Relationship between type of unprovoked venous thromboembolism and cancer location: An individual patient data meta-analysis.

BACKGROUND: Unprovoked venous thromboembolism (VTE) may be the first manifestation of an underlying cancer. We aimed to assess the period prevalence of occult cancer detection stratified by VTE location (deep vein thrombosis [DVT], pulmonary embolism [PE] or both) and the anatomical relationship between occult cancer and VTE. METHODS: Post-hoc analysis of a systematic review and individual patient data meta-analysis of adults with unprovoked VTE with at least 12 months of follow-up. Cancer types were grouped according to thoracic, abdomino-pelvic, or other locations. RESULTS: A total of 2300 patients were eligible including 1218 with DVT only (53%), 719 with PE only (31%), and 363 with both PE and DVT (16%). The pooled 12-month period prevalence of cancer in DVT only, PE only, and DVT + PE was 5.6% (95% CI, 4.4 to 7.2), 4.3% (95% CI, 2.7 to 6.9), and 5.6% (95% CI, 1.7 to 15.5), respectively. Most occult cancers were located in the abdomen (68.4%). The proportion of patients with an abdomino-pelvic cancer was not different in patients with DVT + PE (81%; 95% CI, 54 to 96) than in those with DVT (68%; 95% CI, 57 to 78) or PE alone (65%; 95% CI, 48 to 79). CONCLUSION: The 12-month prevalence of occult cancer was similar in patients with DVT only, PE only, or both. Most cancers were located in the abdomen, and there was no relationship between VTE type and cancer location.

Myeloid-derived suppressor cells in lymphoma: The good, the bad and the ugly.

Lymphomas cause significant morbidity and mortality worldwide. A substantial number of patients ultimately relapse after standard treatment. However, the efficacy of these therapies can be counteracted by the patients' immune system, more specifically by myeloid-derived suppressor cells (MDSC). MDSC are a heterogeneous group of immature myeloid cells that suppress the innate and adaptive immune system via different mechanisms and accumulate under pathological conditions, such as cancer. MDSC play a role in the induction and progression of cancer and immune evasion. Increased numbers of MDSC have been reported in different lymphoma subtypes and are associated with a poor clinical outcome. This review aims to clarify the role of MDSC and their working mechanism in different lymphoma subtypes. Furthermore, the effect of MDSC on immunotherapies will be discussed.

Quantitative structural information from single-molecule FRET.

Single-molecule studies can be used to study biological processes directly and in real-time. In particular, the fluorescence energy transfer between reporter dye molecules attached to specific sites on macromolecular complexes can be used to infer distance information. When several measurements are combined, the information can be used to determine the position and conformation of certain domains with respect to the complex. However, data analysis schemes that include all experimental uncertainties are highly complex, and the outcome depends on assumptions about the state of the dye molecules. Here, we present a new analysis algorithm using Bayesian parameter estimation based on Markov Chain Monte Carlo sampling and parallel tempering termed Fast-NPS that can analyse large smFRET networks in a relatively short time and yields the position of the dye molecules together with their respective uncertainties. Moreover, we show what effects different assumptions about the dye molecules have on the outcome. We discuss the possibilities and pitfalls in structure determination based on smFRET using experimental data for an archaeal transcription pre-initiation complex, whose architecture has recently been unravelled by smFRET measurements.

Single pulse coherence measurements in the water window at the free-electron laser FLASH.

The spatial coherence of free-electron laser radiation in the water window spectral range was studied, using the third harmonic (λ<(3rd) = 2.66 nm) of DESY's Free-electron LASer in Hamburg (FLASH). Coherent single pulse diffraction patterns of 1,2-Dioleoyl-sn-glycero-3-phosphocholine (DOPC) multilamellar lipid stacks have been recorded. The intensity histogram of the speckle pattern around the first lamellar Bragg peak, corresponding to the d = 5 nm periodicity of the stack, reveals an average number of transverse modes of M¯ = 3.0 of the 3rd harmonic. Using the lipid stack as a 'monochromator', pulse-to-pulse fluctuations in the third harmonic λ(3rd) have been determined to be 0.033 nm.

International clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer.

BACKGROUND: Guidelines addressing the management of venous thromboembolism (VTE) in cancer patients are heterogeneous and their implementation has been suboptimal worldwide. OBJECTIVES: To establish a common international consensus addressing practical, clinically relevant questions in this setting. METHODS: An international consensus working group of experts was set up to develop guidelines according to an evidence-based medicine approach, using the GRADE system. RESULTS: For the initial treatment of established VTE: low-molecular-weight heparin (LMWH) is recommended [1B]; fondaparinux and unfractionated heparin (UFH) can be also used [2D]; thrombolysis may only be considered on a case-by-case basis [Best clinical practice (Guidance)]; vena cava filters (VCF) may be considered if contraindication to anticoagulation or pulmonary embolism recurrence under optimal anticoagulation; periodic reassessment of contraindications to anticoagulation is recommended and anticoagulation should be resumed when safe; VCF are not recommended for primary VTE prophylaxis in cancer patients [Guidance]. For the early maintenance (10 days to 3 months) and long-term (beyond 3 months) treatment of established VTE, LMWH for a minimum of 3 months is preferred over vitamin K antagonists (VKA) [1A]; idraparinux is not recommended [2C]; after 3-6 months, LMWH or VKA continuation should be based on individual evaluation of the benefit-risk ratio, tolerability, patient preference and cancer activity [Guidance]. For the treatment of VTE recurrence in cancer patients under anticoagulation, three options can be considered: (i) switch from VKA to LMWH when treated with VKA; (ii) increase in LMWH dose when treated with LMWH, and (iii) VCF insertion [Guidance]. For the prophylaxis of postoperative VTE in surgical cancer patients, use of LMWH o.d. or low dose of UFH t.i.d. is recommended; pharmacological prophylaxis should be started 12-2 h preoperatively and continued for at least 7-10 days; there are no data allowing conclusion that one type of LMWH is superior to another [1A]; there is no evidence to support fondaparinux as an alternative to LMWH [2C]; use of the highest prophylactic dose of LMWH is recommended [1A]; extended prophylaxis (4 weeks) after major laparotomy may be indicated in cancer patients with a high risk of VTE and low risk of bleeding [2B]; the use of LMWH for VTE prevention in cancer patients undergoing laparoscopic surgery may be recommended as for laparotomy [Guidance]; mechanical methods are not recommended as monotherapy except when pharmacological methods are contraindicated [2C]. For the prophylaxis of VTE in hospitalized medical patients with cancer and reduced mobility, we recommend prophylaxis with LMWH, UFH or fondaparinux [1B]; for children and adults with acute lymphocytic leukemia treated with l-asparaginase, depending on local policy and patient characteristics, prophylaxis may be considered in some patients [Guidance]; in patients receiving chemotherapy, prophylaxis is not recommended routinely [1B]; primary pharmacological prophylaxis of VTE may be indicated in patients with locally advanced or metastatic pancreatic [1B] or lung [2B] cancer treated with chemotherapy and having a low risk of bleeding; in patients treated with thalidomide or lenalidomide combined with steroids and/or chemotherapy, VTE prophylaxis is recommended; in this setting, VKA at low or therapeutic doses, LMWH at prophylactic doses and low-dose aspirin have shown similar effects; however, the efficacy of these regimens remains unclear [2C]. Special situations include brain tumors, severe renal failure (CrCl<30 mL min(-1) ), thrombocytopenia and pregnancy. Guidances are provided in these contexts. CONCLUSIONS: Dissemination and implementation of good clinical practice for the management of VTE, the second cause of death in cancer patients, is a major public health priority.

International clinical practice guidelines for the treatment and prophylaxis of thrombosis associated with central venous catheters in patients with cancer.

