Features of durable response and treatment efficacy for capecitabine monotherapy in advanced breast cancer: real-world evidence from a large single-centre cohort.

PURPOSE: In metastatic breast cancer (MBC) population treated with capecitabine monotherapy, we investigated clinical-pathological features as possible biomarkers for the oncological outcome. METHODS: Retrospective study of consecutive MBC patients treated at University Hospitals Leuven starting capecitabine between 1999 and 2017. The primary endpoint was the durable response (DR), defined as non-progressive disease for > 52 weeks. Other main endpoints were objective response rate (ORR), time to progression (TTP) and overall survival (OS). RESULTS: We included 506 patients; mean age at primary breast cancer diagnosis was 51.2 years; 18.2% had de novo MBC; 98.8% were pre-treated with taxanes and/or anthracycline. DR was reached in 11.6%. Patients with DR, as compared to those without DR, were more likely oestrogen receptor (ER) positive (91.5% vs. 76.8%, p = 0.010) at first diagnosis, had a lower incidence of lymph node (LN) involvement (35.6% vs. 49.9%, p = 0.039) before starting capecitabine, were more likely to present with metastases limited to ≤ 2 involved sites (54.2% vs. 38.5%, p = 0.020) and time from metastasis to start of capecitabine was longer (mean 3.5 vs. 2.7 years, p = 0.020). ORR was 22%. Median TTP and OS were 28 and 58 weeks, respectively. In multivariate analysis (only performed for TTP), ER positivity (hazard ratio (HR) = 0.529, p < 0.0001), HER2 negativity (HR = 0.582, p = 0.024), absence of LN (HR = 0.751, p = 0.008) and liver involvement (HR = 0.746, p = 0.013), older age at capecitabine start (HR = 0.925, p < 0.0001) and younger age at diagnosis of MBC (HR = 0.935, p = 0.001) were significant features of longer TTP. CONCLUSION: Our data display relevant clinical-pathological features associated with DR and TTP in patients receiving capecitabine monotherapy for MBC.

New-generation positional therapy in patients with positional central sleep apnea.

PURPOSE: To evaluate the effect of a sleep position trainer (SPT) in patients with positional central sleep apnea (PCSA). METHODS: A multicentre cohort study was conducted. Patients with symptomatic PCSA were included. Effectiveness, compliance and quality of life were assessed at 1- and 6-month follow-up. RESULTS: Sixteen patients were included. Median AHI dropped from 23.4/h [12.9-31.2] to 11.5/h [7.2-24.5] (p = 0.044) after 1-month SPT therapy and in patients who continued treatment, median AHI further decreased after 6 months to 9.7/h [3.4-27.6] (p = 0.075). Median percentage of supine sleep decreased significantly from 37.6 [17.2-51.8] to 6.7 [0.7-22.8] (p < 0.001), after 1 month, and to 6.8 [0.7-22.1] (p = 0.001), after 6 months. Mean compliance over 1 and 6 months was 78.6 ± 35.3 and 66.0 ± 33.3%, respectively. Epworth Sleepiness Scale at baseline was 9.5 [3.3-11.8] and did not significantly decrease after 1 month (11.0 [3.0-13.0]) and 6 months (4.0 [3.0-10.5]) follow-up. Functional Outcomes of Sleep Questionnaire remained stable within the first month. However, after 6 months, there was a significant improvement compared to baseline values, 15.9 [11.9-18.4] vs. 17.8 [14.3-19.2]; p = 0.030. CONCLUSION: This is the first study on effects of positional therapy with a new-generation smart device in patients with PCSA after 1 and 6 months of follow-up. Results of this study show that the SPT is effective in reducing AHI and central AI, feasible in PCSA, and is associated with symptomatic improvement. While the working mechanism behind this effect remains speculative, the effect is positive and considerable.

[Perioperative cardiovasular morbidity and mortality in noncardiac surgical interventions : Measures for optimal anesthesiological care]. / Perioperative kardiovaskuläre Morbidität und Letalität bei nichtherzchirurgischen Eingriffen : Maßnahmen der optimalen anästhesiologischen Betreuung.

