Discrimination of pancreato-biliary cancer and pancreatitis patients by non-invasive liquid biopsy.

BACKGROUND: Current diagnostics for the detection of pancreato-biliary cancers (PBCs) need to be optimized. We therefore propose that methylated cell-free DNA (cfDNA) derived from non-invasive liquid biopsies serves as a novel biomarker with the ability to discriminate pancreato-biliary cancers from non-cancer pancreatitis patients. METHODS: Differentially methylated regions (DMRs) from plasma cfDNA between PBCs, pancreatitis and clinical control samples conditions were identified by next-generation sequencing after enrichment using methyl-binding domains and database searches to generate a discriminatory panel for a hybridization and capture assay with subsequent targeted high throughput sequencing. RESULTS: The hybridization and capture panel, covering around 74 kb in total, was applied to sequence a cohort of 25 PBCs, 25 pancreatitis patients, 25 clinical controls, and seven cases of Intraductal Papillary Mucinous Neoplasia (IPMN). An unbiased machine learning approach identified the 50 most discriminatory methylation markers for the discrimination of PBC from pancreatitis and controls resulting in an AUROC of 0.85 and 0.88 for a training (n = 45) and a validation (n = 37) data set, respectively. The panel was also able to distinguish high grade from low grade IPMN samples. CONCLUSIONS: We present a proof of concept for a methylation biomarker panel with better performance and improved discriminatory power than the current clinical marker CA19-9 for the discrimination of pancreato-biliary cancers from non-cancerous pancreatitis patients and clinical controls. This workflow might be used in future diagnostics for the detection of precancerous lesions, e.g. the identification of high grade IPMNs vs. low grade IPMNs.

Intermediate-dose versus low-dose low-molecular-weight heparin in pregnant and post-partum women with a history of venous thromboembolism (Highlow study): an open-label, multicentre, randomised, controlled trial.

BACKGROUND: Pregnancy-related venous thromboembolism is a leading cause of maternal morbidity and mortality, and thromboprophylaxis is indicated in pregnant and post-partum women with a history of venous thromboembolism. The optimal dose of low-molecular-weight heparin to prevent recurrent venous thromboembolism in pregnancy and the post-partum period is uncertain. METHODS: In this open-label, randomised, controlled trial (Highlow), pregnant women with a history of venous thromboembolism were recruited from 70 hospitals in nine countries (the Netherlands, France, Ireland, Belgium, Norway, Denmark, Canada, the USA, and Russia). Women were eligible if they were aged 18 years or older with a history of objectively confirmed venous thromboembolism, and with a gestational age of 14 weeks or less. Eligible women were randomly assigned (1:1), before 14 weeks of gestational age, using a web-based system and permuted block randomisation (block size of six), stratified by centre, to either weight-adjusted intermediate-dose or fixed low-dose low-molecular-weight heparin subcutaneously once daily until 6 weeks post partum. The primary efficacy outcome was objectively confirmed venous thromboembolism (ie, deep-vein thrombosis, pulmonary embolism, or unusual site venous thrombosis), as determined by an independent central adjudication committee, in the intention-to-treat (ITT) population (ie, all women randomly assigned to treatment). The primary safety outcome was major bleeding which included antepartum, early post-partum (within 24 h after delivery), and late post-partum major bleeding (24 h or longer after delivery until 6 weeks post partum), assessed in all women who received at least one dose of assigned treatment and had a known end of treatment date. This study is registered with ClinicalTrials.gov, NCT01828697, and is now complete. FINDINGS: Between April 24, 2013, and Oct 31, 2020, 1339 pregnant women were screened for eligibility, of whom 1110 were randomly assigned to weight-adjusted intermediate-dose (n=555) or fixed low-dose (n=555) low-molecular-weight heparin (ITT population). Venous thromboembolism occurred in 11 (2%) of 555 women in the weight-adjusted intermediate-dose group and in 16 (3%) of 555 in the fixed low-dose group (relative risk [RR] 0·69 [95% CI 0·32-1·47]; p=0·33). Venous thromboembolism occurred antepartum in five (1%) women in the intermediate-dose group and in five (1%) women in the low-dose group, and post partum in six (1%) women and 11 (2%) women. On-treatment major bleeding in the safety population (N=1045) occurred in 23 (4%) of 520 women in the intermediate-dose group and in 20 (4%) of 525 in the low-dose group (RR 1·16 [95% CI 0·65-2·09]). INTERPRETATION: In women with a history of venous thromboembolism, weight-adjusted intermediate-dose low-molecular-weight heparin during the combined antepartum and post-partum periods was not associated with a lower risk of recurrence than fixed low-dose low-molecular-weight heparin. These results indicate that low-dose low-molecular-weight heparin for thromboprophylaxis during pregnancy is the appropriate dose for the prevention of pregnancy-related recurrent venous thromboembolism. FUNDING: French Ministry of Health, Health Research Board Ireland, GSK/Aspen, and Pfizer.