BACKGROUND: Although long-term indwelling central venous catheters (CVCs) may lead to pulmonary embolism (PE) and loss of the CVC, there is lack of consensus on management of CVC-related thrombosis (CRT) in cancer patients and heterogeneity in clinical practices worldwide. OBJECTIVES: To establish common international Good Clinical Practices Guidelines (GCPG) for the management of CRT in cancer patients. METHODS: An international working group of experts was set up to develop GCPG according to an evidence-based medicine approach, using the GRADE system. RESULTS: For the treatment of established CRT in cancer patients, we found no prospective randomized studies, two non-randomized prospective studies and one retrospective study examining the efficacy and safety of low-molecular-weight heparin (LMWH) plus vitamin K antagonists (VKAs). One retrospective study evaluated the benefit of CVC removal and two small retrospective studies were on thrombolytic drugs. For the treatment of symptomatic CRT, anticoagulant treatment (AC) is recommended for a minimum of 3 months; in this setting, LMWHs are suggested. VKAs can also be used, in the absence of direct comparisons of these two types of anticoagulants in this setting [Guidance]. The CVC can be kept in place if it is functional, well-positioned and non-infected and there is good resolution under close surveillance; whether the CVC is kept or removed, no standard approach in terms of AC duration has been established [Guidance]. For the prophylaxis of CRT in cancer patients, we found six randomized studies investigating the efficacy and safety of VKA vs. placebo or no treatment, one on the efficacy and safety of unfractionnated heparin, six on the value of LMWH, one double-blind randomized and one non randomized study on thrombolytic drugs and six meta-analyses of AC and CVC thromboprophylaxis. Type of catheter (open-ended like the Hickman(®) catheter vs. closed-ended catheter with a valve like the Groshong(®) catheter), its position (above, below or at the junction of the superior vena cava and the right atrium) and method of placement may influence the onset of CRT on the basis of six retrospective trials, four prospective non-randomized trials, three randomized trials and one meta-analysis. In light of these data: use of AC for routine prophylaxis of CRT is not recommended [1A]; a CVC should be inserted on the right side, in the jugular vein, and distal extremity of the CVC should be located at the junction of the superior vena cava and the right atrium [1A]. CONCLUSION: Dissemination and implementation of these international GCPG for the prevention and treatment of CRT in cancer patients at each national level is a major public health priority, needing worldwide collaboration.

[Graft-versus-Host Disease (GvHD) - an update : Part 1: Pathophysiology, clinical features and classification of GvHD]. / Graft-versus-Host-Disease (GvHD) - ein Update : Teil 1: Pathophysiologie, Klinik und Stadieneinteilung der GvHD.

GvHD remains associated with significant morbidity and mortality despite new techniques for allogeneic stem cell transplantation (SCT), such as optimized conditioning regimens. Within the past ten years, the incidence of acute GvHD has remained unchanged and the incidence of chronic GvHD has even increased. The traditional classification of GvHD according to the time of clinical manifestation is now out-dated. Acute GvHD symptoms may even occur after 100 days; vice versa, primary chronic GvHD may already be observed one month after stem cell transplantation. The current classification introduced by the National Institutes of Health includes classic acute GvHD (up to 100 days), late-onset acute GvHD (after 100 days), as well as an overlap syndrome showing features of acute and chronic GvHD and classic chronic GvHD without any time limit. Diagnosis of GvHD of the skin remains difficult because of histological similarities to drug eruptions and viral exanthems. In this first part of the article the pathophysiology, classification, skin manifestations of acute and chronic GvHD and the histopathology will be presented. In a second part the prognosis, prophylaxis and therapy of GvHD will be discussed.

[Graft-versus-host disease (GvHD) - an update. Part 2: prognosis and therapy of GvHD]. / Graft-versus-Host-Disease (GvHD) - ein Update. Teil 2: Prognose und Therapie der GvHD.