Because of new surgical techniques, advanced monitoring modalities and improvements in perioperative care, perioperative mortality and morbidity have been significantly reduced in the last decades; however, patients still suffer from high perioperative mortality and morbidity, especially those with pre-existing cardiovascular diseases. Not only perioperative myocardial infarction but also myocardial injury after non-cardiac surgery, which presents without clinical symptoms, is associated with an adverse outcome. Patients at risk require particular interdisciplinary attention throughout the perioperative phase. The premedication visit is of particular importance. In addition to a thorough patient medical history and physical assessment, the perioperative handling of the patient's pre-existing medication and possible necessity for further preoperative tests should be verified. If necessary and where possible, optimization of the patient's state of health can be planned together with other disciplines. It is the anesthesiologist's responsibility to optimally guide and support patients with pre-existing cardiovascular diseases through the entire surgical procedure. This review summarizes perioperative interventions that have an influence on patient mortality and morbidity and evaluates the underlying evidence. This covers the perioperative handling of cardioprotective medication, choice of the anesthetic regimen, blood pressure management and transfusion regimens. Furthermore, this review highlights recent findings, e.g. perioperative reloading with statins and short-term preoperative initiation of beta blockers. The pros and cons of thoracic epidural anesthesia in patients with an elevated cardiovascular risk are discussed. Not only intraoperative hypotension should be of concern to anesthesiologists but also postoperative hypotension can have a deleterious impact on the outcome. This is relevant in the time period when a significant proportion of patients have already left the monitoring ward. The recently published recommendations by the World Health Organization concerning perioperative hyperoxia might not be beneficial for patients with an elevated cardiovascular risk. Finally, the treatment options for perioperative cardiovascular events are explained and an algorithm for handling of patients with perioperative myocardial injury without clinical ischemic symptoms is suggested (myocardial injury after non-cardiac surgery).

Comparison of brachytherapy and external beam radiotherapy boost in breast-conserving therapy: Patient-reported outcome measures and aesthetic outcome.

OBJECTIVE: This study aimed to estimate the probability of an unfavourable aesthetic outcome (AO) 2 years after breast-conserving therapy (BCT) and evaluate the possible influence of brachytherapy (BT) and external beam radiotherapy (EBRT) boost on patient-reported outcomes (PROs) and AO. PATIENTS AND METHODS: Patients treated with BCT starting April 2015 were prospectively included. Selection of the boost technique followed an in-house flowchart based on the depth of the tumour bed. An electron boost was performed for a superficial clinical target volume (maximum 28 mm under the epidermis), a BT boost was proposed in all other cases. Patients were followed-up for 2 years. AO was scored by the BCCT.core software and the patient. Further PROs were measured with the EORTC QLQ-C30, QOL-BR23 and the BIBCQ questionnaires. RESULTS: The analysis included 175 patients, 80 received a BT boost and 95 an EBRT boost. BT patients were significantly older; had a higher breast cup and band size, body mass index and surgical specimen weight of the wide excision; more seroma at baseline and less positive surgical section margins than patients in the EBRT group, and more patients drank alcohol. Cancer- and breast cancer-specific quality of life (QOL) and body image did not differ between the boost techniques over time. Although mean scores for breast symptoms and sexual enjoyment did differ significantly over time (p = 0.05 and < 0.01, respectively), the effect was due to differences before boost administration. Measured with BCCT.core, AO was unfavourable in 28% of patients 2 years after treatment (31% scored by the patient) and results were similar in the BT and EBRT groups. CONCLUSION: Using the presented flowchart (See Verhoeven et al. [16]), AO and PROs on QOL or body image up to 2 years after BCT are not influenced by the boost technique.

Profiling of volatile organic compounds produced by clinical Aspergillus isolates using gas chromatography-mass spectrometry.

