate, culture, and characterize solid equine MSC from UCB.     

Bilateral alteration in stepping pattern after unilateral motor cortex injury: a new test strategy for analysis of skilled limb movements in neurological mouse models

Mice are becoming increasingly popular to model neurological disease and motor system dysfunction. For evaluation of discrete, chronic motor impairments, skilled limb movements represent a valuable extension of standard mouse test batteries. This study introduces an efficient and sensitive test strategy for comprehensive assessment of skilled fore- and hind-limb stepping in mice. Adult C57BL/6 mice were trained and video-recorded in two walking tasks, the widely used rotorod test and a new ladder rung task. The animals then received a unilateral ischemic lesion in the motor cortex forelimb and hind limb area and were video-recorded on days 12 and 26 post-lesion. Forelimb and hind limb stepping movements were rated using a combination of endpoint measures and qualitative assessment. The results showed that while animals maintained a weight-supported gait, posture and stepping movements were abnormal at both post-operative intervals. The rotorod analysis revealed stepping deficits in both forelimbs that led to adoption of compensatory movement strategies. The ladder rung task revealed stepping errors in ipsi- and contralateral fore- and hind-limbs. The findings demonstrate that this test strategy provides comprehensive assessment of motor impairments in mice and that qualitative movement analysis is a valuable tool for elaborating subtle motor disturbances.     

Macrovascular venous invasion of pancreatic neuroendocrine tumours: impact on surgical outcomes and survival

BackgroundThis study evaluates the impact of macrovascular venous invasion (MVI) on surgical and survival outcomes of pancreatic neuroendocrine tumours (PNETs).MethodsWe retrospectively reviewed data of 125 patients operated for PNETs. Operative, pathological,and survival outcomes were compared between PNETs with and without MVI.ResultsMacrovascular venous invasion was detected in 25 of 125 PNETs (20%) presenting as tumour thrombi (n = 12) or venous wall invasion (n = 13). MVI was associated with larger tumours, a higher rate of lymph node involvement, less differentiated tumours, and a higher rate of perineural invasion. Resection of PNETS with MVI more often necessitated combined hepatic, venous and multivisceral resections, had a higher rate of intraoperative blood transfusion (p = 0.04) but similar morbidity (44% vs. 42%) and mortality (0 vs. 1%) as PNETs without MVI. PNETs with MVI had a lower median overall survival rate (60 vs. 149 months; p = 0.03). Multivariate analysis revealed that PNETs of the pancreatic head, synchronous liver metastases and higher tumour grade were prognostic factors for overall survival.ConclusionsMVI is found in more advanced PNETs. Resection of PNETs with MVI is characterized by increased transfusion rate and reduced overall survival.