Neonatal outcomes associated with time from a high fetal blood lactate concentration to operative delivery.

INTRODUCTION: Adjunctive technologies to cardiotocography intend to increase the specificity of the diagnosis of fetal hypoxia. If correctly diagnosed, time to delivery could affect neonatal outcome. In the present study, we aimed to investigate the effect of time from when fetal distress is indicated by a high fetal blood sample (FBS) lactate concentration to operative delivery on the risk of adverse neonatal outcomes. MATERIAL AND METHODS: We conducted a prospective observational study. Deliveries with a singleton fetus in cephalic presentation at 36+0 weeks of gestation or later were included. Adverse neonatal outcomes, related to decision-to-delivery interval (DDI), were investigated in operative deliveries indicated by an FBS lactate concentration of at least 4.8 mmol/L. We applied logistic regression to estimate crude and adjusted odds ratios (aOR) of various adverse neonatal outcomes, with associated 95% confidence intervals (CI), for a DDI exceeding 20 minutes, compared with a DDI of 20 minutes or less. CLINICALTRIALS: gov Identifier: NCT04779294. RESULTS: The main analysis included 228 women with an operative delivery indicated by an FBS lactate concentration of 4.8 mmol/L or greater. The risk of all adverse neonatal outcomes was significantly increased for both DDI groups compared with the reference group (deliveries with an FBS lactate below 4.2 mmol/L within 60 minutes before delivery). In operative deliveries indicated by an FBS lactate concentration of 4.8 mmol/L or more, there was a significantly increased risk of a 5-minute Apgar score less than 7 if the DDI exceeded 20 minutes, compared with a DDI of 20 minutes or less (aOR 8.1, 95% CI 1.1-60.9). We found no statistically significant effect on other short-term outcomes for deliveries with DDI longer than 20 minutes, compared with those with DDI of 20 minutes or less (pH ≤7.10: aOR 2.0, 95% CI 0.5-8.4; transfer to the neonatal intensive care unit: aOR 1.1, 95% CI 0.4-3.5). CONCLUSIONS: After a high FBS lactate measurement, the increased risk of adverse neonatal outcome is further augmented if the DDI exceeds 20 minutes. These findings give support to current Norwegian guidelines for intervention in cases of fetal distress.

Intrapartum pudendal nerve block analgesia and childbirth experience in primiparous women with vaginal birth: A cohort study.

BACKGROUND: A negative childbirth experience has short- and long-term consequences for both mother and child. This study aimed to investigate the association between intrapartum pudendal nerve block (PNB) analgesia and childbirth experience. METHODS: Primiparous women with a singleton cephalic vaginal live births at term at Oslo University Hospital from January 1, 2017, to June 1, 2019, were eligible for inclusion. The main outcome was total score on a childbirth experience questionnaire (range 1.0-4.0, higher score indicates better childbirth experience). An absolute risk difference of 0.10 was considered clinically relevant. Propensity score matching was used to adjust for differences in baseline characteristics between women with and without PNB. The analyses were stratified by spontaneous vs instrumental birth. Subanalyses of the questionnaire's domains (own capacity, professional support, perceived safety, and participation) were performed. RESULTS: Of 979 participating women, mean age was 32 years. Childbirth experience did not differ between women with and without PNB, either in spontaneous (absolute risk difference of the mean: -0.05, P value 0.36) or in instrumental birth (absolute risk difference of the mean: 0.03, P value 0.61). There were no statistically significant differences between PNB group scores for the separate domains. CONCLUSIONS: Women's childbirth experiences did not differ between birthing people with or without PNB, either in spontaneous or in instrumental births. The clinical implications of our study should be interpreted in light of the pain-relieving effects of PNB.PNB should be provided on clinical indication, including for individuals with severe labor pain.