Volatile organic compounds (VOCs) in exhaled breath may identify the presence of invasive pulmonary aspergillosis. We aimed to detect VOC profiles emitted by in vitro cultured, clinical Aspergillus isolates using gas chromatography-mass spectrometry (GC-MS). Three clinical Aspergillus isolates and a reference strain were cultured while conidiation was prevented. Headspace samples were analyzed using a standardized method. Breath samples of patients from which the cultures were obtained were checked for the presence of the VOCs found in vitro. Each Aspergillus isolate produced a distinct VOC profile. These profiles could not be confirmed in exhaled breath in vivo.

Encapsulated cell device approach for combined electrical stimulation and neurotrophic treatment of the deaf cochlea.

Profound hearing impairment can be overcome by electrical stimulation (ES) of spiral ganglion neurons (SGNs) via a cochlear implant (CI). Thus, SGN survival is critical for CI efficacy. Application of glial cell line-derived neurotrophic factor (GDNF) has been shown to reduce SGN degeneration following deafness. We tested a novel method for local, continuous GDNF-delivery in combination with ES via a CI. The encapsulated cell (EC) device contained a human ARPE-19 cell-line, genetically engineered for secretion of GDNF. In vitro, GDNF delivery was stable during ES delivered via a CI. In the chronic in vivo part, cats were systemically deafened and unilaterally implanted into the scala tympani with a CI and an EC device, which they wore for six months. The implantation of control devices (same cell-line not producing GDNF) had no negative effect on SGN survival. GDNF application without ES led to an unexpected reduction in SGN survival, however, the combination of GDNF with initial, short-term ES resulted in a significant protection of SGNs. A tight fibrous tissue formation in the scala tympani of the GDNF-only group is thought to be responsible for the increased SGN degeneration, due to mechanisms related to an aggravated foreign body response. Furthermore, the fibrotic encapsulation of the EC device led to cell death or cessation of GDNF release within the EC device during the six months in vivo. In both in vitro and in vivo, fibrosis was reduced by CI stimulation, enabling the neuroprotective effect of the combined treatment. Thus, fibrous tissue growth limits treatment possibilities with an EC device. For a stable and successful long-term neurotrophic treatment of the SGN via EC devices in human CI users, it would be necessary to make changes in the treatment approach (provision of anti-inflammatories), the EC device surface (reduced cell adhesion) and the ES (initiation prior to fibrosis formation).

Prediction of long-term clinical outcome in a diverse chronic hepatitis B population: Role of the PAGE-B score.

An abundance of noninvasive scores have been associated with fibrosis and hepatocellular carcinoma (HCC) development. We aimed to compare the prognostic ability of these scores in relation to liver histology in chronic hepatitis B (CHB) patients. Liver biopsies from treatment-naïve CHB patients at one tertiary care centre were scored by a single hepato-pathologist. Laboratory values at liver biopsy were used to calculate the PAGE-B, REACH-B, GAG-HCC, CU-HCC and FIB-4 scores. Any clinical event was defined as HCC development, liver failure, transplantation and mortality. HCC and mortality data were obtained from national database registries. Of 557 patients, 40 developed a clinical event within a median follow-up of 10.1 (IQR 5.7-15.9) years. The PAGE-B score predicted any clinical event (C-statistic.86, 95% CI: 0.80-0.92), HCC development (C-statistic .91) and reduced transplant-free survival (C-statistic .83) with good accuracy, also when stratified by ethnicity, antiviral therapy after biopsy or advanced fibrosis. The C-statistics (95% CI) of the REACH-B, GAG-HCC, CU-HCC and FIB-4 scores for any event were .70 (0.59-0.81), .82 (0.75-0.89), .73 (0.63-0.84) and.79 (0.69-0.89), respectively. The PAGE-B event risk assessment improved modestly when combined with the Ishak fibrosis stage (C-statistic .87, 95% CI: 0.82-0.93). The PAGE-B score showed the best performance in assessing the likelihood of developing a clinical event among a diverse CHB population over 15 years of follow-up. Additional liver histological characteristics did not appear to provide a clinically significant improvement.

NK cells in self-limited HCV infection exhibit a more extensively differentiated, but not memory-like, repertoire.

