Lasse Kjær

Low molecular weight heparin (Innohep) as thromboprophylaxis in outpatients with a plaster cast: a venografic controlled study.

INTRODUCTION The aim of this study was to investigate the incidence of deep vein thrombosis (DVT) in patients immobilized in plaster cast and the possible efficacy of prophylaxis with low molecular weight heparin (LMWH). MATERIAL AND METHODS The study was a randomized, assessor-blinded, open multicenter (three centers) study. All patients over 18 years of age with planned plaster cast on a lower extremity of at least 3 weeks were eligible for participation. Written informed consent was obtained from 300 patients and they were randomized to either 3.500 IU anti-Xa of tinzaparin (Innohep) subcutaneously once daily or no prophylaxis. On the day the cast was removed, ascending unilateral venography was performed. Two experienced radiologists, unaware of treatment, assessed the pictures independently. The radiologist had to obtain consensus as to whether DVT was present or not. RESULTS 300 patients were included (148 in the treatment group and 152 in the control group). Ninety-five were subsequently withdrawn. DVT was diagnosed in 10/99 patients in the treatment group and in 18/106 patients in the control group. This difference is not significant (P=.15, chi(2) test) and the odds ratio was 0.55 (95% confidence interval=0.34-1.26). CONCLUSION DVT in legs after plaster casting is a big problem, with an incidence of almost 20%. An effective prophylactic regime is required. Once-daily dose of 3.500 IU anti-Xa of tinzaparin was not sufficient.

The JAK2 V617F somatic mutation, mortality and cancer risk in the general population

JAK2 V617F is present in the majority of patients with myeloproliferative cancer; however, its prevalence and clinical significance in the general population is unknown. We screened for presence of the mutation in 10,507 participants from the Copenhagen City Heart Study with up to 17.6 years of follow up. Prevalence of the mutation was 0.2% (n=18). All 18 mutation positives died during follow up corresponding to a multifactorially adjusted hazard ratio for early death of 3.0 (95%CI:1.9–4.9). Corresponding hazard ratios for men versus women and 1-year age increases were 1.4 (1.1–1.9) and 1.1 (1.1-1.1). Multifactorially adjusted hazard ratios for any cancer, hematologic cancer and myeloproliferative cancer were 3.7 (1.7–8.0), 58 (13–261) and 161 (12–2,197), respectively. Corresponding hazard ratios were 1.2 (0.8–2.0), 2.3 (0.2–25), 1.3 (0.3–5.4) for men versus women, and 1.0 (1.0–1.1), 1.1 (0.9–1.2), 0.9 (0.8–1.1) for 1-year age increases. In the general population, JAK2 V617F is associated with increased morbidity and mortality, although only present in 18 of 10,507 (0.2%).

Texture analysis in quantitative MR imaging. Tissue characterisation of normal brain and intracranial tumours at 1.5 T.

The diagnostic potential of texture analysis in quantitative tissue characterisation by MR imaging at 1.5 T was evaluated in the brain of 6 healthy volunteers and in 88 patients with intracranial tumours. Texture images were computed from calculated T1 and T2 parameter images by applying groups of common first-order and second-order grey level statistics. Tissue differentiation in the images was estimated by the presence or absence of significant differences between tissue types. A fine discrimination was obtained between white matter, cortical grey matter, and cerebrospinal fluid in the normal brain, and white matter was readily separated from the tumour lesions. Moreover, separation of solid tumour tissue and peritumoural oedema was suggested for some tumour types. Mutual comparison of all tumour types revealed extensive differences, and even specific tumour differentiation turned out to be successful in some cases of clinical importance. However, no discrimination between benign and malignant tumour growth was possible. Much texture information seems to be contained in MR images, which may prove useful for classification and image segmentation.

Molecular diagnostics of myeloproliferative neoplasms.

Since the discovery of the JAK2 V617F mutation in the majority of the myeloproliferative neoplasms (MPN) of polycythemia vera, essential thrombocythemia and primary myelofibrosis ten years ago, further MPN‐specific mutational events, notably in JAK2 exon 12, MPL exon 10 and CALR exon 9 have been identified. These discoveries have been rapidly incorporated into evolving molecular diagnostic algorithms. Whilst many of these mutations appear to have prognostic implications, establishing MPN diagnosis is of immediate clinical importance with selection, implementation and the continual evaluation of the appropriate laboratory methodology to achieve this diagnosis similarly vital. The advantages and limitations of these approaches in identifying and quantitating the common MPN‐associated mutations are considered herein with particular regard to their clinical utility. The evolution of molecular diagnostic applications and platforms has occurred in parallel with the discovery of MPN‐associated mutations, and it therefore appears likely that emerging technologies such as next‐generation sequencing and digital PCR will in the future play an increasing role in the molecular diagnosis of MPN.

In vivo estimation of relaxation processes in benign hyperplasia and carcinoma of the prostate gland by magnetic resonance imaging

Tissue characterization for separating malignant from benign tissue is a clinically very important potential of magnetic resonance imaging (MRI). In this study quantitative determination of T1- and T2-relaxation processes was accomplished in five healthy volunteers, 10 patients with benign hyperplasia of the prostate gland and eight patients with prostatic carcinoma. Histological verification was obtained in all the patients. The measurements were performed on a wholebody MR-scanner operating at 1.5 T using six inversion recovery sequences (TR = 4000 msec) for T1-determination and a 32 spin-echo sequence (TR = 3000 or 2000 msec) for T2-estimation. The T1-relaxation curves all appeared monoexponential, whereas the T2-curves in most cases showed a multiexponential behaviour. A considerable overlap of the relaxation curves was seen. Consequently, we found no statistically significant differences between the T1- or the T2-relaxation times of the three groups investigated. It is concluded that tissue characterization based on relaxation time measurements with MRI does not seem to have a clinically useful role in prostatic disease.