Inhibition of P2X7 receptors by Lu AF27139 diminishes colonic hypersensitivity and CNS prostanoid levels in a rat model of visceral pain.

Visceral pain is a prominent feature of various gastrointestinal diseases. The P2X7 receptor is expressed by multiple cell types including dorsal root ganglion satellite glial cells, macrophages, and spinal microglia, all of which have been implicated in nociceptive sensitization. We have used the selective and CNS penetrant P2X7 receptor antagonist Lu AF27139 to explore this receptor's role in distinct rat models of inflammatory and visceral hypersensitivity. Rats injected with CFA in the hindpaw displayed a marked reduction in hindpaw mechanical threshold, which was dose-dependently reversed by Lu AF27139 (3-30 mg/kg, p.o.). In rats injected with TNBS in the proximal colon, the colorectal distension threshold measured distally was significantly lower than sham treated rats at 7 days post-injection (P < 0.001), indicative of a marked central sensitization. Colonic hypersensitivity was also reversed by Lu AF27139 (10-100 mg/kg) and by the κ-opioid receptor agonist U-50,488H (3 mg/kg, s.c.). Moreover, both Lu AF27139 and U-50,488H prevented a TNBS-induced increase in spinal and brain levels of PGE2 and LTB4, as well as an increase in brain levels of PGF2α and TXB2. Lu AF27139 was well tolerated as revealed by a lack of significant effect on rotarod motor function and coordination at all doses tested up to 300 mg/kg. Thus, P2X7 receptor antagonism is efficacious in a rat model of visceral pain, via a mechanism which potentially involves attenuation of microglial function within spinal and/or supraspinal pain circuits, albeit a peripheral site of action cannot be excluded.

Knowledge of gestational diabetes mellitus at first consultation in a multi-ethnic pregnant population in the Oslo region, Norway - a cross-sectional study.

Objectives: Gestational diabetes mellitus (GDM) is an increasing problem among pregnant women globally and is associated with short- and long-term consequences for both mother and newborn. The aim of this study was to investigate knowledge of GDM among a multi-ethnic pregnant population at first consultation for GDM in the Oslo region in Norway.Design: We conducted a cross-sectional study using baseline data from a randomised controlled study performed at five diabetic outpatient clinics (DOC) in the Oslo region. Pregnant women diagnosed with GDM following an Oral Glucose Tolerance test (OGTT) with a 2-hours blood glucose level of ≥ 9 mmol/l were included. Women filled out a questionnaire on an electronic tablet at the study entry, and additional data were collected through a recruiting form. Descriptive statistics were performed and associations were investigated using Chi-square test and multiple logistic regression analysis.Results: Of 238 women included in the study, 108 (45.4%) were native Norwegian speakers and 130 (54.6%) were non-native Norwegian speakers. 39.5% of the non-native Norwegian speakers were Asian, 22.5% were African, and 15.5% were from Eastern European Countries. Non-native Norwegian speakers were significantly more likely to have poor knowledge of GDM compared to native Norwegian speakers, adjusted OR = 4.5, 95% CI 1.61-12.5. Sensitivity analyses showed this was not due to poor language skills.Conclusions: Ethnic background was associated with the level of knowledge of GDM. Health professionals should be aware of the various knowledge levels concerning GDM and tailor their information towards women's knowledge. Linguistically- and culturally adapted information regarding GDM may improve knowledge gaps among women with immigrant backgrounds.