Natural killer (NK) cells have long been thought of as a purely innate immune cell population, but increasing reports have described developmental and functional qualities of NK cells that are commonly associated with cells of the adaptive immune system. Of these features, the ability of NK cells to acquire functional qualities associated with immunological memory and continuous differentiation resulting in the formation of specific NK cell repertoires has recently been highlighted in viral infection settings. By making use of a unique cohort of monitored, at-risk intravenous drug users in this study, we were able to dissect the phenotypic and functional parameters associated with NK cell differentiation and NK cell memory in patients 3 years after acute HCV infection and either the subsequent self-clearance or progression to chronicity. We observed increased expression of cytolytic mediators and markers CD56bright and NKp46+ of NK cells in patients with chronic, but not self-limited HCV infection. Patients with a self-limited infection expressed higher levels of differentiation-associated markers CD57 and KIRs, and lower levels of NKG2A. A more extensively differentiated NK cell phenotype is associated with self-clearance in HCV patients, while the NK cells of chronic patients exhibited more naïve and effector NK cell phenotypic and functional characteristics. The identification of these distinct NK cell repertoires may shed light on the role NK cells play in determining the outcome of acute HCV infections, and the underlying immunological defects that lead to chronicity.

Omitting radiation therapy in women with triple-negative breast cancer leads to worse breast cancer-specific survival.

PURPOSE: To examine locoregional recurrence (LRR) and breast cancer-specific survival (BCSS) after breast-conserving therapy (BCT) or mastectomy (ME) with or without radiation therapy (RT) in triple-negative breast cancer (TNBC). MATERIAL & METHODS: We identified non-metastatic TNBC cases from a single institution database. BCT, ME with RT (ME + RT) and ME only were compared with respect to LRR and BCSS. Cox regression models were used to analyze the association between prognostic factors and outcome. RESULTS: 439 patients fulfilled the inclusion criteria. Median follow-up was 10.2 years (interquartile range 7.9; 12.4 years). Patients in the BCT (n = 239), ME + RT (n = 116) and ME only (n = 84) group differed with respect to age, pT, pN, lymphovascular invasion, lymph node dissection and chemotherapy administration. Ten-year LRR rates were seven percent, three percent and eight percent for the BCT, ME + RT and ME only group, respectively. pN was associated with LRR. In multivariable analysis LRR were significantly lower in the ME + RT group compared to the BCT and the ME only group (p 0.037 and 0.020, respectively). Ten year BCSS was 87%, 84% and 75% for the BCT, ME + RT and ME only group, respectively. pT, pN, lymph node dissection, lymphovascular invasion and the administration of chemotherapy were associated with BCSS. In multivariable analysis BCSS was significantly lower in the ME only group compared to the BCT group and the ME + RT group (p 0.047 and 0.003, respectively). CONCLUSION: TNBC patients treated with ME without adjuvant RT showed significant lower BCSS compared to patients treated with BCT or ME + RT and significant more LRR compared to ME + RT when corrected for known clinicopathological prognostic factors.

Inducing Hepatitis C Virus Resistance After Pig Liver Transplantation-A Proof of Concept of Liver Graft Modification Using Warm Ex Vivo Perfusion.

Normothermic ex vivo liver perfusion (NEVLP) offers the potential to optimize graft function prior to liver transplantation (LT). Hepatitis C virus (HCV) is dependent on the presence of miRNA(microRNA)-122. Miravirsen, a locked-nucleic acid oligonucleotide, sequesters miR-122 and inhibits HCV replication. The aim of this study was to assess the efficacy of delivering miravirsen during NEVLP to inhibit miR-122 function in a pig LT model. Pig livers were treated with miravirsen during NEVLP or cold storage (CS). Miravirsen absorption, miR-122 sequestration, and miR-122 target gene derepression were determined before and after LT. The effect of miravirsen treatment on HCV infection of hepatoma cells was also assessed. NEVLP improved miravirsen uptake versus CS. Significant miR-122 sequestration and miR-122 target gene derepression were seen with NEVLP but not with CS. In vitro data confirmed miravirsen suppression of HCV replication after established infection and prevented HCV infection with pretreatment of cells, analogous to the pretreatment of grafts in the transplant setting. In conclusion, miravirsen delivery during NEVLP is a potential strategy to prevent HCV reinfection after LT. This is the first large-animal study to provide "proof of concept" for using NEVLP to modify and optimize liver grafts for transplantation.