Evaluation of relaxation time measurements by magnetic resonance imaging: a phantom study

Several circumstances may explain the great variation in reported proton T1 and T2 relaxation times usually seen. This study was designed to evaluate the accuracy of relaxation time measurements by magnetic resonance imaging (MRI) operating at 1.5 tesla. Using a phantom of nine boxes with different concentrations of CuSO4 and correlating the calculated T1 and T2 values with reference values obtained by two spectrometers (corrected to MRI-proton frequency=64 MHz) we found a maximum deviation of about 10 per cent. Measurements performed on a large water phantom in order to evaluate the homogeneity in the imaging plane showed a variation of less than 10 per cent within 10 cm from the centre of the magnet in all three imaging planes. Changing the gradient field strength apparently had no influence on the T2 values recorded. Consequently diffusion processes seem without significance. It is concluded that proton T1 and T2 relaxation times covering the majority of the biologic range can be measured by MRI with an overall accuracy of 5 to 10 per cent. Quality control studies along the lines indicated in this study are recommended.

Radionuclide scanning after total knee replacement: correlation with pain and radiolucent lines. A prospective study.

The authors examined the relationships among Tc-99m radionuclide bone scan findings, pain, and radiolucent lines in 35 postsurgical knees. Our prospective study included bone scans, as well as radiographic and clinical examination three, seven, and 12 months after knee replacement surgery in 35 patients. Twenty-seven patients had no pain 12 months after surgery and eight patients had moderate or severe pain. Prosthetic loosening was seen in one patient. Thirty-three patients exhibited a radiolucent line under the tibial part of the prosthesis. Isotope uptake was the same in the painful and nonpainful knees, and the degree of isotope uptake did not correlate with the development of radiolucent lines around the prosthetic components.

Tissue Characterization of Intracranial Tumors by MR Imaging In Vivo Evaluation of T1- and T2-Relaxation Behavior at 1.5 T

The main purpose of this in vivo study was to provide a detailed description of the T1- and T2-relaxation processes in intracranial tumors at 1.5 T. A total of 100 patients were investigated. Optimal experimental conditions were carefully observed, including the use of long TR values. T1 determination was based on a partial saturation inversion recovery sequence covering 12 or 6 data points. T2 determination involved a multiple spin echo sequence with 32 echoes. Calculations included biexponential analysis of the 12-point T1 data and all T2 data obtained. The results were evaluated in accordance with histopathology. The T1- and the T2-relaxation times of the prevailing tumor types were significantly different (p < 0.0005). However, biologic scatter and overlap between tumor types were considerable. In particular, no discrimination between benign and malignant tumor growth was possible. Biexponential evaluation did not increase the specificity, although a biexponential relaxation behavior was recognized in 37% of the T2 curves. The results indicate that tissue heterogeneity is responsible for most of the scatter in the relaxation times. It is concluded that tissue characterization by MR imaging, based solely on relaxation time measurements, seems to be of no value in the differentiation of intracranial tumors.

Whole Blood Transcriptional Profiling Reveals Deregulation of Oxidative and Antioxidative Defence Genes in Myelofibrosis and Related Neoplasms. Potential Implications of Downregulation of Nrf2 for Genomic Instability and Disease Progression

The Philadelphia-negative chronic myeloproliferative neoplasms - essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF) (MPNs) - have recently been shown to be associated with chronic inflammation, oxidative stress and accumulation of reactive oxygen species (ROS). Using whole blood transcriptional profiling, we report that several oxidative stress and anti-oxidative stress genes are significantly deregulated in MPNs. Among the twenty most up- and downregulated genes, ATOX1, DEFB122, GPX8, PRDX2, PRDX6, PTGS1, and SEPP1 were progressively upregulated from ET over PV to PMF, whereas AKR1B1, CYBA, SIRT2, TTN, and UCP2 were progressively downregulated in ET, PV and PMF (all FDR <0.05). The gene Nrf2, encoding the transcription factor nuclear factor erythroid 2-related factor 2 (NFE2L2 or Nrf2) was significantly downregulated in all MPNs. Nrf2 has a key role in the regulation of the oxidative stress response and modulates both migration and retention of hematopoietic stem cells (HSCs) in their niche. The patogenetic importance of Nrf2 depletion in the context of expansion of the hematopoietic progenitor pool in MPNs is discussed with particular focus upon the implications of concomitant downregulation of Nrf2 and CXCR4 for stem cell mobilization.

Combination therapy with interferon and JAK1-2 inhibitor is feasible: Proof of concept with rapid reduction in JAK2V617F-allele burden in polycythemia vera

We report a 55 year old woman with post-ET PV for 12 years, who experienced resolution of severe constitutional symptoms within 3 days, a marked reduction in splenomegaly and a rapid decline in the JAK2V617F allele burden during combination therapy with interferon-alpha2a and ruxolitinib. Within 4 weeks the patient achieved complete hematological remission with normalization of peripheral blood counts and within 10 months the JAK2V617F-allele burden was reduced from 90% to 28%. Such a rapid decline in the JAK2V617F allele burden is highly unusual in PV-patients during low-dose IFN-alpha2 monotherapy and this finding warrants a prospective study with combination therapy.