Tumor Infiltration with CD20+CD73+ B Cells Correlates with Better Outcome in Colorectal Cancer.

Immunotherapy has become increasingly important in the treatment of colorectal cancer (CRC). Currently, CD73, also known as ecto-5'-nucleotidase (NT5E), has gained considerable interest as a potential therapeutic target. CD73 is one of the key enzymes catalyzing the conversion of extracellular ATP into adenosine, which in turn exerts potent immune suppressive effects. However, the role of CD73 expression on various cell types within the CRC tumor microenvironment remains unresolved. The expression of CD73 on various cell types has been described recently, but the role of CD73 on B-cells in CRC remains unclear. Therefore, we analyzed CD73 on B-cells, especially on tumor-infiltrating B-cells, in paired tumor and adjacent normal tissue samples from 62 eligible CRC patients. The highest expression of CD73 on tumor-infiltrating B-cells was identified on class-switched memory B-cells, followed by naive B-cells, whereas no CD73 expression was observed on plasmablasts. Clinicopathological correlation analysis revealed that higher CD73+ B-cells infiltration in the CRC tumors was associated with better overall survival. Moreover, metastasized patients showed a significantly decreased number of tumor-infiltrating CD73+ B-cells. Finally, neoadjuvant therapy correlated with reduced CD73+ B-cell numbers and CD73 expression on B-cells in the CRC tumors. As promising new immune therapies are being developed, the role of CD73+ B-cells and their subsets in the development of colorectal cancer should be further explored to find new therapeutic options.

Intrapartum pudendal nerve block analgesia and risk of postpartum urinary retention: a cohort study.

INTRODUCTION AND HYPOTHESIS: Pudendal nerve block analgesia (PNB) is used as pain relief in the final stage of childbirth. We hypothesized that PNB is associated with higher rates of postpartum urinary retention. METHODS: We performed a cohort study among primiparous women with a singleton, cephalic vaginal birth at Oslo University Hospital, Norway. Women receiving PNB were included in the exposed group, while the subsequent woman giving birth without PNB was included in the unexposed group. We compared the likelihood of postpartum urinary retention, defined as catheterization within 3 h after birth. Logistic regression analysis stratified by mode of delivery was performed adjusting for epidural analgesia, episiotomy and birth unit. RESULTS: Of the 1007 included women, 499 were exposed to PNB and 508 were unexposed. In adjusted analyses, women exposed to PNB did not differ in likelihood of postpartum urinary retention compared to women unexposed to PNB in either spontaneous (odds ratio[OR]: 0.82, 95% confidence interval [CI] 0.55-1.22) or instrumental (OR 1.45, 95% CI 0.89-2.39) births. Furthermore, no differences between the groups were observed with excessive residual urine volume or catheterization after > 3 h. CONCLUSIONS: PNB was associated with neither risk of postpartum urinary retention nor excessive residual urine volume and is therefore unlikely to hamper future bladder function.

Complications and Effects of Dorsal Root Ganglion Stimulation in the Treatment of Chronic Neuropathic Pain: A Nationwide Cohort Study in Denmark.

OBJECTIVES: Dorsal root ganglion (DRG) stimulation is a novel treatment of chronic neuropathic pain and has been shown to be efficacious across several case reports and randomized trials. However, long-term follow-up is limited, as are reports of complication rates. This study presents efficacy and complications for patients treated with DRG stimulation. MATERIALS AND METHODS: We performed an observational, multicenter cohort study of all patients in Denmark implanted with FDA-approved DRG stimulation systems to treat chronic, neuropathic pain between 2014 and 2018. Follow-up period was one to three years. RESULTS: Forty-three patients underwent trial DRG stimulation; 33 were subsequently fully implanted. Pain location: 58% lower extremity; 21% upper extremity; 21% thoracic/abdominal. At the end of the observation period, 58% of fully implanted patients were still implanted; 42% had fully functional systems. In these patients, average Numerical Rating Scale (NRS)-score of pain was reduced from 6.8 to 3.5 (p = 0.00049) and worst NRS-score was reduced from 8.6 to 6.0 (p = 0.0039) at 12 months follow-up. Pain Catastrophizing Score was reduced from 32 to 15 (p = 0.0039). Thirteen patients experienced complications related to defect leads (39% of implanted systems). In four patients (12%), lead removal left fragments in the root canal due to lead fracture, and three patients suffered permanent nerve damage during attempts to replace broken leads. CONCLUSIONS: This study suggests a significant, clinically relevant effect of DRG stimulation on neuropathic pain, but also demonstrates substantial problems with maintenance and revision of currently available systems. Consequently, treatment with equipment marketed specifically for DRG stimulation is currently paused in Denmark.