Ultra-distal access of the M1 segment with the 5†Fr Navien distal access catheter in acute (anterior circulation) stroke: is it safe and efficient?

BACKGROUND AND AIM: The importance of mechanical thrombectomy in acute stroke treatment has grown over recent years. Mechanical thrombectomy comprises many different techniques. Technical improvements in the catheter material have led to the development of large-bore distal access catheters which can enter tortuous intracranial vessels. This has promising applications for endovascular stroke treatment. This study evaluated the safety and success rate of ultra-distal access of the middle cerebral artery (MCA) M1 segment with the 5 Fr Navien 58 distal access catheter in the treatment of acute stroke in combination with stent retrievers. METHODS: We retrospectively analyzed 81 patients with an acute stroke of the anterior circulation in whom ultra-distal access to the M1 segment was carried out using the Navien 58 catheter with an anchoring technique with a stent retriever for mechanical thrombectomy. Technical complications, success rates of catheter placement, success rates of thrombectomy using the modified Thrombolysis In Cerebral Infarction (mTICI) score, and the procedure times were evaluated. RESULTS: Ultra-distal access with the Navien 58 was successful in 75% (61/81) of cases. Recanalization success with a mTICI score of 2b and better was achieved in 83% overall (67/81), in 90% (55/61) of cases with successful ultra-distal access and in 60% (12/20) of cases without ultra-distal access. No severe adverse effects such as dissections or perforations occurred as a result of the ultra-distal catheter placement in the M1 segment. In 4% (3/81) of the cases a reversible MCA vasospasm occurred. CONCLUSIONS: Ultra-distal placement of the Navien 58 distal access catheter into the M1 segment in acute anterior circulation stroke can be achieved consistently, is safe in practice, and results in good recanalization success rates.

SMAD4 exerts a tumor-promoting role in hepatocellular carcinoma.

Further understanding of the molecular biology and pathogenesis of hepatocellular carcinoma (HCC) is crucial for future therapeutic development. SMAD4, recognized as an important tumor suppressor, is a central mediator of transforming growth factor beta (TGFB) and bone morphogenetic protein (BMP) signaling. This study investigated the role of SMAD4 in HCC. Nuclear localization of SMAD4 was observed in a cohort of 140 HCC patients using tissue microarray. HCC cell lines were used for functional assay in vitro and in immune-deficient mice. Nuclear SMAD4 levels were significantly increased in patient HCC tumors as compared with adjacent tissues. Knockdown of SMAD4 significantly reduced the efficiency of colony formation and migratory capacity of HCC cells in vitro and was incompatible with HCC tumor initiation and growth in mice. Knockdown of SMAD4 partially conferred resistance to the anti-growth effects of BMP ligand in HCC cells. Importantly, simultaneous elevation of SMAD4 and phosphorylated SMAD2/3 is significantly associated with poor patient outcome after surgery. Although high levels of SMAD4 can also mediate an antitumor function by coupling with phosphorylated SMAD1/5/8, this signaling, however, is absent in majority of our HCC patients. In conclusion, this study revealed a highly non-canonical tumor-promoting function of SMAD4 in HCC. The drastic elevation of nuclear SMAD4 in sub-population of HCC tumors highlights its potential as an outcome predictor for patient stratification and a target for personalized therapeutic development.

Loss of intrahepatic HBsAg expression predicts sustained response to peginterferon and is reflected by pronounced serum HBsAg decline.