Graft-versus-host disease (GvHD) remains one of the major complications after allogeneic stem cell transplantation (SCT) and is responsible for morbidity, mortality and decrease in quality of life of patients after SCT. The most important preventive approach is the selection of a donor with best possible HLA compatibility between donor and recipient. Basic prophylaxis of acute GvHD begins already prior to transplantation and usually consists of cyclosporine with or without methotrexate. In the past few years, many new therapies have been introduced for the treatment of acute and chronic GvHD. Extracorporeal photopheresis (ECP), for example, represents a promising treatment option for acute and chronic GvHD with very few side effects. For chronic GvHD mTOR inhibitors (sirolimus, everolimus) may replace calcineurin-inhibitors with the advantage of not inducing malignant skin tumors. Guidelines are available ort he management of acute and chronic GvHD. While pathophysiology, classification and skin manifestations of GvHD have been already presented in the first part of this article, this second part covers the prognosis, prevention and treatment of GvHD.

Ptychographic coherent x-ray diffractive imaging in the water window.

Coherent x-ray diffractive microscopy enables full reconstruction of the complex transmission function of an isolated object to diffraction-limited resolution without relying on any optical elements between the sample and detector. In combination with ptychography, also specimens of unlimited lateral extension can be imaged. Here we report on an application of ptychographic coherent diffractive imaging (PCDI) in the soft x-ray regime, more precisely in the so-called water window of photon energies where the high scattering contrast between carbon and oxygen is well-suited to image biological samples. In particular, we have reconstructed the complex sample transmission function of a fossil diatom at a photon energy of 517 eV. In imaging a lithographically fabricated test sample a resolution on the order of 50 nm (half-period length) has been achieved. Along with this proof-of-principle for PCDI at soft x-ray wavelengths, we discuss the experimental and technical challenges which can occur especially for soft x-ray PCDI.

Single nucleotide polymorphisms in inflammation-related genes are associated with venous thromboembolism.

BACKGROUND: Various genetic risk factors are known to increase the risk of venous thromboembolism (VTE). Increasing evidence suggests a "cross-talk" between the coagulation and inflammatory cascade. Therefore, polymorphisms in genes involved in inflammation may influence susceptibility towards VTE. The aim of the study was to investigate the role of single nucleotide polymorphisms (SNPs) in inflammation genes for susceptibility towards VTE. METHODS: The study group consisted of 108 (47 men and 61 women) Dutch patients with documented VTE and 325 healthy controls from the same geographical area (117 men and 208 women). Odds ratios (OR) and 95% confidence intervals (95% CI) for VTE separately and if indicated by gender were calculated to assess whether genotype and allele frequency were associated with thrombosis. RESULTS: Heterozygosity for SNP -899C/T of the interleukin 1-alpha gene (IL1A -899C/T) was under-represented in VTE patients compared to the control group (OR=0.51, 95% CI 0.32-0.82). The IL6 -174 CC genotype was more frequent in male patients with VTE compared to male controls (OR=4.06, 95% CI 1.43-11.5). Female patients carried significantly more IL13 (intron3) TT genotype (OR=5.60, 95% CI 1.94-18.5) compared to female controls. The allelic frequency of IL4 -589 T allele was significantly increased in female patients (OR=1.72, 95% CI 1.05-2.81) in contrast to men where no differences were observed. CONCLUSION: Four SNPs in inflammatory-related genes of IL1A, IL4, IL6, and IL13 may be associated with VTE. These results need to be confirmed in independent groups with larger number of patients.

A genomic-based approach identifies FXYD domain containing ion transport regulator 2 (FXYD2)gammaa as a pancreatic beta cell-specific biomarker.