Investigating surrogate cerebrospinal fluid matrix compositions for use in quantitative LC-MS analysis of therapeutic antibodies in the cerebrospinal fluid.

As quantitative analysis of biotherapeutics in cerebrospinal fluid (CSF) with LC-MS becomes increasingly widespread, there is a need for method developments towards higher sensitivity. By using artificial CSF (aCSF) in the development phase, the consumption of costly and sparsely available CSF can be limited. The aCSF compositions tested here were made from various dilutions of bovine serum albumin (BSA) or rat plasma to mimic the total protein concentration found in CSF. Focusing on monoclonal antibodies, the aCSF was spiked with human immunoglobulin (hIgG) and prepared with the bottom-up analysis technique using LC-MS. Assuming that the composition of the aCSF would affect the digest, the response from aCSF matrices was compared with CSF from rat, monkey, and dog in terms of estimated sample concentration and matrix effects. The samples were spiked with hIgG in the range of 10 to 1000 ng/mL and volumes of 10 µL were transferred to sample preparation. The results indicate that BSA dilutions from 300 to 2000 µg/mL and rat plasma dilutions of 0.5-2% provide the most accurate concentration estimates when compared with rat CSF. 1000 µg/mL BSA did not produce significantly different concentration estimates for 500 ng/mL samples when compared with CSF from rat, monkey, and dog, and can therefore be used as aCSF for several different species.

Induction of labor and nulliparity: A nationwide clinical practice pilot evaluation.

INTRODUCTION: Induction of labor has become an increasingly common obstetric procedure, but in nulliparous women or women with a previous cesarean section, it can pose a clinical challenge. Despite an overall expansion of medical indications for labor induction, there is little international consensus regarding the criteria for induction, or for the recommended methods among nulliparous women. In this light, we assessed variations in the practice of induction of labor among 21 birth units in a nationwide cohort of women with no prior vaginal birth. MATERIAL AND METHODS: We carried out a prospective observational pilot study of women with induced labor and no prior vaginal birth, across 21 Norwegian birth units. We registered induction indications, methods and outcomes from 1 September to 31 December 2018 using a web-based case record form. Women were grouped into "Nulliparous term cephalic", "Previous cesarean section" and "Other Robson" (Robson groups 6, 7, 8 or 10). RESULTS: More than 98% of eligible women (n=1818) were included and a wide variety of methods was used for induction of labor. In nulliparous term cephalic pregnancies, cesarean section rates ranged from 11.1% to 40.6% between birth units, whereas in the previous cesarean section group, rates ranged from 22.7% to 67.5%. The indications "large fetus" and "other fetal" indications were associated with the highest cesarean rates. Failed inductions and failure to progress in labor contributed most to the cesarean rates. Uterine rupture occurred in two women (0.11%), both in the previous cesarean section group. In neonates, 1.6% had Apgar <7 at 5 minutes, and 0.4% had an umbilical artery pH <7.00. CONCLUSIONS: Cesarean rates and applied methods for induction of labor varied widely in this nationwide cohort of women without a prior vaginal birth. Neonatal outcomes were similar to those of normal birth populations. Results could indicate the need to move towards more standardized induction protocols associated with optimal outcomes for mother and baby.

The provision of epidural analgesia during labor according to maternal birthplace: a Norwegian register study.