There is a lack of knowledge regarding the effect of peginterferon (PEG-IFN) on the expression of intrahepatic hepatitis B core and surface antigen (HBcAg and HBsAg) in chronic hepatitis B (CHB) and its relation with response to therapy. Fifty-two HBeAg-positive and 67 HBeAg-negative CHB patients with paired liver biopsies taken at baseline and after 1 year of PEG-IFN therapy were studied. After PEG-IFN therapy, HBeAg-negative patients showed a significant reduction in both intrahepatic HBcAg (P = 0.04) and HBsAg expression (P < 0.001). In contrast, a reduction in intrahepatic HBcAg expression was not observed in HBeAg-positive patients, while a trend in reduction of intrahepatic HBsAg staining was found (P = 0.09). Post-treatment, 7 (13%) HBeAg-positive and 9 (14%) HBeAg-negative patients had no expression of intrahepatic HBsAg. Patients without any intrahepatic HBsAg expression post-treatment were more likely to achieve a combined response (HBeAg loss with hepatitis B virus (HBV) DNA <2000 IU/mL for HBeAg -positive and HBV DNA <2000 IU/mL and normal alanine aminotransferase for HBeAg-negative CHB): 71% vs 5% for HBeAg-positive (P < 0.001) and 60% vs 16% for HBeAg-negative patients (P = 0.004), respectively. Moreover, a more profound decline of serum HBsAg was observed in patients with absence of intrahepatic HBsAg staining (3.1 vs 0.4 log IU/mL, P < 0.001 and 1.7 vs 0.4 log IU/mL, P = 0.005 for HBeAg-positive and HBeAg-negative CHB, respectively). In conclusion, PEG-IFN reduces expression of intrahepatic HBsAg. Loss of HBsAg as assessed by immunohistochemistry from the liver predicts a sustained response and is reflected in a pronounced serum HBsAg decline.

Launching a permanent out-of-hour interventional radiology service: single-center experience from a German University Hospital.

PURPOSE: To evaluate the feasibility, frequency of use, types of intervention and labor costs of a formal round-the-clock interventional radiology on-call service. MATERIALS AND METHODS: In 11/2011 a formal and permanent out-of-hour interventional radiology rota in addition to the general radiology out-of-hour rota (OOHR) was established. We retrospectively screened the interventional radiology database for procedures completed outside regular working hours, reviewed all interventions and manually selected cases in which the on-call interventionist was called in from home. We determined the type, frequency of use and costs (€/year and procedure) of this service between 1/2012 and 12/2012. The referring physicians' (sub-) specialties were evaluated. RESULTS: During the 12-month period, the on-call interventionists (n = 3) performed 92 procedures OOH. The procedures included angiography and hemorrhage control (n = 36, 39.1 %), angiography and intervention for acute limb ischemia (n = 25, 27.2 %), percutaneous biliary drainage (PTCD) (n = 10, 10.9 %), angiography for non-occlusive ischemia (n = 7, 7.6 %), and other (n = 14, 15.3 %). The total labor costs for the OOHR were €â€Š42,312.21 (€â€Š32,982.60 lump sum for stand-by, €â€Šâ€Š9,329.61 for hours spent on procedures). The labor costs per procedure totaled €â€Š459.92. The referring physicians' specialties were general/visceral (n = 25), vascular surgery (n = 24), internal medicine (n = 21), cardiac/thoracic vascular (n = 9), trauma surgery (n = 5), urology (n = 5), and anesthesiology (n = 3). CONCLUSION: A formal interventional OOHR is practicable in a university hospital setting. Most procedures were requested by general, vascular, and thoracic surgery as well as internal medicine with a focus on hemorrhage control, treatment of acute limb ischemia, and PTCD. The overall labor costs for the OOHR appear moderate. KEY POINTS: • In a university setting an OOHR for IR is feasible.• Labor costs per procedure appear moderate.• Hemorrhage control and treatment of limb ischemia were the most frequent procedures. Citation Format: • Goltz JP, Janssen H, Petritsch B et al. Launching a Permanent Out-of-Hour Interventional Radiology Service: Single-Center Experience from a German University Hospital. Fortschr Röntgenstr 2014; 186: 136 - 141.

Impact of secondary hard substrate on the distribution and abundance of Aurelia aurita in the western Baltic Sea.