AIMS/HYPOTHESIS: Non-invasive imaging of the pancreatic beta cell mass (BCM) requires the identification of novel and specific beta cell biomarkers. We have developed a systems biology approach to the identification of promising beta cell markers. METHODS: We followed a functional genomics strategy based on massive parallel signal sequencing (MPSS) and microarray data obtained in human islets, purified primary rat beta cells, non-beta cells and INS-1E cells to identify promising beta cell markers. Candidate biomarkers were validated and screened using established human and macaque (Macacus cynomolgus) tissue microarrays. RESULTS: After a series of filtering steps, 12 beta cell-specific membrane proteins were identified. For four of the proteins we selected or produced antibodies targeting specifically the human proteins and their splice variants; all four candidates were confirmed as islet-specific in human pancreas. Two splice variants of FXYD domain containing ion transport regulator 2 (FXYD2), a regulating subunit of the Na(+)-K(+)-ATPase, were identified as preferentially present in human pancreatic islets. The presence of FXYD2gammaa was restricted to pancreatic islets and selectively detected in pancreatic beta cells. Analysis of human fetal pancreas samples showed the presence of FXYD2gammaa at an early stage (15 weeks). Histological examination of pancreatic sections from individuals with type 1 diabetes or sections from pancreases of streptozotocin-treated Macacus cynomolgus monkeys indicated a close correlation between loss of FXYD2gammaa and loss of insulin-positive cells. CONCLUSIONS/INTERPRETATION: We propose human FXYD2gammaa as a novel beta cell-specific biomarker.

Risk of thrombosis and infections of central venous catheters and totally implanted access ports in patients treated for cancer.

INTRODUCTION: Thrombosis and infections are well known complications of central venous catheters and totally implanted access ports. These complications lead to increased costs due to prolonged hospitalisation, increased antibiotics use and need for replacement. The objectives of the study were to document the occurrence of catheter related thrombosis and infections in patients with central venous catheters and totally implanted chest ports in cancer patients and to investigate whether factor V Leiden is a risk factor for catheter related thrombosis. MATERIALS AND METHODS: Between February 2002 and November 2004, 43 patients with central venous catheter or totally implanted access port were followed up to document the occurrence of catheter related thrombosis and infections. Patients received chemotherapy either for haematological malignancy or for solid tumours. Factor V Leiden (R506Q) was determined by restriction fragment length polymorphism analysis. Follow-up period ended in April 2007. RESULTS: Catheter related thrombosis occurred in 4 patients (4/43; 9.3%) with a totally implanted access port. None of the 3 patients with factor V Leiden had catheter related infection or thrombosis. Catheter related infections occurred in 15 patients: 10 patients (23.3%; 10/43) with central venous catheter and 5 patients (11.6%; 5/43) with totally implanted access ports. Time to infection was 32.5 days in the central venous catheter group compared to 88 days in the totally implanted access port group. CONCLUSION: A higher incidence of catheter related infections was observed in patients with central venous catheters in contrast to patients with totally implanted access ports were venous thrombosis was more frequent.

Reproducibility of fetal renal pelvis volume measurement using three-dimensional ultrasound.

OBJECTIVE: To assess the reproducibility of fetal renal pelvis volume measurement in hydronephrotic kidneys using transabdominal three-dimensional (3D) ultrasound. METHODS: The fetal renal pelvis volume was measured using 3D ultrasound in one kidney in each of 15 fetuses with hydronephrosis in the second or third trimester of pregnancy. Hydronephrosis was diagnosed when the fetus had an anteroposterior renal pelvis diameter > or = 5 mm. After volume acquisition by one of the observers, the repeatability of volume calculation with manual delineation of the fetal renal pelvis was assessed by six different observers using the Virtual Organ Computer-aided AnaLysis (VOCAL(trade mark)) imaging program. The intraclass correlation coefficients (ICC), coefficient of variation (CV) and within- and between-observer repeatability coefficient (r) were calculated and Bland-Altman plots were constructed. RESULTS: Both intra- and interobserver reliability of the fetal renal pelvis volume measurements were considered to be very good. For intraobserver reliability, the ICC was 0.996 and the CV was 10.8%. For the overall interobserver reliability, the ICC was 0.998 and the CV was 15.7%; the interobserver reliability between pairs of observers had ICCs between 0.994 and 0.999, and CVs between 19.5% and 7.6% for inexperienced and experienced observers, respectively. CONCLUSION: With 3D ultrasound using the VOCAL imaging program, it is technically feasible to reproduce fetal renal pelvis volume measurements. Further research to establish the clinical applications of this technology is warranted.

Bed-sharing and the infant's thermal environment in the home setting.