BACKGROUND: The provision of epidural analgesia during labor is ideally a shared decision between the woman and her health care provider. However, immigrant characteristics such as maternal birthplace could affect decision-making and thus access to pain relief. We aimed to assess disparities in the provision of epidural analgesia in planned vaginal birth according to maternal region of birth. METHODS: We performed a nation-wide register study of 842,496 live-born singleton deliveries in Norway between 2000 and 2015. Maternal birthplace was categorized according to the Global Burden of Disease framework. The provision of epidural analgesia was compared in regression models stratified by parity and mode of delivery. RESULTS: Compared to native-born women, primiparous women from Latin America/Caribbean countries with an instrumental vaginal delivery were most likely to be provided epidural analgesia (OR 2.12, 95%CI 1.69-2.66), whilst multiparous women from Sub-Saharan Africa with a spontaneous vaginal delivery were least likely to be provided epidural analgesia (OR 0.42, 95% C 0.39-0.44). Longer residence time was associated with a higher likelihood of being provided analgesia, whereas effects of maternal education varied by Global Burden of Disease group. CONCLUSIONS: Disparities in the likelihood of being provided epidural analgesia were observed by maternal birthplace. Further studies are needed to consider whether the identified disparities represent women's own preferences or if they are the result of heterogeneous access to analgesia during labor.

Upregulation of CD20 Positive B-Cells and B-Cell Aggregates in the Tumor Infiltration Zone is Associated with Better Survival of Patients with Pancreatic Ductal Adenocarcinoma.

Patients with pancreatic ductal adenocarcinoma (PDAC) normally have a poor long-term prognosis. However, some rare cases of long-term survivors have been reported. The tumor microenvironment, consisting of cellular and stromal components, possibly plays an important role and might influence prognosis. In this context, the role of tumor-infiltrating B-cells and its impact on the survival in patients with PDAC remains controversial. We therefore aimed to assess the prognostic value of CD20-positive B-cells and CD20-positive B-cell aggregates as well as CD138, IgM, Pax5, and Ki67 on the survival of patients with PDAC using immunohistochemistry of FFPE pancreatectomy tissue sections from patients that underwent primary surgery for pT3- and R0-pancreatic adenocarcinoma between 1995 and 2016. Patients with PDAC were matched and grouped in 16 long-term-survivors (LTS, median overall survival (OS): 96 months [range: 61-177 months]) and 16 short-term-survivors (STS, median OS: 16 months [range: 7-32 months]). CD20-positive B-cells and B-cell aggregates in the tumor infiltration zone were significantly upregulated in the LTS-group compared to the STS-group (p = 0.0499 respectively p = 0.0432). Regarding the entire patient cohort (n = 32) CD20 positive B-cell aggregates in the tumor infiltration zone were an independent prognostic marker for overall survival in multivariate analysis (HR 9.2, CI 1.6-51.4, p = 0.012). These results underline the importance of tumor-associated B-cells for prognosis of patients with PDAC. The detailed role of B cells in the pathomechanism of PDAC should be further investigated for predicting outcome, identifying appropriate treatment regimens, and developing novel therapeutic options.

Model-based roentgen stereophotogrammetric analysis using elementary geometrical shape models: 10 years results of an uncemented acetabular cup component.

BACKGROUND: Non-cemented acetabular cup components demonstrated different clinical performance depending on their surface texture or bearing couple. However, clinical osseointegration needs to be proved for each total joint arthroplasty (TJA) design. Aim of this study was to detect the in vivo migration pattern of a non-cemented cup design, using model-based roentgen stereophotogrammetric analysis with elementary geometrical shape models (EGS-RSA) to calculate early cup migration. METHODS: Interchangeable applicability of the model-based EGS-RSA method next to gold standard marker-based RSA method was assessed by clinical radiographs. Afterwards, in vivo acetabular cup migration for 39 patients in a maximum follow up of 120 months (10 years) was calculated using model-based EGS-RSA. RESULTS: For the axes with the best predictive capability for acetabular cup loosening, mean (±SD) values were calculated for migration and rotation of the cup. The cup migrated 0.16 (±0.22) mm along the cranio-caudal axis after 24 months and 0.36 (±0.72) mm after 120 months, respectively. It rotated - 0.61 (±0.57) deg. about the medio-lateral axis after 24 months and - 0.53 (±0.67) deg. after 120 months, respectively. CONCLUSIONS: Interchangeable applicability of model-based EGS-RSA next to gold standard marker-based RSA method could be shown. Model-based EGS-RSA enables an in vivo migration measurement without the necessity of TJA specific surface models. Migration of the investigated acetabular cup component indicates significant migration values along all the three axes. However, migration values after the second postoperative year were within the thresholds reported in literature, indicating no risk for later aseptic component loosening of this TJA design.