This study assessed the impact of secondary hard substrate, as being introduced into marine ecosystems by the establishment of wind farm pillars, on the occurrence and distribution of the moon jelly Aurelia aurita in the southwestern Baltic Sea. A two-year data sampling was conducted with removable settlement plates to assess the distribution and population development of the scyphozoan polyps. The data collected from these samples were used to set up a model with Lagrangian particle technique. The results confirm that anthropogenic created hard substrate (e.g. offshore wind farms) has the potential to increase the abundance of the A. aurita population. The distribution of wind farm borne jellyfish along Danish, German and Polish coasts indicates conflicts with further sectors, mainly energy and tourism.

Evaluation of strained alkynes for Cu-free click reaction in live mice.

INTRODUCTION: We report on our evaluation of the strain-promoted cyclooctyne-azide cycloaddition reaction for use in tumor pretargeting, comprising a side-by-side comparison of probes 1-3 bearing three distinct cyclooctyne moieties based respectively on the 1st and 2nd generation difluorinated cyclooctyne and the 1st generation dibenzocyclooctyne. METHODS: The probes were synthesized and labeled with (177)Lu with high yields. The probe stability and reactivity towards azides were evaluated in PBS and mouse serum, and their blood clearance, biodistribution and in vivo reactivity were evaluated in tumor-free mice. RESULTS: In serum the three probes exhibited sufficient stability for a pretargeting application with half-lives of 12-19h. In PBS, probes 2 and 3 were more reactive towards azido-conjugated Rituximab (Rtx-N3) than 1, but in contrast to 1, their reactivity decreased in mouse serum and mouse serum albumin solutions, as a result of covalent and non-covalent interactions with albumin. Biodistribution data confirmed the interactions with serum proteins in circulation: (177)Lu-1 showed a fast elimination from blood (t1/2,ß = 0.31h), while (177)Lu-2 and (177)Lu-3 were retained in blood for longer periods of time (t1/2,ß = 1.08 and 3.58h, respectively). Dual isotope biodistribution experiments assessing the reaction between (125)I-Rtx-N3 and (177)Lu-1-3 in circulation in mice showed a very limited retention of 2 and 3 in blood rich organs, indicating a minimal reactivity, while no such retention was observed for 1. CONCLUSION: The low reactivity of the studied cyclooctynes, and their serum interactions preclude their use at the low in vivo concentrations typical for pretargeting applications.

Benzopyrene serum concentration after endovenous laser ablation of the great saphenous vein.

BACKGROUND: During endovenous laser ablation (EVLA) of the great saphenous vein, patients often involuntarily mention an uncomfortable "burnt" smell and taste. When applying intense heat to proteins and carbohydrates, it is inevitable that polycyclic aromatic hydrocarbons (PAHs) are formed. This group of PAH includes the human carcinogen benzo[a]pyrene (B[a]P). This study determined the serum concentration of B[a]P just before and after EVLA. METHODS: A total of 20 patients were included. The B[a]P serum concentration was determined just before and directly after EVLA. RESULTS: In 18 patients, B[a]P was determined before and after EVLA. In 2 patients, EVLA was not possible. In this study, no elevated serum concentration of B[a]P was found before and after EVLA. CONCLUSION: It remains to be established which heat products cause the burnt smell and taste sensation in patients during EVLA. Further research is needed to determine whether EVLA can be considered as a safe procedure.

Determinants of vitamin D status in healthy men and women aged 40-80 years.

OBJECTIVES: To determine the contribution of life style and health related factors on vitamin D status in middle-aged and older men and women. STUDY DESIGN: A cross-sectional single-center study in 400 male subjects (40-80 years) and 402 postmenopausal female subjects (56-73 years), conducted in a University Medical Center in the central part of the Netherlands (52 degrees northern latitude). MAIN OUTCOME MEASURES: Medical history, vitamin D, calcium and alcohol intake, physical activity, Body Mass Index, Blood pressure, smoking, total fat body mass and total lean body mass were measured using DEXA. Laboratory analysis included 25-hydroxyvitamin D (25OHD) and sex hormones. RESULTS: Thirty-six percent of men and 51% of women had 25OHD less than 50 nmol/L. In summertime men had significant higher 25OHD as compared to women (81.5 vs 53.3 nmol/L, P=.000) but this difference disappeared come winter. In a saturated model, male gender (B=.16, P=.008), and season (summer vs winter B=.30, P=.000) remained statistically significant. In men, physical activity and season explained 21% of the variance. In women, household physical activity (B=.13, P=.03), sport physical activity (B=.02, P=.02) and estradiol (B=-.003, P=.048) remained in the model,. CONCLUSION: In healthy middle-aged and older men and postmenopausal women, male gender and season were important predictors of vitamin D status. In men, physically activity and season, explained 21% of the variance in vitamin D status. In women, physical activity and estradiol explained 9.3% of the variance in vitamin D.