AIMS: To study bed-sharing and cot-sleeping infants in the natural setting of their own home in order to identify differences in the thermal characteristics of the two sleep situations and their potential hazards. METHODS: Forty routine bed-sharing infants and 40 routine cot-sleeping infants aged 5-27 weeks were individually matched between groups for age and season. Overnight video and physiological data of bed-share infants and cot-sleeping infants were recorded in the infants' own homes including rectal, shin, and ambient temperature. RESULTS: The mean rectal temperature two hours after sleep onset for bed-share infants was 36.79 degrees C and for cot-sleeping infants, 36.75 degrees C (difference 0.05 degrees C, 95% CI -0.03 to 0.14). The rate of change thereafter was higher in the bed-share group than in the cot group (0.04 degrees C v 0.03 degrees C/h, difference 0.01, 0.00 to 0.02). Bed-share infants had a higher shin temperature at two hours (35.43 v 34.60 degrees C, difference 0.83, 0.18 to 1.49) and a higher rate of change (0.04 v -0.10 degrees C/h, difference 0.13, 0.08 to 0.19). Bed-sharing infants had more bedding. Face covering events were more common and bed-share infants woke and fed more frequently than cot infants (mean wake times/night: 4.6 v 2.5). CONCLUSIONS: Bed-share infants experience warmer thermal conditions than those of cot-sleeping infants, but are able to maintain adequate thermoregulation to maintain a normal core temperature.

[Compliance of family physicians with the recommendations of 'Hearing Impairment' guideline by the Dutch College of General Practitioners in treatment of simulated paper cases of hearing loss]. / Overeenstemming tussen het handelen van de huisarts bij papieren casussen van slechthorendheid en de aanbevelingen in de standard 'Slechthorendheid' van het Nederlands Huisartsen Genootschap.

OBJECTIVE: To assess the extent to which the practice of general practitioners (GPs) in dealing with adult hearing-impaired patients complies with the recommendations in the NHG standard on 'Hardness of hearing', one year after its publication. DESIGN: Descriptive. METHOD: Eight paper cases concerning hearing-impaired patients were presented to 10 GPs. The compliance of the GPs' approach with the NHG standard was recorded, and the differences found were motivated by the GPs. RESULTS: Compliance was low for 'anamnesis' (27%), reasonable for 'supplementary examination'--'audiography' (42%) and 'whispered voice test' (12%)--and 'evaluation' (65%), and high for 'physical examination' ('otoscopy' 82%). Adapted questioning for the purpose of establishing the case history was observed. The questioning was adapted in so far as it took into account the information that had already been obtained. 'Management' gave high scores for 'instruction' (85%) and 'referral' (72%). For mostly practical reasons, the whispered voice test, recommended in the NHG standard was scarcely used (12%) whereas the tuning fork tests, which are not advocated in the NHG standard, were often used (43%). CONCLUSION: For the aspects 'otoscopy', 'instruction' and 'referral' the GPs' practice reflected the recommendations contained in the NHG standard 'Hardness of hearing'.

Active genes in junk DNA? Characterization of DUX genes embedded within 3.3 kb repeated elements.

The human genome contains hundreds of repeats of the 3.3 kb family in regions associated with heterochromatin. We have previously isolated a 3.3 kb-like cDNA encoding a double homeodomain protein (DUX1). Demonstration that the protein was expressed in human rhabdomyosarcoma TE671 cells, and characterization of a homologous promoter suggested that functional DUX genes might be present in 3.3 kb elements. In the present study, we describe two nearly identical 3.3 kb/DUX genes derived from PAC 137F16 (DUX3), and TE671 genomic DNA (DUX5), both mapping to all the acrocentric chromosomes. Their promoters harbor a GC and a TATAA box, and the open reading frame of the intronless structural part encodes two DUX proteins differing by alternative translation initiation. The shorter protein of the DUX5 gene is identical to DUX1. Using a protein truncation test, we could show that these two proteins are encoded by total RNA, but not by poly (A)(+) RNA, from different human tissues and cell lines. Our results indicate that active genes of unusual structure are present in chromosome regions characterized by large amounts of heterochromatic repetitive DNA.