Lack of Exposure in a First-in-Man Study Due to Aldehyde Oxidase Metabolism: Investigated by Use of 14C-microdose, Humanized Mice, Monkey Pharmacokinetics, and In Vitro Methods.

Inclusion of a microdose of 14C-labeled drug in the first-in-man study of new investigational drugs and subsequent analysis by accelerator mass spectrometry has become an integrated part of drug development at Lundbeck. It has been found to be highly informative with regard to investigations of the routes and rates of excretion of the drug and the human metabolite profiles according to metabolites in safety testing guidance and also when additional metabolism-related issues needed to be addressed. In the first-in-man study with the NCE Lu AF09535, contrary to anticipated, surprisingly low exposure was observed when measuring the parent compound using conventional bioanalysis. Parallel accelerator mass spectrometry analysis revealed that the low exposure was almost exclusively attributable to extensive metabolism. The metabolism observed in humans was mediated via a human specific metabolic pathway, whereas an equivalent extent of metabolism was not observed in preclinical species. In vitro, incubation studies in human liver cytosol revealed involvement of aldehyde oxidase (AO) in the biotransformation of Lu AF09535. In vivo, substantially lower plasma exposure of Lu AF09535 was observed in chimeric mice with humanized livers compared with control animals. In addition, Lu AF09535 exhibited very low oral bioavailability in monkeys despite relatively low clearance after intravenous administration in contrast to the pharmacokinetics in rats and dogs, both showing low clearance and high bioavailability. The in vitro and in vivo methods applied were proved useful for identifying and evaluating AO-dependent metabolism. Different strategies to integrate these methods for prediction of in vivo human clearance of AO substrates were evaluated.

Improved treatment decisions in patients with esophageal cancer.

BACKGROUND: Patients with esophageal cancer seldom achieve long-term survival. This prospective cohort study investigated the selection of patients likely to benefit from curative treatment and whether information on patients' health-related quality of life (HRQL) would assist treatment decisions in the multidisciplinary team. METHODS: Consecutive patients completed HRQL assessments and clinical data were collected before start of treatment. Logistic regression analyses identified clinical factors associated with treatment intent in patients with stage-III disease. Kaplan-Meier method was used for survival analyses and Cox proportional hazards models were used to assess the impact of clinical factors and HRQL on survival in patients planned for curative treatment. RESULTS: Patients with curative treatment intent (n = 90) were younger, had better WHO performance status and less fatigue than patients with palliative treatment intent (n = 89). Median survival for the total cohort (n = 179) and patients with palliative or curative treatment intent was nine, five and 19 months, respectively. In multivariate Cox regression analyses, performance status (0-1 favorable) and comorbidity (ASA I favorable) were factors of importance for survival, whereas measures of HRQL were not. CONCLUSIONS: Patients performance status and comorbidity must be considered in addition to stage of disease to avoid extensive curative treatment in patients with short life expectancy. This study did not provide evidence to support that information on patients HRQL adds value to the multidisciplinary team's treatment decision process.

Risk factors for severe postpartum hemorrhage: a case-control study.