Prothrombotic disorders in abdominal vein thrombosis.

Abdominal vein thrombosis is a rare, but potentially life-threatening form of venous thrombosis. It mainly involves the hepatic veins (Budd Chiari syndrome, BCS), portal veins (PVT) and mesenteric veins. In recent years several large-scale studies have been performed to study the underlying aetiological factors in these thrombotic disorders. Both inherited and acquired thrombophilia factors are frequently observed in these patients. Factor V Leiden mutation is frequently found in patients with BCS and prothrombin gene variant is seen more frequently in PVT. Myeloproliferative neoplasms (MPNs), including polycythemia vera and essential thrombocythemia, are underlying disorders in 30-40% of patients with abdominal vein thrombosis. Other aetiological factors are paroxysmal nocturnal haemoglobinuria (PNH), autoimmune disorders and hormonal factors. Recently, several new risk factors have been reported and are discussed in this review. BCS and PVT are multi-factorial disorders. In nearly 50% of patients two, and in 16% even three prothrombotic risk factors were found at presentation. Because patients with abdominal vein thrombosis have a high risk of recurrence immediate anticoagulant treatment is necessary. The duration of treatment is still a matter of debate because these patients also have a high risk of bleeding, especially those with portal hypertension. For BCS patients life-long anticoagulant treatment is advised. In patients with PVT it is recommended to tailor treatment to the individual patient based on the presence of an underlying prothrombotic disorder and the risk of bleeding.

Risk factors and outcome of HIV-associated idiopathic noncirrhotic portal hypertension.

BACKGROUND: Idiopathic noncirrhotic portal hypertension (INCPH) has been reported increasingly in patients with HIV infection. AIM: To evaluate the number of nationwide diagnosed HIV-associated INCPH cases and to assess its clinical features, risk factors and outcome. METHODS: All HIV centres in the Netherlands were contacted and requested to notify INCPH cases diagnosed in their population. A case­control study was performed to identify the risk factors of INCPH. The cases were group-matched for duration of follow-up after HIV diagnosis to controls. Controls were selected from a database of HIV patients with negative screening for signs of portal hypertension on abdominal ultrasound. Univariate and multivariate conditional logistic regression analyses were performed. RESULTS: On 1st of July 2011, 18.085 individuals were infected with HIV in the Netherlands. Within this population, sixteen patients with clinically overt INCPH were identified. At the time of INCPH diagnosis, cases had a lower platelet count and a higher ALT level. In univariate and multivariate analyses, didanosine [OR: 1.9 (1.3­2.8)], concomitant didanosine and stavudine treatment [OR: 6.3 (2.1­19.1)] and concomitant didanosine and tenofovir treatment [OR: 5.1 (1.2­22.6)] were independently associated INCPH. During follow-up, 4 patients died [malignancy (n = 3), liver failure (n = 1)]. A significant decline in platelets was observed after didanosine discontinuation (P = 0.003). CONCLUSIONS: HIV-associated clinically relevant idiopathic noncirrhotic portal hypertension appears to be a rarely diagnosed disease. Long-term exposure to didanosine and short-term combination of didanosine and stavudine or tenofovir exposure are associated with idiopathic noncirrhotic portal hypertension. Mortality in HIV-associated idiopathic noncirrhotic portal hypertension is mainly related to HIV-associated disorders. Portal hypertension continues despite didanosine discontinuation