BACKGROUND: In high-income countries, the incidence of severe postpartum hemorrhage (PPH) has increased. This has important public health relevance because severe PPH is a leading cause of major maternal morbidity. However, few studies have identified risk factors for severe PPH within a contemporary obstetric cohort. METHODS: We performed a case-control study to identify risk factors for severe PPH among a cohort of women who delivered at one of three hospitals in Norway between 2008 and 2011. A case (severe PPH) was classified by an estimated blood loss ≥1500 mL or the need for blood transfusion for excessive postpartum bleeding. Using logistic regression, we applied a pragmatic strategy to identify independent risk factors for severe PPH. RESULTS: Among a total of 43,105 deliveries occurring between 2008 and 2011, we identified 1064 cases and 2059 random controls. The frequency of severe PPH was 2.5% (95% confidence interval (CI): 2.32-2.62). The most common etiologies for severe PPH were uterine atony (60%) and placental complications (36%). The strongest risk factors were a history of severe PPH (adjusted OR (aOR) = 8.97, 95% CI: 5.25-15.33), anticoagulant medication (aOR = 4.79, 95% CI: 2.72-8.41), anemia at booking (aOR = 4.27, 95% CI: 2.79-6.54), severe pre-eclampsia or HELLP syndrome (aOR = 3.03, 95% CI: 1.74-5.27), uterine fibromas (aOR = 2.71, 95% CI: 1.69-4.35), multiple pregnancy (aOR = 2.11, 95% CI: 1.39-3.22) and assisted reproductive technologies (aOR = 1.88, 95% CI: 1.33-2.65). CONCLUSIONS: Based on our findings, women with a history of severe PPH are at highest risk of severe PPH. As well as other established clinical risk factors for PPH, a history of severe PPH should be included as a risk factor in the development and validation of prediction models for PPH.

Anaplastic thyroid cancer and hyperfractionated accelerated radiotherapy (HART) with and without surgery.

Anaplastic carcinoma of the thyroid gland (ATC) is one of the most aggressive cancers in humans. With insufficient treatment, the disease most often leads to death in suffocation. From 2002, our treatment strategy has been hyperfractionated accelerated radiotherapy (HART) with high doses (64 Gy) to the neck, followed by surgery 4-8 weeks later if feasible, with the aim to gain control in the neck. After a pathology review, 51 patients were diagnosed with ATC in the period 2002-2014 in the south-east of Norway. Thirty-one received HART, and we present a study of these patients, with death in suffocation as the primary endpoint and survival as the second. No patients treated with HART died in suffocation. Six had a tracheostomy during their course of disease, of whom four were dependent on a tracheal cannula when they died. The best median survival, 19 months, was obtained in the 13 patients where both radiotherapy and surgery were possible as primary treatments. Only surgery came out as a prognostic factor for survival in multivariate analysis. Patients surviving more than 2 years were characterised by having surgery with R0 resection and no or small residual foci of ATC in the specimens. Stage 4C patients survived 3 months only.

Sensing of triacylglycerol in the gut: different mechanisms for fatty acids and 2-monoacylglycerol.

Sensing of dietary triacylglycerol in the proximal small intestine results in physiological, hormonal and behavioural responses. However, the exact physiological pathways linking intestinal fat sensing to food intake and the activation of brain circuits remain to be identified. In this study we examined the role of triacylglycerol digestion for intestinal fat sensing, and compared the effects of the triacylglycerol digestion products, fatty acids and 2-monoacylglycerol, on behavioural, hormonal and dopaminergic responses in behaving mice. Using an operant task in which mice are trained to self-administer lipid emulsions directly into the stomach, we show that inhibiting triacylglycerol digestion disrupts normal behaviour of self-administration in mice, indicating that fat sensing is conditional to digestion. When administered separately, both digestion products, 2-monoacylglycerol and fatty acids, were sensed by the mice, and self-administration patterns of fatty acids were affected by the fatty acid chain length. Peripheral plasma concentrations of the gut hormones GLP-1, GIP, PYY, CCK and insulin did not offer an explanation of the differing behavioural effects produced by 2-monoacylglycerol and fatty acids. However, combined with behavioural responses, striatal dopamine effluxes induced by gut infusions of oleic acid were significantly greater than those produced by equivalent infusions of 2-oleoylglycerol. Our data demonstrate recruitment of different signalling pathways by fatty acids and 2-monoacylglycerol, and suggest that the structural properties of fat rather than total caloric value determine intestinal sensing and the assignment of reward value to lipids.